R. Ebert

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

SummaryIntegrated 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 ≦ 0.05). The contribution to connecting peptide responses was 58.4 ± 7.6% in control subjects and 7.6 ± 14.5% (p ≦ 5 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. A reduced or lost incretin effect in the face of normal gastric inhibitory polypeptide response in Type 2 diabetic patients may be explained by decreased sensitivity of the B cells towards the insulinotropic effect of gastric inhibitory polypeptide or to hyposecretion or reduced effectiveness of as yet unidentified humoral or nervous gut factors with incretin activity.

Effect of the Somatostatin Analogue Sandostatin (SMS 201–995) on Gastrointestinal, Pancreatic and Biliary Function and Hormone Release in Normal Men

The effect of the long-acting somatostatin analogue Sandostatin (SMS 201-995) on intestinal absorption and propagation (mouth-to-caecum transit time; MCTT), on pancreatic secretion and on gall bladder contraction after direct (secretin-pancreozymin test) and indirect stimulation (Lundh meal), and on meal-induced responses of seven gastrointestinal regulatory peptides has been investigated. In a double-blind cross-over study, 9 healthy volunteers completed two 7-day periods with subcutaneous injections of either placebo or 25 micrograms SMS 201-995 twice daily. Mean faecal fat excretion was increased to 19.2 g/day and MCTT was three times longer during the SMS period. After duodenal infusion of a mixture containing D-galactose, D-xylose and triglycerides, SMS 201-995 significantly reduced the serum concentrations of D-galactose but increased serum levels of D-xylose. After 6 days of pretreatment, SMS 201-995 completely suppressed duodenal trypsin, lipase and bilirubin increases in response to endogenous stimulation by a Lundh meal. Concomitantly, cholecystokinin (CCK) release and gall bladder contraction were almost abolished. Compared with placebo, SMS 201-995 significantly diminished pancreatic amylase, trypsin and lipase output after stimulation with CCK, while the secretion of fluid and bicarbonate in response to secretin was unchanged. This inhibition of enzyme response was significantly more marked after a single injection of the analogue than after pretreatment for 7 days and did not reach the level of exocrine pancreatic insufficiency. CCK-induced gall bladder contraction was significantly inhibited by a single dose of 25 micrograms SMS 201-995 but not after 7 days of pretreatment with the somatostatin analogue.

Gastric inhibitory polypeptide (GIP) and insulin in obesity: increased response to stimulation and defective feedback control of serum levels.

SummaryTo investigate the possibility that an abnormality of the entero-insular axis is responsible for the hyperinsulinaemia of obesity, serum immunoreactive gastric inhibitory polypeptide (IR-GIP) and insulin (IRI) were measured after the ingestion of a liquid mixed test meal, glucose or fat, in normal weight and obese subjects. The latter were divided into a group with normal oral glucose tolerance (nOGT) and a group with pathological glucose tolerance (pOGT). Fasting levels of IR-GIP were significantly elevated in the obese group with pOGT. After the mixed meal the overweight subjects showed a significantly greater response of IR-GIP than the controls, with highest levels in the pOGT group. Simultaneously, the IRI response was significantly greater in the obese subjects than in the controls. The increases of IR-GIP and IRI after an oral load of 100 g glucose were normal in the obese subjects, but showed a significantly greater integrated response in the obese patients with pOGT. The ingestion of 100 g fat induced no IRI release but a significantly greater release of IR-GIP in the obese subjects, irrespective of their glucose tolerance. It is concluded that fat is a stronger releaser of IR-GIP than glucose. The effect of a combined load of glucose (30 g) and fat (100 g) was also compared in obese and normal weight subjects with the effect of either alone. Fat but not glucose released significantly more IR-GIP in obese subjects. In normal weight controls, but not in obese subjects, the IR-GIP release after fat plus glucose became significantly smaller than after fat alone. Since only the combined ingestion of glucose and fat and not fat alone releases insulin it is suggested that endogenous insulin inhibits GIP release and that this feedback control between insulin and GIP is defective in patients with obesity.

Hyperinsulinaemia in non-cirrhotic haemochromatosis: impaired hepatic insulin degradation?

