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Thiazolidinediones
Kinds of Thiazolidinediones Selected AbstractsSwitch to oral hypoglycemic agent therapy from insulin injection in patients with type 2 diabetesGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 4 2008Takashi Okamoto Aim: We aimed to determine the feasibility of substituting thiazolidinedione-based therapy for insulin injection therapy in patients with type 2 diabetes. Methods: Thirty-six subjects (17 men and 19 women) aged 67.8 ± 11.3 years with an average insulin dose of 0.46 ± 0.17 U/kg bodyweight, a duration of insulin therapy of 6.1 ± 8.2 years and an average hemoglobin A1c (HbA1c) of 6.8 ± 1.3% were switched from insulin injection therapy to pioglitazone, glimepiride and voglibose combination therapy. Results: The number of subjects achieving HbA1c levels of less than 7% at 4 months was 30. The success rate of switch therapy was 83% (30/36). HbA1c was significantly reduced from 6.7 ± 1.3% to 5.9 ± 0.7% at 4 months after the switch (P < 0.01) in 32 patients who completed the planned 4-month study. No adverse effects including heart failure, liver dysfunction or severe hypoglycemia were observed. The insulin dose and the maximum blood glucose on the switch day were significantly lower and the age was significantly higher in the subjects who achieved HbA1c less than 7% at 4 months compared to those who did not (P < 0.05). Conclusion: Thiazolidinedione-based oral combination therapy may efficiently and safely substitute relatively high-dose insulin injection therapy in patients with type 2 diabetes. [source] ChemInform Abstract: Synthesis and in vivo Antidiabetic Activity of Novel Dispiropyrrolidines Through [3 + 2] Cycloaddition Reactions with Thiazolidinedione and Rhodanine Derivatives.CHEMINFORM, Issue 40 2009Ramalingam Murugan Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Weight changes following the initiation of new anti-hyperglycaemic therapiesDIABETES OBESITY & METABOLISM, Issue 1 2007G. A. Nichols Objective:, The objective of this study was to quantify 1-year weight gain associated with the initiation of sulphonylurea (SU), metformin, insulin and thiazolidinedione (TZD) therapy in a representative real world population of type 2 diabetic patients. Research Design and Methods:, The study population was 9546 members of Kaiser Permanente North-west (KPNW) who initiated an anti-hyperglycaemic drug between 1996 and 2002 and continued use of that drug for at least 12 months without adding other therapies. Change in weight was calculated as the annualized difference between baseline and follow-up weight and was adjusted for demographic and clinical characteristics. We then compared the weight changes observed in patients newly initiating SU, metformin, insulin and TZD therapies. Results:, After adjustment for demographic and clinical characteristics that might affect weight change, metformin initiators lost an average of 2.4 kg while all other groups gained weight. SU initiators gained the least (1.8 kg), followed by insulin initiators (3.3 kg) and TZD subjects (5.0 kg). All comparisons were highly statistically significant. Conclusions:, In an observational study of 1-year weight changes following the initiation of SUs, metformin, insulin or TZDs, we found similar but somewhat smaller weight changes than those previously reported in clinical trials. Our observed weight changes could not be explained by the many other factors we tested and seemed to apply across the full spectrum of diabetes patients. Our report provides valuable information that will allow the patient and clinician to anticipate, and perhaps address, expected weight changes that accompany the initiation of anti-hyperglycaemic drugs. [source] Combination therapy using metformin or thiazolidinediones and insulin in the treatment of diabetes mellitusDIABETES OBESITY & METABOLISM, Issue 6 2005Suzanne M. Strowig The biguanide, metformin, sensitizes the liver to the effect of insulin, suppressing hepatic glucose output. Thiazolidinediones such as rosiglitazone and pioglitazone enhance insulin-mediated glucose disposal, leading to reduced plasma insulin concentrations. These classes of drugs may also have varying beneficial effects on features of insulin resistance such as lipid levels, blood pressure and body weight. Metformin in combination with insulin has been shown to significantly improve blood glucose levels while lowering total daily insulin dose and body weight. The thiazolidinediones in combination with insulin have also been effective in lowering blood glucose levels and total daily insulin dose. Triple combination therapy using insulin, metformin and a thiazolidinedione improves glycaemic control to a greater degree than dual therapy using insulin and metformin or insulin and a thiazolidinedione. There is insufficient evidence to recommend the use of metformin or thiazolidinediones in type 1 diabetic patients. Although these agents are largely well tolerated, some subjects experience significant gastrointestinal problems while using metformin. Metformin is associated with a low risk of lactic acidosis, but should not be used in patients with elevated serum creatinine or those being treated for congestive heart failure. The thiazolidinediones are associated with an increase in body weight, although this can be avoided with careful lifestyle management. Thiazolidinediones may also lead to oedema and are associated with a low incidence of hepatocellular injury. Thiazolidinediones are contraindicated in patients with underlying heart disease who are at risk of congestive heart failure and in patients who have abnormal hepatic function. The desired blood glucose-lowering effect and adverse event profiles of these agents should be considered when recommending these agents to diabetic patients. The potential for metformin or the thiazolidinediones to impact long-term cardiovascular outcomes remains under investigation. [source] Switch to oral hypoglycemic agent therapy from insulin injection in patients with type 2 diabetesGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 4 2008Takashi Okamoto Aim: We aimed to determine the feasibility of substituting thiazolidinedione-based therapy for insulin injection therapy in patients with type 2 