Effects of the novel (Pro(3))GIP antagonist and exendin(9-39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin

AIMS/HYPOTHESIS: This study examined the biological effects of the GIP receptor antagonist, (Pro3)GIP and the GLP-1 receptor antagonist, exendin(9-39)amide.

METHODS: Cyclic AMP production was assessed in Chinese hamster lung fibroblasts transfected with human GIP or GLP-1 receptors, respectively. In vitro insulin release studies were assessed in BRIN-BD11 cells while in vivo insulinotropic and glycaemic responses were measured in obese diabetic ( ob/ ob) mice.

RESULTS: In GIP receptor-transfected fibroblasts, (Pro(3))GIP or exendin(9-39)amide inhibited GIP-stimulated cyclic AMP production with maximal inhibition of 70.0+/-3.5% and 73.5+/-3.2% at 10(-6) mol/l, respectively. In GLP-1 receptor-transfected fibroblasts, exendin(9-39)amide inhibited GLP-1-stimulated cyclic AMP production with maximal inhibition of 60+/-0.7% at 10(-6) mol/l, whereas (Pro(3))GIP had no effect. (Pro(3))GIP specifically inhibited GIP-stimulated insulin release (86%; p<0.001) from clonal BRIN-BD11 cells, but had no effect on GLP-1-stimulated insulin release. In contrast, exendin(9-39)amide inhibited both GIP and GLP-1-stimulated insulin release (57% and 44%, respectively; p<0.001). Administration of (Pro(3))GIP, exendin(9-39)amide or a combination of both peptides (25 nmol/kg body weight, i.p.) to fasted (ob/ob) mice decreased the plasma insulin responses by 42%, 54% and 49%, respectively (p<0.01 to p<0.001). The hyperinsulinaemia of non-fasted (ob/ob) mice was decreased by 19%, 27% and 18% (p<0.05 to p<0.01) by injection of (Pro3)GIP, exendin(9-39)amide or combined peptides but accompanying changes of plasma glucose were small.

CONCLUSIONS/INTERPRETATION: These data show that (Pro(3))GIP is a specific GIP receptor antagonist. Furthermore, feeding studies in one commonly used animal model of obesity and diabetes, (ob/ob) mice, suggest that GIP is the major physiological component of the enteroinsular axis, contributing approximately 80% to incretin-induced insulin release.

Mis-measure of animal contests.

Contests between rivals placing similar value on the resource at stake are commonly won by the rival having greater 'resource holding potential' (RHP). Mutual assessment of RHP difference between rivals is usually expected as an economical means of resolution; weaker rivals can retreat when they detect their relative inferiority, thereby avoiding costly, futile persistence. Models of contest resolution that entail retreat decisions based on estimates of RHP difference predict that contest duration diminishes as RHP difference between rivals increases because the asymmetry is more readily detected. This prediction appears to have been fulfilled in contests of diverse taxa, generating widespread support for assessment of RHP differences in contests. But few studies have considered alternatives in which each rival simply persists in accord with its own RHP ('own RHP-dependent persistence'). In contests decided by own RHP-dependent persistence, in which costs accrue only through each rival's own actions, weaker rivals retreat first because they are inherently less persistent, and contest duration depends primarily on the weaker (losing) rival's RHP rather than RHP difference between the rivals. We show here that the analyses most commonly used to detect effects of RHP difference cannot discriminate between these alternatives. Because RHP difference between rivals tends to be correlated with RHP of the weaker rival in a pair, a negative relation between RHP difference and contest duration may be generated even when decisions of retreat are not based on estimated RHP difference. Many studies purporting to show a negative relation between RHP difference and contest duration may actually reflect an incidental association between weaker rival RHP and RHP difference. We suggest statistical and experimental approaches that may help to discriminate between effects of weaker rival RHP and true effects of RHP difference. We also discuss whether 'true' negative effects of RHP difference on contest duration always reflect retreat decisions based on estimated RHP differences. Copyright 2003 Published by Elsevier Science Ltd on behalf of The Association for the Study of Animal Behaviour.