Diabetes Mellitus according to the curriculum of Medical Biochemistry of MBBS course

1. Diabetes Mellitus
DR. FARHANA ATIA
Associate Professor
Department of Biochemistry
Nilphamari Medical College, Nilphamari

2. Hypoglycemia
Hypoglycemia is characterized by-
 CNS symptoms including confusion, aberrant behavior or
coma
 Blood glucose level <3 mmol/L (≤50 mg/dl)
 Symptoms resolved within minutes following glucose
administration
 Hypoglycemia is a medical emergency (neuron is glucose
obligate cell)
 Glucagon & catecholamines combat hypoglycemia

3. Types of Hypoglycemia
 Insulin Induced Hypoglycemia
 >99% causes are IDDM
 Insufficient carbohydrate intake/ missed meal
 Excess of insulin
 Strenuous exercise
 Excessive alcohol intake

4. Types of Hypoglycemia
 Postprandial hypoglycemia
 Due to exaggerated insulin release following a meal
transient hypoglycemia with mild adrenergic symptom
 BGC return to normal even if the patient is not fed
 So, in DM- frequent small meal rather than usual 3 large
meal is advised
 Alcohol-related hypoglycemia: in malnourished & fasting
condition by inhibiting gluconeogenesis

5. Types of Hypoglycemia
 Fasting Hypoglycemia
 Rare but serious medical problem
 Tends to produce neuroglycopenic symptoms
Causes
1. Hepatocellular damage
2. Adrenal insufficiency
3. Fasting with large amount of ethanol consumption
4. Insulinoma: β cell tumor of pancreas produce inappropriate &
excess insulin increase peripheral uptake of glucose

6. Neonatal Hypoglycemia
 Babies of diabetic mother
 Diabetic mother have elevated insulin
 After delivery baby is unable to suppress it properly, so
 High Insulin in baby leads to Hypoglycemia
 IUGR
 Due to inadequate liver glycogen
 Inborn error of metabolism
 Galactosemia
 Glycogen storage disease

7. Consequence of Hypoglycemia
Adrenergic (neurogenic/
autonomic) symptoms
Neuroglycopenic symptoms
(Impaired delivery of glucose to
brain)
(Due to catecholamines release
in response to hypoglycemia)
Sweating
Tremor
Anxiety
Palpitation
Dizziness
Headache
Confusion
Slurred speech
Drowsiness
Seizure
Coma
Death

8. Glucoregulatory Systems
 Two overlapping systems-
1. Pancreatic α cells- release glucagon
2. Receptors in hypothalamus- respond to abnormally low
concentration of blood glucose & trigger the secretion of
Catecholamines, ACTH, Growth hormone
 Counterregulatory hormone (Oppose the action of insulin
on glucose use)
 Glucagon- ↑ glycogenolysis,↑ gluconeogenesis
 Catecholamine- ↑ glycogenolysis, ↑ lipolysis, (-) insulin secretion
 Cortisol- ↑ gluconeogenesis
 GH- ↓ glucose uptake
Play role in long term maintenance
of blood glucose

9. Lippingcott illustrated reviews Biochemistry; 7th edn; p-319

10. Hyperglycemia
 Increase blood glucose concentration
 Cause
 Diabetes Mellitus
 Intravenous infusion of glucose containing fluid
 Severe stress: Temporary, In cerebro-vascular accident

11. Diabetes mellitus
Diabetes mellitus is a heterogeneous group of syndromes
 characterized by elevation of fasting blood glucose
(FBG)
 caused by a relative or absolute deficiency of insulin
 Leading cause of adult blindness & amputation
 Major cause of renal failure, nerve damage, heart attack,
stroke
11

12. Classification of Diabetes Mellitus
Type 1/ T1D (IDDM)
Type 2/ T2D (NIDDM)
The terms insulin-dependent diabetes mellitus (IDDM) and
noninsulin-dependent diabetes mellitus (NIDDM) are
obsolete
Since many individuals with type 2 DM eventually require
insulin treatment.

