Plasma Levels of Myonectin But Not Myostatin or Fibroblast-Derived Growth Factor 21 Are Associated with Insulin Resistance in Adult Humans without Diabetes Mellitus

Abstract

BackgroundMyokines are a group of protein mediators produced by skeletal muscle under stress or physical exertion. Even though their discovery and effects in cell culture and animal models of disease have elicited great enthusiasm, very little is known about their role in human metabolism. We assessed whether plasma concentrations of three known myokines [myonectin, myostatin, and fibroblast-derived growth factor 21 (FGF-21)] would be associated with direct and indirect indicators of insulin resistance (IR) in individuals who did not have a diagnosis of diabetes.MethodsWe studied 81 adults of both sexes comprising a wide range of body adiposity and insulin sensitivity. All participants underwent a thorough clinical assessment and a 5-point oral glucose tolerance test with calculation of multiple IR and insulin sensitivity indices. Twenty-one of them additionally underwent a hyperinsulinemic–euglycemic clamp with determination of steady-state whole-body insulin-stimulated glucose disposal (“M”). We compared plasma myokine concentrations across quartiles of IR indices and clinical IR surrogates, and explored the correlation of each myokine with the M-value.ResultsPlasma myonectin levels increased monotonically across quartiles of the incremental area under the insulin curve (higher values indicate more IR) (p-trend = 0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI – higher values indicate less IR) (p-trend = 0.012). After multivariate adjustment for other relevant determinants of IR (body mass index, age, and sex), the negative association of myonectin with ISI persisted (standardized beta = −0.235, p = 0.023). Myostatin was not associated with any clinical IR indicator or direct IR index measure. In multivariate analyses, FGF-21 showed a trend toward a positive correlation with glucose disposal that did not reach statistical significance (standardized beta = 0.476, p = 0.091).ConclusionThe secretion of myonectin may constitute an attempt at a compensatory mechanism against IR in humans.

Myonectin deletion promotes adipose fat storage and reduces liver steatosis

“…Many studies (77), including our previous studies (54)(55)(56) and the present study, reinforce the importance of sex as a biologic variable that can influence the impact and phenotypic outcomes of a given genotype. Intriguingly, although our current study and previous findings (62) do not support a major role for myonectin in regulating glucose metabolism, recent reports suggest that circulating myonectin in human blood is correlated with insulin resistance, impaired glucose metabolism, and type 2 diabetes (60,61). Whether myonectin plays a causal role in human carbohydrate metabolism and insulin sensitivity distinct from rodents remains to be determined.…”

“…Fifth, myonectin suppresses liver autophagy (36), an intracellular recycling pathway activated in the unfed state and inhibited in the fed state. Finally, the circulating level of myonectin is associated with insulin resistance and type 2 diabetes in humans (60,61). The caveat of our previous functional studies, however, is the reliance on recombinant protein infusion in mice and the use of established muscle and adipocyte cell lines (28,36); it is unclear whether myonectin (erythroferrone) is required for metabolic homeostasis in a physiologic context (62).…”

Myonectin serum concentration changes after short-term physical activity among young, healthy people

“…Myonectin in response to PhA increases the expression of CD36, fatty acid transport proteins (FATP), and fatty acid binding proteins (FABP) in hepatocytes and adipocyte, resulting in increasing FFA uptake [2]. It is known that myonectin is associated with IR [4][5] and circulating FFA induces IR [12]. It is possible that myonectin is secondarily upregulated in the IR state in order to diminish circulating FFA levels.…”

“…Interestingly, the change in the myonectin serum level after short-term PhA was negatively associated with both insulin in fasting state and HOMA-IR. Toloza et al studied 81 non-diabetic adults and assessed the association between insulin resistance direct and indirect markers and myokines [4]. Fasting myonectin adjusted to BMI, age and sex were found to be negativelyassociated with the Insulin Sensitivity Index (standardized beta = -0.235, p = 0.023).…”

“…Myonectin increases the expression of proteins transporting FFA through hepatocytes and adipocyte cell membranes, causing increasing serum FFA uptake [3]. Toloza et al reported that myonectin level is associated with insulin resistance (IR) in non-diabetic adults [4]. Lim et al observed that long-term, regular PhA decreases both the myonectin serum level and IR measured by the homeostasis model assessment [5].…”