Curcumin suppresses cell proliferation and reduces cholesterol absorption in Caco-2 cells by activating the TRPA1 channel.

BACKGROUND: Curcumin (Cur) is a bioactive dietary polyphenol of turmeric with various biological activities against several cancers. Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Intestinal cholesterol homeostasis is associated with CRC. Chemotherapy for CRC is related to varied adverse effects. Therefore, natural products with anti-cancer properties represent a potential strategy for primary prevention of CRC. METHODS: The present study used Cur as a therapeutic approach against CRC using the Caco-2 cell line. The cells were treated with different concentrations of Cur for different duration of time and then the proliferation ability of cells was assessed using Cell Counting Kit-8 and 5-Ethynyl-2'-deoxyuridine assays. Oil red O staining and cholesterol assay kit were used to evaluate cellular lipid content and cholesterol outward transportation. Finally, the protein expressions of cholesterol transport-related protein and signal transduction molecules were assessed using Western blot assay. RESULTS: Cur inhibited cell proliferation in Caco-2 cells in a dose- and time-dependent manner by activating the transient receptor potential cation channel subfamily A member 1 (TRPA1) channel. Activation of the TRPA1 channel led to increased intracellular calcium, peroxisome proliferator-activated receptor gamma (PPARγ) upregulation, and the subsequent downregulation of the specificity protein-1 (SP-1)/sterol regulatory element-binding protein-2 (SREBP-2)/Niemann-Pick C1-like 1 (NPC1L1) signaling pathway-related proteins, and finally reduced cholesterol absorption in Caco-2 cells. CONCLUSIONS: Cur inhibits cell proliferation and reduces cholesterol absorption in Caco-2 cells through the Ca2+/PPARγ/SP-1/SREBP-2/NPC1L1 signaling by activating the TRPA1 channel, suggesting that Cur can be used as a dietary supplement for the primary prevention of CRC. In Caco-2 cells, Cur first stimulates calcium influx by activating the TRPA1 channel, further upregulates PPARγ and downregulates SP-1/SREBP-2/NPC1L1 signaling pathway, and finally inhibits the absorption of cholesterol. TRPA1, transient receptor potential cation channel subfamily A member 1; NPC1L1, Niemann-Pick C1-like 1; PPARγ, peroxisome proliferator-activated receptor gamma; SP-1, specificity protein-1; SREBP-2, sterol regulatory element-binding protein-2; Cur, curcumin.

Activation of TRPV1 channel by dietary capsaicin improves visceral fat remodeling through connexin43-mediated Ca2+ influx.

BACKGROUND: The prevalence of obesity has dramatically increased worldwide and has attracted rising attention, but the mechanism is still unclear. Previous studies revealed that transient receptor potential vanilloid 1 (TRPV1) channels take part in weight loss by enhancing intracellular Ca2+ levels. However, the potential mechanism of the effect of dietary capsaicin on obesity is not completely understood. Ca2+ transfer induced by connexin43 (Cx43) molecules between coupled cells takes part in adipocyte differentiation. Whether TRPV1-evoked alterations in Cx43-mediated adipocyte-to-adipocyte communication play a role in obesity is unknown. MATERIALS AND METHODS: We investigated whether Cx43 participated in TRPV1-mediated adipocyte lipolysis in cultured 3T3-L1 preadipocytes and visceral adipose tissues from humans and wild-type (WT) and TRPV1-deficient (TRPV1-/-) mice. RESULTS: TRPV1 and Cx43 co-expressed in mesenteric adipose tissue. TRPV1 activation by capsaicin increased the influx of Ca2+ in 3T3-L1 preadipocytes and promoted cell lipolysis, as shown by Oil-red O staining. These effects were deficient when capsazepine, a TRPV1 antagonist, and 18 alpha-glycyrrhetinic acid (18α-GA), a gap-junction inhibitor, were administered. Long-term chronic dietary capsaicin reduced the weights of perirenal, mesenteric and testicular adipose tissues in WT mice fed a high-fat diet. Capsaicin increased the expression levels of p-CaM, Cx43, CaMKII, PPARδ and HSL in mesenteric adipose tissues from WT mice fed a high-fat diet, db/db mice, as well as obese humans, but these effects of capsaicin were absent in TRPV1-/- mice. Long-term chronic dietary capsaicin decreased the body weights and serum lipids of WT mice, but not TRPV1-/- mice, fed a high-fat diet. CONCLUSION: This study demonstrated that capsaicin activation of TRPV1-evoked increased Ca2+ influx in Cx43-mediated adipocyte-to-adipocyte communication promotes lipolysis in both vitro and vivo. TRPV1 activation by dietary capsaicin improves visceral fat remodeling through the up-regulation of Cx43.

Diabetes mellitus is associated with early chronic venous disorder of the lower extremities in Chinese patients with cardiometabolic risk factors.

