1 GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE (GIP): DEVELOPMENT OF DPIV-RESISTANT ANALOGUES WITH THERAPEUTIC POTENTIAL SIMON A. HINKE a , FRANCIS LYNN a , JAN EHSES a , NATHALIE PAMIR a , SUSANNE MANHART b , KERSTIN KÜHN-WACHE b , FRED ROSCHE b , HANS-ULRICH DEMUTH b , RAYMOND A. PEDERSON a and CHRISTOPHER H.S. MCINTOSH a a Department of Physiology, University of British Columbia, Vancouver, Canada, b Probiodrug Research, Biocenter, Halle (Saale), Germany 1. INTRODUCTION Glucose-dependent Insulinotropic Polypeptide (GIP 1-42 ; Figure 1) is a gastrointestinal hormone that is released in response to nutrient intake and stimulates insulin secretion in a glucose-dependent manner 1,2 and was the first established hormonal component (incretin) of the enteroinsular axis identified. Subsequently, intestinal products of the proglucagon gene, GLP-1 7-36 and GIP- 1 7-37 (GLP-1), were also shown to share the ability of stimulating insulin secretion and the dual actions of GIP and GLP-1 are widely considered to be the major hormonal contributors to intestinal regulation of pancreatic endocrine function. There are two major defects in type 2 diabetes that contribute to the hyperglycemia that is characteristic of the disorder: defective responsiveness to glucose and insulin resistance. Current therapies for type 2 diabetics generally involve dietary control plus stimulants of insulin secretion (e.g. sulfonylureas) and/or insulin sensitizers (e.g. metformin, thiazolidinediones). However considerable numbers of patients become resistant to sulfonylurea action and many eventually become insulin-dependent. As a consequence, there is increasing interest in developing alternative methods for stimulating endogenous insulin secretion. Among these, there has been a major emphasis