Problem 11

Study Guide 1
1.Discuss type 2 DM and its pathophysiology
T2DM is a heterogeneous disorder characterized by a combination of reduced tissue sensitivity to insulin and
inadequate secretion of insulin from the pancreas. Formerly known as non–insulin-dependent (NIDDM) or maturity-
onset diabetes. Usually develop in adults who are obese and elderly.
Risk Factors
▪ Obesity, Diet & physical inactivity
▪ Race & ethnicity (Blacks, Asians, Pacific Islanders)
▪ Family h/o type 2 DM
▪ Past H/O- impaired fasting glucose or impaired GTT
▪ H/O gestational DM / delivery of heavy baby > 4 kg
▪ Hypertension & Dyslipidemia
▪ diseases- Polycystic ovary disease, acanthosisa nigricans, vascular disease
Pathophysiology
Multifactorial complex disease
▪ Environmental factors: sedentary lifestyle, dietary habits & obesity
▪ Genetic factors:
o monozygotic & dizygotic twins
o if both parents diabetic- offspring have double risk
o gene polymorphisms - β-cell function & insulin
Insulin Resistance
Obesity promotes insulin resistance. It is hypothesized that excess FFAs induce muscle insulin resistance by
promoting increased synthesis of diacylglycerols and ceramides, both of which can interfere with the normal insulin
signaling pathway. Insulin resistance leads to increased hepatic glucose production and reduced glucose uptake by
peripheral tissues, primarily muscles and adipose tissue.
Beta Cell Dysfunction
At first there is impairment in the first phase of insulin secretion following glucose stimulation and may precede the
onset of glucose intolerance in T2DM. Later the second phase, release of newly synthesized insulin, is impaired.
Role of Incretins
In patients with T2DM, the incretin effect is markedly reduced due to dysregulation (early breakdown occur),
attributing to defects in secretion of GLP-1 and GIP.
2.Discuss how diabetes mellitus is diagnosed
Made on the basis of a blood glucose measurement done because someone suspects diabetes
▪ Acute presentation - Ketoacidosis
▪ Symptoms, eg polyuria, polydipsia, polyphagia, weight loss
▪ High risk person, eg overweight, family history
▪ Complications
o Specific, eg retinopathy, nephropathy
o Not specific, eg myocardial infarct, stroke, infections
▪ Screening
Symptomatic – 1 reading suffices, Asymptomatic – 2 reading on 2 different occasions. GTT never actually done in
clinical practice except in obstetrics [internal med lec.]
Random blood glucose/ Two-hour PG
➢ <5.5 mmol/l – not diabetic
➢ 5.5 – 11.0 – diabetes possible
➢ ≥11.1 – diagnostic of diabetes
Fasting blood glucose→ no meal 8-12hrs before
➢ <5.5 mmol/l – not diabetic WHO→70-100mg/dL or 3.9-5.6mmol/L
➢ 5.5 – 6.9 – diabetes possible
➢ ≥ 7.0 – diagnostic of diabetes
HbA1c
➢ <5.7% - not diabetic
➢ 5.7 - 6.4% - diabetes possible
➢ ≥ 6.5% - diagnostic diabetes
3.Describe the Oral Glucose Tolerance Test (OGTT) and its use in the diagnosis of diabetes
The WHO recommendation is that the OGTT is performed on all individuals whose fasting plasma glucose falls in the
IFG category. OGTT must be performed under standard conditions.
▪ The patient should attend in the morning after an approximately 10-h fast.
▪ To avoid stress- or exercise-related changes in plasma glucose, the person should sit throughout the test.
▪ The test should not be performed during or immediately after an acute illness.
▪ You may be asked to not take certain medications in the lead up to the test
The test is used to determine whether the body has difficulty metabolising intake of sugar/carbohydrate.
During the test, fasting plasma glucose is measured first. The patient is then given anhydrous glucose (75g) dissolved
in 300 mL water;(flavouring with sugar-free lemon and chilling increases palatability and may reduce nausea). to
drink and plasma glucose concentration is measured again after 120 min. In some protocols, glucose is measured after
20, 60, and 120 min.
Normally, plasma glucose should reach peak concentration after approximately 60 min and should return to a near-
fasting state within 120 min. If it remains above 11.1 mmol/L (200 mg/dL/min) in the 120-min sample, diabetes is
diagnosed, even if the fasting blood glucose was normal.

Classification Fasting (mmol/L) 2-hour (mmol/L)

Non-diabetic ≥6.0 <7.8
Pre-diabetic 6.1–6.9 7.8–11.0
Diabetic ≥7.0 ≥11.1
If you are within the impaired glucose tolerance range, you will likely be advised to make lifestyle changes. In some
cases, blood glucose lowering medication may be advised.
If you fall within the diabetic range, it is quite likely that blood glucose medication will be prescribed.
4.Compare the differences between the different blood samples that may be used to obtain Blood Glucose
Levels (BGL)
(i) Sample type
Arterial blood has more glucose than venous blood (because the tissues have typically used some). Capillary blood (eg
fingerprick) is in between, but closer to arterial→capillary is 15% lower than venous
NCBI→BLOOD GLUCOSE is generally measured as the venous plasma level. There is a 3–5 mg/mL difference
between arterial and venous levels, with higher differences in the postprandial state.
Skin prick test→for capillary blood glucose levels at the fingertip have been shown to correlate well with systemic
arterial blood glucose levels. The blood sampled from the skin prick comes from the capillaries of dermis with a small
amount of blood from cut arterioles and venules providing a mix concentration
(ii) Sample preservation
The glucose can be measured in whole blood or separated blood (plasma/serum).
Whole blood has a lower glucose level because the red cells don;t have much glucose in them.
Venous and serum samples will have similar glucose levels, but this depends on how the serum or plasma are
handled. If the serum / plasma is not separated from the cells immediately, the blood cells (which stay alive for many
hours in vitro) will use up some of the glucose and usually generate lactate.
5.Discuss pre-diabetes- diagnosis, risks and control/prevention
Prediabetes is a state in which the body does not respond properly to insulin, so blood glucose levels are higher than
normal, but not in the range for a diagnosis of diabetes. It is generally asymptomatic. Progression to a diagnosis of
diabetes is not inevitable.
The diagnosis of impaired glucose tolerance can be made only using a 75-g oral glucose tolerance test; a 2-h glucose
measurement points to the diagnosis of impaired glucose tolerance when the plasma glucose is found to be greater
than 7.7 mmol/L but less than 11.1 mmol/L. Recently another category, impaired glycated haemoglobin, HbA1c
(A1C 5.7–6.4%), has been added→HbA1c no fasting needed!
The clinical presentation of these conditions is usually characterized by nonketotic hyperglycaemia, insulin resistance,
hyperinsulinism and frequently obesity.
Risk factors for prediabetes:
▪ Being overweight
▪ Being 45 years or older
▪ Having a parent, brother, or sister with type 2 diabetes
▪ Being physically active less than 3 times a week
▪ Ever having gestational diabetes (diabetes during pregnancy)
▪ Having polycystic ovary syndrome
▪ Race and ethnicity are also a factor: African Americans, Hispanic/Latino Americans, American Indians,
Pacific Islanders, and some Asian Americans are at higher risk
Prevention - Healthy lifestyle choices can help you prevent prediabetes and its progression to type 2 diabetes — even
if diabetes runs in your family. These include:
▪ Eating healthy foods
▪ Getting active
▪ Losing excess weight
▪ Controlling your blood pressure and cholesterol
▪ Not smoking
6.Discuss the following:

• Maturity Onset Diabetes of the Young (MODY) [Netters essential biochemistry]

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by young age of onset
(often <25 years), dominant inheritance, and beta cell dysfunction. Many patients are misdiagnosed with type 1
diabetes and treated with insulin
All known types of MODY are due to mutations in proteins that are important for normal development and function of
pancreatic β-cells; often, these proteins also affect the function of the liver. The overall prevalence of MODY is likely
~1 in 1,000
A diagnosis of MODY is commonly entertained if a patient is lean, develops diabetes before 30 years of age, has a
family member who also developed diabetes at such a young age, has no signs of insulin resistance (e.g., acanthosis
nigricans), and either does not require insulin or has a significant plasma concentration of C-peptide.
The most common forms of MODY are MODY-2 and MODY-3. Both are inherited in an autosomal dominant
fashion.
MODY-2 is caused by a heterozygous loss-of-function mutation in the GCK gene, which encodes glucokinase.
Glucokinase is the glucose sensor of the pancreatic β-cell. In the liver, in the fed state, glucokinase helps direct
glucose into glycolysis and glycogen synthesis. Affected patients have a higher set point for glucose-induced insulin
secretion and therefore have mild hyperglycemia even in the fasting state. GCK mutations cause a mild,
asymptomatic, and stable fasting hyperglycemia usually requiring no specific treatment.
MODY-3 is caused by a mutation in the HNF1A gene, which encodes HNF1 homeobox A ( HNF1A ). HNF1A is a
transcription factor that stimulates the transcription of genes, the products of which are involved in the metabolism of
glucose or fatty acids. At birth, patients have a normal concentration of blood glucose. However, they have a severe
defect in insulin secretion that worsens with age. Mutations in the HNF1A and HNF4A cause a progressive pancreatic
β-cell dysfunction and hyperglycemia that can result in microvascular complications. Sulfonylureas are effective in
these patient

• Latent Autoimmune Diabetes in Adults (LADA)

Latent autoimmune diabetes in adults is a slowly progressive form of autoimmune diabetes characterized by older age
at diagnosis, the presence of pancreatic autoantibodies, and the lack of an absolute insulin requirement at diagnosis.
Although patients with LADA present with more preserved β-cell function than those with classic T1DM, they tend to
have a rapid and progressive loss of β-cell function necessitating intensive insulin intervention. Approximately 10% of
all patients diagnosed with T2DM actually have LADA
Features & complications of both i.e. type 1 & 2. LADA occurs in 10% of individuals older than 35 years
Although the exact pathogenesis of LADA is unclear, the underlying immune-mediated destruction of β cells in
patients with this form of the disease leads to insulin dependency more rapidly than in patients with T2DM. (type 1
diabetes)
 • Metabolic Syndrome
The metabolic syndrome refers to a constellation of risk factors for the development of CVD and T2D. Critical
components of the metabolic syndrome, including hyperglycemia, dyslipidemia, abdominal obesity, and hypertension.
The metabolic syndrome is suspected when any three of the following criteria are present:
▪ An abdominal waist circumference of >94 cm in men or >80 cm in women
▪ Serum hypertriglyceridemia of >150 mg/dL or drug treatment for elevated triglycerides
▪ A serum HDL cholesterol of <40 mg/dL in men or <50 mg/dL in women
▪ A blood pressure of >130/85 mmHg or drug treatment for elevated blood pressure
▪ A fasting glucose of >100 mg/dL or drug treatment for elevated blood glucose
 Study Guide 2
1.Compare Type 2 and Type 1 Diabetes in terms of:

• clinical onset
• genetic predisposition
• pathogenesis
• islet cell changes

2.Explain insulin secretion, insulin levels and tissue resistance in relation to the development of Type 2
Diabetes.
Insulin resistance initially leads to hyperinsulinemia and may eventually lead to the development of type 2 diabetes
mellitus if β-cell exhaustion occurs
Insulin resistance leads to increased hepatic glucose production and reduced glucose uptake by peripheral tissues,
primarily muscles and adipose tissue. Insulin resistance alone rarely causes T2DM, since increased insulin
secretion (hyperinsulinism) by beta cells will compensate for insulin resistance and thereby prevent blood
glucose levels from rising. It is only when the beta cells start showing evidence of dysfunction that blood glucose
levels start to increase.
At first, this is characterized by impairment in the first phase of insulin secretion following glucose stimulation and
may precede the onset of glucose intolerance in T2DM.
Later in the disease, the second phase, release of newly synthesized insulin, is impaired.
3.Discuss the role of obesity as a risk factor in the development of Type 2 Diabetes
In obese people, adipose tissue releases inhibitory mediators (including non-esterified fatty acids and cytokines such
as tumor necrosis factor-α [TNF-α]) that interfere with insulin signalling by disrupting propagation of protein–
tyrosine phosphorylation.
Insulin resistance and T2DM are more prevalent in people with upper body–visceral obesity. Levels of non-esterified
fatty acids and TNF-α are preferentially increased in visceral adiposity.
-Adiponectin, which promotes insulin action on its target tissues, is reduced in visceral adiposity.
-An overabundance of non-esterified fatty acids can lead to intracellular accumulations of triglyceride and acyl
coenzyme A (CoA) derivatives, particularly diacylglycerol. These molecules can activate intracellular serine kinase
pathways that induce insulin resistance by blocking the insulin receptor tyrosine kinase signal cascade.
-Adipose tissue macrophages produce proinflammatory cytokines, including tumor necrosis factor–α and
interleukin-6, which can interfere with insulin signaling
-Hyperinsulinemia, caused by insulin resistance, can downregulate the number of insulin receptors on the plasma
membrane, which may further contribute to cellular resistance to insulin action.
-Mitochondrial abnormalities have recently been shown to contribute to the development of T2DM. In diabetics who
are obese, abnormal intracellular triglyceride accumulation in liver and skeletal muscle suggests a defect in
mitochondrial lipid oxidation. A genetic component for defective mitochondrial oxidative phosphorylation has been
suggested.

When to do OGTT in pregnant women?

Risk factors for pregnant women→overweight, family history, more than 40yrs (ogtt prolly 35), history of gestational
diabetes, others; smoking hx,
 Study Guide 3
1.Describe the epidemiology of Type 2 Diabetes in the Pacific
World - In 2017, approximately 462 million individuals were affected by type 2 diabetes corresponding to 6.28% of
the world's population (4.4% of those aged 15-49 years, 15% of those aged 50-69, and 22% of those aged 70+), or a
prevalence rate of 6059 cases per 100,000. Over 1 million deaths per year can be attributed to diabetes alone
Fiji - T2DM prevalence and annual incidence increased in Fiji over 1980-2011. Prevalence was higher in Indians and
men than i-Taukei and women. Incidence was higher in Indians and women. Almost 1 in every 3 Fijians is being
diagnosed with diabetes

2.Describe the risk factors for Type 2 Diabetes

WHO STEP wise Surveys in PICs (WHO)
For six risk factors, data for adults (aged 25–64 years) from published reports of the World Health Organization STEP
wise approach to NCD surveillance, or methodologically similar surveys, were collated, age standardised and
compared across fifteen PICTs.
Risk Factors:
1. Harmful use of Alcohol
2. Physical Inactivity
3. Tobacco smoking
4. Hypertension
5. Diabetes
6. Obesity
Summary of results in PICs (Tara et al; 2015)
i. In most PICT populations, more than half of male current drinkers drank heavily
ii. More than 40% of men and 20% of women were current smokers.
iii. In 10 populations, about 50% or more of women were insufficiently physically active.
 iv. Prevalence of hypertension and diabetes exceeded 20% and 25%, respectively, in several populations.
v. Near or more than half of men and women in all populations were overweight; in most, more than one-third of
both sexes were obese.
NCD Risk Factors: Fiji Step Survey 2011
▪ Tobacco use: 16.6%
▪ Alcohol consumption: 30.6%
▪ Obesity/Overweight: 66.9% (F>M)
▪ Least Physical activity: by women, <35yrs, living in urban areas, indo-Fijians
▪ Lack of consumption of fruits/vegestables: 3% (<recommended 5servings/day)
▪ Kava consumption: associated risks with links to tobacco and alcohol use and unhealthy savories (chasers)
consumption
Risk Factors
▪ Obesity, Diet & physical inactivity
▪ Race & ethnicity (Blacks, Asians, Pacific Islanders)
▪ Family h/o type 2 DM
▪ Past H/O- impaired fasting glucose or impaired GTT
▪ H/O gestational DM / delivery of heavy baby > 4 kg
▪ Hypertension & Dyslipidemia
▪ diseases- Polycystic ovary disease (inc androgen). ,acanthosis nigricans, vascular disease

3.Discus the role of culture in type 2 diabetes in the Pacific

❖
Early studies clearly showed that while diabetes was virtually non-existent in populations indigenous to the
Pacific maintaining a traditional lifestyle, the reverse was true for the urbanized Pacific populations.
❖
In recent decades diabetes prevalence has increased rapidly over time in the indigenous people in the Pacific
region (Polynesian, Melanesian, Micronesian), both in the Pacific islands and in countries such as New Zealand.
❖ Epidemiological evidence indicates that prevalence is generally lowest in traditional Pacific environments, and is
higher in both urban Pacific and adopted metropolitan environments; in the latter environments, prevalence is
markedly higher in Pacific people than in white people.
❖ Prevalence has been increasing rapidly in all three environments, and Pacific people experience greater morbidity
and more complications than white people with diabetes.

