Monogenic Diabetes: Gene directed therapy and mutation specific phenotypes

Single gene mutations cause ~1% of all cases of diabetes and most individuals are diagnosed under 35 years of age. However, the majority of cases of monogenic diabetes are misdiagnosed as type 1 or more frequently type 2 diabetes. This project targeted the challenges in the diagnosis and management of monogenic diabetes through these specific aims: 1. Elucidate the incretin effect in sulphonylurea-treated KATP-related diabetes 2. Expand the clinical phenotype, improve genetic diagnosis and therapeutic options of established monogenic forms of diabetes 3. Identify novel monogenic causes of diabetes Insulin secretion response was studied in 5 adult sulphonylurea-treated subjects with KCNJ11-diabetes in comparison to 5 matched controls. We found that KCNJ11 subjects had higher glucose levels overall, including fasting hyperglycaemia, higher peaks, and delayed normalization following OGTT and during isoglycaemic glucose infusions. Overall insulin and C-peptide responses were not different during OGTT or IGI, but the change from baseline to peak levels was greater in controls. Insulin and C-peptide levels returned to baseline in controls but remained elevated in subjects after 4 hours. Through examination of patients within the Monogenic Diabetes Registry, the clinical phenotypes of those with mutations within GCK, KCNJ11 and EIF2AK3 have been expanded. Additionally the treatment algorithms and diagnostic options for neonatal diabetes mellitus have been challenged. Novel causes of diabetes were identified, including a novel intronic INS mutation leading to diabetes through novel mechanisms and a mutation within H19 leading to diabetes and Russell Silver Syndrome. A precise genetic diagnosis enables targeted therapy, leads to improved quality of life and aids in diagnosis of diabetes in other family members including earlier diagnosis in children. These studies have expanded our understanding of the pathogenesis, diagnosis and treatment of a variety of poorly studied forms of diabetes.