The Effect of Exogenous Glucose-Dependent Insulinotropic Polypeptide in Combination With Glucagon-Like Peptide-1 on Glycemia in the Critically Ill

Lee, Michael Y.; Fraser, Jonathan David; Chapman, Marianne J.; Sundararajan, Krishnaswamy; Umapathysivam, Mahesh M.; Summers, Matthew J.; Zaknic, Antony V.; Rayner, Christopher K.; Meier, Juris J.; Horowitz, Michael; Deane, Adam M.

doi:10.2337/dc13-0307

Cited by 21 publications

(22 citation statements)

References 15 publications

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“…Importantly, however, induction of GIP proved to be irrelevant for LPS‐dependent hyperinsulinaemia and glucose‐lowering, while this has markedly been found to be dependent on GLP‐1 . These findings are supported by recent work from Lee et al ,. showing that addition of GIP to GLP‐1 infusion does not result in additional glucose‐lowering or insulinotropic effects in critically ill patients with acute‐onset hyperglycaemia.…”

Section: Discussionsupporting

confidence: 59%

Glucose‐dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin‐1‐dependent manner in mice

Kahles

Meyer

Diebold

et al. 2016

Diabetes Obesity Metabolism

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Recently, glucagon-like peptide-1 (GLP-1) levels have been found to be increased in response to inflammatory stimuli, leading to insulin secretion and prevention of hyperglycaemia during endotoxemia in mice. In the present study, we assess the relevance of the other incretin hormone, glucose-dependent insulinotropic peptide (GIP), as a regulator of glucose metabolism under inflammatory conditions. We found that lipopolysaccharide (LPS) increased GIP secretion in a time- and dose-dependent manner in C57BL/6J mice. To elucidate the underlying mechanisms, mice were injected with inflammatory cytokines known to be released by LPS. Circulating GIP levels significantly increased in response to interleukin (IL)-1β but not IL-6 or tumour necrosis factor (TNF)-α administration. Using respective knockout mice we found that LPS-mediated GIP secretion was selectively dependent on IL-1 signalling. To evaluate the functional relevance of inflammatory GIP secretion we pretreated mice with the GIP-receptor antagonist (Pro3)GIP. This blunted LPS-induced TNF-α and IL-6 secretion but did not affect LPS-induced insulin secretion or blood glucose-lowering. In conclusion, GIP provides a novel link between the immune system and the gut, with proinflammatory-immune modulatory function but minor glucose regulatory relevance in the context of acute endotoxemia.

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Section: Discussionsupporting

confidence: 59%

Glucose‐dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin‐1‐dependent manner in mice

Kahles

Meyer

Diebold

et al. 2016

Diabetes Obesity Metabolism

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“…A proximal-distal endocrine loop that stimulates GLP-1 secretion has also been suggested. Although GIP was shown to increase GLP-1 secretion from L cells in vitro and in vivo in rodent models (Rocca and Brubaker 1999), exogenous GIP, even at high doses, does not affect plasma GLP-1 concentrations in humans (Edholm et al 2010;Lee et al 2013). In contrast, the antagonism of cholecystokinin (CCK) type 1 receptor attenuates the GLP-1 response to intraduodenal fat infusion (Beglinger et al 2010), indicating that CCK is an "upper gut signal" for the stimulation of GLP-1 secretion.…”

Section: Regulation Of Incretin Hormone Secretionmentioning

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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“…Blood glucose concentrations were measured and recorded immediately, by the investigators, using a blood gas analyser (ABL800 FLEX; Radiometer, Copenhagen, Denmark) [ 20 ]. The monosaccharide 3-OMG is absorbed from the small intestine via the same transporters as glucose, but is not metabolised [ 28 , 29 ], and measurement of serum 3-OMG concentrations provides an accurate measure of glucose absorption in healthy individuals and the critically ill [ 28 , 29 ].…”

