الفهرس 
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Abstract
Glycated proteins, lipids and advanced glycation end-products (AGEs) are a complex and heterogeneous group of compounds that have been implicated in diabetes related complications especially endothelial dysfunction. We particularly investigated alterations in the level of glycosylated hemoglobin (HbA1C) and vasculopathy observed in diabetes and also we studied the effect of some antidiabetic agents on this condition. We used aminoguanidine as an AGEs inhibitor and metformin as a common oral hypoglycemic agent. We used also insulin as a standard antidiabetic drug given alone and in combination with either metformin or aminoguanidine. We have investigated the possible interactions between insulin, metformin or aminoguanidine on some biological parameters as serum glucose, total cholesterol, serum creatinine and serum liver enzymes (ALT and AST).
Experimental diabetes was induced in female rats by intravenous injection of streptozotocin “STZ” (50 mg/kg). Hyperglycemic rats (had glycemia > 350 mg/dl) were randomly divided into 7 groups (each comprised of 12 rats), in addition to a control non-diabetic normal group (Group I, which also comprised of 12 rats). The eight groups were treated according to the following schedule (the treatment was administered once daily, every day and for 6 weeks):
Group I: control non-diabetic rats, which received distilled water (2 ml/kg, orally).
Group II: control diabetic rats, which received distilled water (2 ml/kg, orally).
Group III: received zinc-insulin suspension (6 IU/kg, S.C.).
Group IV: received metformin (100 mg/kg, orally).
Group V: received aminoguanidine (50 mg/kg, S.C.).
Group VI: received both zinc-insulin suspension (4 IU/kg, S.C.) and metformin (50 mg/kg, orally).
Group VII: received both zinc-insulin suspension (6 IU/kg, S.C.) and aminoguanidine (50 mg/kg, S.C.).
Group VIII: received both aminoguanidine (50 mg/kg, S.C.) and metformin (100 mg/kg, orally).
Results of this study indicated the following:
1- Induction of diabetes using STZ (50 mg/kg, I.V.) showed significant increase in serum glucose, HbA1C, total cholesterol and serum creatinine. Also endothelium-dependent vasodilation in response to acetylcholine “ACh” was impaired with increasing the sensitivity of the blood vessels to vasoconstrictor agent, phenylephrine “PhE” (in vivo and in vitro experiments for the evaluation of endothelial dysfunction).
2- Insulin administration produced a significant decrease in serum glucose level of diabetic rats in comparison with its initial diabetic value. Also, it significantly reduced HbA1C, total cholesterol and serum creatinine levels. Insulin prevents the development of impaired endothelium-dependent relaxation in rat isolated thoracic aortic rings. The most likely mechanisms would appear to the preservation of endothelial nitric oxide (NO) production, but the prolongation of the half-life of NO through reduced free radicals, Amadori products (HbA1C%) and AGEs formation may also play a role. In addition, insulin treatment prevents the enhanced contractility to PhE associated with STZ-induced diabetes.
3- Treatment of diabetic rats with metformin lowered both blood glucose and HbA1C% but not restored them to the control non-diabetic values. Also, metformin lowered total cholesterol to its control non-diabetic value. It has been documented that metformin has a dual effect: it lowers blood glucose level, (a well-known and established activity) plus as new research is revealing, it is an effective inhibitor of cross-linking through carbonyl trapping and also an antioxidant. This indicates metformin’s beneficial effects on the partial improving of endothelial function. However, elevated serum creatinine level was established during the treatment with the high dose of metformin when used as a sole therapy.
4- Aminoguanidine did not significantly affect neither the elevated serum glucose nor HbA1C levels, however, endothelial function was partially improved in comparison with control diabetic rats. This action could be due to AGE inhibition as aminoguanidine is an effective inhibitor of cross-linking initiated by glucose molecules. Also, aminoguanidine restored both total cholesterol and serum creatinine to their normal values. However, aminoguanidine resulted in a significant increase in serum liver enzymes, which may by reversible as documented by Whittier et al., (1999) and Singh et al., (2001).
5- Treatment with a combination of low doses of both insulin and metformin lowered serum glucose, HbA1C and total cholesterol levels insignificantly when compared with the lowering of these levels using a high dose of insulin alone. Also, this combination restored the endothelial integrity to its normal condition insignificantly from the action of the high dose of insulin alone. This indicates the insulin-sparing action of metformin, which may be useful in preventing both hypoglycemic episodes and weight gain action of high doses of insulin. Also, low dose of metformin in combination with low dose of insulin resulted in a significant decrease in serum creatinine nearly equal to the control non-diabetic value (c.f. high dose of metformin alone).
6- Addition of aminoguanidine to either insulin or metformin did not produce any additional effect on all measured parameters in comparison with the sole treatment with each of them. However, this addition resulted in significant elevation of serum liver enzymes which may indicates liver toxicity of aminoguanidine.
Conclusion:
1- Glycosylated hemoglobin and consequently advanced glycation end-products, which lead to oxidative stress, resulted in impairment of NO and so affecting vascular function in patients with IDDM.
2- Treatment with aminoguanidine, non-hypoglycemic agent, was effective in improving endothelial dysfunction. However, it did not restore endothelial integrity to its normal conditions.
3- All treatments with aminoguanidine resulted in severe elevation of serum liver enzymes, which may indicate its liver toxicity. Thus, clinical trials on diabetic patients are required to evaluate the efficacy and safety of aminoguanidine especially on liver function.
4- Although aminoguanidine alone resulted in partial improvement of endothelial function, which may be due to its inhibition of AGEs, its addition to either insulin or metformin did not produce any additional advantage in reduction of endothelial dysfunction.
5- High dose of metformin did not produce significant decrease on serum creatinine levels, which may be a result of its partial improvement of the metabolic control or due to an intrinsic effect of metformin. So, it is suggested to avoid the treatment with high doses of metformin especially with patients already have some elevation of serum creatinine (not exceed 1.3 and 1.5 mg/dl in men and women respectively).
6- Metformin is suggested to be used primarily to increase the sensitivity to insulin and ensuring complete reduction of glycemia to normal levels. This can be done by using a low dose of both metformin and insulin avoiding the effect of high doses of both metformin on kidney and also the hypoglycemic episodes and weight gain effect of insulin.