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC188499/
It has been argued that all industrializing societies undergo various "epidemiological transition" stages in which the
transition from Stage Two to Stage Three involves a change from "receding pandemics" to "degenerative and lifestyle
diseases". Continued globalization will mean that more populations in the Pacific, and throughout the world, are
adopting Westernized diets and lifestyles 2. The dynamics of this transition in most Polynesian South Pacific islands
has been relatively unprecedented. These countries are geographically scattered, with contrasting environmental,
social, and political systems, and in varying stages of economic development, but all have been going through a rapid
epidemiological transition. Processes that took place over thousands of years in Western countries have been very
much compacted in time in the Pacific.
4.Describe the changing diet and physical activity in the Pacific populations
❖ The problems of obesity and diabetes in the Pacific occur as much due to a changing environment as to the
lifestyle “choices” individuals can make given their economic and social position.
❖ People will not necessarily eat and drink what doctors or nurses advise them to—but they will eat, smoke, and
drink what is affordable and available to them
❖ Similarly, the promotion of exercise as opposed to productive physical activities is questionable when people
cannot have access to or afford sports and recreational facilities.
❖ Given that the terrain in most Pacific Island countries is ideal for walking and cycling to and from work, such an
opportunity has not been harnessed as we opt for the unhealthier sedentary mode of settling behind driving wheels
and taxis.
❖ Unfortunately, walking or cycling to and from work often becomes a health hazard when roads are not designed
for cyclists or pedestrians but are primarily designed for motor vehicles.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC188499/

5. Discuss how other factors may contribute towards the high prevalence of Type 2 Diabetes in the Pacific
populations.
The NCD global monitoring framework outlines 25 indications for member states that maybe identified as a risk factor
for NCDS some of these indications include:
Behavioural Risk Factors:
Harmful use of alcohol: Adult Per Capita
Consumption
Harmful use of alcohol: heavy episodic
drinking
Harmful use of alcohol: alcohol-related
morbidity and mortality
Physical inactivity in adolescents
Physical inactivity in adults
Salt intake
Tobacco use in adolescents
Tobacco use in adults
Biological Risk Factors:
a) Blood pressure: raised blood pressure
Raised blood glucose/diabetes
Overweight and obesity in adolescents
Overweight and obesity in adults
Saturated fat
Low fruit and vegetable consumption
a) Total Cholesterol: raised.

Another major reason for increase prevalence of diabetes is thought to be the rapid urbanization or
industrialization of the pacific
Studies conducted earlier than 1960’s show that diabetes was virtually non-existant in polynasiean populations which
were maintaining a traditional lifestyle, the reverse was true for the urbanized Polynesian populations. Zimmet and
colleagues indicated that diabetes was virtually unknown prior to 1960, and they were unable to find evidence of any
cases of diabetes in Funafuti, Western Samoa or Nauru before 1945
Thus, the change from traditional environments to a more urban and Western oriented environment appears to be
accompanied by a striking increase in diabetic prevalence. Interestingly, urbanization had not occurred in the
geographically isolated atoll of Manihiki (Cook Islands), but a change from traditional to a modern economy and way
of life with a good cash income from copra and pearl shells was a probable cause for a high prevalence of abnormal
glucose tolerance
Another reason is ethnicity, Some studies have also reported comparisons between Pacific people and other ethnic
groups in the same metropolitan adopted environments. These have demonstrated a consistently higher prevalence of
diabetes among Polynesians as compared to Caucasians
Another reason is genetics:
-James neel proposed “thrifty” theory, he stated metabolism among hunter-gatherer societies frequently facing
intermittent periods of feast-or-famine alimentations enabled them to store excess energy in times of plenty for
subsequent utilization in times of want. This hypothesis suggests that Pacific Islanders traditionally experienced
alternating periods of abundance and famine, but now increasingly have greater access to high energy, low-fibre
refined food and decreasing traditional/physical activity. As a result, they are at greater risk of obesity and life-style
related noncommunicable diseases including diabetes
-thrifty phenotype hypothesis’→ which proposes that Type 2 diabetes originates in poor nutrition in foetal life, and
infancy resulting in impaired pancreatic beta cell development, insulin resistance and accompanying changes in
glucose and lipid metabolism. The individual's ability to be "thrifty" is no longer beneficial in later life given an
increased energy intake, decreased exercise and obesity, resulting in an increased susceptibility to diabetes.
Another reason is lifestyle:
Both the above hypothesis (genetic) are associated with a change to western diet. Due to rapid changes in lifestyle,
risk factors such as obesity, unhealthy diets and physical inactivity have become widespread throughout the region.
Studies found that pacific islanders were less involved in leisure time activities than Caucasians with women being
less active than men among pacific islanders
Another reason is food consumption of people their choices and their perceptions of food→what they can
afford as well.
Hence, poor diet is not simply a health or health education driven decision. It is also very much an economic issue. In
one Pacific country, the leasing of certain traditional and easily accessible shallow waters alongside villages makes
fishing for food illegal in these areas, because of a monopoly established by a fishing company whose major share
holder is a local political leader. In fact, inequitable land distribution supported by the constitutionalisation of
traditional land monopoly ownership is not uncommon in most Pacific Island countries. It is therefore unrealistic to
promote a traditional diet when excess land is not made available for the people to grow traditional food items or fish
for food. Traditional landholders meanwhile ensure that excess fertile land is unavailable except for perhaps a few
head of cattle and occasional "renting" of arable land to economically powerful cash crop farmers.
Political pressure also results in NCDS
Vested commercial interests are not confined within countries, but also affect trade policy. Healthier, low-fat sources
of proteins such as fish generally cost 15% and 50% more than either mutton flaps or imported chicken parts, which
are also more easily accessible and available than fish or indigenous chicken in some Pacific countries. Fiji's decision
to ban the importation of mutton flaps immediately resulted in New Zealand threatening a complaint to the World
Trade Organization
(study: Prevalence and causes of Diabetes in Pacific people, PACIFIC HEALTH DIALOG VOL 10. No. 2. 2003)
 Study Guide 4
1. Describe the clinical presentation of acute complications
a. Revise DKA
Presenting Symptoms
Malaise, dry mouth, headache, polyuria (Polyuria and dehydration result from the osmotic diuresis associated with
hyperglycemia), polydipsia, weight loss, nausea, vomiting, pruritus, abdominal pain, lethargy, shortness of breath,
Kussmaul respirations (hyperventilation in an attempt to compensate for the acidosis), fruity or acetone odor to breath
Signs
Postural dizziness, central nervous system depression, ketonuria, anorexia and signs of dehydration. Glucosuria
(plasma glucose level is higher than the individual's renal threshold, allowing significant amounts of glucose to be lost
in the urine). Deficits of sodium, phosphorus, and magnesium are common. Potassium markedly deficient (serum
potassium concentration may appear normal or elevated because of volume contraction and a shift of potassium out of
the cell and into the blood caused by metabolic acidosis, the total body deficiency of potassium may reach 3 to
5 mEq/kg)
b. Hyperosmolar coma
Presenting symptoms
Polyuria, polydipsia, hypovolemia, dehydration (parched lips, poor skin turgor), hypotension, tachycardia,
hypoperfusion, weight loss, weakness, nausea, vomiting, abdominal pain, hypothermia, stupor, coma, seizures
Signs
Glycosuria and polyuria in HHNKS result from the extreme serum glucose level elevation. As much as 19 g of
glucose per hour may be lost in diuresis, which causes severe volume depletion, increased serum osmolarity,
intracellular dehydration, and loss of electrolytes including potassium. Neurologic changes, such as stupor, correlate
with the degree of hyperosmolarity and are common in HHNKS; thus, this syndrome is sometimes
called hyperosmolar hyperglycemic coma
c. Hypoglycemia
Presenting Symptoms
Adrenergic reaction: pallor, sweating, tachycardia, palpitations, hunger, restlessness, anxiety, tremor’s Neurogenic
reaction: fatigue, irritability, headache, loss of concentration, visual disturbances, dizziness, hunger, confusion,
transient sensory or motor defects, convulsions, coma, death
Hypoglycaemia unawareness is a phenomenon that occurs in individuals without appropriate autonomic warning
symptoms, and recovery from hypoglycaemia may be delayed because of impaired glycogenolysis and hampered
delivery of gluconeogenic substrates to the liver.
2. Describe the clinical presentation of macrovascular disease (Not specific to diabetes)
a. coronary artery disease
CAD→is the most common cause of morbidity and mortality in individuals with DM. Ischemic heart disease, also
referred to as coronary heart disease, is the term associated with an inadequate supply of blood to the myocardium due
to obstruction of the epicardial coronary arteries, usually from atherosclerosis. Patients may have chronic (stable) or
acute (unstable) disease.
Symptoms:
o Shortness of breath
o Easily Fatigue
o Orthopnea, PND
o Pedal edema
o Angina:
Classical/Stable angina→heavy, tight or gripping chest pain in central/retrosternal area, radiate to jaw, arms.
Characterized by:
▪ Central chest pain
▪ Pain can also radiate to left arm, neck, jaw, epigastric region, or back.
▪ Pain does not depend on body position or respiration
▪ Discomfort or breathlessness that is precipitated by exertion or other forms of stress and is relieved by rest or
nitroglycerin
 ▪ Dizziness
▪ Palpitation
Acute Coronary Syndrome→This term encompasses unstable angina and myocardial infarction (MI).
o Unstable angina refers to new-onset or rapidly worsening (crescendo) angina, and angina on minimal exertion or
at rest without myocardial damage.
o In MI there are symptoms at rest and myocardial necrosis occurs, leading to partial thickness, non-ST elevation
MI (NSTEMI) or full-thickness, ST elevation MI (STEMI).
o Acute coronary syndrome may present de novo or against a background of chronic stable angina
o Characterized by:
▪ Pain: like that of angina but more severe and prolonged, which doesn’t improve with rest or nitroglycerin
▪ Breathlessness.
▪ Vomiting: due to vagal stimulation, particularly in inferior MI.
▪ Syncope or sudden death due to arrhythmia.
▪ MI may occasionally be painless, especially in diabetic or elderly patients
People with diabetes have fewer, less severe symptomatic chest pains, possibly owing to autonomic neuropathy
leading to reduced deep pain sensation—so-called ‘silent ischaemia’. Thus, the only symptom of ischaemic heart
disease in a diabetic patient may be breathlessness.

b. Peripheral vascular disease

Peripheral vascular disease (PAD) is a manifestation of systemic atherosclerosis that leads to significant narrowing of
arteries distal to the aorta. Patients with PAD often have no complaints. However, the severity of which depends upon
the degree of arterial narrowing, number of arteries affected, and the activity level of the patients.

The most common symptom of PVD is intermittent claudication. However, at other times it can lead to acute or
critical lower limb ischemia
- intermittent claudication→Pain within a defined group of muscles that is induced by exercise and relieved with
rest defines classic intermittent claudication
Buttock and hip claudication→iliac (aorta) artery can also present with erectile dysfunction
Thigh claudication→femoral artery
Calf→ most common→superficial femoral artery (upper 2/3) popliteal lower 1/3
Foor→tibial and peroneal vessel
- Critical Limb Ischemia
CLI is defined as rest (night) pain, requiring opiate analgesia, and/or tissue loss (ulceration or gangrene), present for >
2 wks, in the presence of an ankle BP < 50 mmHg.
Whereas IC is usually due to single-segment plaque, CLI is always due to multi-level disease
Other symptoms:
-Severe diffuse pain — Diffuse acute limb ischemia is characterized by the sudden onset of extremity pain
progressing to numbness and finally paralysis of the extremity, accompanied by pallor, paresthesias, coolness, and
absence of palpable pulses
-Nonhealing wound/ulcer- ischemic ulcers begin as minor traumatic wounds→fail to heal cuz ↓ BF
-Skin discoloration/gangrene- foot elevated appears white, lowered red. Focal areas of ischemia can progress to
necrosis
6p’s
Pain
Poikilothermic
Pulselessness
Paresthesia
Paralysis
pale

c. Cerebrovascular disease
Cerebrovascular disease involves pathology in the blood vessels of the brain. It can be classified into:
Transient brain ischemia (TIA)→transient episode of neurological dysfunction caused by focal brain, spinal cord or
retinal ischemia without acute infarction →common In diabetes
Intracerebral hemorrhage→bleeding in brain→hematoma spread long white matter pathways
Subarachnoid hemorrhage→rupture of aneurysms, abrupt onset
Ischemia:
- Thrombotic stroke
- Embolic stroke
- Systemic hypoperfusion→Can be due to dec CO, hypoxemia
Signs and symptoms depend on site of vessel affected
Dizziness, nausea, or vomiting
Unusually severe headache
Confusion, disorientation or memory loss
Numbness, weakness in an arm, leg or the face, especially on one side
Abnormal or slurred speech
Difficulty with comprehension
Loss of vision or difficulty seeing
Loss of balance, coordination or the ability to walk

3.Describe the clinical presentation of microvascular disease (specific to diabetes)

a. Retinopathy
Patients might be asymptomatic in the early stages and might be discovered incidentally on fundus examination. As
the disease progresses, the symptoms include
▪ blurred vision
▪ distorted vision – loss of central vision
▪ floaters/black spots
▪ partial or total vision loss (Blindness)
Upon fundoscopy;
Non proliferative Retinopathy: (early)
▪ Micro aneurysms
▪ blocked blood vessels of retina- thickened capillaries
▪ Dots & blots (ruptured micro aneurysms)
▪ Hard and soft exudates
▪ Cotton wool spots
▪ Macular edema
Proliferative Retinopathy: advanced stage
▪ neovascularization
▪ Hemorrhage
 b. Neuropathy
Peripheral Neuropathy:
B/L & symmetrical, Progressive, irreversible -- Paresthesia, pain, muscle atrophy
There is impairment, in a ‘glove and stocking’ distribution, of all modalities of sensation including diminished
vibration sensation. Symptoms may include;
▪ paraesthesiae in the feet
▪ sharp pain in the lower limbs (worse at night and felt mainly on anterior aspect of legs)
▪ burning sensations in the soles of the feet and cutaneous hyperaesthesia.
As the condition advances, weakness and atrophy of the interosseous muscles may develop leading to structural
changes in the foot with loss of lateral and transverse arches, clawing of the toes and exposure of the metatarsal heads
Visceral neuropathy
Cranial nerve/ mono-neuropathy – The nerves most likely to be affected are the 6th and 3rd cranial nerves (resulting in
diplopia), the 7th cranial nerve (resulting in Bell’s palsy)

mononeuropathy→all cranial nerves affected

Autonomic neuropathy
Autonomic neuropathy can be manifested as gastroparesis, urinary retention, erectile dysfunction (secxual response)
sudomotor dysfunction (typically anhidrosis of the extremities with or without hyperhidrosis of the trunk), cardiac
arrhythmias, disturbance of gut motility (diabetic diarrhea or constipation) and orthostatic hypotension
c. Nephropathy
Diabetic nephropathy develops during many years to decades, with a prolonged “silent” period before clinical
detection, followed by more rapid progression to overt renal disease
The hallmark of diabetic nephropathy is the development of proteinuria. The first clinical evidence of incipient
nephropathy is the development of albuminuria, which is quantitatively minor at first (microalbuminuria, urine
albumin-to-creatinine ratio of 30 to 300 mg/g) and then progresses to overt proteinuria, sometimes in the nephrotic
range (>2 g/day)
Passing of foamy urine
You may have symptoms if your nephropathy gets worse. These symptoms include:
▪ Swelling (edema), first in the feet and legs and later throughout your body.
▪ Poor appetite.
▪ Weight loss.
▪ Weakness.
▪ Feeling tired or worn out. (hypoallbuminia→↓osmotic pressure)
▪ Nausea or vomiting.