diabetes. Methods: Thirty-six subjects (17 men and 19 women) aged 67.8 ± 11.3 years with an average insulin dose of 0.46 ± 0.17 U/kg bodyweight, a duration of insulin therapy of 6.1 ± 8.2 years and an average hemoglobin A1c (HbA1c) of 6.8 ± 1.3% were switched from insulin injection therapy to pioglitazone, glimepiride and voglibose combination therapy. Results: The number of subjects achieving HbA1c levels of less than 7% at 4 months was 30. The success rate of switch therapy was 83% (30/36). HbA1c was significantly reduced from 6.7 ± 1.3% to 5.9 ± 0.7% at 4 months after the switch (P < 0.01) in 32 patients who completed the planned 4-month study. No adverse effects including heart failure, liver dysfunction or severe hypoglycemia were observed. The insulin dose and the maximum blood glucose on the switch day were significantly lower and the age was significantly higher in the subjects who achieved HbA1c less than 7% at 4 months compared to those who did not (P < 0.05). Conclusion: Thiazolidinedione-based oral combination therapy may efficiently and safely substitute relatively high-dose insulin injection therapy in patients with type 2 diabetes. [source] Avandamet: combined metformin,rosiglitazone treatment for insulin resistance in type 2 diabetesINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 9 2004C.J. Bailey Summary Insulin resistance is a major endocrinopathy underlying the development of hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance, acting by different cellular mechanisms. The two agents can be used in combination to achieve additive glucose-lowering efficacy in the treatment of type 2 diabetes, without stimulating insulin secretion and without causing hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and markers, indicating a lower cardiovascular risk. Early intervention with metformin is already known to reduce myocardial infarction and increase survival in overweight type 2 patients. Recently, a single-tablet combination of metformin and rosiglitazone, Avandamet, has become available. Avandamet is suitable for type 2 diabetic patients who are inadequately controlled by monotherapy with metformin or rosiglitazone. Patients already receiving separate tablets of metformin and rosiglitazone may switch to the single-tablet combination for convenience. Also, early introduction of the combination before maximal titration of one agent can reduce side effects. Use of Avandamet requires attention to the precautions for both metformin and rosiglitazone, especially renal, cardiac and hepatic competence. In summary, Avandamet is a single-tablet metformin,rosiglitazone combination that doubly targets insulin resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes. [source] Correlates of trabecular and cortical volumetric bone mineral density of the radius and tibia in older men: The osteoporotic fractures in men studyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2010Kamil E Barbour Abstract Quantitative computed tomography (QCT) can estimate volumetric bone mineral density (vBMD) and distinguish trabecular from cortical bone. Few comprehensive studies have examined correlates of vBMD in older men. This study evaluated the impact of demographic, anthropometric, lifestyle, and medical factors on vBMD in 1172 men aged 69 to 97 years and enrolled in the Osteoporotic Fractures in Men Study (MrOS). Peripheral quantitative computed tomography (pQCT) was used to measure vBMD of the radius and tibia. The multivariable linear regression models explained up to 10% of the variance in trabecular vBMD and up to 9% of the variance in cortical vBMD. Age was not correlated with radial trabecular vBMD. Correlates associated with both cortical and trabecular vBMD were age (,), caffeine intake (,), total calcium intake (+), nontrauma fracture (,), and hypertension (+). Higher body weight was related to greater trabecular vBMD and lower cortical vBMD. Height (,), education (+), diabetes with thiazolidinedione (TZD) use (+), rheumatoid arthritis (+), using arms to stand from a chair (,), and antiandrogen use (,) were associated only with trabecular vBMD. Factors associated only with cortical vBMD included clinic site (,), androgen use (+), grip strength (+), past smoker (,), and time to complete five chair stands (,). Certain correlates of trabecular and cortical vBMD differed among older men. An ascertainment of potential risk factors associated with trabecular and cortical vBMD may lead to better understanding and preventive efforts for osteoporosis in men. © 2010 American Society for Bone and Mineral Research [source] Latest news and product developmentsPRESCRIBER, Issue 7 2008Article first published online: 28 APR 200 Referrals from Boots The majority of people requesting Boots' erectile dysfunction or weight management programmes are referred to their GP(Pharm J 2008;280:297). The programmes are run under patient group directions and exclude people with elevated blood pressure, blood glucose or cholesterol. Over 80 per cent of customers screened for the erectile dysfunction programme in Manchester and two-thirds of those screened for the national obesity programme were referred. Vildagliptin: new DPP-4 inhibitor for diabetes Novartis has introduced the DPP-4 inhibitor vildagliptin for the treatment of type 2 diabetes. Two formulations are available: Galvus (vildagliptin 50mg) is licensed for use with metformin, a sulphonylurea or a thiazolidinedione when these agents do not achieve glycaemic control alone, and Eucreas (vildagliptin 50mg plus metformin 850 or 1000mg) is licensed for patients requiring combined therapy with vildagliptin and metformin. Inhibition of DPP-4 blocks the breakdown of the incretin hormones GIP and GLP-1, reducing fasting plasma glucose and postprandial hyperglycaemia. Vildagliptin is the second DPP-4 inhibitor to be introduced; the first was sitagliptin (Januvia), which has similar licensed indications. The third available drug acting on the incretin system is the incretinmimetic exenatide (Byetta); administered by injection, this is licensed for use with metformin and/or a sulphonylurea and is the only agent in this class to be approved for triple therapy. No comparative trials of these agents have been published. A month's treatment with twice-daily