Genetics & Biology of Diabetes Mellitus & its Complications

Graeme I. Bell, PhD and Nancy J. Cox, PhD

Genetics and Biology of Diabetes Mellitus and its Complications

Your genes play an important role in determining if you will develop diabetes during your lifetime. The research in the Bell and Cox laboratories is focused on identifying the genes and pathways that determine susceptibility to diabetes and its complications and then using this information to improve diagnosis and treatment. Our research focuses on both monogenic and polygenic forms of diabetes – the Bell lab focuses on the molecular aspects of these studies, while the Cox lab focuses on statistical genetic analysis.

We have shown that mutations in transcription factors expressed in the insulin-secreting pancreatic beta-cell such as the nuclear receptor hepatocyte nuclear factor (HNF)-4a and the POU-homeodomain transcription factors HNF-1a and HNF-1ß are the causes of a form of diabetes called maturity-onset diabetes of the young (MODY). MODY is characterized by autosomal dominant inheritance and onset in most instances before 25 years of age and often in adolescence.

We showed that mutations in the glycolytic enzyme glucokinase in the heterozygous state are a cause of MODY and in the homozygous state, permanent neonatal diabetes, a form of presenting at birth or shortly thereafter and requiring insulin therapy. MODY was once thought to be an extremely rare form of diabetes but based on our work and that of others, we now know that MODY may account for ~1% of all cases of diabetes. A diagnosis of MODY has implications for prognosis and treatment. Mutations in glucokinase result in a mild form of MODY that can be treated with diet and exercise and these patients rarely develop complications. Patients with MODY due to a mutation in HNF-1a and HNF-4a can be treated with oral hypoglycemic agents and often for a long period of time. Patients with MODY due to a mutation in HNF-1ß usually require insulin and are at increased risk of kidney disease that often precedes the onset of diabetes. A current focus of our genetic studies of monogenic diabetes is permanent neonatal diabetes (Drs. Julie Stoy, Louis Philipson, Honggang Ye, Soo-Young Park and Ms. Veronica Paz). Our studies of type 2 diabetes, a polygenic form of diabetes, showed that genetic variation in the cysteine protease calpain-10 affected risk of this form of diabetes. Ongoing studies of the biology of calpain-10 carried out by Drs. Honggang Ye and Hiroya Sakuma suggest that it regulates, at least in part, insulin receptor levels on the plasma membrane. The pancreatic ß-cell plays a central role in the development of diabetes and we are currently developing mouse models that will allow us to study ß-cell growth and function in living animals (Drs. Chang-Zheng Wang and Soo-Young Park). One such model, the MIP-luc transgenic mouse generated by Dr. Park expresses firefly luciferase in its ß-cells thereby allowing us to use bioluminescent imaging techniques to visualize the ß-cells in living animals and to monitor changes in ß-cell mass in response to various treatments. We anticipate that the combination of human genetics with biological studies in humans and mouse models will provide a better understanding of the diverse causes of diabetes and lead to new therapies.