Rethinking Fragility Fractures in Type 2 Diabetes: The Link between Hyperinsulinaemia and Osteofragilitas.
Isabella D CooperKenneth H BrooklerCatherine A P CroftsPublished in: Biomedicines (2021)
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.
Keyphrases
- bone mineral density
- postmenopausal women
- type diabetes
- insulin resistance
- body composition
- cardiovascular disease
- glycemic control
- adipose tissue
- soft tissue
- oxidative stress
- reactive oxygen species
- bone regeneration
- blood glucose
- cell death
- metabolic syndrome
- ejection fraction
- end stage renal disease
- blood pressure
- high fat diet
- chronic kidney disease
- cell proliferation
- multiple sclerosis
- coronary artery disease
- patient reported outcomes
- skeletal muscle
- fatty acid
- high resolution
- endoplasmic reticulum stress
- smoking cessation
- high fat diet induced