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Improvement of abnormal liver enzymes after rosiglitazone treatment in Chinese type 2 diabetes
Abstract and Figures
Insulin resistance is one of the important underlying abnormalities of type 2 diabetes. The effect of thiazolidinedione on liver functions has been controversial in different studies. In this study, we evaluated the effect of rosiglitazone on liver enzymes in subjects with type 2 diabetes with and without abnormal liver function.
Seventy-three patients with type 2 diabetes taking rosiglitazone 4 mg daily were enrolled in this 3-month study. Forty-two of them had normal liver function (NLF), and 31 had abnormal liver function (ABLF). Blood biochemistries were collected monthly during the treatment period.
At baseline, other than age and liver enzymes, there were no differences in body mass index, fasting plasma glucose, hemoglobin A1c (HbA1c), and lipid profiles between the NLF and ABLF groups. At the end of the treatment, HbA1c was lowered in both groups, but only significantly in the ABLF group (P = 0.027). More importantly, serum concentrations of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the ABLF group decreased significantly (AST: 57.8 ± 26.5 to 47.5 ± 20.2 U/L, P = 0.006; ALT 66.6 ± 35.0 to 51.9 ± 23.5 UL, P = 0.004), while in the NLF group, a similar change was not found.
After 3-month rosiglitazone treatment in subjects with type 2 diabetes with mildly elevated liver enzymes, significant improvement in AST and ALT were observed. Our study provides some hints that rosiglitazone might not be contraindicated in subjects with diabetes with abnormal liver function as previously thought, but further well-designed studies are necessary to clarify this issue.
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... [1,2] Insulin resistance in patients with T2D is also established as factor of elevated levels of liver enzymes, hypertension, dyslipidemia, and atherosclerotic cardiovascular diseases. [3,4] Increased activities of liver enzymes including alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are considered as early surrogate markers of nonalcoholic fatty liver disease. [5,6] Earlier studies reported that the elevated values of these enzymes are related to metabolic syndrome and cardiovascular disease. ...
Background
This research was to examine the effects of synbiotic intake on minerals, liver enzymes, and blood pressure in patients with type 2 diabetes (T2D).
Methods
This randomized, cross-over clinical trial was performed among 62 diabetic patients. Persons were randomly assigned to intake either a synbiotic (n = 62) or a control food (n = 62) for 6 weeks. A 3-week washout period was applied following which persons were crossed over to the alternate intervention arm for an additional 6 weeks. The synbiotic was consisted of Lactobacillus sporogenes (1 × 10⁷ CFU), 0.04 g inulin (HPX) as prebiotic. Persons were asked to consume the synbiotic and control foods 27 g a day. Blood pressure was measured, and blood samples were taken at baseline and after 6-week intervention to assess calcium, magnesium, iron, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin.
Results
The consumption of a synbiotic food, compared to the control food, resulted in a significant rise of calcium (0.66 vs. −0.14 mg/dL, P = 0.03) and iron (5.06 vs. −9.98 mg/dL, P = 0.03). The decrease of total bilirubin (0.08 vs. −0.04 mg/dL; P = 0.009) was also seen in the synbiotic group compared with the control group.
Conclusions
Overall, synbiotic in T2D patients had beneficial effects on calcium, iron, and total bilirubin concentrations.
... 1,2 However, elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) are also associated with MetS. [4][5][6][7][8][9][10][11][12] Many abnormal liver function test (LFT) cases are due to nonalcoholic fatty liver disease (NAFLD). 13 To avoid bias, we enrolled 9,282 subjects over 60 years old without liver ...
Background:We aimed to investigate the relationship between liver function tests (LFTs) and metabolic syndrome (MetS) as several studies have shown positive correlations between some of the LFTs, including alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (γ-GT), and MetS but have not fully explored the same in the elderly. Owing to the progress in public health, the aging of the general population becomes a major issue. Design: We enrolled subjects aged over 60 years who underwent routine health checkups in a Health Screening Center after excluding subjects with a history of hepatitis B or C infection, excessive alcohol consumption, liver fibrosis, cirrhosis, acute hepatitis, diabetes, hypertension, dyslipidemia, cardiovascular disease, or receiving medications for these diseases. Finally, 9,282 participants were eligible for analysis. Statistical Analysis: All data were tested for normal distribution with the Kolmogorov-Smirnov test and for homogeneity of variances with the Levene’s test. A t-test was used to evaluate the differences between the two groups. Univariate and multivariate regressions were used to observe correlations between different parameters. Receiver operating characteristic curves of each LFT were used to predict MetS. Areas under curves and 95% confidence interval were also estimated and compared. Results: With the exception of aspartate aminotransferase and α-fetal protein, the results of LFTs, including total and direct bilirubin, alkaline phosphatase (ALP), ALT, and γ-GT, were altered in the group with MetS. Furthermore, the levels of γ-GT in men and ALP in women were independently associated with all MetS components and had the highest areas under receiver operating characteristic curves. Conclusion: Abnormal LFTs are highly correlated with MetS in the hepatitis-free elderly, with levels of γ-GT in men and ALP in women being the most important factors. LFTs may represent an auxiliary tool for the detection of MetS.
