Hyperinsulinaemia-Osteofragilitas: Comparison
Please note this is a comparison between Version 3 by Beatrix Zheng and Version 2 by Isabella Cooper.

Bone fragility leading to increased risk of low energy (fragility) fractures that is independent of bone mineral density, occurring in individuals with detected and undetected hyperinsulinaemia.



Patients with type 2 diabetes mellitus (T2DM) and/or cardiovascular disease (CVD), conditions of hyperinsulinaemia, have lower levels of osteocalcin and bone remodelling, and increased rates of fragility fractures. Unlike osteoporosis with lower bone mineral density (BMD), T2DM bone fragility “hyperinsulinaemia-osteofragilitas” phenotype presents with normal to increased BMD. Hyperinsulinaemia and insulin resistance positively associate with increased BMD and fragility fractures. 

Hyperinsulinaemia enforces glucose fuelling, which decreases NAD+-dependent antioxidant activity. This increases reactive oxygen species and mitochondrial fission, and decreases oxidative phosphorylation high-energy production capacity, required for osteoblasto/cytogenesis. Osteocytes directly mineralise and resorb bone, and inhibit mineralisation of their lacunocanalicular space via pyrophosphate. Hyperinsulinaemia decreases vitamin D availability via adipocyte sequestration, reducing dendrite connectivity, and compromising osteocyte viability. Decreased bone remodelling and micropetrosis ensues. Trapped/entombed magnesium within micropetrosis fossilisation spaces propagates magnesium deficiency (MgD), potentiating hyperinsulinaemia and decreases vitamin D transport. Vitamin D deficiency reduces osteocalcin synthesis and favours osteocyte apoptosis. 

Carbohydrate restriction/fasting/ketosis increases beta-oxidation, ketolysis, NAD+-dependent antioxidant activity, osteocyte viability and osteocalcin, and decreases excess insulin exposure. Osteocalcin is required for hydroxyapatite alignment, conferring bone structural integrity, decreasing fracture risk and improving metabolic/endocrine homeodynamics. Patients presenting with fracture and normal BMD should be investigated for T2DM and hyperinsulinaemia.

  • hyperinsulinaemia
  • beta hydroxybutyrate
  • osteoporosis
  • type 2 diabetes
  • fragility fractures
  • bone mineral density
  • osteocalcin
  • vitamin D
  • collagen
  • hydroxyapatite
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References

  1. Golub, E.E.; Boesze-Battaglia, K. The role of alkaline phosphatase in mineralization. Curr. Opin. Orthop. 2007, 18, 444–448.
  2. Srikanthan, P.; Crandall, C.J.; Miller-Martinez, D.; Seeman, T.E.; Greendale, G.A.; Binkley, N.; Karlamangla, A.S. Insulin resistance and bone strength: Findings from the study of midlife in the United States. J. Bone Miner. Res. 2014, 29, 796–803.
  3. Crofts, C.A.P.; Zinn, C.; Wheldon, M.; Schofield, M. Hyperinsulinemia: A unifying theory of chronic disease? Diabesity 2015, 1, 34.
  4. Hu, Z.; Ma, C.; Liang, Y.; Zou, S.; Liu, X. Osteoclasts in bone regeneration under type 2 diabetes mellitus. Acta Biomater. 2019, 84, 402–413.
  5. Sipos, W.; Pietschmann, P.; Rauner, M.; Kerschan-Schindl, K.; Patsch, J. Pathophysiology of osteoporosis. Wien. Med. Wochenschr. 2009, 159, 230–234.
  6. Compston, J. Type 2 diabetes mellitus and bone. J. Intern. Med. 2018, 283, 140–153.
  7. Luisa, M.I.; Ruano, B. Bone disease in diabetes. Curr. Diabetes Rev. 2010, 6, 144–155.
  8. Shanbhogue, V.V.; Finkelstein, J.S.; Bouxsein, M.L.; Yu, E.W. Association between insulin resistance and bone structure in nondiabetic postmenopausal women. J. Clin. Endocrinol. Metab. 2016, 101, 3114–3122.
