Potential Autocrine Effects of Type 2 Diabetes–Related Myokines on Human Skeletal Muscle
Authors: LEVY YIFAT AMIR , CIARALDI THEODORE P. , MUDALIAR SUNDER , HENRY ROBERT R. 
Published: June 2018

Myokines are factors secreted by muscle cells that have been suggested to exert an array of autocrine, paracrine and/or endocrine actions. Secretion of a number of these myokines has been reported to be altered in type 2 diabetes (T2D): T2D muscle cells release elevated levels of IL6, IL8, IL15 and GROα, amongst other cyto- and chemokines. Associations have been reported between circulating levels of these factors and metabolic dysfunction. To probe potential autocrine effects of elevated levels of these factors in T2D, human skeletal muscle cells (hSMC) from nondiabetic (ND) and T2D subjects were differentiated into myotubes and treated with varying concentrations of IL6, IL8, IL15 and GROα for 48 hr before analysis of insulin signaling and action (stimulation of glucose uptake), fatty acid oxidation, and cellular markers of inflammatory signaling. Exposure of ND hSMC to levels of the 4 myokines similar to or exceeding those produced by T2D myotubes had no effect on glucose uptake in either the absence or presence of insulin. Basal and insulin-stimulated glucose uptake in T2D hSMC was also unaltered by treatment with the 4 myokines at levels up to double endogenous production. ß-oxidation of palmitate by ND myotubes was not altered by myokine treatment. However, when T2D hSMC were exposed to elevated IL15 levels, ß-oxidation was reduced, by 20-25% (p&lt;0.05). While T2D-related levels of IL8 and GROα had no effects on hSMC metabolism, there were tendencies for both factors to induce an inflammatory response, displayed as an ∼35% reduction in IkBα protein expression.
In summary: 1) Local levels of specific myokines similar to or greater than those seen with T2D have limited impact on glucose and fat metabolism and insulin action in hSMC. 2) Insulin action in hSMC is preserved even in the presence of increased inflammation.
Conclusion: levels of pro-inflammatory cyto- and chemokines sufficient to induce insulin resistance and metabolic dysfunction in muscle are most likely provided by non-myotube sources.

Disclosure
Y. Amir Levy: None. T.P. Ciaraldi: None. S. Mudaliar: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Janssen Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., National Institutes of Health. R.R. Henry: Consultant; Self; Abbott, Alere Inc., AstraZeneca. Research Support; Self; AstaReal. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Hitachi, Ltd.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Johnson & Johnson Services, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Viacyte, Inc.. Consultant; Self; Sanofi-Aventis. Advisory Panel; Self; Sanofi-Aventis.