TYPE 2 DIABETES MELLITUS: FROM HYPERGLYCEMIA-INDUCED BIOCHEMICAL ALTERATIONS TO RENAL HISTOPATHOLOGY

Abstract

Background: Type 2 diabetes mellitus is characterized by insulin resistance, progressive beta-cell dysfunction and chronic hyperglycemia. Persistent elevation of blood glucose initiates biochemical disturbances that affect vascular and renal cells long before advanced kidney failure becomes clinically evident. Among the best described mechanisms are increased advanced glycation end-product formation, activation of the polyol and protein kinase C pathways, increased hexosamine pathway flux, oxidative stress and inflammatory signaling. Objective: This narrative review summarizes the main hyperglycemia-induced biochemical alterations in type 2 diabetes and connects them with the characteristic histopathological changes of diabetic kidney disease. Methods: A narrative literature search was performed using PubMed and reference lists of major reviews. English-language articles on hyperglycemia, oxidative stress, advanced glycation, diabetic kidney disease, renal morphology, glomerular basement membrane changes, mesangial expansion, podocyte injury, nodular glomerulosclerosis, arteriolar hyalinosis and tubulointerstitial fibrosis were prioritized. Classic mechanistic and classification papers were retained when they remained relevant. Results: Chronic hyperglycemia increases mitochondrial and cytosolic oxidative stress and promotes several glucose-dependent pathways that alter endothelial, mesangial, podocyte and tubular cell behavior. Hemodynamic changes, especially glomerular hyperfiltration and intraglomerular hypertension, act together with metabolic injury. The major renal structural lesions include glomerular basement membrane thickening, mesangial matrix expansion, Kimmelstiel-Wilson nodules, podocyte loss, arteriolar hyalinosis, tubular basement membrane thickening, tubular atrophy and interstitial fibrosis. The Renal Pathology Society classification organizes diabetic glomerular lesions from isolated basement membrane thickening to advanced glomerulosclerosis. Conclusion: Diabetic kidney disease is best understood as a whole-nephron process in which chronic hyperglycemia produces biochemical, hemodynamic and inflammatory disturbances that gradually become visible as characteristic renal histopathology. Understanding this sequence helps connect basic biochemistry with the microscopic findings encountered in pathology.