Aims/hypothesis. Cardiovascular disease in diabetes is linked to increased risk of atherosclerosis, increased levels of triglyceride-rich lipoproteins and enhanced hepatic lipogenesis. The hepatic hexosamine pathway has been implicated in signalling for de novo lipogenesis by the liver. In this study, we assessed if decrease of flux through the hexosamine pathway induced by high-dose thiamine therapy counters diabetic dyslipidaemia. Methods. The model of diabetes used was the streptozotocin-induced diabetic rat with maintenance insulin therapy. Normal control and diabetic rats were studied for 24 weeks with and without oral high-dose therapy (7 and 70 mg/kg) with thiamine and benfotiamine. Plasma total cholesterol, HDL cholesterol and triglycerides were determined at 6-week intervals and hepatic metabolites and transketolase activity after death of the rats at 24 weeks.Results. We found that thiamine therapy (70 mg/kg) prevented diabetes-induced increases in plasma cholesterol and triglycerides in diabetic rats but did not reverse the diabetes-induced decrease of HDL. This was achieved by prevention of thiamine depletion and decreased transketolase activity in the liver of diabetic rats. There was a concomitant decrease in hepatic UDP-N-acetylglucosamine and fatty acid synthase activity. Thiamine also normalised food intake of diabetic rats. A lower dose of thiamine (7 mg/kg) and the thiamine monophosphate prodrug benfotiamine (7 and 70 mg/kg) were ineffective. Conclusions/interpretation. High-dose thiamine therapy prevented diabetic dyslipidaemia in experimental diabetes probably by suppression of food intake and hexosamine pathway signalling but other factors may also be involved. Benfotiamine was ineffective.Keywords Cholesterol · Dyslipidaemia · Glycation · Hexosamine · Streptozotocin · Thiamine · Triglycerides Abbreviations: 1,3-bis-PG, 1,3-bisphosphoglycerate · ACC, acetyl-CoA carboxylase · CEL, N ε -(1-carboxyethyl)lysine · CML, N ε -carboxymethyl-lysine · CTEP, cholesteryl ester transfer protein · DAG, diacylglycerol · DHAP, dihydroxyacetonephosphate · F-1,6-bis-P, fructose-1,6-bis-phosphate · FAS, fatty acid synthase · FL, N ε -fructosyl-

The streptozotocin-induced (STZ) diabetic rat experimental model of diabetes on insulin maintenance therapy exhibits dyslipidemia, mild thiamine deficiency, and increased plasma protein advanced glycation end products (AGEs). The reversal of thiamine deficiency by high-dose thiamine and S-benzoylthiamine monophosphate (benfotiamine) prevented the development of incipient nephropathy. Recently, we reported that high-dose thiamine (but not benfotiamine) countered diabetic dyslipidemia. To understand further the differences between the effects of thiamine and benfotiamine therapy, we quantified the levels of the AGEs in plasma protein. We found hydroimidazolone AGE residues derived from glyoxal and methylglyoxal, G-H1 and MG-H1, were increased 115% and 68% in STZ diabetic rats, with respect to normal controls, and were normalized by both thiamine and benfotiamine; whereas N-carboxymethyl-lysine (CML) and N-carboxyethyl-lysine (CEL) residues were increased 74% and 118% in STZ diabetic rats and were normalized by thiamine only. The lack of effect of benfotiamine on plasma CML and CEL residue concentrations suggests there may be important precursors of plasma protein CML and CEL residues other than glyoxal and methylglyoxal. These are probably lipid-derived aldehydes.

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