... Liver is one of the chief storage organs for glucose reserve in the body and plays a crucial role in the maintenance of blood glucose homeostasis. Elevation of biomarker enzymes such as ALT, AST and ALP in serum was presumed to be due to the decreased blood insulin [37] and mainly due to the leakage of these enzymes from the liver cytosol into the blood stream, which gave an indication on the hepatotoxic effect of alloxan. The increased protein catabolism accompanying gluconeogenesis and urea formation that are seen in the diabetic state might be responsible for the elevation of these tissue transaminases. ...
Diabetes mellitus is one of the most common endocrine entities, which coexist with defect in carbohydrate metabolism. The Indian traditional system of medicine prescribed plant phytochemical therapies for diseases including diabetes mellitus. The present study was aimed to evaluate the therapeutic potential of syringic acid (SA) by assaying the activities of key enzymes of carbohydrate metabolism in experimental diabetic rats. Diabetes was induced into male albino Wistar rats by intraperitoneal administration of alloxan (150 mg/kg). SA was administered to diabetic rats intragastrically at 25, 50 and 100 mg/kg b.w daily once for 30 days. The levels of plasma glucose, insulin, hemoglobin (Hb), glycated hemoglobin (HbA1c) and glycogen, levels of carbohydrate metabolic enzymes, liver and kidney markers were evaluated. Oral administration of SA (50 mg/kg) for 30 days, dose dependently improved the glycemic status in diabetic rats. The levels of insulin, Hb and glycogen increased with significant decrease in glucose and HbA1c levels in SA treated rats. The altered activities of carbohydrate metabolic enzymes, hepatic and renal marker were restored to near normal. Histopathological analysis of pancreas revealed that treatment with SA reduced the pancreatic damage induced by alloxan and stimulated β-cell regeneration in diabetic rats. The present findings suggest the antihyperglycemic effect of SA and its therapeutic potential for the management of diabetes.
Nonalchoholic fatty liver disease (NAFLD) has been reported as a hepatic manifestation of metabolic syndrome (MetS); it is common and accounts for 80% of the cases with abnormal liver function tests (LFTs). In addition, several studies have proved that there is a correlation between abnormal LFTs and MetS. Therefore, LFTs may represent the abnormal metabolic status of livers in the patients with MetS. To identify the early state of metabolic dysfunction, we investigate the value of LFTs for the future MetS development in the relatively healthy (non-NAFLD) elderly.
A total of 16,912 subjects met the criteria for analysis. In the first stage of this study, subjects were enrolled in the cross-sectional study in order to find out the optimal cutoff value in different LFTs with higher chances to have MetS. In the second stage of the present study, subjects with MetS at baseline were excluded from the same study group, and a median 5.6-year longitudinal study was conducted on the rest of the group.
Among all LFTs, only aspartate aminotransferase in both genders and the α-fetal protein in women failed to show the significance in distinguishing subjects with MetS by the receiver operating characteristic curve. In the Kaplan-Meier plot, only γ-glutamyl transpeptidase (γ-GT) in men and the alanine aminotransferase (ALT) in women could be used to successfully separate subjects with higher risk of developing the MetS from those with lower risk. Finally, in the multivariant Cox regression model, similar results were identified. Still, the hazard ratio (HR) to have future MetS, γ-GT in men, and ALT in women showed significance (HR = 1.511 in men and 1.504 in women).
Among all the different LFTs, γ-GT (>16 U/L) in male and ALT (>21 U/L) in female were the best predictors for the development of MetS in healthy elderly. These two liver markers could be an ancillary test in predicting future MetS development/diagnosis. Elevation of the LFTs without underlying liver diseases should be treated as a warning sign of the possible MetS development in the elderly.
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen. PPAR-gamma has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates. Naturally occurring compounds such as fatty acids and the prostaglandin D2 metabolite 15-deoxy-delta prostaglandin J2 (15d-PGJ2) bind to PPAR-gamma and stimulate transcription of target genes. Prostaglandin D2 metabolites have not yet been identified in adipose tissue, but are major products of arachidonic-acid metabolism in macrophages, raising the possibility that they might serve as endogenous PPAR-gamma ligands in this cell type. Here we show that PPAR-gamma is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPAR-gamma ligands. PPAR-gamma inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-kappaB. These observations suggest that PPAR-gamma and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR-gamma ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects.
Methods of sample size and power calculations are reviewed for the most common study designs. The sample size and power equations for these designs are shown to be special cases of two generic formulae for sample size and power calculations. A computer program is available that can be used for studies with dichotomous, continuous, or survival response measures. The alternative hypotheses of interest may be specified either in terms of differing response rates, means, or survival times, or in terms of relative risks or odds ratios. Studies with dichotomous or continuous outcomes may involve either a matched or independent study design. The program can determine the sample size needed to detect a specified alternative hypothesis with the required power, the power with which a specific alternative hypothesis can be detected with a given sample size, or the specific alternative hypotheses that can be detected with a given power and sample size. The program can generate help messages on request that facilitate the use of this software. It writes a log file of all calculated estimates and can produce an output file for plotting power curves. It is written in FORTRAN-77 and is in the public domain.