SummaryThis study investigated early alterations of glucose metabolism in idiopathic haemochromatosis. Circulating concentrations of glucose, insulin, C-peptide, glucagon, and gastric inhibitory polypeptide (GIF) were measured after a 100-g oral glucose load in 10 men with idiopathic haemochromatosis in the non-cirrhotic stage of the disease. All had normal glucose tolerance and normal body weight. Ten matched healthy subjects were studied as controls. Insulin concentrations increased to significantly higher levels in patients with idiopathic haemochromatosis than in the control subjects from 30 to 180min after the glucose load (p<0.01), while fasting insulin concentrations were not significantly different (p> 0.05). Concentrations of glucose, glucagon, C-peptide, and GIF were not significantly different at any time (p> 0.05). Thus, patients with idiopathic haemochromatosis show hyperinsulinaemia and hence insulin resistance without impaired glucose tolerance in the non-cirrhotic stage. Since pancreatic insulin secretion (C-peptide), glucagon secretion, and the entero-insulinar axis (GIP) are not impaired in these non-cirrhotic patients with idiopathic haemochromatosis, iron accumulation in the hepatocytes may be responsible for the impaired insulin effect and may cause impaired hepatic insulin extraction.

Preservation of incretin activity after removal of gastric inhibitory polypeptide (GIP) from rat gut extracts by immunoadsorption

SummaryThe action of watery rat gut extracts on glucose-induced insulin release in anaesthetized rats was examined before and after removal of GIP by immunoadsorption. Infusions of GIP-containing rat gut extracts nearly doubled the insulin release induced by intravenous glucose (1g · kg−1 · h−1). Peak insulin secretion was 98±11 mU/l (mean±SEM) after intravenous glucose and increased to 178±16 mU/l following infusion of glucose plus gut extract (p<0.005). After injection of GIP antiserum in sufficient amounts to neutralize the GIP activity in the gut extract preparation, the additional insulin release due to the gut extract was reduced by only 30%. After complete removal of GIP from gut extracts by immunoabsorption, more than 50% of the incretin effect remained. These data suggest that the insulinotropic activity of rat gut extracts can only be partially related to GIP. The existence of additional insulinotropic gut factors which may also be released following oral glucose is postulated.

Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution

SummaryThe influence of impaired digestion on nutrient induced release of gastric inhibitory polypeptide (GIP) and insulin have been investigated in patients with chronic pancreatitis. All patients had massive steatorrhea (>25 g/24 h), and glucose intolerance. A standard liquid test meal comprising fat and glucose were ingested with or without pancreatic enzyme substitution (9.0 g pancreatin). In the presence of pancreatin the response of serum levels of GIP to the test meal was significantly enhanced (81.2 vs 194.5 μg/l×180 min). Concurrently, the insulin response was augmented (3.4 vs 6.4 U/l×180 min), resulting in improved glucose tolerance. Addition of pancreatin also significantly augmented the GIP response to oral fat (100g), but not to oral glucose (100g). In patients with pancreatogenic steatorrhea the insulin response to an IV glucose infusion (0.7g/ kg/h for 90 min) was augmented by oral fat only after addition of 9.0 g pancreatin to the fat load (3.5 vs 7.3 U/l×180 min). After restoration of the GIP response to fat by pancreatin, the inhibitory effect of IV glucose on fat-induced GIP increase was restored. These data indicate that the GIP response to a mixed meal or triglycerides is dependent on the absorption of nutrients. In patients with chronic pancreatitis improvement of pancreatogenic insufficiency reverses the impaired GIP response, restores the incretin effect of fat, and improves glucose tolerance.

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

SummaryThe 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 6 patients with chronic pancreatitis and partial duodenopancreatectomy (Whipples 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 Whipples 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.

