Endocrine Abstracts

Defining the molecular genetics of diabetes gives new insight into the underlying aetiology. Recent work in Type 2 diabetes has suggested that the majority of genes to date result in beta-cell dysfunction but the impact of each polymorphism is relatively modest. In contrast patients with beta-cell monogenic diabetes have beta-cell dysfunction as the result of mutation of a single gene and these allow new insights into subtypes of beta-cell dysfunction and their therapeutic response.

Patients with a glucose-sensing beta-cell defect due to glucokinase mutations have regulated, mild, fasting hyperglycaemia. Oral hypoglycaemic agents or low-dose insulin do not alter glycaemic control in these patients. Patients with hepatic nuclear factor-1alpha (HNF1A) mutations have progressive beta-cell deterioration and require treatment. HNF1alpha patients are 4 times more sensitive to sulphonylureas than matched type 2 diabetic patients. This reflects the defect in HNF1alpha deficiency precedes the K_ATP channel. HNF1beta is expressed in pancreatic stem cells before differentiation into endocrine or exocrine cells, so patients with HNF1B mutations have reduced pancreatic development, resulting in early-onset diabetes and mild exocrine dysfunction. These patients usually rapidly require insulin and are not responsive to sulphonylureas.

Fifty percent of patients diagnosed with diabetes before 6 months have mutations in the K_ATP channel subunits Kir6.2 and SUR1. The mutated KATP channel in these patients does not close in response to increased ATP concentrations, but can be closed when sulphonylureas bind to the sulfonylurea receptor 1 subunit of the channel by an ATP-independent route. These have excellent glycaemic control on high-dose sulphonylureas tablets. The mechanisms for the insulin release mediated by incretins and other non-ATP mediated pathways.

In conclusion, the defining of molecular genetic aetiology in monogenic diabetes has identified several specific beta-cell defects, and these are critical in determining treatment response. Identifying new genes will give new insights into the human beta-cell.