  9. Losada-Grande, E.; Hawley, S.; Soldevila, B.; Martinez-Laguna, D.; Nogues, X.; DIez-Perez, A.; Puig-Domingo, M.; Mauricio, D.; Prieto-Alhambra, D. Insulin use and excess fracture risk in patients with type 2 diabetes: Apropensity-matched cohort analysis. Sci. Rep. 2017, 7, 1–9.
  10. Sassi, F.; Buondonno, I.; Luppi, C.; Spertino, E.; Stratta, E.; Di Stefano, M.; Ravazzoli, M.; Isaia, G.; Trento, M.; Passera, P.; et al. Type 2 diabetes affects bone cells precursors and bone turnover. BMC Endocr. Disord. 2018, 18, 55.
  11. Cipriani, C.; Colangelo, L.; Santori, R.; Renella, M.; Mastrantonio, M.; Minisola, S.; Pepe, J. The interplay between bone and glucose metabolism. Front. Endocrinol. 2020, 11, 122.
  12. Napoli, N.; Strotmeyer, E.S.; Ensrud, K.E.; Sellmeyer, D.E.; Bauer, D.C.; Hoffman, A.R.; Dam, T.T.L.; Barrett-Connor, E.; Palermo, L.; Orwoll, E.S.; et al. Fracture risk in diabetic elderly men: The MrOS study. Diabetologia 2014, 57, 2057–2065.
  13. Crofts, C.; Schofield, G.; Zinn, C.; Wheldon, M.; Kraft, J. Identifying hyperinsulinaemia in the absence of impaired glucose tolerance: An examination of the Kraft database. Diabetes Res. Clin. Pract. 2016, 118, 50–57.
  14. Hill, P.A.; Tumber, A. Ceramide-induced cell death/survival in murine osteoblasts. J. Endocrinol. 2010, 206, 225–233.
  15. Kim, B.J.; Lee, J.Y.; Park, S.J.; Lee, S.H.; Kim, S.J.; Yoo, H.J.; De Pena, S.I.R.; McGee-Lawrence, M.; Isales, C.M.; Koh, J.M.; et al. Elevated Ceramides 18:0 and 24:1 with Aging are Associated with Hip Fracture Risk Through Increased Bone Resorption. Aging (Albany. N. Y.) 2019, 11, 9388–9404.
  16. Smith, M.E.; Tippetts, T.S.; Brassfield, E.S.; Tucker, B.J.; Ockey, A.; Swensen, A.C.; Anthonymuthu, T.S.; Washburn, T.D.; Kane, D.A.; Prince, J.T.; et al. Mitochondrial fission mediates ceramide-induced metabolic disruption in skeletal muscle. Biochem. J. 2013, 456, 427–439.
  17. Hansen, M.E.; Tippetts, T.S.; Anderson, M.C.; Holub, Z.E.; Moulton, E.R.; Swensen, A.C.; Prince, J.T.; Bikman, B.T. Insulin increases ceramide synthesis in skeletal muscle. J. Diabetes Res. 2014, 2014, 765784.
  18. Bell, L.S.; Kayser, M.; Jones, C. The mineralized osteocyte: A living fossil. Am. J. Phys. Anthropol. 2008, 137, 449–456.
  19. Busse, B.; Djonic, D.; Milovanovic, P.; Hahn, M.; Püschel, K.; Ritchie, R.O.; Djuric, M.; Amling, M. Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging Cell 2010, 9, 1065–1075.
  20. Milovanovic, P.; Zimmermann, E.A.; vom Scheidt, A.; Hoffmann, B.; Sarau, G.; Yorgan, T.; Schweizer, M.; Amling, M.; Christiansen, S.; Busse, B. The formation of calcified nanospherites during micropetrosis represents a unique mineralization mechanism in aged human bone. Small 2017, 13, 1602215.
  21. Rolvien, T.; Schmidt, F.N.; Milovanovic, P.; Jähn, K.; Riedel, C.; Butscheidt, S.; Püschel, K.; Jeschke, A.; Amling, M.; Busse, B. Early bone tissue aging in human auditory ossicles is accompanied by excessive hypermineralization, osteocyte death and micropetrosis. Sci. Rep. 2018, 8, 1–11.
