DM Recent

Peshawer school Attack 16 Dec 2014
>145 innocent lives snatched

Action: All political religious
parties, Pak army, Media , judiciary
& whole nation united & military
operation initiated against terrorists
across the country
September 11, 2001 (9/11) attacks

Killing >2996 people
Action: Many governments across
the world united &
passed legislation to combat
terrorism
More dangerous
terrorist….Worldwide
4.9
million
13425
559
9
1
Even more alarming…..
Iceberg of Disease (Diabetes): 1:2
Tip of the
Iceberg
(Diagnosed)
Submerged
Portion
(Undiagnosed,
Subclinical cases,
Carriers)
World wide & Pakistan….
387 million people have DM in 2014
Deaths in adults d/t DM 4.9 million
6.9 million cases of DM in 2014
Prevalence adults (20-79 y) 6.8%
Deaths (adults) due to DM 87,548

Definition
• Clinical syndrome of chronic hyperglycemia
due to absolute or elative insulin deficiency,
resistance or both.
Etiologic Classification of Diabetes
Classical features of type 1 & type 2 DM
Etiology & Pathogenesis
Type 1 diabetes:
• Alteration in immunologic integrity, placing the β cell at special
risk for inflammatory damage, accounts for most cases.
• Autoantibodies to islet cells
• Associated environmental triggers:
– Viruses (e.g., mumps, coxsackie, cytomegalovirus, & hepatitis
viruses)
– Environmental toxins
– Emotional and physical stress
• Genetics
• Genes located on major histocompatibility complex on
chromosome 6 HLA DR3 & DR4 are associated with an increased
risk
Etiology & Pathogenesis
• RISK FACTORS: Type I DM
• Family history: Insulin-dependent or noninsulin-dependent
diabetes in any 1st-degree relatives
• Dietary factors: Breastfeeding may provide a degree of protection

against the disease
• Exposure to cow’s milk at an early age is associated with an

increased risk of the disease
• Maternal age at birth may play a role
• Slightly greater risk for a child if the father has type 1 diabetes
ETIOLOGY AND PATHOPHYSIOLOGY type II DM
• Peripheral insulin resistance Defective insulin secretion, especially in response to a
glucose stimulus
• Increased gluconeogenesis
• Genetic factors: Monogenic (e.g., PPARγ mutations, insulin gene mutations) and
polygenic
• Obesity
• Hemochromatosis
• Drug- or chemical-induced (e.g., glucocorticoids, highly active antiretroviral therapy
[HAART] medications, atypical antipsychotics, post-transplant immunosuppressants)
• 50% concordance in monozygotic twins
• RISK FACTORS
• Family history: 1st-degree relative
• Gestational diabetes (GDM) or history of baby with birth weight ≥4 kg (9 lbs)
• Polycystic ovary syndrome (PCOS)
• Hypertriglyceridemia or low high-density lipoprotein (HDL)
• Ethnicity: African American, Latino, Native American, Asian
• Impaired fasting glucose (IFG)/impaired glucose tolerance (IGT)
• Sedentary lifestyle
Clinical features
Presentation may be:
– Acute
– Subacute
– Asymptomatic
– As a complication
Acute presentation
Young people often present with a 2–6-week
Hx & report the classic triad of symptoms:
– Polyuria: due to the osmotic diuresis that
results when blood glucose levels exceed
the renal threshold
– Thirst: due to loss of fluid & electrolytes
– Weight loss: due to fluid depletion &
accelerated breakdown of fat & muscle
secondary to insulin deficiency
– Ketonuria: is often present in young
people and may progress to ketoacidosis
if these early symptoms are not treated
Subacute presentation
• Clinical onset may be over several months or
years
• Thirst, polyuria & weight loss are typically
present
• Patients may complain nonspecific symptoms:
– Lack of energy
– Visual blurring (owing to glucose-induced changes in
refraction)
– Pruritus vulvae or balanitis that is due to Candida
infection
Asymptomatic diabetes
• Glycosuria or a raised blood glucose may be
detected on routine examination (e.g. for
insurance purposes)
• Glycosuria is not diagnostic of diabetes but
indicates the need for further investigations
• About 1% of the population have renal glycosuria
– This is an inherited low renal threshold for glucose,
transmitted either as a Mendelian dominant or
recessive trait
Complications as the presenting feature
These include:
– Staphylococcal skin infections
– Retinopathy noted during a visit to the optician
– Polyneuropathy causing tingling and numbness in
the feet
– Erectile dysfunction
– Arterial disease, resulting in myocardial infarction
or peripheral gangrene
Laboratory investigations
Diagnostic investigations Other investigations
• Fasting plasma glucose
• Random plasma glucose
Routine investigations
• One abnormal laboratory value is include:
diagnostic in symptomatic • Urine testing for protein
individuals • Full blood count
• Two values are needed in • Urea and electrolytes
asymptomatic people
• Liver biochemistry
• Glucose tolerance test is only
required for borderline cases and • Lipids profile (to exclude an
for diagnosis of gestational associated hyperlipidemia)
diabetes
• HbA1c
Criteria for the diagnosis of diabetes
1Give 75 g of glucose dissolved in 300 mL of water after an

