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Long Term Effects of Aminoguanidine on Insulin Release and Biosynthesis: Evidence That the Formation of Advanced Glycosylation End Products Inhibits B Cell Function¹

Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden; and the Department of Internal Medicine, University of Trondheim, Trondheim, Norway

Address all correspondence and requests for reprints to: Dr. Valdemar Grill, Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital, S-17176 Stockholm, Sweden.

Chronic hyperglycemia has adverse effects on B cell function. We investigated the possible role of advanced glycosylation end products (AGEs) in glucotoxicity. Rat islets were cultured at different glucose concentrations for 1–6 weeks in RPMI 1640. Culture was performed with or without aminoguanidine (AG), which is known to prevent AGE formation in other tissues. AGE-associated fluorescence (370 nm excitation and 440 nm emission) progressively increased during 6 weeks of culture at 38 mM, but not at 11 or 5.5 mM, glucose. The increase in fluorescence was significantly inhibited by AG. The effects of AG on insulin secretion were tested directly after the culture period as well as after a wash-out period of continued culture at 11 mM glucose in the absence of AG. The presence of AG during culture for 1 week at 38 mM glucose failed to affect basal release at 3.3 mM glucose or stimulated release at 27 mM glucose. AG was ineffective whether tested directly after the culture period or after wash-out. When the same culture conditions were prolonged for 6 weeks, culture with AG suppressed basal and stimulated insulin secretion after the culture period. However, after wash-out, previous AG treatment enhanced the insulin response to 27 mM glucose 2-fold compared to culture without AG (P < 0.01). Proinsulin and total protein biosyntheses in 38 mM glucose-cultured islets were increased 40–80% by AG after 6 weeks of culture, and this effect was similar after wash-out. Preproinsulin messenger RNA levels were significantly increased (P < 0.05) after 6 weeks of culture with AG. N^G-Methyl-L-arginine, a nitric oxide synthase inhibitor, failed to mimic the effects of AG. The results indicate that the time-dependent beneficial effects of AG on insulin secretion and biosynthesis are related to inhibitory effects on AGE formation and that accumulation of islet AGEs could be important for glucotoxicity toward B cells.

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