CLS 382 - Lecture 1

Carbohydrate metabolism -
Diabetes
 Glucose levels
• Fasting blood glucose concentration is normally maintained within (3.9-5.5)
mmol/L
• After a meal, “post prandial” glucose levels may rise briefly above 5.5 mmol/L (up
to about 9.0 mmol/L), but should return to fasting levels within 2 hours
• When uncontrolled, hyperglycemia (most often associated with diabetes mellitus
but sometimes occurring in other conditions) may present with levels as high as 20
mmol/L, and in extreme cases, levels up to 60 mmol/L are seen.
• Symptoms of hyperglycemia may include: increased thirst, increased urination,
urinary tract infections, tiredness, blurred vision, slow-healing infections

Fasting Blood Glucose (collected after an 8 to 10 hr fast)

GLUCOSE LEVEL INDICATION

70 - 99 mg/dL (3.9 - 5.5 mmol/L) Normal fasting glucose
100 - 125 mg/dL (5.6 - 6.9 mmol/L) Impaired fasting glucose (pre-diabetes)
≥ 126 mg/dL (7.0 mmol/L) on more than a single test Probable diabetes

https://www.diabetes.co.uk/diabetes_care/blood-sugar-level-ranges.html
https://www.thediabetescouncil.com/what-are-blood-sugar-target-ranges
 Molecular effects of hyperglycemia
Abnormally high blood glucose concentration is harmful for several reasons:
1- Osmotic effect:
• as high glucose increases the osmotic pressure of the blood, resulting in water diffusing
from the cells, to the circulation and eventually excretion from the kidneys.
• leads to tissue dehydration (which in brain cells leads to coma).
2- Protein glycation:
• increased amounts of glucose allows it to react non-enzymatically with amino groups of
amino acid residues in cellular and extracellular proteins.
• associated with chronic complications of diabetes (e.g. neuropathy, nephropathy,
retinopathy)
3- Formation of reactive oxygen species (ROS):
• The reduction of molecular oxygen (O2) produces superoxide (•O2−); the precursor of
most other reactive oxygen species: O2 + e− → •O2−
• ROS are chemically reactive chemical species containing oxygen, and are formed as a
natural byproduct of the normal metabolism of oxygen.
• They have important roles in cell signaling and homeostasis, but need to be controlled,
as imbalance may result in significant damage to cell structures
• ROS may lead to lipid peroxidation (particularly unsaturated fats), DNA damage, and
protein modification. Therefore, ROS contribute to several diabetic complications.
 Insulin resistance - mechanisms
• Signs and symptoms of
insulin resistance may
include:
➢ Increased hunger
➢ Lethargy (tiredness)
➢ Brain fogginess and
inability to focus
➢ High blood sugar
➢ Weight gain (fat storage,
difficulties losing weight)
➢ Increased blood
cholesterol levels
➢ Increased blood pressure
(many people with
hypertension are either
diabetic or pre-diabetic)
 Insulin resistance - mechanisms
1) Physical inactivity
The important role of glucose transporter type 4 (GLUT4)
- GLUT4 facilitates the diffusion of circulating glucose into muscle
and fat cells.GLUT4 is regulated by insulin.
- In skeletal muscle cells, GLUT4 concentration in the plasma
membrane can increase as a result of either exercise or muscle
contraction (physical activity).
- Adipocytes store energy (in the form of fat). Imbalance in
glucose intake and energy expenditure (as in physical inactivity)
could lead to adipose cell growth (and eventually obesity) by:
• hyperplasia (cell number increase)
• hypertrophy (cell size increase)
- Mutations in GLUT4 genes in adipocytes can also lead to
increased GLUT4 expression in adipose cells, which sends excess
glucose to adipose cells → increased glucose uptake by
adipocytes → increased adipose tissue mass →more fat stored.
 Insulin resistance – mechanisms + medciations
2) Hyperglycemia triggers hyperinsulinemia;
- Hyperglycemia and hyperinsulinemia both stimulate hepatic triglyceride synthesis →
results in increased levels of VLDL.
- Eventually, high levels of free fatty acids –from VLDL- impair insulin action.
3) Secretory products of adipocytes
- greater adipose tissue mass leads to an increased amount of tumor necrosis factor TNF
and resistin; both impair insulin receptor function.
• Due to insulin resistance; blood levels of insulin remain high, but glucose is poorly controlled
• Therefore, medications available for diabetics aim to either:
1) increase peripheral tissue sensitivity to insulin
(e.g. thiazolidinediones also called glitazones)
2) reduce hepatic gluconeogenesis
(e.g. metformin -also called glucophage)
3) stimulate insulin secretion from pancreatic  cells
(e.g. sulfonylureas)
• No single drug offers long-lasting therapy for type 2 diabetes (because multiple organs are
affected by these diverse mechanisms)
 Type 1 diabetes
• results from a cellular-mediated autoimmune destruction of the β-cells of the
