Effects of exogenous and endogenous gastric inhibitory polypeptide in obese hyperglycaemic (ob/ob) mice

Abstract

Gastric inhibitory polypeptide, also commonly referred to as glucose-dependent insulinotropic polypeptide or GIP, is a 42 amino acid hormone synthesized and released by the Kcells of the small intestine in response to nutrients. Previous studies have shown that plasma GIP concentrations are inordinately raised in obese hyperglycaemic (oblob) mice, and that oral administration of carbohydrate, protein and especially fat evokes marked plasma GIP responses (Flatt et al., 1983a; P. R. Flatt, C. J. Bailey, P. Kwasowski, T. Page & V. Marks, unpublished work). Overfeeding, K-cell hyperplasia and insensitivity of these cells to suppression by endogenous insulin are envisaged to generate the hypergipaemia (Flatt et al., 1983a,b). Since GIP is a recognized component of the entero-insular axis (Brown, 1982), the raised concentrations in ob/ob mice suggest an important pathogenic role in the promotion of hyperinsulinaemia and related metabolic abnormalities of the ob/ob syndrome (Flatt et al., 1983~). The present study examines the insulinotropic action of exogenous and endogenous GIP in relation to the prevailing hyperglycaemia in ob/ob mice. Obese (oblob) mice from the Aston colony were supplied with a standard pellet diet and maintained as described previously (Flatt & Bailey, 1981a; Bailey et al., 1982). The mice were used at 10-12 weeks of age and starved for 18 h before experimentation. The insulin response to exogenous GIP was examined by intraperitoneal administration of porcine GIP (40pg/kg) (Professor J. C. Brown, University of British Columbia, Canada) together with either glucose (2g/kg) or an equivalent volume of saline (O.l54mmol/l NaC1). Blood samples for determination of plasma concentrations of glucose, insulin and GIP were taken from the cut tail-tips of conscious mice at 0, 5, 15, and 30min. Plasma disappearance of GIP was followed until 180min. The insulin response to endogenous GIP was examined by oral administration of fat (Intralipid, 870mg/kg) followed at 30min by an intraperitoneal injection of either glucose (2g/kg) or an equivalent volume of saline (0.154mmol/l NaCl). Blood samples for plasma glucose, insulin and GIP determination were taken at 0, 30, 60, and 90min. Insulin and GIP were measured by radioimmunoassay (Flatt et al., 1983~). Statistical evaluation was made by Student’s t-test. As shown in Fig. la, intraperitoneal administration of GIP with saline evoked a marked but transient plasma insulin response. Plasma glucose concentrations (not illustrated) were not significantly changed, being within the range 7-l0mmol/l. When GIP was administered with