Background: The relative contribution of insulin resistance vs. adiposity in determining bone mineral density (BMD) and fracture risk in humans remains controversial. The association between BMD, bone turnover, adiposity and insulin resistance in humans remains unclear.
Aim: To evaluate BMD and bone turnover markers (BTM) in a cohort of lean (n=19), overweight/obese insulin-sensitive (Ob-IS, n=18), overweight/obese insulin-resistant (Ob-IR, n=17) and T2D patients (n=17).
Methods: Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp. Non- diabetic overweight/obese individuals were stratified to Ob-IS and Ob-IR based on median glucose infusion rate (GIR, upper vs. bottom, respectively) with separate cut-offs for men and women. Total BMD and body fat mass (FM) were assessed by DXA. BTM (osteocalcin [OC], procollagen type 1 propeptide [P1NP] and collagen type 1 cross-linked C-telopeptide [CTX]) were measured fasting and during clamp hyperinsulinaemia.
Results: Groups were gender- and age-matched (57±1 years). Ob-IS, Ob-IR and T2D were matched for FM (P≥0.3). GIR was similar in lean and Ob-IS (P=1) and approximately 2-fold higher (P<0.001) than GIR measured in Ob-IR and T2D (P=0.4 Ob-IR vs. T2D). BMD was higher in all overweight/obese groups compared to lean subjects (P≤0.05). Lean subjects had significantly higher fasting CTX concentrations than Ob-IR (P=0.02) and T2D (P=0.03). Similarly, fasting OC was significantly higher in lean compared with Ob-IR (P=0.04). In contrast, fasting P1NP was not different between the groups (P=0.2). In response to hyperinsulinaemia, lean individuals suppressed CTX more than both insulin-resistant groups (P=0.03 vs. Ob-IR and P=0.053 vs. T2D). Similarly, lean individuals suppressed OC significantly more than Ob-IR (P=0.04). Interestingly, P1NP concentrations were unaffected by hyperinsulinaemia (P=0.5). Fasting BTM concentrations correlated inversely with fasting insulin (P≤0.04) and glucose (P≤0.05) and positively with GIR (P≤0.02). Change in CTX and OC with hyperinsulinaemia correlated inversely with insulin sensitivity (P≤0.01).
Conclusions: These findings may explain increased fracture risk in insulin-resistant overweight/obese individuals and T2D patients. Further studies are required to elucidate the role of BTM in glucose homeostasis.