Of Mice Not Men? Actions of Interleukin-6 on Glucose Tolerance
Authors: Emma R. McGlone, Tricia M. Tan
Journal: Cell Metabolism (2018)

In mice, interleukin-6 (IL-6) improves glucose tolerance via stimulation of glucagon-like peptide 1 (GLP-1) secretion. In this issue of Cell Metabolism, Lang Lehrskov et al., 2018Lang Lehrskov L. Lyngbaek M.P. Soederlund L. Legaard G.E. Ehses J.A. Heywood S.E. Wewer Albrechtsen N.J. Holt J.J. Karstoft K. Pedersen B.K. Ellingsgaard H. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control.Cell Metab. 2018; 27 (this issue): 1201-1211Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar demonstrate that IL-6 infusion has GLP-1-dependent and -independent actions with opposing effects on glucose tolerance, resulting in an overall improvement in healthy male volunteers but no improvement in male patients with diabetes. In mice, interleukin-6 (IL-6) improves glucose tolerance via stimulation of glucagon-like peptide 1 (GLP-1) secretion. In this issue of Cell Metabolism, Lang Lehrskov et al., 2018Lang Lehrskov L. Lyngbaek M.P. Soederlund L. Legaard G.E. Ehses J.A. Heywood S.E. Wewer Albrechtsen N.J. Holt J.J. Karstoft K. Pedersen B.K. Ellingsgaard H. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control.Cell Metab. 2018; 27 (this issue): 1201-1211Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar demonstrate that IL-6 infusion has GLP-1-dependent and -independent actions with opposing effects on glucose tolerance, resulting in an overall improvement in healthy male volunteers but no improvement in male patients with diabetes. Reduction of post-prandial hyperglycemia is an important goal of diabetes treatment. Two key variables controlling post-prandial hyperglycemia are gastric emptying, which determines rate of delivery of nutrients to absorptive areas of the gut, and the effectiveness of insulin. Glucagon-like peptide 1 (GLP-1) analogs are highly successful therapies for diabetes because they decrease gastric emptying, increase glucose-stimulated insulin secretion, and suppress food intake. In this issue of Cell Metabolism, Lang Lehrskov et al., 2018Lang Lehrskov L. Lyngbaek M.P. Soederlund L. Legaard G.E. Ehses J.A. Heywood S.E. Wewer Albrechtsen N.J. Holt J.J. Karstoft K. Pedersen B.K. Ellingsgaard H. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control.Cell Metab. 2018; 27 (this issue): 1201-1211Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar investigate the effect of interleukin-6 (IL-6) administration on post-prandial glucose excursion in man (see Figure 1). Previous work from the same group had shown that IL-6 stimulates GLP-1 secretion from mouse enteroendocrine cells and from human pancreatic alpha cells in vitro and improves glucose tolerance via enhanced insulin secretion in animal models of diabetes (Ellingsgaard et al., 2011Ellingsgaard H. Hauselmann I. Schuler B. Habib A.M. Baggio L.L. Meier D.T. Eppler E. Bouzakri K. Wueest S. Muller Y.D. et al.Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells.Nat. Med. 2011; 17: 1481-1489Crossref PubMed Scopus (599) Google Scholar). As predicted from the rodent work, when recombinant IL-6 was given to healthy volunteers, there was improved glucose tolerance to an orally ingested meal. However, this was associated with a decrease in insulin secretion. Improved glucose tolerance in the presence of reduced circulating insulin can be explained by slower absorption of nutrients (Gentilcore et al., 2006Gentilcore D. Chaikomin R. Jones K.L. Russo A. Feinle-Bisset C. Wishart J.M. Rayner C.K. Horowitz M. Effects of fat on gastric emptying of and the glycemic, insulin, and incretin responses to a carbohydrate meal in type 2 diabetes.J. Clin. Endocrinol. Metab. 2006; 91: 2062-2067Crossref PubMed Scopus (240) Google Scholar); here, by measuring the appearance of ingested paracetamol in the circulation, Lang Lehrskov et al., 2018Lang Lehrskov L. Lyngbaek M.P. Soederlund L. Legaard G.E. Ehses J.A. Heywood S.E. Wewer Albrechtsen N.J. Holt J.J. Karstoft K. Pedersen B.K. Ellingsgaard H. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control.Cell Metab. 2018; 27 (this issue): 1201-1211Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar demonstrated a reduction in gastric emptying. To see whether the effects on glucose tolerance were indeed secondary to reduced gastric emptying, they next infused the meal directly into the duodenum. This abrogated the effect on glucose tolerance, indicating that the effect of IL-6 on glucose tolerance occurs because of delayed gastric emptying. The decrease in insulin secretion, however, persisted. Circulating IL-6 is moderately elevated by exercise (Muñoz-Cánoves et al., 2013Muñoz-Cánoves P. Scheele C. Pedersen B.K. Serrano A.L. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword?.FEBS J. 2013; 280: 4131-4148Crossref PubMed Scopus (432) Google Scholar). In endurance athletes who ran for 60 min, Lang Lehrskov et al., 2018Lang Lehrskov L. Lyngbaek M.P. Soederlund L. Legaard G.E. Ehses J.A. Heywood S.E. Wewer Albrechtsen N.J. Holt J.J. Karstoft K. Pedersen B.K. Ellingsgaard H. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control.Cell Metab. 2018; 27 (this issue): 1201-1211Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar demonstrated a modest rise in IL-6, which was dramatically increased by blockade of the IL-6 receptor with tocilizumab, presumably due to decreased clearance. Despite the elevation of IL-6, runners in whom IL-6 receptor had been blocked exhibited much faster gastric emptying than without blockade, suggesting that exercise-induced elevation of IL-6 does physiologically slow gastric emptying. In the present study, peripheral circulating GLP-1 levels were not increased by IL-6 either before the meal or in response to the meal. To further investigate whether the effects of IL-6 are mediated by GLP-1, Lang Lehrskov et al., 2018Lang Lehrskov L. Lyngbaek M.P. Soederlund L. Legaard G.E. Ehses J.A. Heywood S.E. Wewer Albrechtsen N.J. Holt J.J. Karstoft K. Pedersen B.K. Ellingsgaard H. