Associations among the plasma amino acid profile, obesity, and glucose metabolism in Japanese adults with normal glucose tolerance.

BACKGROUND: Amino acids (AAs) are emerging as a new class of effective molecules in the etiology of obesity and diabetes mellitus. However, most investigations have focused on subjects with obesity and/or impaired glucose regulation; the possible involvement of AAs in the initial phase of glucose dysregulation remains poorly understood. Furthermore, little attention has been given to possible associations between the pattern/degree of fat deposition and the plasma AA profile. Our objective was therefore to determine the relationships between plasma AA concentrations and the type/degree of obesity and glucose regulation in Japanese adults with normal glucose tolerance. METHODS: Eighty-three subjects with normal glucose tolerance were classified as obese or nonobese and as visceral obesity or nonvisceral obesity. Correlations between the plasma levels of 23 AAs and somatometric measurements, visceral fat area (VFA), subcutaneous fat area (SFA), and 75-g oral glucose tolerance test results were analyzed. RESULTS: Obesity or visceral obesity was associated with higher levels of branched-chain AAs (isoleucine, leucine, and valine), lysine, tryptophan, cystine, and glutamate but lower levels of asparagine, citrulline, glutamine, glycine, and serine (p < 0.04). Age- and gender-adjusted analyses indicated that VFA was positively correlated with tryptophan and glutamate levels, whereas VFA and SFA were negatively correlated with citrulline, glutamine, and glycine levels (p < 0.05). The fasting and 2-h plasma glucose levels or the homeostasis model assessment of insulin resistance were positively correlated with valine, glutamate, and tyrosine levels but negatively correlated with citrulline, glutamine, and glycine levels. The homeostasis model assessment for the ß-cell function index was positively correlated with leucine, tryptophan, valine, and glutamate levels but negatively correlated with citrulline, glutamine, glycine, and serine levels (p < 0.05). CONCLUSIONS: The present study identified specific associations between 10 AAs and the type/degree of obesity, and indices of glucose/insulin regulation, in Japanese adults with preserved glucose metabolism. With the growing concern about the increasing prevalence of obesity and diabetes, the possible roles of these AAs as early markers and/or precursors warrant further investigation.

Validation study on the accuracy of echocardiographic measurements of right ventricular systolic function in pulmonary hypertension.

BACKGROUND: The accuracy of echocardiographic parameters of right ventricular (RV) function has not been sufficiently validated in patients with pulmonary hypertension (PH). The aim of this study was to evaluate whether echocardiographic measurements reliably reflect RV systolic function in PH using cardiac magnetic resonance imaging (CMRI)-derived RV ejection fraction (RVEF) as a gold standard. METHODS: A total of 37 consecutive patients with PH, 20 with pulmonary arterial hypertension, 12 with chronic thromboembolic PH, and five others, were prospectively studied. All patients underwent echocardiography, CMRI, and right-heart catheterization within a 1-week interval. Associations between five echocardiography-derived parameters of RV systolic function and CMRI-derived RVEF were evaluated. RESULTS: All five echocardiography-derived parameters were significantly correlated with CMRI-derived RVEF (percentage RV fractional shortening: r = 0.48, P = .0011; percentage RV area change: r = 0.40, P = .0083; tricuspid annular plane systolic excursion [TAPSE]: r = 0.86, P < .0001; RV myocardial performance index: r = -0.59, P < .0001; and systolic lateral tricuspid annular motion velocity: r = 0.63, P < .0001). Compared with the other indices, TAPSE exhibited the highest correlation coefficient. Of the five echocardiographic measurements, only TAPSE significantly predicted CMRI-derived RVEF in multiple regression analysis (P < .0001). Intraobserver and interobserver reproducibility was favorable for all five indices and was particularly high for TAPSE and systolic lateral tricuspid annular motion velocity. CONCLUSIONS: Echocardiographic measurements are promising noninvasive indices of RV systolic function in patients with PH. In particular, TAPSE is superior to other indices in accuracy.

Overview of Macrophage Migration Inhibitory Factor (MIF) as a Potential Biomarker Relevant to Adiposity.

