Iranian Journal of

---

Background: Gliclazide is a second generation sulfonylurea which its efficacy and safety in the treatment of diabetes has been established. Diamicron MR (30 mg) is a new formulation of gliclazide with modified release which offer once daily dosage administration. This study was designed to assess the effect of combination therapy with diamicron and metformin in the treatment of type 2 diabetes. Methods: 16 patients with type 2 diabetes (2 males, 14 females) more than 35 years old who despite treatment with glibenclamide and metformin had poor diabetes control participated in this clinical trial.HbA1c, lipid profile, liver and renal function tests at the end of study were compared with before. Results: No significant changes was found in FBS, BS2hpp, lipid profile and renal and liver function tests at the end of study. Patients' weight was stable during the study.
Conclusion: Regardless of well efficacy of diamicron in the treatment of new diabetics cases, it is not recommended for patients with poor diabetes control despite of combination therapy with metformin and glibenclamide.

---

Background: Diabetes mellitus is the most common cause of renal failure, blindness, non- traumatic amputation and neuropathy. Homocysteine, a sulfurated amino acid, has a close correlation with Methionine and Cysteine. The conversion of Methionine to Homocysteine and Cysteine is required coenzymes like vitamin B6, B12 and Folate. The effect of Metformin on serum Homocysteine level by decreasing vitamin B12 level in patients with type 2 diabetes mellitus was described previously. Methods: This is a prospective clinical trail study among patients with type 2 diabetes mellitus in Shiraz. 76 patients were divided into two groups (38 patients in each group). First group treated with Metformin 500-2000 mg/day and the second group treated with Glibenclamide 5-20 mg/day with follow up period of at least 6 months. Hb and MCV were used in follow up to detect megaloblastic anemia, indicator of B12 and folate deficiency. Fasting plasma Homocysteine level Hb A1C and blood sugar were measured in baseline and at 3 and 6 months follow up periods. Results: There was no significant difference between age, sex, weight, height and BMI and baseline serum profile between the two groups. Homocysteine level increased significantly in Metformin group at 3 and 6 months(P=0.003 and 0.001 respectively). Mean plasma homocysteine level after 6 months were 10.98±0.58 μmol/l in Metformin and 10.0± 0.88 μmol/l in Glibenclamide group, with significant difference between the two groups (P=0.001). Conclusion: Metformin increases the plasma Homocysteine level. Metformin will accumulate highly in gastrointestinal wall and cause malabsorption of vitamin B12, therefore we can conclude that the use of Metformin for 6 months can cause vitamin B12 malabsorption and increase in plasma homocysteine level. Increase in plasma homocysteine level was 7.54% in our study that is higher in comparing to the other studies. It can be explained by longer duration of Metformin therapy in our study. Rising in Homocysteine levels may have detrimental effect on vessels that need further study.

---

Background: Metformin is usually using for glycemic control in type 2 diabetes mellitus. The drug is the first line for obese patients without renal or liver failure. Different pharmaceutical types of Metformin are available. As a clinical trial, we compared effects of Aria Metformin (product of Aria pharmaceutical company, Iran) with Merck Metformin or Glucophage (product of Merck pharmaceutical company, France), in diabetic patients.
Methods: This double blind randomized clinical trial study performed with 60 non- pregnant diabetic patients, in order to comparison of therapeutic effects of combination therapy (Glibenclamide + Metformin "Aria or Merck") in a 12 weeks period. We evaluated FBS, BS 2hpp, HbA1c, lipid profile, liver function tests, weight, BMI and common or uncommon side effects.
Results: Not only each of two pharmaceutical types of Metformin had the same therapeutic effects for controlling of glycemia, lipid profile and weight, but also there were not difference between them in side effects. Distention was the most common side effects of two types products (33%). There is not significant difference between them in common side effects. 70% of patients were satisfied with each two kinds of Metformin.
Conclusion: It seems, in view of beneficial therapeutic effects of Aria Metformin, low rate of side effects, and finally low cost, Aria Metformin is a good choice.

---

Background: Metformin is used in treatment of non-insulin-dependent diabetes mellitus (NIDDM). The present study was aimed to study the pharmacokinetic and pharmaco-dynamic of metformin 500 mg tablet in healthy volunteers.
Methods: The test and reference metformin hydrochloride 500 mg tablets were administered to 12 healthy volunteers in a cross-over study. Metformin serum concentration and decrease in blood sugar levels (dBSL) were used for study of pharmacokinetic and pharmacodynamic.
Results: There was no correlation between phramacodynamic and pharmacokinetic para-meters. Also there was no increase in dBSL-(AUC0-12) with increase metformin serum concentration-time. The results of our study show that both products could be bioequivalent according to serum concentration and not blood sugar data.
Conclusion: There was no concentration – effect (dBSL) correlation for both products. Metformin didn’t decrease the blood glucose in healthy volunteers. In some volunteers there was no increase in blood sugar after meal and dextrose 20% oral solution administration which could be related to decreased absorption of glucose from gastrointestinal tract caused by metformin.

