PACAP contributes to insulin secretion after gastric glucose gavage in mice

2000 ◽  
Vol 279 (2) ◽  
pp. R424-R432 ◽  
Author(s):  
Karin Filipsson ◽  
Jens Juul Holst ◽  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Insulin Response ◽  
Gastric Inhibitory Polypeptide ◽  
Inhibitory Effect ◽  
Intravenous Glucose ◽  
Parasympathetic Nerves ◽  
Prandial Insulin ◽  
Pituitary Adenylate Cyclase ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Pituitary adenylate cyclase-activating polypeptide (PACAP) is localized to pancreatic ganglia governing the parasympathetic nerves, which contribute to prandial insulin secretion. We hypothesized that this contribution involves PACAP and show here that the PACAP receptor antagonist PACAP-(6—27) (1.5 nmol/kg iv) reduces the 15-min insulin response to gastric glucose (150 mg/mouse) by 18% in anesthetized mice ( P = 0.041). The reduced insulinemia was not due to inhibited release of the incretin factor glucagon-like peptide 1 (GLP-1) because PACAP-(6—27) enhanced the GLP-1 response to gastric glucose. Furthermore, the GLP-1 antagonist exendin-3-(9—39) (30 nmol/kg) exerted additive inhibitory effect on the insulin response when combined with PACAP-(6—27). The PACAP antagonism was specific because intravenous PACAP-(6—27) inhibited the insulin response to intravenous PACAP-27 plus glucose without affecting the insulin response to intravenous glucose alone (1 g/kg) or glucose together with other insulin secretagogues of potential incretin relevance of intestinal (GLP-1, gastric inhibitory polypeptide, cholecystokinin) and neural (vasoactive intestinal peptide, gastrin-releasing peptide, cholinergic agonism) origin. We conclude that PACAP contributes to the insulin response to gastric glucose in mice and suggest that PACAP is involved in the regulation of prandial insulin secretion.

Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice

2004 ◽  
Vol 286 (2) ◽  
pp. R269-R272 ◽  
Author(s):  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Direct Action ◽  
Insulin Response ◽  
Sensory Nerves ◽  
High Dose ◽  
Intravenous Glucose ◽  
Insulin Response To Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

It has been hypothesized that the potent insulinotropic action of the gut incretin hormone glucagon-like peptide-1 (GLP-1) is exerted not only through a direct action on the beta cells but may be partially dependent on sensory nerves. We therefore examined the influence of GLP-1 in mice rendered sensory denervated by neonatal administration of capsaicin performed at days 2 and 5 (50 mg/kg). Control mice were given vehicle. Results show that at 10-16 wk of age in control mice, intravenous GLP-1 at 0.1 or 10 nmol/kg augmented the insulin response to intravenous glucose (1 g/kg) in association with improved glucose elimination. In contrast, in capsaicin-pretreated mice, GLP-1 at 0.1 nmol/kg could not augment the insulin response to intravenous glucose and no effect on glucose elimination was observed. Nevertheless, at the high dose of 10 nmol/kg, GLP-1 augmented the insulin response to glucose in capsaicin-pretreated mice as efficiently as in control mice. The insulin response to GLP-1 from isolated islets was not affected by neonatal capsaicin, and, furthermore, the in vivo insulin response to glucose was augmented whereas that to arginine was not affected by capsaicin. It is concluded that GLP-1-induced insulin secretion at a low dose in mice is dependent on intact sensory nerves and therefore indirectly mediated and that this distinguishes GLP-1 from other examined insulin secretagogues.

scholarly journals Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells)

1999 ◽  
Vol 277 (4) ◽  
pp. R959-R966 ◽  
Author(s):  
Bo Ahrén ◽  
Peter J. Havel
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Insulin Response ◽  
Signal Transduction Pathway ◽  
Intracellular Camp ◽  
Intracellular Content ◽  
Pituitary Adenylate Cyclase ◽  
Insulin Response To Glucose ◽  
Glucagon Like Peptide 1 ◽  
Activate Protein Kinase