overnight fast in persons who have been receiving at least
150–200 g of carbohydrate daily for 3 days before the test.
2A fasting plasma glucose ≥ 126 mg/dL (7.0 mmol) or HbA 1c
of ≥ 6.5% is diagnostic of diabetes if confirmed by repeat
testing.
Autoimmune markers in newly
diagnosed type 1 DM
Treatment Regimens
1. Diet
2. Medications for Treating Hyperglycemia
3. Insulin
4. Transplantation
MANAGEMENT OF TYPE 1
DIABETES
Treatment of type I DM
• In addition to diet and exercise, Insulin is the
only pharmacological treatment for
treatment.
MANAGEMENT OF TYPE 2
DIABETES
Stepwise Management of
Type 2 Diabetes
Insulin ± oral agents
Oral combination
Oral monotherapy
Diet & exercise

Medications for Treating Hyperglycemia
1. Medications that stimulate 3. Medications that affect
insulin secretion by binding to absorption of glucose
sulfonylurea receptor on beta a. Acarbose
cell b. Miglitol
a. Sulfonylureas
b. Meglitinide analogs 4. Incretins
c. D-Phenylalanine derivative a. GLP-1 receptor agonists
b. DPP-4 inhibitors
2. Medications that lower glucose
levels by their actions on the
5. Sodium glucose co transporter 2
liver, muscle & adipose tissue
(SGLT2) inhibitors
a. Metformin
a. Canagliflozin
b. Thiazolidinediones
b. Dapagliflozin
c. Empagliflozin
Sulfonylureas
• First-generation sulfonylureas
– Tolbutamide
– Tolazamide
– Acetohexamide
– Chlorpropamide
• Second-generation sulfonylureas
– Glyburide/glibenclamide (Tablet. Daonil 5 mg)
– Glipizide (Tablet. Minidiab 5 mg)
– Gliclazide (Tablet. Diamicron 30, 60 mg)
– Glimepiride (Tablet. Getryl/ Amaryl 1, 2, 3 & 4mg)
Sulfonylureas
Sulphonylurea
• Long Term Side Effects
– Beta cell exhaustion
• Secondary failure of treatment
– Therefore, use
• Short-acting versions
• Lowest effective doses
– After many years of treatment

• Secondary failure inevitable
Metformin (Glucophage)
• First-line therapy for patients with type 2 diabetes.
• Benefits:
– Tendency to improve both fasting & postprandial
hyperglycemia & hypertriglyceridemia in obese patients
with DM
– No weight gain (which is associated with insulin and
sulfonylurea therapy)
• Maximum dose 2.55 gram per day

