Effects of glibenclamide and metformin on serum uric acid level in patients with type ٢ diabetes mellitus

Objectives: To assess the effect of glibenclamide and metformin on serum uric acid level in patients with type ٢ diabetes. Study design: Case control study. Subjects and Methods: This study was conducted from March ٢٠٠٩ to January ٢٠١٠. Fasting blood sugar and serum uric acid level were measured in patients suffering from type٢ diabetes mellitus who were referred to Al-Wafa Diabetic Center in Mosul City. Group ١: ٣٢ patients on glibenclamide therapy, group ٢: ٤٢ patients on metformin therapy and group ٣: ٤٢ patients on combination therapy, group ٤: ٣٢ patients on restricted diet, and ٢٣ apparently healthy volunteers, were taken as a control group. Results: The study showed a significant increase in the serum uric acid level of the diabetic patients as compared with the control. Glibenclamide and/or metformin showed no significant difference in the serum uric acid level in patients with type ٢ diabetes mellitus. Conclusion: Glibenclamide and/or metformin had no significant effect on serum uric acid level in patients with type ٢ diabetes mellitus.

ric acid is the final catabolic, heterocyclic purine derivative resulting from the oxidation of purines in humans.Due to the loss of hepatic uricase activity during human evolution, uric acid is excreted as such and is not further metabolized into carbon dioxide and ammonia.A major mechanism underlying hyperuricemia is impaired renal excretion of urate ١ .There has been growing interest in the association of hyperuricemia with hyperglycemia ٢ .Uric acid may be a marker of oxidative stress ٣ and may have a potential therapeutic role as an antioxidant ٤, ٥ .Like other strong reducing substances such as ascorbate, uric acid can also act as a prooxidant particularly at elevated levels.
Patients with non-insulin-dependent diabetes mellitus (NIDDM) are at U increased risk for cardiovascular diseases such as hypertension and stroke.Hyperuricemia is a common finding in NIDDM, but its significance as an independent risk factor for cardiovascular disease has remained uncertain ٦,٧ .Serum uric acid level is positively associated with the development of type-٢ diabetes regardless of various study characteristics.Further research should attempt to determine whether it is effective to utilize serum uric acid level as a predictor of type-٢ diabetes for its primary prevention ٨ .
The association of high serum uric acid with insulin resistance has been known since the early part of the ٢٠th century, nevertheless, recognition of high serum uric acid as a risk factor for diabetes has been a matter of debate.In fact, hyperuricemia has always been presumed to be a consequence of insulin resistance rather than its precursor ٨ .Elevated levels of uric acid should alert physicians to the possibility of insulin resistance.The serum uric acid level was associated with insulin resistance and plasma glucose levels more strongly in females than in males in our study population ٩ .Serum uric acid is positively associated with serum glucose in healthy subjects ١٠ .
Evidence has accumulated indicating that the generation of reactive oxygen species (oxidative stress) may play an important role in the etiology of diabetic complications.This hypothesis is supported by evidence that many biochemical pathways strictly associated with hyperglycemia (glucose autoxidation, polyol pathway, prostanoid synthesis, protein glycation) can increase the production of free radicals ١١ .
Drugs with other primary uses, that have known uricosuric properties which decrease serum uric acid levels, such as losartan ١٢ , fenofibrate ١٣,١٤ , where as diuretic ١٥ pyrazinamide ١٦ , elevate serum uric acid levels.The present study was conducted to investigate the effect of glibenclamide and metformin on serum uric acid level in a number of type ٢ diabetic patients.

