Genetic factors associated with elevation of uric acid after treatment with thiazide-like diuretic in patients with essential hypertension.

We investigated changes in blood pressure (BP) and metabolic adverse effects, especially elevation of uric acid (UA), after treatment with a thiazide-like diuretic (TD) in patients with essential hypertension. Furthermore, the role of genetic factors in the elevation of UA by TD was assessed by a 500 K SNP DNA microarray. The subjects included 126 hypertensive patients (57 women and 69 men, mean age 59 ± 12 years) who registered for the GEANE (Gene Evaluation for ANtihypertensive Effects) study. After one month of the nontreatment period, TD, indapamide, angiotensin II receptor antagonist valsartan, and Ca channel blocker amlodipine were administered to all patients for 3 months each in a randomized crossover manner. BP, renal function, serum UA level, and electrolytes were measured at baseline and at the end of each treatment period. Single nucleotide polymorphisms (SNPs) associated with UA elevation after treatment with indapamide were investigated by a genome-wide association study (GWAS). Indapamide significantly decreased both office and home BP levels. Treatment with indapamide also significantly reduced the estimated glomerular filtration rate and serum potassium and increased serum UA. Patients whose UA level increased more than 1 mg/dl showed significantly higher baseline office SBP and plasma glucose and showed greater decline in renal function compared with those who showed less UA increase (<1 mg/dl). Some SNPs strongly associated with an increase in UA after treatment with indapamide were identified. This study is the first report on SNPs associated with UA elevation after TD treatment. This information may be useful for the prevention of adverse effects after treatment with TD.

Myelodysplastic syndrome of del 20q with plasma cell dysplasia.

Deletion of the long arm of chromosome 20 (del 20q) has been observed in patients with myelodysplastic syndrome (MDS) or myeloid malignancies. We experienced an MDS female case of del 20q accompanied by clusters of plasmacytic cells in bone marrow. Her bone marrow cells showed morphological abnormalities in three lineages and the chromosomal abnormality of 46, XX, del (20) (q11.2q13.3). Although the percentage of plasma cells was low in free cells, such cells showed nuclear abnormalities. In bone marrow clots, we also observed clusters of anti-CD38 and anti-CD138 antibody-positive cells. According to the FAB or WHO classification, the diagnosis was unclear. Therefore, we were obliged to term this case as MDS with plasma cell dysplasia. This patient was considered to be a rare case of MDS related to abnormalities in myeloid and B-lymphoid cells.

Effects of angiotensin II receptor blockade on glucose metabolism via AMP-activated protein kinase in insulin-resistant hypertensive rats.

AMP-activated protein kinase (AMPK) mediates metabolic responses of muscle to exercise and is involved in improvement of insulin resistance by endurance exercise. Recent studies have suggested that the renin-angiotensin system (RAS) might negatively modulate insulin-mediated actions, but there has been little investigation of the correlation between RAS and AMPK. To determine the correlations between insulin resistance, the RAS, and AMPK, we performed glucose clamp studies using both insulin and 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) to investigate the effects of various hypotonics on insulin and AMPK sensitivities. Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (SD) and those fed a fructose-rich chow (fructose-fed rats [FFRs]) for 6 weeks. FFRs were treated either with a vehicle or with valsartan or hydralazine for the last 2 weeks. We also performed Western blotting for AMPK, phospho-AMPK, and stimulating glucose transporter (GLUT)-4 proteins in each group. The glucose infusion rate for insulin (GIR(I)) was significantly lower in FFRs (10.5 +/- 1.8 mg/kg/min) than in SD (15.5 +/- 0.4 mg/kg/min), and GIR(I) was improved by valsartan (13.0 +/- 1.0 mg/kg/min) but not by hydralazine (8.3 +/- 1.6 mg/kg/min). The glucose infusion rate for AICAR (GIR(A)) in FFRs (11.1 +/- 2.2 mg/kg/min) was significantly lower than that in SD (15.5 +/- 2.8 mg/kg/min), and GIR(A) was improved by valsartan (17.5 +/- 3.1 mg/kg/min) but not by hydralazine in FFRs (11.8 +/- 1.5 mg/kg/min). Serum triglyceride level was significantly higher in FFRs; however, no difference was observed in serum triglyceride level after AICAR infusion among the groups. The amounts of AMPKalpha protein and the amounts of phospho-AMPK protein in the soleus muscle in basal conditions were not different among SD, FFRs, and FFRs treated with valsartan. There was no difference in the levels of phosphorylation of AMPK in the soleus muscle by AICAR among these three groups. No difference was observed in acetyl-CoA carboxylase (ACC) protein or phospho-ACC in both the basal condition and after AICAR infusion between SD and FFRs. Treatment with valsartan significantly increased GLUT-4 content of the soleus muscle compared with that in FFRs. These results suggest that the RAS has a significant role in the AMPK system and that impairment of response to AICAR in FFRs could be downstream of AMPK or ACC phosphorylation.

