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Insulin resistance and bone: a biological partnership

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Abstract

Despite a clear association between type 2 diabetes (T2D) and fracture risk, the pathogenesis of bone fragility in T2D has not been clearly elucidated. Insulin resistance is the primary defect in T2D. Insulin signalling regulates both bone formation and bone resorption, but whether insulin resistance can affect bone has not been established. On the other hand, evidence exists that bone might play a role in the regulation of glucose metabolism. This article reviews the available experimental and clinical evidence on the interplay between bone and insulin resistance. Interestingly, a bilateral relationship between bone and insulin resistance seems to exist that unites them in a biological partnership.

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References

  1. Napoli N, Chandran M, Pierroz DD et al (2017) Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol 13(4):208–219. https://doi.org/10.1038/nrendo.2016.153

    Article  CAS  PubMed  Google Scholar 

  2. Bonds DE, Larson JC, Schwartz AV et al (2006) Risk of fracture in women with type 2 diabetes: the Women’s Health Initiative Observational Study. J Clin Endocrinol Metab 91(9):3404–3410. https://doi.org/10.1210/jc.2006-0614

    Article  CAS  PubMed  Google Scholar 

  3. Janghorbani M, Van Dam RM, Willett WC, Hu FB (2007) Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 166(5):495–505. https://doi.org/10.1093/aje/kwm106

    Article  PubMed  Google Scholar 

  4. Koh WP, Wang R, Ang LW, Heng D, Yuan JM, Yu MC (2010) Diabetes and risk of hip fracture in the Singapore Chinese Health Study. Diabetes Care 33(8):1766–1770. https://doi.org/10.2337/dc10-0067

    Article  PubMed  PubMed Central  Google Scholar 

  5. Looker AC, Eberhardt MS, Saydah SH (2016) Diabetes and fracture risk in older U.S. adults. Bone 82:9–15. https://doi.org/10.1016/j.bone.2014.12.008

    Article  PubMed  Google Scholar 

  6. Napoli N, Strotmeyer ES, Ensrud KE et al (2014) Fracture risk in diabetic elderly men: the MrOS study. Diabetologia 57(10):2057–2065. https://doi.org/10.1007/s00125-014-3289-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Strotmeyer ES, Cauley JA, Schwartz AV et al (2005) Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults: the health, aging, and body composition study. Arch Intern Med 165(14):1612–1617. https://doi.org/10.1001/archinte.165.14.1612

    Article  PubMed  Google Scholar 

  8. Schwartz AV, Vittinghoff E, Bauer DC et al (2011) Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA 305(21):2184–2192. https://doi.org/10.1001/jama.2011.715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ma L, Oei L, Jiang L et al (2012) Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies. Eur J Epidemiol 27(5):319–332. https://doi.org/10.1007/s10654-012-9674-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Strotmeyer ES, Cauley JA, Schwartz AV et al (2004) Diabetes is associated independently of body composition with BMD and bone volume in older white and black men and women: The Health, Aging, and Body Composition Study. J Bone Miner Res 19(7):1084–1091. https://doi.org/10.1359/JBMR.040311

    Article  PubMed  Google Scholar 

  11. Vestergaard P (2007) Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis. Osteoporos Int 18(4):427–444. https://doi.org/10.1007/s00198-006-0253-4

    Article  CAS  PubMed  Google Scholar 

  12. American Diabetes Association (2018) 3. Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes-2018. Diabetes Care 41(Suppl 1):S28–S37. https://doi.org/10.2337/dc18-S003

    Article  Google Scholar 

  13. Napoli N, Strollo R, Paladini A, Briganti SI, Pozzilli P, Epstein S (2014) The alliance of mesenchymal stem cells, bone, and diabetes. Int J Endocrinol 2014:690783. https://doi.org/10.1155/2014/690783

    PubMed  PubMed Central  Google Scholar 

  14. Burghardt AJ, Issever AS, Schwartz AV et al (2010) High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 95(11):5045–5055. https://doi.org/10.1210/jc.2010-0226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Patsch JM, Burghardt AJ, Yap SP et al (2013) Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res 28(2):313–324. https://doi.org/10.1002/jbmr.1763

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yu EW, Putman MS, Derrico N, Abrishamanian-Garcia G, Finkelstein JS, Bouxsein ML (2015) Defects in cortical microarchitecture among African-American women with type 2 diabetes. Osteoporos Int 26(2):673–679. https://doi.org/10.1007/s00198-014-2927-7

