Dr. Simon Amadeus Hinke: Research Interests and Significant Contributions

Significant contributions primarily focus on the modulation of beta cell responsiveness to the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), and potential therapeutic use of GIP in diabetes mellitus. Two major aspects of GIP physiology were clarified by my research: (i) the blunted responsiveness of the insulin-secreting beta cell to GIP in type II diabetes may result from defective regulation of the GIP receptor in terms of desensitization, internalization and down-regulation, and (ii) does the reduced GIP response in type II diabetes preclude its use as a therapeutic agent? In regards to the first point, we published two studies examining receptor desensitization and internalization (Hinke, SA, et al. Role of glucose in chronic desensitization of isolated rat islets and mouse insulinoma (betaTC-3) cells to glucose-dependent insulinotropic polypeptide. J. Endocrinol. 165:281-291, 2000 and Wheeler, MB, Gelling, RW, Hinke, SA, et al. Characterization of the carboxyl-terminal domain of the rat glucose-dependent insulinotropic polypeptide (GIP) receptor. A role for serines 426 and 427 in regulating the rate of internalization. J. Biol. Chem. 274:24593-24624, 1999.); a parallel study in our laboratory indicated that defective expression of the GIP receptor in a rodent model of type II diabetes was likely responsible for the blunted response to the hormone in this disease state. This down-regulation of the GIP receptor was shown by to be controlled by GIP itself (homologous desensitization), glucose concentration and fatty acids [Condensed / Full].

Several studies were published regarding the therapeutic application of GIP analogues in the treatment of diabetes. We designed a series of modifications to the GIP peptide in order to (a) render the hormone resistant to inactivation by the protease DPIV, which is the primary enzyme responsible for its degradation, and (b) to identify the insulinotropic domains of the molecule to facilitate synthesis of small molecular weight GIP receptor agonists. We described the design, synthesis, DPIV resistance and biological activity of many synthetic peptides (see CV for full publication list). From these studies, several candidate analogues were selected based upon their favourable attributes, and tested in vivo in normal and diabetic rodents. Our paper published in Diabetes was not only the first paper to show that synthetic GIP “super-agonists” have therapeutic potential in the treatment of type II diabetes, providing proof of concept, (and this was demonstrated in the same rodent model which exhibited a reduced response to physiological levels of GIP because of receptor down-regulation), but also was the result of systematic rational drug design (Hinke, SA, et al. Dipeptidyl peptidase IV-resistant [D-Ala2]glucose-dependent insulinotropic polypeptide (GIP) improves glucose tolerance in normal and obese diabetic rats. Diabetes 51:652-661, 2002.). Along the same lines, another study examined GIP, GLP-1, and enzyme resistant analogues, in parallel in vitro and in vivo, as GLP-1 has already been proven to be a therapeutic option to control glycemia in diabetes; this study further reinforces the need to examine GIP in humans more closely (Hinke, SA, et al. [Ser2]- and [(P)Ser2]-Incretin Analogs: Comparison of dipeptidyl peptidase IV resistance and biological activities in vitro and in vivo. J. Biol. Chem. 279: 3998-4006, 2004). The second aim, to create small molecular weight agonist was also successful, and we discovered a novel 14 amino acid bioactive domain of GIP, which could be used as a starting point for development of more potent small molecular weight agonists (Hinke, SA, et al. Identification of a bioactive domain in the amino-terminus of glucose-dependent insulinotropic polypeptide (GIP). Biochim. Biophys. Acta 1547:143-155, 2001).

In a somewhat related field, we were the first to show that DPIV also cleaves and inactivates glucagon (Hinke, SA, et al. Dipeptidyl Peptidase IV Degradation of Glucagon : Characterization of Glucagon Degradation Products and DPIV Resistant Analogs. J. Biol. Chem. 275:3827-3834, 2000). DPIV inhibitors are currently in clinical trials as a new drug class for treating type II diabetes, acting to increase bioactive GIP and GLP-1. Our finding that DPIV also degrades glucagon indicates that drug action during the fasted state may result in undesireable side effects.

Current research is directed at elucidating nutrient regulation of beta cell function, with particular focus on nutrient deprivation versus loss of nutrient sensing.