Amylin increases bone volume but cannot ameliorate diabetic osteopenia

Romero, David F.; Bryer, Haldon P.; Rucinski, Boguslaw; Isserow, J. A.; Buchinsky, Farrel J.; Cvetković, Mirjana; Liu, C. C.; Epstein, Solomon

doi:10.1007/bf00298745

Cited by 31 publications

(18 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…insulin and iGf-i, through their receptors, insulin receptor (ir) and iGf-i receptor (iGf-ir), respectively, share common components in their signal transduction pathways, irS-1/Pi3K/akt/GSK3β. rats with StZ-induced diabetes show low circulating levels of iGf-i as well as insulin (23)(24)(25). in iddm children, inadequate control of blood sugar levels correlates with low plasma iGf-i levels and sluggish growth (26).…”

Section: Introductionmentioning

confidence: 99%

Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation

Hie

Iitsuka²,

Otsuka³

et al. 2011

Int J Mol Med

View full text Add to dashboard Cite

Abstract. insulin-dependent diabetes mellitus (iddm) is known to be associated with an increased risk of osteopenia. However, the cellular and molecular mechanisms for iddminduced alterations of the bone are not well understood. the effects of iddm on bone metabolism were investigated using rats rendered diabetic by an injection of streptozotocin (StZ). after 4 weeks, the diabetic rats exhibited bone loss, low levels of osteocalcin, insulin-like growth factor-i (iGf-i) and bone alkaline phosphatase (alP) activity with normal levels of bone tartrate-resistant acid phosphatase (traP) and cathepsin K activity, and urinary excretion of deoxypyridinoline (dpd). Histological analysis showed a decrease in the number of osteoblasts with a normal number of osteoclasts in the metaphysis of the proximal tibia. the decreased expression of alP, osteoclacin and collagen mrna was associated with a decrease in the expression of runt-related transcription factor 2 (runx2), osterix and distal-less homeobox 5 (dlx5) and an unaltered expression of bone morphogenic protein-2 (BmP2). the protein levels of runx2, phosphorylated glycogen synthase kinase 3β (GSK3β), active β-catenin and β-catenin decreased. the activation of akt was inhibited. the mrna and protein levels of sclerosteosis (Sost) and dickkopf 1 (dkk1), inhibitors of Wnt signaling, increased. the mrna expression of iGf-i and the iGf-i receptor (iGf-ir) was suppressed. these changes observed in the bone of diabetic rats were reversed by treatment with insulin, but not by normalization of the circulating iGf-i levels by treatment with iGf-i. These results suggest that insulin-deficiency in IDDM decreases osteoblastogenesis associated with inhibition of Wnt signaling through the increased expression of Sost and dkk1 and the inhibition of akt activation. Introductioninsulin-dependent diabetes mellitus (iddm, type i diabetes) is known to be associated with decreased bone mass, osteoporosis, and increased fracture rates (1-3). Streptozotocin (StZ)-induced diabetes in rats is a well-recognized model for iddm (4,5). in these rats, bone histology and biochemical markers of bone formation and resorption indicate decreased osteoblastic activity with normal (5), decreased (6,7), or increased (8-10) osteoclastic activity. although these observational studies have provided consistent findings regarding deficits in bone integrity attributable to the diabetic state, little is known about the specific cellular and molecular mechanisms underlying the changes in bone metabolism in iddm.Bone formation is a tightly regulated process characterized by a sequence of events starting with the commitment of osteoprogenitor cells, and their differentiation into pre-osteoblasts and then into mature osteoblasts, which express high levels of alkaline phosphatase (alP), osteocalcin and collagen. osteoblast commitment, differentiation, and function are all governed by several transcription factors, resulting in the expression of phenotypic genes and in the acquisition of the osteoblast phenotype (11). the...

show abstract

Section: Introductionmentioning

confidence: 99%

Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation

Hie

Iitsuka²,

Otsuka³

et al. 2011

Int J Mol Med

View full text Add to dashboard Cite

show abstract

“…We have no explanation for these discordant findings. In most studies that have used male diabetic rats, total 1,25(OH) 2 D 3 concentrations were found to be lower than in the control group in SZ-induced diabetes (Schneider et al 1977, Hough et al 1982, Wilson et al 1982, Nyomba et al 1985, Romero et al 1995 as well as in spontaneous diabetes (Nyomba et al 1989, Verhaeghe et al 1990. However, we have repeatedly found that 1,25(OH) 2 D 3 concentrations in female nongravid diabetic BB rats remain within the control range, both in rats fed a standard diet and in rats fed a restricted Ca-P diet (Verhaeghe et al , 1989(Verhaeghe et al , 1994; in contrast, pregnant and lactating diabetic rats do have lower 1,25(OH) 2 D 3 concentrations (Verhaeghe et al 1986(Verhaeghe et al , 1989.…”

Section: Discussionmentioning

confidence: 98%

“…Serum PTH concentrations were reported to be increased (Schedl et al 1978) or normal (Romero et al 1995) after 9 days of SZ-induced diabetes, but suppressed after 25 (Romero et al 1995) or 48 days (Hough et al 1982) of SZ-induced diabetes. Decreased 1,25(OH) 2 D 3 levels have been reported repeatedly in male SZ-induced diabetic rats (Schneider et al 1977, Hough et al 1982, Wilson et al 1982, Nyomba et al 1985, Romero et al 1995 and in male spontaneously diabetic rats (Nyomba et al 1989, Verhaeghe et al 1990; interestingly, this is not the case in female nongravid spontaneously diabetic rats (Verhaeghe et al , 1989(Verhaeghe et al , 1994. Renal cortical slices from male diabetic rats produced less 1,25(OH) 2 D 3 but more 24,25(OH) 2 D 3 than control rats (Wongsurawat et al 1983); however, kidneys are larger relative to body weight in diabetic rats (Pillion et al 1988).…”

