Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes

Abstract

Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of 'precision diabetes'. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of 'obesity therapies' in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with 'adipose failure' may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.

Keywords: Diabetes; Genetics; Insulin resistance; Leptin; Lipodystrophy; MODY; Neonatal diabetes; Personalised medicine; Precision medicine; Review; Sulfonylurea; Thiazolidinedione.

Fig. 1

Genes linked with monogenic insulin-deficient diabetes encode proteins that play a key role in pancreatic beta cells. Genes marked with a light-blue star are actionable monogenic beta cell diabetes genes. The dashed line between G6P and pyruvate indicates that several steps are involved. G6P, glucose-6-phosphate. This figure is available as part of a downloadable slideset

Fig. 2

Monogenic insulin resistance subtypes and therapeutic strategies. (a) Clustering of severe insulin resistance subtypes according to severity of insulin resistance and lipotoxic features, with reference to health and type 2 diabetes (Type 2 DM). HDL-C, HDL-cholesterol; IR, insulin resistance; NAFLD, non-alcoholic fatty liver disease; PCOS, polycystic ovary syndrome; TG, triacylglycerol. (b) Genes implicated in monogenic severe insulin resistance of different subtypes and potential therapeutic strategies. Possible strategies, supported by case series and clinical experience for each subtype, are indicated in brackets, with reference to the Venn diagram (and labelled A–D). Senolytic therapies are a possible future prospect only. CGL, congenital generalised lipodystrophy; FPLD, familial partial lipodystrophy; FTIs, farnesyl transferase inhibitors; SGLT2i, sodium−glucose cotransporter 2 inhibitor. This figure is available as part of a downloadable slideset