Amylin and bone metabolism in streptozotocin-induced diabetic rats
Amylin and bone metabolism in streptozotocin-induced diabetic rats
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DOI：
10.1359/jbmr.2001.16.5.958
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发表时间：
2001-05-01
影响因子：
6.2
通讯作者：
Barlet, JP
中科院分区：
文献类型：
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作者：
Horcajada-Molteni, MN;Chanteranne, B;Barlet, JP
胰淀素(AMY)是一种由胰岛β细胞与胰岛素(INS)共分泌的37个氨基酸的多肽，在I型糖尿病中不存在，I型糖尿病经常与骨量减少有关。AMY与降钙素受体结合，降低血钙浓度，抑制破骨细胞活性，刺激成骨细胞。在本研究中，我们研究了在链脲佐菌素(STZ)诱导的I型糖尿病啮齿动物模型中，AMY替换对骨丢失的影响。在50只雄性Wistar大鼠中，40只用链脲佐菌素(STZ)造成糖尿病模型(50 mg/kg，5天内血糖浓度11 mM)。10只非糖尿病对照组(CONT)大鼠接受不含链脲佐菌素的柠檬酸缓冲液。糖尿病大鼠分为4组，每日皮下注射AMY(45 mg/kg)、INS(12U/kg)、AMY(45 mg/kg)、INS(12U/kg)或生理盐水(STZ；糖尿病对照组)。经过40天的治疗和5个24小时的尿样采集脱氧吡啶(DPD)后，动物被处死，采血，取股骨。测试左侧股骨的机械阻力(三点弯曲)。采用双能X线骨密度仪(DXA)检测右侧股骨的全骨、骨干(皮质骨)和干骺端(骨小梁)的骨密度。灰化骨灰，测定总骨矿(钙)含量。各处理对股骨长度和直径均无显著影响。未治疗的糖尿病大鼠(STZ；145+/-7N)的骨强度低于非糖尿病对照组(164+/-38；p<；0.05)。STZ组的总骨密度(骨密度)(0.2523±0.0076)g/cm(2)显著低于对照组(0.2826±0.0055)g/cm(2)，干骺端和骨干端的骨密度也显著低于对照组。接受AMY和/或INS治疗的糖尿病大鼠的骨强度和骨密度与非糖尿病对照组没有区别。骨矿物质含量的变化与总BMD(T-BMD)的变化平行。未治疗的糖尿病大鼠血浆骨钙素(OC)浓度(7.6+/-0.9 ng/ml)显著低于非糖尿病对照组(29.8+/-1.7；P<；0.05)或AMY组(20.1+/-0)。7；p<；0。05)。尿DPD排泄量是骨吸收的标志，在未治疗和AMY治疗的糖尿病大鼠中相似(35.0+/-3.1对35.1+/-4.4nmol/mmol肌酐)，在INS治疗的大鼠中居中(49.9+/-2.7)，在两种药物治疗的糖尿病大鼠中正常(58.8+/-8.9对63.2+/-4.5在CONT中)。因此，在我们的糖尿病骨量减少的STZ大鼠模型中，AMY的加入通过抑制吸收和刺激骨形成明显改善了骨指数。
Amylin (AMY) is a 37 amino acid peptide cosecreted with insulin (INS) by pancreatic beta-cells and absent in type I diabetes, a condition frequently associated with osteopenia. AMY binds to calcitonin receptors, lowers plasma calcium concentration, inhibits osteoclast activity, and stimulates osteoblasts. In the present study, we examined the effects of AMY replacement on bone loss in a streptozotocin (STZ)-induced rodent model type I diabetes. Of 50 male Wistar rats studied, 40 were made diabetic with intraperitoneal STZ (50 mg/kg; plasma glucose concentrations >11 mM within 5 days). Ten nondiabetic control (CONT) rats received citrate buffer without STZ. Diabetic rats were divided into four groups in = 10/group) and injected subcutaneously with rat AMY (45 mg/kg), INS (12 U/kg), both (same doses), or saline (STZ; diabetic controls) once per day. After 40 days of treatment and five 24-h periods of urine collection for deoxypyridinoline (DPD), the animals were killed, blood was sampled, and femurs were removed. The left femur was tested for mechanical resistance (three-point bending). The right femur was tested for total, diaphyseal (cortical bone), and metaphyseal (trabecular bone) bone densities using dual-energy X-ray absorptiometry (DXA). Bone was ashed to determine total bone mineral (calcium) content. None of the treatments had any significant effect on femoral length and diameter. Untreated diabetic rats (STZ; 145 +/- 7N) had lower bone strength than did nondiabetic CONT (164 +/- 38; p < 0.05). Total bone mineral density (BMD; g/cm(2)) was significantly lower in STZ (0.2523 +/- 0.0076) than in CONT (0.2826 +/- 0.0055), as were metaphyseal and diaphyseal densities. Diabetic rats treated with AMY, INS, or both had bone strengths and bone densities that were indistinguishable from those in nondiabetic CONT. Changes in bone mineral content paralleled those for total BMD (T-BMD). Plasma osteocalcin (OC) concentration, a marker for osteoblastic activity, was markedly lower in untreated diabetic rats (7.6 +/- 0.9 ng/ml); p < 0.05) than in nondiabetic CONT (29.8 +/- 1.7; p < 0.05) or than in AMY (20.1 +/- 0. 7; p < 0. 05). Urinary DPD excretion, a marker for bone resorption, was similar in untreated and AMY-treated diabetic rats (35.0 +/- 3.1 vs. 35.1 +/- 4.4 nmol/mmol creatinine), intermediate in rats treated with INS (49.9 +/- 2.7), and normalized in diabetic rats treated with both agents (58.8 +/- 8.9 vs. 63.2 +/- 4.5 in CONT). Thus, in our STZ rat model of diabetic osteopenia, addition of AMY improved bone indices apparently by both inhibiting resorption and stimulating bone formation.