The cytokine "macrophage migration inhibitory factor (MIF)" is generally recognized as a proinflammatory cytokine, and MIF is involved in broad range of acute and chronic inflammatory states. With regard to glucose metabolism and insulin secretion, MIF is produced by pancreatic ß cells and acts as a positive regulator of insulin secretion. In contrast, it is evident that MIF expressed in adipose tissues causes insulin resistance. Concerning MIF gene analysis, we found four alleles: 5-, 6-, 7-and 8-CATT at position -794 of MIF gene in a Japanese population. Genotypes without the 5-CATT allele were more common in the obese subjects than in the lean or overweight groups. It is conceivable that promoter polymorphism in the MIF gene is profoundly linked with obesity relevant to lifestyle diseases, such as diabetes. Obesity has become a serious social issue due to the inappropriate nutritional balance, and the consumption of functional foods (including functional foods to reduce fat mass) is expected to overcome this issue. In this context, MIF would be a reliable quantitative biomarker to evaluate the effects of functional foods on adiposity.

Knockdown of macrophage migration inhibitory factor disrupts adipogenesis in 3T3-L1 cells.

Obesity is a condition in which adipose tissue mass is expanded. Increases in both adipocyte size and number contribute to enlargement of adipose tissue. The increase in cell number is thought to be caused by proliferation and differentiation of preadipocytes. Macrophage migration inhibitory factor (MIF) is expressed in adipocytes, and intracellular MIF content is increased during adipogenesis. Therefore, we hypothesized that MIF is associated with adipocyte biology during adipogenesis and focused on the influence of MIF on adipogenesis. To examine the effects of MIF on adipocytes, MIF expression in 3T3-L1 preadipocytes was inhibited by RNA interference, and cell differentiation was induced by standard procedures. The triglyceride content of MIF small interfering RNA (siRNA)-transfected 3T3-L1 cells was smaller than that of nonspecific siRNA-transfected cells. In addition, MIF knockdown apparently abrogated increases in adiponectin mRNA levels during differentiation. Gene expression of peroxisome proliferator-activated receptor (PPAR)gamma, CCAAT/enhancer binding protein (C/EBP)alpha, and C/EBPdelta decreased with MIF siRNA transfection, but C/EBPbeta expression increased. Cell number and incorporation of 5-bromo-2-deoxyuridine into cells decreased from 1-3 d and from 14-20 h, respectively, after induction of differentiation in MIF siRNA-transfected cells, thus suggesting that MIF siRNA inhibits mitotic clonal expansion. Taken together, these results indicated that MIF regulates differentiation of 3T3-L1 preadipocytes, at least partially, through inhibition of mitotic clonal expansion and/or C/EBPdelta expression.

Myocardial imaging with 18F-fluoro-2-deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis.

PURPOSE: Despite accumulating reports on the clinical value of (18)F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET) and magnetic resonance imaging (MRI) in the assessment of cardiac sarcoidosis, no studies have systematically compared the images of these modalities. METHODS: Twenty-one consecutive patients with suspected cardiac sarcoidosis underwent cardiac examinations that included 18F-FDG PET and MRI. The association of 18F-FDG PET and MRI findings with blood sampling data such as serum angiotensin converting enzyme levels was also evaluated. RESULTS: Eight of 21 patients were diagnosed as having cardiac sarcoidosis according to the Japanese Ministry of Health and Welfare Guidelines for Diagnosing Cardiac Sarcoidosis. Sensitivity and specificity for diagnosing cardiac sarcoidosis were 87.5 and 38.5%, respectively, for 18F-FDG PET, and 75 and 76.9%, respectively, for MRI. When the 18F-FDG PET and MRI images were compared, 16 of 21 patients showed positive findings in one (n = 8) or both (n = 8) of the two modalities. In eight patients with positive findings on both images, the distribution of the findings differed among all eight cases. The presence of positive findings on 18F-FDG PET was associated with elevated serum angiotensin-converting enzyme levels; this association was not demonstrated on MRI. CONCLUSIONS: Both 18F-FDG PET and MRI provided high sensitivity for diagnosing cardiac sarcoidosis in patients with suspected cardiac involvement, but the specificity of (18)F-FDG PET was not as high as previously reported. The different distributions of the findings in the two modalities suggest the potential of 18F-FDG PET and MRI in detecting different pathological processes in the heart.

Effects of replacing metformin with pioglitazone on glycemic control in japanese patients with poorly controlled type 2 diabetes mellitus: A 12-week, open-label, prospective study.