    Article  CAS  PubMed  Google Scholar 

  17. Farr JN, Drake MT, Amin S, Melton LJ 3rd, McCready LK, Khosla S (2014) In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res 29(4):787–795. https://doi.org/10.1002/jbmr.2106

    Article  PubMed  PubMed Central  Google Scholar 

  18. Furst JR, Bandeira LC, Fan WW et al (2016) Advanced glycation endproducts and bone material strength in type 2 diabetes. J Clin Endocrinol Metab 101(6):2502–2510. https://doi.org/10.1210/jc.2016-1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Samuel VT, Shulman GI (2016) The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest 126(1):12–22. https://doi.org/10.1172/JCI77812

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cersosimo E, Triplitt C, Mandarino LJ, DeFronzo RA (2000) Pathogenesis of type 2 diabetes mellitus. [Updated 2015 May 28]. In: De Groot LJ, Chrousos G, Dungan K, et al. (eds) Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. Available from: http://www.ncbi.nlm.nih.gov/books/NBK279115/. Accessed 17 Nov 2017

  21. Fulzele K, Riddle RC, DiGirolamo DJ et al (2010) Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142(2):309–319. https://doi.org/10.1016/j.cell.2010.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thrailkill KM, Lumpkin CK Jr, Bunn RC, Kemp SF, Fowlkes JL (2005) Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab 289(5):E735–E745. https://doi.org/10.1152/ajpendo.00159.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hough FS, Pierroz DD, Cooper C, Ferrari SL, Bone IC, Diabetes Working G (2016) Mechanisms in endocrinology: mechanisms and evaluation of bone fragility in type 1 diabetes mellitus. Eur J Endocrinol 174(4):R127–R138. https://doi.org/10.1530/EJE-15-0820

    Article  CAS  PubMed  Google Scholar 

  24. Delgado-Calle J, Sato AY, Bellido T (2017) Role and mechanism of action of sclerostin in bone. Bone 96:29–37. https://doi.org/10.1016/j.bone.2016

    Article  CAS  PubMed  Google Scholar 

  25. Kalaitzoglou E, Popescu I, Bunn RC, Fowlkes JL, Thrailkill KM (2016) Effects of type 1 diabetes on osteoblasts, osteocytes, and osteoclasts. Curr Osteoporos Rep 14(6):310–319. https://doi.org/10.1007/s11914-016-0329-9

    Article  PubMed  PubMed Central  Google Scholar 

  26. Seref-Ferlengez Z, Maung S, Schaffler MB, Spray DC, Suadicani SO, Thi MM (2016) P2X7R-Panx1 complex impairs bone mechanosignaling under high glucose levels associated with type-1 diabetes. PLoS ONE 11(5):e0155107. https://doi.org/10.1371/journal.pone.0155107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Tanaka K, Yamaguchi T, Kanazawa I, Sugimoto T (2015) Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. Biochem Biophys Res Commun 461(2):193–199. https://doi.org/10.1016/j.bbrc.2015.02.091

    Article  CAS  PubMed  Google Scholar 

  28. Huang S, Kaw M, Harris MT et al (2010) Decreased osteoclastogenesis and high bone mass in mice with impaired insulin clearance due to liver-specific inactivation to CEACAM1. Bone 46(4):1138–1145. https://doi.org/10.1016/j.bone.2009.12.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zoch ML, Abou DS, Clemens TL, Thorek DL, Riddle RC (2016) In vivo radiometric analysis of glucose uptake and distribution in mouse bone. Bone Res 4:16004. https://doi.org/10.1038/boneres.2016.4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li Z, Frey JL, Wong GW et al (2016) Glucose transporter-4 facilitates insulin-stimulated glucose uptake in osteoblasts. Endocrinology 157(11):4094–4103. https://doi.org/10.1210/en.2016-1583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cornish J, Naot D (2002) Amylin and adrenomedullin: novel regulators of bone growth. Curr Pharm Des 8(23):2009–2021

    Article  CAS  PubMed  Google Scholar 

  32. Fornari R, Marocco C, Francomano D et al (2017) Insulin growth factor-1 correlates with higher bone mineral density and lower inflammation status in obese adult subjects. Eat Weight Disord. https://doi.org/10.1007/s40519-017-0362-4