Insulin resistance functionally limits endothelium-dependent coronary vasodilation in nondiabetic patients.

Insulin resistance (IR) is now considered to be a risk factor for coronary arterial atherosclerosis and is likely to be involved in a limited endothelium-dependent vasodilatory function in peripheral circulation. We investigated whether IR impairs endothelial vasodilator function in the noninfarcted coronary artery. In 14 nondiabetic patients (10 males, 66 +/- 6 years) who were selected from 214 patients underwent IR evaluation by glucose clamp, a Doppler flow wire was used to measure coronary flow changes (percent volume flow index, %VFI) during intracoronary administration of papaverin (10 mg) and stepwise administration of acetylcholine (Ach; 1, 3, 10 microg/ml per minute) into the non-infarcted left circumflex coronary artery. Insulin resistance was comparatively evaluated by an euglycemic hyperinsulinemic glucose clamp (M value, mg/m(2) per minute) or by a 75g-oral glucose tolerance test (120-min immunoreactive insulin; 120' IRI, pmol/l). Eight patients (57%) were defined as having IR on the basis of results obtained by both the glucose clamp method (M values <167 mg/m(2) per minute) and 120' IRI (>384 pmol/l). There was no difference between papaverin-induced %VFI increases in IR and non-IR subjects (328% +/- 43% vs. 361% +/- 87%). However, IR subjects showed significantly lower Ach-induced %VFI increases in a dose-dependent manner (P < 0.05), especially when low (1 microg/ml per minute) and moderate (3 microg/ml per minute) doses of Ach were used (165% +/- 18% or 248% +/- 29% in non-IR subjects vs. 130% +/- 20% or 183% +/- 41% in IR subjects, P < 0.001, respectively). Moreover, %VFI increase at a low dose of Ach infusion significantly correlated with M values or 120' IRI ([%VFI Ach 1 microg] = 85.9 + 0.35 [M values], r = 0.58, P = 0.038; [%VFI Ach 1 microg] = 176.8 - 0.47.[120' IRI], r = -0.57, P = 0.035). Insulin resistance limits endothelium-dependent coronary vasodilation in association with the severity of IR in non-diabetic patients.

Angiotensin II inhibits glucose uptake of skeletal muscle via the adenosine monophosphate-activated protein kinase pathway.

Adenosine monophosphate-activated protein kinase (AMPK) mediates metabolic responses of muscle to exercise and is involved in improvement of insulin resistance by endurance exercise. Recent studies have suggested that the renin-angiotensin system might negatively modulate insulin-mediated actions, but there has been little investigation of the correlation between the renin-angiotensin system and AMPK. To determine this correlation, we performed studies with glucose clamp in vivo, and glucose uptake by skeletal muscle ex vivo using 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Six-week-old male Sprague-Dawley rats were fed standard chow (standard-diet rats; SD) or fructose-rich chow (fructose-fed rats; FFR) for 6 weeks. At the age of 12 weeks, SD and FFR were treated by oral gavage, either with angiotensin II (Ang II) receptor blockade (ARB; valsartan 30 mg/kg) or vehicle. Thirty minutes after the treatment, we performed glucose clamp studies to measure glucose infusion rates during infusion of insulin (GIR(I)) and of AICAR (GIR(A)), which stimulates AMPK, and studied the effect of ARB on either GIR(I) or GIR(A). In an ex vivo study, we used bilateral fresh soleus muscles from 3-week-old male Sprague-Dawley rats to examine the glucose uptake (measured by (3)H-2-deoxyglucose uptake) of one side of soleus muscle incubated with AICAR with or without Ang II, or with tumor necrosis factor-alpha, in comparison with that of the other (untreated control) side of the muscle. Blood pressure of FFR was significantly higher than that of SD rats. GIR(I) was significantly lower in FFR than in SD, and treatment with ARB did not change GIR(I). GIR(A) of FFR was significantly lower than that of SD, but GIR(A) of FFR treated with ARB was significantly increased compared with that of FFR treated with vehicle. In the ex vivo study, incubation with AICAR significantly increased glucose uptake of soleus muscles, Ang II significantly decreased AICAR-activated glucose uptake in a dose-dependent manner, and ARB canceled the effect of Ang II. The results suggest that acute inhibition of the angiotensin 1 receptor improves glucose metabolism via not insulin but AMPK pathway through the angiotensin 1 receptor in FFR.

