Keywords
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| Blood sugar-glibenclamide-type 2 diabetic mellitus-Vitamin C. |
INTRODUCTION
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| Diabetes mellitus (DM) is one of the major metabolic disorders associated with great deal of morbidity and economic cost.DM is a “ life time” condition, if left untreated ,leads to lethal complications. The disease affects over 150 million people worldwide, a number that is expected to double by 2025.[1] It is estimated that six people die every minute from T2DM globally, a figure that will soon make the disease one of the world’s most prevalent causes of preventable mortality.[2] Incident rate of the disease increases with age, obesity, sedentary lifestyle. It’s been increasingly noted in children.[3,4] It consists of a group of syndromes characterized by hyperglycemia, altered metabolism of lipids, carbohydrates and proteins.[5] The vast majority of patients have type 2 DM .[5] There is reduced > cell mass in Type 2 DM patients,virtually all persons with type 2 DM have a profound deficit in insulin secretion at the first phase release .[6]Apart from hyperglycemia, DM is also characterized by oxidative stress, inflammation, and insulin resistance.[7] Several investigators have implicated the role of free radical-mediated pathology in diabetes mellitus.[8,9] The illness has poor outcome in spite of the best currently available treatments. Hence, development of novel strategies to improve the outcome will be of great benefit. Presently available oral hypoglycemic agents do not show marked improvement in oxidative stress in diabetic patients .[10] Ascorbic acid (vitamin C), an antioxidant vitamin, plays an important role in protecting free radical-induced damage. Previous study has shown decrease in basal vitamin C level in type 2 DM.[11] Vitamin C is structurally similar to glucose and can replace it in many chemical reactions and thus is effective for prevention of nonenzymatic glycosylation of protein.[12]The American Diabetes Association (ADA) criteria for DM includes, symptoms of DM (i.e polyuria, polydipsia, unexplained weight loss) and a random plasma glucose concentration of greater than 200 mg / dl(11.1 mmol),a fasting plasma concentration of greater than 126 mg / dl(7 mmol) or a plasma glucose concentration of greater than 200 mg /dl (11 mmol ) 2 hours after the ingestion of an oral glucose load.[13]Diabetic patients will be having high level of free radicals and low level of antioxidants, including vitamin C. Decreased vitamin C level is associated with increased oxidative stress and hyperglycemia in diabetic patients.[14] |
| Vitamin C or L-ascorbate is an essential nutrient for higher primates, and a small number of other species. The presence of ascorbate is required for a range of essential metabolic reactions in all animals and in plants and is made internally by almost all organisms,humans being one notable exception. Vitamin C deficiency causes scurvy in humans. It is also widely used as a food additive. The pharmacophore of vitamin C is the ascorbate ion. In living organisms, ascorbate is an antioxidant,as it protects the body against oxidative stress and is a cofactor in several vital enzymatic reactions.[15] |
| Vitamin C has an important role in immune function and various oxidative/inflammatory processes, such as scavenging ROS and RNS, preventing the initiation of chain reactions that lead to protein glycation .[16,17] and protecting against lipid peroxidation.[16,18]The oxidized products of vitamin C, ascorbyl radical and dehydroascorbic acid, are easily regenerated to ascorbic acid by glutathione, NADH, or NADPH.[16] In addition, ascorbate can recycle vitamin E and glutathione back from their oxidized forms.[16,19] For this reason, there has been interest in determining whether vitamin C might be used as a therapeutic agent against the oxidative stress and subsequent inflammation associated with T2DM.Vitamin C is an vitally important antioxidant in humans capable of scavenging oxygen derived free radicals. Vitamin C is structurally similar to glucose and can replace it in many chemical reactions and thus is effective in prevention of non enzymatic glycosylation of proteins, a process that plays an important role in the development of diabetic complications. Vitamin C supplementation has been shown to improve glucose tolerance, lipid profile and reduce cutaneous capillary permeability in Type 2 DM. [20] |
| Hence, this study was undertaken to evaluate whether the above mentioned theoretical benefits actually translate into clinically observable benefits in patients of newly diagnosed Type II diabetes mellitus. Glibenclamide, Vitamin C 1g and 2g were used in present study. |
MATERIAL & METHODS
