Glucocorticoid-Induced Insulin Resistance in Men Is Associated With Suppressed Undercarboxylated Osteocalcin

Abstract

In mice, glucocorticoid-induced insulin resistance occurs largely through impaired osteoblast function and decreased circulating undercarboxylated osteocalcin (ucOC). Whether these mechanisms contribute to glucocorticoid-induced insulin resistance in humans has yet to be established. In addition, the effects of glucocorticoids on the exercise-induced increase in circulating ucOC and insulin sensitivity are also unknown. We hypothesized that acute glucocorticoid treatment would lead to basal and postexercise insulin resistance in part through decreased circulating ucOC and ucOC-mediated skeletal muscle protein signaling. Nine healthy men completed two separate cycling sessions 12 hours after ingesting either glucocorticoid (20 mg prednisolone) or placebo (20 mg Avicel). The homeostatic model assessment was used to assess basal insulin sensitivity and a 2-hour euglycemic-hyperinsulinemic clamp was commenced 3 hours after exercise to assess postexercise insulin sensitivity. Serum ucOC and skeletal muscle protein signaling were measured. Single-dose glucocorticoid ingestion increased fasting glucose (27%, p < 0.01) and insulin (83%, p < 0.01), and decreased basal insulin sensitivity (-47%, p < 0.01). Glucocorticoids reduced insulin sensitivity after cycling exercise (-34%, p < 0.01), reduced muscle GPRC6A protein content (16%, p < 0.05), and attenuated protein phosphorylation of mTOR , Akt , and AS160 (59%, 61%, and 50%, respectively; all ps < 0.05). Serum ucOC decreased (-24%, p < 0.01) which correlated with lower basal insulin sensitivity (r = 0.54, p = 0.02), lower insulin sensitivity after exercise (r = 0.72, p < 0.05), and attenuated muscle protein signaling (r = 0.48-0.71, p < 0.05). Glucocorticoid-induced basal and postexercise insulin resistance in humans is associated with the suppression of circulating ucOC and ucOC-linked protein signaling in skeletal muscle. Whether ucOC treatment can offset glucocorticoid-induced insulin resistance in human subjects requires further investigation. © 2018 American Society for Bone and Mineral Research.

Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

“…Short‐term use of GCs in the clinical setting has been suggested to induce muscle insulin resistance via the reduction of ucOC . In support, we found that short‐term (3‐days) CS administration is sufficient to suppress circulating levels of both OC and ucOC.…”

“…ucOC administration not only enhances muscle insulin sensitivity in healthy animals, but also partially restores insulin sensitivity in insulin‐resistant animals that commonly exhibit low ucOC levels . We recently reported that acute GC‐induced insulin resistance in humans (20 mg of prednisolone) strongly correlated with suppressed serum ucOC and ucOC‐associated signaling pathways in muscle . Furthermore, it has also been reported that the restoration of circulating ucOC during CS administration, via heterotopic expression, rescues whole‐body insulin resistance in mice .…”

“…(8)(9)(10) We recently reported that acute GC-induced insulin resistance in humans (20 mg of prednisolone) strongly correlated with suppressed serum ucOC and ucOC-associated signaling pathways in muscle. (3) Furthermore, it has also been reported that the restoration of circulating ucOC during CS administration, via heterotopic expression, rescues whole-body insulin resistance in mice. (10) However, whether ucOC treatment can directly ameliorate GC-induced muscle insulin resistance and the underlying mechanisms still remains unexplored.…”

“…It is well‐documented that frequent and long‐term GC treatment induces adverse side‐effects including metabolic disorders such as obesity, glucose intolerance, and type 2 diabetes (T2DM) . However, recent evidence suggests that even short‐term administration of GCs results in the development of skeletal muscle insulin resistance: the initiating and primary defect of T2DM . Thus, the investigation of the etiology and therapeutic intervention for short‐term GC administration‐induced muscle insulin resistance is of great importance for the prevention and control of T2DM during GC treatment.…”

“…Previous studies have suggested that the beneficial effect of ucOC on glucose uptake likely occurs through enhanced activation (phosphorylated/total ratio) of mTOR complex 2 (mTORC2)-Akt-AS160 cascade within the insulin signaling pathway, as well as signaling proteins within the ucOC signaling pathway (ERK, adenosine monophosphate kinase [AMPK], and PKC) (3,5,(14)(15)(16)(17) (Supplemental Fig. S1).…”