oxyntomodulin and Hyperinsulinism

Topics: Animals; Brain; Feeding Behavior; Genes, fos; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hyperglycemia; Hyperinsulinism; Neurons; Peptide Fragments; Protein Precursors; Rats; Rats, Zucker; Receptors, Glucagon; Venoms

Topics: Blood Glucose; Carbohydrate Metabolism; Dumping Syndrome; Glucagon-Like Peptides; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Intestinal Absorption

To examine the insulinomimetic insulin-independent effects of glucagon-like peptide (GLP)-1 on glucose uptake in type 1 diabetic patients.. We used the hyperinsulinemic-euglycemic clamp (480 pmol. m(-2) x min(-1)) in paired randomized studies of six women and five men with type 1 diabetes. In the course of one of the paired studies, the subjects also received GLP-1 at a dose of 1.5 pmol. kg(-1) x min(-1). The patients were 41 +/- 3 years old with a BMI of 25 +/- 1 kg/m(2). The mean duration of diabetes was 23 +/- 3 years.. Plasma glucose was allowed to fall from a fasting level of approximately 11 mmol/l to 5.3 mmol/l in each study and thereafter was held stable at that level. Plasma insulin levels during both studies were approximately 900 pmol/l. Plasma C-peptide levels did not change during the studies. In the GLP-1 study, plasma total GLP-1 levels were elevated from the fasting level of 31 +/- 3 to 150 +/- 17 pmol/l. Plasma glucagon levels fell from the fasting levels of approximately 14 pmol/l to 9 pmol/l during both paired studies. Hepatic glucose production was suppressed during the glucose clamps in all studies. Glucose uptake was not different between the two studies ( approximately 40 micromol. kg(-1) x min(-1)).. GLP-1 does not augment insulin-mediated glucose uptake in lean type 1 diabetic patients.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Liver; Male; Neurotransmitter Agents; Peptide Fragments; Peptides

This study examined the biological effects of the GIP receptor antagonist, (Pro3)GIP and the GLP-1 receptor antagonist, exendin(9-39)amide.. Cyclic AMP production was assessed in Chinese hamster lung fibroblasts transfected with human GIP or GLP-1 receptors, respectively. In vitro insulin release studies were assessed in BRIN-BD11 cells while in vivo insulinotropic and glycaemic responses were measured in obese diabetic ( ob/ ob) mice.. In GIP receptor-transfected fibroblasts, (Pro(3))GIP or exendin(9-39)amide inhibited GIP-stimulated cyclic AMP production with maximal inhibition of 70.0+/-3.5% and 73.5+/-3.2% at 10(-6) mol/l, respectively. In GLP-1 receptor-transfected fibroblasts, exendin(9-39)amide inhibited GLP-1-stimulated cyclic AMP production with maximal inhibition of 60+/-0.7% at 10(-6) mol/l, whereas (Pro(3))GIP had no effect. (Pro(3))GIP specifically inhibited GIP-stimulated insulin release (86%; p<0.001) from clonal BRIN-BD11 cells, but had no effect on GLP-1-stimulated insulin release. In contrast, exendin(9-39)amide inhibited both GIP and GLP-1-stimulated insulin release (57% and 44%, respectively; p<0.001). Administration of (Pro(3))GIP, exendin(9-39)amide or a combination of both peptides (25 nmol/kg body weight, i.p.) to fasted (ob/ob) mice decreased the plasma insulin responses by 42%, 54% and 49%, respectively (p<0.01 to p<0.001). The hyperinsulinaemia of non-fasted (ob/ob) mice was decreased by 19%, 27% and 18% (p<0.05 to p<0.01) by injection of (Pro3)GIP, exendin(9-39)amide or combined peptides but accompanying changes of plasma glucose were small.. These data show that (Pro(3))GIP is a specific GIP receptor antagonist. Furthermore, feeding studies in one commonly used animal model of obesity and diabetes, (ob/ob) mice, suggest that GIP is the major physiological component of the enteroinsular axis, contributing approximately 80% to incretin-induced insulin release.

Topics: Animals; Cells, Cultured; Cricetinae; Cricetulus; Cyclic AMP; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Mice; Obesity; Peptide Fragments; Postprandial Period; Protein Precursors; Spectrometry, Mass, Electrospray Ionization

We previously developed a canine model of central obesity and insulin resistance by supplementing the normal chow diet with 2 g cooked bacon grease/kg body weight. Dogs fed this fatty diet maintained glucose tolerance with compensatory hyperinsulinemia. The signal(s) responsible for this up-regulation of plasma insulin is unknown. We hypothesized that meal-derived factors such as glucose, fatty acids, or incretin hormones may signal beta-cell compensation in the fat-fed dog. We fed the same fat-supplemented diet for 12 wk to six dogs and compared metabolic responses with seven control dogs fed a normal diet. Fasting and stimulated fatty acid and glucose-dependent insulinotropic peptide concentrations were not increased by fat feeding, whereas glucose was paradoxically decreased, ruling out those three factors as signals for compensatory hyperinsulinemia. Fasting plasma glucagon-like peptide-1 (GLP-1) concentration was 2.5-fold higher in the fat-fed animals, compared with controls, and 3.4-fold higher after a mixed meal. Additionally, expression of the GLP-1 receptor in whole pancreas was increased 2.3-fold in the fat-fed dogs. The increase in both circulating GLP-1 and its target receptor may have increased beta-cell responsiveness to lower glucose. Glucose is not the primary cause of hyperinsulinemia in the fat-fed dog. Corequisite meal-related signals may be permissive for development of hyperinsulinemia.

