Effects of Physiological Variations in Circulating Insulin Levels on Bone Turnover in Humans

Context: Recent studies in mice have demonstrated that insulin signaling in osteoblasts stimulates bone formation and reduces osteoprotegerin production; the latter results in an increase in bone resorption, which then leads to the release of undercarboxylated osteocalcin from bone. Undercarboxylated osteocalcin, in turn, enhances insulin sensitivity. Objective: The objective of the study was to test whether physiological changes in insulin levels regulate bone metabolism in humans. Design: This investigation was an analysis of samples from a prospective study. Setting: The study was conducted at a clinical research unit. Participants and Interventions: Fourteen subjects underwent a 7-h stepped insulin infusion accompanied by a glucose clamp and somatostatin infusion along with replacement infusions of GH and glucagon, thus isolating possible effects of insulin on bone. Insulin was infused at rates achieving low (similar to 150 pmol/liter), intermediate (similar to 350 pmol/liter), or high (similar to 700 pmol/liter) plasma insulin levels. Main Outcome Measures: Bone turnover markers, undercarboxylated osteocalcin, and osteoprotegerin levels at the end of the low, intermediate, and high dose insulin infusions were measured. Results: Values for the outcome measures at the end of the intermediate-and high-dose insulin infusions were no different from values at the end of the low-dose insulin infusion. However, measures of insulin sensitivity (glucose infusion and disappearance rates) correlated positively with C-terminal telopeptide of type I collagen levels. Conclusions: Acute changes in insulin levels, as occur during meals, do not regulate bone turnover, undercarboxylated osteocalcin, or osteoprotegerin levels. However, the correlation of measures of insulin sensitivity with bone resorption suggests the need for further studies in humans on the possible regulation of bone metabolism by insulin. (J Clin Endocrinol Metab 96: 1450-1455, 2011)