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Microsoft word - 13-775-pioglitazone versus metformin-gad.doc

aBiochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt bHormone Evaluation and cBiochemistry Departments, National Organization of Drug Control and Research ABSTRACT
Insulin resistance has been implicated in the pathogenesis of type 2 diabetes. High fat diets cause insulin
resistance. Both metformin and pioglitazone are considered “insulin sensitizers” and used as antihyperglycemic
agents for type 2 diabetes treatment. The aim of this study is to Compare pioglitazone and metformin effects on
carbohydrate metabolism and insulin sensitivity in diabetic and glucose intolerant rats on high fat diet. Male
albino rats were randomized to seven groups. The 1st group received high carbohydrate diet (control). The 2nd,
3rd and 4th groups received high sunflower oil diets for 6 weeks and either left untreated, or given pioglitazone
or metformin during the last 3 weeks. The 5th, 6th, and 7th groups were made diabetic by STZ injection on day
15 of the 6 weeks-high fat diet regimen. They were either left untreated, or given pioglitazone or metformin
during the last 3 weeks. High-fat diet induced glucose intolerance; represented by increase of serum glucose
associated with increase in liver glucose-6-phosphatase and decreases in liver glucose-6-phosphate
dehydrogenase and glucokinase activities. No significant differences were observed between pioglitazone and
metformin. In diabetic rats, both pioglitazone and metformin decreased elevated serum glucose by ~30%. Only
metformin increased hepatic glycogen, and normalized glucose-6-phosphatase activity. On the other hand,
pioglitazone normalized elevated renal glycogen content and increased glucose-6-phosphate dehydrogenase
activity. High sunflower oil diet impaired glucose tolerance. Pioglitazone and metformin had comparable
effects on estimates of carbohydrate metabolism and insulin sensitivity in high-fat fed rats, but different effects
in diabetic rats.
Keywords: Pioglitazone – metformin – carbohydrate metabolism – high fat diet – type 2 diabetes.


carbohydrate and low fiber diets increase the incidence of insulin resistance (McAuley and Mann, 2006). Diabetes mellitus is one of the most common endocrine disorders affecting almost 6% of the world's population. Pioglitazone and metformin are extensively used in Egypt According to report of the International Diabetes and worldwide to treat patients with type II diabetes. Both Federation in 2001, the number of diabetic patients will drugs are considered to be insulin “sensitizers”. However, reach 300 million in 2025. More than 97% of these the full mechanism of action of those two drugs is still patients will have type II diabetes (Adeghate et al., 2006). unraveled and further investigations remain in necessity In Egypt, one study estimated the combined prevalence of to compare their clinical efficacy in different models of diagnosed and undiagnosed diabetes in the Egyptian population ≥ 20 years of age to be 9.3% with a gradient increase from rural (4.9%) to urban areas from lower Pioglitazone, a thiazolidinedione (TZD) insulin sensitizer, (13.5%) to higher (20%) socioeconomic standard is a peroxisome proliferator activated receptor gamma (Herman et al., 1997). (PPAR-γ) agonist. It increases insulin sensitivity by regulating the expression of a variety of genes involved in Insulin resistance, defined as a state of reduced carbohydrate and lipid metabolism, increases GLUT-4 responsiveness to normal circulating levels of insulin, and glucokinase activity, decreases phosphoenol pyruvate plays a major role in the development of type 2 diabetes. carboxykinase (PEPCK) expression, and decreases While there is a genetic component involved in production by fat cell of several mediators that may cause developing insulin resistance, onset appears to be insulin resistance, such as tumor necrosis factor α (TNF triggered by lifestyle. Obesity, along with physical α) and resistin (Cheng and Fantus, 2005; Tjokroprawiro, inactivity, can account for approximately 50% of the 2006). Pioglitazone increases hepatic and peripheral variability in the insulin mediated glucose disposal in insulin sensitivity, thereby inhibiting gluconeogenesis and healthy, non-diabetic, normotensive individuals (Reaven increasing peripheral and splanchnic glucose uptake et al., 2004). High saturated fat, high calorie, processed (Waugh et al., 2006). The prediabetic treatment with *Corresponding author: Tel.: +202-27590717, Fax: +202-27581041, e-mail: Pak. J. Pharm. Sci., Vol.23, No.3, July 2010, pp.305-312 Pioglitazone and metformin in glucose intolerance and diabetes pioglitazone, despite significant weight gain, completely the other used chemicals were of the highest analytical prevents the development of diabetes and enhances β cell function with preservation of islet cell changes in rats Animals