BACKGROUND: Insulin resistance is a critical aspect of the pathophysiology of type 2 diabetes mellitus and is also associated with other risk factors for cardiovascular disease (eg, dyslipidemia and hypertension). Accordingly, insulin resistance is a possible target for lowering plasma glucose concentration and preventing diabetic macroangiopathy. Biguanides, such as metformin, and thiazolidinediones (TZDs), such as pioglitazone, improve insulin resistance. OBJECTIVES: The aims of this study were to assess the effects of replacing a biguanide with a TZD on glycemic control in patients with poorly controlled type 2 diabetes mellitus, and also to identify the factors affecting interpatient variation in the effects of treatment change. METHODS: This was a 12-week, open-label, prospective study in which previously prescribed metformin (500 or 750 mg/d) was replaced with pioglitazone (15 or 30 mg/d) in patients with poorly controlled type 2 diabetes mellitus. Patients with a glycosylated hemoglobin (HbA1c) concentration >7% despite treatment with diet, exercise, and hypoglycemic agents other than TZDs were eligible for the study. Patients who never received TZDs were also eligible for inclusion. Vital signs, metabolic parameters, and arterial stiffness were assessed at baseline and after 12 weeks of treatment with pioglitazone. The primary end point was change in HbA1c concentration after replacing metformin with pioglitazone. Tolerability was assessed by medical history, physical examination, and laboratory tests (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase). RESULTS: Twenty-one Japanese patients (15 women, 6 men; mean [SD] age, 61.8 [8.4] years; body mass index, 25.5 [3.0] kg/m(2)) were included in the study. HbA1c concentration was not significantly changed from baseline after 12 weeks of pioglitazone treatment (8.0% [0.7%] vs 8.2% [0.7%]). Fasting plasma glucose (FPG) concentration also was not significantly changed after the replacement of treatment (156 [27] vs 144 [30] mg/dL). In addition, the resistin concentration did not change significantly from baseline after 12 weeks of pioglitazone treatment (6.6 [3.8] vs 6.4 [3.6] ng/mL). In contrast, significant improvement from baseline was observed in triglyceride (TG) concentrations (157 [109] vs 117 [68] mg/dL; P = 0.003), high-density lipoprotein cholesterol (HDL-C) (55 [12] vs 61 [16] mg/dL; P = 0.016), remnant-like particle cholesterol (6.6 [6.0] vs 5.3 [3.5] mg/dL; P = 0.048), and serum adiponectin (8.8 [4.3] vs 23.3 [11.7] µg/mL; P < 0.001). Pulse wave velocity was also significantly improved (1730 [361] vs 1622 [339] m/sec; P = 0.009). Changes in HbA1c were significantly correlated with serum fasting insulin concentration at baseline in the patients not receiving insulin preparations (r = -0.635, P = 0.013). The percentage change in serum adiponectin concentration was correlated with the percentage changes in HbA1c and FPG concentrations (HbA1c, r = -0.518, P = 0.019; FPG, r = -0.594, P = 0.006). Body weight was significantly increased after treatment (62.6 [11.9] vs 65.5 [12.2] kg; P < 0.001). Mild edema was reported in 5 patients. One patient discontinued treatment due to an increase in serum creatine kinase activity to ~6.6 times the upper limit of normal. CONCLUSIONS: Replacement of metformin with pioglitazone did not produce significant differences in HbA1c and FPG concentrations from baseline after 12 weeks of treatment in these patients with poorly controlled type 2 diabetes mellitus. However, the replacement was effective in a subset of patients whose serum insulin concentrations were high or whose serum adiponectin concentrations were sensitive to TZDs. In addition, the replacement was associated with significant improvements in TG, HDL-C, serum adiponectin concentration, pulse wave velocity, and body weight increase from baseline.

Pilot study of short-term effects of a novel long-acting oral beraprost in patients with pulmonary arterial hypertension.

BACKGROUND: Oral prostacyclin analogs can improve the prognosis of patients with mild to moderate pulmonary arterial hypertension (PAH), but because they often provoke adverse effects, such as flushing and dizziness, administering the optimal dose can be difficult. METHODS AND RESULTS: In the present study, a novel long-acting oral beraprost (TRK-100STP: 0-360 mug/day for 12 weeks) was administered to 4 patients with mild to moderate PAH. The patients tolerated the drug well with mild adverse manifestations and negligible effects on the systemic circulation. In contrast, pulmonary vascular resistance decreased by 27+/-12% and the 6-min walk test distance increased by 11+/-11%. CONCLUSIONS: TRK-100STP is a novel option in the medical management of patients with PAH.