  22. Milovanovic, P.; Busse, B. Phenomenon of osteocyte lacunar mineralization: Indicator of former osteocyte death and a novel marker of impaired bone quality? Endocr. Connect. 2020, 9, R70–R80.
  23. Huang, S.; Kaw, M.; Harris, M.T.; Ebraheim, N.; Mcinerney, M.F.; Najjar, S.M.; Lecka-Czernik, B. Decreased osteoclastogenesis and high bone mass in mice with impaired insulin clearance due to liver-specific inactivation to CEACAM1. Bone 2009, 46, 1138–1145.
  24. Robling, A.G.; Bonewald, L.F. The osteocyte: New insights. Annu. Rev. Physiol. 2020, 82, 485–506.
  25. Carpentier, V.T.; Wong, J.; Yeap, Y.; Gan, C.; Sutton-Smith, P.; Badiei, A.; Fazzalari, N.L.; Kuliwaba, J.S. Increased proportion of hypermineralized osteocyte lacunae in osteoporotic and osteoarthritic human trabecular bone: Implications for bone remodeling. Bone 2012, 50, 688–694.
  26. Qing, H.; Bonewald, L.F. Osteocyte remodeling of the perilacunar and pericanalicular matrix. Int. J. Oral Sci. 2009, 1, 59–65.
  27. Qing, H.; Ardeshirpour, L.; Divieti Pajevic, P.; Dusevich, V.; Jähn, K.; Kato, S.; Wysolmerski, J.; Bonewald, L.F. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J. Bone Miner. Res. 2012, 27, 1018–1029.
  28. Weinkamer, R.; Kollmannsberger, P.; Fratzl, P. Towards a connectomic description of the osteocyte lacunocanalicular network in bone. Curr. Osteoporos. Rep. 2019, 17, 186–194.
  29. Jähn, K.; Kelkar, S.; Zhao, H.; Xie, Y.; Tiede-Lewis, L.A.M.; Dusevich, V.; Dallas, S.L.; Bonewald, L.F. Osteocytes acidify their microenvironment in response to PTHrP in vitro and in lactating mice in vivo. J. Bone Miner. Res. 2017, 32, 1761–1772.
  30. Kitaura, H.; Marahleh, A.; Ohori, F.; Noguchi, T.; Shen, W.-R.; Qi, J.; Nara, Y.; Pramusita, A.; Kinjo, R.; Mizoguchi, I. Osteocyte-related cytokines regulate osteoclast formation and bone resorption. Int. J. Mol. Sci. 2020, 21, 5169.
  31. Nango, N.; Kubota, S.; Hasegawa, T.; Yashiro, W.; Momose, A.; Matsuo, K. Osteocyte-directed bone demineralization along canaliculi. Bone 2016, 84, 279–288.
  32. Wysolmerski, J.J. Osteocytes remove and replace perilacunar mineral during reproductive cycles. Bone 2013, 54, 230–236.
  33. Hao, Z.; Ma, Y.; Wu, J.; Li, X.; Chen, H.; Shen, J.; Wang, H. Osteocytes regulate osteoblast differentiation and osteoclast activity through Interleukin-6 under mechanical loading. RSC Adv. 2017, 7, 50200–50209.
  34. Sánchez-de-Diego, C.; Artigas, N.; Pimenta-Lopes, C.; Valer, J.A.; Torrejon, B.; Gama-Pérez, P.; Villena, J.A.; Garcia-Roves, P.M.; Rosa, J.L.; Ventura, F. Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program. iScience 2019, 15, 79–94.
  35. Bonewald, L.F. The amazing osteocyte. J. Bone Miner. Res. 2011, 26, 229–238.
  36. Lanske, B.; Densmore, M.J.; Erben, R.G. Vitamin D endocrine system and osteocytes. Bonekey Rep. 2014, 3, 494.
  37. Gao, J.; Qin, A.; Liu, D.; Ruan, R.; Wang, Q.; Yuan, J.; Cheng, T.S.; Filipovska, A.; Papadimitriou, J.M.; Dai, K.; et al. Endoplasmic reticulum mediates mitochondrial transfer within the osteocyte dendritic network. Sci. Adv. 2019, 5, eaaw7215.
