Current Diabetes Reviews, 2005, 1, 287-298 287 The Potential Role of Thiamine (Vitamin B1) in Diabetic Complications Paul J. Thornalley* Department of Biological Sciences, University of Essex, Central Campus, Wivenhoe Park, Colchester, Essex CO4 3SQ, United Kingdom Abstract: Accumulation of triosephosphates arising from high cytosolic glucose concentrations in hyperglycemia is one likely or potential trigger for biochemical dysfunction leading to the development of diabetic complications. This may be prevented by disposal of excess triosephosphates via the reductive pentosephosphate pathway. This pathway is impaired in experimental and clinical diabetes by mild thiamine deficiency. The expression and activity of the thiamine-dependent enzyme, transketolase - the pacemaking enzyme of the reductive pentosephosphate pathway, is consequently decreased. Correction of thiamine deficiency in experimental diabetes by high dose therapy with thiamine and the thiamine monophosphate prodrug, Benfotiamine, restores disposal of triosephosphates by the reductive pentosephosphate pathway in hyperglycemia. This prevented multiple mechanisms of biochemical dysfunction: activation of protein kinase C, activation of the hexosamine pathway, increased glycation and oxidative stress. Consequently, the development of incipient diabetic nephropathy, neuropathy and retinopathy were prevented. Both thiamine and Benfotiamine produced other remarkable effects in experimental diabetes: marked reversals of increased diuresis and glucosuria without change in glycemic status. High dose thiamine also corrected dyslipidemia in experimental diabetes – normalizing cholesterol and triglycerides. Dysfunction of b-cells and impaired glucose tolerance in thiamine deficiency and suggestion of a link of impaired glucose tolerance with dietary thiamine indicates that thiamine therapy may have a future role in prevention of type 2 diabetes. More immediately, given the emerging multiple benefits of thiamine repletion, even mild thiamine deficiency in diabetes should be avoided and thiamine supplementation to high dose should be considered as adjunct nutritional therapy to prevent dyslipidemia and the development of vascular complications in clinical diabetes. Keywords: Thiamine, Benfotiamine, Diabetes, Diabetic Complications, Dyslipidemia, Cholesterol, Beta-cell and insulin. THIAMINE: NUTRITIONAL ASPECTS AND MILD thiamine deficiency, however, since it does not take account THIAMINE DEFICIENCY IN DIABETES of changes in TK expression in RBC precursor and other cells; The expression of TK is decreased in thiamine Thiamine (vitamin B1) is an essential micronutrient with deficiency [10]. Assessment of TK activity and plasma a dietary reference intake (DRI) for normal healthy adult thiamine concentration, with respect to normal healthy human subjects of 1.1 mg per day for females and 1.3 mg per control values, gives greater insight into thiamine status. day for males [1;2] (Fig. (1)). Thiamine supplements are usually only given to subjects suffering symptoms of severe There is a paucity of data on thiamine and thiamine- thiamine deficiency – Wernicke-Korsakoff syndrome dependent enzyme status in clinical diabetes mellitus. A (encephalopathy and associated psychosis) [3] and beriberi study of 21 type 1 and 12 type 2 diabetic patients in Norway [4]. This is associated with severe malnutrition, HIV-AIDS, found a 27% decrease of thiamine concentration in whole inadequate intake, uptake and dysfunctional metabolism of blood samples of type 1 patients and no significant decrease thiamine in clinical alcoholism, and increased excretion of in type 2 patients, with respect to normal controls [11]. A thiamine in renal dialysis of subjects with end stage renal study in Japan of 46 diabetic patients (7 type 1, 39 type 2) disease [5-8]. Wernicke-Korsakoff syndrome and beriberi with moderate glycemic control (mean glycated hemoglobin are not symptoms associated with clinical diabetes mellitus HbA1c 9%) found that TK activity of RBCs was lower than although a mild, asymptomatic thiamine deficiency may be the normal range minimum in 79% of diabetic patients and prevalent. the concentration of thiamine in blood plasma was lower Thiamine deficiency is assessed conventionally by than the normal range minimum in 76% of diabetic patients. measuring the percentage below complete saturation of the In patients with abnormally low plasma thiamine thiamine-dependent enzyme transketolase (TK) in red blood concentration, the thiamine effect was 24 ± 16%. In 24 cells (RBCs) – the “thiamine effect”. The normal value of patients given oral thiamine supplements of 3 - 80 mg/day, the thiamine effect in human subjects is in the range 0 –15%, normal plasma thiamine concentrations