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High-dose benfotiamine rescues cardiomyocyte contractile dysfunction in streptozotocin-induced diabetes mellitus

Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, Wyoming

Submitted 15 August 2005 ; accepted in final form 12 September 2005

Diabetic cardiomyopathy is characterized by cardiac dysfunction. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse cardiomyocytes. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg ip). Fourteen days later, control and diabetic (fasting plasma glucose > 13.9 mM) mice were put on benfotiamine therapy (100 mg·kg^–1·day^–1 ip) for another 14 days. Mechanical and intracellular Ca²⁺ properties were evaluated in left ventricular myocytes using an IonOptix MyoCam system. The following indexes were evaluated: peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR₉₀), maximal velocity of shortening/relengthening, resting and rise of intracellular Ca²⁺ in response to electrical stimulus, sarcoplasmic reticulum (SR) Ca²⁺ load, and intracellular Ca²⁺ decay rate (). Two- or four-week STZ treatment led to hyperglycemia, prolonged TPS and TR₉₀, reduced SR Ca²⁺ load, elevated resting intracellular Ca²⁺ level and prolonged associated with normal PS, maximal velocity of shortening/relengthening, and intracellular Ca²⁺ rise in response to electrical stimulus. Benfotiamine treatment abolished prolongation in TPS, TR₉₀, and , as well as reduction in SR Ca²⁺ load without affecting hyperglycemia and elevated resting intracellular Ca²⁺. Diabetes triggered oxidative stress, measured by GSH-to-GSSG ratio and formation of advanced glycation end product (AGE) in the hearts. Benfotiamine treatment alleviated oxidative stress without affecting AGE or protein carbonyl formation. Collectively, our results indicated that benfotiamine may rescue STZ-induced cardiomyocyte dysfunction but not AGE formation in short-term diabetes.

diabetes; ventricular myocyte; contraction; advanced glycation end product

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