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Review

Rethinking Fragility Fractures in Type 2 Diabetes: The Link between Hyperinsulinaemia and Osteofragilitas

1
Translational Physiology Research Group, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK
2
Research Collaborator, Aerospace Medicine and Vestibular Research Laboratory, Mayo Clinic, Scottsdale, AZ 85259, USA
3
School of Public Health and Interdisciplinary Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 0627, New Zealand
*
Author to whom correspondence should be addressed.
Academic Editor: Susan J. Burke
Biomedicines 2021, 9(9), 1165; https://doi.org/10.3390/biomedicines9091165
Received: 22 July 2021 / Revised: 27 August 2021 / Accepted: 2 September 2021 / Published: 6 September 2021
(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance)
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. View Full-Text
Keywords: hyperinsulinaemia; beta hydroxybutyrate; osteoporosis; type 2 diabetes; fragility fractures; bone mineral density; osteocalin; vitamin D; collagen; hydroxyapatite hyperinsulinaemia; beta hydroxybutyrate; osteoporosis; type 2 diabetes; fragility fractures; bone mineral density; osteocalin; vitamin D; collagen; hydroxyapatite
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MDPI and ACS Style

Cooper, I.D.; Brookler, K.H.; Crofts, C.A.P. Rethinking Fragility Fractures in Type 2 Diabetes: The Link between Hyperinsulinaemia and Osteofragilitas. Biomedicines 2021, 9, 1165. https://doi.org/10.3390/biomedicines9091165

AMA Style

Cooper ID, Brookler KH, Crofts CAP. Rethinking Fragility Fractures in Type 2 Diabetes: The Link between Hyperinsulinaemia and Osteofragilitas. Biomedicines. 2021; 9(9):1165. https://doi.org/10.3390/biomedicines9091165

Chicago/Turabian Style

Cooper, Isabella D., Kenneth H. Brookler, and Catherine A. P. Crofts. 2021. "Rethinking Fragility Fractures in Type 2 Diabetes: The Link between Hyperinsulinaemia and Osteofragilitas" Biomedicines 9, no. 9: 1165. https://doi.org/10.3390/biomedicines9091165

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