Immunoreactive Gastric Inhibitory Polypeptide Response Research Articles

Lack of insulinotropic effect of endogenous and exogenous cholecystokinin in man.

Intraduodenal phenylalanine administration (333 mg/min over 60 min) released endogenous cholecystokinin in healthy young subjects as demonstrated radioimmunologically and by intraduodenal bilirubin and pancreatic enzyme output. Concomitantly, there was only a small increase over basal in circulating immunoreactive-insulin and immunoreactive-C-peptide concentrations. In healthy volunteers intraduodenal infusions of saline (10 ml/min), glucose (333 mg/min) or phenylalanine (333 mg/min) were performed for 60 min when plasma glucose was clamped at approximately 8 mmol/l. Phenylalanine enhanced immunoreactive-insulin and immunoreactive-C-peptide responses three-fold more than did the same amount of glucose. Immuno-reactive gastric inhibitory polypeptide responses were small and not different after glucose and phenylalanine administration. Immunoreactive cholecystokinin was significantly stimulated to 9.4 +/- 1.4 pmol/l only by intraduodenal phenylalanine. Plasma phenylalanine concentrations increased into the supraphysiological range (approximately 1.5 mmol/l). Intravenous infusions of phenylalanine achieving plasma concentrations of 1.2 mmol/l stimulated insulin secretion at elevated plasma glucose concentrations (approximately 8 mmol/l clamp experiments), but had no effect at basal plasma glucose concentrations. A small increase in cholecystokinin also was observed. Intravenous infusions of synthetic sulphated cholecystokinin-8 leading to plasma concentrations in the upper postprandial range (8-12 pmol/l) did not augment the immunoreactive-insulin or immunoreactive-C-peptide levels during hyperglycaemic clamp experiments, in the absence or presence of elevated plasma phenylalanine concentrations. It is concluded that the augmentation of the glucose-induced insulin release by intraduodenal administration of phenylalanine cannot be related to cholecystokinin release, but rather is explained by the combined effects of elevated glucose and phenylalanine concentrations. In man, cholecystokinin does not augment insulin secretion caused by moderate hyperglycaemia, elevations of phenylalanine concentrations, or combinations thereof.

Reduced incretin effect in type 2 (non-insulin-dependent) diabetes.

Integrated incremental immunoreactive insulin and connecting peptide responses to an oral glucose load of 50 g and an "isoglycaemic" intravenous glucose infusion, respectively, were measured in 14 Type 2 (non-insulin-dependent) diabetic patients and 8 age- and weight-matched metabolically healthy control subjects. Differences between responses to oral and intravenous glucose administration are attributed to factors other than glucose itself (incretin effect). Despite higher glucose increases, immunoreactive insulin and connecting peptide responses after oral glucose were delayed in diabetic patients. Integrated responses were not significantly different between both groups. However, during "isoglycaemic" intravenous infusion, insulin and connecting peptide responses were greater in diabetic patients than in control subjects as a consequence of the higher glycaemic stimulus. The contribution of incretin factors to total insulin responses was 72.8 +/- 6.9% (100% = response to oral load) in control subjects and 36.0 +/- 8.8% in diabetic patients (p less than or equal to 0.05). The contribution to connecting peptide responses was 58.4 +/- 7.6% in control subjects and 7.6 +/- 14.5% (p less than or equal to 0.05) in diabetic patients. Ratios of integrated insulin to connecting peptide responses suggest a reduced (hepatic) insulin extraction in control subjects after oral as compared to intravenous glucose. This was not the case in diabetic patients. Immunoreactive gastric inhibitory polypeptide responses were not different between control subjects and diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoreactive gastric inhibitory polypeptide response to a meal during the first eighteen months after diagnosis of type 1 (insulin dependent) diabetes mellitus.