vildagliptin 50mg or either strength of vildagliptin plus metformin costs £31.76. Sitagliptin 100mg once daily costs £33.26. Sinusitis symptoms don't guide treatment The severity and duration of symptoms do not help to identify which patients with sinusitis will be helped by antibiotics, a new meta-analysis suggests (Lancet 2008;371: 908-14). The analysis of patient-level data from nine trials involving a total of 2547 adults showed that the number needed to treat (NNT) to cure one patient with rhinosinusitis was 15. Cure took longer to achieve in older patients and in those reporting symptoms for longer or with more severe symptoms. The authors comment that treatment is not justified given the risk of resistance and adverse effects and cost of antibiotics. Draft guidance from the National Institute for Health and Clinical Excellence (NICE) on the management of respiratory infections states that no antibiotic therapy or a delayed antibiotic prescribing strategy should be negotiated for patients with acute sinusitis. Taking cod liver oil leads to fewer NSAIDs Cod liver oil could help some patients with rheumatoid arthritis to reduce their NSAID consumption, according to a study from Dundee (Rheumatology online: 24 March 2008; doi: 10.1093/rheumatology/ ken024). A total of 97 patients were randomised to nine months' treatment with cod liver oil 10g per day or placebo. After 12 weeks, patients attempted to reduce or stop their use of NSAIDs. Significantly more of those taking cod liver oil achieved at least a 30 per cent reduction in NSAID use compared with placebo (39 vs 10 per cent). There were no differences in adverse effects or disease activity. Welsh prescriptions up The reduction in the prescription charge in Wales in 2004 was followed by an increase in prescribing of nonsedating antihistamines in wealthier areas, a study suggests (Health Policy online: 5 March 2008; doi:10.1016/j. healthpol.2008.01.006). In the two years preceding the cut, prescriptions for nonsedating antihistamines increased by about 7 per cent; in the two years after the cut, the increase was nearly 14 per cent. By contrast, there was no change in the rate of increase in the south-east of England (4,5 per cent in both periods). The increased growth in prescribing was statistically significant in the five least deprived but not in the five most deprived health boards in Wales. Aspirin linked with reduced asthma risk Low-dose aspirin is associated with a reduced risk of developing asthma, a new analysis of the Women's Health Study has shown (Thorax online: 13 March 2008; doi:10.1136/ thx.2007.091447). The analysis included 37 270 women with no asthma at baseline who were randomised to take placebo or aspirin 100mg every other day. After 10 years, 872 cases of asthma occurred in women taking aspirin and 963 with placebo, a 10 per cent reduction in risk. However, risk was not reduced in obese women. The mechanism by which aspirin may affect the risk of asthma is unknown. The latest evidence is consistent with findings published by the same investigators after analysis of two other large observational studies, the Physicians' Health Study and the Nurses Health Study. Anastrozole bone loss Long-term follow-up of the ATAC (Anastrozole, Tamoxifen, Alone or in Combination) trial has confirmed that adjuvant therapy with anastrozole (Arimidex) is associated with greater loss of bone mineral density (BMD) than tamoxifen in postmenopausal women with invasive primary breast cancer (J Clin Oncol 2008;26: 1051,7). After five years, median BMD was reduced by 6 and 7 per cent in the lumbar spine and hip with anastrozole compared with approximately 3 and 1 per cent respectively for tamoxifen, though no patients developed osteoporosis. Copyright © 2008 Wiley Interface Ltd [source] Rapid induction of peroxisome proliferator,activated receptor , expression in human monocytes by monosodium urate monohydrate crystalsARTHRITIS & RHEUMATISM, Issue 1 2003Tohru Akahoshi Objective Peroxisome proliferator,activated receptor , (PPAR,) is a member of the nuclear hormone receptor superfamily and functions as a key regulator of lipid and glucose metabolism, atherosclerosis, and inflammatory responses. This study was undertaken to evaluate the biologic role of PPAR, in self-limiting episodes of acute gouty arthritis. To do this, we investigated PPAR, expression by monosodium urate monohydrate (MSU) crystal,stimulated monocytes, and we studied the effects of PPAR, ligands on crystal-induced acute inflammation. Methods PPAR, expression by MSU crystal,stimulated human peripheral blood mononuclear cells was determined by reverse transcription,polymerase chain reaction and immunostaining. Expression of CD36 on monocytes was detected by flow cytometric analysis. The effects of PPAR, ligands on in vitro crystal-induced cytokine production and on in vivo cellular infiltration during crystal-induced acute inflammation were also investigated. Results MSU crystals rapidly and selectively induced PPAR, expression by monocytes. Gene expression was detected as early as 2 hours, and maximum expression was observed at 4 hours after stimulation. The induced PPAR, was functional, since a PPAR, ligand was able to up-regulate CD36 expression on monocytes. A natural ligand of PPAR,, 15-deoxy-,12,14 -prostaglandin J2 (15deoxy-PGJ2), significantly reduced the crystal-induced production of cytokines by monocytes. Indomethacin inhibited cytokine production only at high concentrations, and an antidiabetic thiazolidinedione (troglitazone) failed to exert significant effects. Administration of troglitazone and 15deoxy-PGJ2 significantly prevented cellular accumulation in a mouse air-pouch model of MSU crystal,induced acute inflammation. Conclusion Rapid induction of PPAR, expression on monocytes by MSU crystals may contribute, at least in part, to the spontaneous resolution of acute attacks of gout. [source] ThiaZolidineDiones and the Influence of Media Adverse Reporting on Prescribing Attitudes in PraCTice (TZD-IMPACT) StudyCARDIOVASCULAR THERAPEUTICS, Issue 2 2009Jacob George Prescribing behavior may be linked to media influence rather than to scientific evidence. Recently, the oral diabetic drug class of thiazolidinedione has been under the spotlight because of concerns over their