Endocrine Abstracts

Introduction: Diabetes is associated with increased fracture risk both in patients with type 1 (T1D) and type 2 diabetes (T2D) despite differences in bone mineral density BMD (decreased in T1D and increased in T2D). In T2D, insulin resistance (IR) is selective, with some insulin signaling pathways impaired, while others are overactive due to hyperinsulinemia. It is not clear how different insulin signaling pathways might contribute to the bone phenotypes observed in diabetes. To understand the role of insulin signaling in bone metabolism, we studied patients with severe impairment of all insulin signaling pathways (insulin receptor, INSRmutation) versus severe, selective IR (lipodystrophy, LD). We hypothesizeddifferences in insulin signaling in INSR vs LD might lead to differing bone phenotypes.

Patients and methods: 116 LD and 27 INSR. BMD of the spine, total hip (TH), femoral neck (FN), and 1/3 radius by DXA (age 18–30y); kidney ultrasonography; PTH, serum calcium, phosphorus, magnesium, alkaline phosphatase, osteocalcin, vitamin D 25-(OH), vitamin D 1,25-(OH), HbA1c, and 24-hour calcium excretion were analyzed.

Results: There were no difference in HbA1c in INSR vs LD. BMD was higher in LD vs INSR at the spine (1.167 ± 0.06 vs 0.808 ± 0.07, P < .001), TH (1.120 ± 0.08 vs 0.783 ± 0.07, P < .001) and FN (0.986 ± 0.08 vs 0.687 ± 0.05, P < .001). No difference was found in 1/3 forearm. Kidney stones and nephrocalcinosis were found in 40 and 46.7% of INSR vs 0% and 2.2% of LD patients (P = .0001).

Conclusion: Similar to T1D vs T2D, patients with severe IR due INSR mutation vs lipodystrophy have opposing phenotypes for BMD (low in INSR, high in LD) and renal calcium deposition (high in INSR, normal in LD). These findings are consistent with a model in which insulin action in bone is needed to prevent bone resorption. In the absence of insulin signaling (INSR), there is increased bone resorption, thus increasing Ca filtration by the kidneys and causing renal Ca deposition. In the selective IR with hyperinsulinemia due to LD, enhanced insulin signaling in bone prevents bone resorption, leading to high BMD. Fracture risk for our patients has not been established, thus the clinical significance of the differences in BMD is not known. Further research is needed to clarify the long-term effect of insulin signaling on bone and mineral metabolism.