---

Background: Insulin is first choice for gestational diabetes control, but its needed to frequent injections; one thing that is difficult for pregnant women, so interest to metformin consumption is increased. Metformin easily crosses the placenta and its fetal blood levels is equivalent to the level of the mother's blood. Metformin also easily cross the brain barrier and enter the brain. Possible side effects of metformin compared to insulin on fetus brain development was concerned to design of present study.  

Methods: In this cross-sectional prospective trial, gestational diabetes women were recruited randomly to insulin (64 patients) and metformin (64 patients) groups and compared for pregnancy and neonatal outcome and also six-month-old infancy developmental indexes. The results considered significant if P value was ≤ 0.05.
Results: Six-month body mass index of insulin group women was significantly more than metformin group(P=0.05), but there was not any significant difference in cesarean section, preterm labor, dystocia, preeclampsia and still birth rate between two groups. Also neonatal characteristics, need to admission and six-month-old infancy developmental indexes according to Ages stages questionnaire were no different between two groups.
Conclusion: Metformin consumption in compare to insulin was not associated with maternal, neonatal and six-month-old infancy developmental indexes side effects.

---

Background: High oxidative stress in pregnant women leads to pathogenesis or progression of disease in newborns. The aim of this study was to investigate the Effect of Endurance Training in Maternal Metabolic Syndrome with Metformin on Oxidant and antioxidant Capacity in their Neonates.
Methods: To implementation of this experimental research, 16 female Wistar rats weighing 100 ± 20 gr randomly were divided into 4 groups including metabolic syndrome + control; metabolic syndrome + metformin; metabolic syndrome + endurance training; metabolic syndrome + metformin + endurance training. The metabolic syndrome model was performed using dietary change and confirmed by the Lee index. Metformin 500 mg was also given at a dose of 100 mg/kg, as well as by daily water intake to the rats. endurance training performed at 5 days a week for 15-40 min with speed of 10-25m/min on treadmill for 8 weeks. Pregnancy was confirmed in rats after vaginal plaque was observed After the pregnancy and delivery period of the rats, newborn babies (4 newborns from each mother as the main sample) were prepared one week after birth for explanation.
Results: The results showed that metformin had no significant effect on superoxide dismutase (SOD) and malondialdehyde (MDA) in comparison with control group, but endurance training and endurance training with metformin resulted in increased SOD and MDA reduction in neonatal heart tissue (p=0.000).
Conclusion: According to the results, it seems that the endurance training of mothers with metabolic syndrome has a protective effect on oxidative and antioxidant systems in their offspring.

---

Backgrund: Saffron petals contain flavonoid compounds, glycosides, and anthocyanins. Considering the trend of increasing the use of medicinal plants in modern medicine in order to treat some diseases, the upcoming experiment was designed to investigate the effectiveness of the hydroalcoholic extract of saffron petals and alkaline water in comparison with the commercial drug metformin on the blood glucose level of diabetic rats.
Methods: In this experiment, 28 male Wistar rats were divided into 4 groups. 1) Diabetic animals (negative control), 2) Diabetic animals that received 200 mg of dry saffron petal extract daily, 3) Diabetic animals that had free access to alkaline water, 4) Diabetic animals that received 100 mg/kg BW metformin daily. They did the duration of the experiment was considered to be 28 days. During this period, feed and water consumption will be measured and recorded on a daily basis and weight on a weekly basis. At the end of the experiment, blood biochemical indices were measured.
Results: Weight and blood triglycerides were not affected by experimental treatments. While the feed consumed, water consumed, insulin, glucose, cholesterol, HDL, LDL and liver enzymes were significantly affected by the experimental treatments.
Conclusion: According to the results, the use of alkaline water and saffron petal extract positively reduced the blood glucose of mice and also had significant effects on feed and water consumption, cholesterol, HDL and LDL of animals. However, the definitive confirmation of the results of this experiment requires more studies and investigations in this field.