Low adiponectin level in young normotensive men with a family history of essential hypertension.

Circulating level of adiponectin, an adipocyte-derived protein, is reduced in states of insulin resistance such as obesity and type 2 diabetes. We have previously shown that hypoadiponectinemia is related to insulin resistance in essential hypertension. Recent studies have shown that normotensive subjects with a positive family history of essential hypertension (FH+) have decreased insulin sensitivity compared to subjects with a negative family history of essential hypertension (FH-). We here examined the association between adiponectin concentration and insulin sensitivity in FH+ and FH-. Thirty young, non-obese and normotensive men without a family history of diabetes mellitus were enrolled. A total of 15 subjects were FH+, and the remaining 15 subjects were FH-. Insulin sensitivity index (ISI) was evaluated by the euglycemic hyperinsulinemic glucose clamp technique. Concentrations of adiponectin and other metabolic variables were measured. The FH+ group had significantly lower levels of ISI and adiponectin than did the FH- group. In all of the subjects, ISI was positively correlated with adiponectin concentration and high-density lipoprotein (HDL) cholesterol level and was negatively correlated with insulin level. Adiponectin concentration was the only independent determinant of ISI in a multiple regression analysis. Our results showed that adiponectin level was significantly decreased and that this was accompanied by reduced insulin sensitivity in young, nonobese and normotensive men with a family history of essential hypertension. Phenotype of reduced adiponectin level as an earlier penetrance may be especially useful in genetic analyses of insulin resistance and essential hypertension.

[Magnesium and insulin resistance].

Recently, there are some reports about correlations between insulin resistance and deficiency of magnesium. It is considered that the some of mechanisms of those correlations are magnesium deficiency fail to activate tyrosine kinase of insulin receptor and hyperinsulinemia stimulates magnesium excretion. It is expected that the exact mechanisms between insulin resistance, metabolic syndrome and magnesium metabolism.

Olmesartan ameliorates insulin sensitivity by modulating tumor necrosis factor-alpha and cyclic AMP in skeletal muscle.

We have reported that tumor necrosis factor (TNF)-alpha in skeletal muscle is one of the determinants of insulin resistance and that the renin-angiotensin system may be related to the regulation of TNF-a in skeletal muscle. Recent studies have suggested the involvement of cyclic adenosine monophosphate (cAMP) in the regulation of TNF-a in vascular smooth muscle cells or monocytes. The aim of this study was to determine the relationship between cAMP and TNF-a in skeletal muscle in connection with the renin-angiotensin system. Six-week-old male Sprague-Dawley rats were fed either normal rat chow or fructose-rich chow for 6 weeks. For the last 2 weeks of a 6-week period, the rats were treated with a vehicle or with an angiotensin II type 1 receptor antagonist (olmesartan medoxomil, 0.1 mg/kg/day). TNF-alpha levels in the soleus muscle were significantly higher and cAMP levels in the soleus muscle were significantly lower in fructose-fed rats than in control rats. Olmesartan increased cAMP and reduced TNF-a simultaneously in fructose-fed rats. There was a significant negative correlation between levels of cAMP and TNF-alpha. Moreover, a cAMP analogue reduced TNF-a levels in the soleus muscle. These results indicate that the increase in TNF-alpha via suppression of cAMP may affect the induction of insulin resistance. In addition, the facts that olmesartan increased cAMP and decreased TNF-alpha suggest that a part of the TNF-alpha regulation by angiotensin II might consist of modulation of cAMP through Gi protein activation in skeletal muscle.

Correlations of adiponectin level with insulin resistance and atherosclerosis in Japanese male populations.