4. Review common and serious infections in diabetes

Mechanism of infections?
Hyperglycemia→affects aspects of cellular innate immune system, esp neutrophil and macrophages w ↓chemotaxis,
phagocytosis and killing. ↓level of complement proteins cytokines.
There diabetes is a immunocompromised state→there opportunistic bacteria→anaerobes and fungi infect
-microbes grow better in high glucose environment
-Peripheral vascular disease + neuropathy→predispose skin ulceration→act as entry portal
→↓ BF to tissue also impairs healing (slower collagen synthesis) and immunity
(decreases the supply of white blood cells to the affected area)
-autopathic neuropathy→may lead to urinary retention→↑risk of UTI
Common infections?
Genital infections→candida species (fungal). Balanitis (men) and vulvovaginitis woman

Urine infection→ urethritis, cystitis, vaginitis

Fungal nail infections→toe

Ear, nose and throat infections→ fungal infections of nose and throat are seen exclusively in DM Symptoms include
severe ear pain and ear discharge.
Skin + Soft tissue infections→cellulitis, abscess + boils
Bone and joint infections→osteomyelitis (30% cases in DM) of foot, seotic arthritis more common in DM
Viruses→corona virus (SARS-CoV-2)
Lower Respiratory disease→pulmonary TB ↑↑, influenza, strep pneumoniae
GIT + liver infections→ H.pylori, Hep C/ B, enteroviruses
Serious infection
Soft tissue→anaerobic infections such as necrotizing fasciitis, gas gangrene (clostridium species, rapidly progressive
and foul smell) and synergistic gangrene→spreading type of gangrene(Fournier gangrene of gential and periela
skin→scrotum, penis or perineum,
Bullosis diabeticorum is a spontaneous, noninflammatory, blistering condition of acral skin that is unique to patients
with diabetes mellitus
Ear and nose and throat→malignant (necrotizing) otitis externa, caused by pseudomonas aeruginosa →starts at
external auditory canal spread to adjacent soft tissue, cartilage and bones→severe ear pain
Rhinocerebral mucormycosis→oppurtunistic infection of sinuses, nasal passage, oral cavity + brain by saprophytic
fungi
UTI→pyelonephritis→ can cause insulin resistance (upper UTI is more serious)→can develop into→emphysematous
pyelonephritis (worse state)
5. Prevention: Describe the annual complication screening of diabetic patients including clinical and laboratory
parameters
Approaches to prevention of diabetic complications include the following: (Medscape)
• HbA1c every 3-6 months
• Yearly dilated eye examinations
• Annual microalbumin checks
• Foot examinations at each visit
• Blood pressure < 130/80 mm Hg, lower in diabetic nephropathy
• Statin therapy to reduce low-density lipoprotein cholesterol
LABORATORY TESTS
• HBA1c
• Fasting Blood Sugar
• Creatinine
• Microalbumin: Creatinine
Ratio, Random Urine
• AST
• ALT
• GGT
• Thyroid Stimulating
Hormone
• CBC (Complete Blood
Count)
• Lipid Panel
• ECG

-Screening for nerve damage

and circulation with foot
examinations
People with diabetes should have a foot examination at least once a year. Your feet will be looked at and you can
expect to be tested for the feeling in your feet, including your sense of touch, hot and cold sensations and they may
test for the circulation in your feet as well.
Diabetes can affect the nerves as well as blood circulation which are both important to our feet.
Blisters, burns and cuts are all possible and if you suffer from nerve damage you may not feel the pain.
It may not be easy to spot nerve damage as it comes on very gradually; this is partly why a foot examination once a
year is important.
Blood circulation needs to be checked as good circulation is needed to keep your feet healthy; from the nerves and
muscles inside to the skin outside.
-Screening for eye problems (Retinopathy)
Everyone with diabetes, who is 12 years old or over, should receive a retinal examination once a year.
Screening for cholesterol
level of cholesterol should be tested once a year. A sample of blood will need to be taken, usually from a vein on the
inside of your elbow
Blood pressure screening
Blood pressure is important to check as a high blood pressure level can increase the risk of heart
disease (cardiovascular disease), kidney disease (nephropathy), sight damage ( retinopathy ) and strokes
Screening for kidney disease (nephropathy)
Yearly screening using urine sample
CAD→ECG, through heart examination
6.Briefly describe the treatment of the above complications
DKA
Basics components
▪ Fluid and electrolyte replacement (with careful attention to potassium)
o Normal saline /Ringers boluses 20cc/Kg in 1st hr and repeat till CFT & hypotension are corrected
o After initial resus. -Use ½ strength saline except in very hyperosmolar child
o Monitor hourly serum K+ → 40mEq/L
▪ Insulin, with frequent monitoring using flow chart .
o Continuous low-dose IV infusion – actrapid, humulin
o Dose 0.1 U/kg/hour. Bolus – no longer used → Use Infusion pump
Hyperosmolar coma
DKA and HHNKS show considerable overlap in symptoms and treatment. Insulin infusion should be combined with
fluid repletion over 24 hours. Fluid replacement, with both crystalloids and colloids, is more rapid due to severe
dehydration. Potassium deficits require several days of treatment. Phosphorus and sodium also may be needed.
After an initial period of stabilization with insulin, most patients with type 2 diabetes who present in a hyperosmolar,
hyperglycemic state can be controlled with oral hypoglycemic drugs combined with diet
Hypoglycemia
Eating or drinking 15-20g of fast acting carbohydrate such as glucose tablets, sweets, sugary fizzy drinks or fruit juice
then check blood sugar after 15 minutes
Coronary artery disease
Lifestyle modifications include smoking cessation, regular exercise, weight loss, good control of diabetes and
hypertension, and a healthy diet.
Low dose aspirin, beta-blocker, as-needed nitroglycerin, and moderate to high-intensity statin. If symptoms are not
controlled with this, beta-blocker therapy should be titrated up to heart rates 55-60, and the addition of calcium
channel blocker and long-acting nitrates should be considered
Peripheral vascular disease
First-line treatment typically involves lifestyle modifications. Your doctor will suggest a regular exercise program that
includes walking, a balanced diet, and losing weight.
▪ cilostazol or pentoxifylline to increase blood flow and relieve symptoms of claudication
▪ clopidogrel or daily aspirin to reduce blood clotting
▪ atorvastatin, simvastatin, or other statins to lower high cholesterol
▪ angiotensin-converting enzyme (ACE) inhibitors to lower high blood pressure
▪ diabetes medication to control blood sugar, if you have diabetes
Cerebrovascular disease
Lifestyle modifications include smoking cessation, regular exercise, weight loss, good control of diabetes and
hypertension, and a healthy diet
Aspirin is recommended within 24-48 hours after stroke onset. Oxygen supplementation is recommended when the
oxygen saturation is less than 94%. Antihypertensives especially in hemorrhagic stroke.
Diabetic retinopathy
Mild and moderate cases do not require immediate treatment but are monitored
Medication
▪ Intravitreal anti-VEGF injection: To prevent growth of abnormal blood vessels.
▪ Glucocorticoids: Given in the form of injection or injected as an implant for continuous sustained release of
the drug to reduce macular edema
Procedures
▪ Laser treatment: Abnormal blood vessels are shrunk by the use of heat from a laser.
▪ Vitrectomy: Surgical removal of the clear, jelly-like substance (vitreous gel) that fills the inside of the eye to
relieve traction of the vitreous gel on the retina that may cause its detachment which may lead to blindness.
Lifestyle modification → Diet + Exercise
Diabetic Neuropathy
Proper blood sugar management → Lifestyle modification → Diet + Physical activity
Drugs that can help to manage pain include: anticonvulsant drugs, tricyclic antidepressants, opioids and nonopioid
pain relief medication
Routine foot examination, especially for patients who have evidence of sensory loss, should be performed at every
medical visit, and patients should be instructed to;
▪ inspect their feet daily for cracks, fissures, ulcers, or inflammation.
▪ Keep your feet clean and dry. Moisturize your feet. Trim your toenails carefully.
▪ Patients should avoid walking barefoot (even at home) and should wear protective covering (avoid sandals)
outside.
▪ Thermal injuries can be prevented by avoiding use of heating pads or hot-water bottles on the feet.
▪ Referral to a foot care specialist should be considered for patients with sensory loss, foot deformity, extensive
callus formation, and nonhealing ulcers.
Diabetic Nephropathy
Establishing the presence of microalbuminuria should prompt vigorous efforts to reduce the risk of progression to
nephropathy (and to protect against cardiovascular disease) by:
▪ control of blood pressure
▪ reduction of cardiovascular risk factors
▪ optimisation of glycaemic control.
Blockade of the renin–angiotensin system using either ACE inhibitors or angiotensin 2 receptor blockers (ARBs). This
relieves angiotensin II-mediated vasoconstriction of efferent arterioles downstream from the glomerular capillary tuft,
decreasing glomerular filtration pressure and, therefore, hyperfiltration and protein leak.
 Study Guide 5
1. Describe the pathophysiology of the acute metabolic complications of diabetes
a. Revise DKA
Profound insulin deficiency results in decreased glucose uptake, increased fat mobilization with release of fatty acids,
and accelerated gluconeogenesis, glycogenesis, and ketogenesis. In the absence of insulin, the release of free fatty
acids from adipocytes increases production of ketone bodies (acetoacetate, hydroxybutyrate, and acetone) by the
mitochondria of the liver at a rate that exceeds peripheral use. Accumulation of ketone bodies causes a drop in pH and
triggers the buffering system associated with metabolic acidosis. DKA caused by increased levels of circulating
ketones in the absence of the antilipolytic effect of insulin occurs. Relatively increased glucagon levels also contribute
to activation of the gluconeogenic (glucose-forming) and ketogenic (ketone-forming) pathways in the liver. Ordinarily
ketones are used by tissues as an energy source to regenerate bicarbonate. This balances the loss of bicarbonate, which
occurs when the ketone is formed. Hyperketonemia (increased blood ketone levels) may result from impaired use of
ketones by peripheral tissue, which permits strong organic acids to circulate freely. Bicarbonate buffering then does
not occur, and the individual develops a metabolic acidosis.

b. Hyperosmolar coma
HHNKS differs from DKA in the degree of insulin deficiency (which is more profound in DKA) and the elevation of
glucose levels and degree of fluid deficiency (which are more marked in HHNKS).
HHNKS has synergistic factors, including insulin deficiency and increased levels of counter-regulatory or stress
hormones (glucagon, catecholamines, cortisol, and growth hormone), with increased gluconeogenesis and
glycogenolysis and inadequate use of glucose by peripheral tissues, primarily muscle, characterized by a lack of
ketosis.
Proinflammatory mediators (TNF-α, IL-6, IL-1β) also promote insulin resistance and release of counter-regulatory
hormones contributing to insulin resistance and hyperglycemia.
Because the amount of insulin required to inhibit fat breakdown is less than that needed for effective glucose transport,
insulin levels are sufficient to prevent excessive lipolysis but not to use glucose properly.
2. Describe the pathophysiology of the chronic vascular complications i.e. Macrovascular – atherosclerosis
a. coronary artery disease
b. Peripheral vascular disease
c. Cerebrovascular disease
Diabetes exacts a heavy toll on the vascular system. Endothelial dysfunction, which predisposes to atherosclerosis and
other cardiovascular morbidities, is widespread in diabetes, because of the deleterious effects of persistent
hyperglycemia and insulin resistance on the vascular compartment. The hallmark of diabetic macrovascular disease is
accelerated atherosclerosis involving the aorta and large- and medium-sized arteries. The morphology of
atherosclerosis in patients with diabetes is indistinguishable from that in individuals without diabetes. Myocardial
infarction, caused by atherosclerosis of the coronary arteries, is the most common cause of death in diabetes.
Basic pathogenesis:
-↑glucose level + Amino group (glycosylation) →AGE formed→circulate in the blood!
Effect of AGE: (described in Q 5) basically ↑risk factors for endothelial injury by binding to RAGE receptors on
endothelial surface + Vascular SM→↑Vascular SM proliferation, ↓adhesion of endothelial cells to BM, attract LDL +
CHL, ↑pro-coagulant activity
-diabetes causes dislipidemia→↓HDL
-↑platelet adhesiveness
-↑thromboxane A2
-↓prostacyclin

These all accelerate the Atherosclerosis process which occurs as following:

Lesion progression occurs through interaction of modified lipoproteins, monocyte-derived macrophages, and T
lymphocytes with endothelial cells and smooth muscle cells of the arterial wall
Atherosclerosis progresses in the following sequence:
• Endothelial injury and dysfunction, causing (among other things) increased vascular permeability, leukocyte
adhesion, and thrombosis
• Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall
• Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into
macrophages and foam cells
• Platelet adhesion
• Factor release from activated platelets, macrophages, and vascular wall cells, inducing smooth muscle cell
recruitment, either from the media or from circulating precursors
• Smooth muscle cell proliferation, extracellular matrix production, and recruitment of T cells.
• Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cell)

