The effects of glucose-dependent insulinotropic polypeptide infused at physiological concentrations in normal subjects and Type 2 (non-insulin-dependent) diabetic patients on glucose tolerance and B-cell secretion

Jones, Ian; Owens, D. R.; Moody, A. J.; Luzio, Stephen Denis; Morris, Tracy L.; Hayes, T M

doi:10.1007/bf00296993

Cited by 76 publications

(30 citation statements)

References 34 publications

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“…Although a reduced insulinotropic effect of GIP in patients with type 2 diabetes has uniformly been reported by different investigators [7,8,11,[24][25][26], the underlying defects are as yet unknown. Indeed, if the action of GIP in type 2 diabetes was impaired as a result of a specific defect, e.g.…”

Section: Discussionmentioning

confidence: 95%

Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes

et al. 2005

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Aims/hypothesis: The insulinotropic effect of gastric inhibitory polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion. Materials and methods:On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg −1 min −1 ; 30-90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA. Results: Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucosestimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration. Conclusions/interpretation: These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.

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Section: Discussionmentioning

confidence: 95%

Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes

et al. 2005

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“…There is experimental evidence demonstrating a paucity of GLP-1 release from the L cells of patients with type 2 diabetes [15][16][17]. It is likely that chronic hyperinsulinaemia determined by HFD, and which is also a characteristic of early diabetes and insulin resistance, may exert damaging effects upon L cell function via a feedforward cycle.…”

Section: Discussionmentioning

confidence: 99%

High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats

et al. 2010

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Aims/hypothesis Incretins are hormones released by enteroendocrine cells in response to meals, depending upon absorption of nutrients. The present study aimed to elucidate the mechanisms through which a high-fat diet (HFD) induces insulin resistance and insulin hypersecretion by focusing on the effects on enteroendocrine cells, especially those secreting glucose-dependent insulinotropic polypeptide (GIP). Methods Forty male Wistar rats, 4 months old, were randomised into two groups; one group received a chow diet and the other one received a purified tripalmitin-based HFD ad libitum. An OGTT was performed every 10 days and histological and immunofluorescence evaluations of the duodenum were obtained at 60 days from the beginning of the diets. Plasma glucose, insulin, GIP and glucagon-like peptide-1 (GLP-1) levels were measured. Immunofluorescence analysis of duodenal sections for pancreatic duodenal homeobox-1 (PDX-1), KI67, GLP-1, GIP and insulin were performed. Results Compared with chow diet, HFD induced a progressive significant increase of the glucose, insulin and GIP responses to OGTT, whereas GLP-1 circulating levels were reduced over time. After 60 days of HFD, cellular agglomerates of KI67 and PDX-1 positive cells, negative for insulin and GLP-1 but positive for GIP staining, were found inside the duodenal mucosa, and apoptosis was significantly increased. Conclusions/interpretation With the limitation that we could not establish a causal relationship between events, our study shows that HFD stimulates duodenal proliferation of endocrine cells differentiating towards K cells and oversecreting GIP. The progressive increment of GIP levels might represent the stimulus for insulin hypersecretion and insulin resistance.Keywords Duodenum . Glucose-dependent insulinotropic polypeptide . Glucagon-like peptide-1 . Endocrine cell hyperplasia . High-fat diet . Insulin Abbreviations GIPGlucose-dependent insulinotropic polypeptide GLP-1 Glucagon-like peptide-1 HFD High-fat diet PDX-1 Pancreatic duodenal homeobox-1

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“…Although incretins such as gastric inhibitory polypeptide and GLP-1 have been proposed as possible treatments for patients with diabetes, short term infusion of gastric inhibitory polypeptide has been associated with diminished effectiveness in diabetic patients (50) and desensitization of the gastric inhibitory polypeptide receptor in diabetic rats in vivo (51). Both homologous and heterologous desensitization of GLP-1 receptor signaling has also been observed in islet cell lines in vitro (52)(53)(54).…”

Section: Exendin-4 Transgenic Micementioning

confidence: 99%

Sustained Expression of Exendin-4 Does Not Perturb Glucose Homeostasis, β-Cell Mass, or Food Intake in Metallothionein-Preproexendin Transgenic Mice

Baggio

Adatia

Bock

et al. 2000

Journal of Biological Chemistry

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Activation of glucagon-like peptide (GLP)-1 receptor signaling promotes glucose lowering via multiple mechanisms, including regulation of food intake, glucose-dependent insulin secretion, and stimulation of ␤-cell mass. As GLP-1 exhibits a short t1 ⁄2 in vivo, the biological consequences of prolonged GLP-1 receptor signaling remains unclear. To address this question, we have now generated metallothionein promoter-preproexendin (MT-Ex) transgenic mice. MT-Ex mice process preproexendin correctly, as is made evident by detection of circulating plasma exendin-4 immunoreactivity using high pressure liquid chromatography and an exendin-4-specific radioimmunoassay. Despite elevated levels of exendin-4, fasting plasma glucose and glucose clearance following oral and intraperitoneal glucose tolerance tests are normal in MT-Ex mice. Induction of transgene expression significantly reduced glycemic excursion during both oral and intraperitoneal glucose tolerance tests (p < 0.05) and increased levels of glucose-stimulated insulin following oral glucose administration (p < 0.05). Despite evidence that exendin-4 may induce ␤-cell proliferation, ␤-cell mass and islet histology were normal in MT-Ex mice. MT-Ex mice exhibited no differences in basal food intake or body weight; however, induction of exendin-4 expression was associated with reduced short term food ingestion (p < 0.05). In contrast, short term water intake was significantly reduced in the absence of zinc in fluid-restricted MT-Ex mice (p < 0.05). These findings illustrate that sustained elevation of circulating exendin-4 is not invariably associated with changes in glucose homeostasis, increased ␤-cell mass, or reduction in food intake in mice in vivo.Glucagon-like peptide-1 (GLP-1), 1 a product of the proglucagon gene, is released from gut endocrine cells and potentiates glucose-dependent insulin secretion (1). GLP-1 also regulates gastric emptying, food intake, glucagon secretion, and islet proliferation and hence is currently under investigation as a therapeutic agent for the treatment of diabetes (1). However, a significant limitation to potential GLP-1 therapy in diabetic subjects is the short biological half-life of this peptide (2-4), limiting its ability to control blood glucose for an extended period of time. These considerations have prompted investigation of strategies designed to prolong the duration of GLP-1 action in vivo (5, 6). Exendin-4, a peptide structurally related to but distinct from GLP-1 (7) was originally purified from the venom of a Heloderma suspectum lizard (8, 9). Subsequent characterization of exendin-4 activity demonstrated that the lizard peptide was a potent agonist for the mammalian glucagon-like peptide-1 receptor (GLP-1R) (8 -11). Exendin-4 exhibits a much longer in vivo half-life and prolonged duration of action (11), rendering it more potent for continuous stimulation of GLP-1 receptor signaling and sustained improvement in glucose homeostasis in vivo. Despite the structural homology of lizard exendin-4 and mammalian GLP-1, a ma...

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The effects of glucose-dependent insulinotropic polypeptide infused at physiological concentrations in normal subjects and Type 2 (non-insulin-dependent) diabetic patients on glucose tolerance and B-cell secretion

Cited by 76 publications

References 34 publications

Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes

Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes

High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats

Sustained Expression of Exendin-4 Does Not Perturb Glucose Homeostasis, β-Cell Mass, or Food Intake in Metallothionein-Preproexendin Transgenic Mice

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