exendin-(9-39) and Hyperinsulinism

Bariatric surgery is the most effective treatment for obesity and diabetes. The 2 most commonly performed weight-loss procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, improve glycemic control in patients with type 2 diabetes independent of weight loss. One of the early hypotheses raised to explain the immediate antidiabetic effect of RYGB was that rapid delivery of nutrients from the stomach pouch into the distal small intestine enhances enteroinsular signaling to promote insulin signaling. Given the tenfold increase in postmeal glucagon-like peptide-1 (GLP-1) response compared to unchanged integrated levels of postprandial glucose-dependent insulinotropic peptide after RYGB, enhanced meal-induced insulin secretion after this procedure was thought to be the result of elevated glucose and GLP-1 levels. In this contribution to the larger point-counterpoint debate about the role of GLP-1 after bariatric surgery, most of the focus will be on RYGB.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Peptide Fragments; Postprandial Period; Weight Loss

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

To evaluate the efficacy, pharmacokinetic (PK) profile and tolerability of subcutaneous (s.c.). exendin 9-39 (Ex-9) injection in patients with post-bariatric hypoglycaemia (PBH).. Nine women who had recurrent symptomatic hypoglycaemia after undergoing Roux-en-Y gastric bypass were enrolled in this 2-part, single-blind, single-ascending-dose study. In Part 1, a single participant underwent equimolar low-dose intravenous (i.v.) vs s.c. Ex-9 administration; in Part 2, 8 participants were administered single ascending doses of s.c. Ex-9 during an oral glucose tolerance test (OGTT). Glycaemic, hormonal, PK and symptomatic responses were compared with those obtained during the baseline OGTT.. Although an exposure-response relationship was observed, all doses effectively prevented hyperinsulinaemic hypoglycaemia and improved associated symptoms. On average, the postprandial glucose nadir was increased by 66%, peak insulin was reduced by 57%, and neuroglycopenic symptoms were reduced by 80%. All doses were well tolerated with no treatment-emergent adverse events observed.. Injection s.c. of Ex-9 appears to represent a safe, effective and targeted therapeutic approach for treatment of PBH. Further investigation involving multiple doses with chronic dosing is warranted.

Topics: Adult; Area Under Curve; Cohort Studies; Dose-Response Relationship, Drug; Female; Gastric Bypass; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Half-Life; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Injections, Subcutaneous; Insulin; Middle Aged; Peptide Fragments; Pilot Projects; Postoperative Complications; Postprandial Period; Single-Blind Method

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the β-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism.. Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.

Topics: Animals; Antibodies; Blood Glucose; Congenital Hyperinsulinism; Diazoxide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hyperinsulinism; Mice; Mutation; Sulfonylurea Receptors

The aim of this study was to assess whether exendin-(9-39) will increase fasting and postprandial plasma glucose and decrease the incidence of hypoglycemia in children with hyperinsulinism (HI).. This was an open-label, four-period crossover study. In periods 1 and 2, the effect of three different dosing regimens of exendin-(9-39) (group 1, 0.28 mg/kg; group 2, 0.44 mg/kg; group 3, 0.6 mg/kg) versus vehicle on fasting glucose was assessed in 16 children with HI. In periods 3 and 4, a subset of eight subjects received either vehicle or exendin-(9-39) (0.6 mg/kg) during a mixed-meal tolerance test (MMTT) and an oral protein tolerance test (OPTT).. Treatment group 2 showed 20% (P = 0.037) increase in the area under the curve (AUC) of fasting glucose. A significant increase in AUC of glucose was also observed during the MMTT and OPTT; treatment with exendin-(9-39) resulted in 28% (P ≤ 0.001) and 30% (P = 0.01) increase in AUC of glucose, respectively. Fasting AUC of insulin decreased by 57% (P = 0.009) in group 3. In contrast, AUC of insulin was unchanged during the MMTT and almost twofold higher (P = 0.004) during the OPTT with exendin-(9-39) treatment. In comparison with vehicle, infusion of exendin-(9-39) resulted in significant reduction in likelihood of hypoglycemia in group 2, by 76% (P = 0.009), and in group 3, by 84% (P = 0.014). Administration of exendin-(9-39) during the OPTT resulted in 82% (P = 0.007) reduction in the likelihood of hypoglycemia.. These results support a therapeutic potential of exendin-(9-39) to prevent fasting and protein-induced hypoglycemia in children with HI.

