Adrian Vella, M.D., studies the pathogenesis of type 2 diabetes.

Type 2 diabetes is a common metabolic disorder that arises out of a complex interaction between genes and the environment. The disease is characterized by insulin secretion that is inappropriate to the prevailing glucose concentrations, in part because of defects in insulin synthesis and in part because of defects in the ability of glucose and insulin to stimulate glucose uptake and suppress glucose production. Type 2 diabetes is preceded by an intermediate condition called prediabetes, which occurs during the transition from normal fasting glucose to diabetes. During this time, affected individuals have elevated fasting or postprandial glucose concentrations but do not fulfill the criteria for the diagnosis of diabetes.

Individuals with prediabetes are at high risk of progression to diabetes. For example, people with a fasting glucose greater than 110 milligrams per deciliter (mg/dL), or 6.1 millimoles per liter (mmol/L) — 10 mg/dL (0.6 mmol/L) above normal fasting — have a 40 percent greater risk of developing diabetes. While this is high, the converse argument is that 60 percent of such patients never develop diabetes. Dr. Vella is investigating this heterogeneity; greater understanding will provide clues to the pathogenesis of diabetes.

Focus areas

• Mechanisms of association between TCF7L2 and type 2 diabetes. TCF7L2 is a transcription factor that may modulate signaling pathways necessary for blood glucose homeostasis. It has been shown that individuals with the diabetes-associated variants of this gene secrete less insulin during oral glucose tolerance tests. Dr. Vella's team is working to understand how variation in the TCF7L2 locus affects glucose homeostasis in humans with and without impaired fasting glucose, impaired glucose tolerance or both — and ultimately, how this gene contributes to the development of diabetes.
• Effects of GLP-1 on glucose metabolism. Glucagon-like peptide 1 (GLP-1) is an incretin hormone that powerfully stimulates insulin secretion. The hormonal pathway regulating production of GLP-1 is harnessed by various therapeutic interventions designed to improve glucose homeostasis in people with type 2 diabetes. Dr. Vella's research team is investigating the effect of GLP-1 on whole-body glucose metabolism and how common genetic variation may alter response to GLP-1.
• Effects of weight loss and bariatric surgery on glucose metabolism. Bariatric surgery is associated with remission of type 2 diabetes, providing an invaluable opportunity to understand how caloric restriction and weight loss alter glucose metabolism.

Significance to patient care

A better understanding of the processes that interact to cause the defects present in type 2 diabetes has important implications in terms of preventing and treating the disease. Understanding how genes and the environment interact to affect insulin secretion, insulin action, weight and appetite will help inform more rational treatments for type 2 diabetes.