OBJECTIVE: Adiponectin, which is secreted specifically by adipose tissue, has been shown to have an anti-atherosclerotic effect and to improve insulin resistance. The aim of this study was to determine the correlations of plasma adiponectin concentration with insulin resistance and atherosclerosis. DESIGN AND METHODS: We investigated the relationships of adiponectin concentration with insulin sensitivity, high-sensitivity C-reactive protein (hCRP) and pulse wave velocity (PWV) in male inhabitants of rural communities in Japan. hCRP and PWV were used as an indexes of atherosclerosis. RESULTS: A negative correlation was found between homeostasis model assessment (HOMA) as an index of insulin resistance and adiponectin concentration. Results of stepwise regression analysis for adiponectin showed that age, HOMA and serum triglyceride (TG) were independently correlated with adiponectin. Multiple regression analysis for lipid profile was also performed and revealed that adiponectin and HOMA were independently correlated with TG and serum high density lipoprotein (HDL)-cholesterol but not with serum total cholesterol. A significant negative correlation was found between adiponectin and hCRP in all subjects, and a significant negative correlation between adiponectin and PWV was also found in subjects equal or less than 70 years old. When HOMA was added to this analysis, HOMA was found to be independently correlated with hCRP and PWV, but the adiponectin level did not appear to be a significant predictor of hCRP or PWV. CONCLUSIONS: The results suggest that adiponectin plays a role in lipid metabolism and correlates with atherosclerosis either directly or through insulin resistance.

Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity.

OBJECTIVE: Based on results of in vitro studies, it has been hypothesized that blockade of the renin-angiotensin system (RAS) promotes the recruitment and differentiation of pre-adipocytes and that increased formation of small insulin-sensitive adipocytes counteracts ectopic deposition of lipids, thereby improving insulin sensitivity. We investigated the effect of RAS blockade on insulin sensitivity, adipocyte size, and intramuscular lipid content in fructose-fed rats (FFR) as a model of insulin-resistant hypertension. DESIGN AND METHODS: Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (control) and those fed a fructose-rich chow for 6 weeks. FFR were treated with a vehicle or with 1 mg/kg per day of temocapril, an angiotensin-converting enzyme inhibitor, or 0.1 mg/kg per day of olmesartan, an angiotensin II type 1 receptor blocker, for the last 2 weeks. Insulin sensitivity (M value: mg/kg per min) was estimated by the euglycemic hyperinsulinemic glucose clamp method. Sizes of adipocytes derived from epididymal fat and triglyceride content in the soleus muscle were determined. RESULTS: FFR had lower M value, higher blood pressure, larger adipocyte size, higher ratio of epididymal fat pads over body weight (%fat pads), and higher intramuscular triglyceride than did the control rats. Both temocapril and olmesartan significantly improved the M value and decreased blood pressure and adipocyte size without change in %fat pads in FFR. Adipocyte size was negatively correlated with the M value. Treatment for 2 weeks decreased, but not significantly, intramuscular triglyceride. CONCLUSIONS: RAS blockade decreases adipocyte size without change in epididymal %fat pads accompanied by improvement in insulin sensitivity.

Renal protective role of bradykinin B1 receptor in stroke-prone spontaneously hypertensive rats.

The kallikrein-kinin system plays important roles in blood pressure regulation, metabolism of electrolytes and organ protection. Although the bradykinin B2 receptor (B2R) has been reported to be involved in most of these effects, a role of the bradykinin B1 receptor (B1R) has also been noted recently. The aim of this study was to determine the role of renal B1R in stroke-prone spontaneously hypertensive rats (SHR-SP). Sixteen-week-old SHR-SP and Wistar Kyoto rats (WKY) as a control were used in the experiments. A high level of B1R mRNA was detected in SHR-SP, while the expression in WKY was almost undetectable. Immunohistochemistry revealed a B1R protein in the renal tubules and glomeruli in SHR-SP. The acute injection of a B1 R agonist into SHR-SP increased urinary NOx excretion to a level up to 5-fold higher than that in the SHR-SP treated with vehicle. The infusion of B1 R antagonist for 4 weeks resulted in a significant elevation of blood pressure and urinary albumin excretion and a decrease in urinary NOx excretion in SHR-SP. The administration of B1 R antagonist resulted in renal interstitial and glomerular fibrosis in SHR-SP. Moreover, the expressions of transforming growth factor (TGF) beta1 protein and collagen III mRNA in SHR-SP treated with B1R antagonist were significantly higher than those of SHR-SP treated with a vehicle. The expression and phosphorylation of extracellular signal-regulated protein kinase (ERK) and p38, but not c-Jun N-terminal kinase (JNK), were significantly increased in the SHR-SP treated with B1R antagonist. These results indicated that renal B1R might be over-expressed in a high blood pressure condition, and that this upregulated B1 R may play an important role in renal protection by inhibiting renal fibrosis via an increase of NO production and a suppression of TGFbeta1 expression and mitogen-activated protein kinase (ERK and p38) phosphorylation.

[Adiponectin levels and coronary risk factors in the elderly].