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control.Cell Metab. 2018; 27 (this issue): 1201-1211Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar used exendin 9-39, a GLP-1 receptor antagonist. Addition of exendin 9-39 did not reverse the IL-6-induced decrease in gastric emptying, suggesting a GLP-1-independent pathway. The reduction in insulin secretion, however, was abrogated by blockade of GLP-1 receptors. This is a surprising finding because the canonical effect of GLP-1 is to stimulate insulin secretion. This intriguing GLP-1-mediated inhibitory effect of IL-6 on insulin secretion in man remains unexplained. Recent evidence suggests that GLP-1 can paradoxically inhibit insulin secretion, but this phenomenon has only been demonstrated in response to a high dose infused centrally, mediated by GLP-1 receptors on hindbrain neurons, and associated with sympathetic nervous system (SNS) and hypothalamo-pituitary-adrenal axis activation (Jessen et al., 2017Jessen L. Smith E.P. Ulrich-Lai Y. Herman J.P. Seeley R.J. Sandoval D. D’Alessio D. Central nervous system GLP-1 receptors regulate islet hormone secretion and glucose homeostasis in male rats.Endocrinology. 2017; 158: 2124-2133Crossref PubMed Scopus (25) Google Scholar). In this conjunction, it is noteworthy that the IL-6 infusion increased heart rate and triggered shivering; furthermore, when the meal was infused directly into the duodenum, IL-6 infusion was associated with an increase in circulating glucagon. These effects are reminiscent of SNS stimulation, and there is some evidence that IL-6 can stimulate the SNS directly (März et al., 1998März P. Cheng J.G. Gadient R.A. Patterson P.H. Stoyan T. Otten U. Rose-John S. Sympathetic neurons can produce and respond to interleukin 6.Proc. Natl. Acad. Sci. USA. 1998; 95: 3251-3256Crossref PubMed Scopus (283) Google Scholar), posing the question: do the effects of acute IL-6 infusion on gastric emptying and insulin secretion occur via SNS stimulation? Future studies will be required to address this question. It is natural to ask whether these effects of IL-6 might be exploited for therapy. The present study shows that IL-6 given to patients with mild type 2 diabetes (well controlled on a single agent) caused a reduction in both gastric emptying and insulin excursion following a meal, as it did with healthy volunteers. Importantly, in these patients, no significant improvement in glucose tolerance was seen. If IL-6 in man has two distinct and opposed effects on glucose tolerance (to slow gastric emptying and to decrease insulin secretion), understanding their relative contribution and, therefore, the overall effect on glucose tolerance in different clinical scenarios is paramount. This study provides evidence that the summative effect is to improve glucose tolerance in healthy volunteers but not in patients with mild type 2 diabetes. Does this trend continue with more severe diabetes—that is, would acute IL-6 elevation in severe diabetes worsen glucose tolerance? On the other hand, where β cell ability to secrete insulin is severely compromised, will the effects on gastric emptying outweigh the GLP-1-mediated inhibition of insulin secretion, resulting in an overall clinically favorable effect? Could IL-6 exacerbate the gastroparesis seen in severe diabetes? Finally, could chronic IL-6 elevation exacerbate inflammation and atherosclerosis? In summary, the current evidence is enough to suggest that we will need to look for deleterious metabolic consequences of IL-6 blockade in diseases such as rheumatoid arthritis, which might be exacerbated by concurrent treatment with glucocorticoids. It is not, however, presently obvious whether IL-6-based therapy could be used for the future treatment of type 2 diabetes, and it will be interesting to see whether chronic IL-6 treatment might have more favorable effects on metabolism. The present study shows that there are clearly important differences between the metabolic actions of IL-6 in mice and man, underlining that metabolic control can be species specific; another example of the species specificity of metabolic hormone actions is the thermogenic effect of GLP-1 in rodents (Heppner et al., 2015Heppner K.M. Marks S. Holland J. Ottaway N. Smiley D. Dimarchi R. Perez-Tilve D. Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice.Diabetologia. 2015; 58: 2124-2132Crossref PubMed Scopus (35) Google Scholar) that is not apparent in man (Tan et al., 2013Tan T.M. Field B.C.T. McCullough K.A. Troke R.C. Chambers E.S. Salem V. Gonzalez Maffe J. Baynes K.C.R. De Silva A. Viardot A. et al.Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia.Diabetes. 2013; 62: 1131-1138Crossref PubMed Scopus (158) Google Scholar). It, therefore, behooves us to continue to be wary of extrapolating metabolic studies in rodents to humans. Interleukin-6 Delays Gastric Emptying in Humans with Direct Effects on Glycemic ControlLang Lehrskov et al.Cell MetabolismMay 3, 2018In BriefLehrskov et al. show that acutely elevated IL-6 in humans delays gastric emptying, reduces postprandial blood glucose, and reduces insulin secretion. The delay in gastric emptying and the reduced meal-stimulated insulin secretion are maintained in individuals with type 2 diabetes and may contribute to long-term preservation of beta cell function. Full-Text PDF Open Archive