The changes in plasma concentrations of immunoreactive gastric inhibitory polypeptide (IR-GIP) in response to a standard meal were examined in 21 normal subjects and 15 Type 1 (insulin dependent) diabetic patients 7 days, 14 days, and 3, 6, 9, 12, and 18 months after time of diagnosis. During the first 4 tests significantly lower plasma IR-GIP concentrations were found in the diabetic patients after the standard meal. At 9 months and during the remaining tests there was no difference in IR-GIP concentrations between the diabetic and the normal subjects. The IR-GIP response was normalized faster if the diabetic patients were treated with initial short term intensive insulin therapy than if they were treated conventionally with 1 or 2 daily injections of insulin. beta-Cell function, evaluated by the C-peptide response to the meal, increased significantly during the first 3 months. After 3 months maximal beta-cell function was found while the corresponding IR-GIP responses were significantly lower than those of the normal subjects. Thereafter beta-cell function declined gradually and significantly, coinciding with the normalization of the IR-GIP response. No individual covariation between IR-GIP and beta-cell function during the 18 months was found in any patient. The IR-GIP response to a meal was diminished at the onset of Type 1 (insulin dependent) diabetes mellitus. After the start of insulin therapy the response improved, perhaps as a function of the quality of metabolic control, and within a year it was comparable to that of normal subjects. Lack of endogenous GIP therefore does not explain the diminished beta-cell function in Type 1 diabetes a few months after onset of the disease. No causal relationship between the changes in beta-cell function and IR-GIP during the first 18 months after the onset of the disease seems to exist.

Diminished immunoreactive gastric inhibitory polypeptide response to a meal in newly diagnosed type I (insulin-dependent) diabetics.

The release of immunoreactive gastric inhibitory polypeptide (IR-GIP) in response to a standard meal was examined in 10 normal subjects and 15 type I (insulin-dependent) diabetics 7 days (test I), 14 days (test II), and 3 months (test III) after time of diagnosis. During all three tests, the diabetics had significantly lower plasma IR-GIP concentrations than the controls from 15-90 min after the standard meal. The IR-GIP response in the diabetics measured as the integrated area under the response curve corresponded to 70% of that of normal subjects. beta-cell function evaluated from the C-peptide response to the meal increased significantly from test I to test III whereas the IR-GIP response was similar during all three tests. As GIP is known to potentiate glucose-induced insulin secretion and possibly the biosynthesis of insulin, the low IR-GIP responses in subjects with type I diabetes may significantly influence insulin levels and hyperglycemia.

Gastric inhibitory polypeptide release after oral glucose: relationship to glucose intolerance, diabetes mellitus, and obesity.

Hypersecretion of immunoreactive gastric inhibitory polypeptide (IRGIP) has been reported previously in patients with diabetes mellitus (DM) and obesity. To ascertain the relative contribution of glucose intolerance and obesity to the abnormalities of IRGIP secretion, 114 subjects were studied during a standard oral glucose (75 g) tolerance test; responses of glucose, insulin, C-peptide, IRGIP, and glucagon were evaluated. The subjects were divided into six subgroups according to body weight and the degree of glucose intolerance. In normal weight subjects, the IRGIP response to oral glucose was significantly higher in the patients with impaired glucose tolerance (IGT) and DM than in the healthy control subjects (P less than 0.05). In the obese subjects, no significant differences in mean IRGIP responses could be detected among control, IGT, and DM subjects. In spite of similar IRGIP responses, the obese IGT patients did release more insulin than the obese control subjects, suggesting that incretin factors other than GIP may be operative in this condition. When obese and nonobese patients were compared, the obese subjects with normal glucose tolerance released a greater amount of IRGIP and insulin than the normal weight controls, whereas no significant difference between obese and nonobese could be found within the IGT and DM groups. We conclude that in the absence of obesity, glucose intolerance may induce IRGIP hypersecretion. On the other hand, obesity is associated with IRGIP hypersecretion, and glucose intolerance has no further effect, indicating a different pathogenetic mechanism for the IRGIP abnormalities. In both the obese and nonobese diabetic groups, IRGIP hypersecretion was associated with a failure of plasma glucagon levels to fall after oral glucose; this effect might be related to the glucagonotropic action of this peptide.

