Pathophysiology of diabetes mellitus and its complications: Metabolic events and control

Background: Diabetes mellitus (DM) is a metabolic disorder that is characterized by hyperglycemia and glucose intolerance, which is associated with impaired insulin secretion, peripheral sensitivity and eventual beta-cell dysfunction. This review aimed to summarize the major metabolic pathways leading to both microvascular and macrovascular complications in DM, with an emphasis on the enzymes involved and potential inhibition of the enzymes facilitating these processes as a measure of diabetic control. Methods: Data for this review were sourced online from scientific search engines, including Google Scholar, Scopus, EMBASE, PubMed, ResearchGate, Mendeley, Medline and SpringerLink, using keywords such as 'diabetic complications', 'hyperglycemia-induced diabetic mechanisms', 'diabetic enzymes', and 'diabetic enzyme inhibitors'. A total number of 109 references published online between 1990 and 2020 were generated and cited in this review. Results: The most scourging and dilapidating effects of DM, as well as its associated vascular complications, are classified into four categories, viz.: nephropathy, retinopathy, neuropathy, and cardiovascular disease. Hyperglycemia, which is associated with uncontrolled DM, elicits abnormal metabolism such that the enzymes involved in metabolic events leading to diabetic complications are expressed and amplified. The disorders associated with DM are linked to various metabolic pathways facilitated by enzymatic activities of the polyol pathway, hexosamine biosynthetic pathway, and glucose autoxidation. Also, the disorders are linked to increased synthesis of advanced glycation end-products (AGEs), hexokinase-2 driven glycolytic overload, as well as increased activities of cyclooxygenase (COX), lipoxygenase (LOX) and pyruvate kinase (PKC) enzymes. The inhibition of the enzymes involved in these pathways could serve to mitigate and arrest diabetic complications. Conclusion: Thus, suitable inhibitors for enzymes involved in DM metabolic events could serve as panaceas against DM complications, possibly adding to the growing list of new and more efficacious antidiabetic drugs.