  38. Noble, B.S.; Peet, N.; Stevens, H.Y.; Brabbs, A.; Mosley, J.R.; Reilly, G.C.; Reeve, J.; Skerry, T.M.; Lanyon, L.E. Mechanical loading: Biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. Am. J. Physiol.-Cell Physiol. 2003, 284, C934–C943.
  39. Liu, T.T.; Liu, D.M.; Xuan, Y.; Zhao, L.; Sun, L.H.; Zhao, D.D.; Wang, X.F.; He, Y.; Guo, X.Z.; Du, R.; et al. The association between the baseline bone resorption marker CTX and incident dysglycemia after 4 years. Bone Res. 2017, 5, 1–7.
  40. Saito, M.; Marumo, K. Collagen cross-links as a determinant of bone quality: A possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos. Int. 2010, 21, 195–214.
  41. Gautieri, A.; Passini, F.S.; Silván, U.; Guizar-Sicairos, M.; Carimati, G.; Volpi, P.; Moretti, M.; Schoenhuber, H.; Redaelli, A.; Berli, M.; et al. Advanced glycation end-products: Mechanics of aged collagen from molecule to tissue. Matrix Biol. 2017, 59, 95–108.
  42. Vashishth, D.; Verborgt, O.; Divine, G.; Schaffler, M.B.; Fyhrie, D.P. Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 2000, 26, 375–380.
  43. Frey, J.L.; Li, Z.; Ellis, J.M.; Zhang, Q.; Farber, C.R.; Aja, S.; Wolfgang, M.J.; Clemens, T.L.; Riddle, R.C. Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast. Mol. Cell. Biol. 2015, 35, 1979–1991.
  44. Qian, G.; Fan, W.; Ahlemeyer, B.; Karnati, S.; Baumgart-Vogt, E. Peroxisomes in different skeletal cell types during intramembranous and endochondral ossification and their regulation during osteoblast differentiation by distinct peroxisome proliferator-activated receptors. PLoS ONE 2015, 10, e0143439.
  45. Kim, S.P.; Li, Z.; Zoch, M.L.; Frey, J.L.; Bowman, C.E.; Kushwaha, P.; Ryan, K.A.; Goh, B.C.; Scafidi, S.; Pickett, J.E.; et al. Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner. JCI Insight 2017, 2, e92704.
  46. Kushwaha, P.; Wolfgang, M.J.; Riddle, R.C. Fatty acid metabolism by the osteoblast. Bone 2018, 115, 8–14.
  47. Cooper, I.D.; Crofts, C.A.P.; DiNicolantonio, J.J.; Malhotra, A.; Elliott, B.; Kyriakidou, Y.; Brookler, K.H. Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: Rationale for clinical management. Open Hear. 2020, 7, e001356.
  48. Veech, R.L. The therapeutic implications of ketone bodies: The effects of ketone bodies in pathological conditions: Ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot. Essent. Fat. Acids 2004, 70, 309–319.
  49. Hamanaka, R.B.; Chandel, N.S. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem. Sci. 2010, 35, 505–513.
  50. Newman, J.C.; Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 2014, 25, 42–52.
  51. Newman, J.C.; Verdin, E. β-hydroxybutyrate: A signaling metabolite. Annu. Rev. Nutr. 2017, 37, 51–76.
  52. Anderson, E.J.; Lustig, M.E.; Boyle, K.E.; Woodlief, T.L.; Kane, D.A.; Lin, C.T.; Price, J.W.; Kang, L.; Rabinovitch, P.S.; Szeto, H.H.; et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J. Clin. Investig. 2009, 119, 573–581.
  53. Kobayashi, K.; Nojiri, H.; Saita, Y.; Morikawa, D.; Ozawa, Y.; Watanabe, K.; Koike, M.; Asou, Y.; Shirasawa, T.; Yokote, K.; et al. Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis. Sci. Rep. 2015, 5, 1–11.