cardiovascular safety. We have therefore conducted an electronic questionnaire survey among prescribing physicians in Tayside, Scotland to evaluate the prescribing attitudes and knowledge of the available evidence regarding the cardiovascular safety of thiazolidinedione use. Nationally representative prescribing data thoughout Scotland and Tayside from the IMS Health RSA dataset were also examined. Prescriptions for rosiglitazone alone or in combination with metformin have steadily decreased since the publication of a meta-analysis suggesting harm from rosiglitazone. This was mirrored by a gradual increase in prescriptions of pioglitazone. However, when questioned, the majority of doctors rate the level of information received regarding drug safety information on thiazolidinediones to be low with 68% of respondents scoring 5 or less (scale 1,10) on the level of information received. The source of information regarding drug safety warning was highly varied ranging from journals (21%), scientific meetings (19%) and the news media (15%). The findings of this study clearly show a need to disseminate reliable drug safety information more effectively to prescribers. [source] An antidiabetic thiazolidinedione induces eccentric cardiac hypertrophy by cardiac volume overload in ratsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2004Kenji Arakawa Summary 1.,To assess the involvement of volume overload in the development of cardiac hypertrophy during treatment with an antidiabetic thiazolidinedione, changes in cardiac anatomy and parameters of cardiac volume overload were evaluated in female Sprague-Dawley rats treated with the thiazolidinedione derivative T-174. 2.,Two week administration of T-174 (13 and 114 mg/kg per day) increased absolute and relative heart weights by 11,24%, demonstrating the development of cardiac hypertrophy. There was no evidence of oedema in hearts from treated rats. 3.,Both plasma and blood volumes were increased in T-174-treated rats without any changes in systolic blood pressure and heart rate, whereas haematocrit was decreased. In accordance with the existence of volume overload, both left ventricular end-diastolic pressure and right atrial pressure were increased. Morphometric analysis of hearts revealed that T-174 induced eccentric heart hypertrophy, as characterized by a small increase in wall thickness and a large increase in the chamber volume, which is characteristic of volume overload. Volume overload is suggested as the possible trigger mechanism because blood volume expansion preceded cardiac hypertrophy and there was a high correlation between heart weight and blood volume. 4.,T-174-treated streptozotocin-induced diabetic rats also exhibited blood volume expansion and cardiac hypertrophy. 5.,These findings suggest that cardiac volume overload is induced by plasma volume expansion and contributes to the development of eccentric cardiac hypertrophy during treatment with antidiabetic thiazolidinediones. Although thiazolidinediones are insulin-sensitizing agents, these cardiac effects are likely to be mediated independently of insulin. [source] What are the effects of peroxisome proliferator-activated receptor agonists on adiponectin, tumor necrosis factor-alpha, and other cytokines in insulin resistance?CLINICAL CARDIOLOGY, Issue S4 2004Patrick J. Boyle M.D. Abstract Patients with type 2 diabetes are at high risk of cardiovascular disease. In addition to treating hyperglycemia, the thiazolidinedione (TZD) class of antidiabetic agents may also benefit the cardiovascular complications associated with the disease. The two available TZDs, pioglitazone and rosiglitazone, are peroxisome proliferator-activated receptor-gamma (PPAR-,) agonists that influence gene expression of key proteins involved in regulating glucose and lipid metabolism. Tumor necrosis factor-alpha (TNF-,) and adiponectin are believed to be important in the development of insulin resistance and atherosclerosis. Understanding the role of these cytokines in the inflammatory processes that trigger plaque development might lead to identification of other potential mechanisms that could be exploited to enhance future treatments for patients with diabetes and atherosclerosis. [source] The metabolic syndrome and schizophreniaACTA PSYCHIATRICA SCANDINAVICA, Issue 1 2009J. M. Meyer Objective:, To summarize the accumulated data on metabolic syndrome prevalence in patients with schizophrenia, examine evidence for a biological contribution of the mental illness to metabolic risk and review novel options available for management of prediabetic states. Method:, A Medline search using metabolic syndrome, insulin resistance and insulin sensitivity cross-referenced with schizophrenia was performed on articles published between 1990 and May 2008. Results:, Recent evidence indicates that schizophrenia increases predisposition towards metabolic dysfunction independent of environmental exposure. Both fasting and non-fasting triglycerides have emerged as important indicators of cardiometabolic risk, while metformin, thiazolidinediones and GLP-1 modulators may prove promising tools for managing insulin resistance. Conclusion:, Because of lifestyle, disease and medication effects, schizophrenia patients have significant risk for cardiometabolic disease. Routine monitoring, preferential use of metabolically neutral antipsychotics and lifestyle education are critical to minimizing risk, with a possible role for antidiabetic medications for management of insulin resistant states that do not respond to other treatment strategies. [source] In humans the adiponectin receptor R2 is expressed predominantly in adipose tissue and linked to the adipose tissue expression of MMIF-1DIABETES OBESITY & METABOLISM, Issue 4 2010K. Kos In this study, the regional adipose tissue-adiponectin (AT-ADN) and adiponectin receptor (R1 and R2) expression and their relation with metabolic parameters, circulating and AT-derived cytokine expressions were compared. Paired subcutaneous adipose tissue (SCAT) and visceral adipose tissue (VAT) were taken from 18 lean and 39 obese humans, AT-mRNA expression of adipokines analysed by RT-PCR and corresponding serum levels by enzyme-linked immunosorbent assay (ELISA). R1 and R2 adipocyte expression was compared