Analysis of N-glycan in serum glycoproteins from db/db mice and humans with type 2 diabetes.

Glycosylation has an important role in regulating properties of proteins and is associated with many diseases. To examine the alteration of serum N-glycans in type 2 diabetes, we used the db/db mouse model. Serum N-glycans were fluorescence labeled and applied to HPLC. There were reproducible differences in N-glycan profiles between the db/db mouse model and the db/+ control. The structures of the oligosaccharides, which had changed in their amounts, were analyzed by a two-dimensional mapping method, matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, and exoglycosidase digestion. Those analyses revealed an increase in the N-glycans possessing alpha1,6-fucose in the serum of db/db mice. The level of alpha1,6-fucosyltransferase mRNA was increased in the liver of the db/db mice. The ratio of a biantennary N-glycan with alpha1,6-fucose to that without alpha1,6-fucose in the liver tissue of the db/db mouse was increased relative to the db/+ control. Next, we analyzed the serum N-glycan profile in human subjects with type 2 diabetes and found an increased amount of a biantennary N-glycan that had an alpha1,6-fucose with a bisecting N-acetylglucosamine. In conclusion, the increase in alpha1,6-fucosylation is a striking change in the serum N-glycans of the db/db mice, whereas the change in the fucosylation in humans with type 2 diabetes was small, albeit statistically significant. It is likely that the change is caused, at least partially, by the increase in the alpha1,6-fucosyltransferase mRNA level in the liver. The increased alpha1,6-fucosylation may affect protein properties associated with the pathophysiology of type 2 diabetes.

Estimation of beta-cell function from the data of the oral glucose tolerance test.

Although a hyperbolic relationship between insulin secretion and insulin sensitivity has been shown, the relationship has been often questioned. We examined the relationship using oral glucose tolerance test (OGTT)-derived indexes. A total of 374 Japanese subjects who had never been given a diagnosis of diabetes underwent a 75-g OGTT. In subjects with normal glucose tolerance (NGT), the ln [insulinogenic index (IGI)] was described by a linear function of ln (x) (x, insulin sensitivity index) in regression analysis when the reciprocal of the insulin resistance index in homeostasis model assessment, Matsuda's index, and oral glucose insulin sensitivity index were used as x. Because the 95% confidence interval of the slope of the regression line did not necessarily include -1, the relationships between IGI and x were not always hyperbolic, but power functions IGI x x(alpha) = a constant. We thought that IGI x x(alpha) was an appropriate beta-cell function estimate adjusted by insulin sensitivity and referred to it as beta-cell function index (BI). When Matsuda's index was employed as x, the BI values were decreased in subjects without NGT. Log BI had a better correlation with fasting plasma glucose (PG; FPG) and 2-h PG in non-NGT subjects than in NGT subjects. In subjects with any glucose tolerance, log BI was linearly correlated with 1-h PG and glucose spike (the difference between maximum PG and FPG). In conclusion, the relationship between insulin secretion and insulin sensitivity was not always hyperbolic. The BI is a useful tool in the estimation of beta-cell function with a mathematical basis.

Recovery of protein-losing enteropathy after living-donor lobar lung transplantation in primary pulmonary hypertension.

The patient investigated was a 43-year-old woman with primary pulmonary hypertension (PPH) and refractory protein-losing enteropathy (PLE). She underwent living-donor lobar lung transplantation (LDLLT), which led to remarkable improvement in both pulmonary hypertension and PLE. Although there have been no reports, to our knowledge, that have demonstrated PLE as a complication of PPH, the present case clearly shows how PLE could complicate PPH. In addition, and more importantly, hypo-proteinemia due to PLE should not necessarily be an exclusion criterion for lung transplantation when PPH is involved, because it could markedly improve after transplantation.

Oxidative stress provokes atherogenic changes in adipokine gene expression in 3T3-L1 adipocytes.

