Prevention of Incipient Diabetic Nephropathy by High-Dose Thiamine and Benfotiamine

Abstract

Accumulation of triosephosphates arising from high cytosolic glucose concentrations in hyperglycemia is the trigger for biochemical dysfunction leading to the development of diabetic nephropathy-a common complication of diabetes associated with a high risk of cardiovascular disease and mortality. Here we report that stimulation of the reductive pentosephosphate pathway by high-dose therapy with thiamine and the thiamine monophosphate derivative benfotiamine countered the accumulation of triosephosphates in experimental diabetes and inhibited the development of incipient nephropathy. High-dose thiamine and benfotiamine therapy increased transketolase expression in renal glomeruli, increased the conversion of triosephosphates to ribose-5-phosphate, and strongly inhibited the development of microalbuminuria. This was associated with decreased activation of protein kinase C and decreased protein glycation and oxidative stress-three major pathways of biochemical dysfunction in hyperglycemia. Benfotiamine also inhibited diabetes-induced hyperfiltration. This was achieved without change in elevated plasma glucose concentration and glycated hemoglobin in the diabetic state. High-dose thiamine and benfotiamine therapy is a potential novel strategy for the prevention of clinical diabetic nephropathy.

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

“…In this study we found increased protein damage at sites of development of vascular complications in an established model of experimental incipient diabetic nephropathy, where both thiamine and benfotiamine prevented development of nephropathy [3,13]. Other studies have found degeneration of sciatic nerve and retina characteristic of early-stage diabetic neuropathy and retinopathy in this model [14,15].…”

“…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.…”

“…Renal glomeruli were prepared by differential sieving of fresh renal cortex tissue (100-200 mesh; 0.075-0.150 mm pore fraction size sieve) in saline at 4°C [3]. Excised sciatic nerves were rinsed in PBS, cleaned of connective tissue and small vessels, cut into small pieces, homogenised in 2.0 ml 0.25 mol/l sucrose and centrifuged (900g, 20 min, 4°C).…”

“…Analytes were detected by electrospray positive ionisation multiple reaction monitoring LC-MS/MS and quantified by stable isotopic dilution analysis [12]. Data of MG-H1 and CEL content in renal glomeruli have been published previously [3].…”

“…This counters multiple pathways of biochemical dysfunction linked to the development of vascular complications with doses of the vitamin markedly higher than the dietary reference intake [2]. High-dose therapy with thiamine and the thiamine monophosphate (TMP) derivative benfotiamine prevented the development of microvascular complications in experimental diabetes [3][4][5]. A pilot-scale trial of type 2 diabetic patients with incipient nephropathy (microalbuminuria) showed that high-dose thiamine therapy improved renal function and induced regression of microalbuminuria [6,7].…”