  54. Yu, T.; Robotham, J.L.; Yoon, Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc. Natl. Acad. Sci. USA. 2006, 103, 2653–2658.
  55. Giacomello, M.; Pyakurel, A.; Glytsou, C.; Scorrano, L. The cell biology of mitochondrial membrane dynamics. Nat. Rev. Mol. Cell Biol. 2020, 21, 204–224.
  56. Dallas, S.L.; Prideaux, M.; Bonewald, L.F. The osteocyte: An endocrine cell and more. Endocr. Rev. 2013, 34, 658–690.
  57. Ferron, M. Endocrine functions of bone. In Principles of Endocrinology and Hormone Action; Springer: Cham, Switzerland, 2018; pp. 1–27.
  58. Lai, X.; Price, C.; Modla, S.; Thompson, W.R.; Caplan, J.; Kirn-Safran, C.B.; Wang, L. The dependences of osteocyte network on bone compartment, age, and disease. Bone Res. 2015, 3, 1–11.
  59. Yeung, S.M.H.; Binnenmars, S.H.; Gant, C.M.; Navis, G.; Gansevoort, R.T.; Bakker, S.J.L.; De Borst, M.H.; Laverman, G.D. Fibroblast growth factor 23 and mortality in patients with type 2 diabetes and normal or mildly impaired kidney function. Diabetes Care 2019, 42, 2151–2153.
  60. Kim, H.; Lee, Y.D.; Kim, H.J.; Lee, Z.H.; Kim, H.-H. SOD2 and Sirt3 control osteoclastogenesis by regulating mitochondrial ROS. J. Bone Miner. Res. 2017, 32, 397–406.
  61. Kashiwaya, Y.; Satos, K.; Tsuchiya, N.; Thomas, S.; Fells, D.A.; Veechn, R.L.; Passonneau, J. V Control of glucose utilization in working perfused rat heart. J. Biol. Chem. 1994, 269, 25502–25514.
  62. van de Ven, R.A.H.; Santos, D.; Haigis, M.C. Mitochondrial sirtuins and molecular mechanisms of aging. Trends Mol. Med. 2017, 23, 320–331.
  63. Qiu, X.; Brown, K.; Hirschey, M.D.; Verdin, E.; Chen, D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010, 12, 662–667.
  64. Chen, Y.; Zhang, J.; Lin, Y.; Lei, Q.; Guan, K.L.; Zhao, S.; Xiong, Y. Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Rep. 2011, 12, 534–541.
  65. Dikalova, A.E.; Itani, H.A.; Nazarewicz, R.R.; McMaster, W.G.; Flynn, C.R.; Uzhachenko, R.; Fessel, J.P.; Gamboa, J.L.; Harrison, D.G.; Dikalov, S.I. Sirt3 impairment and SOD2 hyperacetylation in vascular oxidative stress and hypertension. Circ. Res. 2017, 121, 564–574.
  66. Golub, E.E.; Boesze-Battaglia, K. The role of alkaline phosphatase in mineralization. Curr. Opin. Orthop. 2007, 18, 444–448.
  67. Cooper, I.D.; Brookler, K.H.; Kyriakidou, Y.; Elliott, B.T.; Crofts, C.A.P. Metabolic phenotypes and step by step evolution of type 2 diabetes: A new paradigm. Biomed 2021, 9, 800.
  68. Xu, Y.; Liu, L.; Nakamura, A.; Someya, S.; Miyakawa, T.; Tanokura, M. Studies on the regulatory mechanism of isocitrate dehydrogenase 2 using acetylation mimics. Sci. Rep. 2017, 7, 1–10.
  69. Someya, S.; Yu, W.; Hallows, W.C.; Xu, J.; Vann, J.M.; Leeuwenburgh, C.; Tanokura, M.; Denu, J.M.; Prolla, T.A. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010, 143, 802–812.
