Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats
Ying Nie, … , Daniel Pipeleers, Theodore C. Friedman
Ying Nie, … , Daniel Pipeleers, Theodore C. Friedman
Published April 1, 2000
Citation Information: J Clin Invest. 2000;105(7):955-965. https://doi.org/10.1172/JCI7456.
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Article

Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats

Abstract

The pancreatic processing enzymes, PC1 and PC2, convert proinsulin to insulin and convert proglucagon to glucagon and glucagon-like peptide 1 (GLP-1). We examined the effect of streptozotocin (STZ) treatment on the regulation of these enzymes and the production of insulin, glucagon, and GLP-1 in the rat. Pancreatic PC1 and PC2 mRNA increased >2-fold and >4-fold, respectively, in rats receiving intraperitoneal STZ (50 mg/kg) daily for 5 days. Immunocytochemistry revealed that, although pancreatic islet cells in the STZ-treated rats were sparse and atrophic PC1, PC2, glucagon, and GLP-1 immunoreactivity increased dramatically in the remaining islet cells. Heightened PC1 and PC2 expression was seen in cells expressing glucagon but not in insulin-expressing cells. Furthermore, in STZ-treated rats, bioactive GLP-17–36 amide accumulated in pancreatic extracts and serum 3- and 2.5-fold, respectively, over control animals. This treatment also caused a 2-fold increase in the ratio of amidated forms of GLP-1 immunoreactivity to total glucagon immunoreactivity in the pancreas but did not affect the ratio of proinsulin to insulin. We conclude that hyperglycemic rats have an increased expression of prohormone converting enzymes in islet α cells, leading to an increase in amidated GLP-1, which can then exert an insulinotropic effect on the remaining β cells.

Authors

Ying Nie, Masahiro Nakashima, Patricia L. Brubaker, Qiao-Ling Li, Riccardo Perfetti, Erik Jansen, Yasmeen Zambre, Daniel Pipeleers, Theodore C. Friedman

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Figure 1

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RPA of PC1 mRNA in the pancreas of STZ- and vehicle-treated rats. Antise...
RPA of PC1 mRNA in the pancreas of STZ- and vehicle-treated rats. Antisense riboprobes (32P-labeled) for PC1 and β-actin were hybridized to 40 μg total RNA from pancreata of animals treated with STZ (50 mg/kg intraperitoneally daily for 5 days) or vehicle and then digested with RNase as described in Methods. The probe sizes for PC1 and β-actin were 360 and 188 bp, respectively, which were seen in protection assays without RNA and RNase but were absent when tissue mRNA and RNase were added. The protected band sizes for PC1 and β-actin were 305 and 126 bp, respectively, and were absent when yeast tRNA (10 μg) was used instead of tissue RNA. (a) Representative RPA. (b) Densitometric measurement of pancreatic PC1 mRNA levels normalized by β-actin from STZ-treated rats and expressed as percentage (mean ± SEM) of vehicle-treated animals (4–6 animals per group). AP < 0.05.