Genetics of diabetes mellitus and diabetes complications

These GEITP pages do not regularly include general reviews, but this one is an excellent update. Diabetes is a disease of the endocrine system — diagnosed by abnormally high blood glucose levels; the disorder is increasing in frequency and projected worldwide to affect 693 million adults by 2045, a >50% increase from 2017. Vascular complications commonly occur in both the macrovascular system (leading to cardiovascular disease, shortened life span, overall decreased quality of life) and microvascular system (resulting in diabetic kidney disease and kidney failure, retinal disease and blindness, and neuropathy). Although the precise mechanisms of hyperglycemia-induced vascular damage are not fully understood, high levels of intracellular glucose are believed to increase the production of reactive oxygen species (ROS), altering a series of critical downstream pathways (e.g. polyol pathway flux; advanced glycation end-product formation and activation; protein kinase C activation; and hexosamine pathway flux).

Rather than considering diabetes as a single disease, it is a group of conditions broadly categorized by a single diagnostic criterion: hyperglycemia (high blood sugar). Even type-2 diabetes (T2D) — the predominant diabetes subtype, comprising 90–95% of cases — is itself heterogeneous in terms of both mechanisms of action and relationships with health outcomes. Clustering approaches, using clinical or genetic biomarkers, have identified subtypes of T2D that are clinically distinct and differentially associated with diabetic complications, i.e. these studies show a greater risk of diminished renal function among individuals assigned to various insulin-resistance clusters, an increased risk of diabetic retinopathy among patients in the clinically severe insulin-deficiency cluster, and greater risk of coronary artery disease among the decreased pancreatic β-cell function genetic clusters. Intriguingly, no significant differences are seen among the clinical clusters for coronary events, after adjusting for age and gender.

Clinical risk factors and glycemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications — relied on familial linkage-analysis matched to strong-effect loci, candidate-gene studies (unfortunately) prone to false positives, and underpowered genome-wide association studies (GWAS) limited by small sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of gene discoveries for both diabetes and diabetic complications. This review focuses on recent genetic discoveries for diabetes and diabetic complications, empowered primarily through GWAS, and emphasizes the gaps in research for taking genomic discovery to the next level. These GEITP pages highly recommend this review as bedtime educational reading. 😊


Nat Rev Nephrol 2 May 2020; doi: 10.1038/s41581-020-0278-5

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