Impaired feedback control of fat induced gastric inhibitory polypeptide (GIP) secretion by insulin in obesity and glucose intolerance

Abstract. To investigate the role of endogenous insulin on the secretion of immunoreactive gastric inhibitory polypeptide (IR‐GIP) the response of IR‐GIP and immunoreactive insulin (IRI) to an oral fat load (100 g triglyceride) alone and during an intravenous glucose infusion (0.7 g/kg/h) was examined in normal weight and obese subjects. In normal weight subjects the fat induced integrated rise of IR‐GIP was 112.7 ± 9.4 ng/ml/120 min. When glucose and fat were given together this IR‐GIP response was lowered to 46.2 ± 2.9 ng/ml/120 min while the serum IRI response to i.v. glucose and the glucose tolerance were enhanced by fat ingestion. In obese subjects with normal glucose tolerance the GIP suppressing effect of i.v. glucose infusion was less marked than in controls. The integrated IR‐GIP response to fat ingestion was 225.6 ± 20.3 ng/ml/120 min and to fat plus glucose 152.6 ± 14.8 ng/ml/120 min. In obese subjects with glucose intolerance i.v. glucose completely failed to lower the exaggerated secretion of IR‐GIP following oral fat. Thus, a graded abnormality of the GIP response to glucose induced insulin release occurs in obesity with normal and pathological glucose tolerance. After reducing the ideal body weight of six obese subjects with glucose intolerance by hypocaloric diet for 3 weeks the exaggerated rise of IR‐GIP after oral fat was reversed and the lowering effect of i.v. glucose on the IR‐GIP response re‐established.

Lack of Effect of Synthetic Human Gastric Inhibitory Polypeptide and Glucagon-LikePeptide 1 [7-36 Amide] Infused at Near-Physiological Concentrations on Pentagastrin-Stimulated Gastric Acid Secretion in Normal Human Subjects

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 [7-36 amide] (GLP-1) are glucose-dependent insulinotropic gut hormones. Under experimental conditions, both have been shown to reduce stimulated gastric acid secretion. To study their individual and combined effects on pentagastrin-stimulated (0.1 micrograms/kg/h from -90 to 120 min) gastric volume, acid and chloride output, on separate occasions, synthetic human GIP (1 pmol/kg/min) and/or GLP-1 [7-36 amide] (0.3 pmol/kg/min) or placebo (0.9% NaCl with 1% albumin) were infused intravenously (from -30 to 120 min) in 9 healthy volunteers. At 0 min, a glucose infusion was started that mimicked the glycemic profile after an oral glucose load of 50 g/400 ml and allowed for the glucose-dependent insulinotropic action of GIP and GLP-1 [7-36 amide]. Pentagastrin stimulated acid output significantly, but neither GIP nor GLP-1 [7-36 amide] either alone or in combination, reduced pentagastrin-stimulated gastric acid secretion. The circulating concentrations of GIP and GLP-1 [7-36 amide] obtained at steady state during exogenous administration of synthetic peptides were similar to or higher than those reached after oral glucose (endogenous secretion). In conclusion, (penta)gastrin-stimulated gastric acid secretion is not inhibited by physiological circulating concentrations of GIP or GLP-1 [7-36 amide]. Therefore, the insulinotropic action of these intestinal hormones is physiologically more important than their possible role as enterogastrone.

Insulin-dependent inhibition of hepatic glycogenolysis by gastric inhibitory polypeptide (GIP) in perfused rat liver

SummaryThe effect of porcine gastric inhibitory polypeptide on hepatic glycogen metabolism was investigated in the isolated in situ perfused rat liver. Glycogenolysis was stimulated by infusion of glucagon into the portal vein (half maximal effective portal vein concentration ∼30 pmol/1). When glucagon was infused at a final portal vein concentration of 0.5 nmol/l, simultaneous addition of insulin inhibited the glucagon-dependent glycogenolysis in a dose-dependent way (half maximal effective concentration for insulin about 2 nmol/l). Gastric inhibitory polypeptide alone at a concentration of 1 nmol/l reduced glucagon-dependent glycogenolysis only slightly. However, when infused simultaneously at low insulin concentrations (0.1 nmol/1), gastric inhibitory polypeptide suppressed hepatic glucose production dose-dependently up to 70%. The data suggest that gastric inhibitory polypeptide exerts direct metabolic effects on hepatic glycogen metabolism predominantly in a situation where insulin is simultaneously present, e.g. following ingestion of glucose.