Section: Introductionmentioning

confidence: 99%

Calciotrophic hormones during experimental hypocalcaemia and hypercalcaemia in spontaneously diabetic rats

Verhaeghe¹,

Bree²,

Herck³

et al. 1999

Journal of Endocrinology

View full text Add to dashboard Cite

1, (1,25(OH) 2 D 3 ) concentrations have been found to be decreased in diabetic humans and rats. To investigate further the regulation of plasma Ca in diabetes, first we measured Ca 2+ , P, Mg, parathyroid hormone 1-34 (PTH), and total and free 1,25(OH) 2 D 3 in male spontaneously diabetic rats 7 and 28 days after the onset of glycosuria. Secondly, we studied changes in the levels of PTH and 1,25(OH) 2 D 3 in response to hypocalcaemia induced by an i.v. infusion of EGTA (2·5%, wt/vol.) for 24 h, and changes in the levels of 1,25(OH) 2 D 3 in response to an i.v. infusion of rat PTH (10 µg over 24 h) without or with concomitant EGTA infusion (producing hypercalcaemia or normo/ hypocalcaemia respectively), in diabetic and control rats. Ca 2+ , P, Mg and PTH concentrations remained within the control ranges after 7 and 28 days of glycosuria; 1,25(OH) 2 D 3 concentrations were decreased after 7, but not after 28, days of glycosuria. PTH concentrations showed a similar rise during EGTA-induced hypocalcaemia in control and diabetic rats compared with salineinfused rats, whereas 1,25(OH) 2 D 3 concentrations were unchanged in both groups. Total and free 1,25(OH) 2 D 3 levels were comparably (about 3-fold) increased during PTH, but not during combined PTH and EGTA infusion in control and diabetic rats. Total 1,25(OH) 2 D 3 concentrations were lower in the diabetic groups infused with saline or PTH than in their respective controls, and there was a similar trend in the PTH+EGTA-infused group; free 1,25(OH) 2 D 3 levels, however, were normal or increased in the diabetic groups, confirming our previous data.The novel finding of this study is that, despite severe insulin deficiency and altered 1,25(OH) 2 D 3 levels, the in vivo response of PTH levels to hypocalcaemia and the in vivo response of 1,25(OH) 2 D 3 levels to PTH in diabetic rats are comparable with those found in nondiabetic rats.

show abstract

“…3). Romero et al (1995) investigated the effects of AMY (100 pmol/100 g BW, s.c. for 19 days) on bone metabolism in normal and diabetic (streptozotocin-induced) rats. Analysis of the bone histomorphometry showed a low-turnover osteopenia in the diabetic animals.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, AMY has potent effects to lower plasma calcium (Ca) concentration and inhibit osteoclast activity (Datta et al 1989, MacIntyre 1989, and is reported to stimulate osteoblast growth (Cornish et al 1995, 1998b, Romero et al 1995. Although AMY is less potent than calcitonin at calcitonin receptors, it circulates at higher concentrations, and could represent a significant signal at such receptors (Zaïdi et al 1993).…”

Section: Introductionmentioning

confidence: 99%

Amylin inhibits ovariectomy-induced bone loss in rats

Horcajada-Molteni¹,

Davicco²,

Lebecque³

et al. 2000

Journal of Endocrinology

View full text Add to dashboard Cite

Amylin (AMY), a peptide co-secreted with insulin by pancreatic -cells, inhibits bone resorption and stimulates osteoblastic activity. The ovariectomized (OVX) rat is an established animal model for human osteoporosis. Thus, the present experiment was performed to study the effects of AMY on estrogen deficiency-induced bone loss in rats. Thirty-one 6-month-old Wistar rats were randomized by body weight (BW) into two groups. The first underwent surgical OVX (n=21). The second was sham-operated (SH; n=10). Sixty days after surgery, 11 OVX rats were s.c. injected with rat AMY (3 µg/100 g BW/day, for 30 days; OVX+AMY), and 10 with solvent alone in the same way (0·15 ml/100 g BW; OVX). Each rat, housed in an individual cage, was fed daily the mean quantity of diet consumed the day before by SH rats. This diet contained 0·24% calcium and 0·16% phosphorus. The 31 animals were killed on day 90. No difference in daily weight gain and BW was observed between groups. Neither AMY treatment nor OVX had any significant effect upon femoral morphology, femoral failure load, diaphyseal femoral density (representative of cortical bone) and total femoral calcium content. Nevertheless, both distal metaphyseal (representative of cancellous bone) and total femoral bone densities were higher in SH and OVX+AMY than in OVX rats. The highest plasma osteocalcin concentration was measured in OVX+AMY rats. Simultaneously, urinary deoxypyridinoline excretion was lower in OVX+AMY than in OVX rats. These results indicate that in OVX rats, AMY treatment inhibited trabecular bone loss both by inhibiting resorption and by stimulating osteoblastic activity.

show abstract

Amylin increases bone volume but cannot ameliorate diabetic osteopenia

Cited by 31 publications

References 42 publications

Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation

Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation

Calciotrophic hormones during experimental hypocalcaemia and hypercalcaemia in spontaneously diabetic rats

Amylin inhibits ovariectomy-induced bone loss in rats

Contact Info

Product

Resources

About