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Regulation of glucose homeostasis by Dipeptidyl Peptidase IV : studies on counter-regulation and long-term inhibition as diabetes therapy Pospisilik, John Andrew

Abstract

The ubiquitous serine protease dipeptidyl peptidase IV (DP IV) plays a number of physiological roles including hormone inactivation and immune costimulation. Recent attention has been brought to the molecule because of its ability to cleave and inactivate the potent insulin secretagogues (incretins) glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Use of specific DP IV-inhibitors has been shown to protect the active form of these hormones in the circulation thus enhancing their effects at target tissues. In the following study we show first, that the counterregulatory hormone glucagon serves as a physiologically relevant substrate for DP IV. Also, using a model of obesity-related diabetes (fa/fa Zucker rat) and a combination of techniques (oral glucose tolerance testing, pancreas perfusion, immunohistochemistry, and euglycemic-hyperinsulinemic clamp), we show that long-term DP IV-inhibitor (P32/98) therapy ameliorates the type-2 diabetic syndrome through enhancement of both insulin sensitivity and P-cell function. Further, we reveal the applicability of long-term DP IV-inhibitor treatment towards type-1 diabetes. In a model of insulin insufficiency and post-traumatic islet plasticity (streptozotocin-induced diabetic rat), marked improvements in disease severity are shown, associated with enhancement of β-cell survival and islet neogenesis. An in vitro analysis of the anti-apoptotic potential of GIP and GLP-1 implicate the two hormones mechanistically in the in vivo findings. Also, in a model of the autoimmune progression of type-1 diabetes (the BioBreeding rat) we show both a delay and partial prevention of the disease as well as improved glucose homeostasis prior to disease onset, supporting our hypothesis of combined immunosuppression and incretin enhancement and establishing for the first time the potential for DP IV-inhibition in the treatment of type-1 diabetes. In addition to a review of the literature surrounding DP IV and glucose regulation, the findings of the present study are discussed in the context of glucose counterregulation, diabetes and autoimmunity. In summary, the work presented here identifies a novel regulatory mechanism for the effects of the counterregulatory hormone glucagon, demonstrates the benefits of long-term incretin enhancement as a therapy for type-2 diabetes, and establishes DP IV-inhibition as a unique therapeutic strategy in the treatment of type-1 diabetes.

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