• Commonly advised 500 mg three times day with meals or 850
mg or 1000 mg tablet twice daily with breakfast and dinner
Incretins
• Oral glucose provokes a threefold to fourfold higher insulin response
than an equivalent dose of glucose given intravenously
• This is because the oral glucose causes a release of gut hormones esp:
– Glucagon-like peptide 1 (GLP-1)
– Glucose-dependent insulinotropic polypeptide (GIP1)
• This “incretin effect” is reduced in patients with type 2 diabetes
• GLP-1 secretion is impaired in type 2 diabetes pts
• When GLP-1 is infused in type 2 diabetes pts, it stimulates insulin
secretion & lowers glucose levels
• GLP-1, unlike the sulfonylureas, has only a modest insulin stimulatory
effect at normoglycemic concentrations
• This means that GLP-1 has a lower risk for hypoglycemia than the
sulfonylureas
Incretin effect…., mechanism
Problem…..,
• GLP-1 is rapidly proteolyzed by dipeptidyl peptidase
4 (DPP-4) & by other enzymes & is also cleared
rapidly by the kidney
• As a result, GLP-1’s half-life is only 1–2 minutes
• Hence, native peptide cannot be used
therapeutically
• Therefore metabolically stable analogs or derivatives
of GLP-1 developed that are not subject to the same
enzymatic degradation or renal clearance
•
Mechanism of action of DPP4
Alternate approach:
• To inhibit the enzyme
DPP-4 & prolong the
action of endogenously
released GLP-1 & GIP.
GLP-1 receptor agonists &
DPP-4 inhibitors
Sodium-glucose co-transporters 2 (SGLT 2)
inhibitors
• Glucose is freely filtered by the renal glomeruli
and is reabsorbed in the proximal tubules by
the action of SGLT .
• SGLT 2 accounts for 90% of glucose
reabsorption & its inhibition causes glycosuria
in diabetes & lowering plasma glucose levels.
Insulin
• Insulin is indicated for type 1 diabetes as well
as for type 2 diabetic patients
Summary of bioavailability characteristics
of the insulins
Methods of insulin administration
• Insulin syringes and needles
• Insulin pen injector devices
• Insulin pumps
• Inhaled insulin
Methods of insulin administration
1) Insulin syringes and needles-Plastic disposable

syringes are available in 1-mL, 0.5-mL, and 0.3-mL
sizes.
2) Insulin pen injector devices-Insulin pens
eliminate the need for carrying insulin vials and
syringes.
3) Insulin pumps-Insulin infusion pumps are used
for subcutaneous delivery of insulin. These pumps
are small (about the size of a pager) and very easy
to program.
4) Inhaled insulin-A novel method for delivering a
pre-prandial powdered form of insulin by
inhalation (Exubera) has been approved by the
FDA.
Insulin treatment
injections breakfast lunch dinner bedtime

Intermediate/long acting
Short acting Short acting Short acting
breakfast lunch dinner bedtime

injections
Biphasic insulin Biphasic insulin
Complications of Insulin Therapy
 Hypoglycemia
 Insulin allergy
 Immune insulin
resistance
 Lipodystrophy at the
injection site Injection site Lipodystrophy
Transplantation
• Pancreas transplantation at the time of
kidney transplantation is becoming more
widely accepted.
Questions?
Thank you for attention

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Peshawer school Attack 16 Dec 2014

>145 innocent lives snatched

September 11, 2001 (9/11) attacks

387 million people have DM in 2014

Deaths in adults d/t DM 4.9 million

6.9 million cases of DM in 2014

Prevalence adults (20-79 y) 6.8%

Deaths (adults) due to DM 87,548

• Dietary factors: Breastfeeding may provide a degree of protection

• Exposure to cow’s milk at an early age is associated with an

• Maternal age at birth may play a role

1Give 75 g of glucose dissolved in 300 mL of water after an

Insulin ± oral agents

Diet & exercise

– After many years of treatment

• Maximum dose 2.55 gram per day

1) Insulin syringes and needles-Plastic disposable

injections breakfast lunch dinner bedtime

breakfast lunch dinner bedtime

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