Diabetes Mellitus (DM)
1. INTRODUCTION
Diabetes Mellitus (DM) is a chronic metabolic disease characterized by persistent hyperglycemia.
Hyperglycemia means abnormally high glucose levels in blood, usually because of:
- Impaired insulin secretion (pancreas not producing enough insulin)
- Impaired insulin action (body cells not responding to insulin – called insulin resistance)
- Both combined
Diabetes is a multisystem disorder affecting blood vessels, nerves, kidneys, eyes, heart, and immunity.
2. NORMAL PHYSIOLOGY OF GLUCOSE REGULATION
2.1 Pancreatic Structure & Insulin Synthesis
Pancreas has clusters of endocrine cells called Islets of Langerhans:
- β-cells (beta cells) – produce insulin
- α-cells (alpha cells) – produce glucagon
- δ-cells (delta cells) – produce somatostatin
- PP cells – produce pancreatic polypeptide
Insulin is synthesized as: Preproinsulin → Proinsulin → Insulin + C-peptide
C-peptide reflects the body’s natural insulin production.
2.2 Mechanism of Insulin Secretion
Insulin release occurs when blood glucose rises after a meal.
Sequence:
- Glucose enters β-cells via GLUT-2 transporter
- Glucose undergoes metabolism → increases ATP
- ATP closes K⁺ channels on β-cell membrane
- Cell depolarizes → Calcium enters
- Insulin-containing vesicles fuse → Insulin is released into blood
2.3 Actions of Insulin
Insulin is an anabolic hormone (builds tissues).
Effects on major tissues
Liver
- Inhibits gluconeogenesis (producing glucose from non-carbohydrate sources)
- Inhibits glycogenolysis (breakdown of glycogen)
- Promotes glycogenesis (formation of glycogen)
- Promotes lipogenesis (fat formation)
Muscle
- Increases GLUT-4 translocation → more glucose uptake
- Increases protein synthesis
Adipose tissue
- Promotes fat storage
- Inhibits lipolysis (breakdown of fat)
2.4 Role of Glucagon
Secreted when blood sugar falls.
Actions:
- Stimulates glycogenolysis
- Stimulates gluconeogenesis
- Raises blood glucose levels
Thus, INSULIN and GLUCAGON work as a balanced system.
3. PATHOPHYSIOLOGY OF DIABETES MELLITUS
3.1 Type 1 Diabetes Mellitus (T1DM)
Autoimmune destruction of β-cells → absolute insulin deficiency.
Mechanisms:
- Immune system produces autoantibodies against β-cell antigens
- Gradual β-cell destruction
- No insulin → glucose cannot enter cells → severe hyperglycemia
Common before age 20, but may occur anytime.
Clinical signs:
- Sudden weight loss
- Polyuria (excess urination)
- Polydipsia (excess thirst)
- Polyphagia (excess hunger)
- Diabetic ketoacidosis (DKA)
3.2 Type 2 Diabetes Mellitus (T2DM)
Most common type.
Characterized by:
- Insulin resistance – cells do not respond to insulin
- β-cell dysfunction – gradual decline in insulin production
Causes:
- Obesity
- Abdominal fat (visceral fat)
- Physical inactivity
- Genetics
- Chronic inflammation
Mechanisms:
• Insulin receptor signaling fails → GLUT-4 fails to move → glucose cannot enter cells
• Liver continues producing glucose even when blood sugar is already high
• Pancreas tries to compensate → hyperinsulinemia
• β-cells eventually fatigue → insulin levels fall
3.3 Gestational Diabetes Mellitus (GDM)
Diabetes first detected during pregnancy.