13. Type 1 diabetes
 β-cell destruction, usually leading to absolute insulin
deficiency
 Type
 Immune-mediated
 Idiopathic
 Genetic & environmental factor may present
 Abrupt onset of
 Polyurea
 Polyphagia
 Polydipsia

14. Type 2 diabetes
 Impaired insulin action
 Insulin resistance
 Dysfunctional β cell
 Insulin may be Normal/ ↑/ ↓
 Minimum symptom, Less complications
 Not prone to ketosis
 Insulin resistance is the decrease ability of target cell (liver,
adipose tissue, muscle) to respond properly to normal or
elevated circulating concentration of insulin

15. Diabetic prone states
 Gestational diabetes mellitus (GDM):
 Impaired glucose tolerance (IGT):
 Plasma glucose values are above the normal level, but
below the diabetic levels.
 In IGT, the FBS value is 6.1 - 7.0 mmol/L & 2 hour OGTT
value is between 7.8-11.1 mmol/L
 Requires careful follow-up because IGT progresses to frank
diabetes at the rate of 2% patients per year
 Dietary restriction & exercise are advised

16. Diabetic prone states
 Impaired fasting glycemia (IFG):
 In this condition, fasting plasma glucose is above normal
(between 6.1 - 7.0 mmol/L); but the 2 hour post-glucose
value is within normal limits (< 7.8 mmol/L)
 These persons need no immediate treatment; but are to be
kept under constant check up

17. Renal glycosuria
 Renal glycosuria is a benign condition due to a reduced
renal threshold for glucose (N- 10.0mmol/L)
 It is unrelated to diabetes & should not be mistaken as
diabetes.
 It is not accompanied y the classical symptoms of
diabetes

18. Alimentary glycosuria
 In certain individuals, blood glucose level rises rapidly
after meals resulting in its spill over into urine.
 This condition is referred to as alimentary glycosuria.
 It is observed in
 some normal people
 Patients of hepatic diseases
 Hyperthyroidism
 Peptic ulcer

19. Differences
Feature Type 1 DM Type 2 DM
Previous
names
Insulin Dependent diabetes
mellitus(IDDM), also called
Juvenile onset DM
Non insulin dependent
Diabetes mellitus
(NIDDM), also called
Maturity onset DM
Age of Onset Usually during childhood or
puberty
Frequently after the age
of 35
Pattern of onset Abrupt- Symptoms develop
rapidly
Slow – Symptoms
appear gradually
19

20. Differences
Feature Type 1 DM Type 2 DM
Prevalence 10% of the
diagnosed cases
90 % of the diagnosed
cases
Genetic
predisposition
Moderate Very strong
Nutritional state at
the time of onset
Undernourished Mostly obese
20

21. Differences
Feature Type 1 DM Type 2 DM
Biochemical
defect
Auto immune
destruction of β cells,
eliminating production
of insulin
Insulin resistance
combined with inability
of β cells to produce
appropriate amount of
insulin
Plasma insulin Low to absent High in the early stage,
low in the disease of
long duration
21

22. Differences
Feature Type 1 DM Type 2 DM
Acute Complications Hypoglycemia and
ketoacidosis
Hyperosmolar non
ketotic coma
Frequency of ketosis Very common Rare
Treatment Insulin is always
needed, oral
hypoglycemic drugs are
ineffective.
Diet, exercise, oral
hypoglycemic drugs
and insulin in severe
cases
22

23. Metabolic effect of DM
Glucose metabolism- Increased hepatic output and decreased
glucose utilization
 Peripheral uptake- ↓ uptake of glucose in skeletal muscle,
cardiac muscle and adipose tissue (GLUT- 4 receptors are
insulin dependent)
 Gluconeogenesis- ↑
 Glycogenesis- ↓
 Glycogenolysis- ↑
Net effect- Hyperglycemia
23

24. Altered carbohydrate metabolism leads to
 Hyperglycemia
 Glycosuria - When the capacity of the kidneys to absorb glucose
is surpassed.
 Polyuria - osmotic diuresis. An increase in renal loss of glucose is
accompanied by loss of water and electrolytes.
 Polydipsia - Loss of water (and overall volume) activate thirst
mechanism.
 Polyphagia The negative caloric balance which results from the
glucosuria and tissue catabolism leads to an increase in appetite
and food intake.
24

