Genetics of Monogenic Diabetes: Present Clinical Challenges

Abstract

Purpose of ReviewMonogenic forms of diabetes have specific treatments that differ from the standard care provided for type 1 and type 2 diabetes, making the appropriate diagnosis essential. In this review, we discuss current clinical challenges that remain, including improving case-finding strategies, particularly those that have transethnic applicability, and understanding the interpretation of genetic variants as pathogenic, with clinically meaningful impacts.Recent FindingsBiomarker approaches to the stratification for genetic testing now appear to be most effective in identifying cases of monogenic diabetes, and use of genetic risk scores may also prove useful. However, applicability in all ethnic groups is lacking. Challenges remain in the classification of genes as diabetes-causing and the interpretation of genetic variants at the clinical interface.SummarySince the discovery that genetic defects can cause neonatal or young-onset diabetes, multiple causal genes have been identified and there have been many advances in strategies to detect genetic forms of diabetes and their treatments. Approaches learnt from monogenic diabetes are now being translated to polygenic diabetes.

Beta-Cell Dedifferentiation in Type 2 Diabetes: Concise Review

“…In certain populations, such as Asian Indians, the occurrence of abnormal β‐cell function was reported in T2D patients in the absence of insulin resistance . Monogenic diabetes represents another disease class, in which mutations in single genes involved in β‐cell function lead to β‐cell failure independent of insulin resistance . Thus, it has become increasingly clear that, similarly to T1D, T2D is fundamentally a β‐cell disease, which is manifested when β cells succumb to cellular stress triggered by nutrient overload and insulin resistance (Fig.…”

Can Precision Medicine Reduce the Burden of Diabetes?

“…The Precision Medicine Initiative of the National Institutes of Health identified several scientific opportunities for precision medicine research, leveraging electronic health data and 4,5 Improvements in disease classification, for example, offer the opportunity to move beyond identification of the small subset of patients with monogenic forms of diabetes 6 to the characterization of other clinically relevant subtypes of diabetes (eg, subtypes of T2DM that differ in likelihood of complications 5 ). Improved disease classification could create opportunities to tailor the intensity of glucose control and medical surveillance to more precise measures of a patient's risk of adverse events.…”

Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds

“…Breeds such as the Samoyed, Yorkshire Terrier, Australian Terrier and Miniature Schnauzer have all been reported to be at high risk in independent studies, whereas the Boxer, Golden Retriever and German Shepherd Dog are considered to be at low risk of developing DM [ 1 , 2 , 17 , 18 ]. A large number of diabetes susceptibility genes, each contributing relatively small effects, have been identified in human T1D [ 19 ], Type 2 DM (T2D) [ 20 ] and monogenic DM [ 21 ]. This has prompted candidate gene studies in canine DM, which have largely focussed on T1D genes involved with immune function [ 22 – 25 ] and human monogenic diabetes genes [ 26 ].…”