The effect of leptin on insulin secretion is controversial due to conflicting results in the literature. In the present study, we incubated insulin-producing rat insulinoma INS-1 cells for 60 min and examined the effects of recombinant murine leptin (20 nmol/l). We found that leptin (0.1–100 nmol/l) did not affect the insulin response to glucose (1–20 mmol/l). However, when cells were incubated with agents that increase the intracellular content of cAMP, i.e., glucagon-like peptide-1 (100 nmol/l), pituitary adenylate cyclase activating polypeptide (100 nmol/l), forskolin (2.5 μmol/l), dibutyryl-cAMP (1 mmol/l), or 3-isobutyl-1-methylxanthine (100 μmol/l), leptin significantly reduced insulin secretion (by 34–58%, P < 0.05–0.001). In contrast, when insulin secretion was stimulated by the cholinergic agonist carbachol (100 μmol/l) or the phorbol ester 12- O-tetradecanoylphorbol 13-acetate (1 μmol/l), both of which activate protein kinase C, leptin was without effect. We conclude that leptin inhibits insulin secretion from INS-1 cells under conditions in which intracellular cAMP is increased. This suggests that the cAMP-protein kinase A signal transduction pathway is a target for leptin to inhibit insulin secretion in insulin-producing cells.

Reduced gastric inhibitory polypeptide but normal glucagon-like peptide 1 response to oral glucose in postmenopausal women with impaired glucose tolerance

1997 ◽  
pp. 127-131 ◽  
Author(s):  
B Ahren ◽  
H Larsson ◽  
JJ Holst
Keyword(s):  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Postmenopausal Women ◽  
Plasma Levels ◽  
Insulin Response ◽  
Gastric Inhibitory Polypeptide ◽  
Oral Glucose ◽  
Glucose Ingestion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

OBJECTIVE: The gastrointestinal hormones, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), are both released from the gut after oral glucose ingestion and stimulate insulin secretion. This study examined the release of these hormones in subjects with impaired glucose tolerance (IGT), which precedes the development of non-insulin-dependent diabetes. DESIGN AND METHODS: Six postmenopausal women with IGT, aged 59 years, underwent a 75 g oral glucose tolerance test and plasma levels of GIP and GLP-1 were determined regularly during the following 2 h. The results were compared with those in seven age- and weight-matched women with normal glucose tolerance (NGT). RESULTS: Basal plasma levels of GIP and GLP-1 were not different between the groups. In response to the oral glucose ingestion, plasma levels of both GIP and GLP-1 increased in both groups. The plasma GIP increase after glucose ingestion was, however, reduced in women with IGT. Thus, the GIP response as determined as the area under the curve for the 60 min after oral glucose was 34.8 +/- 3.2 pmol/l per min in women with IGT versus 56.4 +/- 7.8 pmol/l per min in those with NGT (P = 0.021). In contrast, the GLP-1 response to oral glucose was not different between the groups. By definition, the glucose response to oral glucose was markedly increased in women with IGT, and the insulin response during the second hour after glucose ingestion was exaggerated. CONCLUSIONS: The GIP response to oral glucose is impaired in postmenopausal women with IGT, whereas the plasma GLP-1 response is not affected.

scholarly journals Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors

2018 ◽  
Vol 314 (5) ◽  
pp. R639-R646 ◽  
Author(s):  
Andrea Tura ◽  
Roberto Bizzotto ◽  
Yuchiro Yamada ◽  
Yutaka Seino ◽  
Giovanni Pacini ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Clearance ◽  
Second Phase ◽  
Incretin Hormones ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Double Deletion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
First Phase Insulin Secretion

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10−3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10−3 l/min in DIRKO mice vs. 0.54 ± 0.03 10−3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.

Reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon-like peptide 1 or gastric inhibitory polypeptide in humans

2007 ◽  
Vol 293 (3) ◽  
pp. E849-E856 ◽  
Author(s):  
Juris J. Meier ◽  
Jens J. Holst ◽  
Wolfgang E. Schmidt ◽  
Michael A. Nauck
Keyword(s):  
Gastric Inhibitory Polypeptide ◽  
Insulin Clearance ◽  
Oral Glucose ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Glucose Administration ◽  
Glucose Ingestion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Hepatic Insulin Clearance