25. Lipid metabolism in DM
 Adipolysis
 Increased levels of plasma free fatty acids
 Fatty acid oxidation- Increased
 Majority of the acetyl-CoA is not oxidized by the TCA cycle
but is metabolized into the ketone bodies
 Used for energy production
 Exacerbates the reduced utilization of glucose furthering the
ensuing hyperglycemia
 Diagnosed by smelling the breath
25

26. Lipid metabolism in DM
 Hypertriglyceridemia
 VLDLc and LDLc- High
 HDLc –low
Net effect-
Ketoacidosis
Dyslipidemia (Atherogenic profile)
26

27. Protein metabolism in DM
 Insulin deficiency  increased catabolism of protein.
 Elevated concentrations in plasma amino acids.
 Amino acids serve as precursors for hepatic and renal
gluconeogenesis.
 Hyperglycemia seen in IDDM.
27

28. Water and Electrolyte imbalance in DM
 Dehydration is a frequent finding , Polyuria is responsible
for dehydration.
 Hypokalemia
 Total body K is low
 False hyperkalemia due to non functioning of Sodium
Potassium ATPase pump. Caution is needed during
Insulin administration.
28

29. 29

30. Immediate complications of DM
 Hyperglycemia
 Hyperosmolarity
 Dyslipidaemia
 Ketosis
 Muscle loss

31. Delayed complications of DM
 Macro vascular complication
 Stroke, MI, Reno vascular disease, Limb ischemia
 Micro vascular complication
 Retinopathy
 Nephropathy
 Neuropathy
 Cataract

32. Lippingcott illustrated reviews Biochemistry; 7th edn; p-347

33. Glucose tolerance test (GTT)
 All drugs known to influence carbohydrate metabolism should be
discontinued (2 days)
 The subject should avoid strenuous exercise on the previous day
of the test
 Person should be in an overnight fasting state
 During the course of GTT, the person should be comfortably
seated & should refrain from smoking & exercise

34. Procedure for GTT
 Glucose tolerance test should be conducted preferably in
the morning (ideal 9 to 11 AM).
 A fasting blood sample is drawn and urine collected.
 The subject is given 75 g glucose orally, dissolved in
about 300 ml of water, to be drunk in about 5 minutes

35. Procedure for GTT
 Blood & urine samples are collected at 30 minute intervals
for at least 2 hours
 All blood samples are subjected to glucose estimation
while urine samples are qualitatively tested for glucose

37. Condition
Plasma glucose concentration as mmol/l
(mg/dl)
Normal IGT Diabetes
Fasting
<6.1
(<110)
<7.0
(<126)
>7.0
(>126)
2 hours after
glucose
<7.8
(<140)
<11.1
(<200)
>11.1
(>200)
Diagnostic criteria for OGTT (WHO 1999)

38. Glycated Hemoglobin (HbA1C)
 Refers to the glucose derived products of normal adult
hemoglobin (HbA)
 Glycation is a post-translational, non-enzymatic addition
of sugar residue to amino acids of proteins
 Among the glycated hemoglobin, the most abundant
form is HbA1c
 HbA1c is produced by the condensation of glucose with
N-terminal valine of each β-chain of HbA

39. Diagnostic importance of HbA1c
 The rate of synthesis of HbA1c is directly related to the
exposure of RBC to glucose
 HbA1c reflects the mean blood glucose level over
previous 8 weeks
 HbA1c concentration is about 4-6% of total HbA₁
 In diabetic patients, HbA1c is elevated (15%)

40. Microalbuminuria
 Microalbuminuria is defined as the excretion of 30-300 mg of
albumin in urine per day
 Microalbuminuria represents an intermediary stage between
normal albumin excretion (2.5-30 mg/d) & macroalbuminuria
(>300 mg/d)
 The small increase in albumin excretion predicts impairment in
renal function in diabetic patients
 It indicates reversible renal damage