A large international consortium comprising over 100 research centers has taken a significant step toward a better understanding of the complex biological links between genes and type 2 diabetes in two new studies: one that found ten novel genetic markers for diabetes-related biological traits and another that found three new variants linked to raised levels of glucose seen in type 2 diabetes.

As well as giving new insights into the complex biology behind type 2 diabetes, the researchers said the findings reveal five new associations that directly influence the risk of diabetes, and they hope they will also drive forward research to better understand the biology of the disease and develop new treatments.

The two studies, which were funded by the Wellcome Trust, the UK’s Medical Research Council and other funders including Diabetes UK, are published in the 17 January advance online issue of Nature Genetics. The research was done by the Meta-Analyses of Glucose and Insulin-related Traits Consortium (MAGIC), whose members comprise over 100 institutions in many different countries, including the UK, US, France, Switzerland, Denmark, Germany, Finland, Greece, Spain, Sweden, Iceland, Italy, Croatia, The Netherlands, and Australia.

In the first study the researchers found 10 new genetic markers for biological traits that characterize type 2 diabetes. In the second study, they identified three new variants that are linked to raised levels of glucose seeen in a common test for type 2 diabetes.

The need for this kind of collaboration has never been so important: type 2 diabetes, which accounts for 95 per cent of cases of diabetes, is on the rise worldwide. The World Health Organization (WHO) estimates that between 170 and 285 million people worldwide have diabetes, and without urgent action, deaths caused by the disease are likely to double in the next decade.

Type 2 diabetes occurs when the body becomes resistant to the effects of insulin, the enzyme that stops glucose accumulating to dangerous levels in the blood, and when the insulin-producing beta cells in the pancreas stop working properly. The disease is strongly linked to obesity, a history of diabetes, impaired glucose metabolism and population of origin.

Type 1 diabetes is an autoimmune disease where the body’s own defences attack the insulin-producing beta cells in the pancreas.

A person is defined as having diabetes when they have raised levels of glucose in their blood either when fasting or 2 hours after an “oral glucose challenge” (a glucose “meal”).

For the studies, the researchers analysed huge sets of genetic data from more than 100,000 people of European descent and examined several commonly used measures of diabetes, including levels of fasting glucose and insulin and blood sugar levels two hours after an oral sugar challenge.

By scanning data from population studies of people without diabetes, they looked for links between glucose leves and SNPs, single letter changes in the genome that can act as genetic markers for particular traits or diseases.

They found 9 new genetic regions linked to fasting glucose, 16 linked to insulin production, but only one region linked to insulin resistance.

Co-author Dr Inês Barroso, from the Metabolic Disease Group at the Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK, told the media that they were very pleased to find so many SNPs linked with raised glucose, but were particularly “amazed that we found only one strong association with levels of insulin”.

“We don’t think this is a technical difference, but that the genetics is telling us that the two measures, insulin and glucose, have different architectures, with fewer genes, rarer variants or greater environmental influence affecting insulin resistance,” she explained.

The researchers suspect there are more genetic factors waiting to be discovered: their investigations so far explain about 10 per cent of the genetic effect on fasting glucose, and they think it will take another type of study to find rarer variants with a larger impact.

For these studies the researchers used genome-wide approaches and found many diabetes risk loci that had not been found before in case control studies that compared healthy people and people with diabetes.

Such genome-wide studies of healthy populations as these two are considered important complements to those that look for variants that affect risk: they show that you can find genetic determinants in large groups of unaffected people rather than just looking at small pools of patients with diabetes.

While these studies uncovered new information about genetic links, they also shed light on the biological pathways that lead to diabetes.

Co-author Professor Mark McCarthy of the Oxford Centre for Diabetes, Endocrinology and Metabolism at Oxford University, UK, said:

“Our knowledge of type 2 diabetes is slowly being added to with these genetic studies as we are beginning to unravel the complex pathways that lead to the common endpoint of disease.”

In the second study, where they analyzed the glucose challenge, the researchers found three new genetic associations, including one with a gene called GIPR-A, which makes a protein that, when we start eating, stimulates the release of insulin to control glucose.

The researchers said that GIPR is part of a key decision point in the metabolism of glucose. The variant they found is linked to an impaired response to the glucose “meal” and elevated levels of glucose.

Professor Nick Wareham of the MRC Epidemiology Unit at the University of Cambridge Institute of Metabolic Science told the media that diseases like type 2 diabetes have so many common traits that finding solid connections to the genetic regions underlying the physical features of the disease is not easy and it is only with the scale of collaborative effort and funding such as went into these studies that we can tackle the vast amounts of data involved.

“New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.”
Josée Dupuis, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Nicole Soranzo, Anne U Jackson, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Anna L Gloyn, et al.
Nature Genetics (Advance online publication 17 January 2010)

“Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.”
Richa Saxena, Marie-France Hivert, Claudia Langenberg, Toshiko Tanaka, James S Pankow, Peter Vollenweider, Valeriya Lyssenko, Nabila Bouatia -Naji, Josée Dupuis, Anne U Jackson, et al.
Nature Genetics (Advance online publication 17 January 2010)

Source: Wellcome Trust Sanger Institute.

Written by: Catharine Paddock, PhD