PVD→arterial atheroma→arterial insufficiency→intermittent claudication

Renal vascular disease for Macroscopic complication→renal artery stenosis

Describe the pathophysiology of the Microvascular complications

a. Retinopathy
Hyperglycemia leads to the activation of alternative pathways of glucose metabolism, including the polyol pathway.
The oxidative stress, protein kinase C activation, and non-enzymatic protein glycation lead to advanced glycation
endproducts (AGEs). The result of these alternative pathways is the activation of cytokines along with the growth
factors and vascular endothelial dysfunction, which eventually leads to increased vascular permeability and
microvascular occlusion. As with all diabetic microangiopathy in general, the basement membrane of retinal blood
vessels is thickened. In addition, the number of pericytes relative to endothelial cells diminishes.
Three stages of retinopathy lead to loss of vision:
non-proliferative (stage I), characterized by thickening of the retinal capillary basement membrane and an increase in
retinal capillary permeability, vein dilation, microaneurysm formation, and superficial (flame-shaped) and deep (blot)
hemorrhages;
pre-proliferative (stage II), a progression of retinal ischemia with areas of poor perfusion that culminate in infarcts;
proliferativ e (stage III), the result of neovascularization (angiogenesis) and fibrous tissue formation within the retina
or optic disc
Micro-occlusions → retinal ischemia
Microaneurysms → hemorrhage (Dots/blots)
Retinal exudates → "soft" (microinfarcts) or "hard" (deposits of plasma proteins and lipids)
Structural changes in the retinal microcirculation → physiologic breakdown in blood-retinal barrier→ leaky →
macular edema→ visual loss
Nonperfusion of the retina → up-regulation of VEGF → retinal angiogenesis → new vessels that sprout from existing
vessels
neovascular membranes extend along the potential plane between the retinal internal limiting membrane and the
posterior hyaloid →separate vitreous humor from internal limiting membrane of the retina →posterior vitreous
detachment massive hemorrhage
Organization of the retinal neovascular membrane may wrinkle the retina, disrupting the orientation of retinal
photoreceptors and producing visual distortion, and may exert traction on the retina, separating it from the retinal
pigment epithelium (retinal detachment).
Retinal neovascularization → development of a neovascular membrane on iris surface → Contraction of the iris
neovascular membrane→ adhesions between iris and trabecular meshwork → occluding aqueous outflow → ↑
intraocular pressure (neovascular glaucoma).
 b. Nephropathy
Three lesions are encountered: (1) glomerular lesions; (2) renal vascular lesions, principally arteriolosclerosis; and (3)
pyelonephritis, including necrotizing papillitis
As the kidney becomes damaged by diabetes, the afferent arteriole (leading to the glomerulus) becomes vasodilated to
a greater extent than the efferent glomerular arteriole. This increases the intraglomerular filtration pressure, further
damaging the glomerular capillaries. This raised intraglomerular pressure also leads to increased local shearing forces,
which likely contribute to mesangial cell hypertrophy and increased secretion of extracellular mesangial matrix
material. This process eventually leads to glomerular sclerosis.
▪ The glomerular capillary basement membranes are thickened throughout their entire length.
▪ mesangial expansion - increased matrix production & glycosylation of matrix proteins
▪ glomerular sclerosis- intra glomerular hypertension + hyaline narrowing of the vessels
The glomerular lesions take the form of ovoid or spherical, often laminated, nodules of matrix situated in the
periphery of the glomerulus
Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then
spreads to affect the tubules. One special pattern of acute pyelonephritis, necrotizing papillitis (or papillary necrosis)
which is destruction of the renal pyramids by infarct necrosis

c. Neuropathy
The underlying pathologic mechanism includes both metabolic and vascular factors related to chronic hyperglycemia
with inflammation, ischemia, oxidative stress, advanced glycation end products, and increased formation of polyols
contributing to demyelination, nerve degeneration, and delayed conduction
Vaso nevorum → thicken → ↓blood supply → ischemia → damage nerves → nerve repair mechanisms delayed →
Axonal degeneration → sensory nerve fibers.
Nerve degeneration begins in the periphery, but the pathologic condition also can include the spinal cord and the
posterior root ganglia.
4. Describe the pathophysiology of immune dysfunction in diabetes mellitus
Chemotaxis of leukocytes and macrophages is impaired by hyperglycaemia, leading to prolonged inflammatory phase
of wound healing by slowing rates of collagen synthesis and decreased granulation tissue formation.
Due to Glycosylation of basement membrane protein, there is vascular changes (narrowing, hyaline arteriosclerosis,
leaky BM, decrease blood flow) which impairs host defense particularly decreased neutrophil function (chemotaxis,
adherence to the endothelium, phagocytosis, microbicidal activity)
Impaired Macrophage function due to Glycosylation of cytoskeletal protein
• impaired cytokine production
• vascular changes- reduces host defense
• BV thickening- Impaired inflammation
Patients with diabetes are at increased risk for perioperative infections, including wound infections. They are also at
increased risk for staphylococcal infections, Fournier gangrene, and candidiasis.
Diabetes = decreased metabolism = decreased immunity
5. Describe glycosylation and AGEs
Glycosylation (glycation)
-is the process by which a carbohydrate is covalently attached to a target macromolecule, typically proteins and lipids
-glycation is a process when glucose covalently attaches to an assortment of proteins nonenzymatically. It occurs
roughly inn proportion to the severity of hyperglycemia
-these proteins include hemoglobin A¬1¬, crystalline lens of eye, basement membrane
- Non-enzymatic glycosylation of Hb is irreversible, so level of HbA1c (glycosylated Hb in RBCs) is measured
routinely and serves as a marker for:
o Monitoring hyperglycemia.
o Glycemic control.
o On-going hyperglycemia-related protein damage.

-The initial glycation products (known chemically as Schiff bases) are labile and can dissociate rapidly. With time,
these labile products undergo complex chemical rearrangements to form stable advanced glycosylation end-products
(AGEs), consisting of a glucose derivative covalently bound to the protein amino group.
As a result, the structure of the protein is permanently altered, and its function may be affected. For example, albumin
and immunoglobulin G(IgG) do not normally bind to collagen, but they adhere to glycated collagen.
Effect of AGE:
A-AGEs bind to a specific receptor (RAGE)→present on the surface of: inflammatory cells (macrophages & T cells),
endothelium, vascular smooth muscle
Causes:
(1) release of pro-inflammatory cytokines & growth factors
(2) generation of reactive oxygen species
(3) increased pro-coagulant activity
(4) proliferation of vascular smooth muscle cells synthesis of extracellular matrix
B-AGEs directly cross-link extracellular matrix proteins which resist proteolytic digestion
-Collagen type I molecules in large vessels- decreases elasticity- stress and endothelial injury (enhance
atherosclerosis)
-Type IV collagen in basement membrane:
decreases endothelial cell adhesion
increases extravasation of fluid
decreases protein removal & deposition
Attracts LDL, CHL - athero-genesis
-capillaries- glycated basement membrane - thickening - diabetic micro- angiopathy
 Study Guide 6
1. Provide an overview of anaerobic infections
• Anaerobic bacteria are bacteria that do not live or grow in the presence of oxygen.
• Anaerobic bacteria do not have cytochrome system for oxygen metabolism.
• Lack the capacity to utilize O2 as a terminal electron acceptor.
• Anaerobes generate energy by fermentation
• They grow at low oxidation-reduction potential sites, such as necrotic, revascularized tissue.
Aerobic bacteria have detoxifying pathway which consists of enzymes:

• Superoxidase dismutase
• Catalase
• Peroxidase
They detoxify oxygen reactive species e.g., H2O2, O2-, OH+ which are toxic products and make them into non toxic
products like H20 and O2. Anaerobic does not have detoxifying enzymes.

2. Describe the characteristics and classifications of anaerobic bacteria

According to the tolerance to oxygen there are three categories of anaerobic bacteria

• Obligate anaerobes: need an oxygen-free environment to live. They cannot grow in places with oxygen
(clostridium)
• Aerotolerant anaerobes: do not use oxygen to live but tolerate atmospheric oxygen for a limited time.
• Facultative anaerobes: use fermentation to grow in places without oxygen but use aerobic respiration in
places with oxygen.

Spore forming anaerobic bacteria:

• Clostridium tetani
• Clostridium botulinum
• Clostridium perfringens
 • Clostridium difficile.
• Clostridium septicum
• Clostridium novyi
• Clostridium histolyticum
• Clostridium sordellii
Formation of spores
When vegetative bacteria realize its environment is not suitable → cell division and partitioning happens → formation
of spore coat which protects spores for prolonged period from the environment → get to host → spore changes to
vegetative bacteria

Non spore forming anaerobic bacteria

Gram negative bacilli:

• Bacteroides
• Prevotella
• Porphyromonas
• Fusobacterium
Gram negative cocci

• Veillonella
Gram positive bacilli

• Actinomyces
• Lactobacilli
• Propionibacterium
• Eubacterium
Gram positive cocci

• Peptostreptococcus
• Peptococcus
Anaerobes clinically important

• Clostridia – C tetani; C perfringens; C difficile; C botulinum

• Bacteroides
• Prevotella
• Porphyromonas
• Actinomyces
• Fusobacterium
 • Anaerobic streptococci

3. Describe the most likely sites for anaerobes to harbour

The non-spore forming anaerobic bacteria that cause infections are normally found as a normal flora in the body.
Sites with normal anaerobic flora:

• Mouth
• Throat
• Vagina
• Cervix
• Skin folds
• Intestine
Anaerobes grow at low oxidation – reduction sites like necrotizing revascularized tissue

4.Describe different types of infection caused by non-spore forming anaerobic bacteria

Oxygen is excluded from the tissue when the local blood supply is impaired by trauma, obstruction, or surgical
manipulation. Anaerobes multiply well in dead tissue. Multiplication of aerobic or facultative organisms in association
with anaerobes in infected tissue also diminishes oxygen concentration and develops a habitat that supports growth of
anaerobic bacteria.
Head and neck:
1. Odontogenic infections from dental or soft tissue possibly progressing to periapical abscesses, at times extending to
bone
2. Both anaerobic and aerobic pathogens in chronic sinusitis, chronic mastoiditis, peritonsillar abscess, and chronic
otitis media
3. Complications: Deep neck space infections, brain abscesses, mediastinitis
4. Specific examples of anaerobic infections in head and neck:
a. Ludwig angina: Bilateral infection of sublingual and submandibular spaces that causes swelling of the base
of the tongue with potential airway compromise. Usually mixed aerobic and anaerobic flora
b. Lemierre syndrome: Jugular vein suppurative thrombophlebitis caused by anaerobic bacteria:
Fusobacterium necrophorum
Pleuropulmonary
1. May involve anaerobes present in the oropharynx
2. Anaerobic bacteria more likely in those with gingivitis or periodontitis
3. Manifestations: Necrotizing pneumonia, empyema, lung abscess
Intraabdominal
1. Disruption of intestinal integrity leading to infection involving anaerobic bacteria
2. Bacteria from colonic neoplasm, perforated appendicitis, diverticulitis, or bowel surgery, causing bacteremia,
peritonitis, at times intraabdominal abscesses
Female genital tract
1. Anaerobes in bacterial vaginosis, salpingitis, endometritis, pelvic abscesses, septic abortion; infections tend to be
mixed
2. Possible pelvic thrombophlebitis when resolving pelvic infection is accompanied by new or persistent fever
Other anaerobic infections
1. Skin and soft tissue infection at any site
2. More commonly associated infections: Synergistic gangrene, bite wound infections, infected decubitus ulcers
3. Clinical significance of anaerobes in diabetic foot infections unclear
4. Anaerobic bacteremia is not common with source usually intraabdominal, followed by female genital tract,
pleuropulmonary, and head and neck infections
5. Osteomyelitis especially when associated with decubitus ulcers or vascular insufficiency
6. Facial bone osteomyelitis from adjacent infections of the teeth or sinuses.

5.Describe the characteristics of a possible anaerobic infection

A foul-smelling infection or drainage from an abscess is diagnostic of anaerobic infection. Other clues to anaerobic
infection include tissue necrosis and gas production at the infection sites.
Criteria of Non-spore forming anaerobic infection
▪ Infection adjacent to a mucosal surface
 ▪ They tend to form closed space infections, (lung, brain, pleura, peritoneum, pelvis)
▪ Polymicrobial infections
▪ Foul- smelling pus, Necrotic gangrenous tissue and abscess formation
▪ Black discoloration of exudates, Gas production at the infection site
▪ Bacteraemia or endocarditis with NO growth on aerobic blood cultures.

6.Describe the characteristics and pathogenesis of different group of spore forming anaerobic bacteria.
Clostridium tetani
▪ Obligate anaerobe found in soil
▪ Long slender gram +ve bacilli with terminal spore

Pathogenesis: Tetanus
Spore enter through Burns, deep puncture wounds, ear or dental infections, animal bites, abortion → anaerobic
condition → germinate → vegetative bacteria → release exotoxins; Tetanolysin & Tetanospasmin(neurotoxin) →
enter blood → axon → cell body by retrograde axonal transport → bind to ganglioside receptors at presynaptic
inhibitory motor nerve ending → block GABA release → unopposed Ach activity → spastic paralysis
Clostridium perfringens
▪ Aerotolerant anaerobe found in environment & intestine
▪ Gram +ve slightly curved bacilli with subterminal spore
Causes;
▪ Clostridial myonecrosis- Gas gangrene
▪ Cellulitis and fasciitis
▪ Necrotizing enteritis
▪ Food poisoning:
Pathogenesis: Gas gangrene

Spore in soil → enter wound → anaerobic condition → germinate → release αtoxin (lecithinase), βtoxin, theta toxin,
hyaluronidase, collagenas, Dnase → lecithinase lyse erythrocytes, platelets, leukocytes, and endothelial cells
→production of gas in tissues → distension of tissue ↓blood supply → β theta toxins + hyaluronidase → necrosis →
spread of infection, hemolytic anemia, toxemia, death
Clostridium Botulinum
▪ Obligate anaerobe
▪ Gram +ve bacilli with Sub terminal spore
▪ Types A,B,E and sometimes F cause illness in humans
Types:
▪ Foodborne botulism- caused by eating (canned)foods that contain botulinum toxin
▪ Intestinal botulism (infant and child/adult)- caused by ingesting spores of the bacteria which germinate and
produce toxin in the intestines
▪ Wound botulism - C. botulinum spores germinate in the wound
▪ Inhalation botulism - Aerosolized toxin is inhaled (bioterrorism)
Pathogenesis: Botulism
Spore in canned food→ anaerobic condition → germinate → release toxin → ingested → blood (from wound aswell)
→ presynaptic motor neurons (PNS + CN) → proteolysis of SNARE proteins by light chain of toxin → inhibit release
of Ach → NO CONTRACTION → paralysis(flaccid) → symmetrical descending paralysis

Clostridium difficile
▪ Obligate anaerobe in git
▪ Gram +ve bacilli
▪ associated with being hospitalized or taking certain antibiotics (oral clindamycin)
Endogenous infection - After antibiotic use → ↓↓ Intestinal normal flora →Colonization of C.difficile
Exogenous infection - spores detected in hospital rooms of infected patients
Pathogenesis: Pseudomembanous ulcerative colitis
Colonization →Enterotoxin →Toxin A [enterotoxin] &Toxin B [cytotoxin] → binds to intestinal brush border
membranes at specific receptor sites →cytotoxin causes cell death and tissue necrosis → Pseudomembanous
colitis[fibrin, mucus and leukocytes seen by colonoscopy]
7. Describe the method of culture of anaerobic bacteria
Sample collection
o Material for anaerobic culture is best obtained by
▪ Tissue biopsy
▪ Aspiration using a needle and syringe.
o Use of swabs is a poor alternative because of the exposure of the specimen to the oxygen.
o Aspirate the specimen using a NEEDLE AND SYRINGE is the best and convenient way for sampling
following the usual procedure and remove the air from syringe immediately.
o If no pus or fluid comes on aspiration inject sterile saline subcutaneously and resample.
o The last and least way is to use deep swab and rapidly to transfer to anaerobic transport media.
o To cultivate anaerobes, the specimen should not be exposed to air

Culture of Specimen
o Clinical specimens suitable for anaerobic culture
▪ blood
▪ bile
▪ bone marrow
▪ cerebrospinal fluid
▪ direct lung aspirate
▪ tissue biopsy from a normally sterile site
▪ fluid from a normally sterile site (like a joint)
▪ Dental abscess
▪ abdominal or pelvic abscess
▪ surgical wound

o Clinical specimen unsuitable for anaerobic culture.

