The Effects of TNF-α on GLP-1-Stimulated Plasma Glucose Kinetics

Lehrskov-Schmidt, Louise; Lehrskov-Schmidt, Lars; Nielsen, Signe Tellerup; Holst, Jens J.; Møller, Kirsten; Solomon, Thomas P. J.

doi:10.1210/jc.2014-4244

Cited by 17 publications

(11 citation statements)

References 26 publications

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“…Acute exposure to TNF-a increased GLP-1 secretion from human NCIH716 EECs; however, GLP-1 levels were not increased in mice after acute TNF-a injection (4 mg/kg) (Kahles et al, 2014), nor in healthy, young male human subjects after 4-6 hr of intravenous TNF-a infusion (1 mg/m 2 body surface area per hr), a dose that produces circulating TNF-a levels of $30 pg/mL (Lehrskov-Schmidt et al, 2015;Nielsen et al, 2013). In contrast, chronic exposure to TNF-a inhibited GLP-1 secretion from EECs in vitro, whereas administration of the TNF-a blocker, etanercept, to high-fat-diet-fed mice improved the secretion of GLP-1 from primary murine EEC cultures derived from the etanercept-treated mice ex vivo (Gagnon et al, 2015).…”

Section: Glp-1: a Target And Mediator Of The Inflammatory Responsementioning

confidence: 87%

The Cardiovascular Biology of Glucagon-like Peptide-1

2016

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Glucagon-like peptide-1, produced predominantly in enteroendocrine cells, controls glucose metabolism and energy homeostasis through regulation of islet hormone secretion, gastrointestinal motility, and food intake, enabling development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. GLP-1 also acts on the immune system to suppress inflammation, and GLP-1R signaling in multiple tissues impacts cardiovascular function in health and disease. Here we review how GLP-1 and clinically approved GLP-1R agonists engage mechanisms that influence the risk of developing cardiovascular disease. We discuss how GLP-1R agonists modify inflammation, cardiovascular physiology, and pathophysiology in normal and diabetic animals through direct and indirect mechanisms and review human studies illustrating mechanisms linking GLP-1R signaling to modification of the cardiovascular complications of diabetes. The risks and benefits of GLP-1R agonists are updated in light of recent data suggesting that GLP-1R agonists favorably modify outcomes in diabetic subjects at high risk for cardiovascular events.

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Section: Glp-1: a Target And Mediator Of The Inflammatory Responsementioning

confidence: 87%

The Cardiovascular Biology of Glucagon-like Peptide-1

2016

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“…On the contrary, GLP-1 administration has been found to reduce circulating IL6 concentrations in humans, which suggests the existence of a negative feedback loop as part of the anti-inflammatory capacities of GLP-1 [ 13 ]. Surprisingly however, administration of TNFα, as an alternative inflammatory stimulus with strong IL6 inducing potential, failed to increase GLP-1 concentrations in mice and humans [ 6 , 14 ]. This illustrates the complexity of a yet incompletely understood regulative mechanism of GLP-1 secretion.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 predicts inflammation-induced increase of Glucagon-like peptide-1 in humans in response to cardiac surgery with association to parameters of glucose metabolism

Lebherz

Kahles

Piotrowski

et al. 2016

Cardiovasc Diabetol

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ObjectiveGlucagon-like peptide-1 (GLP-1) is an incretin hormone, which gets secreted in response to nutritional stimuli from the gut mediating glucose-dependent insulin secretion. Interestingly, GLP-1 was recently found to be also increased in response to inflammatory stimuli in an interleukin 6 (IL-6) dependent manner in mice. The relevance of this finding to humans is unknown but has been suggested by the presence of high circulating GLP-1 levels in critically ill patients that correlated with markers of inflammation. This study was performed to elucidate, whether a direct link exists between inflammation and GLP-1 secretion in humans.Research design and methodsWe enrolled 22 non-diabetic patients scheduled for cardiac surgery as a reproducible inflammatory stimulus with repeated blood sampling before and after surgery.ResultsMean total circulating GLP-1 levels significantly increased in response to surgery from 25.5 ± 15.6 pM to 51.9 ± 42.7 pM which was not found in a control population. This was preceded by an early rise of IL6, which was significantly associated with GLP-1 under inflammatory but not basal conditions. Using repeated measure ANCOVA, IL6 best predicted the observed kinetics of GLP-1, followed by blood glucose concentrations and cortisol plasma levels. Furthermore, GLP-1 plasma concentrations significantly predicted endogenous insulin production as assessed by C-peptide concentrations over time, while an inverse association was found for insulin infusion rate.ConclusionWe found GLP-1 secretion to be increased in response to inflammatory stimuli in humans, which was associated to parameters of glucose metabolism and best predicted by IL6.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0330-8) contains supplementary material, which is available to authorized users.