with 17 other human tissues. ADN-gene expression was lower in VAT than SCAT [mean (SD) 1.54 (1.1) vs. 2.84 (0.87); p < 0.001], and lower in obese subjects (VAT : p = 0.01;SCAT : p < 0.001). SCAT-ADN correlated positively with serum ADN (r = 0.33;p = 0.036) but not VAT-ADN. AT expressions of ADN and macrophage migration inhibiting factor (MMIF), IL18 and cluster of differentiation factor 14 (CD14) in both depots showed inverse correlations. R1 and R2 were expressed ubiquitously and R2 highest in SCAT, and this is much higher (×100) than R1 (×100). R expression was similar in lean and obese subjects and unrelated to the metabolic syndrome, however, receptors correlated with VAT-MMIF (R 1: r = 0.4;p = 0.008;R 2: r = 0.35,p = 0.02) and SCAT-MMIF expression (R 2: r = 0.43;p = 0.004). Unlike ADN, its receptors are expressed in many human tissues. Human R2 expression is not highest in the liver but in AT where it is associated with MMIF expression. The adiponectin-dependent insulin-sensitizing action of thiazolidinediones is thus probably to differ amongst species with weaker effects on the human liver. [source] Exenatide: a review from pharmacology to clinical practiceDIABETES OBESITY & METABOLISM, Issue 6 2009R. Gentilella Background:, Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying. Methods:, In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c ,11%), or by thiazolidinediones (with or without metformin) and treated for periods from 16 weeks to 3 years, exenatide (5 ,g b.i.d. s.c. for the first 4 weeks of treatment and 10 ,g b.i.d. s.c. thereafter) reduced HbA1c, fasting and postprandial glucose, and body weight dose dependently, and was similar to insulin glargine and biphasic insulin aspart in reducing HbA1c. Body weight diminished with exenatide, whereas it increased with both insulin preparations. Positive effects on the lipid profile and a reduction in C-reactive protein were also recorded with exenatide. Treatment extensions up to 3 years showed that benefits were maintained in the long term. Adverse events were usually mild to moderate in intensity, and generally the frequency decreased with continued therapy. The most common was nausea (whose incidence may be reduced by gradual dose escalation from 5 ,g b.i.d. to 10 ,g b.i.d.), vomiting, diarrhoea, headache and hypoglycaemia (almost exclusively in patients treated with a sulphonylurea). Results and conclusions:, Exenatide is a new, promising therapeutic option for type 2 diabetic patients inadequately controlled by oral agents, before insulin therapy, offering the added benefits of body weight reduction and tight postprandial glucose control. [source] Current treatment of non-alcoholic fatty liver diseaseDIABETES OBESITY & METABOLISM, Issue 3 2009Mohamed H. Ahmed Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in Western World and frequently associated with insulin resistance and overweight and occurs often with type 2 diabetes. Interestingly, NAFLD is not only regarded as a hepatic component of the metabolic syndrome but also as an independent risk factor and a marker for increase in cardiovascular disease (CVD). Significantly, NAFLD is associated with an increased risk of all-cause mortality and predicts future CVD events independent of age, sex, LDL-cholesterol and features of metabolic syndrome. Although there was initial concern about drug toxicity with NAFLD, increasing evidence suggests that commonly used drugs such as metformin and statins do not cause harm and the thiazolidinediones (TZDs) may even confer a therapeutic benefit in NAFLD. Interestingly, medical and surgical treatments of obesity show potential benefit in treating NAFLD. In this review, we have focused on the safety and therapeutic impact of TZDs, statins, metformins and obesity medications in NAFLD. The potential benefit of bariatric surgery and the role of weight loss per se in treating NAFLD are also discussed. [source] Hepatic dysfunction and insulin insensitivity in type 2 diabetes mellitus: a critical target for insulin-sensitizing agentsDIABETES OBESITY & METABOLISM, Issue 9 2008P. D. Home The liver plays an essential role in maintaining glucose homeostasis, which includes insulin-mediated processes such as hepatic glucose output (HGO) and uptake, as well as in clearance of insulin itself. In type 2 diabetes, the onset of hyperglycaemia [itself a potent inhibitor of hepatic glucose output (HGO)], alongside hyperinsulinaemia, indicates the presence of hepatic insulin insensitivity. Increased HGO is central to the onset of hyperglycaemia and highlights the need to target hepatic insulin insensitivity as a central component of glucose-lowering therapy. The mechanisms underlying the development of hepatic insulin insensitivity are not well understood, but may be influenced by factors such as fatty acid oversupply and altered adipocytokine release from dysfunctional adipose tissue and increased liver fat content. Furthermore, although the impact of insulin insensitivity as a marker of cardiovascular disease is well known, the specific role of hepatic insulin insensitivity is less clear. The pharmacological tools available to improve insulin sensitivity include the biguanides (metformin) and thiazolidinediones (rosiglitazone and pioglitazone). Data from a number of sources indicate that thiazolidinediones, in particular, can improve multiple aspects of hepatic dysfunction, including reducing HGO, insulin insensitivity and liver fat content, as well as improving other markers of liver function and the levels of mediators with potential involvement in hepatic function, including fatty acids and adipocytokines. The current review addresses this topic from the perspective of the role of the liver in maintaining glucose homeostasis, its key involvement in the pathogenesis of type 2 diabetes and the tools currently available to reduce hepatic insulin insensitivity. [source] The effect of thiazolidinediones on adiponectin serum level: a meta-analysisDIABETES OBESITY & METABOLISM, Issue 5 2008N. Riera-Guardia Background and aims:, Adiponectin is a hormone mainly produced by white adipose tissue. Decreased levels of adiponectin are linked with visceral obesity, insulin resistance states, and cardiovascular diseases. Recently, several studies have pointed out