Genetics of diabetes

Abstract

Diabetes mellitus is a complicated disease characterized by a complex interplay of genetic, epigenetic, and environmental variables. It is one of the world's fastest-growing diseases, with 783 million adults expected to be affected by 2045. Devastating macrovascular consequences (cerebrovascular disease, cardiovascular disease, and peripheral vascular disease) and microvascular complications (like retinopathy, nephropathy, and neuropathy) increase mortality, blindness, kidney failure, and overall quality of life in individuals with diabetes. Clinical risk factors and glycemic management alone cannot predict the development of vascular problems; multiple genetic investigations have revealed a clear hereditary component to both diabetes and its related complications. In the twenty-first century, technological advancements (genome-wide association studies, next-generation sequencing, and exome-sequencing) have led to the identification of genetic variants associated with diabetes, however, these variants can only explain a small proportion of the total heritability of the condition. In this review, we address some of the likely explanations for this "missing heritability", for diabetes such as the significance of uncommon variants, gene-environment interactions, and epigenetics. Current discoveries clinical value, management of diabetes, and future research directions are also discussed.

Keywords: Common variants; Genome-wide association studies; Gestational diabetes mellitus; Maturity-onset diabetes of young; Rare variants; Type 1 diabetes; Type 2 diabetes.

Figure 1

Types of diabetes and their symptoms. Hyperglycemia and potential metabolic pathways in the pathogenesis of diabetic complications (microvascular and macrovascular) are also indicated. AGE: Advanced glycation end-products; RAGE: Receptor for advanced glycation end-products; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; GDM: Gestational diabetes mellitus; MODY: Maturity-onset diabetes of young.

Figure 2

Predicted percentage increase in the global prevalence of diabetes mellitus from 2021 to 2045[24].

Figure 3

Pathogenesis of gestational diabetes mellitus, type 2 diabetes mellitus-ominous octet, and type 1 diabetes mellitus. Pharmacological glycemic management targets have also been shown here. DPP-4: Dipeptidyl peptide-4 inhibitor; GLP-1RA: Glucagon-like peptide-1 receptor agonist; SGLT2: Sodium-Glucose co-transporter 2 inhibitor; IL-2: Interleukin-2; IFN-γ: Interferon gamma.