topiramate and Insulin-Resistance

Patients with POAG have lower corneal endothelial cell density than healthy controls of the same age. This may be attributed to mechanical damage from elevated IOP and toxicity of glaucoma medications.. Mycophenolic acid was detected in all cats. The dose 10 mg/kg given q12h for 1 week was tolerated (n = 3). The efficacy of MMF as an immunosuppressant and long-term safety in cats of this dosage regimen is unknown.. T

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Long-term treatment with topiramate reduces body weight and improves insulin sensitivity in obese humans. Our aim was to evaluate the effect of topiramate treatment for 4 weeks on insulin sensitivity and secretion, independent of weight loss.. Randomized, double-blind, crossover, placebo-controlled study.. Thirteen obese (BMI 36.6 ± 1.3 kg/m(2) (mean ± s.e.m.)), insulin-resistant (homeostasis model of assessment-insulin resistance 2.0 ± 0.2) women received topiramate (T, maximum dose of 75 mg) and placebo (P) for 4 weeks, separated by a 4-week washout period. Insulin sensitivity and β-cell function were assessed using a two-step hyperinsulinemic euglycemic clamp with stable isotopes and a hyperglycemic clamp.. Hepatic and peripheral insulin sensitivities were not affected by topiramate treatment (glucose disposal rate (step 1 (insulin infusion rate 10 MU/M(2) per min) T: 17.5 ± 0.8 vs P: 18.5 ± 1.0 μmol/kg(LBM) per min, t=1.016, P=0.33; step 2 (insulin infusion rate 40 mU/m(2) per min) T: 27.9 ± 3.2 vs P: 28.8 ± 1.9 μmol/kg(LBM) per min, t=0.418, P=0.68)). Subjects lost a small amount of weight during the topiramate period (T: -1.0 ± 0.2 vs P: -0.1 ± 0.2 kg, t=2842, P=0.15). There were no changes in body fat mass, blood pressure, and fasting glucose. β-Cell function was not affected by topiramate as evidenced by an unaltered area under the curve of early (0-10 min; T: 1929.6 ± 265.7 vs P: 2024.7 ± 333.6 pmol/l, t=-0.357, P=0.73) and late (80-120 min; T: 28,017.7 ± 5029.9 vs P: 31,567.7 ± 5376.2 pmol/l, t=-1.481, P=0.16) phase insulin levels during hyperglycemia. The use of topiramate was associated with significant side effects such as paresthesia, nausea, dizziness, and concentration problems.. Low-dose topiramate treatment for 4 weeks, relative to placebo, had no significant effect on insulin sensitivity in overweight/obese adult females without established diabetes.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Double-Blind Method; Female; Fructose; Humans; Insulin; Insulin Resistance; Insulin Secretion; Middle Aged; Obesity; Topiramate; Young Adult

To examine the metabolic effects and body composition changes after topiramate treatment of obese type 2 diabetic patients (DM2) for 11 months.. Thirty-eight DM2 on diet or sulfonylurea treatment participated in this randomized double-blind placebo-controlled trial. Thirteen placebo-treated and nine topiramate-treated patients completed the trial. Patients were randomized to treatment with topiramate 96 mg b.i.d. or placebo (6-week run-in phase, 2-months titration phase, 9-months maintenance phase).. Insulin sensitivity was measured with euglycaemic hyperinsulinemic clamps. Weight, HbA1c, fasting glucose, blood lipids and safety variables were measured at regular intervals. Body composition was determined with computerized tomography. Meal tests were performed to evaluate postprandial glucose and insulin levels. Three-day diet recalls were carried out to evaluate energy ingestion.. The mean age was 58.6+/-7.1 years, body weight 98.1+/-16.1 kg, BMI 33.0+/-4.5 kg/m(2), and glycosylated hemoglobin (HbA1c) 7.3+/-0.9%. In topiramate-treated patients, there were significant reductions in HbA1c (1.1+/-0.9%), fasting plasma glucose, body weight (-6.6+/-3.3%), as well as body fat, lean body mass, postprandial glucose and free fatty acid levels but there were no significant changes in insulin sensitivity. The daily average energy intake decreased more in the topiramate group than in the placebo group. Paresthesia and central nervous system-related side effects were the main causes for the dropout rate.. Topiramate treatment of overweight DM2 reduced body weight and body fat, and was associated with a marked improvement in glycaemic control whereas no significant improvement in insulin-stimulated glucose uptake was demonstrated. Further studies are required to clarify whether this effect might occur through changes in insulin sensitivity in the liver and/or pancreatic insulin secretion.