AIM: To determine the relationship between adiponectin level and coronary risk factors in men. METHODS: The subjects were 395 elderly men in two rural communities (Tanno, Sobetsu) in Japan. Blood pressure in the sitting position (SBP/DBP), after overnight fasting, plasma glucose level (FPG), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL) and serum adiponectin were measured. The subjects were divided into two adiponectin level groups, a high adiponectin level (> or = 7.94 microg/ml) group (H-Adipo group) and a normal adiponectin level (< 7.94 microg/ml) group (N-Adipo group), and into two age groups, 70 years of age or older (70 or older group) and less than 70 years of age (under 70 group). RESULTS: Adiponectin showed negative correlations with BMI, FPG, TC and TG and positive correlations with age, SBP and HDL. In multiple regression analysis using adiponectin as a dependent variable. BMI, SBP, FPG, TG and HDL were selected as independent variables. Age and HDL in the H-Adipo group were significantly higher than those in the N-Adipo group, and BMI, FPG, TC and TG in the H-Adipo group were significantly lower than those in the N-Adipo group. In the 70 or older group. SBP and adiponectin were significantly higher and BMI, DBP, FPG, TC and TG were significantly lower than those in the under 70 group. The mean number of total coronary risk factors in the 70 or older group (1.71) was significantly lower than that in the under 70 group (2.06). CONCLUSIONS: Coronary risk factors other than systolic blood pressure were significantly reduced in the older subjects.

Role of adiponectin in insulin-resistant hypertension and atherosclerosis.

Insulin resistance is one of the major risk factors associated with development of hypertension and atherosclerosis. Recent studies have shown that adiponectin, an adipocyte-derived hormone, may be involved in insulin resistance and development of atherosclerosis in diabetes patients. The aim of this study was to examine adiponectin levels in patients with essential hypertension to determine the relationships between adiponectin levels and insulin sensitivity and to examine the relationship of adiponectin with pulse wave velocity (PWV) in a general population based on the results of an epidemiological survey in Japan. In a clinical study, 20 normotensives (NT) and 30 non-treated essential hypertensives (EHT) were hospitalized, and euglycemic hyperinsulinemic glucose clamp (GC) was performed to evaluate insulin sensitivity defined as M value. EHT were divided into insulin-resistant EHT (EHT-R) and insulin-nonresistant EHT (EHT-N) according to the mean -1 SD of the M value of NT as a cut-off point. Fasting plasma glucose (FPG), immunoreactive insulin (IRI), and adiponectin concentrations were measured. There were no significant differences in body mass index (BMI) or FPG among the NT, EHT-N, and EHT-R groups. The M value and adiponectin concentration in EHT-R were significantly lower than those in the NT or EHT-N. The IRI level in the EHT-R was significantly higher than those in the other groups. A positive correlation between adiponectin concentration and M value was found in all subjects, and adiponectin concentration and M value were found to be significant determinants of each other in multiple regression analysis. In an epidemiological study, we studied 391 male inhabitants of rural communities in Hokkaido, Japan. Systolic blood pressure (SBP), BMI, FPG, IRI, and adiponectin were measured in all subjects early in the morning. Homeostasis model assessment (HOMA) values were calculated as an index of insulin sensitivity, and PWV was used as an index of atherosclerosis. A negative correlation between HOMA values and adiponectin concentration was found in all of the subjects. Multiple regression analysis revealed that adiponectin was a significant determinant for PWV in subjects less than 70 years of age. The results of the clinical study indicate that EHT-R had not only hyperinsulinemia but also a low concentration of adiponectin. The results of multiple regression analysis for determinants of degree of PWV using data obtained in the epidemiological study suggest that adiponectin plays a role in antiatherosclerosis, partly through improvement of insulin resistance.

Circulating resistin levels in essential hypertension.

