Researchers identify new gene variants associated With glucose, insulin levels

Study findings provide additional information on glucose regulation, potential therapeutic targets

A major international study with leadership from Massachusetts General Hospital (MGH) researchers has identified 10 new gene variants associated with blood sugar or insulin levels. Two of these novel variants and three that earlier studies associated with glucose levels were also found to increase the risk of type 2 diabetes. Along with a related study from members of the same research consortium, associating additional genetic variants with the metabolic response to a sugary meal, the report will appear in Nature Genetics and has been released online.

"Only four gene variants had previously been associated with glucose metabolism, and just one of them was known to affect type 2 diabetes. With more genes identified, we can see patterns emerge," says Jose Florez, MD, PhD, of the MGH Diabetes Unit and the Center for Human Genetic Research, co-lead author of the report. "Finding these new pathways can help us better undertand how glucose is regulated, distinguish between normal and pathological glucose variations and develop potential new therapies for type 2 diabetes."

Both studies were conducted by the Meta-Analyses of Glucose and Insulin-related Traits Consortium (MAGIC), a collaboration among researchers from centers in the U.S., Canada, Europe and Australia that analyzed gene samples from 54 previous studies involving more than 122,000 individuals of European descent. The study co-led by MGH scientists - along with colleagues from Boston University, University of Cambridge, University of Oxford and the University of Michigan - began by analyzing about 2.5 million gene variations (called SNPs) from 21 genome-wide searches for variants associated with glucose and insulin regulation in more than 46,000 nondiabetic participants. The 25 most promising SNPs from the first phase were then tested in more than 76,000 nondiabetic participants in 33 other studies, leading to new associations of nine SNPs with fasting glucose levels and one with fasting insulin and with a measure of insulin resistance.

Analysis of genetic data from additional studies involving both diabetic and nondiabetic participants found that five glucose-level-associated variants - two of those newly identified and three discovered in previous studies - were also shown to raise type 2 diabetes risk. Most of the diabetes-associated variants appear to act through their impact on insulin secretion by the pancreatic beta cells and not by insulin resistance, which suggests, the authors note, that environmental factors such as diet, lifestyle and obesity may play a larger role in insulin resistance than in insulin secretion.

"The fact that not all genes involved with raising glucose levels increase diabetes risk tells us that it's not the mere fact of raising glucose that's important but rather how glucose is raised. It's one thing to increase glucose slightly within the normal range and quite another to affect a pathway that eventually leads to progressive glucose elevation, beta-cell failure or insulin resistance - in other words type 2 diabetes, " says Florez, who is an assistant professor of Medicine at Harvard Medical School. "We've still only identified about 10 percent of the genetic contribution to glucose levels in nondiabetic individuals, so we need to investigate the impact of other, possibly more complex or rare forms of gene variation, along with the role of gene-environment interactions, in causing type 2 diabetes. Performing similar studies in non-European populations will also be essential."

In-s Barroso, PhD, of the Wellcome Trust Sanger Institute, Cambridge, England, is the co-lead author of the Nature Genetics report; and additional corresponding authors are Mark McCarthy, MD, University of Oxford, and Michael Boehnke, PhD, University of Michigan. Equally contributing first authors are Jos-e Dupuis, PhD, Boston University; Claudia Langenberg, PhD, University of Cambridge; Inga Prokopenko, PhD, University of Oxford; Richa Saxena, PhD, MGH; and Nicole Soranzo, PhD, Wellcome Trust Sanger Institute. The current study and many of the earlier studies were largely supported by grants from the National Institutes of Health.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.