An in vivo analysis of pancreatic protein and insulin biosynthesis in a rat model for non-insulin-dependent diabetes

M. A. Permutt, K. Kakita, P. Malinas, I. Karl, S. Bonner-Weir, G. Weir, S. J. Giddings

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Abstract

The purpose of these experiments was to estimate insulin biosynthesis in vivo in a rat model for non-insulin-dependent diabetes. Insulin biosynthesis rates were determined in 4-wk-old animals that had been injected with 90 mg/kg of streptozotocin 2 d postpartum. Control and diabetic animals did not differ in body weight or fasting plasma glucose. Fed plasma glucose was significantly elevated (186 ± 13 μg/dl vs. 139 ± 7 mg/dl, P < 0.05) and pancreatic insulin content was reduced (41 ± 2 μg/g vs. 63 ± 8 μg/g, P < 0.05) in the diabetic rats. Insulin biosynthesis was estimated in vivo by measuring and comparing [3H]leucine incorporation into proinsulin with that into total pancreatic protein 45 min after injection. Insulin biosynthesis was 0.391 ± 0.07% of pancreas protein synthesized in control rats and 0.188 ± 0.015% (P < 0.05) in diabetic rats. In animals of the same age, the fractional and absolute rate of pancreatic protein synthesis were determined. Total pancreatic protein synthesis was not reduced in streptozotocin treated animals (185.5 ± 14.1%/d vs. 158.6 ± 14.9%/d, NS) but was markedly reduced in control rats after a 48-h fast (to 70.8 ± 5.5%/d, P < 0.01). Because total pancreatic protein synthesis was not decreased in the diabetic rats, the decrease in the fraction of radiolabel incorporated into insulin seems to represent an absolute decrease in the rate of insulin biosynthesis in this animal model for diabetes. Through RNA blot hybridization with 32P-labeled cloned rat insulin complementary DNA, proinsulin messenger RNA (mRNA) was estimated as the rate of insulin biosynthesis in control and diabetic animals. There was a 61% reduction in proinsulin mRNA at 4 wk and an 85% reduction at 7 wk (P < 0.001) in the diabetic animals. After streptozotocin injection in neonatal rats, there is marked β-cell damage and hyperglycemia. β-cell regeneration occurs with return to normoglycemia, but with age hyperglycemia develops. The reduction in insulin synthesis and proinsulin mRNA seemed disproportionate with the more modest reduction in β-cell number. The importance of these observations is that, in this animal model, diabetes is associated with a limited ability to regenerate β-cell mass and to synthesize insulin. The relationship between the defect in glucose-stimulated insulin release and impaired insulin biosynthesis has yet to be determined.

Original languageEnglish
Pages (from-to)1344-1350
Number of pages7
JournalJournal of Clinical Investigation
Volume73
Issue number5
DOIs
StatePublished - Jan 1 1984

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    Permutt, M. A., Kakita, K., Malinas, P., Karl, I., Bonner-Weir, S., Weir, G., & Giddings, S. J. (1984). An in vivo analysis of pancreatic protein and insulin biosynthesis in a rat model for non-insulin-dependent diabetes. Journal of Clinical Investigation, 73(5), 1344-1350. https://doi.org/10.1172/JCI111337