an increase in adiponectin serum levels in subjects undergoing treatment with thiazolidinediones (TZD). The aim of this study is to systematically review the current state of evidence of the effect of TZD on adiponectin serum level with special attention to avoid publication bias. Materials and methods:, An extensive literature search was performed. Meta Analysis Version 2.0 computer program was used to calculate statistical differences in means and 95% confidence interval (CI). Publication bias was assessed using different statistical approaches. Results:, In the meta-analysis including 19 studies the overall standardized mean difference was 0.94 (95% CI, 0.81,1.06) which means that subjects treated with TZDs on average had means of adiponectin concentration that were about 1 standard deviation higher than the comparison groups even after controlling for possible biases. Conclusions:, The results obtained agree with a moderate increase of serum adiponectin. The results clearly reveal an increase of endogenous serum adiponectin levels by intake of TZDs and may point to a potential new option to manage obesity-related diseases. [source] AMP-activated protein kinase: role in metabolism and therapeutic implicationsDIABETES OBESITY & METABOLISM, Issue 6 2006Greg Schimmack AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge which becomes activated in situations of energy consumption. AMPK functions to restore cellular ATP levels by modifying diverse metabolic and cellular pathways. In the skeletal muscle, AMPK is activated during exercise and is involved in contraction-stimulated glucose transport and fatty acid oxidation. In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. In the liver, AMPK inhibits the production of glucose, cholesterol and triglycerides and stimulates fatty acid oxidation. Recent studies have shown that AMPK is involved in the mechanism of action of metformin and thiazolidinediones, and the adipocytokines leptin and adiponectin. These data, along with evidence that pharmacological activation of AMPK in vivo improves blood glucose homeostasis, cholesterol concentrations and blood pressure in insulin-resistant rodents, make this enzyme an attractive pharmacological target for the treatment of type 2 diabetes, ischaemic heart disease and other metabolic diseases. [source] The metabolic syndrome: evolving evidence that thiazolidinediones provide rational therapyDIABETES OBESITY & METABOLISM, Issue 4 2006Kathleen L. Wyne The metabolic syndrome, also known as the dysmetabolic syndrome, syndrome X or the insulin resistance syndrome, refers to the clustering of cardiovascular disease risk factors that are present in many individuals who are at increased risk for both cardiovascular events and type 2 diabetes. Prediabetic subjects typically exhibit an atherogenic pattern of cardiovascular risks that is associated with hyperinsulinaemia. Thus, identification of components of the metabolic syndrome is important if patients are to be treated early enough to prevent cardiovascular events and other complications related to diabetes. Therapies targeted to specific components of the metabolic syndrome such as improving glycaemic control, managing dyslipidaemia and reducing the prothrombotic state should help to minimize cardiovascular risk, particularly if initiated early. Traditional pharmacologic agents used to manage the individual components of the metabolic syndrome do not typically impact the other components. The thiazolidinediones, a new class of agents that improve insulin resistance, have the ability, in addition to their glucose-lowering effects, to exert several powerful anti-atherogenic properties, including anti-inflammatory effects in the vascular endothelium, redistribution of visceral fat and reduction of insulin resistance, hyperinsulinaemia and hyperproinsulinaemia. This makes the thiazolidinediones ideal candidates for the early treatment of many components associated with the metabolic syndrome. [source] Insulin resistance , a common link between type 2 diabetes and cardiovascular diseaseDIABETES OBESITY & METABOLISM, Issue 3 2006Harold E. Lebovitz Evidence suggests that diabetes and cardiovascular disease (CVD) may share an underlying cause(s), a theory known as the ,common soil' hypothesis. Insulin resistance is central both to the progression from normal glucose tolerance to type 2 diabetes and to a constellation of cardiovascular risk factors known as the metabolic syndrome. These risk factors include visceral obesity and dyslipidaemia characterized by low levels of high-density lipoprotein cholesterol, hypertriglyceridaemia and raised small dense low-density lipoprotein particle levels. Changes in adipose tissue mass and metabolism may link insulin resistance and visceral obesity, a condition that is common in type 2 diabetes. Furthermore, weight reduction, increased physical activity, metformin and acarbose have been shown to reduce the development of type 2 diabetes in genetically predisposed subjects and may decrease the high cardiovascular risk of patients with diabetes. Some fatty acid derivatives can affect energy metabolism by activating peroxisome proliferator-activated receptors (PPARs), nuclear receptors that play a key role in energy homeostasis. These receptors represent an ideal therapeutic target for reducing cardiovascular risk, because they are involved in the regulation of both insulin action and lipid metabolism. In addition to lifestyle changes, PPAR, agonists such as thiazolidinediones are frequently beneficial and have been shown to ameliorate insulin resistance, while activation of PPAR, (e.g. by fibrates) can lead to improvements in free fatty acid oxidation and lipid profile, and a reduction in cardiovascular events. The development of agents with both PPAR, and PPAR, activity promises added benefits with amelioration of insulin resistance, delayed progression to and of type 2 diabetes and a reduction of CVD. [source] Combination therapy using metformin or thiazolidinediones and insulin in the treatment of diabetes mellitusDIABETES OBESITY & METABOLISM, Issue 6 2005Suzanne M. Strowig The biguanide, metformin, sensitizes the liver to the effect of insulin, suppressing hepatic glucose output. Thiazolidinediones such as rosiglitazone and