Endocrine pancreatic control of the release of gastric inhibitory polypeptide. A possible physiological role for C-peptide.

Intravenous infusion in anaesthetized rats of rat II C-peptide at a dose which produced circulating levels of 22.8 +/- 1.8 nmol/l after 30 min, resulted in a significant reduction (141 +/- 7 to 50 +/- 4 pmol/l, p < 0.001, mean +/- SEM) in the immunoreactive gastric inhibitory polypeptide response to an intestinal perfusion with a fat emulsion. Immunoreactive insulin levels were unchanged from basal in this study. It is suggested that C-peptide must be considered as a candidate for the endocrine pancreatic factor which exerts a negative feedback upon gastric inhibitory polypeptide release.

Gastric inhibitory polypeptide (GIP), gastrin and insulin: response to test meal in coeliac disease and after duodeno-pancreatectomy.

The response of serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG) and insulin (IRI) to a mixed standard meal was measured in 15 controls, 6 patients with coeliac disease, 26 patients with chronic pancreatitis and partial duodenopancreatectomy (Whipple's procedure). Serum levels of IR-GIP, IRG and IRI were significantly reduced in patients with coeliac disease. The serum glucose increase was significantly smaller only during the first hour after the meal. Since small intestinal GIP- and G-cells are situated mainly in the glands of duodenal and jejunal mucosa their absolute number is not significantly reduced in coeliac disease. It is suggested that the release of IR-GIP and duodenal IRG is influenced by the rate of absorption of nutrients. In patients with chronic pancreatitis the IR-GIP release is significantly greater than in controls, the IRG release normal and the IRI response delayed. After Whipple's procedure the IR-GIP response is increased significantly while the IRG secretion is abolished. This demonstrates that the duodenum is not necessary for GIP release and that pancreatic and jejunal gastrin are without clinical significance.

Gastric inhibitory polypeptide. Its physiologic release and insulinotropic action in the dog.

Studies were carried out in conscious dogs in which the immunoreactive gastric inhibitory polypeptide (IR-GIP) response to graded doses of oral fat (triglycerides) and glucose was investigated. The IR-GIP response to the doses of triglycerides used was greater and more prolonged than the response to the glucose loads employed. In addition, the relative insulinotropic potencies of exogenous porcine GIP and IR-GIP released by fat as against those released by oral glucose were assessed. When glucose was administered by the oral route, the immunoreactive insulin (IRI) response was magnified above the IRI response to a comparable intravenous glucose load. The serum IRI response to oral glucose was accompanied by a concomitant rise in serum IR-GIP levels, suggesting a causal relationship. IR-GIP released by oral fat was shown to augment the IRI response to an intravenous glucose load, resulting in an improvement of glucose tolerance. Fat-released IR-GIP augmented IRI levels to a lessor degree than either oral glucose or an infusion of porcine GIP.

The effect of somatostatin on release and insulinotropic action of gastric inhibitory polypeptide.

Studies were carried out in conscious dogs in which the effect of intravenous somatostatin on immunoreactive gastric inhibitory polypeptide (IR-GIP) release was investigated. In addition, the inhibitory action of somatostatin on the insulin response to pure porcine GIP was assessed. Intravenous administration of somatostatin resulted in a delayed IR-GIP and immunoreactive insulin (IRI) response to oral glucose. Somatostatin also delayed the IR-GIP response to the ingestion of fat. In both types of experiments, initial depression of IRI levels was followed by a sharp rise in IRI release. Intravenous infusion of somatostatin produced 80% inhibition of the IRI response to pure porcine GIP. It was concluded that somatostatin inhibits the physiological release of IR-GIP and the insulinotropic action of exogenous porcine GIP.