pancreas, usually leading to absolute insulin deficiency
• previously termed insulin-dependent diabetes, or juvenile-onset diabetes, accounts
for only 5–10% of those with diabetes
• Markers of the immune destruction of the β-cell include:
➢ islet cell autoantibodies
➢ autoantibodies to insulin
➢ autoantibodies to related enzymes (e.g. glutamic acid decarboxylase GAD, or
tyrosine phosphatases IA-2 and IA-2β).
• One (or usually more) of these autoantibodies are present in 85–90% of individuals
when fasting hyperglycemia is initially detected.
• Autoimmune destruction of β-cells has multiple genetic predispositions and is also
related to environmental factors that are still poorly defined.
• Although patients are rarely obese when they present with this type of diabetes, the
presence of obesity is not incompatible with the diagnosis.
• These patients are also prone to other autoimmune disorders
(e.g. Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac
sprue, autoimmune hepatitis, myasthenia gravis and pernicious anemia).
 Gestational diabetes
• Gestational diabetes is a condition in which women without diabetes develop
hyperglycemia during pregnancy. For most women, it generally has few or no noticeable
signs/symptoms.
• However, it increases the risk of mothers depression and pre-eclampsia; a pregnancy
disorder characterized by the onset of high blood pressure and a significant amount
of protein in the urine (Proteinuria ≥ 300 mg of protein in a 24-hr urine sample).
• Babies born to mothers with poorly treated gestational diabetes are at risk of:
➢ Macrosomia- (very large babies ≥ 9 pounds or more) are more likely to become wedged in the
birth canal, sustain birth injuries or require a C-section birth).
➢ Early (preterm) birth and respiratory distress syndrome. Early birth may be recommended
because the baby is large. Such may experience respiratory distress syndrome - a condition
that makes breathing difficult. Babies with this syndrome may need assistance breathing until
their lungs mature and become stronger.
➢ Babies may have low blood sugar after birth (extra glucose in your bloodstream crosses the
placenta, which triggers your baby's pancreas to make extra insulin).
➢ If untreated, it can also result in a stillbirth.
➢ In the long term, children are at higher risk of being overweight and developing type 2
diabetes.
• Prevention is not guaranteed, but by maintaining a healthy weight and exercising before
and during pregnancy in addition to a healthy diet and exercise help.
• Treatment may require a diabetic diet and possibly insulin injections; most women are
able to manage their blood sugar well.
 HbA1c
• Glycation is the nonenzymatic addition of glucose to amino groups of proteins.
• HbA1c is a glycated hemoglobin in which glucose is bound specifically to the N-
terminal valine of the hemoglobin β chain.
• HbA1c constitutes the major portion of the glycated hemoglobins. Unlike other
glycated hemoglobin fractions, HbA1c can be separated easily based on a
difference in net charge.
• Total GHB is a term used to refer to all glycated Hb species. Total GHB is composed
of HbA1c, and Hb glycated with glucose at other sites, including the glycated N
terminus of the α chain and the glycated ε amino groups of lysine residues.
• It can be measured by affinity chromatographic methods.
• Four basic types of methods are used most commonly to measure HbA1c:
i. ion-exchange high-performance liquid chromatography (HPLC)
ii. boronate affinity HPLC
iii. enzymatic assays
iv. immunoassays
 HbA1c levels
“Normal” Hemoglobin A1c levels?
• For people without diabetes, the
normal range for the hemoglobin
A1c level is between 4% and 5.6%.
• Hemoglobin A1c levels between
5.7% and 6.4% leaves people at
higher risk of diabetes.
• Levels of 6.5% or higher likely
suggest diabetes.
 Type 2 Diabetes Diagnosis Criteria
The American Diabetes Association (ADA) criteria for the diagnosis of diabetes are any of
the following:
• Hemoglobin A1c (HbA1c) level of 6.5% or higher;
the test should be performed in a laboratory using a method that is certified by the National
Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes
Control and Complications Trial (DCCT) reference assay, or
• Fasting plasma glucose (FPG) level of 126 mg/dL (7 mmol/L) or higher;
fasting is defined as no caloric intake for at least 8 hours, or
• 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral
glucose tolerance test (OGTT), or
• A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with
classic symptoms of:
➢ classic symptoms of hyperglycemia (polyuria, polydipsia, polyphagia, weight loss)
or
➢ hyperglycemic crisis (Diabetic ketoacidosis -DKA- and hyperglycemic hyperosmolar
state -HHS-; the most serious and life-threatening hyperglycemic emergencies in
diabetes).

