BIOCHEMISTRY OF DIABETES MELLITUS PATHOGENESIS: THE UNIFYING MECHANISM OF HYPERGLYCEMIC DAMAGE AND QUANTITATIVE ASSESSMENT OF METABOLIC PATHWAYS

Abstract

Diabetes mellitus is a metabolic disease defined by chronic hyperglycemia resulting from defective insulin secretion, defective insulin action, or both; oxidative stress represents the common biochemical denominator of β-cell damage and of the long-term complications of hyperglycemia [30]. According to the unifying mechanism proposed on the basis of two decades of experimental work, hyperglycemia-driven overproduction of superoxide by the mitochondrial electron transport chain links the four previously separate pathogenetic pathways — the polyol pathway, advanced glycation end product formation and RAGE signaling, protein kinase C activation, and the hexosamine pathway — into a single cascade of cellular damage [3]. This review presents the pathway-by-pathway biochemistry with its quantitative, laboratory-measurable markers (e.g., MG-H1 rising ~5-fold within 6 weeks and fructosyl-lysine from 6-fold at 3 weeks to 13-fold at 12 weeks in diabetic nerve endoneurial proteins [7]; serum GPX 45.1 ± 8.8 vs. 51.5 ± 9.2 U/gHb and NO 7.6 ± 0.9 vs. 8.9 ± 1.6 µmol/L in patients, P < 0.05 [16]), translates the molecular axes into the tissue pathology of diabetic peripheral neuropathy, and identifies mechanism-matched therapeutic counter-agents (α-lipoic acid, benfotiamine, aminoguanidine) — including glucose-independent neuroprotection by chitosan [27]. The article is written from a clinical-chemistry department's perspective: every pathogenetic axis is expressed as a measurable biomarker panel, directly transferable to experimental and clinical assessment of disease-modifying correction