    PubMed  Google Scholar 

  33. Christensen JD, Lungu AO, Cochran E et al (2014) Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy. J Clin Endocrinol Metab 99(8):E1493–E1500. https://doi.org/10.1210/jc.2014-1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yuksel O, Dokmetas HS, Topcu S, Erselcan T, Sencan M (2001) Relationship between bone mineral density and insulin resistance in polycystic ovary syndrome. J Bone Miner Metab 19(4):257–262

    Article  CAS  PubMed  Google Scholar 

  35. Stolk RP, Van Daele PL, Pols HA et al (1996) Hyperinsulinemia and bone mineral density in an elderly population: The Rotterdam Study. Bone 18(6):545–549

    Article  CAS  PubMed  Google Scholar 

  36. Abrahamsen B, Rohold A, Henriksen JE, Beck-Nielsen H (2000) Correlations between insulin sensitivity and bone mineral density in non-diabetic men. Diabet Med 17(2):124–129

    Article  CAS  PubMed  Google Scholar 

  37. Shanbhogue VV, Finkelstein JS, Bouxsein ML, Yu EW (2016) Association between insulin resistance and bone structure in nondiabetic postmenopausal women. J Clin Endocrinol Metab 101(8):3114–3122. https://doi.org/10.1210/jc.2016-1726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dennison EM, Syddall HE, Aihie Sayer A, Craighead S, Phillips DI, Cooper C (2004) Type 2 diabetes mellitus is associated with increased axial bone density in men and women from the Hertfordshire Cohort Study: evidence for an indirect effect of insulin resistance? Diabetologia 47(11):1963–1968. https://doi.org/10.1007/s00125-004-1560-y

    Article  CAS  PubMed  Google Scholar 

  39. Aguirre L, Napoli N, Waters D, Qualls C, Villareal DT, Armamento-Villareal R (2014) Increasing adiposity is associated with higher adipokine levels and lower bone mineral density in obese older adults. J Clin Endocrinol Metab 99(9):3290–3297. https://doi.org/10.1210/jc.2013-3200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kanazawa I (2012) Adiponectin in metabolic bone disease. Curr Med Chem 19(32):5481–5492

    Article  CAS  PubMed  Google Scholar 

  41. Hernandez JL, Olmos JM, Pariente E et al (2010) Metabolic syndrome and bone metabolism: the Camargo Cohort Study. Menopause 17(5):955–961. https://doi.org/10.1097/gme.0b013e3181e39a15

    Article  PubMed  Google Scholar 

  42. von Muhlen D, Safii S, Jassal SK, Svartberg J, Barrett-Connor E (2007) Associations between the metabolic syndrome and bone health in older men and women: the Rancho Bernardo Study. Osteoporos Int 18(10):1337–1344. https://doi.org/10.1007/s00198-007-0385-1

    Article  Google Scholar 

  43. Sayers A, Lawlor DA, Sattar N, Tobias JH (2012) The association between insulin levels and cortical bone: findings from a cross-sectional analysis of pQCT parameters in adolescents. J Bone Miner Res 27(3):610–618. https://doi.org/10.1002/jbmr.1467

    Article  CAS  PubMed  Google Scholar 

  44. Verroken C, Zmierczak HG, Goemaere S, Kaufman JM, Lapauw B (2016) Insulin resistance is associated with smaller cortical bone size in non-diabetic men at the age of peak bone mass. J Clin Endocrinol Metab. https://doi.org/10.1210/jc.2016-3609

    Google Scholar 

  45. Choi YJ, Kim DJ, Lee Y, Chung YS (2014) Insulin is inversely associated with bone mass, especially in the insulin-resistant population: the Korea and US National Health and Nutrition Examination Surveys. J Clin Endocrinol Metab 99(4):1433–1441. https://doi.org/10.1210/jc.2013-3346

    Article  CAS  PubMed  Google Scholar 

  46. Shin D, Kim S, Kim KH, Lee K, Park SM (2014) Association between insulin resistance and bone mass in men. J Clin Endocrinol Metab 99(3):988–995. https://doi.org/10.1210/jc.2013-3338

    Article  CAS  PubMed  Google Scholar 

  47. Ahn SH, Kim H, Kim BJ, Lee SH, Koh JM (2015) Insulin resistance and composite indices of femoral neck strength in Asians: the fourth Korea National Health and Nutrition Examination Survey (KNHANES IV). Clin Endocrinol (Oxf). https://doi.org/10.1111/cen.12958

