Bone Marker Proteins at Baseline and After Insulin-Induced Hypoglycaemia in Type 2 Diabetes

Type 2 diabetes (T2D) is associated with normal or higher bone mineral density (BMD), but there is a higher fracture rate. Hypoglycaemia does not affect BMD but may cause fractures directly through falls and may affect bone cellular metabolism. We examined circulating bone marker proteins (BMPs) in response to induced hypoglycaemia in T2D versus controls. A prospective exploratory parallel study design was conducted in T2D patients (<i>n</i> = 23) and healthy controls (<i>n</i> = 23) who underwent blood SOMAscan proteomic analysis of bone biomarkers at baseline, hypoglycaemia, and post-hypoglycaemia time points. Unadjusted repeated measures linear mixed modeling was used for analysis. Linear mixed modeling of the proteins showed that the way most BMPs changed over time did not differ between groups. At baseline, Dickkopf-related protein 1 (DKK1), cathepsin A, cathepsin S, and cathepsin Z were increased in T2D versus controls (<i>p</i> < 0.05), whilst fibroblast growth factor 23 (FGF23) was lower in T2D versus controls (<i>p</i> ≤ 0.05). Following hypoglycemia, transient changes from baseline occurred in DKK1, cathepsin A, cathepsin G, cathepsin H, cathepsin S, cathepsin Z, parathyroid hormone (PTH), Sphingosine kinase 1 and 2 (SPK1/2), and interleukin-1 beta (IL1 beta) over the post-hypoglycaemia time course. There was decreased cathepsin S in T2D from baseline to 24 h compared to the control group, and increased cathepsin Z at 24 h for both groups overall compared to baseline (<i>p</i> < 0.05). Baseline-raised cathepsins (A, S, Z) in T2D may enhance osteoclastic resorption, whilst raised DKK1 could inhibit osteoblast differentiation and suppress bone formation. Hypothetically, this may lead to a decline in bone quality through a resorption-enhanced, low bone formation imbalance. The effects of hypoglycaemia on bone physiology appear to extend significantly beyond the initial insult, as seen for cathepsin S and Z, which differed at 24 h compared to baseline.