Tumour necrosis factor‐alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers

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

doi:10.1002/dmrr.2441

Cited by 22 publications

(13 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with previous reports (3)(4)(5)8), the infusion of TNF-␣ at high doses was accompanied by systemic inflammation with fever, malaise, and discomfort in all subjects. In vivo studies also show that TNF-␣ infusion can induce insulin resistance (3-5) but is not likely to affect glucose-stimulated insulin secretion (8).…”

Section: Discussionsupporting

confidence: 92%

“…Glucose tolerance depends on insulin sensitivity and insulin secretion. We (3) and others (4,5) have shown that high physiological levels of TNF-␣ reduce insulin sensitivity in vivo. TNF-␣ also reduces glucose-stimulated insulin secretion, at least in vitro (6,7), whereas a human in vivo study reported reduced basal insulin levels with no effect on glucose-stimulated insulin secretion (8).…”

Section: Discussionmentioning

confidence: 89%

See 1 more Smart Citation

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

Lehrskov-Schmidt

Lehrskov-Schmidt²,

Nielsen³

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 89%

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

Lehrskov-Schmidt

Lehrskov-Schmidt²,

Nielsen³

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…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: 98%

The Cardiovascular Biology of Glucagon-like Peptide-1

2016

View full text Add to dashboard Cite

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.

show abstract

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Tumour necrosis factor‐alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers

Abstract: In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect.

Cited by 22 publications

References 32 publications

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

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

The Cardiovascular Biology of Glucagon-like Peptide-1

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

Contact Info

Product

Resources

About