European Journal of Pharmacology 684 (2012) 161167

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European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Endocrine Pharmacology

Effects of topiramate on diabetes mellitus induced by streptozotocin in rats

Amani Nabil Shak
Department of Pharmacology, Faculty of Medicine, Cairo University, Egypt

a r t i c l e

i n f o

a b s t r a c t
Topiramate currently approved for marketing as antiepileptic drug also possesses anti-diabetic activity. The aim of this study was to determine the antidiabetic effect of topiramate in a rat model of diabetes mellitus. Diabetes was induced by a single injection of streptozotocin to fasted rats. Diabetic animals were divided into untreated; insulin treated; topiramate treated with 25, 50 and 100 mg/kg; and combined insulin plus topiramate treatment in the previous doses. All medications were given once daily started after the rise of blood glucose for three weeks. Control rats were divided into untreated; vehicle treated and rats given topiramate in the previous doses. Body weight, blood-glucose and insulin levels were measured. Histopathological examination, immunohistochemical and morphometric studies of islets of the pancreas were done. Topiramate 50 and 100 mg/kg resulted in a signicant decrease in the blood glucose and increase in the insulin levels as well as the number of islets and the count and mass of beta cells. Combined treatment to diabetic rats with insulin and topiramate induced a better response than either alone. Further experimental and clinical studies are needed to explore the different mechanisms of action of topiramate as antidiabetic both in insulin dependent and non-insulin-dependent diabetes mellitus. 2012 Elsevier B.V. All rights reserved.

Article history: Received 1 August 2011 Received in revised form 14 March 2012 Accepted 23 March 2012 Available online 3 April 2012 Keywords: Diabetes mellitus Pancreatic hormone receptor Streptozotocin Topiramate

1. Introduction The incidence and prevalence of diabetes mellitus have continued to increase globally, despite a great deal of research, with the resulting burden resting more heavily on tropical, developing countries. Diabetes mellitus is an endocrine disorder of carbohydrate metabolism resulting primarily from inadequate insulin release (type 1 insulin-dependent diabetes mellitus) or insulin insensitivity coupled with insufcient compensatory insulin release (type 2 noninsulin-dependent diabetes mellitus) (Wild et al., 2004). Besides insulin, glucagon, and pancreatic polypeptides, islets secrete L-glutamate, gamma aminobutyric acid (GABA) and somatostatin as paracrine-like modulators (Hayashi et al., 2003; Kanno et al., 2002; Moriyama and Hayashi, 2003). Although the modes of action of these paracrine modulators are less characterized, they recently showed that - and -cells of the pancreas communicate with each other through L-glutamate and GABA, which act as intercellular transmitters, to regulate precisely their endocrine functions (Moriyama and Hayashi, 2003). Topiramate is a novel therapeutic agent structurally unrelated to the other anticonvulsants, currently approved for marketing as an antiepileptic drug. It is a sulfamate-substituted monosaccharide, 2, 3:4, 5-bis-O-(1-methylethylid-ene)-beta-D-fructopyranose sulfamate;

interestingly, topiramate was invented during a search for new antidiabetic drug (Sachdeo, 2003). Although the precise mechanism of action of topiramate as antiepileptic drug is not known, studies have shown that topiramate seems to act through multiple mechanisms (Czapiski et al., 2005; Guerrini and Parmeggiani, 2006). Clinical studies reported that topiramate treatment reduced body weight and decreased fasting blood glucose levels in obese patients with or without type 2 diabetes (Eliasson et al., 2007; Myung et al., 2009). It is unclear whether the blood-glucose-normalizing phenomenon observed during topiramate treatment is an independent primary effect or the consequence of reduced food intake and weight loss (Liang et al., 2005). Based on the pharmacology, mechanisms and previous studies the present experiment was designed to demonstrate the blood glucose lowering effect of various doses of topiramate and whether this is through body weight lowering, insulin secretagogue or beta cell regenerating effects in streptozotocin induced diabetes mellitus in rats. 2. Material and methods 2.1. Experimental animals This study was approved by our institution's (kasr el eini hospital) Animal Care Committee and the guidelines were strictly adhered to. Male adult albino SpragueDawley rats, matched for age and weight (between 210 and 230 g), were used for the experiment. Rats

74 a tereet elzomor Haram Giza, Egypt. Tel.: + 20 1223507023. E-mail address: nabilamani123@hotmail.com. 0014-2999/$ see front matter 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2012.03.042

