Effect of GIP and GLP-1 antagonists  on insulin release in the rat

Tseng, Chi Chuan; Zhang, Xiao Ying; Wolfe, M. Michael

doi:10.1152/ajpendo.1999.276.6.e1049

Cited by 56 publications

(61 citation statements)

References 27 publications

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“…6. These actions include effects on hexose transport in the intestine (Tseng et al 1999) or actions on liver, muscle or adipose tissue (O'Harte et al 1998, Yip & Wolfe 2000, Rudovich et al 2004). However, it may be possible that the reduction in basal plasma glucose concentrations by daily GIP(3-42) treatment led to reduced glucose toxicity in these animals and thus contributed to the improvement of their diabetic status.…”

Section: Discussionmentioning

confidence: 99%

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

Parker

Lavery

Irwin

et al. 2006

Journal of Endocrinology

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Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and AbstractGlucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important enteroendocrine hormones that are rapidly degraded by an ubiquitous enzyme dipeptidyl peptidase IV to yield truncated metabolites GIP(3-42) and GLP-1(9-36)amide. In this study, we investigated the effects of sub-chronic exposure to these major circulating forms of GIP and GLP-1 on blood glucose control and endocrine pancreatic function in obese diabetic (ob/ob) mice. A once daily injection of either peptide for 14 days had no effect on body weight, food intake or pancreatic insulin content or islet morphology. GLP-1(9-36)amide also had no effect on plasma glucose homeostasis or insulin secretion. Mice receiving GIP(3-42) exhibited small but significant improvements in non-fasting plasma glucose, glucose tolerance and glycaemic response to feeding. Accordingly, plasma insulin responses were unchanged suggesting that the observed enhancement of insulin sensitivity was responsible for the improvement in glycaemic control. These data indicate that sub-chronic exposure to GIP and GLP-1 metabolites does not result in physiological impairment of insulin secretion or blood glucose control. GIP(3-42) might exert an overall beneficial effect by improving insulin sensitivity through extrapancreatic action.

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Section: Discussionmentioning

confidence: 99%

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

Parker

Lavery

Irwin

et al. 2006

Journal of Endocrinology

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“…In previous studies where exendin amide was administered to rats, postprandial insulin release was reduced by 50-70% [16,18]. Other studies concluded that the incretin effects of GIP and GLP-1 account for greater than 50% of meal-induced insulin release, with the insulin response decreased by 72% following administration of the GIP receptor-antagonist, GIP(7-30)-NH 2 (ANTGIP), to chow-fed rats [44,45]. These values are broadly in line with our study.…”

Section: Discussionmentioning

confidence: 99%

“…injection (n=8) of saline (0.9% (w/v) NaCl; control), (Pro 3 )GIP (25 nmol/kg body weight), exendin(9-39)amide (25 nmol/kg body weight) or a combination of both peptides (each at 25 nmol/kg body weight). These doses will result in high concentrations of antagonist (µmol/l) relative to endogenous GIP or GLP-1 (pmol/l range) [46], and have been shown in other studies to abolish oral glucose or peptide-induced insulin increase [26,45]. Following injection (8 ml/kg body weight; final volume), the mice were allowed to re-feed for 15 min, and the food intake monitored.…”

Section: Effects Of (Pro3)gip and Exendin(9-39)amide On Plasma Glucosmentioning

confidence: 99%

Effects of the novel (Pro3)GIP antagonist and exendin(9–39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin

et al. 2003

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Aims/hypothesis. This study examined the biological effects of the GIP receptor antagonist, (Pro 3 )GIP and the GLP-1 receptor antagonist, exendin(9-39)amide. Methods 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. Results. 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 (Pro 3 )GIP, exendin(9-39)amide or combined peptides but accompanying changes of plasma glucose were small. Conclusions/interpretation. 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. [Diabetologia (2003) 46:222-230] Keywords Enteroinsular axis, GIP receptor antagonist, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, insulin release. The insulin secretory activity of pancreatic beta cells can be modulated in both a positive or negative manner by several peptide hormones and neurotransmitters [1,2,3]. The two intestinal hormones, glucosedependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1-(7-36)amide (GLP-1) have long been recognised as potent stimulators of insulin secretion under physiological conditions, and for that reason they are considered important incretin hormones [4,5,6]. The effects of both GIP and GLP-1 are glucose-dependent, providing a safeguard against potentially hazardous hypoglycaemic episodes, and as a

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“…Analyses based on the FDA Adverse Event Reporting System (FAERS) showed that incretinmimetic drugs are linked with increased incidence of pancreatitis and pancreatic cancer compared with other anti-diabetic drugs [160][161][162] [161]. Based on this evidence, FDA investigates reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin-mimetic drugs [71].…”

Section: Cancermentioning

confidence: 99%

Adverse Effects of GLP-1 Receptor Agonists

2014

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■ AbstractGlucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.

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Effect of GIP and GLP-1 antagonists on insulin release in the rat

Cited by 56 publications

References 27 publications

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

Effects of the novel (Pro3)GIP antagonist and exendin(9–39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin

Adverse Effects of GLP-1 Receptor Agonists

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