Male Wistar albino rats weighing 170–190 g, purchased Metformin is the only available biguanide in the market. from National Research Centre, Cairo, Egypt, were used The mechanisms of metformin-mediated improvement of in the study. The rats were kept in controlled environment insulin sensitivity have remained obscure, despite and fed ad libitum throughout the study. Study protocols multiple pathways of action being proposed, including a were approved by the local ethics committee in the decrease of hepatic glucose production, an increase of peripheral glucose utilization and a reduction of intestinal glucose absorption. It has been documented that Diets
metformin activates 5'AMP activated protein kinase Rats were randomly assigned to either one of two diet
(AMPK) in hepatocytes, thereby reducing activity of
regimens; control rats (n=9) were fed high carbohydrate acetyl CoA carboxylase and lowering expression of diet (20% Kcal protein, 10% fat, 70% carbohydrate) , all lipogenic transcription factor as well as inhibiting hepatic the rest of rats (n=70) were fed high-fat diet (20% Kcal gluconeogenesis (Cheng et al., 2006). The Diabetes protein, 60% fat, 20% carbohydrate). Diets used in this Prevention Program (DPP) found that metformin study (outlined in table 1) are given ad libitum for 6 decreased new diagnosis of type 2 diabetes by 31% with weeks. Food was withdrawn 5 hours before blood more pronounced reduction in young under 45 years by sampling on day 42. Rats had free access to water 44% and in the obese with body mass index (BMI)>35 by throughout the study. Rats were weighed at the beginning of the study and then weekly till the end of the study. Both pioglitazone and metformin appear to have Table 1: Composition of diets used in this study
additional effects in ameliorating oxidative stress and
inflammation; rendering them attractive tools for
prevention of insulin resistance and diabetes (Molavi et To our knowledge, very few studies are available that directly compare the effects of pioglitazone and metformin on different pathways of carbohydrate metabolism in experimental models of glucose intolerance and insulin resistance. Reports about the comparison between the two drugs with regard to efficacy of glycemic control as related to modulation of metabolism are scarce as well. For the objectives of adding information to these unraveled areas, we studied the effects of pioglitazone and metformin monotherapy on key enzymes of HMP (hexose monophosphate) shunt, gluconeogenesis and glycolysis in liver, as well as on hepatic and renal glycogen contents in experimental models of glucose intolerance and diabetes. Estimates did not pick major differences between the effects of the two drugs. Some distinctions are displayed in the results. MATERIALS AND METHODS
Experimental design
Rats were randomly divided into 7 groups. The first group Chemicals
(n=9) received high carbohydrate diet for 6 weeks (42 Pioglitazone HCl was provided by the raw materials days) and left untreated (control group). All the other 6 department of NODCAR (National Organization of Drug groups received high-fat diet continuously for 6 weeks. Control and Research, Cairo, Egypt). Metformin HCl was Among the 6 groups, following 3 weeks of high-fat diet kindly provided by CID pharmaceuticals, Cairo, Egypt. ingestion, three groups (each n=8) were treated with Streptozotocin, Glucose-6-phosphate sodium salt, either pioglitazone (2.7 mg/kg/day, suspended in distilled glucokinase, NADP and ATP were purchased from water and given by oral tube) (HF Pio), metformin (180 Sigma-Aldrich Chemical Co. (St. Louis, MO, USA). All mg/kg/day, dissolved in distilled water and given by