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

Abstract

Aims/hypothesis The aim of this study was to quantify protein damage by glycation, oxidation and nitration in a rat model of diabetes at the sites of development of microvascular complications, including the effects of thiamine and benfotiamine therapy. Methods Diabetes was induced in male Sprague-Dawley rats by 55 mg/kg streptozotocin and moderated by insulin (2 U twice daily). Diabetic and control rats were given thiamine or benfotiamine (7 or 70 mg kg −1 day −1 ) over 24 weeks. Plasma, urine and tissues were collected and analysed for protein damage by stable isotopic dilution analysis MS. Results There were two-to fourfold increases in fructosyllysine and AGE content of glomerular, retinal, sciatic nerve and plasma protein in diabetes. Increases in AGEs were reversed by thiamine and benfotiamine therapy but increases in fructosyl-lysine were not. Methionine sulfoxide content of plasma protein and 3-nitrotyrosine content of sciatic nerve protein were increased in diabetes. Plasma glycation free adducts were increased up to twofold in diabetes; the increases were reversed by thiamine. Urinary excretion of glycation, oxidation and nitration free adducts was increased by seven-to 27-fold in diabetes. These increases were reversed by thiamine and benfotiamine therapy. Conclusions/interpretation AGEs, particularly argininederived hydroimidazolones, accumulate at sites of microvascular complication development and have markedly increased urinary excretion rates in experimental diabetes. Thiamine and benfotiamine supplementation prevented tissue accumulation and increased urinary excretion of protein glycation, oxidation and nitration adducts. Similar effects may contribute to the reversal of early-stage clinical diabetic nephropathy by thiamine.

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].…”

Деривати Тіаміну Та Аналоги Вітаміну B1: Біохімія, Структура І Значення В Патогенезі Діабетичних Ускладнень

“…Benfotiamine has shown to effect in the diabetic neuropathy patients with reduction in pain score and improve neurophysiological parameters [4]. Benfothiamine significantly reduced inflammatory (10-300 mg/kg) and neuropathic (75-300 mg/kg) nociception in non-diabetic and diabetic rats [7].…”

“…Thiamine reversed hyperglycemiainduced dysfunction in cultured endothelial cells [3]. Thiamine and benfotiamine have been demonstrated in vitro to counteract the da maging effects of hyperglycemia on cultured vascular cells [4]. In addition, thiamine has been reported to improve endothelium vasodilation in patients with hyperglycemia [5].…”

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]…”