Osteocalcin and vitamin D status are inversely associated with homeostatic model assessment of insulin resistance in Canadian Aboriginal and white women: the First Nations Bone Health Study☆ , ☆☆ Hope A. Weiler a, ⁎, Julie Lowe a , John Krahn b , William D. Leslie c a School of Dietetics and Human Nutrition, McGill University, Montreal, QC, Canada, H9X 3V9 b University of Saskatchewan, Saskatoon, Canada c Faculty of Medicine, University of Manitoba, Winnipeg, Canada Received 15 May 2011; received in revised form 4 December 2011; accepted 21 December 2011 Abstract Objective: Osteocalcin, a protein synthesized by osteoblasts, and vitamin D status have independently been implicated in energy metabolism and glucose regulation. This study was conducted to simultaneously explore the relationships among osteocalcin, vitamin D status and indicators of glucose metabolism and adiposity in a mixed-ethnicity cohort of adult women. Design: Cross-sectional. Methods: Aboriginal and white women (n=368) over 25 years of age (45.3±13.6 years) were studied for measures of osteocalcin and 25-hydroxy vitamin D [25(OH)D] plus glucose metabolism including glucose, insulin, C-peptide, hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR). Measures of adiposity included body mass index (BMI) plus total body fat and trunk fat from dual-energy X-ray absorptiometry. Results: Aboriginal women had higher BMI, fat and markers of dysglycemia. Osteocalcin was not different between groups, but 25(OH)D was lower in Aboriginal women. Osteocalcin was inversely related to all five parameters of glucose metabolism, whereas 25(OH)D was inversely related to insulin, C-peptide and HOMA- IR. After accounting for age, ethnicity or adiposity using regression analyses, glucose, HbA1c and HOMA-IR were inversely related to both osteocalcin and 25(OH) D. However, only 25(OH)D was inversely related to C-peptide, and neither osteocalcin nor 25(OH)D was related to insulin. Conclusions: These data from a unique mixed Aboriginal and white population suggest that both vitamin D and osteocalcin are involved in glucose control. © 2013 Elsevier Inc. All rights reserved. Keywords: Osteocalcin; Vitamin D; Glucose; Ethnicity 1. Introduction The relationship between osteocalcin and glucose homeostasis and insulin sensitivity in both animals [1] and humans [2] is relatively new. Osteocalcin is specifically secreted by osteoblasts [1], but also endothelial cells [3] and embryonic stem cells [4]. Mice lacking osteocalcin have reduced insulin secretion, insulin sensitivity and glucose tolerance, with beta-cell proliferation accompanied by in- creased visceral fat [1]. In experimental studies, the uncarboxylated form of osteocalcin stimulates insulin expression in beta-cells, enhances insulin sensitivity in adipocytes and improves glucose intolerance [1]. In middle-aged men and after adjustment for age and body mass index (BMI), uncarboxylated osteocalcin associates with enhanced beta-cell function, but carboxylated osteocalcin associates with improved insulin sensitivity [5,6]. An inverse association between carboxylated osteo- calcin and glucose metabolism exists in men [7–9] and women [10]. In a prospective analysis, osteocalcin inversely related to glucose and homeostatic model assessment of insulin resistance (HOMA-IR), and those with higher osteocalcin had a lower rise in glucose 3 years later [11]. Further proof of principle originates from research in adults receiving treatment for diabetes mellitus type 2; osteocalcin was higher with better response to treatment [12]. Additionally, glucose tolerance and insulin sensitivity partially improved in obese mice given daily injections of osteocalcin [13]. Regardless of whether carboxylation of osteocalcin is critical in the relationship to insulin resistance, the question that remains Available online at www.sciencedirect.com Journal of Nutritional Biochemistry 24 (2013) 412 – 418 ☆ Funding: Supported by grant from the Canadian Institutes for Health Research, the Manitoba Health Research Council, and the Health Sciences Centre Foundation. The lead author (H.W.) is in receipt of a Canada Research Chair salary award. ☆☆ Declaration of interest: W.D. Leslie has received honoraria and research support from Merck Frosst Canada and unrestricted educational and research grants from Sanofi-Aventis; Procter & Gamble Pharmaceuticals Canada, Inc.; Novartis Pharmaceuticals Canada, Inc.; Amgen Pharmaceuti- cals, Inc.; Genzyme Canada Ltd. He has served on advisory boards for Novartis Pharmaceuticals Canada, Inc.; Amgen Pharmaceuticals, Inc.; Genzyme Canada Ltd. ⁎ Corresponding author. Tel.: +1 514 398 7905; fax: +1 514 398 7739. E-mail address: hope.weiler@mcgill.ca (H.A. Weiler). 0955-2863/$ - see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jnutbio.2011.12.007