Topics: Adipocytes; Adult; Aged; Anti-Obesity Agents; Body Composition; Cells, Cultured; Cytokines; Diabetes Mellitus, Type 2; Dietary Fats; Double-Blind Method; Drug Therapy, Combination; Female; Fructose; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Middle Aged; Obesity; Overweight; Placebos; Sulfonylurea Compounds; Topiramate; Weight Loss

To monitor weight regain after therapy discontinuation in patients with migraine experiencing weight loss during topiramate (TPM) treatment.. Patients with migraine without aura were enrolled in this observational prospective study. Weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, and ghrelin, and homeostatic model assessment of insulin resistance (HOMA-IR) were evaluated before starting TPM (T1), at 3 (T2) and 6 (T3) months of treatment and 6 months after withdrawal of TPM (T4). Weight loss/regain was considered as a change of 5% of pre-TPM body weight.. A total of 241 patients were analyzed. Of these, 87 (36%) patients experienced weight loss on TPM medication. During TPM therapy significant reductions in mean values of weight (p<0.001), BMI (p<0.001), waist circumference (p<0.01), HOMA-IR (p<0.01), and leptin (p<0.01) were observed. After TPM discontinuation, all of these parameters showed a clear trend to increase at T4, achieving pre-TPM values in 27 patients. Among potential predictors, only HOMA-IR before starting TPM (parameter estimate=1.36, effect size=0.75; p=0.006) was significantly associated with weight regain after therapy discontinuation.. Loss of body weight is a reversible effect, which at 6 months after TPM discontinuation shows a clear trend to return to baseline values. HOMA-IR is the only predictive factor of weight regain.

Topics: Adult; Body Mass Index; Central Nervous System Agents; Cholesterol; Female; Fructose; Humans; Insulin Resistance; Linear Models; Male; Migraine without Aura; Prognosis; Prospective Studies; Severity of Illness Index; Topiramate; Waist Circumference; Weight Gain; Weight Loss; Young Adult

Topiramate improves insulin sensitivity, in addition to its antiepileptic action. However, the underlying mechanism is unknown. Therefore, the present study was aimed at investigating the mechanism of the insulin-sensitizing effect of topiramate both in vivo and in vitro.. Male C57Bl/6J mice were fed a run-in high-fat diet for 6 weeks, before receiving topiramate or vehicle mixed in high-fat diet for an additional 6 weeks. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp. The extent to which the insulin sensitizing effects of topiramate were mediated through the CNS were determined by concomitant i.c.v. infusion of vehicle or tolbutamide, an inhibitor of ATP-sensitive potassium channels in neurons. The direct effects of topiramate on insulin signalling and glucose uptake were assessed in vivo and in cultured muscle cells.. In hyperinsulinaemic-euglycaemic clamp conditions, therapeutic plasma concentrations of topiramate (∼4 μg·mL(-1) ) improved insulin sensitivity (glucose infusion rate + 58%). Using 2-deoxy-D-[(3) H]glucose, we established that topiramate improved the insulin-mediated glucose uptake by heart (+92%), muscle (+116%) and adipose tissue (+586%). Upon i.c.v. tolbutamide, the insulin-sensitizing effect of topiramate was completely abrogated. Topiramate did not directly affect glucose uptake or insulin signalling neither in vivo nor in cultured muscle cells.. In conclusion, topiramate stimulates insulin-mediated glucose uptake in vivo through the CNS. These observations illustrate the possibility of pharmacological modulation of peripheral insulin resistance through a target in the CNS.

Topics: Animals; Anticonvulsants; Blood Glucose; Cell Line; Central Nervous System; Diet, High-Fat; Disease Models, Animal; Fructose; Infusions, Intraventricular; Insulin; Insulin Resistance; KATP Channels; Male; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Potassium Channel Blockers; Signal Transduction; Topiramate

Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis.

