Impaired PRMT1 activity in the liver and pancreas of type 2 diabetic Goto-Kakizaki rats.
OBJECTIVE
Arginine methylation catalyzed by protein N-arginine methyltransferase (PRMT) 1 is implicated in a variety of cellular processes, although the potential role of PRMT1-mediated methylation in glucose intolerance has not been defined. This study aims to investigate whether alteration of PRMT1 activity contributes to the clinical features of type 2 diabetes.


METHODS
Goto-Kakizaki (GK) rats were used as a rodent model of type 2 diabetes. Catalytic activity of PRMT1 and arginine methylation were determined by an in vitro methyltransferase assay and immunoblotting, respectively. Hepatic insulin signaling events, insulin secretion, and pancreatic glucose metabolism were assessed by studies using HepG2 hepatoma cells and isolated pancreatic islets. Methyltransferase activity was attenuated by transfection of a small interfering RNA against PRMT1 (PRMT1-siRNA) or by pretreatment with an inhibitor of methyltransferase, 5'-deoxy-5'-(methylthio)adenosine (MTA).


RESULTS
Non-obese, diabetic GK rats exhibited a decrease in their hepatic and pancreatic PRMT1 activity, as compared to the control Wistar rats, which was associated with the impaired arginine methylation of several proteins in the tissues. Transfection of PRMT1-siRNA diminished the agonist-induced activation of insulin signaling and the subsequent suppression of gluconeogenic genes expression in the liver-derived cells. Pretreatment with MTA attenuated the glucose-stimulated insulin secretion, but not glucose utilization, in isolated pancreatic islets of Wistar controls, and its pattern was comparable to that of the GK rats undergoing similar modulation.


CONCLUSIONS
The present data demonstrates that the impaired PRMT1 activity may be implicated in glucose intolerance in GK rats through the disturbed hepatic glucose metabolism and insulin secretion.
Iwasaki
Hiroaki
H
Division of Endocrinology and Metabolism, Department of Internal Medicine, Toshiba Rinkan Hospital, 7-9-1 Kami-tsuruma, Sagamihara, Kanagawa 228-8585, Japan. hiwasaki-dm@umin.net
D000818:Animals; D001120:Arginine / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D017353:Gene Deletion; D015870:Gene Expression; D005943:Gluconeogenesis / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008745:Methylation; D010179:Pancreas / Q000201:enzymology*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar
D007328:Insulin; D034741:RNA, Small Interfering; D001120:Arginine; C541817:PRMT1 protein, rat; D011484:Protein-Arginine N-Methyltransferases