Glucose-dependent insulinotropic polypeptide augmentation of insulin. Physiology or pharmacology?

Glucose-dependent insulinotropic polypeptide (GIP) is said to be a major physiologic factor in the augmentation of the insulin response to oral glucose. Whether GIP promotes insulin release at physiologic concentrations of glucose or GIP, however, is questionable. To investigate this further, volunteers were infused with 10, 20, or 40 g intravenous (i.v.) glucose, with or without simultaneous GIP infusion, to produce plasma levels of GIP or glucose similar to those seen after oral glucose. The effect of 40 g i.v. glucose with three times the original dose of GIP was also investigated. No significant enhancement of glucose-stimulated insulin secretion was seen when GIP was infused with 10 or 20 g i.v. glucose; however, with 40 g a doubling of the insulin response occurred. The higher dose of GIP caused a further increase in insulin response (30-min increment, 972 +/- 191 pmol/L; compared with glucose alone, 356 +/- 100 pmol/L, P less than 0.01; and compared with low GIP, 602 +/- 247 pmol/L, P less than 0.02). The glucose increment after the 40-g i.v. dose was +9.2 mmol/L. The concentration of GIP and glucose required to produce significant potentiation of the insulin response appears to be in the pharmacologic, rather than physiologic, range.

Scope and specificity of acarbose in slowing carbohydrate absorption in man.

Fifty-gram carbohydrate tolerance tests were performed on healthy volunteers to test the activity and specificity of an alpha-glucoside hydrolase inhibitor, acarbose (BAY g 5421). Two hundred milligrams acarbose reduced the area under the blood glucose response curve by 89% (P less than 0.001) after sucrose by 80% (P less than 0.002) after starch, by 19% (N.S.) after maltose, with no effect on glucose. Breath hydrogen measurements indicated an almost complete malabsorption of the sucrose. At 50 mg acarbose, some reduction in blood glucose and insulin response to sucrose was still seen, but no significant hydrogen production. It is suggested that at lower doses, acarbose may prolong the time course over which carbohydrate is absorbed as does dietary fiber; as with fiber, it may be a useful adjunct to diabetic therapy.

Bombesin: action on gut hormones and calcium in man.

Bombesin, a peptide with widespread biological actions, has been demonstrated in human tissues by immunological methods. To investigate its effect in man, synthetic bombesin was infused at low doses in six male volunteers. Bombesin at 2.4 pmol kg-1 min-1 produced significant rises in plasma insulin, glucagon, pancreatic polypeptide, gastrin, cholecystokinin, motilin, glucose-dependent insulinotropic polypeptide, neurotensin, enteroglucagon, vasoactive intestinal polypeptide, and serum calcium. In contrast, bombesin caused a profound fall in parathyroid hormone levels and reduced plasma glucose concentrations. A late rise in plasma calcitonin was also observed. Bombesin had no significant effect on the pituitary hormones, TSH, GH, PRL, or cortisol. No hormonal changes or alterations in calcium were noted during saline infusions. Bombesin has a marked stimulatory effect on gastrointestinal hormones, which is unique and opposite to the effect of somatostatin, a potent inhibitor of gut hormone release. Bombesin also influences calcium-regulating hormones, either directly or through its action on gut hormones. The bombesin concentrations achieved with the dosages used were low enough to indicate a possible physiological role for the endogenous peptide.

Slow release dietary carbohydrate improves second meal tolerance.

Breakfasts of lentils or wholemeal bread of identical carbohydrate content were taken by seven healthy volunteers. The lentils produced a significant 71% (p less than 0.001) reduction in the blood glucose area and flattened the plasma insulin and gastric inhibitory polypeptide responses by comparison with the bread. In addition, the lentil breakfast was followed by a significantly flatter blood glucose response to the standard bread lunch which followed 4 h later (by 38%, p less than 0.01). The blood glucose pattern was mimicked by feeding the bread breakfast slowly over the 4 h before lunch. Giving a bread breakfast containing a quarter of the carbohydrate reduced the breakfast glucose profile but resulted in a significantly impaired blood glucose response to lunch (168% of control, p less than 0.01). These results, together with breath hydrogen studies, performed on a separate group of four volunteers, indicate that the flattened response to lentils is not due to carbohydrate malabsorption. Slow release or "lente" carbohydrate foods such as lentils may form a useful part of the diets of those with impaired carbohydrate tolerance.

A radioimmunoassay of gastric inhibitory polypeptide in human plasma.

A sensitive radioimmunoassay for the measurement of human gastric inhibitory polypeptide (GIP), using pure porcine GIP, has been developed. Cross-reactivity of the antiserum with all available mammalian gut peptide preparations was negligible with the exception of glucagon when it was approximately 1%. Two major molecular forms of GIP were detectable in plasma and tissue extracts, one of large molecular size and the other corresponding to the elution coefficient of pure porcine standard. Concentrations of GIP in plasma from 50 normal subjects after overnight fasting were 9 +/- 1.0 (S.E.M.) pmol/l rising to a peak of 34 +/- 2.8 pmol/l following the ingestion of a small mixed test meal. Ingestion of glucose or fat resulted in a similar rise of plasma GIP, whereas no change was observed after the ingestion of protein.

