ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Sci Rep. 2020;10(1):3078. doi: 10.1038/s41598-020-59743-4

Short summary: This study describes a specific mechanism of reduced bone formation secondary to hyperglycaemia. In hyperglycaemic states, advanced glycation end products (AGEs) downregulate the highly selective magnesium transporter expression of NIPA2 in osteoblasts. This results in magnesium deficiency, which is associated with osteoporosis.

Comment: A meta-analysis of studies among T2DM populations showed a higher risk of hip fractures among younger than older persons, among women than men, among those using insulin than non-insulin users, and among those with disease duration of more than 10 years compared to shorter duration.¹ Increased risk of fracture was associated with insulin treatment, hypoglycaemic episodes, microvascular complications and loss of bone mass.² Further, chronic hyperglycaemia favours non-enzymatic reactions between glucose and proteins, producing advanced glycation end products (AGEs), which affect bone formation. Among young girls, insulin resistance and chronic inflammation were associated with lower total bone mineral content.³

Magnesium is a crucial mineral; approximately 50–60% of total body magnesium is stored in bones. Its influx and efflux in mammalian cells are mediated by metal ion transporters. Magnesium deficiency is associated with osteoporosis and several studies found an association between T2DM and magnesium deficiency.

The NIPA2 gene (non-imprinted in Prader-Willi/Angelman syndrome), which is located adjacent to the imprinted domain in the Prader-Willi syndrome deletion region of chromosome 15, encodes a highly selective magnesium transporter that is involved in the transport of magnesium ions into cells.

This group of researchers previously reported that AGEs regulate the expression of NIPA2 in osteoblasts in a concentration-dependent manner.⁴ Here, they showed that NIPA2 expression was reduced both in db/db mice and in-vitro models of osteoporosis in T2DM. Further, overexpression of NIPA2 increased osteoblast function. Mitophagy (a process that selectively degrades damaged mitochondria) accelerated the osteogenic dysfunction. Vice versa, inhibition of mitophagy rescued the function of osteoblasts, such that the level of mitophagy in the high glucose environment was negatively regulated by NIPA2.

Taken together, these results suggest that NIPA2 positively regulates the osteogenic capacity of osteoblasts via the mitophagy pathway in T2DM.

References:

1. Vilaca T, Schini M, Harnan S, et al. The risk of hip and non-vertebral fractures in type 1 and type 2 diabetes: A systematic review and meta-analysis update. Bone 2020;137:115457. doi: 10.1016/j.bone.2020.115457 [published Online First: 2020/06/02]

2. Hetherington-Rauth M, Bea JW, Blew RM, et al. Relationship of cardiometabolic risk biomarkers with DXA and pQCT bone health outcomes in young girls. Bone 2019;120:452–58. doi: 10.1016/j.bone.2018.12.013 [published Online First: 2018/12/21]

3. Zhao W, Zhang WL, Yang B, et al. NIPA2 regulates osteoblast function via its effect on apoptosis pathways in type 2 diabetes osteoporosis. Biochem Biophys Res Commun 2019;513(4):883–90. doi: 10.1016/j.bbrc.2019.04.030 [published Online First: 2019/04/21].