Topics: Analysis of Variance; Animals; Diet, High-Fat; Fructose; Glucose Tolerance Test; Glucose Transporter Type 2; Insulin Resistance; Intra-Abdominal Fat; Liver; Male; Organ Size; Protein-Tyrosine Kinases; Rats; Rats, Wistar; Receptors, Adiponectin; Topiramate; Tumor Necrosis Factor-alpha

Topiramate is newly approved as anticonvulsant that seems to promote body weight loss in humans. The present study was designed to evaluate the weight-controlling properties of topiramate in dietary obese female rats in comparison with sibutramine.. Fifty rats were assigned as normal, high fat diet (HFD), HFD + sibutramine (7.5 mg/kg, p.o.), HFD + topiramate (25 mg/kg, p.o.) and HFD + topiramate (50 mg/kg, p.o.). Body weight was registered, anxiety was tested in Vogel's test and blood pressure (BP) was measured. In addition, liver index, adipose tissue index, fasting blood glucose and serum lipid profile were measured in all groups. Further, serum insulin, leptin and adiponectin were determined.. Feeding with HFD induced a significant increase in body weight of rats as well as insulin resistance and serum lipids as compared to normal group (p<0.05). These measurements were suppressed by sibutramine treatment. However, a significant elevation in BP and anxiety behavior were detected as compared with HFD group (p<0.05). Topiramate (50 mg/kg, p.o.) group showed weight loss, improved insulin resistance, lessened anxiety behavior without influence on BP.. Our data ensures the findings that topiramate has a weight controlling properties with no anxiogenic or hypertensive effects. Further investigations are needed to determine the utility of topiramate in the clinical management of obesity.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Blood Pressure; Cyclobutanes; Female; Fructose; Insulin; Insulin Resistance; Leptin; Lipids; Obesity; Rats; Topiramate; Weight Loss

Topiramate is an anticonvulsant agent effective in the prophylaxis of migraine, which also induces weight reduction by an unknown mechanism. We investigated the effect of topiramate on metabolic and endocrine parameters in patients with migraine independently of any intention to lose body weight. Six patients (26-61 years old, body mass indices [BMI] 20.9-32.1 kg/m(2)) with migraine were treated with an average dose of 100 mg topiramate/day over a period of 20 weeks. The following parameters were measured every 4-8 weeks: BMI, body fat proportion, waist and hip circumference, HOMA insulin resistance, fasting serum-/plasma concentrations of adiponectin, leptin, ghrelin, vascular endothelial growth factor (VEGF), cortisol, interleukin-6 and tumor necrosis factor (TNF)-alpha. Profound metabolic changes were observed for the whole treatment period. Compared with the baseline value, 20 weeks of treatment reduced the BMI by 7.2+/-1.4%, body fat proportion by 11.6+/-3.6%, waist circumference by 4.2+/-1.2%, leptin by 39.2+/-6.5% and HOMA insulin resistance by 37.3+/-5%, while adiponectin was increased by 69.9+/-17.3% (P<0.05, respectively). VEGF concentrations increased during the week 2-4 by 177.4+/-39.4% (P<0.05) followed by a continuous decrease. There were trends for a reduction in ghrelin concentration, whereas cortisol, interleukin-6 and TNF-alpha values were unchanged. In summary, in this small sample of migraine patients topiramate treatment was associated with increased insulin sensitivity, increased adiponectin concentration and a reduction of body fat in all treated patients. The role of increased VEGF concentrations prior to these metabolic changes is not clear and might, hypothetically, involve a centrally mediated effect of topiramate on body weight regulation.

Topics: Adiponectin; Adipose Tissue; Adult; Anti-Obesity Agents; Anticonvulsants; Body Mass Index; Cytokines; Female; Fructose; Hip; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Migraine Disorders; Prospective Studies; Topiramate; Vascular Endothelial Growth Factors; Waist Circumference; Weight Loss

We aimed to investigate the effects of topiramate monotherapy on anthropometric indexes, insulin resistance, and serum leptin and lipid levels in 33 premenopausal women (mean age+/-standard deviation: 26.7+/-7.1years) with cryptogenic epilepsy. Body mass index (BMI), waist circumference and serum leptin, insulin and lipid levels were measured at baseline and at 6months after initiation of topiramate. We found reductions in BMI (p<0.001), waist circumference (p<0.001) and serum high-density lipoprotein (HDL) cholesterol levels (p=0.011). We also found significant improvements in insulin resistance (p=0.023), but not in serum leptin levels (p=0.45). Our results suggest that topiramate treatment in women with epilepsy is associated with reduced BMI and waist circumference and improvement in insulin resistance; however, according to our data, topiramate treatment is also associated with lower HDL cholesterol levels, which may substantially increase vascular disease.

