Monogenic diabetes: a gateway to precision medicine in diabetes

Abstract

Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%-5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.

Figure 1. Schematic representation of glucose-induced insulin secretion and MODY-associated genes.

The pancreatic K_ATP channel directly regulates insulin secretion. It is a hetero-octamer formed by four subunits of the inward rectifier potassium channel 11 (Kir6.2, encoded by KCNJ11) and four sulfonylurea receptor 1 (SUR1, encoded by ABCC8) subunits. Glucose enters the β cell and glucokinase phosphorylates glucose to glucose-6-phosphate, which further breaks down in the glycolysis and citric acid cycle to produce ATP. The increased ATP/MgATP ratio leads to the closure of the K_ATP channel and causes depolarization of the β cell membrane and subsequent activation of voltage-gated calcium channels. Calcium flows into the cell through activated voltage-gated calcium channel and triggers the insulin to be released from the β cell. Transcription factors (HNF1A, HNF4A, HNF1B, NEUROD1, PDX1, and RFX6) constitute a network that regulates the expression of insulin and β cell development and proliferation. The MODY-associated genes are labeled in red.

Figure 2. Proposed diagnostic algorithm for monogenic diabetes.

Though the majority of patients diagnosed between 6 and 12 months have T1D, NDM can exist in these patients; genetic testing should be considered if they test negative for autoantibody, have extrapancreatic features, or have unusual family history (1, 2). High prevalence of MODY was observed in C-peptide–positive T2D diagnosed before 30 years regardless of metabolic syndrome status (116).