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| This randomized controlled study was carried out in the outpatient Department of Diabetology, Government General Hospital, Chennai, from December 2008 to may 2009. This was a prospective, open label, randomized, Comparative, controlled clinical trial. Patients attending diabitology OPD were invited to participate in the study.The inclusion criteria were: Newly diagnosed Type 2 DM patients with fasting Blood glucose between 140-250mg/dl(7.8mmol–13.9mmol), of either sex within the age group of 35-65 years.Exclusion criteria were:Patient with Type1DM,Patient with fasting glucose level >250 mg /dl (13.9 mmol), DM related complications (Diabetic neuropathy, Diabetic nephropathy, Diabetic retinopathy) ,Body mass index (BMI) > 30,Patients with hypertension, History of Renal Stones, Patients with evidence of gastrointestinal tract, endocrine, renal, hepatic, cardiovascular abnormalities and any other major systemic illness, Pregnant and lactating women, Patient who cannot comply the protocol, Patient not willing to give written informed consent. The study protocol was approved by the Institute Ethics Committee. |
| A detailed medical and general physical examination was performed. Patients were enrolled after informed and written consent as per the inclusion and exclusion criteria. current medical history and diagnosis were noted during the first visit. Patients were randomly assigned into 3 groups with 30 patients in each group.Group I patients received glibenclamide 5 mg twice a day orally for 8 weeks, Group II patients received glibenclamide 5mg twice a day and vitamin C 500mg twice a day orally for 8 weeks, while Group III patients received glibenclamide 5mg twice a day and vitamin C 500mg 4 times /day orally for 8 weeks.After enrollment into the study ,follow-up was performed after 4 weeks,8 weeks. At each follow up visit, fasting, post prandial blood sugar were recorded .Investigations such as hemogram (Hb,TLC ),serum creatinine,SGOT,SGPT,blood urea, Urine routine : Albumin,microscopic examination,ECG were performed during the first visit and at the end of 8 week of study period. The primary end point was to evaluate efficacy of vitamin C 1g and 2g as an add on therapy to oral hypoglycaemic agent (glibenclamide ) in reducing blood glucose level, in newly diagnosed Type 2 diabetes mellitus patients.The secondary end point was to evaluate the tolerability of vitamin C ( 1g and 2g) as an add on therapy to oral hypoglycemic agent (glibenclamide) in reducing blood glucose level,in newly diagnosed Type 2 diabetes mellitus patients. Patients who didnot complete the full 8 weeks of therapy as per the study regulations were not included for statistical analysis. Safety was assessed in terms of subjective systemic adverse effects. subjective symptoms such as Diarrhea, nausea, vomiting, Giddiness, Fatigue, Headache. |
| Statistical analysis: Statistical methods used were Chi-square, paired T-test, and one way ANOVA. P<0.05 was considered significant,P<0.001 was considered as highly significant,while P>0.05 was considered as insignificant. |
CLINICAL STUDY CHART
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RESULTS
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| A total of 170 patients screened,28 patients were found to have FBS >250 mg / dl ,19 patients had history of ischemic heart disease, 26 patients had increase in blood pressure, 3 patients had asthma,2 patients had history of kidney stones,2 patients had cataract and history of cataract operation.They were excluded from the study. 90 patients who fulfilled inclusion criteria were recruited for the study. Each patient under treatment for 8 weeks. Clinical and laboratory parameters were assessed at the baseline, at end of 4th wk and end of 8th wk. Only 83 patients completed the study. Statistical analysis done for age and BMI with one way ANOVA, Sex distribution and adverse effect with using Chisquare test, FBS,PPBS using Repeated Measure ANOVA, SGOT, SGPT, urea, creatinine, bilirubin were assessed statistically assessed using student t test (paired t test). |
| Baseline readings of FBS and PPBS of 3groups were compared .All the 3 groups were similar and comparable. Regarding demographic characteristics, parameters such as age distribution(p<0.94), body mass index(p<0.94) and sex distribution(p<0.8) were taken into account and analyzed for any statistical significance. There was no significant difference among the study groups in demographic characteristics and body mass index. Other haematological and biochemical parameters like complete hemogram, blood urea, serum Creatinine, Liver function tests such as SGOT, SGPT, Serum alkaline phosphatase, Total bilirubin, Total protein, albumin were measured at the baseline, at the end of 8th week and found to have no statistical difference among the study groups. Group I patients received only glibenclamide, showed FBS level prior to treatment