Mechanism:
- Pregnancy hormones (human placental lactogen, estrogen, progesterone) cause insulin resistance
- Pancreas cannot compensate → hyperglycemia
3.4 Secondary Diabetes
Due to:
- Pancreatic diseases (pancreatitis, pancreatic cancer)
- Endocrine excess (Cushing’s, acromegaly)
- Drugs (steroids, antipsychotics)
- Genetic disorders
4. WHY DOES HYPERGLYCEMIA DAMAGE ORGANS?
(Pathogenesis of Complications)**
Chronic hyperglycemia leads to:
4.1 Advanced Glycation End Products (AGEs)
High glucose attaches to proteins → forms AGEs
These cause:
- Vessel wall thickening
- Inflammation
- Oxidative stress
4.2 Polyol Pathway Activation
Glucose converted into sorbitol
Sorbitol accumulates → cell swelling → nerve & lens damage
→ leads to neuropathy and cataracts
4.3 Protein Kinase C Activation
Causes:
- Vasoconstriction
- Retinal damage
- Renal damage
4.4 Oxidative Stress
Excess glucose produces free radicals
Damages:
- Endothelium
- DNA
- Mitochondria
5. CLINICAL FEATURES OF DIABETES
5.1 Classic Features
- Polyuria
- Polydipsia
- Polyphagia
- Weight loss (mainly in T1DM)
- Fatigue
- Blurred vision
- Recurrent infections
5.2 Complications
Acute
- DKA (ketoacidosis)
- HHS (hyperosmolar hyperglycemic state)
- Severe hypoglycemia
Chronic
Microvascular:
- Retinopathy
- Nephropathy
- Neuropathy
Macrovascular:
- Coronary artery disease
- Stroke
- Peripheral vascular disease
6. INVESTIGATIONS IN DIABETES
6.1 Blood Glucose Tests
Fasting Plasma Glucose (FPG)
Measured after 8 hours of fasting.
High fasting glucose = impaired hepatic glucose regulation.
Postprandial Plasma Glucose (PPG)
Measured 2 hours after food.
Reflects ability of pancreas to handle a glucose load.
Random Plasma Glucose
Useful for symptomatic patients.
6.2 Oral Glucose Tolerance Test (OGTT)
Patient drinks 75 g glucose.
Blood glucose measured fasting & after 2 hours.
Shows how efficiently the body clears glucose.
6.3 HbA1c (Glycated Hemoglobin)
Represents average blood glucose for last 3 months.
Mechanism:
Glucose binds to hemoglobin in RBCs → forms HbA1c
Higher glucose = higher HbA1c
Useful for diagnosis and monitoring.
6.4 Urine Investigations
Urine glucose
Appears when blood sugar > renal threshold (180 mg/dL)
Urine ketones
Indicates fat breakdown; important in suspected DKA.
Microalbuminuria
Very early marker of diabetic kidney disease.
6.5 Tests for Complications
Kidney
- Serum creatinine
- eGFR
- Urine albumin-creatinine ratio
Eyes
- Fundus examination
- OCT (when needed)
Nerves
- Monofilament test
- Vibration sense
- Nerve conduction studies (advanced)
Cardiovascular
- Lipid profile
- ECG
- Carotid Doppler (if needed)
6.6 Immunological Tests (Type 1 DM)
Presence of autoantibodies:
- GAD (Glutamic acid decarboxylase) antibody
- IA-2 antibody
- ZnT8 antibody
- Islet cell antibody (ICA)
These confirm autoimmune destruction of β-cells.
7. DIABETIC KETOACIDOSIS (DKA) – PATHOPHYSIOLOGY IN SIMPLE TERMS
Occurs mainly in Type 1 diabetes.
Sequence:
- No insulin → cells cannot take up glucose
- Body thinks it is starving → breaks fat rapidly
- Fat breakdown produces ketone bodies
- Ketones accumulate → blood becomes acidic
- Dehydration + acidosis = dangerous, life-threatening condition
Clinical features:
Fruity breath, Kussmaul breathing, abdominal pain, vomiting.
8. HYPEROSMOLAR HYPERGLYCEMIC STATE (HHS)
Typical of T2DM in elderly.
Mechanism:
- Severe hyperglycemia
- Extreme dehydration
- No significant ketoacidosis
Very high mortality.
9. SUMMARY
Diabetes = chronic hyperglycemia due to insulin defect.
Type 1 = absolute insulin deficiency.
Type 2 = insulin resistance + β-cell failure.
Chronic high glucose causes vascular, neural, renal & retinal damage.
Diagnosis uses FPG, PPG, OGTT, HbA1c.
Monitoring includes checking for kidney, eye, nerve & heart involvement.
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