oral Pak. J. Pharm. Sci., Vol.23, No.3, July 2010, pp.305-312 tube) (HF Met), or no drug (HF) for 3 weeks. The other 3 supernatant was used for glucokinase assay according to groups were rendered diabetic by intraperitoneal injection the method of Jamdar and Greengard (Jamdar and of streptozotocin (50 mg/kg) freshly prepared in 0.1M Greengard, 1970). One unit of glucokinase is defined as citrate buffer at pH 4.5 on day 15 and allowed to drink micro moles of NADP/NADPH formed per minute per oral glucose 5% w/v overnight. Minimal dose of insulin gram fresh liver tissue at 37◦C. Two hundred fifty mg (1unit/rat) was given for each rat on 2nd and 3rd day after fresh liver tissue was digested with 5 ml 30% KOH and streptozotocin administration (Wohaieb and Godin, 0.5 ml of the digested tissue was used for glycogen 1987). Induction of diabetes was confirmed on day 21 precipitation using 3 ml absolute ethanol. Glycogen was when serum glucose level was at least 250 mg/dl (Seki et then isolated by centrifugation for 15 minutes at 4000 rpm al., 2004). Diabetic rats were then randomly divided into and determined according to Montgomery method three groups, diabetic untreated (STZ-HF) (n=7) and (Montgomery, 1975). The same above procedure was diabetic treated with either pioglitazone (STZ-HF Pio) used for renal glycogen determination but using 2 ml of (n=6) or metformin (STZ–HF Met) (n=6) with the same protocol as that of high-fat fed rats (table 2). Blood glucose, triglycerides and insulin
Blood sampling and tissue collection
Blood glucose and triglycerides levels were determined in On day 42 blood samples were collected in plastic the sera using UDI (United Diagnostic Industry) glucose centrifuge tubes and allowed to clot at 4oC for 30 minutes. and triglycerides enzymatic kits, respectively, whereas Serum was then separated by centrifugation at 3000 rpm serum insulin was estimated using rat insulin ELISA kit for 20 minutes. On day 43, rats were killed. Livers and kidneys were separated, washed with ice-cold saline, plotted dry with filter paper, weighed and prepared at Statistical analysis
once for studying enzyme activities and glycogen All statistical analyses were performed using Statistical contents. Package for Social Science (SPSS) version 10 software and Microsoft Excel. All values were presented as means Enzyme activities and glycogen content
± S.E. (standard error). Comparisons among groups were One hundred mg fresh liver tissue was immediately made by application of two-way analysis of variance homogenized in 4 ml ice cold EDTA/physiological saline ANOVA followed by one way ANOVA and LSD post solution and centrifuged at 15000 rpm for 20 minutes at hoc analysis. Differences were considered statistically 1.5oC. 0.5 ml of the clear supernatant was used for glucose-6-phosphate dehydrogenase assay as described by Löhr and Waller (Löhr and Waller, 1974). One unit of glucose-6-phosphate dehydrogenase is defined as the amount of enzyme needed to convert 1 µmol of glucose- Experiments on high fat-fed rats
6-phosphate per minute to 6-phosphogluconate at 25oC. As shown in table 3, HF rats did not show significant For glucose-6-phosphatase assay, another 100 mg fresh differences in body, liver and kidney weights when liver tissue was similarly homogenized in 4 ml ice cooled compared with control rats. Similarly, serum triglycerides citrate buffer and centrifuged at 15000 rpm for 30 minutes and insulin were not significantly affected. On the other at 1.5oC. 0.1 ml of the clear supernatant was used for hand, serum glucose level was significantly elevated in glucose-6-phosphatase assay as described by Taussky and HF rats by 18%. This elevation was associated with 18% Shorr (Taussky and Shorr, 1953). One unit of glucose-6- increase in glucose-6-phosphatase activity, 31% decrease phosphatase is defined as micro moles of inorganic in glucose-6-phosphate dehydrogenase activity, and 46% phosphate liberated per minute per gram fresh liver tissue decrease in glucokinase activity as compared with control at 37oC. One gram fresh liver tissue was homogenized rats. Moreover, liver glycogen content was reduced by with 9 ml Tris-KCl-EDTA buffer and centrifuged at 15000 rpm for 1 hour at 1.5oC. 0.025 ml of the clear Table 2: Assignments of the study groups to drugs and diets.