Topics: Blood Glucose; Child; Congenital Hyperinsulinism; Cross-Over Studies; Fasting; Glucose; Humans; Hyperinsulinism; Insulin; Insulin, Regular, Human; Peptide Fragments; Postprandial Period

Although patients with diabetes mellitus (DM) often exhibit hypertension, the mechanisms responsible for this correlation are not well known. We hypothesized that the bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are affected by the levels of glucose, insulin, or incretins (glucagon like peptide-1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP]) in patients with DM. To investigate whether RVLM neurons are activated by glucose, insulin, GLP-1, or GIP, we examined changes in the membrane potentials of bulbospinal RVLM neurons using whole-cell patch-clamp technique during superfusion with various levels of glucose or these hormones in neonatal Wistar rats. A brainstem-spinal cord preparation was used for the experiments. A low level of glucose stimulated bulbospinal RVLM neurons. During insulin superfusion, almost all the RVLM neurons were depolarized, while during GLP-1 or GIP superfusion, almost all the RVLM neurons were hyperpolarized. Next, histological examinations were performed to examine transporters for glucose and receptors for insulin, GLP-1, and GIP on RVLM neurons. Low-level glucose-depolarized RVLM neurons exhibited the presence of glucose transporter 3 (GLUT3). Meanwhile, insulin-depolarized, GLP-1-hyperpolarized, and GIP-hyperpolarized RVLM neurons showed each of the respective specific receptor. These results indicate that a low level of glucose stimulates bulbospinal RVLM neurons via specific transporters on these neurons, inducing hypertension. Furthermore, an increase in insulin or a reduction in incretins may also activate the sympathetic nervous system and induce hypertension by activating RVLM neurons via their own receptors.

Topics: Animals; Animals, Newborn; Central Nervous System Agents; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Transporter Type 3; Hyperinsulinism; Hypoglycemia; Insulin; Medulla Oblongata; Membrane Potentials; Neurons; Peptide Fragments; Peptides; Rats, Wistar; Tetrodotoxin; Tissue Culture Techniques

Hypoglycemia and hyperglycemia are both predictors for adverse outcome in critically ill patients. Hyperinsulinemia is induced by inflammatory stimuli as a relevant mechanism for glucose lowering in the critically ill. The incretine hormone GLP-1 was currently found to be induced by endotoxin, leading to insulin secretion and glucose lowering under inflammatory conditions in mice. Here, we describe GLP-1 secretion to be increased by a variety of inflammatory stimuli, including endotoxin, interleukin-1β (IL-1β), and IL-6. Although abrogation of IL-1 signaling proved insufficient to prevent endotoxin-dependent GLP-1 induction, this was abolished in the absence of IL-6 in respective knockout animals. Hence, we found endotoxin-dependent GLP-1 secretion to be mediated by an inflammatory cascade, with IL-6 being necessary and sufficient for GLP-1 induction. Functionally, augmentation of the GLP-1 system by pharmacological inhibition of DPP-4 caused hyperinsulinemia, suppression of glucagon release, and glucose lowering under endotoxic conditions, whereas inhibition of the GLP-1 receptor led to the opposite effect. Furthermore, total GLP-1 plasma levels were profoundly increased in 155 critically ill patients presenting to the intensive care unit (ICU) in comparison with 134 healthy control subjects. In the ICU cohort, GLP-1 plasma levels correlated with markers of inflammation and disease severity. Consequently, GLP-1 provides a novel link between the immune system and the gut with strong relevance for metabolic regulation in context of inflammation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Blood Glucose; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperinsulinism; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Male; Mice, Knockout; Middle Aged; Peptide Fragments; Receptors, Glucagon; Young Adult

Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a 1-month chronic blockage of brain GLP-1 signaling by exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin resistance in HFD mice. Furthermore, food intake was dramatically increased, but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.

Topics: Animals; Blood Glucose; Body Temperature Regulation; Brain Stem; Carbon Dioxide; Diabetes Mellitus, Type 2; Dietary Fats; Energy Metabolism; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperinsulinism; Insulin Resistance; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Motor Activity; Muscle, Skeletal; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxygen Consumption; Peptide Fragments; Physical Endurance; Proglucagon; RNA, Messenger; Signal Transduction; Uncoupling Protein 2

Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Brain; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Glycogen; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Nuclear Proteins; Osmosis; Peptide Fragments; Phosphatidylinositol 3-Kinases; Phosphorylation; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Transcription Factors

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