pioglitazone enhance insulin-mediated glucose disposal, leading to reduced plasma insulin concentrations. These classes of drugs may also have varying beneficial effects on features of insulin resistance such as lipid levels, blood pressure and body weight. Metformin in combination with insulin has been shown to significantly improve blood glucose levels while lowering total daily insulin dose and body weight. The thiazolidinediones in combination with insulin have also been effective in lowering blood glucose levels and total daily insulin dose. Triple combination therapy using insulin, metformin and a thiazolidinedione improves glycaemic control to a greater degree than dual therapy using insulin and metformin or insulin and a thiazolidinedione. There is insufficient evidence to recommend the use of metformin or thiazolidinediones in type 1 diabetic patients. Although these agents are largely well tolerated, some subjects experience significant gastrointestinal problems while using metformin. Metformin is associated with a low risk of lactic acidosis, but should not be used in patients with elevated serum creatinine or those being treated for congestive heart failure. The thiazolidinediones are associated with an increase in body weight, although this can be avoided with careful lifestyle management. Thiazolidinediones may also lead to oedema and are associated with a low incidence of hepatocellular injury. Thiazolidinediones are contraindicated in patients with underlying heart disease who are at risk of congestive heart failure and in patients who have abnormal hepatic function. The desired blood glucose-lowering effect and adverse event profiles of these agents should be considered when recommending these agents to diabetic patients. The potential for metformin or the thiazolidinediones to impact long-term cardiovascular outcomes remains under investigation. [source] Insulin resistance, diabetes and cardiovascular risk: approaches to treatmentDIABETES OBESITY & METABOLISM, Issue 6 2005Daniel E. Rosenberg Abstract:, The prevalence of diabetes is increasing worldwide. Insulin resistance and diabetes mellitus are major predictors of cardiovascular ischaemic disease. Other risk factors for cardiovascular death including hypertension, dyslipidaemia, smoking and visceral obesity are especially lethal in diabetics. C-reactive protein, plasminogen activator inhibitor-1, matrix metalloproteinases and other emerging risk factors and their roles are continually being researched and discovered. Treatment of this syndrome must be aimed at lifestyle modification, glycaemic control and management of concomitant risk factors. Diet and exercise play a vital role in the treatment of diabetes and the metabolic syndrome. Weight reduction and increased physical activity will improve insulin resistance, hyperglycaemia, hypertension and dyslipidaemia. Hypertension management has been shown to be especially important in diabetics to prevent cardiovascular events. Likewise, multiple clinical trials show that reduction of cholesterol is even more vital in diabetics than the general population for risk reduction of coronary disease. There is a great deal of evidence that tight control of glycaemia is essential to treatment of this condition. There are a variety of available pharmacological agents available including metformin, insulin secretagogues, alpha-glucosidase inhibitors, thiazolidinediones and insulin. The mechanisms and side effects of these medications are discussed. As macrovascular disease is the major cause of morbidity and mortality, an early, aggressive, multi-factorial approach to treatment of the metabolic syndrome and diabetes is vital to prevent adverse cardiac outcomes. [source] Islet adaptation to insulin resistance: mechanisms and implications for interventionDIABETES OBESITY & METABOLISM, Issue 1 2005B. Ahrén Abstract:, Insulin sensitivity and insulin secretion are reciprocally related such that insulin resistance is adapted by increased insulin secretion to maintain normal glucose and lipid homeostasis. The relation between insulin sensitivity and secretion is curvilinear and mathematically best described as a hyperbolic relation. Several potential mediators have been suggested to be signals for the beta cells to respond to insulin resistance such as glucose, free fatty acids, autonomic nerves, fat-derived hormones and the gut hormone glucagon-like peptide-1 (GLP-1). Failure of these signals or of the pancreatic beta cells to adequately adapt insulin secretion in relation to insulin sensitivity results in inappropriate insulin levels, impaired glucose intolerance (IGT) and type 2 diabetes. Therefore, treatment of IGT and type 2 diabetes should aim at restoring the normal relation between insulin sensitivity and secretion. Such treatment includes stimulation of insulin secretion (sulphonylureas, repaglinide and nateglinide) and insulin sensitivity (metformin and thiazolidinediones), as well as treatment aimed at supporting the signals mediating the islet adaptation (cholinergic agonists and GLP-1). Both, for correct understanding of diabetes pathophysiology and for development of novel treatment modalities, therefore, the non-linear inverse relation between insulin sensitivity and secretion needs to be acknowledged. [source] PPAR, and the thiazolidinediones: molecular basis for a treatment of ,Syndrome X'?DIABETES OBESITY & METABOLISM, Issue 4 2002C. Sewter First page of article [source] Why insulin sensitizers but not secretagogues should be retained when initiating insulin in type 2 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2008Philip Raskin Abstract The stringent targets set for HbA1c levels in type 2 diabetes are currently achieved by fewer than half the patients in the United States. Failure to manage hyperglycaemia in the early stages of disease results in progressive loss of ,-cell function, which ultimately necessitates the initiation of insulin therapy. At this point, choices have to be made on whether to continue oral anti-diabetic drug therapy and, if so, with which agent(s). Historically, sulfonylureas have been the mainstay of oral anti-diabetic drug therapy; however, their long-term efficacy in patients with depleted ,-cell capacity is doubtful, and other classes of