Topics: Animals; Blood Glucose; Blotting, Northern; Dietary Fats; Dogs; Fasting; Fatty Acids, Nonesterified; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucose; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin Resistance; Islets of Langerhans; Kinetics; Magnetic Resonance Imaging; Male; Obesity; Peptide Fragments; Receptors, Glucagon; Reverse Transcriptase Polymerase Chain Reaction

1. We investigated whether abnormalities of gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (7-36 amide) (GLP-1) contribute to the hypertriglyceridaemia and hyperinsulinaemia in hypertriglyceridaemic subjects. Serum triglycerides and plasma glucose GIP, GLP-1 and immunoreactive insulin (IRI) concentrations were measured before and after a mixed meal in 15 hypertriglyceridaemic patients and in eight healthy normotriglyceridaemic control subjects. 2. Integrated post-prandial GIP concentrations were greater than in controls (P < 0.05) and correlated positively with both fasting and integrated post-prandial triglyceride concentrations (P < 0.05 for both). Fasting and integrated post-prandial IRI levels were higher in hypertriglyceridaemic subjects than in controls (P < 0.02 and P < 0.05 respectively) and correlated positively with fasting triglycerides (P < 0.02 and P < 0.001 respectively) and integrated post-prandial triglycerides (P < 0.005 and P < 0.05 respectively). There was no correlation between GIP concentrations and either fasting or post-prandial IRI levels. Fasting and post-prandial concentrations of GLP-1 were similar in patients and controls. 3. Hypertriglyceridaemic subjects have post-prandial hyperGIPaemia in addition to the well-documented hyperinsulinaemia. We found no association between GIP and insulin. There is, however, clear evidence for an association between post-prandial GIP concentrations and triglyceride levels. We suggest that this association may depend on changes in lipoprotein lipase activity and that there may be a feedback loop between GIP and triglyceride lipolysis.

Topics: Adult; Blood Glucose; Cholesterol; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hyperinsulinism; Hypertriglyceridemia; Male; Middle Aged; Peptide Fragments; Postprandial Period; Statistics, Nonparametric

We investigated the contributions made by the entero-insular axis, proinsulin and the fractional hepatic extraction of insulin to the hyperinsulinaemia characteristic of polycystic ovarian syndrome (PCOS). We measured plasma glucose, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (7-36 amide) (GLP-1(7-36) amide), immunoreactive insulin (IRI), intact proinsulin (IPI), and C-peptide concentrations during a 75 g oral glucose tolerance test in seven normal weight women with PCOS and eight healthy women. Women with PCOS had higher fasting (P = 0.05) and integrated (P < 0.01) IRI concentrations than controls. Fasting C-peptide levels were similar in both groups but integrated C-peptide (P < 0.05) concentrations were greater in PCOS subjects than controls. Fasting and integrated concentrations of glucose, GIP and GLP-1(7-36) amide were similar in subjects with PCOS and controls. Although fasting IPI concentrations were similar in both groups, integrated IPI concentrations were higher (P = 0.05) in patients with PCOS. Women with PCOS had similar fasting but higher (P < 0.05) integrated IRI:C-peptide molar ratios than controls. Fasting and integrated IPI:IRI molar ratios were similar in both groups. These results confirm that lean women with PCOS have peripheral hyperinsulinaemia. The mild fasting hyperinsulinaemia is due to increased pancreatic secretion, whereas the stimulated hyperinsulinaemia is due to both pancreatic hypersecretion and reduced fractional hepatic extraction of insulin. Hyperproinsulinaemia is modest and appropriate in PCOS, GIP and GLP-1(7-36) amide do not contribute to the stimulated hyperinsulinaemia in PCOS.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Neurotransmitter Agents; Peptide Fragments; Polycystic Ovary Syndrome; Proinsulin

A 65-year-old male presented with postprandial hypoglycemic episodes. He had normal glucose tolerance, but plasma glucose reached a hypoglycemic level of 31 mg/dl at 120 min during 75 g oral glucose tolerance test. He had markedly increased insulin response to oral glucose but not to intravenous glucose, intravenous arginine or intravenous glucagon. Hyperresponse of insulin after oral but not intravenous glucose suggested the possible involvement of insulinotropic hormonal factor in the gut (incretin) in hyperinsulinemia of this patient. Therefore we evaluated the secretory response of glucagon like peptide-1 (GLP-1), a most likely candidate for incretin, to oral and intravenous glucose administration. Plasma GLP-1 response to oral glucose was almost five times greater than that of normal subjects. On the other hand, there was no significant response in plasma GLP-1 after intravenous glucose. These results suggest that hypersecretion of GLP-1 may be responsible for the hyperinsulinemia after oral glucose in this patient.

Topics: Aged; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Male; Peptide Fragments; Protein Precursors

The diurnal profiles of pancreatic glucagon, insulin, pancreatic polypeptide (PP), and enteroglucagon were studied in five obese non-diabetic subjects (195 +/- 11 per cent of ideal body weight) and in six age matched controls. All the subjects were served with ordinary mixed meals five times during the day. The obese subjects were normoglycemic but hyperinsulinemic. Both groups showed rapid increases in PP to all meals, but the PP-response was significantly impaired in the obese group during the first part of the day. Normal subjects showed significant enteroglucagon responses to all meals, and had elevated levels throughout the day. In obese subjects, levels and responses were much lower at all times. Pancreatic glucagon profiles were similar. It is concluded that the possible role of abnormalities of PP and enteroglucagon secretion in the pathogenesis of human obesity deserves further study.

Topics: Adult; Animals; Circadian Rhythm; Female; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Male; Mice; Obesity; Pancreatic Polypeptide