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Chronically Elevated TNFα Level in Obese Patients Impairs Secretion of GLP-1

Several studies have shown that tumor necrosis factor α (TNFα) impairs glucose tolerance through inhibition of glucose-stimulated insulin secretion by β-cells, and induction of insulin resistance through impairment of insulin receptor signaling. Moreover, some studies have demonstrated that TNFα-neutralizing biologics (including etanercept and infliximab) improve glucose tolerance. However, the mechanisms are unknown.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that maintain normoglycemia. These peptides are released after meal ingestion by L- and K-cells, respectively, and initiate glucose-stimulated insulin secretion.

The authors hypothesized that chronically elevated TNFα levels found in obesity play a role in the reduction of GLP-1 secretion, thereby contributing to the impaired oral glucose tolerance. They determined the direct effects of TNFα on GLP-1 secretion using the human and mouse GLP-1-producing intestinal L-cell lines, NCI-H716 and GLUTag, respectively. They also gave the mouse an anti-TNFα biological (etanercept) to examine the role of TNFα in modulating both impaired glucose tolerance and GLP-1 release by the primary intestinal L-cell in diet-induced obesity.

In the animal experiments, the mice were fed a high-fat diet for 14 weeks, with etanercept (Embrel® 20 mg/kg SC 3-times a week) or saline (control) during the last two weeks. Oral glucose tolerance tests were done using 2g/kg glucose and blood samples were collected and analyzed for insulin and active GLP-1. The L-cell lines collected in humans is a tumor-derived from a colorectal adenocarcinoma in a 33-year-old male patient. The cells were treated with either media alone as a control or with TNFα.

The results showed that although acute treatment of NCI-H716 cells with TNFα seem to enhance GLP-1 release, chronic TNFα exposure reduces GLP-1 expression and cellular content. A 24-hour treatment with 0.5 ng/mL of TNFα markedly reduced mRNA expression of the prohormone for GLP-1, proglucagon, to 52.6 ± 11.0% of the controls (p < 0.05). NCI-H716 cells that were pretreated with TNFα had reduced GLP-1 secretory response compared to the control. Similar results were seen in GLUTag L-cell line. Enhanced secretion of insulin in the mice after the two weeks of treatment of etanercept was not seen when compared to the control group. However, glucose tolerance was improved in the etanercept treatment group. Therefore, the authors suggest further studies in this area to better understand the mechanisms underlying the improved glucose tolerance in etanercept-treated animals.

The authors concluded that the findings in this study provide a potential mechanism that explains the impaired glucose tolerance in obesity. More studies should be done on whether anti-TNFα biologics can be used to enhance GLP-1 levels in the treatment of obesity.

Practice Pearls:

  • Obese patients have chronically elevated TNFα levels.
  • Acute exposure of TNFα seem to enhance GLP-1 release, but chronic exposures reduces GLP-1 expression and cellular content.
  • More studies should be done on whether anti-TNFα biologics can be used to enhance GLP-1 levels in the treatment of obesity.

Gagnon J, Sauve M, Zhao W, Stacey HM, Wiber SC, Bolz SS, and Brubaker PL. “Chronic exposure to tumor necrosis factor α impairs secretion of glucagon-like peptide-1” Journal of Clinical Endocrinology & Metabolism, 6 Aug 2015. Web. 7 Sep 2015.