Insulin resistance is considered one of the earliest features of many metabolic diseases like Type 2 diabetes, and major efforts are aimed at improving insulin function to combat this problem. An Australian research team provides evidence that elevated insulin levels caused by insulin resistance may play a large role in illness by shutting off a natural cellular garbage disposal system. Their finding begs a re-evaluation of treatment strategies.
On the road to pre-diabetes and ultimately diabetes, people first become unable to use insulin to metabolise carbohydrates. This ‘insulin resistance’, as it is known, leads to ever-increasing amounts of insulin being produced by the body in an effort to control sugar levels in the blood.
Unfortunately, this comes at a cost, because insulin controls many functions in the body other than carbohydrate metabolism. Until recently, it was assumed that all functions of insulin would be defective in the insulin resistant state, but a growing body of new evidence, including this latest study from Sydney’s Garvan Institute of Medical Research, suggests it is not the case.
It becomes increasingly clear, and therefore worrying, that some insulin-dependent functions are not defective in pre-diabetes, and so are over-stimulated when insulin is overproduced in the body. This is likely to explain some of the other diseases associated with insulin resistance and Type 2 diabetes.
Garvan’s Dr Katherine Tonks, Associate Professor Jerry Greenfield, Professor Donald Chisholm AO and Professor David James led a study that examined insulin action in 4 groups of people – a lean and healthy control group, an obese yet ‘insulin sensitive’ (ie metabolically healthy) group, an obese ‘insulin resistant’ group, and a group with Type 2 diabetes.
The study examined the various molecules, or proteins, that are altered in a cell as a result of exposure to insulin. One such insulin-regulated protein is FOXO, increased activity of which is associated with a profound increase in life span in a range of animals, and likely people. FOXO acts by regulating the levels of other cellular proteins that are responsible for cleaning up cellular garbage. Defects in this process are associated with many diseases including diabetes.
In contrast to their expectation, the Garvan group found that insulin regulation of FOXO was completely normal in muscle from the pre-diabetes and diabetes individuals (hence not insulin resistant), a cause for concern because insulin inhibits the activity of the FOXO protein. In healthy individuals, insulin levels are only elevated for a short time each day, leaving FOXO active to clear garbage from the cell the rest of the time.
In prediabetes, insulin levels are chronically elevated, leaving FOXO chronically inactive, and so unable to switch on garbage disposal pathways.
Given the protective nature of FOXO when it is allowed to function, its dysregulation over many years would create a great deal of damage, ultimately reducing life of the cell.
These results are published in Diabetologia, now online.
“We are now using the term ‘selective insulin resistance’ to describe the variability of the body’s response to insulin,” said Dr Katherine Tonks, who undertook the study as part of her PhD.
Professor David James, head of diabetes and obesity research at Garvan, believes the FOXO finding points to a new way of thinking about diabetes, and potentially other diseases associated with obesity that may have something to do with junk accumulating in cells.
“In the pre-diabetic state, we predict that this junk disposal unit is completely blocked,” he said. “If we could find a way of keeping FOXO switched on in the appropriate organs, we might be able to keep the system healthy.”