High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

Abstract

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-

Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes

“…Increased AGE and MetSO residue content of peptides in portal venous plasma was found in previous studies [30], consistent with absorption of glycated and oxidised peptides from digested food. The four-to 27-fold increase in urinary excretion of pentosidine, CML and MG-H1 free adducts in diabetic rats without similar proportional increase in food consumption found herein, however, suggests the contribution of AGEs in food to AGEs exposure is low in the diabetic state [9]. The link of urinary excretion of protein glycation, oxidation and nitration free adducts to flux of endogenous adduct formation is compromised where there is metabolism and repair of the free adducts.…”

“…Benfotiamine uses the reduced folate carrier-1 (RFC-1) and phosphatase activity for thiamine delivery [2]. Decreased production of RFC-1 in diabetes and loading of tissues with TMP by benfotiamine approaching levels that inhibit thiamine pyrophosphokinase may impair thiamine delivery by benfotiamine in diabetes [9,33]. Unexpectedly, benfotiamine therapy increased concentrations of plasma glycation and oxidation free adducts in diabetic rats, relating to decreased clearance and increased tubular re-uptake of AGE and MetSO free adducts.…”

“…Thiamine and benfotiamine were given orally after induction of diabetes, mixed with the chow, at high dose (7 and 70 mg kg −1 day −1 ) over 24 weeks to STZ diabetic and healthy control rats. Metabolic control (fasting glucose and HbA 1 ), decline in renal function (urinary albumin excretion) and GFR (creatinine clearance), body weight and food consumption were characterised [3,9]. After 24 weeks, a 24 h urine collection was made and the rats were killed, blood samples collected and plasma prepared.…”

Human pericyte–endothelial cell interactions in co-culture models mimicking the diabetic retinal microvascular environment

“…It has been repeatedly demonstrated that thiamine and its analogue benfotiamine have the potential to correct most of the known metabolic abnormalities induced by high glucose in isolated cells [7][8][9] and to prevent microangiopathy in animals with experimental diabetes [10][11][12]. Besides, initial evidence shows a potential role for this vitamin also in the prevention of nephropathy in diabetic subjects [13].…”

Efficient Transdermal Delivery of Benfotiamine in an Animal Model

“…The application of benfotiamine and the resulting activation of the enzyme transketolase in the diabetic, hyperglycemic system can also produce beneficial effects on general nerve health. Benfotiamine has been shown in many preclinical [21,[31][32][33][34][35][36][37][38][39][40][41][42][43] as well as clinical studies [44][45][46][47][48][49][50][51][52][53][54][55][56][57] to prevent the formation of AGEs [21,53] and eventually with continued treatment to reverse the symptoms associated with the neuropathy [46,47,52,57]. By increasing intracellular levels of thiamine, benfotiamine indirectly induces enzymatic and biochemical pathways [58][59][60] through elevated concentrations of thiamine diphosphate resulting in a reduced level of damaging glucose-derived chemical protein species [21,22,32,[37][38][39][60][61]…”