Bone's responses to mechanical loading are impaired in type 1 diabetes

Abstract

Diabetes adversely impacts many organ systems including the skeleton. Clinical trials have revealed a startling elevation in fracture risk in diabetic patients. Bone fractures can be life threatening: nearly 1 in 6 hip fracture patients die within one year. Because physical exercise is proven to improve bone properties and reduce fracture risk in non-diabetic subjects, we tested its efficacy in type 1 diabetes. We hypothesized that diabetic bone's response to anabolic mechanical loading would be attenuated, partially due to impaired mechanosensing of osteocytes under hyperglycemia. Heterozygous C57BL/6-Ins2Akita/J (Akita) male and female diabetic mice and their age- and gender-matched wild-type (WT) C57BL/6J controls (7-month-old, N=5-7 mice/group) were subjected to unilateral axial ulnar loading with a peak strain of 3500 με at 2Hz and 3 min/day for 5 days. The Akita female mice, which exhibited a relatively normal body weight and a mild 40% elevation of blood glucose level, responded with increased bone formation (+6.5% in Ct.B.Ar, and 4 to 36-fold increase in Ec.BFR/BS and Ps.BFR/BS), and the loading effects, in terms of changes of static and dynamic indices, did not differ between Akita and WT females (p≥0.1). However, loading-induced anabolic effects were greatly diminished in Akita males, which exhibited reduced body weight, severe hyperglycemia (+230%), diminished bone formation (ΔCt.B.Ar: 0.003 vs. 0.030 mm2, p=0.005), and suppressed periosteal bone appositions (ΔPs.BFR/BS, p=0.02). Hyperglycemia (25mM glucose) was further found to impair the flow-induced intracellular calcium signaling in MLO-Y4 osteocytes, and significantly inhibited the flow-induced downstream responses including reduction in apoptosis and sRANKL secretion and PGE2 release. These results, along with previous findings showing adverse effects of hyperglycemia on osteoblasts and mesenchymal stem cells, suggest that failure to maintain normal glucose levels may impair bone's responses to mechanical loading in diabetics.

Metabolic milieu associates with impaired skeletal characteristics in obesity

“…Clinical findings in pediatric populations suggest insulin resistance to precede bone maturation [18] and impair muscle-bone unit development [16]. This is supported by recent animal data showing that hyperglycemia reduces responses to mechanical loading [33]. …”

A new perspective on mechanisms governing skeletal complications in type 1 diabetes

“…showed that exposure to high glucose reduced flow‐induced PGE 2 release (Fig. ) and soluble RANKL secretion from osteocytes, and altered regulation of osteocyte apoptosis in response to mechanical stimulation . Considerable reduction of load‐induced anabolic response in ulnae of adult Akita mice was also observed .…”

Effects of Type 1 Diabetes on Osteoblasts, Osteocytes, and Osteoclasts

“…The impact of T1D on bone response to mechanical loading had been investigated, both in vivo and in vitro [88]. Male Akita mice, a model of severe insulin-deficiency diabetes, demonstrate impaired bone formation in response to repetitive mechanical loading of the ulna, when compared to wild-type mice or to female Akita mice (a model of milder blood glucose elevation) [88].…”

“…The impact of T1D on bone response to mechanical loading had been investigated, both in vivo and in vitro [88]. Male Akita mice, a model of severe insulin-deficiency diabetes, demonstrate impaired bone formation in response to repetitive mechanical loading of the ulna, when compared to wild-type mice or to female Akita mice (a model of milder blood glucose elevation) [88]. Consistent with these findings, exposure of MLO-Y4 osteocytes to hyperglycemic culture conditions has been shown to: 1) impair the osteocyte mechanosignaling response to oscillatory fluid shear stress [88, 89]; and to 2) attenuate the expected activation of anti-apoptotic pathways [88].…”