were achieved in 20 mild thiamine deficiency is 15 – 25%, and severe thiamine patients and normal RBC TK activity in 15 patients [12]. In a deficiency >25% [9]. This is not a satisfactory assessment of study of 100 type 2 diabetic patients in Israel with HbA1c of 9.2%, TK activity of RBCs was lower than the minimum normal range in 18% of diabetic patients [13]. A small study in Italy of 10 type 1 diabetic children with normal renal *Address correspondence to this author at the Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, function found that plasma thiamine concentration was U.K.; Tel/Fax: +44 1206 873010; E-mail: [email protected] deceased 34%, with respect to normal healthy controls, and 1573-3998/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd. 288 Current Diabetes Reviews, 2005, Vol. 1, No. 3 Paul J. Thornalley OH OH NH2 CH3 a. CH3 NH2 – HO N N + SH N N S HO– CH3 N H O CH3 N Thiamine Thiamine (thiazolium cation) (acyclic form cation) O O – b. O p O– O p O NH CH NH2 CH 2 3 3 OH Non-specific OH esterase N N N N S SH (-benzoic acid ) CH N B O CH3 N H O 3 O Cyclisation Benfotiamine O (–OH–) O p O– CH3 NH2 OH + N N S CH3 N Thiamine monophosphate Fig. (1). Thiamine and Benfotiamine. a. Solution species of thiamine. b. Metabolism of Benfotiamine. was normalised in a placebo-controlled intervention with the maintenance insulin therapy to moderate hyperglycemia, the lipophilic thiamine derivative benzoxymethyl-thiamine (50 plasma thiamine concentration was decreased 54%, with mg/day) [14]. respect to normal controls [15] (Fig. (2)). This was induced in the diabetic state despite dietary intake of thiamine 9-fold Mild thiamine deficiency is prevalent in experimental in excess of the DRI for rats [16]. The primary cause of the diabetes. In streptozotocin-induced (STZ) diabetic rats with thiamine deficiency was a marked increased renal clearance Fig. (2). Effect of high dose thiamine and Benfotiamine therapy on plasma thiamine status in STZ diabetic rats and controls. a. Plasma thiamine concentration and b. plasma thiamine monophosphate concentration. Key: C, control; CT70, control + 70 mg/kg thiamine; CB70, control + 70 mg/kg Benfotiamine; D, diabetic; DT7, diabetic + 7 mg/kg thiamine; DT70, diabetic + 70 mg/kg thiamine; DB7, diabetic + 7 mg/kg Benfotiamine; DB70, diabetic + 70 mg/kg Benfotiamine. Data are mean ± SEM (n = 6 – 13). From [15]. The Potential Role of Thiamine (Vitamin B1) Current Diabetes Reviews, 2005, Vol. 1, No. 3 289 of thiamine. The renal clearance of thiamine increased 8-fold [17]. There was an associated decreased activity of TK in renal glomeruli, liver and RBCs, attributed to decreased expression of TK [15;17]. There was also decreased thiamine concentration in the liver and heart of adult STZ diabetic rats [18] – although in our study thiamine pyrophosphate (TPP) but not thiamine concentration was decreased in the liver of STZ diabetic rats [15;17]. The decrease in TK activity of RBCs developed after 12 weeks of diabetes concomitant with a progressive increase in the renal clearance of thiamine and increased albuminuria with duration of diabetes [17]. After only 3 - 4 weeks of diabetes, pregnant STZ rats did not develop decreased TK activity in RBCs - although their pups had significantly decreased TK activity of RBCs. This was corrected by maternal thiamine therapy during gestation (ca. 20 – 25 mg/kg/day) [19]. The development of thiamine deficiency with increased renal clearance and albuminuria in STZ diabetic rats suggests that abnormal renal handling of thiamine may be an early feature of impairment of renal function in diabetes. MEMBRANE TRANSPORTERS OF THIAMINE AND METABOLISM TO THIAMINE MONOPHOSPHATE AND THIAMINE PYROPHOSPHATE. DYS- FUNCTIONAL THIAMINE METABOLITE TRANS- PORT AND METABOLISM IN DIABETES Thiamine is an organic cation and utilizes high affinity organic cation transporters to cross cell membranes at normal physiological concentrations. At high concentrations, thiamine may cross cell membranes by passive diffusion of the thiazolium ring-opened, unionized form (Fig. (1a)). The genes for thiamine transporters are members of the SLC (solute carrier) 19A gene family with each encoding proteins with approximately 25% overall amino-acid identity. Three Fig. (3). Membrane transport of thiamine, thiamine members of this family have been identified: SLC19A2 and monophosphate and thiamine pyrophosphate. (a) Intestinal SLC19A3 - encoding thiamine transporters THTR1 [20] and epithelium, (b) tissues, and (c) renal proximal tubule. The main THTR2 [21]; and SLC19A1 – encoding the reduced folate directions of thiamine metabolite flow are shown. Mitochondrial transporter RFC-1 which transports folic acid and also flows and TPP binding to enzymes in the intestinal