Correction of Abnormal Bone and Mineral Metabolism in Chronic Streptozotocin-Induced Diabetes Mellitus in the Rat by Insulin Therapy

Stephen Hough, Louis V. Avioli, Michele A. Bergfeld, Michael D. Fallon, Eduardo Slatopolsky, Steven L. Teitelbaum

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181 Scopus citations


Mineral homestasis and skeletal morphology were studied in freely fed control, streptozotocin-induced diabetic, and insulin-treated diabetic rats 7 weeks after the induction of diabetes. The untreated diabetic animals were characterized by modest hypercalcemia, hyperphosphatemia, and striking hypercalciuria and phosphaturia. Insulin treatment corrected the hypercalcemia and markedly reduced the calciuria (P < 0.001), but had no significant effect on the urinary phosphate levels. Circulating immunoreactive parathyroid hormone (iPTH) was detectable in only 6% of untreated diabetic animals compared to 30% of controls. Furthermore, in untreated diabetic animals, the circulating levels of iPTH, when detectable, approximated the lower limits of the assay. The urinary cAMP levels of untreated diabetic animals were markedly decreased. Both iPTH and urinary cAMP approximated control levels in insulin-treated rats. Conversely, plasma immunoreactive calcitonin was increased in the diabetic rats compared to control animals (P < 0.001) and was partially corrected by insulin treatment (P < 0.05). Plasma corticosterone was elevated 10-fold in the untreated diabetic rats and was not significantly influenced by insulin therapy. The bone histology of the diabetic animals reflected the biochemical changes. Parameters of skeletal turnover, notably the quantity of nonmineralized bone matrix, reflecting boneforming sites (P < 0.01), and the numbers of osteoclasts (P < 0.025), were significantly diminished in the diabetic animal. Furthermore, diabetic vertebrae failed to assume a tetracycline label. Biochemical parameters of bone turnover, namely skeletal alkaline phosphatase activity and urinary hydroxyproline excretion, were likewise decreased. Untreated diabetes resulted in growth arrest, as evidenced by a significant reduction (P < 0.005) in the width of the epiphyseal growth plate. Insulin therapy in these chronically diabetic rats resulted in the normalization of all histometric parameters of skeletal turnover and growth. We conclude that prolonged streptozotocin-induced diabetes mellitus in the rat results in reduced bone turnover and growth arrest, which are completely corrected by insulin therapy. Whether this response to therapy reflects a direct insulin effect on skeletal tissue or results from the associated correction of mineral derangements and decreased PTH secretion which characterize the chronic experimental diabetic state remains to be resolved.

Original languageEnglish
Pages (from-to)2228-2234
Number of pages7
Issue number6
StatePublished - Jun 1981


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