Fat added to diabetes risk
A new study by Australian researchers challenges conventional wisdom about the causes of diabetes.
The new research points to fat tissue as a source of disease, and widens understanding beyond the traditional focus on liver and pancreas as the main culprits.
The study was centred around the surprising finding that protein kinase C epsilon (PKCe), known to be involved in diabetes, is not acting in the liver or the pancreas as was once assumed.
Researchers have long known that PKCe is important for the development of diabetes.
Mice that have no PKCe produced anywhere in the body do not develop diabetes-like symptoms – even under conditions where other mice become diabetic.
“We have known for some time that if you remove PKCe entirely from mice and feed them a high-fat diet they do not become glucose intolerant. In fact, they are protected from becoming diabetes-like,” says Associate Professor Carsten Schmitz-Peiffer from the Garvan Institute of Medical Research, who led the research.
Diabetes researchers use a high-fat diet (HFD) to induce type 2 diabetes in mice. Following a HFD, most mice become ‘glucose intolerant’ – they are unable to control their blood sugar after eating.
In particular, the liver becomes ‘insulin resistant’ - it no longer responds to the pancreatic hormone insulin.
“The big surprise was that when we removed PKCe production specifically in the liver – the mice were not protected. For over a decade, it’s been assumed that PKCe is acting directly in the liver – by that logic, these mice should have been protected against diabetes,” said Dr Schmitz-Peiffer.
“We were so surprised by this, that we thought we had developed our mice incorrectly. We confirmed the removal and tested it in several different ways, but they still became glucose intolerant when given a HFD.”
The hunt was on to determine where PKCe was working to progress glucose intolerance.
“What we found,” explains Dr Schmitz-Peiffer, “is that if we removed PKCe production solely from fat tissue, the mice were protected from becoming glucose intolerant, similar to when we removed PKCe from the entire animal. So PKCe isn’t progressing diabetes from the liver, but in fact, it is acting from fat tissue to worsen the disease.”
PKCe has been known to be expressed in multiple tissues, but Dr Schmitz-Peiffer’s findings now point to a new function in fat tissue.
“Under the microscope, the fat cells looked very different,” he said.
“In HFD-fed mice with PKCe removed from the fat tissue, we saw mostly small, healthy fat cells. And in HFD-fed mice with PKCe intact - which are glucose intolerant - we saw more of the unhealthy, engorged fat cells, that tend to have less access to oxygen and become inflamed.”
For Dr Schmitz-Peiffer, it is clear this could have wide-ranging and complex implications for diabetes.
“We know that fat tissue is a lot more than just an inert mass for storing fat,” he explains, “it’s a very dynamic organ, it sends many messages and releases factors that communicate with the rest of the body, including the liver.”
“If PKCe is changing the nature of fat and affecting the overall health of fat cells, it’s changing the types of messages it sends and factors it releases – which could be acting on the liver and possibly other organs to interfere with glucose metabolism.”
The team is now working on an orally available peptide that can disrupt PKCe activity.