Comparative Effects of Prolonged and Intermittent Stimulation of the Glucagon-Like Peptide 1 Receptor on Gastric Emptying and Glycemia

Umapathysivam, Mahesh M.; Lee, Michael Y.; Jones, Karen L.; Annink, Christopher E.; Cousins, Caroline E.; Trahair, Laurence G.; Rayner, Christopher K.; Chapman, Marianne J.; Nauck, Michael A.; Deane, Adam M.

doi:10.2337/db13-0893

Cited by 133 publications

(121 citation statements)

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“…Several studies failed to show any effect of DPP-4 inhibitors on gastric emptying in health or type 2 diabetes (9,(26)(27)(28), probably related to changes in other peptides that regulate gastric emptying (e.g., reduced conversion of peptide YY to ) (29), and differences in test meal, subject characteristics, or duration of DPP-4 inhibition. Sustained exposure to elevated GLP-1 during prolonged DPP-4 inhibition may potentially cause tachyphylaxis for its effect on gastric emptying (30). Furthermore, the magnitude of GLP-1 secretion is dependent on the load and nutrient composition of the meal (1) and may be influenced by concurrent medications (e.g., metformin) (31).…”

Section: Discussionmentioning

confidence: 99%

A Protein Preload Enhances the Glucose-Lowering Efficacy of Vildagliptin in Type 2 Diabetes

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et al. 2016

Diabetes Care

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OBJECTIVENutrient "preloads" given before meals can attenuate postprandial glycemic excursions, at least partly by slowing gastric emptying and stimulating secretion of the incretins (i.e., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). This study was designed to evaluate whether a protein preload could improve the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin to increase incretin concentrations, slow gastric emptying, and lower postprandial glycemia in type 2 diabetes. RESEARCH DESIGN AND METHODSTwenty-two patients with type 2 diabetes treated with metformin were studied on four occasions, receiving either 50 mg vildagliptin (VILD) or placebo (PLBO) on both the evening before and the morning of each study day. The latter dose was followed after 60 min by a preload drink containing either 25 g whey protein (WHEY) or control flavoring (CTRL), and after another 30 min by a 13 C-octanoate-labeled mashed potato meal. Plasma glucose and hormones, and gastric emptying, were evaluated. RESULTSCompared with PLBO/CTRL, PLBO/WHEY reduced postprandial peak glycemia, increased plasma insulin, glucagon, and incretin hormones (total and intact), and slowed gastric emptying, whereas VILD/CTRL reduced both the peak and area under the curve for glucose, increased plasma intact incretins, and slowed gastric emptying but suppressed plasma glucagon and total incretins (P < 0.05 each). Compared with both PLBO/WHEY and VILD/CTRL, VILD/WHEY was associated with higher plasma intact GLP-1 and GIP, slower gastric emptying, and lower postprandial glycemia (P < 0.05 each). CONCLUSIONSIn metformin-treated type 2 diabetes, a protein preload has the capacity to enhance the efficacy of vildagliptin to slow gastric emptying, increase plasma intact incretins, and reduce postprandial glycemia.The "incretin" hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major determinants of postprandial glycemia (1). The latter is an important target in patients with type 2 diabetes, particularly those with modestly elevated HbA 1c (2). In health, both incretins stimulate insulin secretion in a glucose-dependent manner (1). However, the effect of GIP is substantially diminished in type 2 diabetes (3), whereas GLP-1

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Section: Discussionmentioning

confidence: 99%

A Protein Preload Enhances the Glucose-Lowering Efficacy of Vildagliptin in Type 2 Diabetes

Little

Bound

et al. 2016

Diabetes Care

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“…It will be important to determine whether the acute effects that we observed are maintained with chronic administration. We assessed the acute responses to GLP-1, and it is now recognised that the slowing of GE by exogenous GLP-1 is subject to tachyphylaxis with sustained exposure [43,44].…”

