Amylin and bone metabolism in streptozotocin-induced diabetic rats

Amylin (AMY) is a 37 amino acid peptide cosecreted with insulin (INS) by pa ncreatic beta -cells and absent in type I diabetes, a condition frequently associated with osteopenia. AMY binds to calcitonin receptors, lowers plasm a calcium concentration, inhibits osteoclast activity, and stimulates osteo blasts. 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 non diabetic control (CONT) rats received citrate buffer without STZ. Diabetic rats were divided into four groups in = 10/group) and injected subcutaneous ly with rat AMY (45 mg/kg), INS (12 U/kg), both (same doses), or saline (ST Z; 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 tes ted for mechanical resistance (three-point bending). The right femur was te sted for total, diaphyseal (cortical bone), and metaphyseal (trabecular bon e) bone densities using dual-energy S-ray absorptiometry (DXA). Bone was as hed to determine total bone mineral (calcium) content. None of the treatmen ts had any significant effect on femoral length and diameter. Untreated dia betic rats (STZ; 145 +/- 7N) had lower bone strength than did nondiabetic C ONT (164 +/- 38; p < 0.0,5). Total bone mineral density (BMD; g/cm(2)) was significantly lower in STZ (0.2523 <plus/minus> 0.0076) than in CONT (0.282 6 +/- 0.0055), as were metaphyseal and diaphyseal densities. Diabetic rats treated with AMY, INS, or both had bone strengths and bone densities that w ere indistinguishable from those in nondiabetic CONT. Changes in bone miner al content paralleled those for total BMD (T-BRID). Plasma osteocalcin (OC) concentration, a marker for osteoblastic activity, was markedly lower in u ntreated diabetic rats (7.6 +/- 0.9 ng/ml); p < 0.05) than in nondiabetic C ONT (29.8 <plus/minus> 1.7; p < 0.05) or than in AMY (20.1 <plus/minus> 0. 7; p < 0. 05). Urinary DPD excretion, a marker for bone resorption, was sim ilar in untreated and AMY-treated diabetic rats (35.0 <plus/minus> 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 diabeti c osteopenia, addition of AMY improved bone indices apparently by both inhi biting resorption and stimulating bone formation.