was 184.29+_25.54.After treatment ,FBS level reduced to 171.90+_23.19, 164.31+-22.44 at the end of 4th week and 8th week. The reduction in FBS were compared, there was statistically significant (P< 0.0068 ) difference when compared with the baseline readings. The PPBS level in this group before treatment was 220.15+_24.44 and after treatment 210.4+_24.72,198.51+-21.41 at the end of 4th week and 8th week. The reduction in PPBS were compared, there was statistically significant (P< 0.002 )difference when compared with the baseline readings. Group II patients received both glibenclamide and vitamin C 1g , showed FBS level prior to treatment was 184.31+_28.36 .After treatment ,FBS level reduced to 171.69+_30.27, 160.13+-28.56 at the end of 4th week and 8th week. The reduction in FBS were compared, there was statistically significant (p< 0.0074) difference when compared with the baseline readings. The PPBS level in this group before treatment was 219.21+_29.44 and after treatment 210.33+_24.57, 198.03+-22.43 at the end of 4th week and 8th week. The reduction in PPBS were compared, there was statistically significant (P< 0.007 ) difference when compared with the baseline readings. |
| When we compared FBS and PPBS in between groups, group III patients showed statistical significant reduction in PPBS (P< 0.02) at the end of 8th week. There was reduction in FBS but the difference between the groups were not statistically significant. |
| The safety analysis was performed on all patients who completed the study. Mild adverse effects such as nausea, vomiting ,diarrhea, giddiness, headache and fatigue occurred among study groups.21.3% of group I patients, 10.7% of group II, 25% of group III patients showed adverse effects but the difference was not statistically significant(P>0.07). |
DISCUSSION AND CONCLUSION
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| Diabetic patients have high level of free radicals and low level of antioxidants.High level of free radicals induce oxidative stress leading to endothelial dysfunction.Insulin is the major harmone in regulating blood glucose level. The main function of insulin is to promote glucose uptake and blood vessel relaxation in muscles. Blood vessel relaxation is mainly due to release of nitric oxide by vascular endothelial cells. Relaxation of blood vessel (vasodilatation) leads to increased blood flow to the muscle which account for approximately 25% increase in glucose disposal by insulin.The endothelial cells damaged by the free radicals leads to impairment in endothelial function which results in insulin resistance. Insulin resistance is the major cause of type II diabetic mellitus. The current treatment is targeted to improve insulin sensitivity. Endothelial dysfunction is a hallmark of type 2 diabetes related to hyperglycemia and oxidative stress. This endothelial dysfunction may worsen insulin resistance. It may be possible that vitamin C as an antioxidant can probably reduce insulin resistance by improved endothelial function and lowering oxidative stress.Among the available oral hypoglycemic agents, only few drugs have antioxidant property which will improve insulin sensitivity and reduce blood sugar level. Studies suggest that supplementation of Vitamin C,an antioxidant, reduce the insulin resistance by improved endothelial function and lowering oxidative stress. Thereby helps in reducing blood glucose level in type 2 DM. |
| There have been relatively few studies reporting the effect of vitamin C on blood glucose in type II diabetes patients. In clinical study conducted at Diabetes Research Center , Shahid Sadoughi University Of Medical Sciences, Iran,vitamin C 500 mg & 1000mg were administered for a period of 6 weeks to patients with type 2 DM. Vitamin C 1000mg showed statistically significant reduction in fasting blood glucose.4 Clinical study conducted by Chen et al, daily consumption of 800 mg of ascorbic acid for 4 weeks in type II diabetic patients caused no significant changes in fasting blood sugar .In the present study, we compared vitamin C(1g verus 2g) along with oral hypoglycaemic agent. We have observed that group III patients showed statistical significant reduction in PPBS at the end of the study. It could be due to improvement in the glucose uptake by tissues. It indicates antioxidant nature of vitamin C improving insulin sensitivity. We can see the difference in the results when compared to our study ,this may be due to racial variation of patients. This study showed Vitamin C 2 gm with glibenclamide reduces PPBS level significantly. In Conclusion supplementation with Vitamin C 2g/day in addition to the normal diet and treatment improving plasma glucose (PPBS)in type 2 diabetes patients. |
Tables at a glance
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Figures at a glance
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