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were maintained on standard rat chow and tap water ad lib throughout the study; and were housed two per cage at room temperature. 2.2. Animal grouping

- Sodium citrate buffer: Fisher Scientic - 2-Deoxy-D-glucose (2-DG): Sigma Chemical Company - FLEX Polyclonal Guinea Pig Anti-Insulin kit: Life Trade Egypt Company under license of Dako Laboratories, Carpinteria, CA, USA 2.4. Measurements

The animals were randomly assigned into two main groups; the number of rats in each group represented the nal number after deaths. Group 1 Diabetes was induced by a single intraperitoneal injection of freshly dissolved streptozotocin (STZ) 60 mg/kg body weight in 0.1 M sodium citrate buffer, pH = 4.5 (Ganda et al., 1976; Zahra et al., 2008), to 18 h fasted rats. STZ is diluted in recently prepared Na-Citrate buffer immediately prior to injection to avoid degradation of the STZ. Animals with fasting blood glucose above 200 mg/dl were included in the study as diabetics (Mahmoud et al., 2009). In a pilot study, measurement of fasting serum glucose concentration 48 h after injection of STZ identied diabetes with massive hyperglycemia. Blood glucose levels were maintained elevated for three weeks after induction of diabetes. Topiramate solutions were prepared fresh by dissolving the powdered form of the drug in water. Diabetic animals (48 rats) were randomly divided into four groups. - Diabetic untreated rats (six rats). - Insulin treated diabetic rats: diabetic rats were treated by insulin NPH (Insulin Zinc suspension) 17 unit/kg/day subcutaneously once per day in the morning (Haughton et al., 1999), started after rise of blood glucose, for three weeks (six rats). - Topiramate treated diabetic rats: diabetic rats were treated by topiramate 25, 50 and 100 mg/kg (Jason et al., 2005; Kudin et al., 2004) in a volume of 3 ml water by oral gavage, started after the rise of blood glucose, once daily, for three weeks (18 rats). - Insulin + topiramate treated diabetic rats: diabetic rats were treated by insulin s.c. plus 25, 50 and 100 mg/kg topiramate (oral) started after the rise of blood glucose, once daily, for three weeks (18 rats). Death of some hyperglycemic animals was observed between days 2 and 4 post-STZ (60 mg/kg). Prior administration of 2-deoxy-Dglucose (2-DG), 0.5 ml intraperitoneally up to 30 min before STZ protects against its acute lethal -cytotoxicity (Ganda et al., 1976). Group 2 Control normoglycemic rats (30 rats): they were randomly divided into three groups. - Untreated rats were left to the end of the experiment for histopathological examination of the normal pancreas (six rats). - Normoglycemic rats were given equivalent volume of 0.1 M sodium citrate buffer (six rats). - Normoglycemic rats were given topiramate 25, 50 and 100 mg/kg (oral) for the whole length of the experiment (18 rats). 2.3. Drugs, reagents and solutions - Streptozotocin (STZ) powder: Sigma Chemical Company - Topiramate solutions were prepared fresh by dissolving the powdered form of the drug in water: Ortho-McNeil-Janssen Pharmaceuticals, Inc. - Insulin NPH (Insulin Zinc suspension): Novo Nordisk, Denmark