We examined the effect of three months of rosiglitazone treatment (4 mg b.i.d.) on whole-body insulin sensitivity and in vivo peripheral adipocyte insulin sensitivity as assessed by glycerol release in microdialysis from subcutaneous fat during a two-step (20 and 120 mU.m(-2).min(-1)) hyperinsulinemic-euglycemic clamp in nine type 2 diabetic subjects. In addition, the effects of rosiglitazone on liver and muscle triglyceride content were assessed by (1)H-nuclear magnetic resonance spectroscopy. Rosiglitazone treatment resulted in a 68% (P < 0.002) and a 20% (P < 0.016) improvement in insulin-stimulated glucose metabolism during the low- and high- dosage-insulin clamps, respectively, which was associated with approximately 40% reductions in plasma fatty acid concentration (P < 0.05) and hepatic triglyceride content (P < 0.05). These changes were associated with a 39% increase in extramyocellular lipid content (P < 0.05) and a 52% increase in the sensitivity of peripheral adipocytes to the inhibitory effects of insulin on lipolysis (P = 0.04). In conclusion, these results support the hypothesis that thiazolidinediones enhance insulin sensitivity in patients with type 2 diabetes by promoting increased insulin sensitivity in peripheral adipocytes, which results in lower plasma fatty acid concentrations and a redistribution of intracellular lipid from insulin responsive organs into peripheral adipocytes.
Although non-alcoholic steatohepatitis (NASH) was considered relatively uncommon prior to the middle of the last decade, over the past three years there has been an explosion of studies on various aspects of NASH with one study reporting that after hepatitis C, NASH was the most common diagnosis in patients presenting largely with persistent abnormalities of liver function tests. The field of NASH has come a long way in a relatively short space of time. This article considers advances in knowledge that have arisen as a result of these studies and highlights areas for further work.
To investigate the effects of rosiglitazone (RSG) on insulin sensitivity and regional adiposity (including intrahepatic fat) in patients with type 2 diabetes.
We examined the effect of RSG (8 mg/day, 2 divided doses) compared with placebo on insulin sensitivity and body composition in 33 type 2 diabetic patients. Measurements of insulin sensitivity (euglycemic hyperinsulinemic clamp), body fat (abdominal magnetic resonance imaging and DXA), and liver fat (magnetic resonance spectroscopy) were taken at baseline and repeated after 16 weeks of treatment.
There was a significant improvement in glycemic control (glycosylated hemoglobin -0.7 +/- 0.7%, p < or = 0.05) and an 86% increase in insulin sensitivity in the RSG group (glucose-disposal rate change from baseline: 17.5 +/- 14.5 micro mol glucose/min/kg free fat mass, p < 0.05), but no significant change in the placebo group compared with baseline. Total body weight and fat mass increased (p < or = 0.05) with RSG (2.1 +/- 2.0 kg and 1.4 +/- 1.6 kg, respectively) with 95% of the increase in adiposity occurring in nonabdominal regions. In the abdominal region, RSG increased subcutaneous fat area by 8% (25.0 +/- 28.7 cm(2), p = 0.02), did not alter intra-abdominal fat area, and reduced intrahepatic fat levels by 45% (-6.7 +/- 9.7%, concentration relative to water).
Our data indicate that RSG greatly improves insulin sensitivity in patients with type 2 diabetes and is associated with an increase in adiposity in subcutaneous but not visceral body regions.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcriptional factor belonging to the nuclear receptor superfamily. PPARgamma, which is predominantly expressed in adipose tissue, plays a major regulatory role in glucose metabolism and adipogenesis. Interestingly, recent studies have demonstrated PPARgamma expression in monocytes/macrophages and its antiinflammatory activities. However, it is unclear whether alveolar macrophages (AMs) express functional PPARgamma. The present study was conducted to investigate the expression of PPARgamma by AMs and to elucidate its functional role. Using reverse transcription-polymerase chain reaction and Western blotting, we demonstrated the strong expression of PPARs messenger RNA and protein in freshly isolated human AMs. Ligands of PPARgamma, 15-deoxy-delta(12,14)prostaglandin J2, and troglitazone significantly decreased LPS-induced tumor necrosis factor-alpha production by AMs. These ligands markedly upregulated the expression of CD36, a scavenger receptor that mediates the phagocytosis of apoptotic neutrophils. Indeed, ligand-treated AMs ingested a significantly higher number of apoptotic neutrophils than untreated AMs. These data indicate that PPARgamma expressed by AMs play an antiinflammatory role through inhibiting cytokine production and increasing their CD36 expression together with the enhanced phagocytosis of apoptotic neutrophils, which is an essential process for the resolution of inflammation. This suggests the potential therapeutic application of PPARgamma ligands in inflammatory disorders of the lung.
TNF-alpha caused insulin resistance on glucose uptake and on insulin signalling in fetal brown adipocytes. Since treatment with TNF-alpha activates stress kinases, including c-jun NH2 terminal kinase (JNK), and p42/p44 and p38 mitogen-activated protein kinases (MAPK), we explored the contribution of these pathways to insulin resistance by TNF-alpha. Rosiglitazone is used to treat Type 2 diabetes as it improves insulin sensitivity in vivo. However, its ability to ameliorate TNF-alpha-induced insulin resistance in brown adipocytes remains to be explored.
We used fetal rat primary brown adipocytes cultured with TNF-alpha, with or without stress kinase inhibitors or rosiglitazone, and further stimulated with insulin. Then, we measured glucose uptake and GLUT4 translocation. To determine the insulin signalling cascade, we submitted cells to lysis, immunoprecipitation and immunoblotting.