▪ Coughed sputum.
▪ Swab (Nasopharyngeal, Throat, superficial skin lesion, Rectal, Vaginal or cervical )
▪ Voided or catheterized urine
▪ Feces

o Anaerobic media contain reducing substances

o For culture of strict anaerobes all traces of oxygen must be removed from medium
▪ Anaerobic blood agar
▪ Thyoglycolate broth
 ▪ Brain heart infusion broth
▪ Cooked meat broth

Culture Methods

✓ Chemical exclusion of O2 (anaerobic Gas Pak system)

o These are commercially available, disposable sachets containing a dry powder or pellets, which, when
kept in an appropriately sized airtight jar, produce an atmosphere free of elemental oxygen gas (O2).
o After the inoculated plates are kept in the jar, Gaspak envelope, with water added, is placed inside & the
lid screwed tight.
o Sodium bicarbonate and sodium borohydride are mixed with a small amount of water to produce CO2 and
H+
o Uses H2 to convert air O2 to H2O in the presence of a catalyst.
o The catalyst is palladium contained in the lid of the jar.
o Anaerobic indicator strips included to monitor the anaerobic condition.
Identification
o Plates are checked at > 18-24 hours for faster growing species like Cl. Perfringens & B.fragilis & daily
thereafter up to > 5-7 days for slowly growing species like Actinomyces, Eubacterium & Propionibacterium
o Genus is determined by
▪ gram stain
▪ cellular morphology
▪ Gas-liquid chromatography
o Species determination is based on fermentation of sugars & other biochemical determination.

8. Describe the drug sensitivities for most anaerobes

Metronidazole→imp, oral or IV

9. Provide an overview of methicillin-resistant Staphylococcus aureus (MRSA) infections in diabetic patient

o Staphylococcus aureus is the most commonly isolated pathogen in diabetic foot infections.
o Methicillin-resistant S. aureus (MRSA) strains have been isolated more frequently in many communities
worldwide.
o MRSA infections are associated with lower infection cure rates, higher amputation rates, and increased mortality
o MRSA is the term used for any strain of Staphylococcus aureus that has developed resistance to β- lactam
antibiotics, which include the penicillins (methicillins, oxacillin, dicloxacillin etc.) and cephalosporins
o MRSA causes a variety of disseminated, lethal infections in humans.
o Has the ability to easily transfer resistant genes to other species directly and indirectly

o The risk for MRSA isolation increases in the presence of nasal carriage of MRSA, prior use of antibacterials or
hospitalization, larger ulcer size and longer duration of the ulcer.
o The standard therapy for MRSA infections is vancomycin
o Because of limitations of this agent, other new anti-MRSA antibiotics such as linezolide or daptomycin are used
 Study Guide 7
1. Discuss the pharmacology of different insulin preparations
There are three insulin preparations available on the Fiji EMF and are discussed below. The usage of these
preparations is discussed later. Insulin is given using conventional disposable insulin syringes. Insulin pens and pre-
filled syringes are expensive options and are available only in the private sector. The preferred sites of injection are
the abdominal wall, the deltoids and the thighs. It is recommended that these sites be rotated regularly
Insulin Pens
These are insulin delivery devices available in many different brands and models, mainly for personal use. They
generally fall into two (2) groups: reusable pens and disposable pens.

• Reusable insulin pens are loaded with an insulin filled cartridge before use and replaced by another cartridge
when empty. Set of five (5) replaceable cartridges are usually available with each cartridge containing either
150 or 300 units of soluble, intermediate or mixed insulin. Needles are available separately.
• Disposable insulin pens come filled with insulin and are discarded when empty. Needles are available
separately and disposable pens may be available in sets of five (5).
There are advantages and disadvantages of using the insulin pens:

• Advantages are that they are discreet, user friendly, insulin is pre-filled, pen is easily portable and convenient
for injections away from home.
• Disadvantages are that the pens maybe more expensive, not all types of insulin maybe available and they do
not allow mixing of insulin.
Insulin Pumps (also known as continuous subcutaneous insulin infusion therapy)
These are small, computerized insulin delivery devices which can be worn on the belt or kept in the pockets of
patients. The pumps allow for a continuous flow of rapid-acting insulin into the body through a catheter inserted under
the skin of the abdomen. The insulin pump is designed to deliver a continuous amount of insulin, 24 hours a day
according to a programmed plan unique to each pump wearer. The amount of insulin delivered can be changed by the
user. The insulin pump is an alternative to multiple daily injections for intensive insulin therapy (which includes
frequent blood glucose monitoring as well). The pumps also have the capability of recording the history of insulin
delivery and this could be downloaded onto a computer for analysis.
In recent times insulin pump technology is being combined with continuous blood glucose monitoring system. When
the feedback loop is complete (insulin delivery based on feedback of the blood glucose level) the system may function
as artificial pancreas.
Note: Very small numbers of patients in Fiji are using the insulin pens and even fewer may be using the pump.
However, visitors to the country may be using these devices and may seek your advice or help
Insulin treatment in type 2 diabetes
(i) Deciding when to start
• Failure of oral hypoglycemic agents – insulin therapy should not be delayed. Early treatment delays
complications and preserves beta cell function.
• Patients undergoing major surgery
• Critically ill patients
• Pregnancy
(ii) Administering insulin with oral hypoglycemic drugs
• As outpatient treatment, initiate with Isophane or mixed insulin 10 units subcutaneously at bedtime and
adjust dose according to blood sugar levels.
• If the blood sugar is not controlled then use Isophane or mixed insulin 10 units subcutaneously twice daily
with subsequent adjustment of the dose according to blood glucose levels.
• Oral hypoglycemic agents should not be stopped with the commencement of insulin therapy though
adjustments can be made as required.
(iii) Insulin regimens
(a) Multiple-dose (“QID”) regimen
 This regimen is more suited for stabilization of blood sugar for inpatients.

• Soluble insulin starting with 5 units subcutaneously 30 minutes before each meal AND
• Isophane 8 units subcutaneously twice a day.
• Insulin doses should be adjusted based on the blood sugar levels.
(b) Twice daily regimen
This regimen can be used for control of blood sugar for both inpatients and outpatients.

• Mixtard insulin70/30, starting with 10 units in the morning and 5 units in the evening subcutaneously 30
minutes before meals. Adjust insulin dose to control blood sugars.
If mixed insulin preparation is unavailable then use:

• Isophane insulin 10 units in the morning and 5 units in the evening subcutaneously 30 minutes before
meal. Doses are adjusted to control the blood sugar levels.
In principle, two-thirds of the insulin dose should be administered in the morning and one third in the evening.
However, insulin doses should be adjusted based on the blood sugar levels and increments of 5 units per dose are
recommended. If blood sugar level remains uncontrolled then contact the medical registrar at your divisional hospital
For both regimens give 5 units insulin subcutaneously if blood glucose not controlled

2. Explain the roles of amylin and GLP-1 in blood glucose regulation

The physiological effects of glucagon-like peptide-1 (GLP-1) are of immense interest because of the potential
clinical relevance of this peptide. Produced in intestinal L-cells through posttranslational processing of the
proglucagon gene, GLP-1 is released from the gut in response to nutrient ingestion. Peripherally, GLP-1 is known to
affect gut motility, inhibit gastric acid secretion, and inhibit glucagon secretion.
In the central nervous system, GLP-1 induces satiety, leading to reduced weight gain.
In the pancreas, GLP-1 is now known to induce expansion of insulin-secreting β-cell mass, in addition to its most
well-characterized effect: the augmentation of glucose-stimulated insulin secretion.
GLP-1 is believed to enhance insulin secretion through mechanisms involving the regulation of ion channels
(including ATP-sensitive K+ channels, voltage-dependent Ca2+ channels, voltage-dependent K+ channels, and
nonselective cation channels) and by the regulation of intracellular energy homeostasis and exocytosis.

The neuroendocrine hormone amylin is co-secreted with insulin by pancreatic islet β cells. Its secretion is stimulated
by food components such as glucose and arginine.
The secretion of insulin and amylin is regulated not only by the concentration of glucose in the blood but also
increased by the incretin effect.
Amylin affects glucagon secretion, inhibits its secretion stimulated by amino acids and reduces endogenous glucose
production during the postprandial period. Amylin acts as modulator of glycogen synthesis, glucose consumption and
has an influence on insulin resistance induction in skeletal muscle and probably also in the liver.
In diabetic patients, ß-cell destruction results not only in the insulin deficiency, but also in C-peptide and amylin
reduced secretion. Amylin is clearly involved in glucose homeostasis through the inhibition of gastric emptying and
postprandial hepatic glucose production, eventually reducing postprandial glucose fluctuations. Synthetic
pramlintide-amylin analogue-has been shown to improve glycemic control in patients with diabetes. Amylin
replacement with pramlintide may be a supplement to insulin therapy in patients with diabetes mellitus.
Incretins = GIP and GLP-1 , Amylin is not an incretin

3. Identify the current targets for drug therapy in Type 2 DM

Results of various randomized trials in diabetic patients have shown that control of hyperglycemia delays the onset
and slows the progression of microvascular complications. However, its effect on macrovascular disease remains
uncertain
The first step in the control of hyperglycemia is setting an appropriate glycemic target in each individual. In younger
patients with no complications of diabetes a near normal glycemic target can be aimed for, while in older patients with
cardiovascular disease and multiple vascular risk factors, a higher glycemic target should be the goal. Intensive
glucose control in the latter poses adverse effects from the multiple drugs used and the risk of hypoglycemia

2012 guidelines

2012 guidelines
Other targets:
• No smoking
• Alcohol <2 standard drinks/day
• Exercise – at least 30 mins walking 4 or more days/week.

4.Discuss the different classes of oral hypoglycaemic agents

1.BIGUANIDES - Metformin
 ▪ First line unless contraindicated. biguanides also in PCOS because PCOS has high sugar level associated with
PCOS
▪ Phenformin→older, discontinues cause causes lactic acidosis
MOA:
▪ Primary effect – activate AMPK → ↓hepatic gluconeogenesis
▪ Secondary effect - ↑ tissue insulin sensitivity
500mg max.3g/day in divided doses 2-3 times orally with or after meals
▪ Cleared by kidney (100%)
▪ No weight gain [good for obese], no risk of hypoglycemia [used alone], no inc. in insulin
Adverse effects: nausea; anorexia; vomiting; diarrhoea; weakness, ↓B12 absorption (anemia)
Contraindications: CHF; renal impairments; hepatic impairments, age >80 → risk of lactic acidosis. Stopped for 48
hours before surgery or administration of contrast radiography.
2.SULFONYLUREAS - Glibenclamide and Glipizide
▪ Combined with metformin if diabetes control is inadequate.
MOA:
▪ Binds to SUR 1 receptors on K+ channels → close channel → depolarization → ↑insulin exocytosis
▪ ↓gluconeogenesis + ↓glycogenolysis
Glipizide → single dose up to 15 mg/day orally with meals and in two divided doses above 15 mg up to a maximum
of 40 mg/day.
▪ Cleared by liver and kidneys → older patients + renal impairment.
Glibenclamide → 2.5 mg to 20 mg daily orally with meals and in two divided doses above 10 mg up to a maximum
of 20 mg/day.
▪ Cleared by kidneys → younger patients
Adverse effects: dermatologic reactions, heartburn, hypoglycaemia, nausea, vomiting, dizziness, weight gain!
Contra-indications: hypersensitivity, DKA, Type I DM, pregnancy, and lactating mothers
3.THIAZOLIDINEDIONES (glitazones)– Pioglitazone
▪ monotherapy but can be combined with dual or triple therapy
MOA:
▪ Binds and activates Peroxisome Proliferator Activated Receptor Gamma [nuclear factor] → ↓insulin
resistance in muscles & adipose tissues + ↑I sensitivity → ↑glucose uptake
15-30 mg as a single dose
Adverse effects: Oedema [combo with sulfonylurea/insulin], weight gain and precipitation of heart failure, fractures,
URTI, anemia, headache, hepatotoxicity
Contra-indications: hypersensitivity, DKA, active liver disease, moderate to severe hepatic impairment, chronic heart
failure.
4.α- GLUCOSIDASE INHIBITORS – Acarbose, miglitol→not in fiji)
▪ monotherapy or combined
▪ prevent postprandial glucose surges
MOA:
 ▪ Inhibits α glucosidase in intestinal brush border → ↓conversion of oligosaccharides into glucose → ↓glucose
absorption + ↑ time for carb absorption
25 mg three times a day to 100 mg tds as required. Taken with the first bite of a meal.
Adverse effects: abdominal pain, diarrhoea, flatulence, hypersensitive skin reactions: rash, erythema etc, low serum
iron
Contra-indications: DKA, inflammatory bowel disease, colonic ulceration, partial intestinal obstruction, disorders of
GI digestion or absorption, severe renal impairment
5.MEGLITINIDE DERIVATIVES – Repaglinide; Nateglinide
▪ short-acting insulin secretagogues than sulfonylureas → lesser risk of hypoglycemia
MOA
▪ Same as sulfonylureas → binds to allosteric site
Adverse effects: headache, hypoglycaemia, URTI arthralgia, chest pain, constipation, dizziness, flu-like symptoms
Contra-indications: hypersensitivity, DKA, Type I DM
6.GLUCAGON-LIKE PEPTIDE- 1 AGONIST – Exenatide
MOA:
▪ Mimic endogenous incretin GLP-1 → ↑insulin release, ↓ glucagon, and ↓gastric emptying
Adverse effects: nausea, diarrhoea, hypoglycaemia (with sulfonylurea), vomiting, headache, constipation, dyspepsia,
fatigue, urticaria, upper respiratory tract infection, urinary tract infection, dizziness
Contra-indication: hypersensitivity, patients with personal/family history of medullary thyroid carcinoma, patients
with multiple endocrine neoplasia syndrome type 2
7.AMYLINOMIMETIC – Pramlintide
▪ improvement of long-term control of glucose levels
▪ indicated for the treatment of type 1 or type 2 diabetes in combination with insulin
MOA:
▪ mimics amylin → slows gastric emptying, ↓ glucagon release & regulate appetite
Adverse effects: nausea, headache, vomiting, anorexia, severe hypoglycemia, dizziness, fatigue, abdominal pain
Contra-indications: hypersensitivity, gastroparesis, HbA1c (> 9%)
8.DIPEPTIDYL PEPTIDASE IV INHIBITORS – Sitagliptin
MOA:
▪ inhibits DPP4 → ↓degradation of GLP1 → ↑insulin secretion
Adverse effects: nasopharyngitis, diarrhoea, headache, constipation, peripheral oedema, nausea
Contra-indication: hypersensitivity, type 1 diabetes mellitus, DKA
9.SODIUM-GLUCOSE CO-TRANSPORTER 2 INHIBITORS - Dapagliflozin, Canagliflozin
▪ Mild osmotic diuresis → glucose in urine
MOA:
▪ competitively and selectively block SGLT2 channels in proximal convoluted tubule → ↓glucose reabsorptiob
Adverse effects: UTI, vaginal yeast infections, thirst, hypoglcaemia (combo with insulin or sulfonylureas)
Contraindications: hypersensitivities, severe renal impairment, end stage renal disease, dialysi
5. Describe the current therapeutic guidelines for Type 2 DM
General step wise:
- Establish targets of treatment
- Healthy eating plans
- Education in self monitoring and approaches to coping with emergencies
- Exercise program
- Other risk factor reduction, eg smoking cessation, Alcohol intake
- Institution of appropriate drug treatment if required
- Screening for, and treatment of, complications of diabetes

