Home Topics Drug Discovery Insulin-Producing Beta Cells Proliferate When the Brakes Are Off

Insulin-Producing Beta Cells Proliferate When the Brakes Are Off

The top two images show the pancreas of normal mice, with a wide view at left and a zoomed-in view of the area in the box on the right, showing the insulin-producing islets in lighter purple. The bottom two images show the pancreas of a mouse that lacked two immune-system factors called TLR2 and TLR4; the zoomed-in view shows how large the islets are because of the growth of insulin-producing beta cells inside them. [Qi lab, University of Michigan]

Western-type diets that are laden with carbohydrates and fats put extra demand on the body’s pancreatic islets to produce enough insulin to control blood sugar levels. If this demand can’t be met, then diabetes can result. Research by a University of Michigan-headed team of scientists has now suggested that it may be possible to trigger increased production of insulin. Their studies in mice showed that switching off two toll-like receptors (TLRs) effectively takes the brakes of islet cell expansion in the pancreas, and allows pancreatic islets to ramp up production of insulin-producing β cells, but only in response to a high-fat diet (HFD).

The researchers say the discovery that TLR2, TLR4, and HFD play a combined role in regulating β cell production could lead to new approaches for treating diabetes and obesity. “These data reveal a regulatory mechanism controlling the proliferation of β cells in diet-induced obesity and suggest that selective targeting of the TLR2/TLR4 pathways may reverse β cell failure in patients with diabetes,” they concluded in their published paper in Nature Immunology, which is titled, “Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity.”

Eating a high-energy Western diet or high-fat diet does trigger the expansion of pancreatic islets and some, albeit modest proliferation of β cells. “In diet-induced obesity, increased metabolic burden increases production of insulin by increasing secretion per β cell and/or by increasing β cell numbers,” the authors explained. However, the molecular mechanisms that allow this to happen aren’t understood.

TLRs are a family of cell surface and intracellular proteins that normally recognize invading pathogens such as bacteria and fungi, and play a role in alerting the immune system. “TLR2 and TLR4 in immune cells have the ability to sense molecular patterns from invading pathogens and to bridge the innate and adaptive immune responses,” the researchers explained.

Interestingly, reports also have suggested that loss of either TLR2 or TLR4 in mice fed a high-fat diet reduces systemic inflammation in the liver and fat, and can improve insulin sensitivity. The latest studies, headed by the University of Michigan’s Ling Qi, PhD, professor, molecular & integrative physiology, together with University of Michigan Medical School and Cornell University colleagues, found that when mice engineered to lack both TLR2 and TLR4 were fed a high-fat diet, their pancreatic islets swelled significantly, to the point that they could be seen with the naked eye.

The researchers made the discovery on the back of experiments that were originally designed to investigate the role of the immune system, and TLR2 and TLR4, in the development of adipose tissue inflammation in obese mice. The team’s subsequent studies in the TLR2- and TLR4-deficient mice found that loss of both of the proteins effectively removed a block on β cell proliferation in animals fed a high-fat diet. Encouragingly, β cell function was maintained and blood sugar controlled in the HFD-fed mice that lacked TLR2 and TLR4.

Both the proteins had to be disabled to unlock diet-related β cell proliferation. If either TLR2 or TLR4 was present the islets didn’t expand or generate additional β cells “… activation of either TLR2 or TLR4 was sufficient to suppress β cell proliferation in mice,” the scientists wrote. Further experiments ruled out a potential role for any factors circulating in the blood in allowing islet expansion, and suggested that “TLR2 and TLR4 deficiency affected HFD-induced β cell replication in an islet-intrinsic manner,” they continued. Pathway analysis indicated that in parallel with chronic consumption of high-fat foods, signaling pathways mediated by TLR2 and TLR4 downregulated the activation of MEK/Erk kinases, which blocked key molecules involved in cell replication from entering the nucleus, and so prevented β cell proliferation.

“Future studies will address whether blocking TLR2 and TLR4 signaling, using small molecule antagonists, genetic editing, or bipotent TLR2/TLR4 antibodies, may enhance β cell replication, the scientists concluded. “Delineation of the immediate downstream pathways of TLR2/TLR4 in β cells may also help guide future efforts to target them as a promising strategy to expand β cells in diabetes.

Qi and his team are now working to identify the role that a high-fat diet plays in islet expansion in the context of TLR2 and TLR4. “Something associated with high-fat-induced obesity plays a key role in this process, but we don’t yet know what,” he said. Qi also suggested that the discovery that negative factors can block β cell expansion indicates that approaches to boosting β cell numbers that focus solely on amplifying positive factors may not be effective.

For TLR2/TLR4 depletion to be feasible as a therapeutic strategy, scientists will have to find a way to disable the proteins specifically in islets. This could then improve the outcome of islet transplant therapy, so the researchers aim to study the effects of gene editing in islet β cells prior to transplanting islets into mice.