The effects of ileal transposition and jejunoileal bypass on food intake and GI hormone levels in rats.

Male Wistar rats received three different types of small intestinal surgery. Two groups of rats had either 10 or 20 cm of lower ileum transposed to mid-duodenum. A third comparison group of rats had 85% jejunoileal bypass. All three experimental groups showed a sustained post-operative reduction in food intake and a change in body weight gain. Measurements made 36 days after surgery showed that all experimental groups had a large increase in basal and meal-stimulated enteroglucagon. The total-integrated plasma levels of gastrin, GIP, insulin and blood glucose were significantly reduced. At sacrifice, there were large increases in the wet weight of the small intestine and pancreas. These changes were probably due to the chronic stimulation of the lower ileum with nutrient-rich chyme and may be due to the release of ileal hormones.

The pharmacokinetics of porcine glucose-dependent insulinotropic polypeptide (GIP) in man.

The pharmacokinetics of porcine glucose-dependent insulinotropic polypeptide were investigated in six healthy volunteers. At the maximum infusion dose (0 . 5 pmol kg-1 min-1) a plateau concentration of 115 +/- 5 . 0 pmol/l plasma was obtained. On discontinuation of the infusion, the half-time of disappearance was calculated to be 20 . 3 +/- 1 . 2 min. The metabolic clearance rate was 2 . 6 +/- 0 . 1 ml kg-1 min-1 and the apparent space of distribution was 75 . 8 +/- 5 . 7 ml kg-1. Blood glucose, pancreatic and gastrointestinal hormones remained at basal concentrations throughout. No side effects were noted by any of the subjects studied.

Gut hormone changes after jejunoileal (JIB) or biliopancreatic (BPB) bypass surgery for morbid obesity.

The treatment of obesity by intestinal bypass provides a unique model for the investigation of gut hormone release from the functionally deranged bowel. We have examined the postprandial response of eight circulating gut or pancreatic peptide hormones in 16 preoperative obese patients, 20 patients with jejunoileal bypass, 38 patients with biliopancreatic bypass and 13 age and sex-matched controls. Basal and post-meal hormone concentrations were determined by specific radioimmunoassay methods. Reductions of the upper small intestinal hormones, motilin and gastric inhibitory polypeptide were found in both types of surgery. Conversely, the ileal hormones neurotensin and enteroglucagon were elevated following surgery. This pattern is consistent with the known distribution of these hormones. Variations of response due to surgical differences were noted for gastrin and the enteropancreatic axis, which was more markedly disturbed after biliopancreatic bypass. The alterations of hormone release closely reflect the anatomical changes induced by each particular surgical technique.

Gut hormone responses in subjects with a permanent ileostomy.

The fasting and postprandial levels of insulin, gastric inhibitory polypeptide, gastrin, motilin, human pancreatic polypeptide, enteroglucagon and neurotensin have been measured in 10 subjects with a permanent ileostomy and in 10 healthy control subjects matched for age and sex. Most of the levels were similar in the two groups but the group that had undergone ileostomies had significantly raised basal motilin and postprandial neurotensin levels while the basal enteroglucagon levels were significantly low. The possible implications of these findings are discussed.

Developmental aspects of gastric inhibitory polypeptide (GIP) and its possible role in the enteroinsular axis in neonates.

Little is known on the development of the release of gastric inhibitory polypeptide (GIP) in neonates or on its potential role in the enteroinsular axis. Using cross-section data collection we studied: (a) 100 preterm neonates either at birth (cord blood), or before or after a feed on the sixth or 24th day and (b) 63 term neonates at birth or on the sixth day. Blood samples were assayed for GIP, insulin and glucose. At birth plasma GIP concentrations were low compared with fasting adults (p less than 0.01). Basal plasma levels were significantly higher at six days in fed infants, but not in a group of sick preterm infants who had never been fed orally. On the sixth day there was no GIP response to a feed, but by 24th day there was a marked postprandial elevation (p less than 0.01). In preterm infants the insulin response was 68% greater at 24 days than at six days in spite of a similar glycaemic response. We hypothesize that this increasing postnatal insulin response to enteral feeding may be due to the commencement of the postprandial release of GIP, thought to be an important effector in the enteroinsular axis.

The effect of glucose-dependent insulinotropic polypeptide infused at physiological concentrations on the release of insulin in man.