Changes in hepatic insulin clearance can occur after oral glucose or meal ingestion. This has been attributed to the secretion and action of gastric inhibitory polypeptide (GIP) and glucagon-like peptide (GLP)−1. Given the recent availability of drugs based on incretin hormones, such clearance effects may be important for the future treatment of type 2 diabetes. Therefore, we determined insulin clearance in response to endogenously secreted and exogenously administered GIP and GLP-1. Insulin clearance was estimated from the molar C-peptide-to-insulin ratio calculated at basal conditions and from the respective areas under the curve after glucose, GIP, or GLP-1 administration. Oral glucose administration led to an ∼60% reduction in the C-peptide-to-insulin ratio ( P < 0.0001), whereas intravenous glucose administration had no effect ( P = 0.09). The endogenous secretion of GIP or GLP-1 was unrelated to the changes in insulin clearance. The C-peptide-to-insulin ratio was unchanged after the intravenous administration of GIP or GLP-1 in the fasting state ( P = 0.27 and P = 0.35, respectively). Likewise, infusing GLP-1 during a meal course did not alter insulin clearance ( P = 0.87). An inverse nonlinear relationship was found between the C-peptide-to-insulin ratio and the integrated insulin levels after oral and during intravenous glucose administration. Insulin clearance is reduced by oral but not by intravenous glucose administration. Neither GIP nor GLP-1 has significant effects on insulin extraction. An inverse relationship between insulin concentrations and insulin clearance suggests that the secretion of insulin itself determines the rate of hepatic insulin clearance.

Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes

2004 ◽  
Vol 286 (6) ◽  
pp. E882-E890 ◽  
Author(s):  
David A. D'Alessio ◽  
Torsten P. Vahl
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Cell Mass ◽  
Insulin Response ◽  
Gastrointestinal Hormones ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Treatment Of Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP-1) is a product of proglucagon that is secreted by specialized intestinal endocrine cells after meals. GLP-1 is insulinotropic and plays a role in the incretin effect, the augmented insulin response observed when glucose is absorbed through the gut. GLP-1 also appears to regulate a number of processes that reduce fluctuations in blood glucose, such as gastric emptying, glucagon secretion, food intake, and possibly glucose production and glucose uptake. These effects, in addition to the stimulation of insulin secretion, suggest a broad role for GLP-1 as a mediator of postprandial glucose homeostasis. Consistent with this role, the most prominent effect of experimental blockade of GLP-1 signaling is an increase in blood glucose. Recent data also suggest that GLP-1 is involved in the regulation of β-cell mass. Whereas other insulinotropic gastrointestinal hormones are relatively ineffective in stimulating insulin secretion in persons with type 2 diabetes, GLP-1 retains this action and is very effective in lowering blood glucose levels in these patients. There are currently a number of products in development that utilize the GLP-1-signaling system as a mechanism for the treatment of diabetes. These compounds, GLP-1 receptor agonists and agents that retard the metabolism of native GLP-1, have shown promising results in clinical trials. The application of GLP-1 to clinical use fulfills a long-standing interest in adapting endogenous insulinotropic hormones to the treatment of diabetes.

GLP-1-(9–36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion

2002 ◽  
Vol 282 (4) ◽  
pp. E873-E879 ◽  
Author(s):  
Carolyn F. Deacon ◽  
Astrid Plamboeck ◽  
Søren Møller ◽  
Jens J. Holst
Keyword(s):  
Insulin Secretion ◽  
Therapeutic Potential ◽  
Intravenous Glucose ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Independent Effects ◽  
Insulinotropic Effect ◽  
Insulin Responses

Glucagon-like peptide 1 (GLP-1) is a potent anti-hyperglycemic hormone currently under investigation for its therapeutic potential. However, due to rapid degradation by dipeptidyl peptidase IV (DPP IV), which limits its metabolic stability and eliminates its insulinotropic activity, it has been impossible to assess its true efficacy in vivo. In chloralose-anesthetized pigs given valine-pyrrolidide (to block endogenous DPP IV activity), the independent effects of GLP-1-(7–36) amide on glucose and insulin responses to intravenous glucose were assessed, and the metabolite generated by DPP IV, GLP-1-(9–36) amide, was investigated for any ability to influence these responses. GLP-1-(7–36) amide enhanced insulin secretion ( P < 0.03 vs. vehicle), but GLP-1-(9–36) amide was without effect, either alone or when coinfused with GLP-1-(7–36) amide. In contrast, GLP-1-(9–36) amide did affect glucose responses ( P < 0.03). Glucose excursions were greater after saline (121 ± 17 mmol · l−1 · min) than after GLP-1-(9–36) amide (73 ± 19 mmol · l−1 · min; P < 0.05), GLP-1-(7–36) amide (62 ± 13 mmol · l−1 · min; P < 0.02) or GLP-1-(7–36) amide + GLP-1-(9–36) amide (50 ± 13 mmol · l−1 · min; P < 0.005). Glucose elimination rates were faster after GLP-1-(7–36) amide + (9–36) amide (10.3 ± 1.2%/min) than after GLP-1-(7–36) amide (7.0 ± 0.9%/min; P < 0.04), GLP-1-(9–36) amide (6.8 ± 1.0%/min; P < 0.03), or saline (5.4 ± 1.2%/min; P < 0.005). Glucagon concentrations were unaffected. These results demonstrate that GLP-1-(9–36) amide neither stimulates insulin secretion nor antagonizes the insulinotropic effect of GLP-1-(7–36) amide in vivo. Moreover, the metabolite itself possesses anti-hyperglycemic effects, supporting the hypothesis that selective DPP IV action is important in glucose homeostasis.

