Background: Diabetes mellitus (DM) is a disorder in which blood sugar levels are abnormally high because either absolute or relative insulin deficiency. Treatment of diabetes involves diet, exercise, education and for most people, drugs. Oral antidiabetic drugs and/or insulin doses may be affected by co-administration of many drugs including aspirin. Dose adjustments may be necessary. The pain killer effect of aspirin is best known for its effects on the two cyclooxygenase enzymes (COX1 & COX2), but, recently, aspirin could specifically inhibit the protein I-kappa-β-kinase beta (IKK-beta). This kinase is used for its role in the cascade of signals that activate the nuclear factor kappa-b (NF-kappa-B) family of cellular genes which regulate inflammatory and immune responses. Now, it turns out that IKK-beta also works in another pathway to contribute to insulin resistance by interfering with insulin signaling. Objective: In view of the recent rodent data demonstrating a potentially important role of IKKβ in mediating insulin resistance and the ability of salicylates to inhibit IKKβ activity, we decided to examine the role of different doses of aspirin (low, moderate and high) in experimentally induced diabetic rats. Materials and Methods: DM in rats were induced by administration of nicotinamide (NAD), 15 min prior to the single dose of streptozotocin STZ i.p. Ninety male albino rats were used in this study. They were divided into 6 main groups. The first was served as control which receives no medications. The second group was diabetic induced rats as mentioned above. The third group was controlled by insulin after induction of D.M. Groups from the fourth to the six consist of 20 diabetic induced rats and further subdivided into rats taking either aspirin alone in different doses (low, moderate or high) or aspirin and insulin. At the end of the protocol, fasting blood sugar level (FBS), glycosylated hemoglobin (HBA1c%), total serum proteins, C-peptide, lipid profile and C-reactive proteins were measured. Results: Different doses of aspirin showed that moderate and to a greater extent high dose aspirin administration to diabetic rats have greater impact on fasting blood glucose levels whether treated with insulin or not. Again, HBA1c% in diabetic rats treated with insulin and receiving HDA was lower than diabetic rats treated with insulin only or even taking LDA in addition. On the contrary, different doses of aspirin (LDA, MDA&HDA) administration to diabetic rats have no any influence on HBA1c% as compared to normal non-diabetic rats. TGs in diabetic rats receiving MDA alone was elevated as compared to normal non-diabetic rats. Again, moderate and HDA in diabetic rats not taking insulin had high TGs level as compared to diabetic rats treated with insulin only. Conclusion: The study concluded that the inflammatory pathways hold a substantial part in insulin resistance in type 2 DM. The influence of salicylate compounds on insulin sensitivity is multifactorial especially in high doses, and involves both beneficial and deleterious effects depending on the species and experimental model studied.
Diabetes mellitus (DM) is a disorder in which blood sugar levels are abnormally high because either absolute or relative insulin deficiency. The levels of sugar in the body vary normally throughout the day. They rise after a meal and return to normal within about 2 hours after eating. In type 1 diabetes (IDDM), more than 90% of the insulin-producing cells of the pancreas are permanently destroyed. Only about 10% of all people with DM have type 1 disease. Most people who have type 1 DM develop the disease before age of 30. In type 2 diabetes (NIDDM), the pancreas continues to produce insulin, sometimes even at higher than normal levels. However, the body develops resistance to the effects of insulin, so there is not enough insulin to meet the body’s needs. Type 2 DM may occur in children and adolescents, but usually begins in people older than 30 years and becomes progressively more common with age. About 15% of people older than 70 years have type 2 DM. Certain racial and cultural groups are at increased risk of developing type 2 DM. Type 2 DM tend to run in families. Obesity is the chief risk factor for developing type 2 DM and 80% - 90% of people with this disease are obese. Certain diseases and drugs are known to affect the body uses insulin and can lead to type 2 DM. High levels of corticosteroids and pregnancy are the most common causes of altered insulin use. [
Treatment of diabetes involves diet, exercise, education and for most people, drugs. If a person with DM keeps blood sugar levels tightly controlled, complications are less likely to develop. Oral antidiabetic drugs and/or insulin doses may be affected by co-administration of many drugs including aspirin. Dose adjustments may be necessary. Potentiation of oral antidiabetic agents may be caused partially by displacement from serum proteins. Glipizide & gliburide, because of their non-ionic binding characteristics, may not be affected as much as other oral agents; however caution in concomitant use is recommended [
The pain killer effect of aspirin is best known for its effects on the two cyclooxygenase enzymes (COX1 & COX2), but, recently, aspirin could specifically inhibit the protein I-kappa-B-kinase beta (IKK-beta). This kinase is used for its role in the cascade of signals that activate the nuclear factor kappa-b (NF-kappa-B) family of cellular genes which regulate inflammatory and immune responses. Now, it turns out that IKK-beta also works in another pathway to contribute to insulin resistance by interfering with insulin signaling [1-7].
Insulin resistance is a primary factor in the development of type 2 diabetes, Yuan et al. hypothesized that IKKβ is a key downstream mediator in this process and demonstrated that high doses of salicylates, inhibit IKKβ activity [
DMin rats were induced by administration of nicotinamide (NAD) (230 mg/kg, i.p.), 15 min prior to the single dose of streptozotocin (STZ) (65 mg/kg, i.p.) [19,20]. Control animals were received an equal volume of saline. The STZ solution contained STZ in saline with a sodium citrate buffer, pH 4.0. The blood glucose levels (by using standard diagnostic kits) were recorded to monitor the degree of diabetes.