    Google Scholar 

  48. Srikanthan P, Crandall CJ, Miller-Martinez D et al (2014) Insulin resistance and bone strength: findings from the study of midlife in the United States. J Bone Miner Res 29(4):796–803. https://doi.org/10.1002/jbmr.2083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Clowes JA, Hannon RA, Yap TS, Hoyle NR, Blumsohn A, Eastell R (2002) Effect of feeding on bone turnover markers and its impact on biological variability of measurements. Bone 30(6):886–890

    Article  CAS  PubMed  Google Scholar 

  50. Levinger I, Seeman E, Jerums G et al (2016) Glucose-loading reduces bone remodeling in women and osteoblast function in vitro. Physiol Rep. https://doi.org/10.14814/phy2.12700

    PubMed  PubMed Central  Google Scholar 

  51. Clowes JA, Robinson RT, Heller SR, Eastell R, Blumsohn A (2002) Acute changes of bone turnover and PTH induced by insulin and glucose: euglycemic and hypoglycemic hyperinsulinemic clamp studies. J Clin Endocrinol Metab 87(7):3324–3329. https://doi.org/10.1210/jcem.87.7.8660

    Article  CAS  PubMed  Google Scholar 

  52. Basu R, Peterson J, Rizza R, Khosla S (2011) Effects of physiological variations in circulating insulin levels on bone turnover in humans. J Clin Endocrinol Metab 96(5):1450–1455. https://doi.org/10.1210/jc.2010-2877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Levinger I, Brennan-Speranza TC, Jerums G et al (2015) The effect of hyperinsulinaemic-euglycaemic clamp and exercise on bone remodeling markers in obese men. Bonekey Rep 4:731. https://doi.org/10.1038/bonekey.2015.100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ivaska KK, Heliovaara MK, Ebeling P et al (2015) The effects of acute hyperinsulinemia on bone metabolism. Endocr Connect 4(3):155–162. https://doi.org/10.1530/EC-15-0022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Viljakainen H, Ivaska KK, Paldanius P et al (2014) Suppressed bone turnover in obesity: a link to energy metabolism? A case-control study. J Clin Endocrinol Metab 99(6):2155–2163. https://doi.org/10.1210/jc.2013-3097

    Article  CAS  PubMed  Google Scholar 

  56. Tonks KT, White CP, Center JR, Samocha-Bonet D, Greenfield JR (2017) Bone turnover is suppressed in insulin resistance, independent of adiposity. J Clin Endocrinol Metab 102(4):1112–1121. https://doi.org/10.1210/jc.2016-3282

    Article  PubMed  Google Scholar 

  57. Maddaloni E, D’Onofrio L, Lauria A et al (2014) Osteocalcin levels are inversely associated with Hba1c and BMI in adult subjects with long-standing type 1 diabetes. J Endocrinol Invest 37(7):661–666. https://doi.org/10.1007/s40618-014-0092-7

    Article  CAS  PubMed  Google Scholar 

  58. Westberg-Rasmussen S, Starup-Linde J, Hermansen K et al (2017) Differential impact of glucose administered intravenously or orally on bone turnover markers in healthy male subjects. Bone 97:261–266. https://doi.org/10.1016/j.bone.2017.01.027

    Article  CAS  PubMed  Google Scholar 

  59. Hansen KB, Vilsboll T, Bagger JI, Holst JJ, Knop FK (2010) Reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet impairs the incretin effect in healthy subjects. J Clin Endocrinol Metab 95(7):3309–3317. https://doi.org/10.1210/jc.2010-0119

    Article  CAS  PubMed  Google Scholar 

  60. Reid IR (2008) Relationships between fat and bone. Osteoporos Int 19(5):595–606. https://doi.org/10.1007/s00198-007-0492-z

    Article  CAS  PubMed  Google Scholar 

  61. Sanz C, Vazquez P, Blazquez C, Barrio PA, Alvarez Mdel M, Blazquez E (2010) Signaling and biological effects of glucagon-like peptide 1 on the differentiation of mesenchymal stem cells from human bone marrow. Am J Physiol Endocrinol Metab 298(3):E634. https://doi.org/10.1152/ajpendo.00460.2009