x = High carbohydrate diet, + = High fat diet, ∆ = Pioglitazone (2.7mg/kg/day), • = Metformin (180 mg/kg/day), S = Streptozotocin (50 mg/kg) Pak. J. Pharm. Sci., Vol.23, No.3, July 2010, pp.305-312 Pioglitazone and metformin in glucose intolerance and diabetes Oral administration of pioglitazone (2.7 mg/kg/day) for glucose level by 32% and 29%, respectively. This 21 days was able to significantly decrease body weight decrease was associated with significant decrease in and glucose-6-phosphatase activity by 12% and 22%, kidney glycogen by 52% and significant increase in respectively as compared to HF group. Meanwhile, glucose-6-phosphate dehydrogenase activity by 20% in glucose-6-phosphate dehydrogenase activity was the pioglitazone group. In the metformin group, however, increased by 29%. Other parameters were affected by blood glucose level decrease was associated with pioglitazone administration but not significantly under the significant increase in liver glycogen by 125% and conditions of the experiment. We were not able to detect significant decrease in glucose-6-phosphatase activity by significant differences between results of the 29%. The significant differences between the two aforementioned pioglitazone group and the results of oral treatments were elicited in liver and kidney glycogen administration of metformin (180 mg/kg/day) for 21 days. contents and activities of glucose-6-phosphate dehydrogenase and glucose-6-phosphatase. Experiments on high fat-fed STZ diabetic rats
As compared to control rats, STZ-HF rats showed DISCUSSION
significant decreases in body weight, serum insulin, and liver glycogen by 17%, 51% and 85%, respectively. The main objective of our study is to compare the effects These were associated with significant increases in kidney of pioglitazone and metformin on carbohydrate weight by 42%, renal glycogen by 92% and serum metabolism and insulin sensitivity in prediabetic and glucose by 314%. Serum triglycerides were not altered diabetic states. We are unaware of similar study that significantly. With regard to liver carbohydrate focuses on the similarities and differences between the metabolizing enzymes, significant increase in glucose-6- two drugs on carbohydrate metabolism. Although it is phosphatase activity by 22% and decreases in glucose-6- commonly stated that thiazolidinediones lower glucose phosphate dehydrogenase and glucokinase activities by concentration primarily by increasing glucose uptake and 47% and 65%, respectively were observed in STZ-HF rats metformin by decreasing glucose production, the data as compared to control animals (table 3). supporting these statements are scarce and often contradictory (Inzucchi, 2002; Kerpichnikov et al., 2002). Oral administration of pioglitazone (2.7 mg/kg/day) and In vitro and animal studies have identified multiple metformin (180 mg/kg/day) significantly reduced blood potential targets for these drugs (Basu et al., 2008). Table 3: The effects of administration of pioglitazone and metformin for 21 days on study parameters in
high fat-fed and STZ diabetic rats. Data are presented as mean ± S.E.
a Significance from control at p<0.05 b Significance from high fat-fed rats for groups HF Pio, HF Met , STZ-HF at p<0.05 c Significance from STZ-HF diabetic rats for groups STZ-HF Pio and STZ-HF Met at p<0.05 d Significance from STZ-HF Pio for group STZ-HF Met at p<0.05.
Pak. J. Pharm. Sci., Vol.23, No.3, July 2010, pp.305-312 Moreover, the results have not always been consistent in Impairment of insulin production by streptozotocin added to the results of high-fat diet several modifications. Compared to the HF-group, STZ-HF animals experienced For these reasons, we tested the drugs in two models of lower body weights, hepatic glycogen contents, serum impaired glucose tolerance; one is induced by high-fat insulin and activities of glucose-6-phosphate dehydro- diet only (prediabetic state) and the other is induced by genase and glucokinase. Meanwhile higher renal weight, high-fat diet associated with impaired insulin secretion renal glycogen content, and serum glucose were observed. This pattern well complies with the reported biochemical changes in experimental model of type II diabetes. The model of high-fat diet-induced glucose intolerance had been extensively used by others and was shown to Doses chosen for pioglitazone and metformin in this study impair carbohydrate metabolism, increase hepatic glucose are in harmony with their therapeutic doses in human, production and induce insulin resistance (Wilkes et al., being equivalent to 30 mg/day for pioglitazone and 2000 1998; Mithieux et al., 2002; Henriksen et al., 2008). It is mg/day for metformin. Drugs were administered for 3 generally accepted that high-fat diets can be used to weeks to study their effects when given as chronic generate a valid rodent model for the metabolic syndrome treatments, and were administered concomitantly with with insulin resistance and compromised ß-cell function diet to study their effects under uncontrolled diet (Buettner et al., 2006). Sunflower oil, which is used in this study to induce glucose intolerance, is very similar in composition to safflower (carthame) oil that has been In presence of high-fat diet, administration of pioglitazone used in previous