2.4.1. Body weight Body weight was measured in gram, at the start, 48 h, one week, two weeks and three weeks after STZ injection. 2.4.2. Biochemical parameter Blood samples (about 1 ml) were obtained from the retro-orbital sinus of the fasted animals using heparinized capillary tubes. Fresh samples were used for estimating fasting blood-glucose (mg/dl), using glucose enzymatic-colorimetric assay test (Diagnosticum Rt.). Samples were taken at the start of the experiment, 48 h, one week, two weeks and three weeks after STZ injection. Samples for determination of fasting serum insulin (ng/ml) were taken at the start (basal), 48 h after diabetes induction and at the end of the experiments. Serum was stored at 20 C and was analyzed using a Rat Insulin ELISA Kit (Crystal Chem Inc.). 2.4.3. Histological study Animals were killed by cervical dislocation at the end of the experiment. The pancreas was xed in Bouin's solution for 24 h, parafn-processed. Parafn-embedded sections were cut at 5 m and stained with hematoxylin and eosin (HE), and subjected to light microscopic examination (Drury and Wallington, 1980). 2.4.4. Immunohistochemical and morphometric study of islets Pancreatic section was mounted on separate slides coated with poly-L-lysine; sections were stained immunohistochemically with an indirect method using the labeled avidinstreptavidin method and guinea-pig anti-insulin serum. For all groups, negative controls were performed with substitution of the primary antibodies with phosphate-buffered saline (PBS) (Yavuz et al., 2003). Morphometric analysis was made by the point-counting method using an 8 8 mm grid (256 squares and 289 intersections) mounted on the eyepiece of the microscope. The islet proles were examined to estimate (a) the number of islets in each section of the pancreas, (b) the beta cell mass (mg), and (c) the number of b-cells of the pancreatic islets. All sections were blinded before quantitation. 2.5. Statistical analysis All values were expressed as mean S.D. obtained from a number of experiments (n). Computer package SPSS 9.0 was used for data management and analysis. ANOVA test was used for comparison between the groups in each study arm. Morphometric data were analyzed by the Student's t-test. Differences with P b 0.05 were considered to be statistically signicant. 3. Results 3.1. Body weight Prior to STZ administration, the average weight of the rats was 220 10.5 g. The body weight of control rats treated with citrate and topiramate 25 mg/kg remained unchanged, while control rats under topiramate 50 and 100 mg/kg showed a decrease in the body weight that started after 7 days continued for 14 days and gradually reaching near normal weights by 21 days (Table 1). The adult diabetic rats showed progressive signicant weight loss that started 48 h after diabetes mellitus was experimentally induced

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Table 1 Mean body weight in gram (mean S.D.) in the different groups studied. Body weight was measured at the start (basal) and after induction of diabetes mellitus with STZ 60 mg/kg. Treatment was started 48 h after induction of DM. Groups Mean body weight in g (mean S.D.) Basal (before diabetes induction) Control citrate Control topiramate (mg/kg) 220 10.50 25 50 100 190 12.75 25b 50a 100a 25 50 100 Time after diabetes induction/onset of treatment 48 h 218 11.0 1 week 220 7.90 219 8.50 207 11.00 205 10.85 175 11.50 200 12 .52 191 10.85 169 12.00 168 11.73 202 15.00 202 10.56 204 9.87 2 weeks 225 11.66 220 10.65 197 8.00a 199 7.50a 165 10.0 206 9.6 4 197 8.86 175 9.55 176 10 .05 205 12.44 207 13.55 205 15.00 3 weeks 218 8.05 218 9.50 208 10.35 209 7.9 3 143 10.55 210 13.46 205 10.65 191 11.85 190 12.55 215 10.58 211 10.60 210 15.00

Untreated DM a,c DM + insulin DM + topiramate (mg/kg)

DM + insulin + topiramate (mg/kg)

a b c

P b 0.05 versus basal level and controls. P b 0.05 versus basal level, control citrate and control topiramate 25 mg/kg. P b 0.05 versus treated DM with insulin alone and insulin + topiramate.

decreasing gradually over time to the end of the experimental period (Table 1). However, there was a gradual increase in the body weight of diabetic rats treated with either insulin alone or combined insulin plus topiramate with insignicant difference between groups. In diabetic rats treated with topiramate only, the dose of 25 mg/kg produced an insignicant effect on body weight, but topiramate 50 and 100 mg/kg produced a more decrease in the body weight continued without reaching the normal body weight until the end of the experiment (Table 1). 3.2. Blood glucose levels The mean fasting blood glucose level of normal rats was 105 7.45 mg/dl. After single intraperitoneal injection of STZ 60 mg/kg, the fasting blood-glucose showed maximum levels after 48 h that were maintained signicantly high in diabetic untreated rats to the end of the experiment. Treated control normal rats maintained a normal blood-glucose level throughout the experiment (Table 2). Treatment of diabetic rats produced a progressive signicant decrease in the blood-glucose levels; insulin administration induced improvement in the blood glucose concentrations without attainment of regular glucose values at the end of the experiment; while combined treatment with insulin + various doses of topiramate
Table 2 Mean fasting blood-glucose levels in mg/dl (mean S.D.) in the different groups studied. Groups

induced relevant progressive decrease in the blood-glucose levels reaching normal levels after three weeks of treatment (Table 2). Diabetic rats treated with topiramate alone showed the highest blood-glucose levels in comparison to other treated rats.

