Abstract
Aims/HypothesisPancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes.MethodsIn this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass.ResultsPioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.Conclusions/InterpretationThese data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.
Highlights
It is appreciated that insulin-secreting pancreatic beta-cells have a finite life span and that dying beta-cells are continuously replaced throughout life [1,2,3,4,5,6]
Islet Beta-cell Regeneration: Effect of Pioglitazone We first investigated the effect of Pio in a previously reported model of functional beta-cell regeneration in the native pancreas following STZ-induced diabetes [17]
To define the combined effects of sub-optimal islet mass, immunosuppression, Pio and alogliptin, we developed a model of syngeneic islet transplantation where only 50–75 MIP-luc islets were transplanted under the kidney capsule of syngeneic albino C57BL/6 mice that had been pre-treated with STZ to induce diabetes (Fig. 5a)
Summary
It is appreciated that insulin-secreting pancreatic beta-cells have a finite life span and that dying beta-cells are continuously replaced throughout life [1,2,3,4,5,6]. Insulin-secreting pancreatic beta-cells can further proliferate in response to increasing demand for insulin and after physiological injury [2,7,8,9,10,11,12,13]. These observations raise the possibility of enhancing the base-line replication of beta-cells as a therapeutic approach for the treatment of patients with type 1 or type 2 diabetes. A better understanding of the molecular mechanisms that promote betacell proliferation and/or regeneration and the identification of beta-cell replication-based therapies is necessary for beta-cell regeneration to become a clinical reality
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