oral anti-diabetic drugs, notably the insulin sensitizers, may prove more reliable. These agents (metformin and thiazolidinediones) appear to provide various benefits over and above sustained glycaemic control, which may variably include reduced loss of ,-cell function as well as improvements to cardiovascular risk factors, morbidity, and mortality. Metformin also limits weight gain associated with insulin therapy. This manuscript presents the case that when insulin therapy is initiated it should be tailored to individual needs through combination with one or more insulin sensitizers rather than a secretagogue. Copyright © 2007 John Wiley & Sons, Ltd. [source] Cardiovascular effects of the thiazolidinedionesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2006Rehan Qayyum Abstract Thiazolidinediones, used for the treatment of diabetes mellitus type 2, modulate gene expression by binding to nuclear transcription factor, peroxisome proliferator-activated receptor-gamma. Peroxisome proliferator,activated receptor-gamma is expressed in several tissues, therefore, thiazolidinediones have biological effects on multiple organ systems. Here, we describe evidence that thiazolidinediones have beneficial effects on the cardiovascular system independent of their antidiabetic effect. Studies in animals have clearly shown that thiazolidinediones decrease blood pressure, left ventricular hypertrophy, development of atherosclerotic lesions, and protect myocardium from ischemia/reperfusion injury. Although relatively few studies in humans have been reported, the preponderance of available evidence suggests a beneficial effect of thiazolidinediones. Thus, by modulating gene expression, thiazolidinediones may provide a novel method for the prevention and treatment of cardiovascular diseases. Copyright © 2005 John Wiley & Sons, Ltd. [source] Insulin resistance in type 2 diabetes: role of fatty acids,DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S2 2002Peter Arner Abstract Insulin resistance is one of the key factors responsible for hyperglycaemia in type 2 diabetes and can result in a number of metabolic abnormalities associated with cardiovascular disease (insulin resistance syndrome), even in the absence of overt diabetes. The mechanisms involved in the development of insulin resistance are multifactorial and are only partly understood, but increased availability of free fatty acids (FFAs) is of particular importance for the liver and skeletal muscle. The role of FFAs in type 2 diabetes is most evident in obese patients who have several abnormalities in FFA metabolism. Because of a mass effect, the release of FFAs from the total adipose tissue depot to the blood stream is increased and the high concentration of circulating FFAs impairs muscle uptake of glucose by competitive inhibition. In upper-body obesity, which predisposes individuals to type 2 diabetes, the rate of lipolysis is accelerated in visceral adipose tissue. This results in a selective increase in FFA mobilisation to the portal vein, which connects visceral fat to the liver. A high ,portal' FFA concentration has undesirable effects on the liver, resulting in dyslipidaemia, hyperinsulinaemia, hyperglycaemia and hepatic insulin resistance. Recently, a new class of antidiabetic agents, the thiazolidinediones (TZDs) or ,glitazones' has been developed. A prominent effect of these agents is the lowering of circulating FFA levels and it is believed, but not yet proven, that this interaction with FFAs constitutes a major mechanism behind the glucose-lowering effect of the TZDs. Copyright © 2002 John Wiley & Sons, Ltd. [source] The mode of action of thiazolidinediones,DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S2 2002Hans Hauner Abstract The thiazolidinediones (TZDs) or ,glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR,), a nuclear receptor. TZD-induced activation of PPAR, alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and the GLUT4 glucose transporter. TZDs reduce insulin resistance in adipose tissue, muscle and the liver. However, PPAR, is predominantly expressed in adipose tissue. It is possible that the effect of TZDs on insulin resistance in muscle and liver is promoted via endocrine signalling from adipocytes. Potential signalling factors include free fatty acids (FFA) (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumour necrosis factor-, (TNF-,), which is overexpressed in obesity and insulin resistance. Although there are still many unknowns about the mechanism of action of TZDs in type 2 diabetes, it is clear that these agents have the potential to benefit the full ,insulin resistance syndrome' associated with the disease. Therefore, TZDs may also have potential benefits on the secondary complications of type 2 diabetes, such as cardiovascular disease. Copyright © 2002 John Wiley & Sons, Ltd. [source] New use of rosiglitazone decreased following publication of a meta-analysis suggesting harmDIABETIC MEDICINE, Issue 7 2008B. R. Shah Abstract Aims It is uncertain whether meta-analyses lead to changes in prescribing practices. We studied trends in the prescribing of glucose-lowering therapy before and after the publication of a meta-analysis suggesting harm from rosiglitazone. Methods We examined the prescription records of all residents of Ontario, Canada, aged , 66 years. For each week between January and December 2007, we identified new users of five categories of glucose-lowering medications: rosiglitazone, pioglitazone, metformin, glibenclamide (glyburide) and insulin. The effect of the meta-analysis was assessed using interventional autoregressive integrated moving-average models. Results Following the release of the meta-analysis, there was a sudden decline in new users of rosiglitazone (P = 0.01), mirrored by a nearly identical but transient increase in new users of pioglitazone (P < 0.001). There was also a net decline in new users of thiazolidinediones as a class (P < 0.001). The number of new users of other glucose-lowering medications did not change. Conclusions A highly-publicized meta-analysis regarding rosiglitazone's potential harms led to an abrupt decline in new users of the drug, as well as a transient surge in new use of pioglitazone. [source] | ||||||||||||||||||||||||||||||||||||||||