Section: Methodsmentioning

confidence: 99%

“…Our group has reported that exogenous GLP-1 retains its potent glucose-lowering effect in the critically ill patient during enteral feeding because it stimulates insulin secretion and slows gastric emptying [ 16 - 18 ]. Slower gastric emptying may be undesirable, however, particularly in relation to the potential to exacerbate gastroesophageal reflux [ 17 ] and compromise enteral feeding [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…Our group has reported that, in the critically ill patient, GIP at a dose considered slightly above postprandial physiological concentrations (2 pmol/kg/minute) when administered with another potent insulinotropic hormone, GLP-1, does not have an additive glucose-lowering effect [ 20 ]. However, the effects of GIP when administered as a sole agent at doses that are pharmacological in this group are unknown.…”

Section: Introductionmentioning

confidence: 99%

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Effects of glucose-dependent insulinotropic polypeptide on gastric emptying, glycaemia and insulinaemia during critical illness: a prospective, double blind, randomised, crossover study

et al. 2015

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IntroductionInsulin is used to treat hyperglycaemia in critically ill patients but can cause hypoglycaemia, which is associated with poorer outcomes. In health glucose-dependent insulinotropic polypeptide (GIP) is a potent glucose-lowering peptide that does not cause hypoglycaemia. The objectives of this study were to determine the effects of exogenous GIP infusion on blood glucose concentrations, glucose absorption, insulinaemia and gastric emptying in critically ill patients without known diabetes.MethodsA total of 20 ventilated patients (Median age 61 (range: 22 to 79) years, APACHE II 21.5 (17 to 26), BMI 28 (21 to 40) kg/m2) without known diabetes were studied on two consecutive days in a randomised, double blind, placebo controlled, cross-over fashion. Intravenous GIP (4 pmol/kg/min) or placebo (0.9% saline) was infused between T = −60 to 300 minutes. At T0, 100 ml of liquid nutrient (2 kcal/ml) containing 3-O-Methylglucose (3-OMG), 100 mcg of Octanoic acid and 20 MBq Tc-99 m Calcium Phytate, was administered via a nasogastric tube. Blood glucose and serum 3-OMG (an index of glucose absorption) concentrations were measured. Gastric emptying, insulin and glucagon levels and plasma GIP concentrations were also measured.ResultsWhile administration of GIP increased plasma GIP concentrations three- to four-fold (T = −60 23.9 (16.5 to 36.7) versus T = 0 84.2 (65.3 to 111.1); P <0.001) and plasma glucagon (iAUC300 4217 (1891 to 7715) versus 1232 (293 to 4545) pg/ml.300 minutes; P = 0.04), there were no effects on postprandial blood glucose (AUC300 2843 (2568 to 3338) versus 2819 (2550 to 3497) mmol/L.300 minutes; P = 0.86), gastric emptying (AUC300 15611 (10993 to 18062) versus 15660 (9694 to 22618) %.300 minutes; P = 0.61), glucose absorption (AUC300 50.6 (22.3 to 74.2) versus 64.3 (9.9 to 96.3) mmol/L.300 minutes; P = 0.62) or plasma insulin (AUC300 3945 (2280 to 6731) versus 3479 (2316 to 6081) mU/L.300 minutes; P = 0.76).ConclusionsIn contrast to its profound insulinotropic effect in health, the administration of GIP at pharmacological doses does not appear to affect glycaemia, gastric emptying, glucose absorption or insulinaemia in the critically ill patient.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12612000488808. Registered 3 May 2012.

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The Effect of Exogenous Glucose-Dependent Insulinotropic Polypeptide in Combination With Glucagon-Like Peptide-1 on Glycemia in the Critically Ill

Cited by 21 publications

References 15 publications

Glucose‐dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin‐1‐dependent manner in mice

Glucose‐dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin‐1‐dependent manner in mice

Incretins

Effects of glucose-dependent insulinotropic polypeptide on gastric emptying, glycaemia and insulinaemia during critical illness: a prospective, double blind, randomised, crossover study

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