Blood glucose and the responses of insulin and glucose-dependent insulinotropic polypeptide (GIP) were measured in 12 healthy, normal weight subjects after drinking 50 g glucose. On a subsequent occasion each subject was given a simultaneous infusion of GIP and glucose to mimic the plasma concentrations observed in the first test. The peak GIP concentration after oral glucose was 22.3 +/- 1.9 pmol/l (mean +/- SEM), but was higher after GIP infusion at 36.3 +/- 4.6 pmol/l, (p less than 0.005). The blood glucose levels following oral glucose peaked at 6.3 +/- 0.5 mmol/l which was the same as seen after intravenous glucose. The insulin response to oral glucose was, however, far higher (431.3 +/- 58.2 pmol/l) than that obtained after GIP and glucose infusion (191.6 +/- 30.9 pmol/l, p less than 0.001). Thus it has not proved possible to explain completely the oral enhancement of insulin release by the action of GIP alone.

Gut hormones in acute diarrhoea.

The gut hormone response to a breakfast meal was studied in 12 subjects hospitalised for an episode of acute diarrhoea (presumed infective) who were otherwise well and in 13 healthy control subjects. Fasting blood glucose concentrations were low but basal insulin concentrations were raised. Basal concentrations of pancreatic polypeptide and both basal and postprandial responses of motilin, enteroglucagon, and vasoactive intestinal polypeptide (VIP) were also significantly greater than controls. No abnormalities in plasma concentrations of gastrin, gastric inhibitory polypeptide (GIP) or pancreatic glucagon were found. The suggested physiological actions of the raised hormones may be relevant to the pathophysiology of diarrhoea.

Enteroglucagon and GIP after oral glucose in patients with prolactinoma and acromegaly.

We have performed oral glucose tolerance tests (OGTT) in nine patients with prolactinomas, eight patients with active acromegaly, five patients with acromegaly in remission and nine normal controls, and measured blood glucose, plasma insulin, pancreatic glucagon, enteroglucagon, gastric inhibitory polypeptide (GIP) and GH during the test. Patients with prolactinomas and with active acromegaly were hyperinsulinaemic and five of the nine patients with prolactinomas had impaired glucose tolerance, with blood glucose levels that were significantly higher than the normal controls. Prolactinoma patients had higher GIP levels than those with active acromegaly and both showed a failure of suppression of pancreatic glucagon. Of particular interest was the finding that enteroglucagon, a putative gut growth factor, was low in active acromegaly when compared with acromegaly in remission, but similar to normal in the rest of the patients.

Effect of partial ileal bypass on the gut hormone responses to food in man.

The integrated response of the regulatory peptides of the gastrointestinal tract to a test meal was studied in six hypercholesterolaemic patients who had undergone partial ileal bypass (PIB) and compared with responses in ten age- and sex-matched controls. Plasma motilin was found to rise significantly whereas plasma pancreatic polypeptide release was impaired after PIB. Plasma cholecystokinin rose promptly in both controls and the partial ileal bypass patients, and the latter group showed marked further rises, at 60 and 120 minutes after the meal, which were significantly higher than controls. Basal and postprandial plasma gastrin, gastric inhibitory peptide, neurotensin, enteroglucagon, insulin and pancreatic glucagon were similar in the two groups.

Gut hormone responses in the irritable bowel syndrome.

Fasting and postprandial levels of gastrin, insulin, gastric inhibitory polypeptide, pancreatic polypeptide, motilin, enteroglucagon and neurotensin were measured in 42 patients with irritable bowel syndrome (IBS). No overall major abnormalities of secretion of any of these peptides were found, although minor differences from normal of pancreatic polypeptide and neurotensin were observed. It is doubtful whether abnormalities of gut hormone secretion play an important role in the pathophysiology of IBS.

Breast vs bottle: endocrine responses are different with formula feeding.

Differences in pancreatic and gut-hormone release between breast-fed and bottle-fed infants have not been documented although these hormones may play a key role in postnatal adaptation. In a study of 77 six-day-old healthy term infants, bottle-fed neonates ('Cow and Gate Premium') had significant changes in plasma-concentrations of insulin, motilin, enteroglucagon, neurotensin, and pancreatic polypeptide after feeding, whereas in breast-fed infants these changes were reduced or absent. Basal levels of gastric inhibitory polypeptide, motilin, neurotensin, and vasoactive intestinal peptide were also higher in the bottle-fed infants than in those who were breast-fed. These findings may partly explain differences in the deposition of subcutaneous fat and in stool frequency between breast-fed and bottle-fed neonates.

Colonic inhibition of gastric secretion in man.

The effect of colonic infusion of various solutions on submaximal pentagastrin-stimulated gastric secretion was determined in healthy volunteers. Hypertonic (823 mOsm/kg) glucose, mannitol, and saline, and also isotonic glucose significantly induced a marked and sustained inhibition of gastric acid secretion of 74%, 66%, 79%, and 54%, respectively. A similar degree of inhibition was obtained for pepsin secretion with hypertonic glucose and mannitol. Isotonic triglycerides and isotonic saline solutions had no significant effect on gastric acid secretion. Hypertonic glucose, mannitol, and saline infusions significantly increased plasma concentrations of enteroglucagon, whereas other solutions had no effect. No correlation, however, was found between the percentage rise of enteroglucagon and the percentage inhibition of gastric secretion obtained from any of the three hypertonic solutions. The physiological significance of these findings remains to be established.