-For all patients with type 2 diabetes, Non-Pharmacological (SNAP) intervention is essential. This approach can
produce good glucose control.
-Drug therapy should only be considered if:
→Uncomplicated newly diagnosed diabetic patients who are unable to control blood sugars with lifestyle intervention
within 6 weeks.
→Newly diagnosed patients with diabetic complications.
-The decision to commence glucose lowering medications is based on the degree of hyperglycaemia and the presence
or absence of symptoms.
-In general, the use of oral glucose medications should be considered if despite SNAP intervention the fasting glucose
levels are above 7 mmol/L and/ or HbA1c is > 7.0%.
-Metformin is now generally considered to be first line treatment unless contraindicated.
-A sulphonyl urea group of agent like glipizide or glibenclamide is added later if the blood sugar
levels are still not adequately controlled.
-Treatment with other oral glucose lowering medications (glitazones, alpha glucosidase inhibitors) and/or insulin
needs to be determined on an individual basis.
-Glucose control progressively deteriorates over time requiring an increase in drug therapy to maintain glycemic
control.
-About 50% of patients will require insulin therapy in addition to oral medications within 5 to 10 years of diagnosis
of Type 2 diabetes (secondary failure).
-In these patients combining oral glucose lowering medications with insulin minimizes the amount of insulin required
 Study Guide 8
Discuss the nutritional goals for people with Type 2 Diabetes and practical ways to achieving the following:
MEDICAL NUTRITION THERAPY
Definition — Medical nutrition therapy (MNT) includes a nutrition prescription tailored for people with diabetes
based on medical, lifestyle, and personal factors. MNT is an integral component of diabetes management and diabetes
self-management education.
MNT for type 2 diabetes should consider five key aspects:
●Weight management and increased physical activity
●Caloric intake (balanced with caloric expenditure)
●Consistency in day-to-day carbohydrate intake at meals and snacks
●Nutritional content
●Timing of meals and snacks
Meal content, quantity, and timing are particularly important for patients who are treated with insulin secretagogues or
traditional insulin regimens.
The process of MNT involves selecting an appropriate meal planning approach and educational materials based on
assessment of a person's ability or willingness to learn, motivation to make changes in eating habits, clinical and
nutrition goals, diabetes medications, activity level, and lifestyle.

1. Near-normal blood glucose levels as possible by balancing food intake with activity and medications or
insulin
Sugar There are 2 different types of sugars: simple and complex. Simple sugars such as table sugar and sugary foods
and fizzy drinks raise blood sugar levels very quickly which is not good. Complex sugars like starchy foods raise
blood sugar levels slowly and contain a lot of fibre which is also good for the body
-Use less sugar in tea, coffee, or other drinks. If you add more than one teaspoon of sugar to each drink, try to cut
down gradually.
-Reduce drinking fizzy drinks and other sugary soft drinks – drink fresh water, fresh coconut juice, unsweetened fruit
juice, low fat or soy milk instead.
➢ Food Intake and Anti - Diabetic Medications
-All RDNs providing MNT in diabetes care should assess and monitor medication changes in relation to the nutrition
care plan.
-For adults using fixed daily insulin doses, consistent carbohydrate intake with respect to time and amount, while
considering the insulin action time, can result in improved glycemia and reduce the risk for hypoglycemia.
-When consuming a mixed meal that contains carbohydrate and is high in fat and/or protein, insulin dosing should not
be based solely on carbohydrate counting. A cautious approach to increasing mealtime insulin doses is suggested;
continuous glucose monitoring (CGM) or self-monitoring of blood glucose (SMBG) should guide decision-making for
administration of additional insulin
Timing of food intake — Consistent timing of food intake is an important aspect of nutrition in type 2 diabetes
patients treated with insulin secretagogues or traditional insulin regimens.
-Insulin regimens that are based on the injection of roughly the same amount of insulin at the same time each day
(twice-daily premix or basal plus oral medications) require some attention to consistency in meal timing. If meal time
varies widely, then blood glucose profiles will fluctuate as well, with little chance of achieving low A1C values
without a substantial risk of hypoglycemia.
-In contrast, basal-bolus insulin regimens offer patients with type 2 diabetes who require insulin more flexibility in
meal timing. Meal timing consistency is also important for patients with type 2 diabetes who are taking oral
medications that promote insulin secretion, such as sulfonylureas or meglitinides.
2. Optimal blood pressure and lipid levels
Optimal BP <130/80 optimal cholesterol <4mmol/L
A diet that is low in sodium and high in fruits, vegetables, and low-fat dairy products can help keep blood pressure
under control
Eating a diet low in saturated and trans fats and cholesterol can help to reduce your cholesterol levels and decrease
these risks
The body needs some fat – but not as much as what most people eat. Fats are essential to give body energy and
support cell growth. Fats also help protect the body organs and helps keep the body warm. The major fats in foods are
‘good’ fats (monounsaturated fats and polyunsaturated fats) or ‘bad’ fats (saturated fats and trans fats) Eating fatty
foods in large amounts increases weight and raises the blood
cholesterol level, which is also a risk factor for heart attacks and strokes. It is recommended that you reduce fat and oil
in your daily diet.
3.Appropriate calories for achieving and maintaining a healthy, desirable body weight
Significant weight loss can be attained with lifestyle programs that achieve a 500–750 kcal/day energy deficit, which
in most cases is approximately 1,200–1,500 kcal/day for women and 1,500–1,800 kcal/day for men, adjusted for the
individual's baseline body weight. Clinical benefits typically begin upon achieving 3–5% weight loss, and the benefits
of weight loss are progressive; more intensive weight-loss goals (>5%, >7%, >15%, etc.) may be pursued if needed.

▪ Eating small, regular meals.

▪ More than half the total energy intake is from carbohydrates with controlled intake of saturated and trans fatty
acids.
▪ Encouraging high-fibre, low-glycaemic-index carbohydrates and ↓ sucrose and alcohol
▪ Advice about regular exercise at least 30mins a day of brisk walking/gardening
The Plate Method
▪ Fill half with nonstarchy vegetables [salad, green beans, broccoli, cauliflower, cabbage, and carrots].
▪ Fill one quarter with a lean protein [chicken, turkey, beans, tofu, or eggs]
▪ Fill one quarter with carb foods. [grains, starchy vegetables (such as potatoes and peas), rice, pasta, beans,
fruit, and yogurt].
▪ choose water or a low-calorie drink

4.Manage risk factors and prevent complications of diabetes, both acute (hypoglycaemia and short-term illness)
and long-term (micro- and macrovascular disease)
Smoking:

Alcohol:

Exercise:
Hypoglycemia:
Targets for pre-meal blood glucose of between 4 and 7 mmol/L and post-meal values of less than 8.5 mmol/L may be
set for most patients, provided there is no significant hypoglycaemia risk
▪ All patients on insulin or sulphonylurea should be educated on the symptoms of hypoglycaemia and how to
treat it. [palpitations, fatigue, sweating]
▪ If conscious and swallow safe, then they should take 15 to 20 g of oral glucose: 200 mL fresh fruit juice/4 jelly
beans/4 to 5 dextrose tablets
▪ Once resolved, the patient should eat some complex carbohydrate (e.g., sandwich). Eat small regular meals,
don’t skip meals
Stress:

Micro & Macrovascular:

The focus of type 2 diabetes management is ultimately to prevent development of microvascular (retinopathy,
neuropathy, nephropathy) and macrovascular (coronary artery, cerebrovascular and peripheral vascular disease)
complications associated with it. This is achieved by targeting glycaemia and controlling cardiovascular risk factors.
▪ Statins, asprin, ACE inhibitors + Lifestyle modification + glycemic control
▪ Eye and Foot checkups and referral if indicated
 Study Guide 9
1. Describe the therapeutic goals in the management of the diabetic patient and how the likelihood of long-term
complications may be decreased
Initial goals (secondary treatment)
• ensure that symptoms have been eliminated
This is achieved by reducing hyperglycaemia; patients who need insulin immediately. All others normally begin on
diet alone→moving to diet and oral hypoglycaemic agents, or diet and insulin as indicated. All treatments must be
adjusted to ensure that patients are symptom-free. Education of patients plays an important role in enhancing the
quality of life, and needs to be maintained over many years.
• lean patients should gain weight
• obese patients should lose weight
• children should grow normally
• patient education on the glycemic monitoring and hypoglycemic symptoms
• prevention of long-term diabetic complications
The aims of the St Vincent Declaration are to set goals and 5-year targets to improve quality of life and life
expectancy for people with diabetes mellitus and to reduce the serious complications associated with the disease
Maintenance of health by reduction of risk factors and preventing the development of diabetic complications
The needs here are for:
• achievement of optimal blood glucose control
• detection and control of hypertension
• assessment and control of hyperlipidaemia
• assessment of the need for antiplatelet medication
• cessation of smoking
• regular complications screening procedures (neuropathy, nephropathy, retinopathy screening)
• identifying macrovascular complications early and treating it
2.Describe the highlights of important clinical trials relating to the long-term management of type 2 diabetes,
including the UK Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial
(DCCT), and the implication of these trials for the long-term control of type 2 diabetes
Diabetes Control and Complications Trial (DCCT)
The Diabetes Control and Complications Trial (DCCT) published in 1993, is a landmark multicentre trial designed to
test the proposition that the complications of diabetes mellitus are related to elevation of the plasma glucose
concentration. The study design was simple. Two groups of patients were followed long term, one treated
conventionally (goal: clinical well-being; called the standard treatment group) and another treated intensively (goal:
normalization of blood glucose; called the intensive treatment group).
RESULTS
The DCCT followed >99% of the cohort for a mean of 6.5 years and demonstrated a 35–76% reduction in the early
stages of microvascular disease (diabetic retinopathy, nephropathy, and neuropathy) with INT, with a median
HbA1c of 7%, compared with CONV, with a median HbA1c of 9%. The benefit of intensive therapy resulted in a delay
in the onset and a major slowing of the progression of these three complications. Finally, the benefits of intensive
therapy were seen in all categories of subjects regardless of age, sex, or duration of diabetes.
CONCLUSIONS
DCCT/EDIC has demonstrated the effectiveness of INT in reducing the long-term complications of T1DM and
improving the prospects for a healthy life span.
Implications of Diabetes control and complications trial

• The Diabetes Control and Complications Trial (DCCT), showed that intensive glycaemic control reduces the
incidence and progression of microvascular complications (retinopathy, nephropathy and neuropathy) in type 1
diabetes. Type 2 diabetes remained uncertain.

• The major adverse effect of INT was a threefold increased risk of hypoglycaemia

• Patients with type 2 diabetes frequently have other risk factors for macrovascular disease, such as hypertension
and hyperlipidaemia, the former having a prevalence of 40%-60% Antihypertensive therapy reduces the risk of
both cardiovascular and cerebrovascular disease in the general population , type 2 diabetes was again not clear.
United Kingdom Prospective Diabetes Study (UKPDS)
The United Kingdom Prospective Diabetes Study (UKPDS) was conceived to explore the uncertainties in DCCT and
provide clearer guidelines for the management of type 2 diabetes.
The United Kingdom Prospective Diabetes Study (UKPDS) recruited 5,102 patients with newly diagnosed type 2
diabetes in 23 centers within the U.K. between 1977 and 1991. Patients were followed for an average of 10 years to
determine
1) whether intensive use of pharmacological therapy to lower blood glucose levels would result in clinical
benefits (i.e., reduced cardiovascular and microvascular complications)
2) whether the use of various sulfonylurea drugs, the biguanide drug metformin, or insulin have specific
therapeutic advantages or disadvantages.
3) In addition, patients with type 2 diabetes who were also hypertensive were randomized to “tight” or “less
tight” blood pressure control to ascertain the benefits of lowering blood pressure and to ascertain whether the
use of an ACE inhibitor (captopril) or β-blocker (atenolol) offered particular therapeutic advantages or
disadvantages.
SUMMARY OF THE MAIN RESULTS AND CONCLUSIONS OF THE UKPDS
The UKPDS results establish that retinopathy, nephropathy, and possibly neuropathy are benefited by lowering blood
glucose levels in type 2 diabetes with intensive therapy, which achieved a median HbA1c of 7.0% compared with
conventional therapy with a median HbA1c of 7.9%. The overall microvascular complication rate was decreased by
25%.
These results materially increase the evidence that hyperglycaemia causes, or is the major contributor, to these
complications. Every percentage point decrease in HbAlc (e.g., 9 to 8%), there was a 35% reduction in the risk of
complications.

The results demonstrate that the risks of complications can be significantly lowered even in the range of
hyperglycaemia where HbAlc levels are <8.0%.
No significant effect of lowering blood glucose on cardiovascular complications was observed. A 16% reduction
(which was not statistically significant, P = 0.052) in the risk of combined fatal or nonfatal myocardial infarction and
sudden death was observed.
The highest average annual incidence of major hypoglycaemic events was 2.3% of patients per year in those receiving
insulin therapy.
The study showed that lowering blood pressure to a mean of 144/82 mmHg significantly reduced strokes, diabetes-
related deaths, heart failure, microvascular complications, and visual loss.
Vigorous blood pressure control reduces microvascular and macrovascular events; beta blockers and angiotensin-
converting enzyme (ACE) inhibitors appear to be equally effective in this regard
What are the risks of aggressive glucose or blood pressure control?
In the UKPDS, at the glycaemic levels achieved, a small fraction of patients had a major episode of hypoglycaemia
regardless of the pharmacological therapy used, and one patient died from hypoglycaemia over the 27,000 patient-
years of intensive therapy. Thus, the risk of hypoglycaemia should not discourage attaining HbAlc levels approaching
normal.
UKPDS found no increase in the rates of myocardial infarction or diabetes-related deaths when participants treated
intensively with sulfonylurea drugs were compared with those treated conventionally.
UKPDS showed no increase in cardiovascular events or mortality in patients assigned insulin therapy, even though
their fasting plasma insulin levels were higher than those of the conventionally treated patients.

