Metabolic de arrangements in Diabetes mellitus . Answer in mbbs 1st year level for 5 marks
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Metabolic Derangements in Diabetes Mellitus (5 Marks)
Definition: Diabetes mellitus is a syndrome of deranged carbohydrate, fat, and protein metabolism resulting from either absolute insulin deficiency (Type 1) or insulin resistance/relative deficiency (Type 2) - Guyton and Hall Textbook of Medical Physiology, p. 973.
Since insulin is the principal anabolic hormone, its lack (or ineffectiveness) shifts the body into a catabolic state, deranging metabolism of all three major foodstuffs:
1. Carbohydrate Metabolism
- Decreased peripheral uptake and utilization of glucose by muscle and adipose tissue (insulin-dependent GLUT-4 transport fails).
- Increased hepatic glycogenolysis and gluconeogenesis (from amino acids and glycerol) due to loss of insulin's inhibitory effect on liver enzymes.
- Net result: Hyperglycemia (plasma glucose can reach 300-1200 mg/dL).
- When blood glucose exceeds the renal threshold (~180-200 mg/dL), it exceeds tubular reabsorptive capacity → glycosuria → osmotic diuresis → polyuria → dehydration and compensatory polydipsia.
2. Fat (Lipid) Metabolism
- Loss of insulin's antilipolytic action → increased lipolysis in adipose tissue → raised free fatty acids and glycerol in blood.
- Excess fatty acids are taken up by the liver, converted to acetyl-CoA, and diverted to ketogenesis (acetoacetate, beta-hydroxybutyrate, acetone) since TCA cycle capacity is overwhelmed.
- Excess FFA also increases hepatic cholesterol and VLDL synthesis, contributing to dyslipidemia and long-term atherosclerosis.
- Accumulation of ketoacids causes a high anion-gap metabolic acidosis, i.e., Diabetic Ketoacidosis (DKA), seen mainly in Type 1 diabetes - Costanzo Physiology, p. 448-449.
3. Protein Metabolism
- Insulin normally promotes amino acid uptake and protein synthesis; its deficiency causes increased proteolysis and decreased protein synthesis.
- Released amino acids are used for hepatic gluconeogenesis, further worsening hyperglycemia.
- Net effect: negative nitrogen balance, muscle wasting, weight loss, and loss of lean body mass (catabolic state).
4. Fluid and Electrolyte Disturbances
- Osmotic diuresis from glycosuria → loss of water and electrolytes (Na+, K+, PO4) → ECF volume contraction, hypotension.
- Lack of insulin shifts K+ out of cells (insulin normally drives K+ into cells via Na+/K+-ATPase) → tendency toward hyperkalemia despite total body K+ depletion.
- Severe dehydration and acidosis can progress to hypovolemic shock, coma, and death if untreated.
Summary Table
| Substrate | Change | Mechanism | Consequence |
|---|---|---|---|
| Carbohydrate | ↑ Blood glucose | ↓ uptake, ↑ gluconeogenesis/glycogenolysis | Glycosuria, osmotic diuresis |
| Fat | ↑ Lipolysis, ↑ ketogenesis | Loss of antilipolytic insulin action | Ketoacidosis, dyslipidemia |
| Protein | ↑ Catabolism | ↓ synthesis, ↑ proteolysis | Muscle wasting, weight loss |
| Fluid/electrolyte | Dehydration, hyperkalemia | Osmotic diuresis, impaired cellular K+ uptake | Shock, arrhythmia risk |
Long-term consequence: Chronic hyperglycemia causes non-enzymatic glycosylation and vascular injury, leading to microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (coronary artery disease, stroke) complications - Guyton and Hall Textbook of Medical Physiology, p. 973.
Sources: Guyton and Hall Textbook of Medical Physiology, p. 973; Costanzo Physiology 7th Edition, p. 448-449.
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