JDRF-funded scientists provided new evidence that a two-drug combination can extend the function of pancreatic islet transplants that have begun to fail and restore insulin  independence in some transplant recipients with type 1 diabetes (T1D). This research finding was presented at the American Diabetes Association’s 72nd Scientific Sessions in Philadelphia in June 2012 by Peter  Senior, M.D., Ph.D., medical director of the Clinical Islet Transplant Program at the University of Alberta, Canada.

Islet transplantation is a life- changing treatment for some individuals with T1D. In this procedure, clusters of hormone-producing cells, including insulin-producing beta  cells, are transplanted from a donor pancreas into  the liver  of an individual with T1D. When the procedure is successful, the transplanted islets engraft or embed themselves into  the recipient’s liver, produce insulin,  and restore physiological regulation of glucose to the patient. Some transplant recipients become fully insulin-independent, meaning they  are no longer reliant on insulin  injections or a pump for survival. Other recipients are able to drastically reduce their insulin  needs. However, maintaining insulin independence in the long  term is a challenge. For a variety of reasons,  transplanted islets often fail over  time,  so that recipients must resume or increase their insulin  therapy.

Dr. Senior  and his colleagues had two goals  in mind when  they  tested the combination therapy of sitagliptin and pantoprazole. They asked whether these drugs could improve how  well transplanted beta  cells release  insulin  in response to blood glucose and whether the drugs could prevent beta  cell death and stimulate the growth of new beta cells in transplant recipients.

Sitagliptin is an FDA-approved drug for the treatment of type 2 diabetes that promotes beta  cell survival and function. Pantoprazole, also FDA-approved, is used to treat gastroesophageal reflux disease, or GERD. Researchers have previously shown that a combination of sitagliptin and high  doses of a drug similar in action to pantoprazole trigger new beta cell formation in animal  models of T1D.

The study team recruited eight individuals who  had received islet transplants from two months to 12 years prior to the start of the study and were  showing signs of early  transplant failure. These subjects were  treated with 100 mg sitagliptin per day and 40 mg pantoprazole twice daily  for six months. By the end of the treatment period, five of the eight subjects had regained insulin  independence. The study participants tolerated the drugs well, and none of them experienced an increase in episodes of hypoglycemia.

While these findings are encouraging, it is important to note that only  four of the five patients maintained their insulin  independence at six months after the drug treatment period ended. Furthermore, the insulin  dosage increased after the treatment was stopped for six months in the other patients. This outcome suggests that the drug combination of sitagliptin and pantoprazole may improve metabolic control and the function of transplanted islets during the treatment, but  there is a lack of evidence for a sustained increase in functional beta  cell mass or regeneration of beta  cells in the failing islet transplant setting.

“The drugs’ effect on islet transplants is important as we continue to look  for ways to maintain long-term islet graft function,” explains Albert Hwa, Ph.D., Breakthrough T1D senior  scientific program manager of cure therapies. “In addition, without a means to directly measure functional beta  cell mass, islet transplant recipients provide a unique opportunity to test these drugs’ effect on beta  cell mass.”

This study sheds light on a key Breakthrough T1D research area—improving beta  cell survival and function in islet transplant recipients, as well  as in newly diagnosed individuals with T1D who might have some remaining beta  cells in their pancreases. Breakthrough T1D is supporting a clinical research study with a similar combination of drugs—sitagliptin and lansoprazole—with the goal  to restore beta  cell function in people with new- onset  T1D. This multicenter study, known as the REPAIR-T1D trial,  is led by Alex  Rabinovitch, M.D., of the Sanford Research  Center in Sioux Falls, ND. The trial  is in progress with 54 enrolled subjects.

Key point: Researchers at the University of Alberta have reported that  a two-drug combination, sitagliptin and pantoprazole, can restore insulin independence in some islet transplant recipients with early signs of transplant failure. The effect was not  sustained after withdrawal of the drugs;  there was lack of evidence for durable effects on beta  cell function or increased beta cell mass. Breakthrough T1D continues to support research to improve long-term islet transplant function and to promote beta  cell regeneration in all people with T1D.