Exposure to TNF-alpha for 24 h impairs insulin stimulation of the phosphatidylinositol (PI) 3-kinase activity associated with IRS-2 and Akt activity. Pretreatment with PD98059 or PD169316, which inhibit p42/p44MAPK and p38MAPK respectively, restored insulin signalling and insulin-induced glucose uptake in the presence of TNF-alpha. However, in the presence of SP600125, an inhibitor of JNK, TNF-alpha still produced insulin resistance. Rosiglitazone ameliorated insulin resistance by TNF-alpha in brown adipocytes, restoring completely insulin-stimulated glucose uptake and insulin-induced GLUT4 translocation to plasma membrane in parallel to the insulin signalling cascade IRS-2/PI 3-kinase/Akt.
Rosiglitazone treatment impaired TNF-alpha activation of p38 and p42/p44MAPK, restoring insulin signalling and leading to normalisation of glucose uptake.
It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease ranging in severity from steatosis to cirrhosis. Type 2 diabetes mellitus is a cause of primary NAFLD. Thiazolidinediones have been shown to enhance insulin sensitivity, improve glycemic control in type 2 diabetes patients and to improve the histologic markers of nonalcoholic steatohepatitis. This study aims to determine the safety and effectiveness of rosiglitazone in inadequately controlled type 2 diabetes patients with NAFLD.
Taiwanese type 2 diabetes patients with inadequate control on insulin secretagogues and metformin, with no history of significant alcohol ingestion, with mildly elevated serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and a diagnosis of fatty liver determined by ultrasonography were enrolled. Patients were treated for 24 weeks with rosiglitazone, 4-8 mg daily. Primary endpoints were change in AST and ALT levels from baseline and reduction in A1C < 6.5%.
Out of a total of 68 patients, 60 (88.2%) completed the study treatment without serious adverse events. Treatment in two (2.9%) patients was discontinued due to elevated AST or ALT levels to more than three times the upper limit of normal, and noncompliance or loss of follow-up in six (8.8%) patients. Of the 60 patients who completed the study treatment, mean fasting plasma glucose, A1C, fasting plasma insulin, mean ALT and homeostasis model assessment for insulin resistance were all significantly reduced. Normal AST and ALT levels were achieved and maintained for at least three consecutive measurements and through to the end of the study period in 20 (33.3%) patients. Weight increased by a mean of 2.6 +/- 2.4 kg (p < 0.001).
Rosiglitazone was reasonably well tolerated in patients with inadequately controlled type 2 diabetes and NAFLD. One-third of patients showed improved liver function after treatment.
Rosiglitazone is an insulin-sensitizing agent. We aimed to assess the effects of rosiglitazone on a methionine- and choline-deficient diet (MCDD) model of nonalcoholic steatohepatitis (NASH) in rats. Wistar rats were fed either MCDD or a control diet in the 4-week induction study; they were given saline or 4 mg/kg/day rosiglitazone. After the induction study period, the rats were divided into four groups and fed MCDD or given a control diet for an additional 8 weeks and received saline or rosiglitazone. Serum and tissue samples were obtained. Rosiglitazone improved inflammation in NASH and improved ALT, alkaline phosphatase, and interleukin-6 levels in the induction study and interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels in the treatment study. Our preliminary study is the first to show the anti-inflammatory effects of rosiglitazone in NASH. Rosiglitazone's effect on cytokines may be a key mechanism of its anti-inflammatory effect in NASH.
Recent data have revealed that the plasma concentration of inflammatory mediators, such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), is increased in the insulin resistant states of obesity and type 2 diabetes, raising questions about the mechanisms underlying inflammation in these two conditions. It is also intriguing that an increase in inflammatory mediators or indices predicts the future development of obesity and diabetes. Two mechanisms might be involved in the pathogenesis of inflammation. Firstly, glucose and macronutrient intake causes oxidative stress and inflammatory changes. Chronic overnutrition (obesity) might thus be a proinflammatory state with oxidative stress. Secondly, the increased concentrations of TNF-α and IL-6, associated with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction. This might interfere with the anti-inflammatory effect of insulin, which in turn might promote inflammation.
In obesity, insulin resistance appears frequently after activation of proinflammatory molecules. Caspase-generated cytokeratin-18 (CK-18) fragments are produced during the apoptosis of hepatic cells. The main objective in the present study is to investigate the relationship between insulin resistance and caspase-generated CK-18 fragments in patients with severe obesity.
Sixty-two patients selected for bariatric surgery were clinically studied (sex, age, weight, waist diameter, body mass index, arterial pressure and type 2 diabetes mellitus) and analytic parameters were measured in blood (glucose concentration, cholesterol, triglycerides, insulin, glycosylated hemoglobin, aspartate aminotransferase, alanine aminotransferase, high-sensitivity C-reactive protein, adiponectin, interleukin 6, interleukin 18 and CK-18 fragments). Patient group division was based on 70th percentile of insulin resistance as measured by homeostasis model assessment (HOMA) and also according to liver histology.
Patients with greater insulin resistance (percentile > 70th) showed higher values of CK-18 fragments, interleukin 6 and transaminases. A positive correlation between the HOMA score, value of CK-18 fragments and triglyceride level was found. A correlation between CK-18 fragments with interleukin 6, triglycerides and transaminases was also observed. HOMA score and value of CK-18 fragments correlated with the degree of liver fibrosis.