Increased oxidative stress has been associated with obesity-related disorders. In this study, we investigated how oxidative stress, in different ways of exposure, regulates gene expression of various adipokines in 3T3-L1 adipocytes. Exposure to 100-500microM H(2)O(2) for 10min, as well as exposure to 5-25mU/ml glucose oxidase for 18h, similarly decreased adiponectin, leptin, and resistin mRNAs, and increased plasminogen activator inhibitor-1 mRNA. Secretion levels of adipokines were also changed by oxidative stress in parallel with mRNA expression levels. Although a peak increase in plasminogen activator inhibitor-1 mRNA was achieved between 4 and 8h after exposure to H(2)O(2) for 10min, significant decreases in adiponectin and resistin mRNA were observed after 16h, while leptin mRNA was decreased earlier. Our results suggest that oxidative stress, even of short duration, has a significant impact on the regulation of various adipokine gene expressions favoring atherosclerosis.

Small cell carcinoma of the lung exclusively localized within the left descending pulmonary artery.

We encountered a 69-year-old woman displaying a filling defect within the left descending pulmonary artery (PA) on a chest CT scan and pulmonary angiography. A subsequent 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan demonstrated focal uptake in the left hilum. A cytologic examination of transbronchial needle aspiration specimens revealed small cell carcinoma. The patient underwent concurrent radiation therapy and chemotherapy with cisplatin and etoposide, resulting in tumor shrinkage and recanalization of the involved PA. This is the first case of small cell carcinoma localized exclusively within the PA, and positive findings on FDG-PET facilitated the unexpected diagnosis.

Focal uptake on 18F-fluoro-2-deoxyglucose positron emission tomography images indicates cardiac involvement of sarcoidosis.

AIMS: To evaluate the value of (18)F-fluoro-2-deoxyglucose positron emission tomography ((18)F-FDG PET) in detecting cardiac sarcoidosis. METHODS AND RESULTS: Thirty-two patients with sarcoidosis and thirty controls were recruited. All subjects underwent cardiac (18)F-FDG PET after a 6 h fasting period, and subjects with sarcoidosis underwent blood testing, ECG, echocardiography, and (67)Ga and (99m)Tc-sestamibi (MIBI) scintigraphy. We classified (18)F-FDG PET images into four patterns ('none', 'diffuse', 'focal', and 'focal on diffuse') and found that all the control subjects exhibited either none (n=16) or diffuse (n=14) pattern. In contrast, fifteen subjects with sarcoidosis exhibited none, seven exhibited diffuse, eight exhibited focal, and two exhibited focal on diffuse patterns, with the prevalence of the focal and focal on diffuse patterns being significantly higher in the sarcoidosis group when compared with the control group (P<0.001). None of the 32 subjects with sarcoidosis exhibited abnormal findings on (67)Ga scintigraphy, and 4 exhibited abnormal findings on (99m)Tc-MIBI scintigraphy. CONCLUSION: Focal uptake of the heart on (18)F-FDG PET images is a characteristic feature of patients with sarcoidosis. Furthermore, (18)F-FDG PET has the potential to detect cardiac sarcoidosis that cannot be diagnosed by (67)Ga or (99m)Tc-MIBI scintigraphy.

Addition of oral sildenafil to beraprost is a safe and effective therapeutic option for patients with pulmonary hypertension.

Although sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of pulmonary hypertension (PH), safety and effectiveness have not been studied during coadministration with beraprost, an oral prostacyclin analogue. To address this issue, we administered oral beraprost (40 microg) on day 1 and beraprost (40 microg) plus sildenafil (25 mg) on days 2 to 6 patients with moderate to severe PH. Although sildenafil plus beraprost produced transient flushing in 2 of 6 patients, systemic hemodynamics and arterial and venous gas analyses were similar in comparisons between the 2 treatment groups. In contrast, sildenafil plus beraprost therapy resulted in a 2.2-fold greater reduction in mean pulmonary arterial pressure and a 1.6-fold greater reduction in pulmonary vascular resistance compared with beraprost alone, and reductions in these parameters persisted longer with combination therapy than with beraprost alone. Addition of oral sildenafil to beraprost appears to represent a safe and effective therapeutic option, at least in the acute phase, for patients with pulmonary hypertension.

Troglitazone ameliorates abnormal activity of protein tyrosine phosphatase in adipose tissues of Otsuka Long-Evans Tokushima Fatty rats.

