PMID- 34572351
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230921
IS  - 2227-9059 (Print)
IS  - 2227-9059 (Electronic)
IS  - 2227-9059 (Linking)
VI  - 9
IP  - 9
DP  - 2021 Sep 6
TI  - Rethinking Fragility Fractures in Type 2 Diabetes: The Link between 
      Hyperinsulinaemia and Osteofragilitas.
LID - 10.3390/biomedicines9091165 [doi]
LID - 1165
AB  - 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.
FAU - Cooper, Isabella D
AU  - Cooper ID
AUID- ORCID: 0000-0001-7374-4340
AD  - Translational Physiology Research Group, School of Life Sciences, University of 
      Westminster, 115 New Cavendish Street, London W1W 6UW, UK.
FAU - Brookler, Kenneth H
AU  - Brookler KH
AD  - Research Collaborator, Aerospace Medicine and Vestibular Research Laboratory, 
      Mayo Clinic, Scottsdale, AZ 85259, USA.
FAU - Crofts, Catherine A P
AU  - Crofts CAP
AUID- ORCID: 0000-0001-6109-8513
AD  - School of Public Health and Interdisciplinary Studies, Faculty of Health and 
      Environmental Sciences, Auckland University of Technology, Auckland 0627, New 
      Zealand.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20210906
PL  - Switzerland
TA  - Biomedicines
JT  - Biomedicines
JID - 101691304
PMC - PMC8472634
OTO - NOTNLM
OT  - beta hydroxybutyrate
OT  - bone mineral density
OT  - collagen
OT  - fragility fractures
OT  - hydroxyapatite
OT  - hyperinsulinaemia
OT  - osteocalin
OT  - osteoporosis
OT  - type 2 diabetes
OT  - vitamin D
COIS- The authors declare no conflict of interest.
EDAT- 2021/09/29 06:00
MHDA- 2021/09/29 06:01
PMCR- 2021/09/06
CRDT- 2021/09/28 01:05
PHST- 2021/07/22 00:00 [received]
PHST- 2021/08/27 00:00 [revised]
PHST- 2021/09/02 00:00 [accepted]
PHST- 2021/09/28 01:05 [entrez]
PHST- 2021/09/29 06:00 [pubmed]
PHST- 2021/09/29 06:01 [medline]
PHST- 2021/09/06 00:00 [pmc-release]
AID - biomedicines9091165 [pii]
AID - biomedicines-09-01165 [pii]
AID - 10.3390/biomedicines9091165 [doi]
PST - epublish
SO  - Biomedicines. 2021 Sep 6;9(9):1165. doi: 10.3390/biomedicines9091165.