Onset and severity of vascular complications in both type 1 and 2 diabetes are clearly associated with the duration and degree of hyperglycaemia. Supra-physiological concentrations of glucose cause a number of alterations in small and large vessels, the mechanisms of which are not yet fully understood. Among possible mechanisms, increased formation of advanced glycation end products (AGE), increased aldose reductase (AR) activation with consequent hyperglycaemic pseudohypoxia, glucose-induced activation of protein kinase C through de novo synthesis of the lipid second messenger, diacylglycerol and increased flux through the hexosamine biosynthetic pathway seem to playmajor roles. It has been hypothesized that the possible common denominator (‘unifying mechanism’) of these apparently independent biochemical pathways is highglucose- induced excess production of reactive oxygen species (ROS) inside the endothelium, as a result of increased flux through the Krebs’ cycle
Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
ROS can partially inhibit glyceraldehyde-phosphate dehydrogenase, resulting in the accumulation of glycolytic metabolites, among which glyceraldehyde-3-phosphate (G3P) is particularly active in glycating proteins and AGE formation.
Thiamine acts as a co-enzyme for (1) transketolase, which shifts G3P from glycolisis into the pentosephosphate shunt, (2) pyruvate-dehydrogenase, which converts pyruvate (the final product of glycolisis) into acetyl-CoA, which then enters the Krebs’ cycle, and (3) α-keto-glutarate-dehydrogenase, which catalyses the oxidation of α-keto-glutaric acid to succinyl-CoA in the Krebs’ cycle. As a result, thiamine could prevent cell damage induced by hyperglycaemia by removing excess G3P from the cytoplasm (fig 1)
Thiamine corrects delayed replication and decreases production of lactate andadvanced glycation end-products in bovine retinal and human umbilical vein endothelial cells cultured under high glucose conditions.
Previous studies suggested that polyol pathway hyperactivity is implicated in the pathogenesis of diabetic retinopathy.Aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, catalyzes the reduction of glucose to the corresponding sugar alcohol, sorbitol, which is then converted to fructose by sorbitol dehydrogenase. The flux through this alternative route increases significantly when supranormal glucose levels saturate hexokinase, the enzyme responsible for transforming glucose into glucose 6-phosphate, the first metabolite of glycolysis, and the sugar becomes widely available to AR. In these conditions, sorbitol, which is slowly metabolized and not readily diffusible through cell membranes, may accumulate, leading to imbalances in intracellular homeostasis and contributing to the development of the long-term complications of diabetes.(fig2)
Potentially, thiamine could prevent cell damage induced by hyperglycemia by removing excess G3P from the cytoplasm and facilitating utilization of acetyl-CoA derived from accelerated glycolysis. Wehave shown previously that thiamine and its lipophilic analogue benfotiamine, which has higher bioavailability after oral administration, normalize cell replication, lactate production, and AGE formation in human umbilical vein and bovine retinal endothelial cells cultured in high glucose concentrations. Thiamine was also found to inhibit albumin glycation in vitro and to increase transketolase (TK) activity while decreasing the triosephosphate pool and methylglyoxal formation in human red blood cells incubated in high glucose
Thiamine and benfotiamine correct polyol pathway activation induced by high glucose in vascular cells. Activation of transketolase may shift excess glycolytic metabolites into the pentose phosphate cycle,accelerate the glycolytic flux, and reduce intracellular free glucose,thereby preventing its conversion to sorbitol. This effect on the polyol pathway, together with other beneficial effects reported for thiamine in high glucose, could justify testing thiamine as a potential approach to the prevention and/or treatment of diabetic complications.
Regulation of Intracellular Glucose and Polyol Pathway by Thiamine and Benfotiamine in vascular Cells Cultured in High Glucose
SONIA TARALLO e DANIELA DE MARIA (Patologia Clinica)