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“…Critically ill patients exhibit systemic inflammation. However, systemic inflammation induced by TNF-α infusion in healthy human volunteers does not affect glucose-stimulated insulin secretion [ 41 ] or the incretin effect [ 20 ], despite inducing IR and reducing the suppressive effect of GLP-1 on endogenous glucose production [ 19 , 20 ]. On one hand, in cell studies, TNF-α alone does not impair insulin secretion, but, when combined with other proinflammatory cytokines, it induces β-cell dysfunction [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, glucose normalisation with insulin treatment also improves β-cell function and the incretin effect in type 2 diabetes [ 16 – 18 ]. Furthermore, clinical studies by our group demonstrate that systemic inflammation induced by tumour necrosis factor (TNF)-α infusion impaired the suppression of GLP-1 on endogenous glucose production [ 19 ], but did not change the incretin effect [ 20 ], in healthy humans. These findings suggest that the incretin effect may become impaired in critical illness as a consequence of hyperglycaemia rather than inflammation per se.…”

Section: Introductionmentioning

confidence: 99%

The incretin effect in critically ill patients: a case–control study

et al. 2015

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IntroductionPatients admitted to the intensive care unit often develop hyperglycaemia, but the underlying mechanisms have not been fully described. The incretin effect is reduced in patients with type 2 diabetes. Type 2 diabetes and critical illness have phenotypical similarities, such as hyperglycaemia, insulin resistance and systemic inflammation. Previous studies have shown beneficial effects of exogenous glucagon-like peptide (GLP)-1 on glycaemia in critically ill patients, a phenomenon also seen in patients with type 2 diabetes. In this study, we hypothesised that the incretin effect, which is mediated by the incretin hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP), is impaired in critically ill patients.MethodsThe incretin effect (i.e., the relative difference between the insulin response to oral and intravenous glucose administration) was investigated in a cross-sectional case–control study. Eight critically ill patients without diabetes admitted to a mixed intensive care unit and eight healthy control subjects without diabetes, matched at group level by age, sex and body mass index, were included in the study. All subjects underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the next day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide and plasma levels of GLP-1, GIP, glucagon and proinflammatory cytokines were measured intermittently. The incretin effect was calculated as the increase in insulin secretion during oral versus intravenous glucose administration in six patients. The groups were compared using either Student’s t test or a mixed model of repeated measurements.ResultsBlood glucose levels were matched between the OGTT and the IVGI in both groups. Compared with control subjects, proinflammatory cytokines, tumour necrosis factor α and interleukin 6, were higher in patients than in control subjects. The endogenous response of GIP and glucagon, but not GLP-1, to the OGTT was greater in patients. The insulin response to the OGTT did not differ between groups, whereas the insulin response to the IVGI was higher in patients. Consequently, the calculated incretin effect was lower in patients (23 vs. 57 %, p = 0.003).ConclusionsIn critically ill patients, the incretin effect was reduced. This resembles previous findings in patients with type 2 diabetes.Trial registrationClinicalTrials.gov identifier: NCT01347801. Registered on 2 May 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1118-z) contains supplementary material, which is available to authorized users.

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The Effects of TNF-α on GLP-1-Stimulated Plasma Glucose Kinetics

Abstract: TNF-α induces systemic inflammation and reduces plasma GLP-1, thereby reducing the suppression of EGP during GLP-1 infusion. This may have clinical relevance if GLP-1 analog drugs are used for the treatment of hyperglycemia in critically ill patients.

Cited by 17 publications

References 26 publications

The Cardiovascular Biology of Glucagon-like Peptide-1

The Cardiovascular Biology of Glucagon-like Peptide-1

Interleukin-6 predicts inflammation-induced increase of Glucagon-like peptide-1 in humans in response to cardiac surgery with association to parameters of glucose metabolism

The incretin effect in critically ill patients: a case–control study

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