Type 2 diabetes mellitus: A complex interaction between genes and the environment

Diabetes mellitus (DM) is responsible for substantial morbidity and death, with costs of about $170 billion a year in the United States. Therefore, preventing DM is an important goal.

Adrian Vella, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, Minn., says: "The states of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are associated with a high rate of progression to type 2 DM. However, the risk is heterogeneous. For example, in Olmsted County, Minn., 40 percent of people with a fasting plasma glucose level of 110 mg/dL or greater progress to overt diabetes within 10 years, as opposed to 5 percent of those with a fasting plasma glucose level of less than 95 mg/dL."

Questions for Dr. Vella and his team include the following:

  • Which patients with IFG will have DM eventually?
  • Why does diabetes not develop in about 60 percent of people with IFG within 10 years?
  • Why is there heterogeneity of pancreatic beta cell function in patients with prediabetes?

Dr. Vella answers: "It is clear that diabetes arises out of a complex interaction between genes and the environment. A variant in TCF7L2 confers the strongest genetic predisposition to DM and is associated with progression to DM from the prediabetic state. However, the mechanisms by which this occurs are still unidentified.

"TCF7L2 encodes a transcription factor that regulates proglucagon expression in the gut. Hence, it was assumed that this gene predisposed to diabetes through changes in incretin hormone secretion and, perhaps, beta cell responsiveness to incretins. However, in a study examining glucagon-like peptide-1 (GLP-1), secreted in response to an oral challenge, we demonstrated that the diabetes-associated allele of TCF7L2 did not alter concentrations of active and total GLP-1.

"Moreover, in a separate cohort, insulin secretion in response to pharmacological concentrations of GLP-1 was likewise unaffected by TCF7L2. Other diabetes-associated variants in WFS1 and KCNQ1 also do not alter these parameters.

"Intriguingly, variation in GLP-1R alters response to infused GLP-1, but the clinical significance of this in predicting response to incretin-based therapy is unknown. More importantly, GLP-1 secretion does not seem to decrease as beta cell function decreases in prediabetes — implying that defects in GLP-1 secretion do not play a part in the pathogenesis of DM."

Dr. Vella continues: "In an Olmsted County cohort of persons without DM, we have observed a parallel decrease in insulin secretion and action as fasting and postprandial glucose concentrations rise. At present, we are actively exploring mechanisms, such as the timing and amplitude of insulin secretion, that might explain this coupling. Persons with diabetes-associated common genetic variation seem to be particularly affected by this coupling of insulin secretion and action."

Bariatric surgery and type 2 DM remission

Another active area of research for Dr. Vella's laboratory is the remission of type 2 DM associated with bariatric surgery for medically complicated obesity. Dr. Vella explains: "The surgery that is most commonly undertaken for this purpose is Roux-en-Y gastric bypass, with remission rates of about 80 percent for type 2 DM.

"In such circumstances, caloric restriction, incretin hypersecretion in response to increased delivery of calories to the hindgut, vagal denervation, and, perhaps, altered bile acid kinetics and secretion may all play a role in the remission of DM. Moreover, remission — or lack thereof — after such surgery again provides an opportunity to examine the heterogeneity of beta cell function present in such patients and may provide further insights into the plasticity, or otherwise, of islet function at various stages of metabolic disease."