Patients and methods
This is a case control study which was conducted in the Department of Pharmacology, College of Medicine, Univrsity of Mosul and Al-Wafa Diabetic Center in Mosul from March, ٢٠٠٩ to January, ٢٠١٠.Five groups were enrolled for this study: the first group included ٣٢ type-٢ diabetic patients , their ages ranged between ٣٢ to ٧٠ years treated with glibenclamide, the second group included ٤٢ type ٢ diabetic patients, their ages ranged between ٢٧ to ٧٥ years treated with metformin, the third group included ٤٢ type ٢ diabetic patients, their ages ranged between ٤٢ to ٦٦ years treated with combination of these two drugs (glibenclamide and metformin), the fourth group included ٣٢ type ٢ diabetic patients on restricted diet therapy only, their ages ranged between (٢٨-٨٥ years) and the fifth group included ٢٣ apparently healthy volunteers participated as a control group, their ages ranged between ٢٨ to ٥٦ years .
Five ml of venous blood samples were collected from each individual (patient and control) after at least ١٢ hours fasting.Fasting blood sugar was measured using a glucose oxidase method ١٧ which is available as a kit manufactured by Biomaghreb.Serum uric acid was assessed by uricase enzymatic method ١٨ by using a special kit (Biolabo).

Statistical analysis
Values were quoted as mean±SE.P < ٠.٠٥ was considered to be statistically significant.Unpaired t-test was used to compare the data obtained in this study.

Results
Table ١ shows the characteristics of the study participants.The table shows the ages of the individual and the number of males and females in the five groups.
Comparison between fasting blood sugar and serum uric acid level of glibenclamide, metformin, combination and diet groups with those of the control showed a significant elevation of all parameters.Comparison of fasting blood sugar and serum uric acid level of glibenclamide, metformin and combination groups with those of diet showed a significant elevation for fasting blood sugar and a non significant differences for serum uric acid level.Comparison between fasting blood sugar and serum uric acid level of glibenclamide and metformin, no significant differences were found between them (Table ٢).

Discussion
Hyperuricemia has previously been described as strong predictor of well defined cerebrovascular complications in patients with type ٢ diabetes ٧ .The present study showed a significant elevation of serum uric acid level of the diabetic patients as compared with the control individuals.The patients are hyperglycemic, as evident by the high concentration of fasting blood sugar.
Variations in uric acid levels have been increasingly associated with insulin resistance, hyperinsulinemia, and diabetes ١٩, ٢٠ .In ٢٠٠٩, a study was conducted by kodama and saito ٨ , they reported that uric acid levels are higher in subjects with prediabetes and early type-٢ diabetes than in healthy.In type-٢ diabetes, Hyperuricemia seems to be associated with the insulin-resistant syndrome and with early onset or increased progression to overt nephropathy, while hypouricemia is associated with worse metabolic control, hyperfiltration and a late onset or decreased progression to overt nephropathy ٢٠ , Interestingly, serum uric acid levels were increased in type ٢ diabetic patients and this phenomenon seemed to be more profound in male diabetic patients ٢١ .
This study is in contrast to the study conducted by Gotoh et al, they reported that serum uric acid levels in diabetics are significantly lower than those in nondiabetic subjects ٢٢ .
The finding of this study showed no significant difference between serum uric acid levels of diet group with glibenclamide, metformin group, this findings are similar to those of Luque et al., where they reported that there was no change in serum uric level observed with metformin for treatment of polycystic ovary syndrome ٢٣ , so as the study done by Fruehwald and Oltmanns ٢٤ .
In contrast to these results, Gregorio and Manfrini in ١٩٩٦, reported that metformin lowered uric acid in elderly type-٢ diabetic patients ٢٥ .Gokcel and Gumurdulu in research concerning the evaluation of the safety and efficacy of metformin in the treatment of obesity, they reported that metformin administration resulted in a significant reduction in serum uric acid levels in obese patients ٢٦ .Barskova et al. reported that metformin reduce production of uric acid in patient with gout and insulin resistant ٢٧ .
The present study revealed that glibenclamide had no significant effect on serum uric acid levels in patients with type-٢ diabetes.These finding are similar to the studies conducted by Cheach ٢٨ , and Carvalho et al. ٢٩ .There findings might indicate that, hypoglycemic agents have no effect on the serum uric acid level of the diabetic patients and does not affect the balance between urate production and renal excretion.Conclusion glibenclamide, metformin or their combination had no significant effect on serum uric acid level in patient with type ٢ diabetes mellitus as evident by non significant differences between patients taking these drugs and patients on diet only.

Table ١ .
The characteristic of study participants