Samuel E. Crockett

Stimulation of Secretion of Gastric Inhibitory Polypeptide and Insulin by Intraduodenal Amino Acid Perfusion

The effect of intraduodenal or intravenous administration of a 30-gm mixed amino acid solution of serum gastric inhibitory polypeptide (GIP), alpha-amino nitrogen (AAN), glucose, and insulin concentrations was studied in 10 normal subjects. Initially, an intraduodenal amino acid perfusion (15 ml per min X 60 min) was performed in each subject and was followed in 1 to 2 weeks by an intravenous infusion. Peak AAN concentrations occurred at 60 min after both routes of administration, but were greater with intravenous infusion, 145 +/- 5.7 mug per ml vs. 89 +/- 4.4 mug per ml (P less than 0.001). Although serum AAN levels were significantly lower after intraduodenal administration, incremental insulin concentrations were greater after intraduodenal perfusion, 77.3 +/- 8.8 muM per ml vs. 43.1 +/- 5.6 muU per ml (P less than 0.005). Total integrated insulin secretion was also greater after intraduodenal amino acids, 5000 vs. 2400 muU-min ml-1 (P less than 0.005). With intravenous amino acid infusion, serum GIP concentrations remained below the assay detection limit. After intraduodenal perfusion, a mean maximum GIP increment of 468 pg per ml occurred at 15 min. In all subjects peak GIP concentrations occurred at 15 min and preceded the maximum insulin rise by 15 to 30 min. Total integrated GIP secretion was significantly greater after intraduodenal amino acid perfusion, 13,000 pg-min ml-1 vs. no measurable response with intravenous infusion. In separate studies performed in 12 subjects, no significant changes in serum GIP concentrations occurred after intraduodenal perfusion of 0.45% saline, 0.9% saline, or 10% mannitol. The results of this study demonstrate that intraduodenal amino acid administration stimulates the secretion of GIP and suggest that endogenously released GIP may be important in the enteric mediated release of insulin.

Gastric inhibitory polypeptide (GIP) in maturity-onset diabetes mellitus.

Serum GIP, insulin, and glucose concentrations were determined during a standard oral glucose tolerance test in 80 individuals, 45 of whom were normal and 35 of whom had adult-onset diabetes mellitus according to USPHS criteria. As a group, the diabetics had fasting hyperglycemia (219 ± 17 mg./dl.) and, in response to glucose, displayed a peak serum glucose of 373 ± 23 mg./dl. and sustained hyperglycemia (315 ± 24 mg./dl.) at 180 minutes. There were no statistically significant differences in absolute serum insulin levels between the two groups. However, insulin secretion was delayed, IRI increments were smaller, and the IRI concentrations were inappropriately low for the simultaneous serum glucose concentrations in the diabetics at every time interval tested. Mean fasting serum GIP was 335 ± 30 pg./ml. in the diabetics as against 262 ± 15 pg./ml. in normal individuals (p < 0.025). After the ingestion of glucose, diabetics had significantly higher (p < 0.001) mean serum GIP levels between five and 120 minutes. By 180 minutes, serum GIP levels remained above fasting in both groups, but the diabetics had higher than normal serum concentrations (p < 0.05). Peak serum GIP concentrations, which occurred at 30 minutes in both groups, were 1,376 ± 106 and 806 ± 75 pg./ml. in the diabetics and normals, respectively (p < 0.001). Total integrated serum GIP was also greater in diabetics than normals (140,852 ± 14,208 vs. 64,602 ± 8,719 pg.-min./ml.−1, p < 0.001). The higher serum GIP concentrations observed following glucose ingestion in diabetics could not be attributed to obesity or age. We conclude that both fasting and glucose-stimulated GIP concentrations are higher than normal in obese adult-onset diabetics. The significance of this observation is uncertain. However, since our current understanding suggests the GIP may be an important enteric signal for the release of insulin in man, and because GIP has been shown to stimulate the release of immunoreactive glucagon, GIP may play a role in the pathogenesis of diabetes mellitus.

