Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. 1288 30

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 beta-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.
 ...
PMID:The potential role of thiamine (vitamin B1) in diabetic complications. 1822 Jun 5

Thiamine supplementation may prevent and reverse early-stage diabetic nephropathy. This probably occurs by correcting diabetes-linked increased clearance of thiamine, maintaining activity and expression of thiamine pyrophosphate-dependent enzymes that help counter the adverse effects of high glucose concentrations-particularly transketolase. Evidence from experimental and clinical studies suggests that metabolism and clearance of thiamine is disturbed in diabetes leading to tissue-specific thiamine deficiency in the kidney and other sites of development of vascular complications. Thiamine supplementation prevented the development of early-stage nephropathy in diabetic rats and reversed increased urinary albumin excretion in patients with type 2 diabetes and microalbuminuria in two recent clinical trials. The thiamine monophosphate prodrug, Benfotiamine, whilst preventing early-stage development of diabetic nephropathy experimentally, has failed to produce similar clinical effect. The probable explanations for this are discussed. Further definitive trials for prevention of progression of early-stage diabetic nephropathy by thiamine are now required.
 ...
PMID:Emerging role of thiamine therapy for prevention and treatment of early-stage diabetic nephropathy. 2134 11

Diabetic Kidney Disease (DKD) represents a worldwide public health problem, due to its ever growing incidence and high costs connected to the imposed therapies regarding substitution of kidney functions. DKD includes all the anatomical, clinical and functional alterations that occur at kidney level in a patient with Diabetes Mellitus (DM), as a result of numerous metabolic and haemodynamic factors at the level of kidney microcirculation, based on a polygenous genetical polymorphism that generates an individual susceptibility for this complication. DKD is found in 20-40% of DM patients and it represents the main cause of chronic kidney disease. In DKD pathogeny, an important part is played by the oxidative stress determined by hyperglycemia. Among the mechanisms by which hyperglycemia may affect the kidney we may enumerate polyol pathway activation, C protein-kinase activation (PKC), non-enzymatic protein glycosylation. Out of the highly reactive molecules involved in the oxidative stress of DKD, an important role is attributed to *O2-, *NO and ONOO-. The role of oxidative stress played in DKD pathogeny is also supported by the promising results of some antioxidant therapies in DKD: AGE inhibitors (pyridorin, 2,3 diamino-phenazine, bromo-phenylacetic thiazolium, aminoguanidine/pimagedine), diacylglycerol pathway inhibitors (vitamin E, thiamine, benfotiamine, aminoguanidine), PKC inhibitors (ruboxistaurin), transketolase activators (thiamine and benfotiamine).
 ...
PMID:Oxidative stress in diabetic kidney disease. 2152 58