Discovering Genes for Diabetes and Obesity

While knowing a person's genetic risk for diabetes is not significantly more predictive than a lifestyle assessment (family history, age, BMI, etc.) in determining whether a patient will develop diabetes, identifying genes contributing to the inherited risks for diabetes affords a greater understanding of the disease's pathophysiology. Learning about the underlying mechanisms of diabetes could one day lead to additional therapies and a cure.

International consortiums such as Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) provide the large groups of subjects necessary for genetic epidemiology studies. The CHARGE diabetes working group has searched for rare mutations altering the proteins coded by genes that affect diabetes, glucose, insulin, obesity and other related traits.

Mark Goodarzi, MD, PhD, director of the Division of Endocrinology, Diabetes and Metabolism and director of Endocrine Genetics Laboratory, is a member of CHARGE and collaborates with the Diabetes and Obesity Research Institute. He is the co-convener of the Type 2 Diabetes Working Group of CHARGE.

Unlike rare genetic diseases that are caused by a single gene mutation, diabetes has many gene contributors whereby each variant has a small effect. Genome mapping has allowed genetic researchers to discover greater numbers of genes affecting common traits or conditions such as diabetes. Genetic studies have elucidated zinc transporters in beta cells that could be a target for treating diabetes. Goodarzi's research also has reported that insulin clearance is more determined by genetics than is insulin resistance or insulin secretion. The insulin clearance genes may impact the risk of diabetes.

The CHARGE Type 2 Diabetes-Glycemia Working Group international study focusing on genotyping exomes to identify protein-altering genetic variants that affect fasting glucose and insulin levels.

• Assembled data from more than 60,000 individuals from more than 20 cohorts.
• Meta-analysis combining data from all participating cohorts identified a naturally occurring mutation, an alanine (Ala) to threonine (Thr) change at amino acid position 316, in the glucagon-like peptide-1 receptor (GLP-1R) that regulates fasting glucose, with the Thr allele associated with reduced glucose levels.
• Additional analyses, in over 16,000 cases of Type 2 diabetes and 81,000 controls, found that the Thr allele lowers the risk of Type 2 diabetes by 14 percent.
• In a subset of subjects who had undergone oral glucose tolerance testing, the Thr allele was found to be associated with increased two-hour glucose and decreased acute insulin secretion.
• The hypothesis that the Thr allele may result in glucagon-like peptide-1 (GLP-1) receptors with increased basal activity but reduced response to GLP-1 may explain the observed associations.
• In silico models of receptors with the Thr allele documented a significant effect on the conformation of the receptor within the cell membrane, supporting that it may impact GLP-1R function.

GLP-1R is the target of anti-diabetic agents such as exenatide and liraglutide (analogs of the incretin GLP-1, an insulin secretion–stimulating hormone that is released by the gut into the circulation upon food intake). The association of variation in GLP-1R with fasting glucose and Type 2 diabetes represents the third instance wherein genetic epidemiology identified a gene that codes for a direct drug target in Type 2 diabetes, the other examples being KCNJ11 (codes for the target of sulfonylureas) and PPARG (codes for the target of thiazolidinediones). In these examples, the drug preceded the genetic discovery. Today, there are over 130 loci for Type 2 diabetes, fasting glucose and fasting insulin. Given that three of these loci code for targets of potent anti-hyperglycemic agents, these genetic discoveries represent an extremely promising source of potential targets for future diabetes therapies.

This work, recently published in Nature Communications, sheds important light on the genetic role of the incretin system in the inheritance of Type 2 diabetes.