Greater degree of insulin resistance induces apoptosis of hepatic cells as measured by the serum levels of CK-18 fragments.
Obesity induces an insulin-resistant state in adipose tissue, liver, and muscle and is a strong risk factor for the development of type 2 diabetes mellitus. Insulin resistance in the setting of obesity results from a combination of altered functions of insulin target cells and the accumulation of macrophages that secrete proinflammatory mediators. At the molecular level, insulin resistance is promoted by a transition in macrophage polarization from an alternative M2 activation state maintained by STAT6 and PPARs to a classical M1 activation state driven by NF-kappaB, AP1, and other signal-dependent transcription factors that play crucial roles in innate immunity. Strategies focused on inhibiting the inflammation/insulin resistance axis that otherwise preserve essential innate immune functions may hold promise for therapeutic intervention.
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor family of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and repression. Expression of PPAR-gamma is an early and pivotal event in the differentiation of adipocytes. Several agents that promote differentiation of fibroblast lines into adipocytes have been shown to be PPAR-gamma agonists, including several prostanoids, of which 15-deoxy-delta-prostaglandin J2 is the most potent, as well as members of a new class of oral antidiabetic agents, the thiazolidinediones, and a variety of non-steroidal anti-inflammatory drugs (NSAIDs). Here we show that PPAR-gamma agonists suppress monocyte elaboration of inflammatory cytokines at agonist concentrations similar to those found to be effective for the promotion of adipogenesis. Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).
Rosiglitazone maleate (Avandia, SmithKline Beecham, Philadelphia, Pennsylvania) is a new oral hypoglycemic agent approved for the treatment of type 2 diabetes. It acts primarily by increasing insulin sensitivity. In controlled trials, there has been no evidence of rosiglitazone-induced hepatocellular injury.
To report a case of hepatocellular injury in a patient receiving rosiglitazone.
Case report.
Community teaching hospital.
61-year-old man receiving rosiglitazone, 4 mg/d for 2 weeks.
Discontinuation of rosiglitazone therapy.
Clinical evaluation and assessment of liver function test results were done daily during hospitalization and periodically after discharge. The outpatient record was also reviewed.
After receiving rosiglitazone for 2 weeks, the patient presented with anorexia, vomiting, and abdominal pain. Liver function tests revealed severe hepatocellular injury. Discontinuation of rosiglitazone therapy led to rapid improvement of liver function and resolution of symptoms.
Rosiglitazone may be associated with hepatocellular injury. We believe that patients receiving rosiglitazone should have liver enzyme levels monitored earlier and more frequently than initially recommended.
Rosiglitazone maleate is the second approved oral hypoglycemic agent of the thiazolidinedione class. The first, troglitazone, has been associated with liver failure, occasionally resulting in liver transplantation or death. There have been no reports to date of rosiglitazone-associated elevations in the alanine aminotransferase level or hepatotoxicity.
To report the clinical characteristics of liver failure developing in a patient receiving rosiglitazone.
Case report.
University hospital.
69-year-old man taking rosiglitazone, 4 mg/d.
Discontinuation of rosiglitazone therapy and treatment with lactulose, vitamin K, fresh frozen plasma, ventilatory assistance, and intensive care unit support.
Blood test monitoring, including toxicology screening, liver function tests, coagulation studies, serum chemistries, and complete blood counts.
After 21 days of rosiglitazone therapy, hepatic failure developed. Other causes of hepatic failure, such as viruses and toxins, were excluded, although it is possible that congestive heart failure was also a causative factor. The patient recovered fully with supportive care.
Rosiglitazone may be associated with hepatic failure.
The thiazolidinediones are a new class of compounds for treatment of type 2 diabetes. Troglitazone became available in the United States in 1997 but was withdrawn from the market in March 2000 because it caused severe idiosyncratic liver injury. Rosiglitazone and pioglitazone have been available since 1999. Because these drugs directly improve insulin resistance and decrease plasma insulin levels (a risk factor for coronary artery disease), they may decrease risk for cardiovascular disease in patients with type 2 diabetes. Research on the non-glucose lowering effects of troglitazone and, to a lesser extent, of rosiglitazone and pioglitazone have demonstrated changes in several cardiovascular risk factors associated with the insulin resistance syndrome. These beneficial effects include a decrease in blood pressure, correction of diabetic dyslipidemia, improvement of fibrinolysis, and decrease in carotid artery intima-media thickness. Other in vitro effects related to the ability of these agents to bind a newly described class of receptors (peroxisome proliferator-activated receptors) may also have implications for atherosclerosis. However, these drugs increase low-density lipoprotein (LDL) cholesterol levels and may favorably change LDL particle size and susceptibility to oxidation (although the implications of the latter changes are not dear). Furthermore, these drugs tend to cause weight gain. The authors' enthusiasm for these drugs has diminished somewhat because of reported adverse events, including rare liver failure. Nevertheless, because of the mechanism of action of the thiazolidinediones, clinical trials designed to determine whether they (or similar "insulin sensitizers") decrease cardiovascular events in people with type 2 diabetes will be of interest.
