**5. Thiamine and diabetes**

Experimental evidence suggests that thiamine transport maybe abnormal in diabetes.In experimental diabetes, these was diminished intestinal absorption of thiamine and TMP. Mild deficiency of thiamine in diabetes may induce increased expression of THR1 as found in frank thiamine deficiency. In streptozocin induced diabetic rats with supportive insulin therapy to regulate hyperglycemia, 54% decreased plasma thiamine concentration was reported in contrast to normal controls [190]. This was induced in the diabetic state despite high dietary intake (9 fold) in excess of DRI for rats. The primary cause was marked increased renal clearance of thiamine which was increased by 8 fold. In streptozotocin-induced diabetic rats, there was decreased transketolase expression and activity in renal glomeruli, liver, skeletal muscle and RBCs after 12 weeks of diabetes was found associated with progressive increase in the renal clearance of thiamine and increased albuminuria with duration of diabetes, suggesting that abnormal renal handling of thiamine may occur early in the process of impairment of renal function in diabetes [190]. In experimental diabetes, similar low plasma thiamine concentration was associated with low TK activity and expression in renal glomer‐ uli.Reduced activity of PDH was also noticed due to thiamine depletion. Similar impairment of thiamine-related metabolism may occur in the diabetic retina and peripheral nerves predisposing these tissues to the adverse effects of hyperglycaemia.

#### **5.1. Effect of thiamine therapy in diabetes: On glycemic control in experimental and animal model**

Thiamine therapy was found to decrease hyperglycemia in cirrhosis, insulin resistance of muscle and inadequate insulin secretion by β cells. In thiamine responsive megaloblastic anaemia too hyperglycemia is linked to impaired insulin secretion due to mutated high affinity thiamine transporter. Therapeutic intervention by thiamine in both cases is likely to involve improved β cell metabolism and insulin secretion. This effect was not noticed in permanent insulin deficiency of the STZ diabetic rat model where most of the pancreatic β cells are damaged or destroyed and resultantly no improvement in glycemic control is observed. It is not yet known if thiamine or benfotiamine improve glycemic control in type 2 diabetic animal model.

#### **5.2. Mild thiamine deficiency in diabetics and improved post therapy thiamine status in clinical studies**

patients with seizure disorders such as epilepsy. The water soluble thiamine HCl form is safe in humans in oral doses less than or equal to several hundred milligrams via oral route. A UK EVM found that a small clinical trial in Alzheimers patients revealed no adverse effects of thiamineHCl at daily oral intakes of 6000 to 8000mg for five to six months. A randomized double blind placebo controlled trial was conducted in India for therapy of primary dysme‐ norrhea, a daily oral dose of 100mg thiamine was given to 556 females for 60-90 days and no adverse effects were noted.In extremely rare cases of allergic sensitivity were noted solely in patients using thiamine by the parenteral route and were probably due to the injection vehicle and it not been reported to be carcinogenic or mutagenic. No known genetic microsomal

Experimental evidence suggests that thiamine transport maybe abnormal in diabetes.In experimental diabetes, these was diminished intestinal absorption of thiamine and TMP. Mild deficiency of thiamine in diabetes may induce increased expression of THR1 as found in frank thiamine deficiency. In streptozocin induced diabetic rats with supportive insulin therapy to regulate hyperglycemia, 54% decreased plasma thiamine concentration was reported in contrast to normal controls [190]. This was induced in the diabetic state despite high dietary intake (9 fold) in excess of DRI for rats. The primary cause was marked increased renal clearance of thiamine which was increased by 8 fold. In streptozotocin-induced diabetic rats, there was decreased transketolase expression and activity in renal glomeruli, liver, skeletal muscle and RBCs after 12 weeks of diabetes was found associated with progressive increase in the renal clearance of thiamine and increased albuminuria with duration of diabetes, suggesting that abnormal renal handling of thiamine may occur early in the process of impairment of renal function in diabetes [190]. In experimental diabetes, similar low plasma thiamine concentration was associated with low TK activity and expression in renal glomer‐ uli.Reduced activity of PDH was also noticed due to thiamine depletion. Similar impairment of thiamine-related metabolism may occur in the diabetic retina and peripheral nerves pre-