Ninety male albino rats (150 - 200 g for each rat) were used in this study. They will be divided into 6 main groups. The first was served as control which receives no medications. The second group was diabetic induced rats as mentioned above. The third group was controlled by insulin after induction of D.M., the dose of which was decided according to blood glucose level and weight of each rat. The first three groups consist of 10 rats each. Groups from the fourth to the six consist of 20 diabetic induced rats and further subdivided as follows:
GIV a: consists of 10 rats that received low dose aspirin orally (100 mg/kg/day) for 14 days.
GIV b: consists of 10 rats that received low dose aspirin orally (100 mg/kg/day) for 14 days and insulin.
GV a: consists of 10 rats that receive moderate dose aspirin orally (300 mg/kg/day) for 14 days.
GV b: consists of 10 rats that received moderate dose aspirin orally (300 mg/kg/day) for 14 days and insulin.
GVI a: consists of 10 rats that received high dose aspirin orally (600 mg/kg/day) for 14 days.
GVI b: consists of 10 rats that received high dose aspirin orally (600 mg/kg/day) for 14 days and insulin.
The dose of insulin was calculated according to the weight of the rat and the blood glucose level.
At the end of the protocol, overnight fasting blood samples were collected from the rat tail of each of the 6 groups and the following parameters were measured:
1) Fasting blood sugar level (FBS).
2) Glycosylated hemoglobin (HBA1c).
3) Total serum proteins.
4) C-peptide.
5) Lipid profile.
6) C-reactive proteins.
Data analysis was performed using SPSS software, version 16. All results are expressed as means ± SD. Difference between the experimental groups were evaluated by Kruskal-Wallis, followed by the Mann-Whitney test (for significant variables), for multiple comparisons on ranks. The ranks of the data rather than their values were used to calculate the statistic. Data were ranked by ordering them from lowest to highest and assigning them, in order, the integer values from 1 to the sample size. Ties were resolved by assigning tied values the mean of the ranks they would have received if there were no ties. Accordingly, the mean rank score was calculated for each group by dividing the sum of the ranks by the sample size of that group. Differences were considered statistically significant with P values < 0.05.
Tables 1(a), (b) and
Tables 1(a), (b) and
MDA & HDA in treated diabetic rats with insulin resulted in significant reduction of FBS levels as compared to treated diabetic rats with insulin only (P <0.001) or that treated with insulin and given LDA (P < 0.05 & 0.001 respectively).
Tables 2(a), (b) and
Tables 2(a), (b) &
Tables 3(a), (b) & Figures 5 and 6 showed that C-peptide levels were lower significantly in all diabetic rats whether taking aspirin or aspirin and insulin in different
doses as compared to normal non-diabetic rats (P< 0.001 for all groups). No significant differences were observed between diabetic rats taking insulin or not, aspirin alone or aspirin and insulin in different doses.
Tables 4(a), (b) and figure 7 showed that diabetic rats taking MDA had a significant higher serum TGs level as compared to normal non-diabetic rats (P < 0.05). Moderate and high dose aspirin in diabetic rats had significant increased serum TGs levels as compared to either diabetic rats treated with insulin or diabetic rats not taking insulin but on low dose aspirin (P < 0.05).
Tables 4(a), (b) and figure 8 showed that treated diabetic rats with insulin and taking moderate dose aspirin had significant higher serum TGs levels as compared to either normal non-diabetic rats or treated diabetic rats taking insulin (P < 0.05)
Although the hypoglycemic potential of salicylate therapy was demonstrated more than 100 years ago [
Our study using different doses of aspirin [low (LDA), moderate (MDA) and high dose (HDA)], showed that moderate and to a greater extent high dose aspirin administration to diabetic rats have greater impact on fasting blood glucose levels whether treated with insulin or
not. Again, HBA1c% (glycosylated hemoglobin%) in diabetic rats treated with insulin and receiving HDA was lower than diabetic rats treated with insulin only or even taking LDA in addition. On the contrary, different doses of aspirin (LDA, MDA & HDA) administration to diabetic rats have no any influence on HBA1c% as compared to normal non-diabetic rats.
Although the mechanisms by which salicylates affect glucose metabolism are not completely elucidated, studies have described both inhibitory effects on hepatic glucose production [26,27] and improved insulin action from inhibition of kinases IKKβ (inhibitor of Kβ). Since Pickup et al. [
The positive impact of moderate and high dose aspirin on FBS levels in our study could be explained by the two mechanisms mentioned (inhibition of hepatic glucose production and reduction of peripheral insulin resistance), however, HBA1c% reduction by higher doses of aspirin in insulin treated rats only supported the second mechanism of enhancing peripheral insulin action through inhibition of NF-kβ & IKKβ. These results are in accordance with Yaun hypothesis [
The liver is the key organ of insulin resistance in type 2 DM. Decreased hepatic insulin sensitivity may lead to increased hepatic gluconeogenesis, post-prandial hyperinsulinemia and increased formation of triglycerides (TGs) [
Although the carefully performed study by Kim et al. [
The study concluded that the inflammatory pathways hold a substantial part in insulin resistance in type 2 DM. The influence of salicylate compounds on insulin sensitivity is multifactorial especially in high doses, and involves both beneficial and deleterious effects depending on the species and experimental model studied. This could not preclude patients from taking low dose aspirin to prevent cardiovascular disease [
This study was sponsored by Institute of Scientific Research and Revival of Islamic Heritage with grant no. 43109010.
The authors would like to thank Prof. Moataz AbdelFattah, Professor of Medical Statistics and Clinical Epidemiology, Medical Research Institute, Alexandria University, Egypt for his statistical advice throughout preparation of this manuscript.