studies for that purpose (Wilkes or metformin caused almost similar biochemical changes, but with few exceptions. Both drugs did not show et al., 2002). Sunflower oil is very abundant in Egypt and represents the main oil used in significant effects in this model with regard to liver and kidney weights, serum glucose and insulin levels, and glucokinase activity. On the other hand, they significantly It was previously reported that rats fed HF diets for 3 improved glucose-6-phosphate dehydrogenase activity weeks exhibited moderate hepatic insulin resistance as and normalized glucose-6-phosphatase activity. These compared with rats fed HF diets for 6 weeks (Mithieux findings are consistent with the findings of Sugiyama et al. for pioglitazone effect on glucose-6-phosphatase al., 2002). The 6 weeks model was thus used in this study. Results demonstrated that the 6 week sunflower-rich diet activity and oppose their findings for pioglitazone on increased hepatic glucose output through several glucokinase activity, which showed increased hepatic mechanisms; significant reduction in hepatic glycogen glucokinase activity by pioglitazone. This may be deposition, stimulation of the gluconeogenic glucose-6- attributed to the differences in the insulin resistance phosphatase activity and decreased hepatic glucose model used, as Sugiyama et al. used genetically obese utilization through reducing the activities of the HMP Wistar rats (Sugiyama et al., 1990). For metformin, these shunt enzyme glucose-6-phosphate dehydrogenase and findings are consistent with those of Mithieux et al. (2002). The shift of glucose-6-phosphate flux to HMP shunt, mediated by reduction of glucose-6-phosphatase The molecular mechanisms behind high-fat diet-induced and increase in glucose-6-phosphate dehydrogenase, is glucose intolerance are still not fully revealed. However, also consistent with the findings of Kletzien et al. (1992) several mechanisms were postulated. One study for pioglitazone and Mithieux et al. (2002) for metformin correlated the increased glucose intolerance caused by (Kletzien et al., 1992; Mithieux et al., 2002). high-fat diet to the elevated levels of plasma NEFA However, it was noticeable that the decrease of glucose-6- (nonesterified fatty acids) (Wang et al., 2002). Others phosphatase activity was not accompanied by stimulation referred to the elevated circulating leptins, PPAR-gamma of hepatic glycogenesis. Rather, a remarkable decrease in genotype susceptibility, increased fatty acid oxidation in liver glycogen was observed for both drugs as compared muscles, and deficiency in muscle mitochondria (Ahren to normal and untreated HF animals. These data and Scheurink, 1998; Kadowaki et al., 2003; Bringolf et contradict the findings of Mithieux et al. for metformin al., 2005; Hancock et al., 2008). Özela et al. indicated and that of Sugiyama et al. for pioglitazone (Mithieux et that neither defects in insulin receptor function nor al., 2002; Sugiyama et al., 1990). In the former study elevated membrane glycoprotein PC-1 activities are liver glycogen content was dramatically increased by 3-5 involved in the development of insulin resistance in rats times by concomitant administration of 50 mg/kg/day with high-fat feeding, and the insulin resistance induced metformin with high-fat diet for 6 weeks. In the second with high-fat feeding is likely due to postreceptor defects study 0.3-3 mg/kg/d for 7 days pioglitazone enhanced in skeletal muscle (Özela et al., 1996). The door is still insulin-stimulated glycogen synthesis in genetically-obese hyperglycemic rats. Meanwhile, our results are consistent with the findings of Radziuk and Pye who reported the Pak. J. Pharm. Sci., Vol.23, No.3, July 2010, pp.305-312 Pioglitazone and metformin in glucose intolerance and diabetes decrease of both gluconeogenesis and glycogen synthesis effect on body weight, where metformin is known to by metformin and with those of Otto et al. who reported decrease or at least not to increase body weight and inhibition of glycogen synthesis by metformin in cultured pioglitazone is known to increase body weight via water rat hepatocytes (Radziuk and Pye, 2001; Otto et al., retention (Cheng and Fantus, 2005). The increase in kidney weight in STZ-HF Met group is correlated with Contradictory data for the metabolic effects of pioglitazone and metformin are not uncommon in STZ-HF rats showed increased glucose-6-phosphatase literature. One of the observed differences between activity associated with reduced activities of both pioglitazone and metformin is the more pronounced glucose-6-phosphate dehydrogenase and glucokinase reduction in body weight of rats on pioglitazone therapy. activities. This shift is mainly induced by the high These rats showed reduced rate of body weight gain from glucagon/insulin ratio in STZ animals. Similar to its effect in HF rats, metformin was able in STZ-HF rats to normalize glucose-6-phosphatase activity. This is To compare the effects of pioglitazone and metformin in consistent with the findings of Heishi et al., who found the diabetic state, rats were fed high-fat diet before STZ reduction of glucose-6-phosphatase gene expression injection and this feeding was continued throughout the associated with reduction of glucose-6-phosphatase