Reducing Inflammation Plays Key Role In Type 1 Diabetes Therapy

The findings, which appear in the Online Early Edition of the Proceedings of the National Academy of Sciences (PNAS) this week, offer a possible new prototype for therapies to restore normal blood glucose levels in diabetes patients and suggest a previously unrecognized role for inflammation in the disease.

"Type 1 diabetes is known to develop as a consequence of autoimmune destruction of insulin-producing pancreatic beta cells," explains senior author Terry Strom, MD, Director of the Transplantation Research Center at BIDMC and Professor of Medicine at Harvard Medical School. "But in addition to the long-recognized role of T-cell-dependent immune-system-mediated islet destruction, this work reveals for the first time that a form of inflammation in fat and muscle [is also acting to] prevent insulin from disposing blood glucose into tissues that require glucose."

Formerly known as juvenile-onset or insulin-dependent diabetes, Type 1 diabetes develops when the body's immune cells attack and destroy its own pancreatic beta cells. Without beta cells, the body is unable to produce insulin, a hormone needed to convert glucose into energy. To prevent the development of serious complications, more than 21 million individuals with Type 1 diabetes -- primarily children and young adults -- must receive as many as three injections of insulin each day.

Previous attempts to treat existing Type 1 diabetes were primarily focused on restoring immune tolerance, which in healthy individuals is achieved when immune system cells "turn off" so as not to overreact and attack one's own cells. In individuals with Type 1 diabetes, the process of immune tolerance fails to work properly, thereby permitting the self-destruction of the body's beta cells.

But lead author Maria Koulmanda, MSc, PhD, director of Non-Human Primate Research in BIDMC's Transplantation Research Center, wondered if there might also be a role for inflammation in the disease process.

"We knew that in cases of type 2 [non-insulin dependent] diabetes, a form of inflammation in muscle and fat prevents insulin from triggering the transfer of glucose from the blood into important insulin-sensitive tissues," explains Koulmanda, who is also Assistant Professor of Surgery at HMS. "We thought that in addition to autoimmune destruction of insulin-producing cells, there might also be inflammation-induced insulin resistance [in type 1 diabetes.]"

To test this hypothesis, the authors administered a "cocktail" of three separate agents (rapamycin plus agonist IL-2- and antagonist-type, mutant IL-15-related Ig fusion proteins) in a NOD (non-obese diabetes) mouse model of type 1 diabetes. The therapy regimen, which included two novel immunoglobulin-fusion proteins, was aimed at both increasing tolerance and decreasing inflammation.

As predicted, following two to four weeks of treatment, the mice that had received the triple therapy maintained normal levels of blood sugar. In contrast, the control group of diabetic mice did not survive, despite receiving insulin.

The authors then conducted a molecular analysis which confirmed that the treatment had eliminated insulin resistance and relieved inflammation in the animals' fat and muscle tissues.

"Although the treatment halted the progressive loss of insulin producing cells, the restoration of normal blood glucose levels actually was the result of inflammation being ablated in fat and muscle cells," explains Strom. "By blocking the inflammation, we were able to restore the animals' abilities to respond to insulin."

"Our findings are very promising," adds Koulmanda. "Type 1 diabetes is a serious disease requiring that children and young adults take insulin two to three times a day."

And, she adds, despite this arduous therapy, insulin treatment does not prevent the occurrence of serious late-arising complications, including kidney failure, blindness and widespread cardiovascular disease.

"In clinical practice, it is not currently possible to identify when and if an individual will develop type 1 diabetes," says Koulmanda. "Therefore, it is urgent to identify treatments that can restore normal blood glucose levels in patients with new-onset diabetes before insulin-producing cells are totally destroyed. We hope that our findings offer new hope in the long search for a cure of type 1 diabetes."

This study was funded by grants from the Juvenile Diabetes Research Foundation and the National Institutes of Health.

In addition to Koulmanda and Strom, coauthors include BIDMC investigators Prabhakar Putheti, PhD, Nicolas Degauque, MD, Zhigang Fan, MD, Hang Shi, PhD, Xin Xiao Zheng, MD, and Jeffrey Flier, MD; Ejona Budo MSc, Andi Qipo, MD, and Hugh Auchincloss, Jr., MD, of Massachusetts General Hospital; and Susan Bonner-Weir, PhD of Joslin Diabetes Center.