Section: Discussionmentioning

confidence: 99%

Effects of exogenous glucagon-like peptide-1 on blood pressure, heart rate, gastric emptying, mesenteric blood flow and glycaemic responses to oral glucose in older individuals with normal glucose tolerance or type 2 diabetes

et al. 2015

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Aims/hypothesis A postprandial fall in BP occurs frequently in older individuals and in patients with type 2 diabetes. The magnitude of this decrease in BP is related to the rate of gastric emptying (GE). Intravenous administration of glucagon-like peptide-1 (GLP-1) attenuates the hypotensive response to intraduodenal glucose in healthy older individuals. We sought to determine the effects of exogenous GLP-1 on BP, GE, superior mesenteric artery (SMA) flow and glycaemic response to oral ingestion of glucose in healthy older individuals and patients with type 2 diabetes. Methods Fourteen older volunteers (six men, eight women; age 72.1±1.1 years) and ten patients with type 2 diabetes (six men, four women; age 68.7±3.4 years; HbA 1c 6.6±0.2% [48.5± 2.0 mmol/mol]; nine with blood glucose managed with metformin, two with a sulfonylurea and one with a dipeptidyl-peptidase 4 inhibitor) received an i.v. infusion of GLP-1 (0.9 pmol kg −1 min −1 ) or saline (154 mmol/l NaCl) for 150 min (t=−30 min to t= 120 min) in randomised order. At t=0 min, volunteers consumed a radiolabelled 75 g glucose drink. BP was assessed with an automated device, GE by scintigraphy and SMA flow by ultrasonography. Blood glucose and serum insulin were measured. Results GLP-1 attenuated the fall in diastolic BP after the glucose drink in older individuals (p<0.05) and attenuated the fall in systolic and diastolic BP in patients with type 2 diabetes (p<0.05). GE was faster in patients with type 2 diabetes than in healthy individuals (p<0.05). In both groups, individuals had slower GE (p<0.001), decreased SMA flow (p<0.05) and a lower degree of glycaemia (p<0.001) when receiving GLP-1. Conclusions/interpretation Intravenous GLP-1 attenuates the hypotensive response to orally administered glucose and decreases SMA flow, probably by slowing GE. GLP-1 and 'short-acting' GLP-1 agonists may be useful in the management of postprandial hypotension.

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“…There is also recent evidence that continuous exposure to GLP-1 is associated with tachyphylaxis for its effects on gastric emptying, which may occur at the level of vagal nerve (Nauck et al 2011a;Umapathysivam et al 2014). Consequently, the efficacy of exogenous GLP-1 for slowing gastric emptying and reducing postprandial glycaemic excursions is attenuated with prolonged infusion but can be maintained with intermittent infusion (Umapathysivam et al 2014).…”

Section: Metabolic Actions Of Incretin Hormonesmentioning

confidence: 99%

Incretins

Wu¹,

Rayner²,

Horowitz³

2015

Metabolic Control

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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the known incretin hormones in humans, released predominantly from the enteroendocrine K and L cells within the gut. Their secretion is regulated by a complex of integrated mechanisms involving direct contact for the activation of different chemo-sensors on the brush boarder of K and L cells and several indirect neuro-immuno-hormonal loops. The biological actions of GIP and GLP-1 are fundamental determinants of islet function and blood glucose homeostasis in health and type 2 diabetes. Moreover, there is increasing recognition that GIP and GLP-1 also exert pleiotropic extra-glycaemic actions, which may represent therapeutic targets for human diseases. In this review, we summarise current knowledge of the biology of incretin hormones in health and metabolic disorders and highlight the therapeutic potential of incretin hormones in metabolic regulation.

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Comparative Effects of Prolonged and Intermittent Stimulation of the Glucagon-Like Peptide 1 Receptor on Gastric Emptying and Glycemia

Cited by 133 publications

References 22 publications

A Protein Preload Enhances the Glucose-Lowering Efficacy of Vildagliptin in Type 2 Diabetes

A Protein Preload Enhances the Glucose-Lowering Efficacy of Vildagliptin in Type 2 Diabetes

Effects of exogenous glucagon-like peptide-1 on blood pressure, heart rate, gastric emptying, mesenteric blood flow and glycaemic responses to oral glucose in older individuals with normal glucose tolerance or type 2 diabetes

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