Insulin-induced attenuation of glucose-stimulated gastric inhibitory polypeptide secretion

Administration of exogenous insulin before and after intraduodenal glucose results in blunting of the GIP response to glucose. Physiologic levels of serum insulin were attained. Therefore, the present study suggests the existence of negative feedback regulation of GIP release by endogenous insulin (pancreatico-GIP axis).

The effect of increasing doses of ingested glucose on insulin and gastric inhibitory polypeptide (GIP) concentrations in man.

Gastric inhibitory polypeptide (GIP) is insulinotropic in vivo and in vitro. It is released following glucose ingestion and is a leading candidate as a mediator of the enteroinsular axis. To investigate the GIP response to increasing amounts of oral glucose, and its relationship to glucose levels and insulin secretion, fourteen normal volunteers ingested 25, 50 and 75 g of glucose at random with 5–7 days between each test. Serum insulin, glucose and GIP concentrations were measured and total integrated incremental responses were determined. Peak mean responses to glucose, insulin and GIP occurred at 30 min following each glucose ingestion. There were no significant differences in glucose concentrations at any interval with the varying glucose doses. Mean peripheral insulin concentrations were significantly increased ater 50 or 75 g of glucose as compared with the 25 g dose (P<0.02). Mean GIP concentrations were significantly greater (P<0.03) between 15 and 180 min with both the 50 and 75 g glucose stimulus. Total integrated areas under the response curves for glucose, insulin and GIP showed a graded increase in circulating insulin and GIP (P<0.01) as the amount of ingested glucose was increased from 25 to 75 g. These findings show that increasing doses of glucose stimulated greater levels of GIP and insulin and further support the insulinotropic properties of endogenous GIP in man.

Lack of cardiac inotropic effect of tolbutamide in intact man

Abstract Tolbutamide has been reported to have a positive inotropic effect in animal and human hearts in in vitro experiments, but its cardiac effects in humans are not well known. The effects of acute tolbutamide administration in man were investigated by sensitive measurements of systolic time intervals. No positive inotropic effect was observed in 11 diabetic subjects treated for 7 days with 1.5 g of tolbutamide orally. The intravenous administration of 1 g of tolbutamide in four nondiabetic subjects likewise showed no significant inotropic effect in intact man.

Cholecystokinin and gastric inhibitory polypeptide not glucagonotropic in dogs

Abstract The role of cholecystokinin (CCK) and gastric inhibitory polypeptide (GIP) as stimulators of glucagon secretion under physiologic conditions is uncertain. Previous studies have utilized CCK preparations now known to have been contaminated with GIP and possibly other gastrointestinal peptides. The present study was designed to determine if physiologic doses of highly purified (99%) CCK and GIP stimulate pancreatic glucagon release in the dog. Six adult, conscious, conditioned dogs weighing 20 to 25 kg each, were given intravenous infusions of CCK or GIP after an overnight fast. Peripheral blood, collected at time zero and thereafter at 15-min intervals for 120 min, was assayed for radioimmunoreactive GIP and glucagon (30K antisera). During the infusion of 200 and 400 ng/kg/hr of GIP, peak mean GIP concentrations of 678 ± 103 (SEM) and 1404 ± 171 pg/ml, respectively, were reached by 60 min. A 200 ng/kg intravenous bolus of GIP resulted in a peak mean serum GIP concentration of 2150 ± 275 pg/ml at 15 min. Peripheral mean basal glucagon concentrations of 48 ± 9 pg/ml did not change significantly during the GIP infusion or following the bolus infusion of GIP. CCK infused at 500 ng/kg/hr, a dose assumed to produce physiologic serum CCK concentrations, did not significantly change the mean basal glucagon level of 41 ± 1 pg/ml during the 120-min study period. We conclude that under the conditions of this study, neither CCK nor GIP are glucagonotropic in the dog.