Endocrine Abstracts

The molecular genetics of monogenic diabetes have been defined in the last decade. Most of these genes result in beta-cell dysfunction. Studying these patients has given new insights into the role of key genes in the fetal and adult beta-cell.

Hepatic Nuclear Factor (HNF)-1β mutations causing renal cysts and diabetes (RCAD). HNF-1β mutations are associated with reduced beta-cell development resulting in diabetes, exocrine dysfunction and pancreatic atrophy and as a result of fetal hypoinsulinaemia – low birth weight. Patients with glucokinase (GCK) mutations have a stable glucose sensing defect while patients with transcription factor mutations show a progressive beta-cell defect. In HNF-1α MODY, we showed a 4 × greater fall in fasting glucose than in BMI matched type 2 patients. This pharmacogenetics effect reflects the defect in the beta-cell being prior to the K_ATP channel where sulphonylureas act. Differences are seen in MODY fetal beta-cell with birth weight being reduced in GCK, normal in HNF-1α and increased in HNF-4α.

Mutations in Kir6.2 are the major cause of permanent neonatal diabetes. All mutations showed reduced channel closure in response to ATP. Despite being insulin dependent these patients can discontinue insulin injections and show improved glycaemic control on high dose sulphonylureas which act to close the K_ATP channel by a non-ATP dependent route. The excellent control is achieved without restoration of the first phase insulin response.

A molecular genetic diagnosis (see www.diabetesgenes.org) helps explain clinical features, predicts prognosis and can improve treatment. Study of monogenic patients gives new insights into the role of these critical proteins in man.