OBJECTIVE: Resistin, a novel cysteine-rich protein secreted by adipocytes, has been proposed to serve as a link between obesity and insulin resistance in rodents, but this has remained controversial. Most of the data obtained in previous studies are restricted to mRNA levels in tissues. DESIGN AND PATIENTS: We examined the association between insulin resistance and circulating protein levels of resistin in 33 essential hypertensive patients (EHT) and 18 normotensive subjects (NT). Insulin sensitivity (M-value) was evaluated by the euglycaemic hyperinsulinaemic glucose clamp technique. RESULTS: Using a cutoff point of mean - 1 SD of the M-value in the NT, the EHT were divided into two groups: one group of 12 insulin-resistant patients (EHT-R) and one group of 21 noninsulin-resistant patients (EHT-N). There were no intergroup differences in age, gender, body mass index (BMI; range: 20.1-30.4 kg/m2), fasting glucose and total cholesterol. The EHT-R had significantly higher levels of fasting insulin and triglyceride than did the NT and the EHT-N. The EHT-R had higher levels of free fatty acid and lower levels of high-density lipoprotein cholesterol than did the EHT-N. The M-value was negatively correlated with fasting insulin, free fatty acid, and triglyceride. Circulating resistin levels were not significantly different among the three groups and were not correlated with the M-value, BMI, blood pressure, or lipid variables. CONCLUSIONS: Our results suggest that circulating resistin levels are not related to insulin resistance, at least in patients with essential hypertension, although disturbance of lipid metabolism may be associated with insulin resistance.

Chinese medicine, Jiang-Tang-Ke-Li, improves insulin resistance by modulating muscle fiber composition and muscle tumor necrosis factor-alpha in fructose-fed rats.

Insulin resistance and hyperinsulinemia are common findings in patients with essential hypertension. These impairments in glucose metabolism are commonly associated with diabetes mellitus, hypertension, and dyslipidemia, which are high risk factors of cardiovascular diseases, and recent evidence indicates that they may play a role in the development of coronary artery disease. The aim of this study was to determine the effect of Jiang-Tang-Ke-Li (JTKL), a traditional Chinese medicine used to treat diabetes mellitus in China, on insulin resistance and hypertension in fructose-fed rats (FFR). Systolic blood pressures in the FFR groups were significantly higher than that in the control group, although JTKL had no effect on systolic blood pressure for the last 2 weeks of treatment with the medicine. The average rate of glucose infusion during a glucose clamp, as an index of insulin sensitivity (M value), was significantly lower in the FFR than in the control rats, and treatment with JTKL for 2 weeks significantly increased the M value to that of the control. Treatment with Panax ginseng (PG), a component of JTKL, for 2 weeks also significantly increased the M value of FFR to the control level. The composite ratio of type I fibers in soleus muscle decreased significantly in the FFR compared to that in the control, and treatment with JTKL led to recovery of the composite ratio of type I fibers to the same level as that of the control group. The M value showed a significant positive correlation with the composite ratio of type I fibers and a significant negative correlation with the composite ratio of type II fibers. Tumor necrosis factor (TNF)-alpha levels were significantly higher in the soleus and extensor digitorum longus (EDL) muscles of the FFR than in those of the control rats. Treatment with JTKL for 2 weeks significantly lowered TNF-alpha levels to the control levels. M values showed a significant negative correlation with TNF-alpha in both the soleus and EDL muscles. The results suggest that the Chinese medicine JTKL, which contains PG as one of its valid components, improves insulin resistance by modulating muscle fiber composition and TNF-alpha in skeletal muscles in hypertensive and insulin-resistant FFR.

The effect of tumor necrosis factor-alpha on tissue specificity and selectivity to insulin signaling.

Recent studies have indicated that tumor necrosis factor (TNF)-alpha plays a significant role in insulin resistance. It has been proposed that selective impairment of insulin signaling in glucose metabolism is related to the development of atherosclerosis, although the mechanisms are not clear. The aim of this study was to elucidate the effect of TNF-alpha on tissue specificity and selectivity to insulin signaling. L6 myotubes and rat aortic vascular smooth muscle cells (VSMC) were cultured. Cells were stimulated with insulin pretreated with or without TNF-alpha. The protein extracts were used for electrophoresis and immunoblotting studies to examine phosphorylation of insulin receptor (IR)-beta, insulin receptor substrate (IRS)-1 and extracellular signal-regulated kinase (ERK). IR-beta phosphorylation was not affected by TNF-alpha in L6 or in VSMC. TNF-alpha significantly (p<0.05) inhibited IRS-1 phosphorylation by insulin but had no effect on ERK in L6. TNF-alpha had no effect on either IRS-1 phosphorylation or ERK in VSMC. Insulin induced ERK phosphorylation in a dose-dependent manner in VSMC. These results suggests that TNF-alpha plays a significant role in the tissue specificity and signal selectivity of insulin resistance. The pathway related to glucose metabolism is selectively impaired by TNF-alpha in skeletal muscle, and this impairment may induce compensatory hyperinsulinemia, which in turn would stimulate the pathway related to the cell proliferation in vascular tissues and possibly enhance the progression of atherosclerosis.