  70. Liu, Z.; Solesio, M.E.; Schaffler, M.B.; Frikha-Benayed, D.; Rosen, C.J.; Werner, H.; Kopchick, J.J.; Pavlov, E.V.; Abramov, A.Y.; Yakar, S. Mitochondrial function is compromised in cortical bone osteocytes of long-lived growth hormone receptor null mice. J. Bone Miner. Res. 2019, 34, 106–122.
  71. Spencer, G.; Genever, P. Long-term potentiation in bone-A role for glutamate in strain-induced cellular memory? BMC Cell Biol. 2003, 4, 9.
  72. Spencer, G.; Hitchcock, I.; Genever, P.G. Emerging neuroskeletal signalling pathways: A review. FEBS Lett. 2004, 559, 6–12.
  73. Sonagra, A.D. Normal pregnancy-A state of insulin resistance. J. Clin. Diagnostic Res. 2014, 8, CC01.
  74. Saito, A.; Yoshimura, K.; Miyamoto, Y.; Kaneko, K.; Chikazu, D.; Yamamoto, M.; Kamijo, R. Enhanced and suppressed mineralization by acetoacetate and β-hydroxybutyrate in osteoblast cultures. Biochem. Biophys. Res. Commun. 2016, 473, 537–544.
  75. Ferron, M.; Lacombe, J. Regulation of energy metabolism by the skeleton: Osteocalcin and beyond. Arch. Biochem. Biophys. 2014, 561, 137–146.
  76. Li, J.; Zhang, H.; Yang, C.; Li, Y.; Dai, Z. An overview of osteocalcin progress. J. Bone Miner. Metab. 2016, 34, 367–379.
  77. Grabacka, M.; Pierzchalska, M.; Dean, M.; Reiss, K. Regulation of ketone body metabolism and the role of PPARα. Int. J. Mol. Sci. 2016, 17, 2093.
  78. Arnett, T.R. Osteocytes: Regulating the mineral reserves? J. Bone Miner. Res. 2013, 28, 2433–2435.
  79. Gröber, U.; Schmidt, J.; Kisters, K. Magnesium in Prevention and Therapy. Nutrients 2015, 7, 8199–8226.
  80. DiNicolantonio, J.J.; O’Keefe, J.H.; Wilson, W. Subclinical magnesium deficiency: A principal driver of cardiovascular disease and a public health crisis. Open Hear. 2018, 5, e000668.
  81. Kostov, K. Effects of magnesium deficiency on mechanisms of insulin resistance in type 2 diabetes: Focusing on the processes of insulin secretion and signaling. Int. J. Mol. Sci. 2019, 20, 1351.
  82. Drake, M.T.; Clarke, B.L.; Khosla, S. Bisphosphonates: Mechanism of action and role in clinical practice. Mayo. Clin. Proc. 2008, 83, 1032–1045.
  83. Zhu, D.; Mackenzie, N.C.W.; Millán, J.L.; Farquharson, C.; MacRae, V.E. The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells. PLoS ONE 2011, 6, e19595.
  84. Brandenburg, V.M.; Kramann, R.; Koos, R.; Krüger, T.; Schurgers, L.; Mühlenbruch, G.; Hübner, S.; Gladziwa, U.; Drechsler, C.; Ketteler, M. Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: A cross-sectional study. BMC Nephrol. 2013, 14, 1–10.
  85. De Maré, A.; D’haese, P.C.; Verhulst, A. The role of sclerostin in bone and ectopic calcification. Int. J. Mol. Sci. 2020, 21, 3199.
  86. Tyson, J.; Bundy, K.; Roach, C.; Douglas, H.; Ventura, V.; Segars, M.F.; Schwartz, O.; Simpson, C.L. Mechanisms of the osteogenic switch of smooth muscle cells in vascular calcification: WNT signaling, BMPs, mechanotransduction, and EndMT. Bioengineering 2020, 7, 88.
