Dorothy Hodgkin Lecture 2021: Drugs, genes and diabetes.

Glycaemic response to metformin and sulphonylureas is heritable - with ~34-37% of variation explainable by common genetic variation. The premise of this review is that by understanding how genetic variation contributes to drug response we can gain insights into the mechanisms of action of diabetes drugs. Here I focus on two old drugs, metformin and sulphonylureas, where I would suggest we still have a lot to learn about their mechanism of action or their optimal use in clinical care. The fact that reduced function variants of the key transporter that takes metformin into the liver (OCT1) do not alter glycaemic response to metformin suggests that metformin does not need to get into the liver to work. A subsequent GWAS of metformin response identifies a robust variant that alters GLUT2 expression - which may support increasing evidence that metformin works primarily in the gut. For sulphonylureas, observation from patients with neonatal diabetes due to activating KATP channel mutations treated with sulphonylureas identified a novel role for sulphonylureas to enable beta-cell incretin response. This work led to recent studies of low dose sulphonylurea (20 mg gliclazide) in T2DM, which identified that at this dose sulphonylureas augment the incretin effect and increase beta-cell glucose sensitivity, without increasing hypoglycaemia risk. This work, prompted by studies in monogenic diabetes, suggests that we have historically been using sulphonylureas at too high a dose. With increasing availability of genetic data pharmacogenomic studies in patients with diabetes should reveal mechanistic insights into old and new diabetes drugs, with the potential for optimized use and novel therapies.