Extra:
Intensive therapy for diabetes
The intensive-therapy regimen was designed to achieve blood glucose values as close to the normal range as possible
with three or more daily insulin injections or treatment with an insulin pump. Conventional therapy consisted of one
or two insulin injections per day
Conventional Therapy
The general consensus on treatment of type 2 diabetes is that life style management at the forefront of therapy options.
In addition to exercise, weight control and medical nutrition therapy, oral glucose lowering drugs, and injections of
insulin are the conventional therapies

3. Discuss individualization of therapy and targets of therapy in patients with diabetes

Management of individuals with type 2 diabetes involves complex decision-making to attain good glycemic control.
Individualization of therapy is a current trend in health care, particularly for chronic diseases, and is based on the
hope that personalized approaches can ultimately result in improved outcomes. Algorithmic approaches have been
utilized traditionally; however, such “one-size-fits-all” approaches are rigid, suboptimal, and seldom consider
important variables involved in an individual’s diabetes care. Personalized care of type 2 diabetes presents as a “real-
world” approach, providing care that is responsive to individuals’ specific and unique needs, preferences, and values.
Structured personalized care has been associated with reduced risks of myocardial infarction (MI) and diabetes-related
end points in a 19-year registry.
What Factors Do We Need to Consider in Personalized Diabetes Management?
Clinical characteristics
1. Patient age and life expectancy
Important in determining individual goals. The younger a patient is, the longer the exposure to hyperglycemia, and the
greater the risk of complications. Thus, younger patients may benefit from more stringent A1C goals, especially given
that they typically do not have comorbid conditions. Early intensive glycemic control significantly reduces the rates of
complications over time, suggesting the presence of a “legacy effect.” On the other hand, patients who are older at
diagnosis may have coexisting conditions and a shorter life expectancy and could warrant less stringent A1C goals.
According to up-to-date:
-A1c value of < 7% for most patient 6% in UKPDS)
-A1c value of <8% for older patients with co-morbidities
-A1c value more stringent in pregnancy <6%
2. Glycemic control history
Inadequate glucose control is usually the result of a combination of factors, including poor adherence, failure to
understand the disease, and, as a consequence, delayed use of insulin for glycemic control. In these settings, it is
important to address the cause of poor disease management. Aiming for an A1C as close to normal as possible with
avoidance of hypoglycemia should be attempted.
3. Comorbid condition
The presence of other medical conditions can directly affect the nature and degree of glycemic control strategies
implemented. Coexisting conditions may decrease life expectancy or result in debility and an increased risk of side
effects from treatment modalities. In such situations, a realistic approach would be to target the A1C to a less intensive
range than in otherwise healthy individuals.
Patients with Obesity for example: A sustained weight loss of even 5 to 10 percent of initial body weight in
overweight individuals can have a lasting beneficial impact on serum glucose, dyslipidemia, and hypertension. In
Look AHEAD (Action for Health in Diabetes), a randomized trial of an intensive lifestyle intervention to increase
physical activity and decrease caloric intake versus standard diabetes education in people with type 2 diabetes, a
modest weight loss of 8.6 percent of initial weight at one year was associated with significant improvements in blood
pressure, glycemic control, FBG, high-density lipoprotein (HDL) cholesterol, and triglyceride levels and significant
reductions in the use of diabetes, hypertension, and lipid-lowering medications
Counting calories and fat grams in these patients can be beneficial:
Calorie and fat gram targets were based on initial body weight and targets were selected to promote weight loss of 1 to
2 pounds per week, providing 25 to 30 percent of calories from fat and <10 percent saturated fat. In Look AHEAD,
the calorie and fat gram goals were as follows:

•Persons weighing less than 114 kg (250 lb)→1200 to 1500 kcal per day, 40 to 50 g fat per day

•Persons weighing 114 kg (250 lb) or more→1500 to 1800 kcal per day, 50 to 60 g fat per day
4.vascular complication
Microvascular complication→patients with these complications at time of diagnosis→need early intensive glycemic
control (medication therapy)
5.Risk of hypoglycemia
Severe hypoglycemia, requiring the assistance of another party, is a major impediment to good glycemic control and is
a common accompaniment of intensive insulin therapy in diabetes. Hypoglycemia is more likely to be associated with
cardiac ischemia
In patients with autonomic neuropathy, there is increased risk of hypoglycemia unawareness and cardiac mortality.
Increased rates of hypoglycemia have been reported in older individuals with cognitive impairment and dementia. In
these settings, less intensive A1C targets are considered acceptable.

Personal characteristics:
In the absence of symptoms, patients may not perceive their disease as serious enough to warrant taking medications.
Treatment inertia can often arise from “psychological insulin resistance” or resistance to starting injectable therapies.
Complex medication regimens such as frequent dosing regimens that interfere with an individual’s lifestyle are
recognized barriers to adherence.

Psych socioeconomic factors

1. Support system
Patients’ living conditions and family support system should be adequately assessed when prescribing therapy.
Hypoglycemia is a major risk of therapy, particularly with intensive insulin regimens using basal-bolus therapy. For
example, intensive insulin therapy may not be appropriate for individuals who live alone with no routine contact with
other individuals such as family, friends, or neighbors.
2.Psychological status
Depression is common in patients with diabetes→should be screened and appropriately referred.
Patients may have difficulty coping with the stress of taking multiple daily injections and managing their activities of
daily life. Negative stereotypes associated with type 2 diabetes can lead to psychological and behavioral issues in
patients. Deterioration in glycemic control can be an important clue to a change in cognitive abilities.
Mitigating strategies such as education, counseling, and social support are essential
3.Economic issues
The costs of treatment are prohibitive for many individuals. Newer agents for the treatment of diabetes, while
effective, are expensive. Less expensive options can be utilized as effectively and should be considered when
customizing therapy goals.
4. Quality of life
In the management of diabetes, QOL encompasses all the variables discussed above. It has been reported that
improved A1C measures are associated with favorable mood. Overall, QOL in patients with diabetes can be
significantly improved by simple interventions such as education and counseling to improve coping skills.

SLI:
Effect of diet on menopause?
In a one-year intervention study in over 17,000 menopausal women, those eating more vegetables, fruit, fiber and soy
experienced a 19% reduction in hot flashes compared to the control group. The reduction was attributed to the
healthier diet and weight loss
Menopause effect in DM?
During menopausal transition, various phenotypical and metabolic changes occur, affecting body weight, adipose
tissue distribution and energy expenditure as well as insulin secretion and sensitivity. Taken together, these can
predispose women to the development of type 2 diabetes mellitus
Many women in midlife experience climacteric symptoms, including hot flashes and night sweats. A vicious cycle of
subsequent excessive energy intake, sedentary lifestyle and stress may then start and further deteriorate the
phenotypical and biochemical alterations of menopausal women
Abdominal fat deposition and decreased muscle mass due to sarcopenia after menopause lead to systemic low-grade
inflammation . Visceral adiposity augments the production of cytokines, contributing to the development of insulin
resistance in the peripheral tissues. Furthermore, menopause is a state of relative androgen excess
Effect of stress on circulation?

Effect of menopause on women?

Irregular periods.
Vaginal dryness.
Hot flashes.
Chills.
Night sweats.
Sleep problems.
Mood changes.
Weight gain and slowed metabolism.
 Study Guide 10
1. Discuss the burden of disease of diabetes mellitus and the impact of this disease on the health system,
population, and the economy.
Disease burden:
Disease burden is the impact of a health problem on a given population, and can be measured using a variety of
indicators such as mortality, morbidity or financial cost. This allows the burden of disease to be compared between
different areas, for example regions, towns or electoral wards.It also makes it possible to predict future health care
needs.
Disease burden is often measured using two widely accepted indicators that facilitate comparison of the burden of
different diseases and take into account both death and morbidity in a single measure:
Quality-Adjusted Life-Years (QALY) are a measure of the life expectancy corrected for loss of quality of that life
caused by diseases and disabilities. Some health interventions do not prolong life but do significantly improve the
quality of life; QALY take into account both quantity (length) and the quality of life generated by a healthcare
intervention. A year of life in perfect health is given a QALY of 1 whilst a year of complete functional impairment
(e.g. death) has a QALY of 0.
Disability-Adjusted Life-Years (DALY) reflect the potential years of life lost due to premature death (YLL) and
equivalent years of 'healthy' life lost by virtue of being in states of poor health or disability. These disabilities can be
physical or mental. One DALY can be thought of as one lost year of 'healthy' life.
Diabetes:
The prevalence rate for non-communicable diseases (NCDs) in the low and middle-income countries has been
growing steadily, presenting a major threat to people, families, and communities while hindering the potential
achievement of development goals
The global economic burden of NCD study also reported that NCDs are likely to cause around US$47 trillion in
output loss within the next two decades
Impact on economy:
Despite being a developing nation, Fiji has one of the highest rates of NCDs in the world where it accounts for more
than 80 percent of all deaths, of which most are premature
In 2018, Fiji recorded the highest death rate from diabetes compared to any other country with 188 fatalities per
100,000. The burden of NCD-related deaths on Fiji’s output is under-researched, despite the high rate of NCD
prevalence and mortality. Some of studies involving cost-of-illness analysis estimated FJ$8.8 million in cost arising
from stroke mortality among young people and approximately FJ$49 million in output loss from rheumatic heart
disease related premature mortality annually
Overtime, NCDs will reduce the quality and quantity of a country’s labor force, affecting and lowering the national
income.
-Workers with NCDs are more likely to get regularly sick, which will reduce their efficiency in terms of using
machinery and equipment in production whereas NCD mortality will reduce the size of skilled and unskilled labor
essential for long run economic growth. In this context, the firms endure an additional cost of training and hiring new
workers for the positions left vacant by workers suffering from a particular type of NCD
-NCD related morbidity will reduce the capital stock since savings will be used for the treatment of NCDs instead of
investment purposes (The economic burden of non-communicable disease mortality in the South Pacific: Evidence
from Fiji)
-Health-care funding largely comes from taxation revenue, but with a low tax base from a small pool of taxable
income earners, the government's allocation resources are limited. The outcome of an underfunded health care system
is that an inadequate pot of money has to go a long way, and cannot cope with a booming disease-burdened
population→Fijis health care budget impacted as diabetes medications are free!
The estimated financial cost and economic burden of diabetes in Fiji reached a staggering $124 million (NZ$84
million) in 2014 with health experts sounding an urgent need for people to relook at their lifestyles and eating habits.
Health care costs for people with diabetes were 2.4 X higher than non-diabetics.
Fiji→Consumed US$13.6mill – 39% of the health budget.
20% of offshore expenditure on health was for diabetes complications (e.g. no dialysis available in Fiji).
Impact on health system:
Diabetes decreases quality and length of life, and is associated with numerous complications, particularly
cardiovascular events such as myocardial infarction, stroke and heart failure. Despite treatment and management
advances, diabetes remains the leading cause of renal failure, lower limb amputation and blindness among adults
Fiji which is a developing country→lacks resources/ enough trained personnel→↑stress on the system
SOPD diabetes clinics always full→↓quality of care
Certain complications→such as foot ulcers require surgery→take up space in hospitals
Most health care is funded by government→↑demand for insulin/ dressing etc→↑cost of health care sector
Impact on individual/population:
Individuals incur direct costs→for drugs, medica care
Indirect costs→loss of work due to condition, pain and anxiety, discrimination, harder to find jobs,
shortened work life take early retirement
Leads to emotional, financial issues in families→Stress
Population→↑rate of mortality and morbidity
Almost half of diabetes deaths occur in people
under the age of 70 years
• 1 in every 7 people between the ages 25 - 64
years have diabetes in Fiji
• 17% of diabetics lose their sight or become
disabled due to amputations

2. chronic kidney diseases as a complication of DM

is very common. What is the burden to the health care system especially for dialysis and renal transplant?
One potential outcome of chronic kidney disease (CKD) is end-stage renal disease (ESRD), requiring costly renal
replacement therapy in the form of dialysis or transplantation.
In developed countries, ESRD is a major cost driver for health-care systems, with annual growth of dialysis programs
ranging between 6% and 12% over the past two decades and continuing to grow, particularly in developing countries.
Although the incidence of ESRD shows signs of leveling off in developed countries, perhaps in part because of
increased awareness of CKD, no such trend is seen in developing countries or minority populations. Over 2 million
people now require renal replacement therapy to sustain life worldwide, but this likely represents less than 10% of
those who need it.
In middle-income countries, efforts continue to reduce the cost of chronic dialysis, and to make kidney transplantation
more widely available; but nevertheless renal replacement therapy remains unaffordable for the majority of the
affected and causes severe financial hardship for those who have access to it.
Another 112 countries, with a combined population of over 600 million people, cannot afford renal replacement at
all—resulting in the death of over 1 million people annually from untreated kidney failure
Costs to healthcare systems and employers increase with CKD severity. Prior to (12-24 months) dialysis initiation,
costs increase substantially due to hospitalization. Annual US total cost per patient (c/p/p) with CKD (stages 3-5)
range from $6,026 to $30,398
With the rapid growth of the dialysis population in recent years, the dialysis costs have kept increasing in various
countries, and the ESRD patients have become a heavy burden on society and families
Hemodialysis in Fiji
 Study Guide 11
1. Explain how primordial, primary, secondary, and tertiary prevention would apply specifically to type 2
diabetes in the Pacific, on an individual and at a community level.
2. Provide specific examples for intervention, reasonably able to be carried out, for each level of prevention for
Type 2 diabetes in the Pacific

The Diabetes Prevention and Care can be divided into Primary, Secondary and Tertiary prevention.
1.PRIMARY PREVENTION- The two strategies suggested for the primary
prevention are:

• POPULATION BASED STRATEGY- The development of prevention programmes for Diabetes based on the
elimination of environmental risk factors is possible. The prevention of development of even the risk factors
so called, primordial prevention, should be implied.
• HIGH RISK STRATEGY- Correction of risk factors once they appear like sedentary life style, over-nutrition,
obesity, smoking, high blood pressure and elevated cholesterol will reduce the risk of diabetes. It targets the
high-risk target population.
2. SECONDARY PREVENTION- This implies the adequate treatment of Diabetes once detected. Treatment can be
based on diet alone, diet and anti-diabetic drugs or diet and insulin. Routine checks of blood sugar, body weight, urine
for proteins and ketones and visual acuity should be done to effectively reduce complications. The methods used in it
can be:

• Patient self-care.
• Home Blood glucose monitoring.
• Glycosated Haemoglobin Estimations at half yearly intervals.
3. TERTIARY PREVENTION- At the tertiary level the special Diabetes clinics should be organised and
establishment of units capable of providing diagnostic and management skills of high order should be done.
All the ways of prevention can work in unison to reduce the mortality and morbidity associated with Diabetes, but in
the coming times the stress should be on the primordial and the primary prevention.
3. Discuss the goals of The National Diabetes Centre in Fiji and the various constraints in trying to meet these
goals
Goals of the National Diabetes Plan
The National commitment to Diabetes is to reduce prevalence by 5% by 2014 and improve the delivery of Diabetes
services. To be able to deliver this, the health system needs to:
▪ Promote the Health and Welfare of people with Diabetes and provide support for their families.
▪ Promote a better understanding and awareness of Diabetes in the general community.
▪ Develop and implement innovative and cost effective ambulatory care services that complement the work of
other health care professionals.
▪ Develop and maintain high standards of care through a range of quality improvement activities.
▪ Conduct high quality clinical and educational research.
▪ Provide up to date and innovative training of health professionals.
▪ Maintain a comprehensive database to support all the activities of the health facilities including screening high
risk persons and supporting planning and research on Diabetes care in our community.
The aim of the diabetes management guidelines is to:
▪ Recognize early, diagnose and manage Diabetes effectively.
▪ Help defer or delay the onset of complications.
▪ Manage complications effectively with the available resources.
▪ Have an effective referral system for optimum intervention at every level.
Constraints
Healthcare providers have identified that patient-related factors associated with poor glycaemic control among patients
with T2DM include patients’ poor adherence to prescribed treatment and management plans; patients’ poor attitude
(described as lack of motivation to look after their own health, with too much dependence on their healthcare
providers); patients’ lack of, or limited knowledge of, diabetes, its complications and treatment goals; patients’ culture
and beliefs on traditional treatment of diabetes; and lack of family, employer and community support.
I also believe the Fijian government needs to place more money/funds into programs that will encourage healthy
eating and exercising. Government involvement in the greenhouse initiative would be subsidized when in the public
school system. There is too much processed food and junk that kids have access to every day, part of the reason that
the earliest age of DM 2 instance in Fiji is 12! If governmental spending went more into education and prevention at
the school level, it could start a new generation of healthy individuals for the years to come.
NO strips at health centres

4. Discuss the prevention modalities and principles that are outlined in the WHO PEN Model in the prevention
of DM including other essential NCDs
The WHO package of essential noncommunicable (PEN) disease interventions (3) is a conceptual framework for
strengthening equity and efficiency in primary health care in low-resource settings.
The World Health Organization (WHO) projects that over the next 10 years, the largest increase in deaths from
cardiovascular disease (CVD), cancer, respiratory disease and diabetes will occur in developing countries. Current
epidemiological evidence indicates that four major NCDs – CVD (heart disease and stroke), cancer, chronic
respiratory disease and diabetes – together are responsible for 28 million deaths a year and make the largest
contribution to the NCD burden in LMIC
Goals of PEN
To close the gap between what is needed and what is currently available to reduce the burden, health-care costs and
human suffering due to major NCDs by achieving higher coverage of essential interventions.
■ To achieve universal access to high-quality diagnosis and patient-centred treatment
■ To reduce the suffering and socioeconomic burden associated with major NCDs
■ To protect poor and vulnerable populations from heart disease, stroke, hypertension cancer, diabetes, asthma and
chronic respiratory disease
■ To provide effective and affordable prevention and treatment through primary care
■ To support early detection, community engagement and self-care
Public health solutions for prevention and control of NCDs
For preventions and control of NCDs, comprehensive public health approaches that target the human lifespan are
required. Such interventions should target people in infancy, childhood, adolescence and adulthood as listed below.
Application of these interventions has already
resulted in declining CVD trends in many high-
income countries.
Population-wide approaches to prevention have the
potential to substantially avert the NCD burden

-Objective 2 of the NCD Action Plan highlights the

need to establish national policies and plans for
NCD prevention and control. The ongoing work of
WHO in collaboration with Ministries of Health, addresses the important issue of context specific adaptation of tools
for the integration of NCDS into primary care.
Major NCDs can be addressed in primary care using cost effective interventions. Currently, in many settings vertical
programs in primary care focus on single risk factors such as hypertension. In addition, the single risk factor approach
does not take into cognizance the continuous relationship between blood pressure, blood glucose, blood cholesterol
and cardiovascular risk. An integrated approach is particularly important for low resource settings for efficient
utilization where all risk factors are considered
-Ensuring fair health opportunities for everyone is crucial if governments want to uphold the values of equal
opportunity, social justice, and solidarity. There are growing social inequalities in heart disease, stroke, diabetes,
asthma and cancer
Specific intervention for specific disease:

Role of ministry of health in effective and equitable care for NCDs in low resource setting (PEN strategy)
WHOs work in this area aims to provide guidance to Ministries of Health address the question; “What can be done for
NCD prevention and control in PHC with a modest increase in investment ?”.
The priority conditions that have been selected for this effort include cardiovascular disease, diabetes, chronic
respiratory disease and cancer. The selection was based on the following criteria:
■ They are major public health issues that contribute the most to the global NCD burden.
■ Evidence-based interventions are available for addressing the condition.
■ These conditions share behavioral risk factors: tobacco use, unhealthy diet and physical inactivity.
■ They are the focus of the Global NCD Action Plan.
Diabetes specific interventions + preventions:

Treatment framework according to PENS

 Study Guide 12
1. Relate social mobilisation to the prevention of diabetes, or other non-communicable diseases
What is social mobilization?
Social mobilization is the process of bringing together allies to raise awareness of and demand for a particular
program, to assist in the delivery of resources and services and to strengthen community participation for
sustainability and self-reliance.
“Allies” include decision- and policy-makers, opinion leaders, NGOs such as professional and religious groups, the
media, the private sector, communities and individuals. Social mobilization generates dialogue, negotiation and
consensus, engaging a range of players in interrelated and complementary efforts, taking into account the needs of
people (NCBI)
In the context of health development, social mobilization is viewed as one of the tools of health promotion. It is an
approach that provides individuals and groups with knowledge and skills and mediates between different interest
groups to create environments that support and promote health. In the health sector, social mobilization is closely
linked to, and supports, other health development processes such as service delivery, infrastructure and human
resource development, preventive interventions, and advocacy for health. (WHO)
The critical contribution of social mobilization to health development is to enhance the participation of various
actors, leading to increased knowledge of, control over, and ownership of, health interventions.

Community mobilization aims to mobilize and engage community members to address a particular cause.
Engagement of community mobilizers needs to happen early and individuals need to be involved from the definition
of the problem through to the generation of adequate solutions.
The list below provides some of the many ways to mobilize community members however use your creativity to think
of other ways to mobilize community members.
Community meetings to discuss an issue with community leaders, which may include traditional, religious and local
political leaders, among others.
Public debates in which community members question leaders on a specific, predetermined topic. These debates can
be recorded on the radio and then broadcast.
Puppet shows and participatory theatre where audiences are encouraged to participate by developing alternative
scenarios that would lead to better outcomes.
Village literacy fairs where information about a predetermined topic is shared.
Dance and concerts conveying key messages. The events can be recorded and screened through cinema units or
made to go viral on the Internet.
Mobile cinema units screening short films addressing a specific topic and followed by discussions and
questions/answer sessions. Sporting events and competitions where messages are conveyed before and after the games
and at halftime.
Listening groups to listen to and discuss a particular radio program.
Quiz competitions between teams addressing knowledge of a specific topic.
Print media such as leaflets and cartoon strips for distribution in the community.
Community coalitions made up of people who practice desired behaviors, or who have survived the outbreak and can
act as positive role models and decrease stigma.
Door-to-door sessions where mobilizers enter household to discuss the outbreak and protective practices in privacy.
Storytelling in which a narrator recounts a pertinent story which may be real or fictional, to highlight key messages
and the importance of protective behaviors.

2. Discuss social marketing in health promotion

Social marketing applies commercial marketing strategies to promote public health.
What is social marketing?
“the application of proven concepts and techniques drawn from the commercial sector to promote changes in diverse
socially important behaviors such as drug use, smoking, sexual behavior... This marketing approach has an immense
potential to affect major social problems if we can only learn how to harness its power.”
Social marketers use a wide range of health communication strategies based on mass media; they also use mediated
(for example, through a healthcare provider), interpersonal, and other modes of communication; and marketing
methods such as message placement (for example, in clinics), promotion, dissemination, and community level
outreach. Social marketing encompasses all of these strategies.
Communication channels for health information have changed greatly in recent years.
One-way dissemination of information has given way to a multimodal transactional model of communication. Social
marketers face challenges such as increased numbers and types of health issues competing for the public's attention;
limitations on people's time; and increased numbers and types of communication channels, including the internet.
A multimodal approach is the most effective way to reach audiences about health issues.
The six basic stages are: (in social marketing)
- Developing plans and strategies using behavioral theory
- Selecting communication channels and materials based on the required behavioral change and knowledge of
the target audience;
- Developing and pretesting materials, typically using qualitative methods; implementing the communication
program or “campaign”
- Assessing effectiveness in terms of exposure and awareness of the audience, reactions to messages, and
behavioral outcomes (such as improved diet or not smoking);
- Refining the materials for future communications.
- The last stage feeds back into the first to create a continuous loop of planning, implementation, and
improvement.
 Social marketing now uses commercial marketing techniques—such as
analyzing target audiences, identifying the objectives of targeted behavior
changes, tailoring messages, and adapting strategies like branding—to
promote the adoption and maintenance of health behaviors.

How is social marketing used to change health behavior?

Social marketing uses behavioural, persuasion, and exposure theories to
target changes in health risk behaviour. Social cognitive theory based on response consequences (of individual
behaviour), observational learning, and behavioural modelling is widely used.
Persuasion theory indicates that people must engage in message “elaboration” (developing favourable thoughts about
a message's arguments) for long term persuasion to occur.
Exposure theorists study how the intensity of and length of exposure to a message affects behaviour.
Social marketers use theory to identify behavioural determinants that can be modified.
For example, social marketing aimed at obesity might use behavioral theory to identify connections between
behavioral determinants of poor nutrition, such as eating habits within the family, availability of food with high calorie
and low nutrient density (junk food) in the community, and the glamorization of fast food in advertising. Social
marketers use such factors to construct conceptual frameworks that model complex pathways from messages to
changes in behavior
Example of social marketing conceptual framework

Implications for healthcare practitioners

This brief overview indicates that social marketing practices can be useful in healthcare practice.
Firstly, during social marketing campaigns, such as antismoking campaigns, practitioners should reinforce media
messages through brief counselling.
Secondly, practitioners can make a valuable contribution by providing another communication channel to reach the
target audience.
Finally, because practitioners are a trusted source of health information, their reinforcement of social marketing
messages adds value beyond the effects of mass communication.
3.Discuss some risk factors that are common across the major NCDs

4.List some health promotion activities currently undertaken in Fiji to reduce the risk factors for non-
communicable diseases.
Community Outreach Program
This Program will utilize DFI’s 12 member Core Volunteers, 28 peer groups, trained health Doctors and Nurses to run
school and community based advocacy based projects.
▪ High School Students Workshops, Teachers Trainings, Sporting Events and Community Awareness.
These events are nationwide and will be covered by all media outlets and DFI’s social media platforms & official
website. The Community Outreach Program targets the community at large and will heavily employ digital media by
way of ePosters and informative video commercials as a tool to drive awareness through social media
Project 2–One Child One Machine Program
The project aims to equip every child with a glucometer, currently, assistance is given to underprivileged children
around Fiji. Total of 135 machines since 2014.
Project 3 – Foot Care
The project has trained to train more than 400 nurses, 350 Physicians, and 120 other specialties such as Dietitians,
Physiotherapists, Counselors, Community Rehabilitation Assistants and Community Health Workers, etc in foot care.
Established 15 dedicated foot clinics from the 3 pre-existing and equipped more than 80% of health facilities with a
basic podiatry toolkit. Screened more than 50,000 Fijians in the communities.
Project 4 – Tellemedicine help line
With the support of FRIEND Fiji, Diabetes Fiji Inc and the Ministry of Health and Medical Service with MSP and Fiji
Cancer Society established the telemedicine Helpline (165) for people in the Central Division with aims to provide
continuous optimum care for people living with chronic disease conditions, who are attending government healthcare
facilities during this pandemic
The Alliance for Healthy Living
The Alliance for Healthy Living is a coalition formed by Diabetes Fiji, Consumer Council of Fiji and the National
Food and Nutrition Centre (the “Core Group”) in partnership with various civil society groups and members of the
public. The Core Group is made up medical and dental practitioners, researchers, consumer advocates, nutritionists
etc who have come together to advocate for policies on the sale of sugar sweetened beverages (sugary drinks) to
Fijians.
5.Define the term “IEC”.
Information, Education and Communication (IEC) materials are used to convey public health messaging in order to
support the overarching behaviour change strategy developed to respond to a public health problem. IEC materials
include a range of products like:
 ▪ Infographics, flyers, leaflets, brochures
▪ social media posts, television adverts, audio spots for radio
▪ posters, billboards or murals

6. List the IEC materials are available from the National Diabetes Centre regarding the prevention and control
of non-communicable diseases and from the Secretariat for the Pacific Community
Proposed action plan to SPC to identify focus areas, potential collaborative initiatives and areas of support that are
required to strengthen their association’s (diabetes Fiji) role and functions

Non-Communicable Diseases Strategic Plan 2015 - 2019

Diet

• Media and other educational campaigns to support healthier eating, including provision of recipes using local
foods and promotion of gardening
• Educational programs on reading nutrition labels on processed foods to assist consumers with making
healthier choices
• Encourage religious leaders to support low salt, low sugar diet for all religious members during holy week
celebrations
Physical activity

• Ongoing, targeted mass-media campaigns to promote physical activity, particularly among the less active
(including use of sports icons)
Tobacco

• Encourage settings-based tobacco-free policies (eg church, community) as part of tobacco-free Pacific
• Conduct awareness raising programs on dangers of tobacco, in schools and communities
• Support compliance with no smoking, no alcohol, no kava consumption in holy weeks in the religious
calendars
Alcohol & kava

• Support compliance with no smoking, no alcohol, no kava consumption in holy weeks in the religious
calendars
• Encourage communities to adopt own alcohol restrictions and kava restrictions
• Increase effective media activities on the dangers of alcohol abuse (including home brew)
Clinical
 • Develop a screening unit to oversee all screening activities for NCDs (eg cancer, diabetes, rheumatic heart
disease). This unit will ensure continuum of care from screening to treatment, data system, manage and
follow-up cases and will co-ordinate role of CSOs.

7. Discuss the usefulness of these materials in the prevention and control of diabetes and the other non-
communicable diseases
The strategy aims to improve the general well-being of individuals, families and communities by encouraging people
to be responsible for their own actions through their own efforts, with emphasis on behavior change. Examples
include:

• promoting healthy behavior for reducing progression of ageing process

• encouraging elderly people or care givers to seek treatment immediately for any type of health issues
• promoting effective home treatment and encouraging families to look up for the special nutritional
requirement of elderly persons
• IEC is also a critical aspect of programs addressing other important health issues such as tobacco smoking and
alcohol.