My research focuses on the modes of action of gastrointestinal hormones involved in the regulation of insulin secretion and fat metabolism, and the pathophysiological consequences of altered function in obesity and non-insulin dependent diabetes mellitus (NIDDM). This consists of the following areas of study:
A. The GIP receptor and its signal transduction mechanisms
GIP (gastric inhibitory polypeptide, glucose-dependent insulinotropic polypeptide) is synthesized in the intestine and has two well characterized biological actions: inhibition of acid secretion (enterogastrone action) and the stimulation of insulin release (incretin effect) (1). We have cloned the pancreatic GIP receptor (2-3), and are studying the specific domains involved in ligand binding and signal-transduction using receptor chimeras (4) and point-mutated and truncated forms (5) of the receptor produced by site-directed mutagenesis. The possibility that there are different receptor subtypes in other tissues, which are involved in different actions, is also being investigated. We have recently identified a novel new pathway by which GIP acts on the pancreatic insulin-secreting beta cell that may be involved in the regulation of islet cell differentiation and mitogenesis.
B. Changes in responsiveness to incretins in obesity and non-insulin dependent diabetes mellitus
Insulin secretion is altered in human obesity and NIDDM. Animal models of these conditions are being studied to determine the origin of altered responsiveness to GIP in these animals (7). We have recently shown that the expression of the GIP receptor in a Vancouver strain of the obese Zucker rat has greatly reduced expression of the GIP receptor and reduced signal-transduction (8). Such studies should provide clues as to the origins of the reduced sensitivity to incretins in the human disorders.
C. The metabolism of incretins in normal and disease states
There is currently great interest in using incretins in the treatment of NIDDM in humans. We are defining the biologically active region of the GIP molecule (12-14) and attempting to develop long acting analogs. In addition, the alternative strategy of inhibiting DP IV, and thus increasing endogenous incretins, is being studied. In the studies with Probiodrug, Germany, one of these inhibitors has been shown to dramatically improve glucose tolerance in diabetic rats (14, 15), and is currently undergoing clinical trials.