    Article  CAS  PubMed  Google Scholar 

  62. Yamada C, Yamada Y, Tsukiyama K et al (2008) The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 149(2):574–579. https://doi.org/10.1210/en.2007-1292

    Article  CAS  PubMed  Google Scholar 

  63. Nuche-Berenguer B, Moreno P, Portal-Nunez S, Dapia S, Esbrit P, Villanueva-Penacarrillo ML (2010) Exendin-4 exerts osteogenic actions in insulin-resistant and type 2 diabetic states. Regul Pept 159(1–3):61–66. https://doi.org/10.1016/j.regpep.2009.06.010

    Article  CAS  PubMed  Google Scholar 

  64. Iepsen EW, Lundgren JR, Hartmann B et al (2015) GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. J Clin Endocrinol Metab 100(8):2909–2917. https://doi.org/10.1210/jc.2015-1176

    Article  CAS  PubMed  Google Scholar 

  65. Luo G, Liu H, Lu H (2016) Glucagon-like peptide-1(GLP-1) receptor agonists: potential to reduce fracture risk in diabetic patients? Br J Clin Pharmacol 81(1):78–88

    Article  PubMed  CAS  Google Scholar 

  66. Palermo A, D’Onofrio L, Eastell R, Schwartz AV, Pozzilli P, Napoli N (2015) Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous?A narrative review. Osteoporos Int 26(8):2073–2089. https://doi.org/10.1007/s00198-015-3123-0

    Article  CAS  PubMed  Google Scholar 

  67. Dube JJ, Amati F, Toledo FG et al (2011) Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. Diabetologia 54(5):1147–1156. https://doi.org/10.1007/s00125-011-2065-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ihle R, Loucks AB (2004) Dose–response relationships between energy availability and bone turnover in young exercising women. J Bone Miner Res 19(8):1231–1240. https://doi.org/10.1359/JBMR.040410

    Article  PubMed  Google Scholar 

  69. Shah K, Armamento-Villareal R, Parimi N et al (2011) Exercise training in obese older adults prevents increase in bone turnover and attenuates decrease in hip bone mineral density induced by weight loss despite decline in bone-active hormones. J Bone Miner Res 26(12):2851–2859. https://doi.org/10.1002/jbmr.475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Villareal DT, Fontana L, Das SK et al (2016) Effect of two-year caloric restriction on bone metabolism and bone mineral density in non-obese younger adults: a randomized clinical trial. J Bone Miner Res 31(1):40–51. https://doi.org/10.1002/jbmr.2701

    Article  CAS  PubMed  Google Scholar 

  71. Colleluori G, Napoli N, Phadnis U, Armamento-Villareal R, Villareal DT (2017) Effect of weight loss, exercise, or both on undercarboxylated osteocalcin and insulin secretion in frail, obese older adults. Oxid Med Cell Longev 2017:4807046. https://doi.org/10.1155/2017/4807046

    Article  PubMed  PubMed Central  Google Scholar 

  72. Karsenty G, Olson EN (2016) Bone and muscle endocrine functions: unexpected paradigms of inter-organ communication. Cell 164(6):1248–1256. https://doi.org/10.1016/j.cell.2016.02.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ferron M, Lacombe J, Germain A, Oury F, Karsenty G (2015) GGCX and VKORC1 inhibit osteocalcin endocrine functions. J Cell Biol 208(6):761–776. https://doi.org/10.1083/jcb.201409111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee NK, Sowa H, Hinoi E et al (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130(3):456–469. https://doi.org/10.1016/j.cell.2007.05.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sabek OM, Nishimoto SK, Fraga D, Tejpal N, Ricordi C, Gaber AO (2015) Osteocalcin effect on human beta-cells mass and function. Endocrinology 156(9):3137–3146. https://doi.org/10.1210/EN.2015-1143

    Article  CAS  PubMed  Google Scholar 

  76. Ferron M, McKee MD, Levine RL, Ducy P, Karsenty G (2012) Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 50(2):568–575. https://doi.org/10.1016/j.bone.2011.04.017

    Article  CAS  PubMed  Google Scholar 

  77. Ferron M, Wei J, Yoshizawa T et al (2010) Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142(2):296–308. https://doi.org/10.1016/j.cell.2010.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bilotta FL, Arcidiacono B, Messineo S et al (2017) Insulin and osteocalcin: further evidence for a mutual cross-talk. Endocrine. https://doi.org/10.1007/s12020-017-1396-0