Topics: Adolescent; Adult; Anthropometry; Anticonvulsants; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Epilepsy; Female; Fructose; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Topiramate; Young Adult

To explore the mechanism of topiramate-induced weight loss in epilepsy children by monitoring metabolism indices.. Children with epilepsy were treated with topiramate at their first clinical visit. Metabolism indices including body mass index (BMI) and its SD scores, leptin, adiponectin, leptin/adiponectin (L/A), lipid profile-insulin and Homeostasis Model Assessments (HOMA) index were collected before and after treatment.. Topiramate treatment significantly reduced L/A (t = 2.156, p = 0.031), and markedly increased the serum level of adiponectin (t = 3.124, p = 0.002). Moreover, there were no relationships between the metabolism indices and dosages of topiramate (p > 0.05).. Our studies find that topiramate treatment in epilepsy children increases energy metabolism, resulting in weight loss. It has been demonstrated that adiponectin play a significant role in metabolic regulations.

Topics: Adiponectin; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Body Weight; Case-Control Studies; Child; Epilepsy; Female; Fructose; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Metabolism; Statistics, Nonparametric; Topiramate

We have studied the in vivo and in vitro effects of Topiramate (TPM) in female Zucker diabetic fatty (ZDF) rats. After weight matching, drug treatment had a marked effect to lower fasting glucose levels of relatively normoglycemic animals as well as during an oral glucose tolerance test. The glucose clamp studies revealed a approximately 30% increased glucose disposal, increased hepatic glucose output (HGO) suppression from approximately 30 to 60%, and an increased free fatty acid suppression from 40 to 75%. Therefore, TPM treatment led to enhanced insulin sensitivity at the level of tissue glucose disposal (increased ISGDR), liver (increased inhibition of HGO), and adipose tissue (enhanced suppression of lipolysis). When soleus muscle strips of control or TPM-treated ZDF rats were studied ex vivo, insulin-stimulated glucose transport was not enhanced in the drug-treated animals. In contrast, when isolated adipocytes were studied ex vivo, a marked increase (+55%) in insulin-stimulated glucose transport was observed. In vitro treatment of muscle strips and rat adipocytes showed no effect on glucose transport in muscle with a 40% increase in insulin-stimulated adipocyte glucose transport. In conclusion, 1) TPM treatment leads to a decrease in plasma glucose and increased in vivo insulin sensitivity; 2) insulin sensitization was observed in adipocytes, but not muscle, when tissues were studied ex vivo or in vitro; and 3) TPM directly enhances insulin action in insulin-resistant adipose cells in vitro. Thus the in vivo effects of TPM treatment appear to be exerted through adipose tissue.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Deoxyglucose; Eating; Fatty Acids, Nonesterified; Female; Fructose; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Liver; Muscle, Skeletal; Ovary; Rats; Rats, Zucker; Topiramate

We show that Topiramate (TPM) treatment normalizes whole body insulin sensitivity in high-fat diet (HFD)-fed male Wistar rats. Thus drug treatment markedly lowered glucose and insulin levels during glucose tolerance tests and caused increased insulin sensitization in adipose and muscle tissues as assessed by euglycemic clamp studies. The insulin-stimulated glucose disposal rate increased twofold (indicating enhanced muscle insulin sensitivity), and suppression of circulating FFAs increased by 200 to 300%, consistent with increased adipose tissue insulin sensitivity. There were no effects of TPM on hepatic insulin sensitivity in these TPM-treated HFD-fed rats. In addition, TPM administration resulted in a three- to fourfold increase in circulating levels of total and high-molecular-weight (HMW) adiponectin (Acrp30). Western blot analysis revealed normal AMPK (Thr(172)) phosphorylation in liver with a twofold increased phospho-AMPK in skeletal muscle in TPM-treated rats. In conclusion, 1) TPM treatment prevents overall insulin resistance in HFD male Wistar rats; 2) drug treatment improved insulin sensitivity in skeletal muscle and adipose tissue associated with enhanced AMPK phosphorylation; and 3) the tissue "specific" effects are associated with increased serum levels of adiponectin, particularly the HMW component.

Topics: Adiponectin; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Blood Glucose; Dietary Fats; Fatty Acids, Nonesterified; Fructose; Glucose Clamp Technique; Insulin; Insulin Resistance; Liver; Male; Multienzyme Complexes; Muscle, Skeletal; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Topiramate