study. High-fat feeding induced insulin resistance and activity in livers of obese diabetic db/db mice (Heishi et STZ injection induced partial β cell destruction and al., 2006). However, the insignificant effect of metformin insulin deficiency, giving a diabetic model similar to the on glucose-6-phosphate dehydrogenase activity pathophysiologic changes in type 2 diabetic human, being contradicts the findings of Ashokkumar et al. that preceded by insulin resistance state before β cell failure demonstrated the ability of metformin to restore glucose- and appearance of overt diabetes (Cheng and Fantus, 6-phosphate dehydrogenase activity almost to control levels. However, this experiment was done in neonatal STZ induced diabetic rats, where a single 100 mg/kg STZ With regard to the effects of pioglitazone and metformin injection was given to 2 days old rats (Ashokkumar et al., on diabetic rats, both drugs succeeded to reduce serum 2005). On the other hand, pioglitazone was able in STZ- glucose level elevated by STZ by ~30 %. This complies HF rats to increase glucose-6-phosphate dehydrogenase with the findings of Pavo et al. who reported comparable activity, similar to its effect on HF rats. improvement in glycemic control by pioglitazone and metformin in patients with type II diabetes (Pavo et al., Finally, our salient conclusions of this study are: 1) High-sunflower oil diet impairs glucose tolerance and disrupts carbohydrate metabolism via decreasing The decrease of glycogen content in liver (insulin hepatic glycogen content and impairing activities of dependent tissue) and the increase in kidneys (insulin glucose-6-phosphatase, glucose-6-phosphate dehy- independent tissue) in STZ animals well complies with previous reports (Gad et al., 2006). Only pioglitazone was 2) STZ induced diabetes caused marked elevation in able to reduce elevated renal glycogen content in STZ-HF serum glucose level associated with marked decrease rats. On the other hand, only metformin increased hepatic in serum insulin level and body weight, impairment glycogen content. These observations are similar to the of carbohydrate metabolism as demonstrated by findings of Okine et al. who observed an increase in dramatic decrease in hepatic glycogen content, hepatic glycogen content of STZ induced diabetic mice increase in renal glycogen content and impairment of after metformin administration (Okine et al., 2005). This activities of glucose-6-phosphatase, glucose-6- contradicts our findings of metformin effect on hepatic phosphate dehydrogenase and glucokinase. glycogen content of HF rats, suggesting that the inhibitory 3) In high-fat diet rats, metformin and pioglitazone had effect of metformin on glycogen synthesis is lost under almost similar effects; both activated glucose-6- phosphate flux to HMP shunt, mediated by reduction of glucose-6-phosphatase and increase in glucose-6- Previous studies have shown that STZ diabetic rats exhibited severe loss of body weight associated with a 4) In diabetic high-fat diet rats, metformin and significant increase in kidney weight as well as kidney pioglitazone equally depressed elevated serum weight to body weight ratio (Gad et al., 2006). These glucose level by ~30%. Pioglitazone therapy was alterations were also evident in our study. Reduced body associated with a decrease in renal glycogen and an weight of STZ-HF rats was further reduced by metformin, increase in glucose-6-phosphate dehydrogenase though not significant, and was slightly increased by activity. On the other hand, metformin therapy was pioglitazone. This is consistent with the well known associated with an increase in hepatic glycogen and properties of metformin and pioglitazone concerning their normalization of glucose-6-phosphatase activity. Pak. J. Pharm. Sci., Vol.23, No.3, July 2010, pp.305-312 Further comparative studies between pioglitazone and action of the Egyptian plants Fenugreek and Balanites. metformin are recommended on the metabolic, cellular Molecular and Cellular Biochemistry, 281: 173-183.
and molecular levels to show whether or not pioglitazone Hancock CR, Han DH, Chen M, Terada S, Yasuda T, has any added favorable actions than the cheaper, safer, Wright DC and Holloszy JO (2008). High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc. Natl. Acad. Sci. USA., 105(22):
Heishi M, Ichihara J, Teramoto R, Itakura Y, Hayashi K, This research is partially funded by Hormone Evaluation Ishikawa H, Gomi H, Sakai J, Kanaoka M, Taiji M and Department at National Organization of Drug Control and Kimura T (2006). Global gene expression analysis in Research (NODCAR), Cairo, Egypt. Metformin was liver of obese diabetic db/db mice treated with kindly supplied by CID Pharmaceuticals, Cairo, Egypt. metformin. Diabetologia, 49(7): 1647-1655.
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Microsoft word - sitagliptin

Sitagliptin Phosphate Set to Soar in Sales Main Bullet points: On June 26, 2012 Evaluate Pharma revealed its World Preview 2018 projections, which touted Sitagliptin Phosphate as a future blockbuster drug. Sitagliptin Phosphate (Januvia) is estimated to glean 10 billion dollars in sales annually by 2018. The patent for Januvia expires on April 24, 2017. By the year 20

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