Protein tyrosine phosphatases (PTPases) play an essential role in the regulation of steady-state phosphorylation of the insulin receptor and other proteins in the insulin signaling pathway. To determine the role of PTPases in adipose tissue in the development into an insulin-resistant state, we examined PTPase activities and protein levels of three major candidate PTPases in adipose tissues of 26-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Particulate PTPase activities in visceral and epididymal adipose tissues of OLETF rats were increased compared to those in Long-Evans Tokushima Otsuka (LETO) rats, non-insulin-resistant controls. Cytosolic PTPase activities in these tissues were conversely decreased in OLETF rats. In subcutaneous adipose tissues, those changes were not observed. Western blot analysis showed that the amounts of leukocyte antigen-related PTPase (LAR), PTPase 1B (PTP1B), and src homology 2-containing PTPase (SH-PTP2) were increased in particulate fractions of visceral and epididymal fat of OLETF rats. On the other hand, those in the cytosolic fractions were slightly decreased. Troglitazone was administered to OLETF rats to examine the effect of the drug on the changes in PTPase activity and distribution. Troglitazone treatment restored those alterations in PTPase activity in the particulate fraction and the amounts of LAR, PTP1B and SH-PTP2 in both fractions of visceral and epididymal adipose tissues of OLETF rats. Although it remains unknown whether such effects of troglitazone are mediated by peroxisome proliferator-activated receptor y, these data provide useful information for understanding the significance of PTPase in insulin-resistant rats and the molecular mechanism of troglitazone action.

A case of diabetes, deafness, cardiomyopathy, and central sleep apnea: novel mitochondrial DNA polymorphisms.

We describe a case of diabetes mellitus complicated by neurosensory hearing loss, cardiomyopathy, and sleep apnea syndrome. A 48-year-old man who was admitted for treatment of a lacerated tendon of the right shoulder was also found to require preoperative control of diabetes, a condition that had been diagnosed 4 years earlier. The family pedigree suggested maternal inheritance of diabetes. The patient also had neurosensory hearing loss and the central type of sleep apnea syndrome. His myocardium was hypertrophic and the ultrastructural analysis showed morphologically abnormal mitochondria. On the basis of the apparent characteristic manifestations, we speculated that he had a mitochondrial disease. To elucidate the responsible mutation of mitochondrial DNA, we sequenced the patient's entire mitochondrial DNA derived from blood leukocytes and found 40 sequence variants. Three of those, 5466 A/G, 7912 G/A, and 10601 T/C, have not yet been reported. Nine of the 40 variants were accompanied by an amino acid replacement, including 5466 A/G. Although we could not determine the most significant mutation, the variants of mitochondrial DNA may have been associated with this patient's unusually variable clinical manifestations.

Ganglioside GM3 participates in the pathological conditions of insulin resistance.

Gangliosides are known as modulators of transmembrane signaling by regulating various receptor functions. We have found that insulin resistance induced by tumor necrosis factor-alpha (TNF-alpha) in 3T3-L1 adipocytes was accompanied by increased GM3 ganglioside expression caused by elevating GM3 synthase activity and its mRNA. We also demonstrated that TNF-alpha simultaneously produced insulin resistance by uncoupling insulin receptor activity toward insulin receptor substrate-1 (IRS-1) and suppressing insulin-sensitive glucose transport. Pharmacological depletion of GM3 in adipocytes by an inhibitor of glucosylceramide synthase prevented the TNF-alpha-induced defect in insulin-dependent tyrosine phosphorylation of IRS-1 and also counteracted the TNF-alpha-induced serine phosphorylation of IRS-1. Moreover, when the adipocytes were incubated with exogenous GM3, suppression of tyrosine phosphorylation of insulin receptor and IRS-1 and glucose uptake in response to insulin stimulation was observed, demonstrating that GM3 itself is able to mimic the effects of TNF on insulin signaling. We used the obese Zucker fa/fa rat and ob/ob mouse, which are known to overproduce TNF-alpha mRNA in adipose tissues, as typical models of insulin resistance. We found that the levels of GM3 synthase mRNA in adipose tissues of these animals were significantly higher than in their lean counterparts. Taken together, the increased synthesis of cellular GM3 by TNF may participate in the pathological conditions of insulin resistance in type 2 diabetes.