http://care.diabetesjournals.org/content/33/Supplement_1/S62

https://www.diabetes.org.uk/professionals/position-statements-reports/diagnosis-
ongoing-management-monitoring/new_diagnostic_criteria_for_diabetes
 Late complications of diabetes mellitus
• DM is not only characterized by hyperglycaemia, but also by the occurrence of:
➢ Microangiopathy: abnormalities in the walls of small blood vessels; associated with poor
glycaemic control.
➢ Retinopathy: may lead to blindness because of:
• vitreous hemorrhage from proliferating retinal vessels, or
• edema affecting the macula; the part of the eye which provides us with our central
vision.
➢ Nephropathy: which may ultimately lead to renal failure.
• In early stages there is kidney hyperfunction, associated with increased GFR,
increased glomerular size and microalbuminuria
• In later stages, there is increasing proteinuria, followed by marked decline in renal
function, resulting in uremia.
➢ Neuropathy: may become evident as diarrhoea, postural hypotension, impotence,
neurogenic bladder and neuropathic foot ulcers due to microangiopathy of nerve blood
vessels and abnormal glucose metabolism in nerve cells.
➢ Macroangiopathy: where both:
• hyperinsulinemia (associated with insulin resistance) and
• Type 2 diabetes
may play a key role in accelerating atherosclerosis, and premature coronary heart
disease,
What should be included in diabetes education?
➢ Definition of diabetes
➢ Descriptions and instructions for monitoring diabetes
➢ Guidance on healthy eating
➢ Recommendations for regular exercise
➢ Instructions on preventing complications

What are the goals of diabetes management?

The goals of diabetes therapy are to:
➢ Ensure normal growth and development in children
➢ Eliminate symptoms of hyperglycemia
➢ Avoid symptoms of hypoglycemia
➢ Control blood glucose levels, lipids and blood pressure; in order to
prevent (or reduce) the frequency and severity of diabetic complications
 Metabolic Syndrome
• The term metabolic syndrome is used to describe a state of:
1) Insulin resistance
2) Dyslipidemia
3) Obesity
4) Atherosclerosis
5) Hypertension
6) Glucose intolerance
• Individuals with this syndrome are at greater risk of cardiovascular complications
• Insulin resistance (in adipose tissue) leads to an increase in lipase action, which
causes increased lipolysis of stored triglycerides (TGAs) to free fatty acids.
• When fatty acids arrive to the liver, they are converted to TGAs and cholesterol
associated with a decrease in beneficial HDL
• Obesity is linked to various chronic conditions;
➢ maturity onset diabetes of the young (MODY)
➢ hypercholesterolemia
➢ hypertension
➢ heart ailment
➢ cancers
➢ gout and arthritis
 Metabolic Syndrome – diagnostic criteria
Individuals present with -at least- 3 of the following findings:
1) Waistline ≥ 40 inches (men)
≥ 36 inches (women)
2) Blood pressure > 130/85 mmHg (Stage 1 hypertension)
or if the patient is already taking blood pressure lowering medications
3) Impaired fasting blood glucose > 100 mg/dL or 5.6 mmol/L (pre-diabetes)
or if the patient is already taking glucose lowering medications
4) Triglyceride levels (fasting) > 150 mg/dL or 1.7 mmol/L
borderline triglyceride levels (150 to 199 mg/dL or 1.70 to 2.25 mmol/L)
and high triglyceride levels (200 to 499 mg/dL or 2.26 to 5.64 mmol/L)
require an overall cardiac risk assessment
very high triglyceride levels (500 mg/dL or 5.65 mmol/L or higher)
require treatment that is aimed at reducing the risk of acute pancreatitis
5) HDL levels < 40 mg/dL or 1 mmol/L (men)
< 50 mg/dL or 1.3 mmol/L (women)