2023-06-09 11:27:47
The risk of type 2 diabetes increases with age, but also with increasing obesity, too little exercise or due to a genetic predisposition. If left untreated, the metabolic disease causes problems in nerves and blood vessels, which can lead to complications in the eye or foot, among other things, and increase the risk of heart attack and stroke.
The most important molecule on the way to diabetes is insulin. People with type 2 diabetes cannot control their blood sugar levels correctly. This is either because their pancreas doesn’t produce enough insulin when blood sugar rises, or because their cells are less responsive to insulin, in which case it’s called insulin resistance.
Post-meal insulin acts on muscle and adipose tissue
“Most studies on insulin resistance have examined fasting subjects a few hours after the last meal,” says the head of the present work, Professor Claudia Langenberg, who heads the Computational Medicine working group at BIH and is director of the newly founded one at Queen Mary University in London, UK Institute for Precision Medicine. “During this time, insulin mainly affects the liver. But for most of our lives we are not sober, more or less just after a meal. And that’s where insulin acts on muscles and fat tissue.” Little is known about this of all things, and at the same time it is precisely here that the cause of insulin resistance with the subsequent type 2 diabetes is suspected.
Professor Sir Stephen O’Rahilly, co-director of the Wellcome MRC Institute for Metabolic Sciences at the University of Cambridge and also involved in the study, explains: “We know that there are people with a rare congenital disease who have insulin in their blood works perfectly normally on liver cells in the fasted state, but not after a meal when it acts on muscle and adipose tissue. What we didn’t know was whether this problem is also present in the general population and whether it is linked to the development of type 2 diabetes.”
Genetic analysis of 55,000 subjects from 28 studies
In order to get clarity here, the international team examined the genetic data from 28 studies with a total of 55,000 participants. They looked for genetic variants that affect insulin levels two hours after a sugary drink.
The scientists discovered ten regions in the genome that were associated with insulin resistance after sugar drinks. The researchers had already noticed eight of these regions in previous studies: they were associated with a higher risk of type 2 diabetes.
Glucose transporter brings blood sugar into cells
One of these regions appeared in a gene called GLUT4: This is the gene for a transport protein in the cell membrane of fat and muscle cells that transports blood sugar – glucose – into the cells. The conspicuous variant meant that GLUT4 was less active in muscle cells.
In further experiments, the scientists examined fat cells from mice. There they switched off individual genes from the ten regions found and observed the effects. “We found 14 different genes that all play a role in glucose transport,” reports Claudia Langenberg. “They influence the amount of the glucose transporter GLUT4 on the surface of the cells. The less GLUT4 there is on the cell surface, the more difficult it is for the cells to absorb glucose from the blood.”
Targeted intervention possible?
Claudia Langenberg hopes that this discovery will also lead to new ways of preventing type 2 diabetes. “Our work shows how the combination of dynamic metabolic tests in large numbers of subjects, together with genetic information, unearths findings that are important for medicine. We now have a better understanding of how post-meal blood glucose levels are regulated, and this opens up the possibility of targeting this.”
The Wellcome Trust, the Medical Research Council and the National Institute for Health and Care Research supported the research.
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