    Google Scholar 

  79. Wei J, Ferron M, Clarke CJ et al (2014) Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. J Clin Invest 124(4):1–13. https://doi.org/10.1172/JCI72323

    Article  PubMed  CAS  Google Scholar 

  80. Mizokami A, Yasutake Y, Gao J et al (2013) Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice. PLoS ONE 8(2):e57375. https://doi.org/10.1371/journal.pone.0057375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mizokami A, Yasutake Y, Higashi S et al (2014) Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion. Bone 69:68–79. https://doi.org/10.1016/j.bone.2014.09.006

    Article  CAS  PubMed  Google Scholar 

  82. Fulzele K, Lai F, Dedic C et al (2017) Osteocyte-secreted Wnt signaling inhibitor sclerostin contributes to beige adipogenesis in peripheral fat depots. J Bone Miner Res 32(2):373–384. https://doi.org/10.1002/jbmr.3001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yao Q, Yu C, Zhang X, Zhang K, Guo J, Song L (2017) Wnt/beta-catenin signaling in osteoblasts regulates global energy metabolism. Bone 97:175–183. https://doi.org/10.1016/j.bone.2017.01.028

    Article  CAS  PubMed  Google Scholar 

  84. Fernandez-Real JM, Izquierdo M, Ortega F et al (2009) The relationship of serum osteocalcin concentration to insulin secretion, sensitivity, and disposal with hypocaloric diet and resistance training. J Clin Endocrinol Metab 94(1):237–245. https://doi.org/10.1210/jc.2008-0270

    Article  CAS  PubMed  Google Scholar 

  85. Jung KY, Kim KM, Ku EJ et al (2016) Age- and sex-specific association of circulating osteocalcin with dynamic measures of glucose homeostasis. Osteoporos Int 27(3):1021–1029. https://doi.org/10.1007/s00198-015-3315-7

    Article  CAS  PubMed  Google Scholar 

  86. Alissa EM, Alnahdi WA, Alama N, Ferns GA (2014) Serum osteocalcin is associated with dietary vitamin D, body weight and serum magnesium in postmenopausal women with and without significant coronary artery disease. Asia Pac J Clin Nutr 23(2):246–255. https://doi.org/10.6133/apjcn.2014.23.2.06

    CAS  PubMed  Google Scholar 

  87. Bao Y, Ma X, Yang R et al (2013) Inverse relationship between serum osteocalcin levels and visceral fat area in Chinese men. J Clin Endocrinol Metab 98(1):345–351. https://doi.org/10.1210/jc.2012-2906

    Article  CAS  PubMed  Google Scholar 

  88. Kindblom JM, Ohlsson C, Ljunggren O et al (2009) Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res 24(5):785–791. https://doi.org/10.1359/jbmr.081234

    Article  CAS  PubMed  Google Scholar 

  89. Lenders CM, Lee PD, Feldman HA et al (2013) A cross-sectional study of osteocalcin and body fat measures among obese adolescents. Obesity (Silver Spring) 21(4):808–814. https://doi.org/10.1002/oby.20131

    Article  CAS  Google Scholar 

  90. Movahed A, Larijani B, Nabipour I et al (2012) Reduced serum osteocalcin concentrations are associated with type 2 diabetes mellitus and the metabolic syndrome components in postmenopausal women: the crosstalk between bone and energy metabolism. J Bone Miner Metab 30(6):683–691. https://doi.org/10.1007/s00774-012-0367-z

    Article  CAS  PubMed  Google Scholar 

  91. Saleem U, Mosley TH Jr, Kullo IJ (2010) Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler Thromb Vasc Biol 30(7):1474–1478. https://doi.org/10.1161/ATVBAHA.110.204859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yeap BB, Chubb SA, Flicker L et al (2010) Reduced serum total osteocalcin is associated with metabolic syndrome in older men via waist circumference, hyperglycemia, and triglyceride levels. Eur J Endocrinol 163(2):265–272. https://doi.org/10.1530/EJE-10-0414

    Article  CAS  PubMed  Google Scholar 

  93. Knapen MH, Schurgers LJ, Shearer MJ, Newman P, Theuwissen E, Vermeer C (2012) Association of vitamin K status with adiponectin and body composition in healthy subjects: uncarboxylated osteocalcin is not associated with fat mass and body weight. Br J Nutr 108(6):1017–1024. https://doi.org/10.1017/S000711451100626X

