The effect of diet composition on plasma and intestinal concentrations of immunoreactive gastric inhibitory polypeptide (GIP) and intestinal K cell density was examined in obese hyperglycaemic (ob/ob) mice. The mice were reared from 3 to 11 weeks of age on either stock diet, a high fat (HF) cafeteria diet or a high carbohydrate (HC) cafeteria diet. The HF cafeteria diet increased the concentration of GIP in plasma (75%) and in the intestine (118%) and increased the density (54%) of GIP-secreting K cells in the upper jejunum compared with the stock diet. Plasma and intestinal GIP concentrations were not significantly altered by the HC cafeteria diet, although the density of K cells in the upper jejunum was increased (45%). The extent of hyperglycaemia and hyperinsulinaemia in ob/ob mice was not significantly altered by the HF and HC cafeteria diets. The results indicate that an increased amount of dietary fat chronically stimulates the production and secretion of GIP, and enhances intestinal K cell density in ob/ob mice.Obese hyperglycaemic (ob/ob) mice exhibit a par¬ ticularly severe obesity and hyperinsulinaemia, marked hyperphagia and moderate hyperglycae¬ mia (Bray & York 1979; Bailey et al. 1982). Recent studies have identified excessive concentrations of immunoreactive gastric inhibitory polypeptide (GIP) in the small intestine and plasma of these mice (Flau et al. 1983, 1984a) associated with hyperplasia and increased hormone content of the intestinal GIP-secreting cells (Polak et al. 1975). Considerable evidence has implicated GIP as a physiological component of the enteroinsular axis (Brown 1982;Creutzfeldt et al. 1983), and hypersécrétion of GIP has been suggested as a factor contributing to the hyperinsulinaemia of ob/ob mice (Flatt et al. 1984a,b). The raised GIP concentrations of ob/ob mice render this mutant a convenient model for studies of GIP physiology. As noted in other species (Brown 1982), orally administered fat elicits a greater acute plasma GIP response than other nutrients in ob/ob mice (Flatt et al. 1984a), but the long-term effects of different dietary components on plasma and intestinal GIP remain to be established.The present study examines the chronic effects of excess fat and excess carbohydrate on the de¬ velopment of raised GIP concentrations in young ob/ob mice fed for 8 weeks on high fat and high carbohydrate cafeteria diets. Materials and Methods AnimalsObese hyperglycaemic (ob/ob) mice and lean (+/+) mice on the Aston background were housed as previ¬ ously (Flatt et al. 1984a). The origin and characteristics of these mice have been described elsewhere (Flatt & Bailey 1981;Bailey et al. 1982). DietsGroups of mice were fed either stock diet (Mouse breeding diet,
The role of GIP in the pathogenesis of spontaneous syndromes of obesity-diabetes was examined in ob/ob mice of the Aston stock and db/db mice of the C57BL/KsJ background. Compared with lean controls, fed adult ob/ob and db/db mice, respectively, exhibited 1.8-fold and 2.1-fold increases in body weight, 1.8-fold and 2.8-fold elevations of plasma glucose, and 15.4-fold and 5.6-fold elevations of plasma insulin. As indicated by the relative magnitude of the hyperglycemia and hyperinsulinemia, db/db mice displayed a particularly severe form of diabetes. Plasma GIP concentrations of ob/ob and db/db mice were elevated 15.1-fold and 6.2-fold, respectively; the increments closely corresponded with the degrees of hyperinsulinemia. Small intestinal weight was increased 1.4-fold and 1.8-fold in ob/ob and db/db mice, respectively, but the intestinal GIP content expressed as microgram/g intestine or microgram/intestine was raised only in ob/ob mice (1.9-fold and 2.8-fold, respectively). Since glucose stimulation of insulin release is defective in both mutant strains, the results strongly implicate pathologically raised GIP concentrations in the hyperinsulinemia and related metabolic abnormalities of the obesity-diabetes syndromes. It is suggested that hypersecretion of GIP results in part from loss of normal feedback inhibition by endogenous insulin.
Gastric inhibitory polypeptide (GIP), a recognized component of the enteroinsular axis, is raised in the plasma and intestine of obese hyperglycaemic (ob/ob) mice. To evaluate the control of plasma GIP and its role in the hyperinsulinaemia of the ob/ob syndrome, GIP and insulin were determined at different ages in fed mice, and at 10-12 weeks of age after fasting/refeeding and administration of GIP, different nutrients and insulin to mice fasted for 18 h. Plasma GIP and insulin were raised in adult (10- and 20-week-old) compared with younger (3- and 5-week-old) mice, although GIP was not increased in the presence of hyperinsulinaemia at 3 weeks of age. Fasting suppressed and refeeding promptly restored plasma GIP and insulin concentrations. Administration of GIP to mimic postprandial concentrations evoked a marked but transient insulin response which was protracted in the presence of rising hyperglycaemia. Orally administered fat, glucose and amino acids raised GIP concentrations with fat having a particularly strong effect. Glucose and amino acids also evoked prominent increases of insulin, but fat produced only a small rise in insulin in the absence of increasing glucose concentrations. Consistent with glucose-potentiation, a mixture of all three nutrients greatly augmented the insulin response without further increase of plasma GIP. Glucose-induced increase in endogenous insulin and doses of exogenous insulin up to 100 units/kg did not suppress basal, fat-stimulated or glucose-stimulated GIP release. The results indicate that raised GIP concentrations make an important contribution to the hyperinsulinaemia and related metabolic abnormalities of the ob/ob syndrome.
Melatonin, free and total cortisol, insulin, C-peptide and glucose-dependent insulin-releasing peptide (GIP) were measured in the plasma of twelve normal volunteers (eight women and four men), at hourly intervals for 24 h following a meal and subsequent fasting. One volunteer was excluded from calculations due to a possible effect of stress on melatonin secretion. Melatonin and cortisol showed the normal 24-h variation with peak values at 0200-0500 h, and 0900 h respectively. Following post-prandial stimulation, gut hormones remained basal throughout the sampling period. No significant relationship was found between 24-h melatonin secretion and basal, or stimulated gut hormone secretion. Melatonin secretion did relate significantly to body weight, suggesting that data concerning pineal effects in endocrine physiology and pathology, and affective disease, should be reviewed in the light of these observations.
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