3.3. Blood insulin levels Fasting serum insulin levels in the control rats receiving either citrate buffer or various doses of topiramate demonstrated insignificant change from basal insulin level (2.9 0.14 ng/ml) all throughout the experiment (Fig. 1). A signicant decrease in the plasma insulin level to 0.53 0.08 ng/ml was observed 48 h after diabetes induction. This hypoinsulinemia was maintained to the end of the experiment. In contrast, administration of insulin to diabetic rats produced an increase in the plasma insulin level to reach 2.5 0.2 ng/ml after three weeks of treatment but without reaching basal insulin level (Fig. 1). In diabetic rats treated with topiramate alone, dose of 25 mg/kg resulted in an insignicant increase in blood insulin level while 50 and 100 mg/kg caused a signicant increase when measured after three weeks of treatment. In addition, diabetic rats treated with insulin plus topiramate demonstrated higher insulin levels at the end of the experiment period (Fig. 1).

Mean blood glucose levels (mg/dl, mean S.D.) Basal (before diabetes induction) Time after diabetes induction/onset of treatment 48 h 106 6.82 1 week 107 5.84 105 4.54 110 6.67 108 6.85 347 33.78 197 19.58 340 25.56 300 20.80 296 18.45 199 18.54a 200 15.67a 198 15.00a 2 weeks 105 6.90 106 7.50 108 3.55 102 8.67 369 35.00 183 27.34 335 32.58 260 30.50 245 25.56 169 27.45a 170 19.78a 165 23.58a 3 weeks 105 5.50 109 4.58 107 5.87 108 4.67 375 40.65 140 22.00d 328 28.97 241 25.55d 223 27.50d 115 16.55d 110 13.95d 101 10.60d

Control citrate Control topiramate (mg/kg)

105 7.45 25 50 100

Untreated DMa DM + insulina DM + topiramatea,b (mg/kg)

387 35.70 25 50 100 25 50 100

c

DM + insulin + topiramateb (mg/kg)

a b c d

P b 0.05 versus basal level and controls. P b 0.05 versus untreated DM. P b 0.05 versus treated groups. P b 0.05 versus treated DM after 1 and 2 weeks.

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Fig. 1. Blood insulin levels measured at the end of the experiment in the different groups studied. Results are shown as mean S.D. *P b 0.05 versus other groups. P b 0.05 versus untreated diabetes and diabetes + topiramate.

3.4. Histological study Rats were killed at the end of the study for histopathological examination of the pancreas (only sections containing eight or more islets were selected for evaluation). Sections of the pancreas revealed regular beta cell granules in the normal and control groups of rats (Fig. 2A). In untreated diabetic rats, changes were evident 21 days after STZ 60 mg/kg, in the form of a reduction in the number of pancreatic islets that were irregularly shaped, and appeared relatively small and atrophic. The beta-cells appeared small, degranulated, with marked vacuolation and dark scanty cytoplasm (Fig. 2B). On the contrary, histopathological examination of the topiramate alone and insulin plus topiramate treated diabetic rats revealed a variable degree of improvement in the number of pancreatic islets and degree of vacuolations (Fig. 2C). 3.5. Immunohistochemistry Immunohistochemical staining using an anti-insulin antibody demonstrated no change in the count of beta cells/islet in control rats (Fig. 3A), while the untreated rats receiving STZ demonstrated a signicant decrease in the number of beta cells/islet with signicant decrease in the insulin expression (Fig. 3B). Treatment of diabetic rats with insulin only or topiramate 25 mg/kg did not result in a signicant increase in the count of beta cells; while 50 and 100 mg/kg of topiramate alone or combined with insulin improved both the reduced beta-cell number and insulin expression to near those of control rats (Fig. 3C). 3.6. Morphometric analysis The number of pancreatic islets per unit area as well as the number of beta-cells/islet were signicantly increased (P b 0.05) in rats treated with topiramate 50 and 100 mg/kg alone or combined with insulin compared with diabetic untreated rats. Moreover, a signicant increase in the mass of endocrine tissue was observed in topiramate treated animals (Table 3). 4. Discussion In this study, the weight, the levels of blood glucose and insulin, immunohistochemical and morphometric analysis after using a 60 mg/kg dose of STZ ensured induction of diabetes in rats. All these parameters were seen in adult rats within two days of STZ administration and were maintained in untreated rats all throughout

Fig. 2. Light microscopy of the pancreas (H and E, 400) of: A. control groups showing normal pancreatic islet with cluster of beta-cells. B. STZ-induced diabetic rats showing degranulation of beta-cells and severe vacuolation of the pancreatic islets. C. Recovery of the beta-cells evident in topiramate alone and insulin + topiramate treated diabetic rats with variable degrees. The islet cells are regenerated, and there is a reduction in the vacuolation caused by administration of STZ.