Granulomatous hepatitis has many causes. Drugs are an important etiologic factor. Several oral hypoglycemic agents are available for treatment of type II diabetes. Rosiglitazone, a thiazolidinedione, is a newer agent in this class. It has not been shown to be hepatotoxic in the premarketing trials. However, a few case reports have implicated it as a cause of acute hepatocellular injury. The authors report a case of granulomatous hepatitis associated with use of rosiglitazone. Liver function tests should be done regularly to monitor patients on this medication.
Troglitazone treatment has been associated with idiosyncratic hepatic reaction leading to hepatic failure and death in some patients. This raises questions regarding whether all thiazolidinediones or peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonists are hepatotoxic and whether data from clinical trials are adequate to detect a signal of potentially serious drug-related hepatotoxicity. The purpose of this study was to assess whether the idiosyncratic liver toxicity reported with troglitazone is molecule-specific or a thiazolidinedione class effect, based on liver enzyme data collected prospectively during phase 2/3 clinical trials with rosiglitazone, a new, potent, and specific member of the thiazolidinedione class.
This is an analysis of liver function in type 2 diabetic patients at baseline and serially in 13 double-blind, 2 open-label active-controlled, and 7 open-label extension studies of rosiglitazone treatment conducted in outpatient centers throughout North America and Europe. The study comprised > 6,000 patients aged 30-80 years with type 2 diabetes. Patients underwent baseline liver function studies and were excluded from clinical trials if they had an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase value 2.5 times greater than the upper limit of the reference range. The main outcome measures were liver enzyme levels, which were assessed at screening, at baseline, and every 4 weeks for the first 3 months of treatment and at 6- to 12-week intervals thereafter. Patients with at least one on-therapy ALT value >3 times the upper limit of the reference range were identified, and their case records examined in detail.
At baseline, 5.6% of the patients with type 2 diabetes (mean HbA(1c) 8.5-9.0%) had serum ALT values between 1.0 and 2.5 times the upper limit of the reference range. On antidiabetic therapy, most of those patients ( approximately 83%) had a decrease in ALT values, many into the normal range. The percentages of all patients with an on-therapy ALT value >3 times the upper limit of the reference range during double-blind and open-label treatment were as follows: rosiglitazone-treated 0.32%, placebo-treated 0.17%, and sulfonylurea-, metformin-, or insulin-treated 0.40%. The respective rates of ALT values >3 times the upper limit of the reference range per 100 person-years of exposure were 0.29, 0.59, and 0.64.
No evidence of hepatotoxic effects was observed in studies that involved 5,006 patients taking rosiglitazone as monotherapy or combination therapy for 5,508 person-years. This is in keeping with hepatic data from clinical trials of another member of the class, pioglitazone, and in contrast to the clear evidence of hepatotoxic effects observed during the troglitazone clinical trial program. These findings suggest that the idiosyncratic liver toxicity observed with troglitazone is unlikely to be a thiazolidinedione or a PPAR-gamma agonist class effect. Poorly controlled patients with type 2 diabetes may have moderate elevations of serum ALT that will decrease with improved glycemic control during treatment with rosiglitazone or other antihyperglycemic agents.
Troglitazone maleate (Rezulin) has been associated with severe hepatotoxicity, which led to its withdrawal from the U.S. market in March 2000. Rosiglitazone maleate (Avandia) is being marketed as a safe alternative in the treatment of type 2 diabetes mellitus. We report a case of severe thiazolidinedione-induced cholestatic hepatitis in a 56-year-old female patient at a university hospital who was given rosiglitazone, 8 mg/day, after she developed milder hepatotoxicity while taking troglitazone. Rosiglitazone was discontinued, and the patient was treated with prednisone, azathioprine, and ursodiol. Clinical evaluation and liver biopsy were performed and liver function tests were monitored. After being switched from troglitazone to rosiglitazone the patient developed a severe cholestatic hepatitis with marked jaundice and moderate increases in serum alkaline phosphatase and gamma-glutamyltranspeptidase but only mild increases in serum aminotransferases. Discontinuation of rosiglitazone and treatment with prednisone, azathioprine, and ursodiol led to improvement, albeit with residual injury, dropout of intrahepatic bile ducts, and persisting elevations of serum alkaline phosphatase. Rosiglitazone is not always a safe alternative in patients who have had hepatotoxicity to troglitazone. It is important to monitor the serum alkaline phosphatase in addition to the serum aminotransferases in patients taking thiazolidinediones.
Thiazolidinediones (TZDs) are insulin-sensitising drugs that are ligands for the nuclear receptor PPAR gamma. They have been shown to inhibit PMA-stimulated secretion of TNFalpha from human monocytes, although only at concentrations well in excess of circulating levels observed during TZD therapy, suggesting a mechanism of action independent of PPAR gamma activation. Here we show that insulin-sensitising concentrations of the TZD rosiglitazone partially inhibit serum- or LPS- (but not PMA-) stimulated TNF alpha secretion from primary human monocytes, with an IC(50) of around 50nM. We also show that the observed effects are independent of PPAR gamma-mediated regulation of the lipid phosphatase PTEN. Reversed stimulus specificity, IC(50) in the insulin-sensitising range, and the fact that partial inhibition of TNF alpha secretion is also observed with a structurally unrelated PPAR gamma agonist, GW7845, demonstrate a mechanism of action distinct from that observed with higher TZD concentrations. These findings thus represent the first report of a PPAR gamma-dependent and therapeutically relevant anti-inflammatory action of TZDs in isolated human monocytes.