    Article  CAS  PubMed  Google Scholar 

  94. Shea MK, Booth SL, Gundberg CM et al (2010) Adulthood obesity is positively associated with adipose tissue concentrations of vitamin K and inversely associated with circulating indicators of vitamin K status in men and women. J Nutr 140(5):1029–1034. https://doi.org/10.3945/jn.109.118380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kunutsor SK, Apekey TA, Laukkanen JA (2015) Association of serum total osteocalcin with type 2 diabetes and intermediate metabolic phenotypes: systematic review and meta-analysis of observational evidence. Eur J Epidemiol 30(8):599–614. https://doi.org/10.1007/s10654-015-0058-x

    Article  CAS  PubMed  Google Scholar 

  96. Shea MK, Dawson-Hughes B, Gundberg CM, Booth SL (2017) Reducing undercarboxylated osteocalcin with vitamin k supplementation does not promote lean tissue loss or fat gain over 3 years in older women and men: a Randomized Controlled Trial. J Bone Miner Res 32(2):243–249. https://doi.org/10.1002/jbmr.2989

    Article  CAS  PubMed  Google Scholar 

  97. Knapen MHJ, Jardon KM, Vermeer C (2017) Vitamin K-induced effects on body fat and weight: results from a 3-year vitamin K2 intervention study. Eur J Clin Nutr. https://doi.org/10.1038/ejcn.2017.146

    PubMed  Google Scholar 

  98. Centi AJ, Booth SL, Gundberg CM, Saltzman E, Nicklas B, Shea MK (2015) Osteocalcin carboxylation is not associated with body weight or percent fat changes during weight loss in post-menopausal women. Endocrine 50(3):627–632. https://doi.org/10.1007/s12020-015-0618-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Maser RE, James Lenhard M, Balagopal PB, Kolm P, Peters MB (2013) Effects of surgically induced weight loss by Roux-en-Y gastric bypass on osteocalcin. Surg Obes Relat Dis 9(6):950–955. https://doi.org/10.1016/j.soard.2012.08.006

    Article  PubMed  Google Scholar 

  100. Bredella MA, Greenblatt LB, Eajazi A, Torriani M, Yu EW (2017) Effects of Roux-en-Y gastric bypass and sleeve gastrectomy on bone mineral density and marrow adipose tissue. Bone 95:85–90. https://doi.org/10.1016/j.bone.2016.11.014

    Article  PubMed  Google Scholar 

  101. Ivaska KK, Huovinen V, Soinio M et al (2017) Changes in bone metabolism after bariatric surgery by gastric bypass or sleeve gastrectomy. Bone 95:47–54. https://doi.org/10.1016/j.bone.2016.11.001

    Article  CAS  PubMed  Google Scholar 

  102. Schafer AL, Sellmeyer DE, Schwartz AV et al (2011) Change in undercarboxylated osteocalcin is associated with changes in body weight, fat mass, and adiponectin: parathyroid hormone (1-84) or alendronate therapy in postmenopausal women with osteoporosis (the PaTH study). J Clin Endocrinol Metab 96(12):E1982–E1989. https://doi.org/10.1210/jc.2011-0587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Schwartz AV, Schafer AL, Grey A et al (2013) Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials. J Bone Miner Res 28(6):1348–1354. https://doi.org/10.1002/jbmr.1865

    Article  CAS  PubMed  Google Scholar 

  104. Biver E, Salliot C, Combescure C et al (2011) Influence of adipokines and ghrelin on bone mineral density and fracture risk: a systematic review and meta-analysis. J Clin Endocrinol Metab 96(9):2703–2713. https://doi.org/10.1210/jc.2011-0047

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Clinical Transplant Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20163, Milan, Italy

    Caterina Conte

  2. Division of Endocrinology, Mount Sinai School of Medicine, New York, NY, USA

    Solomon Epstein

  3. Division of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Rome, Italy

    Nicola Napoli

  4. Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, MO, USA

    Nicola Napoli

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  1. Caterina Conte
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  2. Solomon Epstein
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  3. Nicola Napoli
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Correspondence to Caterina Conte.

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Conte, C., Epstein, S. & Napoli, N. Insulin resistance and bone: a biological partnership. Acta Diabetol 55, 305–314 (2018). https://doi.org/10.1007/s00592-018-1101-7

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