the study which indicated irreversible destruction of islets of Langerhans' cells. Administration of insulin NPH once daily to diabetic rats resulted in a gradual increase in rat's body weight, improvement in bloodglucose concentration. A rise in blood insulin level was observed but without improvement in the count of beta cells/islet. All parameters did not reach normal initial levels after three weeks of treatment with insulin. Haughton et al. (1999) concluded that all insulin regimens given to STZ-induced diabetic rat model induced weight gain at least comparable to that of controls, but glucose regulation differed. Attempted normalization of glucose values was limited by hypoglycemia (Kaleem et al., 2008). Following insulin treatment, body weight started to rise; this could be attributed to the insulin role in promoting lipogenesis as well as its inhibitory role on protein catabolism (positive nitrogen balance) and insulin increases leptin release from adipocytes (Mueller et al., 1998; Rentsch and Chiesi, 1996).

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Fig. 3. Immunohistochemistry staining of the pancreatic tissues (400) of: A. control normal rats showing beta-cells that are intensely stained by the anti-insulin antibody. B. STZ-induced diabetic rats showing beta-cells weakly stained for insulin. C. Treated diabetic rats with topiramate 50 and 100 mg/kg alone and combined with insulin showing moderate staining of insulin.

From the present results, topiramate 25 mg/kg produced no effect on rat's body weight, minimal signicant lowering effect on bloodglucose with no effect on serum insulin or count of beta cells/islet of
Table 3 Morphometric analysis (mean S.D.) of pancreases from rats in the different groups studied. Groups Control citrate Control topiramate (mg/kg) Untreated DMa,c DM + insulina,c DM + topiramatea (mg/kg) DM + insulin + topiramate (mg/kg)
a b c

Number of islets/mm2 25 50 100 3.5 0.1 3.5 0.16 3.3 0.2 3.5 0.2 1.6 0.2 1.7 0.3 1.65 0.1 2.4 0.1 2.5 0.2 1.75 0.2 2.8 0.1 2.9 0.3

Beta-cell mass (mg) 15.7 0.43 15.1 0.26 15.4 0.32 15.5 0.31 5.5 0.24 6 0.25 5.3 0.15 8.5 0.14 10.2 0.21 6.5 0.12 12.0 0.26 12.5 0.31

Beta-cell number/islet 160 12.5 158 10.9 162 9.7 160 10.7 58 7 65 6 62 6.8 80 5.9 95 9.7 65 6.7 140 10.5 147 12.4

25c 50b 100b 25a,c 50b 100b

P b 0.05 versus controls. P b 0.05 versus untreated DM and DM + insulin. P b 0.05 versus treated groups with 50 and 100 mg/kg topiramate.