scholarly journals Coingestion of Acylglycerols Differentially Affects Glucose-Induced Insulin Secretion via Glucose-Dependent Insulinotropic Polypeptide in C57BL/6J Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2118-2126 ◽  
Author(s):  
Akira Shimotoyodome ◽  
Daisuke Fukuoka ◽  
Junko Suzuki ◽  
Yoshie Fujii ◽  
Tomohito Mizuno ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Dietary Fat ◽  
Energy Homeostasis ◽  
Insulin Response ◽  
Postprandial Blood Glucose ◽  
Dependent Manner ◽  
Nutrient Metabolism ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Chylomicron Formation

The precise role of fat in postprandial glycemia and insulinemia has not been thoroughly researched because postprandial blood glucose and concurrent insulin secretion are largely assumed to be proportional to carbohydrate intake. Recent studies have suggested that dietary fat differentially regulates the postprandial insulin response. To explore this, we examined the effects of coadministered fat on glucose-induced glycemia and insulinemia in C57BL/6J mice. The insulin response to glucose was augmented by the addition of glycerol trioleate (TO) in a dose-dependent manner, which was associated with enhanced glucose transport from the circulation to muscle and adipose tissues. To investigate the mechanism underlying fat-induced hyperinsulinemia, we examined the release of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1. TO increased GIP secretion, whereas glucagon-like peptide-1 secretion was unaffected. TO-induced hyperinsulinemia was significantly attenuated by the pretreatment of mice with a specific GIP antagonist. Diacylglycerol (DAG) promoted lower postprandial GIP and triglyceride responses and, when ingested with glucose, a lower insulin response compared with triacylglycerol of a similar fatty acid composition. Pluronic L-81, an inhibitor of chylomicron formation, reduced not only the triglyceride response but also TO-induced GIP secretion, indicating that the lower GIP response after DAG ingestion may be associated with retarded chylomicron formation in the small intestine. We conclude that dietary fat augments glucose-induced insulinemia via gut-derived GIP and, thereby, influences postprandial nutrient metabolism in mice. DAG promotes a lower GIP and thereby reduced insulin responses compared with triacylglycerol, which may differentially influence postprandial energy homeostasis.

scholarly journals Role of a Dual Glucose-Dependent Insulinotropic Peptide (GIP)/Glucagon-like Peptide-1 Receptor Agonist (Twincretin) in Glycemic Control: From Pathophysiology to Treatment

Life ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 29
Author(s):  
Maria Chiara Pelle ◽  
Michele Provenzano ◽  
Isabella Zaffina ◽  
Roberta Pujia ◽  
Federica Giofrè ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Insulin Secretion ◽  
Phase 1 ◽  
Synergetic Effect ◽  
Insulin Response ◽  
Gut Hormones ◽  
Acute Effect ◽  
Oral Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two gut hormones, defined incretins, responsible for the amplification of insulin secretion after oral glucose intake. Unlike GLP-1, GIP has little acute effect on insulin secretion and no effect on food intake; instead it seems that the GIP may be an obesity-promoting hormone. In patients with type2 diabetes mellitus (T2DM) some studies found a downregulation of GIP receptors on pancreatic β cells caused by hyperglycemic state, but the glucagonotropic effect persisted. Agonists of the receptor for the GLP-1 have proven successful for the treatment of diabetes, since they reduce the risk for cardiovascular and renal events, but the possible application of GIP as therapy for T2DM is discussed. Moreover, the latest evidence showed a synergetic effect when GIP was combined with GLP-1 in monomolecular co-agonists. In fact, compared with the separate infusion of each hormone, the combination increased both insulin response and glucagonostatic response. In accordance with theseconsiderations, a dual GIP/GLP-1receptor agonist, i.e., Tirzepatide, known as a “twincretin” had been developed. In the pre-clinical trials, as well as Phase 1–3 clinical trials, Tirzepatideshowedpotent glucose lowering and weight loss effects within an acceptable safety.

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