Bone is another casualty in the war against insulin resistance, as it remains insulin-sensitive. — ASN Events
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Bone is another casualty in the war against insulin resistance, as it remains insulin-sensitive. (#95)

Katherine Tonks 1 2 , Chris White 3 4 , Jackie Center 2 5 , Donald Chisholm 1 , Dorit Samocha-Bonet 1 , Jerry Greenfield 1 2
  1. Diabetes & Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. Department of Endocrinology, St. Vincent's Hospital, Sydney, NSW, Australia
  3. School of Medical Sciences, UNSW, Sydney, NSW, Australia
  4. Department oF Endocrinology & Metabolism, Prince of Wales Hospital, Sydney, NSW, Australia
  5. Osteoporosis and Bone Biology Division, Graven Institute of Medical Research, Sydney, NSW, Australia

Background: In humans, the relative contribution of insulin resistance (IR) andadiposity in determining bone density and fracture risk is unknown. Paradoxically, type 2 diabetes (T2D) associates with increased fracture risk despite obesity's association with higher BMD.

Aim: Determine whether IR plays a role in bone turnover marker (BTM) profile independent of obesity.

Methods: We studied lean (n=19), overweight/obese insulin-sensitive (Ob-IS, HOMA-IR<1.5, n=15), overweight/obese insulin-resistant (Ob-IR, HOMA-IR>3, n=20) and T2D volunteers (n=17). Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp (glucose infusion rate/fat free mass [GIR/FFM]); total BMD and fat mass (FM) by DXA; and subcutaneous (SCF), visceral (VF) and liver fat by CT. 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 age-matched (57±9years). Ob-IS, Ob-IR and T2D were matched for SCF and VF, and Ob-IR and T2D had more liver fat than lean (p<0.001). GIR/FFM and fasting insulin were similar between lean and Ob-IS (both p=1) and 2-fold higher (GIR/FFM) or lower (fasting insulin) in Ob-IR and T2D (all p≤0.01; Ob-IR vs. T2D  GIR/FFM p=0.09, and fasting insulin p=1). 

BMD correlated with FM and FFM (both p<0.01). There were no significant differences between groups’ BMD Z-scores. Fasting BTM concentrations correlated with GIR/FFM (p≤0.02) and inversely with fasting insulin (p≤0.04).

Ob-IR (p=0.0005) and T2D (p=0.016) subjects had lower fasting CTx than lean. Similarly, fasting OC was lower in Ob-IR than lean (p=0.003) and Ob-IS (p=0.003). Fasting P1NP trended to be lower in Ob-IR than Ob-IS (PANOVA=0.02, adjusted p=0.06). In response to hyperinsulinaemia, insulin-sensitive volunteers suppressed both CTx (lean p=0.0008, Ob-IS p=0.03) and OC (lean p=0.003, Ob-IS p=0.03) to levels observed in Ob-IR, who were already suppressed in the basal state. In addition, lean volunteers suppressed CTx more than T2D (p=0.04).

Conclusions: BMD correlates with FM. BTM correlate inversely with insulin levels, are suppressed in IR where basal hyperinsulinaemia exists, and do not suppress further with clamp hyperinsulinaemia. This suggests CTx and OC remain insulin-responsive, even in IR states. This is independent of adiposity, and may explain increased fracture risk in insulin-resistant individuals with apparently normal BMD.