  87. Song, L. Calcium and bone metabolism indices. Adv. Clin. Chem. 2017, 82, 1–46.
  88. Saleem, U.; Mosley, T.H.; Kullo, I.J. Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 1474–1478.
  89. Razny, U.; Fedak, D.; Kiec-Wilk, B.; Goralska, J.; Gruca, A.; Zdzienicka, A.; Kiec-Klimczak, M.; Solnica, B.; Hubalewska-Dydejczyk, A.; Malczewska-Malec, M. Carboxylated and undercarboxylated osteocalcin in metabolic complications of human obesity and prediabetes. Diabetes. Metab. Res. Rev. 2017, 33, e2862.
  90. Guney, G.; Sener-Simsek, B.; Tokmak, A.; Yucel, A.; Buyukkagnici, U.; Yilmaz, N.; Engin-Ustun, Y.; Ozgu-Erdinc, A.S. Assessment of the relationship between serum vitamin D and osteocalcin levels with metabolic syndrome in non-osteoporotic postmenopausal women. Geburtshilfe Frauenheilkd. 2019, 79, 293–299.
  91. Riquelme-Gallego, B.; García-Molina, L.; Cano-Ibáñez, N.; Sánchez-Delgado, G.; Andújar-Vera, F.; García-Fontana, C.; González-Salvatierra, S.; García-Recio, E.; Martínez-Ruiz, V.; Bueno-Cavanillas, A.; et al. Circulating undercarboxylated osteocalcin as estimator of cardiovascular and type 2 diabetes risk in metabolic syndrome patients. Sci. Rep. 2020, 10, 1–10.
  92. Wei, J.; Karsenty, G. An overview of the metabolic functions of osteocalcin. Rev. Endocr. Metab. Disord. 2015, 16, 93–98.
  93. Hill, H.; Grams, J.; Walton, R.G.; Liu, J.; Moellering, D.R.; Garvey, W.T. Carboxylated and uncarboxylated forms of osteocalcin directly modulate the glucose transport system and inflammation in adipocytes. Horm. Metab. Res. 2014, 46, 341–347.
  94. Popko, J.; Karpińnski, M.; Chojnowska, S.; Maresz, K.; Milewski, R.; Badmaev, V.; Schurgers, L.J. Decreased levels of circulating carboxylated osteocalcin in children with low energy fractures: A pilot study. Nutrients 2018, 10, 734.
  95. Moser, S.C.; van der Eerden, B.C.J. Osteocalcin—A versatile bone-derived hormone. Front. Endocrinol. 2019, 9, 794.
  96. Aguayo-Ruiz, J.I.; García-Cobián, T.A.; Pascoe-González, S.; Sánchez-Enríquez, S.; Llamas-Covarrubias, I.M.; García-Iglesias, T.; López-Quintero, A.; Llamas-Covarrubias, M.A.; Trujillo-Quiroz, J.; Rivera-Leon, E.A. Effect of supplementation with vitamins D3 and K2 on undercarboxylated osteocalcin and insulin serum levels in patients with type 2 diabetes mellitus: A randomized, double-blind, clinical trial. Diabetol. Metab. Syndr. 2020, 12, 73.
  97. Tsuchida, A.; Yamauchi, T.; Ito, Y.; Hada, Y.; Maki, T.; Takekawa, S.; Kamon, J.; Kobayashi, M.; Suzuki, R.; Hara, K.; et al. Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J. Biol. Chem. 2004, 279, 30817–30822.
  98. Ferron, M.; Hinoi, E.; Karsenty, G.; Ducy, P. Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc. Natl. Acad. Sci. USA. 2008, 105, 5266–5270.
  99. Wei, J.; Hanna, T.; Suda, N.; Karsenty, G.; Ducy, P. Osteocalcin promotes β-cell proliferation during development and adulthood through Gprc6a. Diabetes 2014, 63, 1021–1031.
  100. Meier, J.J.; Bhushan, A.; Butler, A.E.; Rizza, R.A.; Butler, P.C. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: Indirect evidence for islet regeneration? Diabetologia 2005, 48, 2221–2228.
  101. Muoio, D.M.; Newgard, C.B. Mechanisms of disease: Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes. Nat. Rev. Mol. Cell Biol. 2008, 9, 193–205.