diabetic rats. While topiramate 50 and 100 mg/kg lowered body weight of control and diabetic rats and blood glucose, increase serum insulin level and count of beta cells/islet were evident more with topiramate 100 mg/kg per day. It is clear from the study that the blood glucose-lowering effect observed during topiramate treatment is a primary effect not a consequence of reduced weight as evident by the negative correlation between rat's body weight and blood-glucose level in response to various doses of topiramate. The doses of topiramate selected 25100 mg/kg per day were equivalent to 0.6252.5 times the recommended human dose (RHD) which is 400 mg/day on a mg/m 2 basis according to topiramate (Topiramate) material safety data sheet supplied by the Santa Cruz Biotechnology in 2009. Furthermore the oral rat lowest published toxic dose (TDLo) is 100 mg/kg per day. These doses were selected to obtain a broader range of information on the effects of topiramate on body weight, blood glucose, serum insulin and count of beta cells/islet as the plasma concentration and hence the effect of topiramate may be expected to increase in proportion to the dose administered (Report on the Deliberation Results, 2007). Recent studies reported the activity of topiramate on body weight loss, increase in energy expenditure and peripheral sensitization to insulin action (Krymchantowski and Tavares, 2004). Topiramate has been reported to cause a decrease in the body weight in some epileptic patients receiving topiramate during clinical evaluation, in obese patients with or without type 2 diabetes and in post-marketing clinical studies (Eliasson et al., 2007; Myung et al., 2009). In a study by Liang and his co-workers, they chronically treated female Zucker diabetic fatty (ZDF) rats (fed with a diabetogenic diet) and db/db mice with topiramate (30300 mg/kg per day). The data showed that topiramate treatment markedly reduced blood-glucose levels in both ZDF rats and db/db mice without a signicant reduction in body weight gain. The data suggested that topiramate treatment reduce blood-glucose concentrations in female ZDF rats independently of weight loss. Jason et al. (2005) found the same results in ZDF rats, and they concluded that topiramate treatment leads to a decrease in plasma glucose and increased in vivo insulin sensitivity; insulin sensitization was observed in adipocytes, but not muscle when tissues were studied ex vivo or in vitro and topiramate directly enhances insulin action in insulin-resistant adipose cells in vitro. Alberto et al. (2011) reported a case of unusually long-lasting remission of type 1 diabetes in a patient with generalized seizures treated with oral topiramate that was added to preexisting valproic acid and maintained thereafter. The pancreatic islet secretes neurotransmitters and modulates hormone secretion (Suckow et al., 2006) for regulating blood glucose. Islet cells are composed of at least four kinds of cells: glucagon-secreting alpha-cells, insulin-secreting beta-cells, somatostatin-secreting deltacells, and pancreatic polypeptide-secreting F-cell (Kanno et al., 2002; Maechler and Wollheim, 2001; Moriyama and Hayashi, 2003). In -cells, GABA an inhibitory neurotransmitter is stored in synaptic-like secretory microvesicles, distinct from insulin granules (Garry et al., 1986) and secreted through exocytosis (Chessler et al., 2002). Glutamate decarboxylase, and GABA transaminase have as well been found in beta-cells (Hyung and Hyoung, 2000). The released GABA seems to bind to ionotropic GABAA receptors on -cells, resulting in an inhibition of glucagon secretion (Bailey et al., 2007; Xu et al., 2006) in addition binds to metabotropic GABAB receptors on beta-cells to stimulate release of insulin (Brice et al., 2002). GABA or its agonist inhibits the release of somatostatin, which is produced by the pancreatic D-cells by binding to somatostatin receptors (Kimura et al., 2001). Studies have shown that topiramate augments the activity of the neurotransmitter GABA at some subtypes of the GABAA receptor,

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indicating a possible mechanism through potentiation of the activity of GABA (Guerrini and Parmeggiani, 2006; Herrero et al., 2002). Topiramate also demonstrates antagonism of the -amino-3hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) kainate subtype of the glutamate excitatory amino acid receptor (Gibbs et al., 2002). The islet of Langerhans contains in addition L-glutamate, which is the major excitatory neurotransmitter of the central nervous system. Islet cells express ionotropic (iGluRs) and metabotropic glutamate receptors (mGluRs) (Brice et al., 2002; Uehara et al., 2004), named after agonists who bind to them: -amino-3-hydroxyl-5-methyl-4isoxazole-propionate (AMPA) and N-methyl-D-aspartate (NMDA). The pancreatic cells possess all components of a glutamate system. Therefore, these glutamate systems can be called peripheral glutamatergic systems (Hayashi et al., 2001; Moriyama et al., 2000). Glutamate receptors -amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) ionotropic glutamate receptors (iGluRs) modulate the secretion of insulin and glucagon in the pancreas, opening the possibility of treatment of diabetes via glutamate receptor antagonists (Ivan et al., 2008). Activation of ionotropic glutamate receptors (iGluRs) leads to an increase in cytosolic Ca 2+ concentration ([Ca 2+]i). If these receptors are over stimulated, the sustained increase in ([Ca 2+]i) can induce cell dysfunction and ultimately lead to cell death (Duchen, 2000). In diabetes, cumulative evidence shows that Ca 2+ homeostasis may be impaired, and defects in Ca 2+ regulation in several tissues, including the nervous system, have been reported (Biessels et al., 2002). The protective effects of topiramate on pancreatic beta-cells could be explained by enhanced capacity of lipid clearance as topiramate inhibits the activity of lipoprotein lipase in different white adipose tissue depots, accounting for the reduction in fat deposition (Francesca et al., 2006; Ravnskjaer et al., 2005; Richard et al., 2000). Topiramate may thereby indirectly improve beta-cell function through these metabolic effects in addition to direct trophic effects on the beta cell. Demonstration of neogenesis in animal models does not necessarily mean that an agent is neogenic in humans (Service et al., 2005). 5. Conclusions In conclusion, topiramate raises new hope as an antidiabetic agent by its body weight lowering effect, insulin secretagogue and sensitization and regeneration of pancreatic beta cells. Further experimental and clinical studies are needed to explore the different mechanisms of action of topiramate in various doses as antidiabetic both in insulin dependent and non-insulin-dependent diabetes mellitus. References
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