Insulin resistance (IR) commonly is associated with nonalcoholic steatohepatitis (NASH). To establish whether IR causes NASH, this study was undertaken to determine if improving IR would improve the histologic features that define NASH. Thirty adults with prior biopsy evidence of NASH were enrolled to receive rosiglitazone, 4 mg twice daily for 48 weeks. All patients were overweight (body mass index [BMI] > 25 kg/m(2)) and 23% were severely obese (BMI > 35 kg/m(2)); 50% had impaired glucose tolerance or diabetes. Liver biopsy specimens were obtained before beginning treatment and at treatment completion. Twenty-six patients had posttreatment biopsies; of these, 22 had initial protocol liver biopsies that met published criteria for NASH on subsequent blinded evaluation. Within this initial NASH group, the mean global necroinflammatory score significantly improved with treatment and biopsies of 10 patients (45%) no longer met published criteria for NASH after treatment. Significant improvement in hepatocellular ballooning and zone 3 perisinusoidal fibrosis also occurred. Five patients withdrew early; the 25 patients completing 48 weeks of treatment had significantly improved insulin sensitivity and mean serum alanine aminotransferase (ALT) levels (104 initially, 42 U/L at the end of treatment). Adverse effects led to withdrawal of 3 patients (10%). Weight gain occurred in 67% of patients and the median weight increase was 7.3%. Within 6 months of completing treatment, liver enzyme levels had increased to near pretreatment levels. In conclusion, improving insulin sensitivity with rosiglitazone resulted in improved histologic markers of NASH, an observation suggesting that insulin resistance contributes to its development and that improving insulin sensitivity may be important in treating this liver disease.
Recent data have revealed that the plasma concentration of inflammatory mediators, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), is increased in the insulin resistant states of obesity and type 2 diabetes, raising questions about the mechanisms underlying inflammation in these two conditions. It is also intriguing that an increase in inflammatory mediators or indices predicts the future development of obesity and diabetes. Two mechanisms might be involved in the pathogenesis of inflammation. Firstly, glucose and macronutrient intake causes oxidative stress and inflammatory changes. Chronic overnutrition (obesity) might thus be a proinflammatory state with oxidative stress. Secondly, the increased concentrations of TNF-alpha and IL-6, associated with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction. This might interfere with the anti-inflammatory effect of insulin, which in turn might promote inflammation.
We have recently demonstrated a potent antiinflammatory effect of troglitazone, an agonist of peroxisome proliferates activated receptor γ (PPARγ) and a partial agonist of PPARα in both the nondiabetic obese and diabetic obese subjects. We have now investigated the antiinflammatory actions of rosiglitazone, a selective PPARγ agonist. Eleven nondiabetic obese subjects and 11 obese diabetic subjects were each given 4 mg of rosiglitazone daily for a period of 6 wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk (6 wk after the cessation of rosiglitazone). Eight obese subjects and five obese diabetic subjects were also included in the study as control groups. Fasting blood samples were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. Nuclear factor κB (NFκB)-binding activity in mononuclear cells, plasma monocyte chemoattractant protein-1 (MCP-1), TNF-α, soluble intercellular adhesion molecule-1, C-reactive protein (CRP), and serum amyloid A (SAA) were measured. Blood glucose concentration changed significantly at 8 wk only in the obese diabetic subjects after rosiglitazone treatment for 6 wk, whereas insulin concentration decreased significantly at 6 wk in both groups. NFκB-binding activity in mononuclear cell nuclear extract fell in both obese and obese diabetic subjects (P < 0.02). Rosiglitazone treatment resulted in a reduction in plasma MCP-1 and CRP in both groups (P < 0.05). Plasma TNF-α and SAA concentrations were inhibited significantly in the obese group (P < 0.05) but not in the obese diabetic subjects. NFκB-binding activity and plasma MCP-1, CRP, SAA, and TNF-α did not change in the obese and obese diabetic control groups. We conclude that rosiglitazone, a selective PPARγ agonist, exerts an antiinflammatory effect at the cellular and molecular level, and in plasma. These observations may have implications for atherogenesis in the long term in subjects treated with rosiglitazone and possibly other thiazolidinediones.
The aim of this study was to assess the incidence of liver failure in association with antidiabetic treatment using pioglitazone vs. other oral antidiabetic medications.
The study was a retrospective analysis of claim data from the PharMetrics Patient-Centric Database that had over 1.12 million enrollees with type 2 diabetes. All patients, > or =18 years of age with type 2 diabetes, who had initiated treatment either with a thiazolidinedione (pioglitazone and rosiglitazone), sulfonylurea or metformin were identified and matched on the basis of propensity scores, which served as a proxy for severity of disease. The primary measure of interest was the incidence of liver failure or hepatitis post-index date. In addition to unadjusted comparisons, Cox proportional hazard models were employed to estimate the risk of developing liver failure or hepatitis.