  102. ACCORD; Gerstein, H.C.; Miller, M.E.; Byington, R.P.; Goff, D.C.; Bigger, J.T.; Buse, J.B.; Cushman, W.C.; Genuth, S.; Ismail-Beigi, F.; et al. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 2008, 358, 2545–2559.
  103. Ferron, M.; McKee, M.D.; Levine, R.L.; Ducy, P.; Karsenty, G. Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 2012, 50, 568–575.
  104. Gerosa, L.; Lombardi, G. Bone-to-brain: A round trip in the adaptation to mechanical stimuli. Front. Physiol. 2021, 12, 565.
  105. Moriishi, T.; Ozasa, R.; Ishimoto, T.; Nakano, T.; Hasegawa, T.; Miyazaki, T.; Liu, W.; Fukuyama, R.; Wang, Y.; Komori, H.; et al. Osteocalcin is necessary for the alignment of apatite crystallites, but not glucose metabolism, testosterone synthesis, or muscle mass. PLoS Genet. 2020, 16, e1008586.
  106. Manolagas, S.C. Osteocalcin promotes bone mineralization but is not a hormone. PLoS Genet. 2020, 16, e1008714.
  107. Shea, M.K.; Booth, S.L.; Gundberg, C.M.; Peterson, J.W.; Waddell, C.; Dawson-Hughes, B.; Saltzman, E. 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. 2010, 140, 1029–1034.
  108. Kirk, B.; Feehan, J.; Lombardi, G.; Duque, G. Muscle, Bone, And fat crosstalk: The biological role of myokines, osteokines, and adipokines. Curr. Osteoporos. Rep. 2020, 18, 388–400.
  109. Bilotta, F.L.; Arcidiacono, B.; Messineo, S.; Greco, M.; Chiefari, E.; Britti, D.; Nakanishi, T.; Foti, D.P.; Brunetti, A. Insulin and osteocalcin: Further evidence for a mutual cross-talk. Endocrine 2018, 59, 622–632.
  110. Rolvien, T.; Krause, M.; Jeschke, A.; Yorgan, T.; Püschel, K.; Schinke, T.; Busse, B.; Demay, M.B.; Amling, M. Vitamin D regulates osteocyte survival and perilacunar remodeling inhuman and murine bone. Bone 2017, 103, 78–87.
  111. Carrelli, A.; Bucovsky, M.; Horst, R.; Cremers, S.; Zhang, C.; Bessler, M.; Schrope, B.; Evanko, J.; Blanco, J.; Silverberg, S.J.; et al. Vitamin D storage in adipose tissue of obese and normal weight women. J. Bone Miner. Res. 2017, 32, 237–242.
  112. de Pergola, G.; Nitti, A.; Bartolomeo, N.; Gesuita, A.; Giagulli, V.A.; Triggiani, V.; Guastamacchia, E.; Silvestris, F. Possible role of hyperinsulinemia and insulin resistance in lower vitamin D levels in overweight and obese patients. BioMed Res. Int. 2013, 2013.
  113. Raisingani, M.; Preneet, B.; Kohn, B.; Yakar, S. Skeletal growth and bone mineral acquisition in type 1 diabetic children; Abnormalities of the GH/IGF-1 axis. Growth Horm. IGF Res. 2017, 34, 13–21.
  114. Goran, M.I.; Gower, B.A. Longitudinal study on pubertal insulin resistance. Diabetes 2001, 50, 2444–2450.
  115. Kelsey, M.M.; Zeitler, P.S. Insulin resistance of puberty. Curr. Diab. Rep. 2016, 16, 64.
  116. Lieben, L.; Masuyama, R.; Torrekens, S.; Van Looveren, R.; Schrooten, J.; Baatsen, P.; Lafage-Proust, M.H.; Dresselaers, T.; Feng, J.Q.; Bonewald, L.F.; et al. Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J. Clin. Investig. 2012, 122, 1803–1815.
  117. Tresguerres, F.G.F.; Torres, J.; López-Quiles, J.; Hernández, G.; Vega, J.A.; Tresguerres, I.F. The Osteocyte: A multifunctional cell within the bone. Ann. Anat. 2020, 227, 151422.
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