---

Background: Myogenin (MyoG) and Myostatin (Mstn) play role in muscle growth and wasting, respectively. The present study aimed to investigate the combined effect of High-intensity Interval Training (HIIT) and Metformin drug (Metf) on gene expression of MyoG and Mstn in skeletal muscle of type 2 diabetic mice.
Methods: 25 mice (C57BL/6) were assigned to two groups, including 1) Control © (n=5), and 2) HFD (n=20). The mice of the HFD group were fed a high-fat diet for 16 weeks. After 16 weeks, the mice with over 200 mg/dl were selected as diabetic mice. Then, the diabetic mice were divided into four groups including 1) Control Diabetic (CD) (n=5), 2) Diabet with Metf (DM) (n=5), 3) Diabet with HIIT (DH) (n=5) 4) Diabet with Metf and HIIT (DMH) (n=5). The mice of experimental groups underwent the interventions for eight weeks. The Real-Time–PCR methods were used to measure the mRNA expression of MyoG and Mstn in the Rectus-Femoris muscle.
Results: HIIT (but no Metf) upregulated the gene expression of MyoG (p=0.05). Metformin did not affect Mstn expression (p=0.45), However, HIIT downregulated the expression of Mstn (p=0.001). Metformin did not affect decreasingly or incrementally the downregulating effect of HIIT on Mstn expression (p=0.95).
Conclusion: Metf may not positively or negatively affect the expression changes of MyoG and Mstn induced by HIIT in skeletal muscle of mice with type 2 diabetes.

---

Background: Under hyperglycemic conditions, inflammatory processes with damage to the peripheral nerves are involved in the occurrence of neuropathy. This study aimed to compare the anti-inflammatory effects of metformin (synthetic drug) with gallic acid (natural compound) in hyperglycemic conditions.
Methods: Hyperglycemia was induced in male rats by the intraperitoneal injection of Streptozotocin (STZ) at a dose of 60 mg/Kg. For this research, rats were divided into four groups. Two groups were healthy control and hyperglycemic control rats that did not receive any drugs. The other two groups were hyperglycemic rats, which respectively received Metformin at a dose of 300 mg/kg/day and gallic acid at a dose of 40 mg/kg/day. At the end of the 8-week period, the rats in all groups were anesthetized and a sample of their sciatic nerve was taken to measure the expression level of genes related to pro-inflammatory cytokines IL-6, IL-1β and TNF-α. Data analysis was done by SPSS software and comparison between average data was done by one-way ANOVA and Tukey's post hoc test.
Results: Induction of hyperglycemic conditions in rats increased the expression of genes related to pro-inflammatory cytokines IL-6 (p=0/000), IL-1β (p=0/008) and TNF-α (p=0/005). However, administration of metformin and gallic acid to hyperglycemic rats for 8 weeks reduced the expression of IL-6, IL-1β and TNF-α genes (p˂0.05).
Conclusion: Gallic acid, like metformin, with its anti-inflammatory properties, can be effective in improving complications caused by hyperglycemic conditions, especially neuroinflammation, and it is hoped that it will be clinically useful for diabetic patients in the future.

---

Background: This study aimed to assess the synergistic reno-preventive effects of valproate sodium (VPS) and metformin (MET) on alloxan-induced diabetic nephropathy and to elucidate their mechanisms of action through investigation of the effects on renal modulation of the pro-inflammatory expression and enhancing the expression of Sirt1 and Bcl-2.
Methods: Type 1 diabetes mice (25-30 g) models was established using a single dose i.p of alloxan (120 mgkg^-1), and the diabetic mice were treated with three doses of VPS (10, 20, and 40 mg/kg) and MET (200 mg/kg), respectively for a period of 28 days. Then, specific test were done to evaluate inflammatory genes expression and histopathological changes in the mice kidneys.
Results: The obtained data revealed that the treatment of diabetic mice with VPS and MET led to significant decreases in the blood glucose levels; thereby reflecting the improvement of the impaired kidney function. The treatment with MET and VPS in combination was the most potent in decreasing the elevated renal mRNA levels of inflammatory genes expressions in diabetic mice. Meanwhile, significant increase in the expression of Sirt1and Bcl2 was observed in the kidney of diabetic mice receiving MET/VPS as compared with the diabetic group. Moreover, the treatment of diabetic mice with MET/VPS successfully prevented the diabetes-induced histopathological deleterious changes of kidney.
Conclusion: It can be concluded that MET and VPS in combination can prevent alloxan-induced diabetic nephropathy through attenuating inflammatory pathways and decreasing inflammatory genes expressions together probably with the suppression of oxidative stress, inflammation and apoptosis.