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

Abstract

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. (Endocrinology 108: 2228, 1981) T HE COEXISTENCE of diabetes meUitus and altered bone and mineral metabolism has been established by a number of investigators both in diabetic patients and in animals with experimentally induced insulin deficiency syndromes (1-5). However, the pathogenesis of these alterations, their natural evolution, and their response to therapy remain ill defined. Earlier clinical studies implicated poor metabolic control, ketoacidosis, and nutritional deprivation (1), but recent reports indicate that skeletal derangements in diabetes are not

Effects of streptozotocin diabetes and fasting on intracellular sodium and adenosine triphosphate in rat soleus muscle.

“…The weight change per day after SZ injection in the diabetic rats remained below the control level for the entire sampling period, a result similar to that reported by others (Hough, Avioli, Bergfeld, Fallon, Slatopolsky & Teitelbaum, 1981).…”

MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus

“…Employing short-term (2-week) animal models of streptozotocin diabetes, the low BMD observed in insulinopenic diabetes was earlier explained by secondary hyperparathyroidism and increased bone resorption resulting from a negative calcium balance (impaired intestinal calcium absorption; hypercalciuria) (69,70). Using more appropriate animal models of chronic diabetes (8-10 weeks), and employing time-spaced tetracycline labelled bone histomorphometry, bone formation and resorption were found to be markedly suppressed (71,72,73,74).…”

“…Furthermore, in knockout models of insulin receptor substrate 1 or 2 (IRS1; IRS2), the main intracellular substrates of the insulin receptor, bone formation and resorption are markedly reduced (93,94). The administration of insulin to animals with experimental diabetes has also been shown to correct the decreased bone turnover that characterizes the chronic diabetic state (71,95). Insulin deficiency as a cause of the low bone formation in T1DM therefore appears attractive.…”

The Effect of Type 1 Diabetes Mellitus on the Craniofacial Complex

“…The occurrence of different abnormalities indicating altered bone formation after inducing DM with streptozotocin (STZ) is well documented (Giglio and Lama, 2001;Hough et al, 1981;Tein et al, 1998). Streptozotocin-induced diabetes mellitus (STZ-DM), caused by the destruction of pancreatic β-cells and is similar to T1DM in human, is characterized by mild to moderate hyperglycemia, glucosuria, polyphagia, hypoinsulinemia, hyperlipidemia, and weight loss.…”