**7. Therapeutic implications**

**6. Summary**

42 Treatment of Type 2 Diabetes

nalley 2006

Thus final summarization of these studies indicates that high dose thiamine repletion may decrease the risk of micro and macrovascular disease and counter incipient nephropathy in diabetes. The effect of thiamine occurred independent of control of hyperglycaemia, blood pressure and statin/fibrate therapy, suggesting that high dose thiamine therapy may produce improvements in the prevention of dyslipidaemia and diabetic nephropathy in addition to those produced by current therapy for control of hyperglycaemia, blood pressure, cholesterol and lipids. Since dyslipidemia and microalbuminuria are reversible in type 2 diabetic patients, it is possible that high dose thiamine therapy might improve renal function and metabolic control through reduction in biochemical dysfunction and improvement in thiamine depend‐ ant enzyme activities in diabetic patients with existing dyslipidaemia and microalbuminuria. However, it appears that there may be noticeable variations in these parameters on the basis

**Figure 8.** Metabolic Mechanism for Supression of Hepatic Lipogenesis in Diabetes by Thiamine.Adapted from PJ Thor‐

Based on the data above, the first ever randomized, double blinded, placebo controlled clinical intervention trial registered with the World Health Organization involving high dose B1 therapy was conducted by Dr.Saadia ShahzadAlam of the Pharmacology Deptt (Co-Principal Investigator 1) of Federal Postgraduate Medical Institute Lahore for a period of 5 months to study the effect of high dose thiamine therapy on biochemical profile and activities of thiamine dependant enzymes on type 2 diabetics in the Pakistani population. This trial was also pioneering internationally on the subject of diabetic nephropathy and the effect of thiamine supplementation on it. 40 type 2 micoalbuminuric diabetic patients at the Diabetes Clinic of Shaikh Zayed Hospital Lahore were administered 300mg/day (100mg tablets Administration of 300mg B1 TDS) / placebo for 3 months followed by a 2 month washout period. The results of this trial were quite interesting and have been published internationally, plasma thiamine levels of both thiamine and placebo groups were significantly depleted as compared to normal controls. There were significant baseline derangements of incipient diabetic nephropathy (microalbuminuria), glycemic control parameters FBS and glycated hemoglobin, lipid profile including total cholesterol, HDL, LDL, triglycerides and VLDL in type 2 microalbuminuric diabetics as compared to healthy individuals. Following 3 months 300 mg/day thiamine administration there was significant improvement of urinary albumin excretion, and preser‐ vation of glomerular filtration rate suggested that these occurred due to thiamine replenish‐ ment and decreased glycated hemoglobin and LDL cholesterol levels were observed in the washout period as a delayed effect. Additionally following thiamine therapy significant reduction in plasma levels of sVCAM-1, noticeable and an inverse linkage between thiamine therapy and vWF was apparent in this group as compared to placebo, suggested noticeable benefit with reduction in the risk factors of type 2 diabetes. Significant changes in other serum and urinary biomarkers profile were also observed in type 2 diabetics following thiamine therapy in a simultaneously carried out proteomic study. Three thiamine dependant enzymes PDE3, PDE1β, AKGDHE1 and Transketolase were determined to be dysfunctional at baseline in type 2 microalbuminuric diabetic patients in comparison to normal healthy controls, and improved in both activity and gene expression with high dose thiamine therapy While importantly no hepatic or renal adverse effects were encountered prior, during therapy or as a residual effect, post washout thus fortifying the previously established human safety track record of thiamine.[ 200]. We hope that these findings would contribute to knowledge regarding the role of thiamine therapy at 300mg/day dosage on biochemical profile and molecular aspects of those vital thiamine dependant enzymes and help in providing improved, safe and more effective treatment for type 2 diabetic patients with incipient nephropathy, dyslipidemia with expected decrease risk of heart disease and kidney failure.