**5.1. Effect of thiamine therapy in diabetes: On glycemic control in experimental and animal**

Thiamine therapy was found to decrease hyperglycemia in cirrhosis, insulin resistance of muscle and inadequate insulin secretion by β cells. In thiamine responsive megaloblastic anaemia too hyperglycemia is linked to impaired insulin secretion due to mutated high affinity thiamine transporter. Therapeutic intervention by thiamine in both cases is likely to involve improved β cell metabolism and insulin secretion. This effect was not noticed in permanent insulin deficiency of the STZ diabetic rat model where most of the pancreatic β cells are damaged or destroyed and resultantly no improvement in glycemic control is observed. It is not yet known if thiamine or benfotiamine improve glycemic control in type 2 diabetic animal

variations increase susceptibility to thiamine toxicity [214].

disposing these tissues to the adverse effects of hyperglycaemia.

**5. Thiamine and diabetes**

40 Treatment of Type 2 Diabetes

**model**

model.

Mild thiamine deficiency has been observed in diabetics in different international stud‐ ies.There is paucity of data on thiamine and thiamine dependant enzyme status in clinical diabetes mellitus. In Japan a study of 46 diabetic patients (7 type 1, 39 type 2) with moderate glycemic control (glycated hemoglobinA1c 9%) found lower diabetic RBC TK activity in 79% of patients and a concomitant decrease in thiamine level in 76% of diabetics. Oral thiamine supplementation 3-80mg/day increased thiamine levels (20 patients) and TK activity (15 patients). In a larger Israel study of 100 type 2 diabetic patients (glycated HbAic 9.2%), TK activity was lower than the minimum normal range in 18% of diabetics. A smaller Italian study of 10 type 1 diabetic children with normal renal function found plasma thiamine concentration to be decreased by 34% with respect to normal healthy controls and was normalized in a placebo controlled intervention with lipophilic thiamine derivative benzoxymethyl thiamine (50mg/day).

#### **5.3. Intervention of high dose thiamine therapy in biochemical dysfunction in diabetes and the prevention of microvascular dysfunction, neuropathy, dyslipidemia complications**

Microvascular disease (nephropathy, retinopathy and neuropathy) a common debilitating manifestation of chronic diabetes mellitus, has no effective therapy. Hyperglycaemia in diabetic subjects is an essential element for development of both microvascular and macro‐ vascular complications risk factor DCCT 2003. High doses of thiamine and its derivative Sbenzoylthiamine monophosphate (Benfotiamine) are proposed as a new therapy to counteract biochemical dysfunction leading to the development of microvascular complications [114]. High dose thiamine and Benfotiamine may counter the development of microvascular complications by activation of the reductive pentosephosphate pathway. Interestingly by activation of the hexosamine pathway the glucose-mediated induction of lipogenic enzymes, glycerophosphate dehydrogenase (GPDH), fatty acid synthase (FAS) and acetyl-CoA carbox‐ ylase, was stimulated in liver and adipocytes(Fig 8). In turn, this diverts metabolic flux away from the hexosamine pathway, decreased lipogenesis and correct diabetic dyslipidaemia as shown below (Fig 8).

Drugs such as cerivastatin decreased total and LDL cholesterol, triglycerides, microalbumi‐ nuria and increased HDL cholesterol in type 2 diabetic patients. However, normal levels of these metabolite were not achieved. Interestingly pharmacologically combined therapy of vit B1, B6 and B12 did not augur well in diabetics having diabetic nephropathy and substantial adverse outcomes associated with high dose vitamin B6, B9 and B12 co-supplementation in patients with advanced diabetic nephropathy was brought to light Recently concluded Diabetic Intervention with Vitamins to Improve Nephropathy (DIVINE) study produced an unexpected accelerated decline in renal function. The reasons could have been multipronged ranging from toxic accumulation of folate and B12 in patients of diabetic nephropathy with low GFR or competitive inhibition of TMP and TPP transport at the level of RFC1 transporter by high dose folate at key sites such as the kidney and vascular cells thus adversely affecting sharing of thiamine between tissues rich in thiamine and those deficient in it [183].

**Figure 8.** Metabolic Mechanism for Supression of Hepatic Lipogenesis in Diabetes by Thiamine.Adapted from PJ Thor‐ nalley 2006

### **6. Summary**

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 of geographical, racial and pharmacogenetic factors. So the need of the hour was an indepth study as a double blind placebo controlled clinical trial to study the effect of high dose thiamine therapy on biochemical profile and activities of thiamine dependant enzymes in type 2 diabetic patients in our multiracial population in Pakistan.