There was no significant difference in the 1- and 2-year incidence rates of liver failure or hepatitis (primary and secondary diagnoses) between the pioglitazone monotherapy group and the respective comparator groups. In Cox proportional hazard models controlling for age, pre-index total healthcare costs, Charlson comorbidity index, procedures and a hospitalization or Emergency room (ER) visit for pre-index hyperglycaemia, and pioglitazone were not associated with an increased risk of liver failure or hepatitis, compared to all other defined groups. Furthermore, no primary or secondary diagnosis of liver failure was reported in the pioglitazone group during the follow-up period.
Results of retrospective data analysis demonstrate no evidence of increased risk of liver failure or hepatitis for patients initiating therapy on pioglitazone, compared to other oral antidiabetic agents. Pioglitazone therapy was not associated with an increased risk of liver failure at 2 years relative to other oral antidiabetic therapies.
Resistin is a protein secreted from adipose tissue that is thought to play a role in insulin sensitivity. We examined the effects of rosiglitazone and metformin on the plasma resistin levels in individuals with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus who showed poor glycemic control with glimepiride (4 mg/d) were randomized to rosiglitazone (4 mg/d) and metformin (500 mg bid) treatment groups. All subjects continued glimepiride treatment as well. The plasma concentrations of resistin were measured at baseline and at 6 months of treatment for both groups. The anthropometric parameters, fasting plasma glucose, HbA1c, total cholesterol, triglyceride, high-density lipoprotein cholesterol, free fatty acids, and adiponectin concentrations were also measured. After 6 months of treatment, the reduction in plasma glucose levels was similar between the 2 groups. There were no significant changes in the lipid profiles of either group during the study period. The plasma resistin levels decreased in the rosiglitazone group (2.49 +/- 1.93 vs 1.95 +/- 1.59 ng/ml; P < .05) but increased in the metformin group (2.61 +/- 1.69 vs 5.13 +/- 2.81 ng/ml; P < .05). The plasma adiponectin concentrations were increased in the rosiglitazone group (2.91 +/- 1.46 vs 4.23 +/- 1.77 microg/ml; P < .05) but were unchanged in the metformin group. In summary, rosiglitazone treatment decreased the plasma resistin levels whereas metformin treatment increased them in patients with type 2 diabetes mellitus showing poor glycemic control with sulfonylurea therapy. These results suggest that the observed changes in plasma resistin levels are not the consequences of improved insulin resistance, nor are they consequences of glycemic control. Considering the potential role of resistin in insulin resistance, decrease in resistin levels may contribute to improving insulin action with rosiglitazone treatment.
It is generally accepted that non-alcoholic fatty liver disease will be the most frequent liver disease in the near future and that the management of patients with non-alcoholic fatty liver disease will be a challenge for hepatologists in the next decades.
Non-alcoholic fatty liver disease is considered the hepatic manifestation of the metabolic syndrome, in which insulin resistance plays a crucial role. Although steatosis will often not progress to severe liver disease, in some patients, it results in cirrhosis and even hepatocellular carcinoma. Therefore, it is important to identify those patients at risk for developing fibrosis. Age, diabetes, obesity and hypertriglyceridaemia are independent risk factors for fibrosis in patients with elevated serum alanine aminotransferase levels and steatosis on ultrasound. The presence of multiple metabolic disorders increases the risk.
Apart from diet, exercise and correction of underlying metabolic abnormalities, no specific treatment is available at the moment. Theoretically, thiazolidinediones are an attractive way to treat non-alcoholic fatty liver disease, because they improve insulin resistance. Some preliminary studies with thiazolidinediones were encouraging, as steatosis, inflammation and fibrosis improved in a substantial number of patients. Although no serious side effects occurred in the pilot studies, we should look vigilantly for hepatotoxicity, as the first generation thiazolidinediones proved to be toxic for the liver.
In the present investigation, we studied the effects of thiazolidinedione (TZD) treatment on insulin-stimulated fatty acid (FA) and glucose kinetics in perfused muscle from high-fat (HF)-fed rats. We tested the hypothesis that TZDs prevent FA-induced insulin resistance by attenuating proinflammatory signaling independently of myocellular lipid levels. Male Wistar rats were assigned to one of three 3-wk dietary groups: control chow fed (CON), 65% HF diet (HFD), or TZD- (troglitazone or rosiglitazone) enriched HF diet (TZD + HFD). TZD treatment led to a significant increase in plasma membrane content of CD36 protein in muscle (red: P = 0.01, and white: P = 0.001) that correlated with increased FA uptake (45%, P = 0.002) and triacylglycerol (TG) synthesis (46%, P = 0.03) during the perfusion. Importantly, whereas HF feeding caused increased basal TG (P = 0.047), diacylglycerol (P = 0.002), and ceramide (P = 0.01) levels, TZD treatment only prevented the increase in muscle ceramide. In contrast, all of the muscle inflammatory markers altered by HF feeding ( upward arrowNIK protein content, P = 0.009; upward arrowIKKbeta activity, P = 0.006; downward arrowIkappaB-alpha protein, P = 0.03; and upward arrowJNK phosphorylation, P = 0.003) were completely normalized by TZD treatment. Consistent with this, HFD-induced decrements in insulin action were also prevented by TZD treatment. Thus our findings support the notion that TZD treatment causes increased FA uptake and TG accumulation in skeletal muscle under insulin-stimulated conditions. Despite this, TZDs suppress the inflammatory response to dietary lipid overload, and it is this mechanism that correlates strongly with insulin sensitivity.