A 50-year-old male presented with a history of chest pain, polyuria and polydipsia since last 5 years. Investigations showed HbAlc level of 12%, cardiac enzymes were normal, while urinalysis showed proteinuria. What is the pathogenesis?

Pathogenesis: A Detailed Explanation

The patient’s presentation points towards a complex interplay of diabetic complications. The high HbA1c (12%) indicates chronic hyperglycemia, reflecting average blood glucose levels over the past 2-3 months. This sustained hyperglycemia is the central driver of the observed pathology.

1. Polyuria and Polydipsia

Hyperglycemia exceeds the renal threshold for glucose reabsorption, leading to glucosuria. Glucose in the urine creates an osmotic diuresis, drawing water along with it, resulting in increased urine output (polyuria). This fluid loss leads to dehydration, stimulating thirst and causing excessive fluid intake (polydipsia). This is a classic presentation of uncontrolled diabetes.

2. Chest Pain & Cardiovascular Involvement

While cardiac enzymes are normal, chest pain in a diabetic patient warrants careful consideration. Diabetes accelerates atherosclerosis, the buildup of plaques in the arteries. Hyperglycemia promotes endothelial dysfunction, increased LDL oxidation, and inflammation, all contributing to plaque formation. The patient likely has coronary artery disease (CAD), potentially causing angina (chest pain) due to myocardial ischemia. Normal cardiac enzymes suggest the chest pain isn’t due to an acute myocardial infarction, but rather stable angina exacerbated by diabetic vascular changes. Diabetic patients often present with atypical chest pain due to autonomic neuropathy.

3. Proteinuria & Renal Involvement

Proteinuria indicates damage to the glomerular filtration barrier in the kidneys. Chronic hyperglycemia leads to diabetic nephropathy, a leading cause of end-stage renal disease. The pathogenesis involves several mechanisms:

• Glomerular Hyperfiltration: Initially, hyperglycemia causes afferent arteriolar dilation and efferent arteriolar constriction, increasing glomerular pressure and filtration rate.
• Glomerular Basement Membrane Thickening: Hyperglycemia promotes non-enzymatic glycosylation of proteins in the glomerular basement membrane, leading to thickening and altered permeability.
• Mesangial Expansion: Increased glucose metabolism in the mesangium leads to accumulation of extracellular matrix, causing mesangial expansion and ultimately glomerular sclerosis.
• Podocyte Damage: Hyperglycemia and advanced glycation end-products (AGEs) directly damage podocytes, leading to proteinuria.

The proteinuria observed in this patient is a sign of established diabetic nephropathy.

4. Interrelation of Pathogenesis

These three manifestations are interconnected. Chronic hyperglycemia initiates a cascade of events affecting multiple organ systems. Cardiovascular disease and renal disease are common microvascular and macrovascular complications of diabetes, significantly increasing morbidity and mortality. The normal cardiac enzymes do not rule out cardiovascular involvement, but suggest a chronic rather than acute process.

Symptom/Finding	Pathogenic Mechanism
Polyuria/Polydipsia	Glucosuria leading to osmotic diuresis and dehydration
Chest Pain	Accelerated atherosclerosis and coronary artery disease
Proteinuria	Diabetic nephropathy: glomerular hyperfiltration, basement membrane thickening, mesangial expansion, podocyte damage
HbA1c 12%	Chronic hyperglycemia reflecting poor glycemic control