BACKGROUND: Metabolic syndrome has received great attention because it poses a potential cardiovascular hazard, which increases the risk of lower extremity atherosclerosis. However, the relationship between the components of metabolic syndrome and the onset of chronic venous disorder of the lower extremities remains unexplained. METHODS: This study investigated the characteristics of cardiometabolic risk factors of early chronic venous disorder of the lower extremities in subjects with cardiometabolic risk. The characteristics of risk factors and diabetes-related complications in diabetic patients with early chronic venous disorder of the lower extremities were also investigated. In addition, the association between early chronic venous disorder and atherosclerosis of the lower extremities was analysed. The study examined 782 subjects with cardiometabolic risk factors, including obesity, hypertension, diabetes mellitus and dyslipidaemia. Lower extremity venous function was measured by digital photoplethysmography. RESULTS: Women had a higher prevalence of early chronic venous disorder than did men (p < 0.01). Male subjects with early chronic venous disorder had a higher systolic blood pressure than those with normal venous function (p < 0.01), and female subjects with early chronic venous disorder had a higher fasting plasma glucose level than did controls (p < 0.05). The prevalence of diabetes mellitus is also significantly higher in female patients with early chronic venous disorder (p = 0.000). Diabetic patients with early chronic venous disorder not only had higher fasting plasma glucose and total cholesterol levels but also had more serious macrovascular complications than the control group. The independent risk factors of early chronic venous disorder in female subjects with cardiometabolic risks were age and fasting plasma glucose in men it was only age Women face a two times greater risk than men. The independent risk factors of early chronic venous disorder in diabetic patients were age, gender, HbA1c and triglyceride levels Women had an almost 12 times greater risk of early chronic venous disorder than men. Among the diabetic patients, the prevalence of early chronic venous disorder did not differ by ankle-brachial index. CONCLUSION: Female subjects with cardiometabolic risk factors or female diabetic patients face a greater risk of early chronic venous disorder than do male subjects. Diabetic patients with early chronic venous disorder had more serious macrovascular complications than did the controls, and the early venous function was found to be correlated with the blood glucose level and triglyceride status.

A Novel Heterozygous NF1 Variant in a Neurofibromatosis-Noonan Syndrome Patient with Growth Hormone Deficiency: A Case Report

Neurofibromatosis-Noonan syndrome (NFNS), a rare autosomal-dominant hereditary disease, is characterized by clinical manifestations of both neurofibromatosis type 1 (NF1) and NS. We present a case of NFNS with short stature caused by a heterozygous nonsense variant of the NF1 gene. A 12-year-old boy was admitted because of short stature, numerous café-au-lait spots, low-set and posteriorly rotated ears, sparse eyebrows, broad forehead, and inverted triangular face. Cranial and spinal magnetic resonance imaging showed abnormal nodular lesions. Molecular analysis revealed a novel heterozygous c.6189 C > G (p.(Tyr2063*)) variant in the NF1 gene. The patient was not prescribed recombinant growth hormone (GH) therapy because exogenous GH may have enlarged the abnormal skeletal lesions. During follow-up, Lisch nodules were found in the ophthalmologic examination. NFNS, a variant form of NF1, is caused by heterozygous mutations in the NF1 gene. The mechanism of GH deficiency caused by NF1 is still unclear. Whether NFNS patients should be treated with exogenous GH remains controversial.

Long-Term High-Fat Diet Decreases Renal Insulin-Degrading Enzyme Expression and Function by Inhibiting the PPARγ Pathway.

SCOPE: Long-term high-fat diet (HFD) causes insulin resistance, which is a primary etiological factor in the development of obesity and type 2 diabetes mellitus. Impaired insulin clearance is not only a consequence but also a cause of insulin resistance. The kidney is a major site of insulin clearance, where the insulin-degrading enzyme (IDE) plays a vital role in the proximal tubule. Thus, the study investigates the role of renal IDE in the regulation of insulin resistance in HFD-induced obese mice. METHODS AND RESULTS: Twenty four-weeks of HFD in C57BL/6 mice causes insulin resistance and impaires insulin clearance, accompanied by a decrease in renal IDE expression and activity. Palmitic acid decreases IDE mRNA and protein expressions in HK-2 cells. RNA-Seq analysis found that the PPAR pathway is involved. 24-weeks of HFD decreases renal PPARγ, but not PPARα or PPARß/δ mRNA expression. The inhibition of IDE expression by palmitic acid is prevented by the PPARγ agonist rosiglitazone. The amount of PPARγ bound to the promoters of IDE is decreased in palmitic acid-treated cells. Rosiglitazone improves insulin clearance and insulin resistance and increases renal IDE expression in HFD fed-mice. CONCLUSION: Long-term HFD decreases renal IDE expression and activity, and causes insulin resistance, which involves PPARγ.

TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice.

Nonalcoholic fatty liver is characterized by the fatty deformation and lipid deposition of hepatic parenchymal cells that are associated with cardiometabolic diseases. In this study, we report the effect of capsaicin on its receptor, transient receptor potential vanilloid 1 (TRPV1) cation channel, in preventing fatty liver formation. Functional TRPV1 has been detected in hepatocytes and liver tissues. TRPV1 activation by capsaicin reduced lipid accumulation and triglyceride level in the liver from wild-type (WT) mice. However, these effects were absent in the liver from TRPV1(-/-) mice. Chronic dietary capsaicin increased the hepatic uncoupling protein 2 (UCP2) expression in WT but not in TRPV1(-/-) mice (P < 0.01). We conclude that TRPV1 long-time activation might prevent high-fat diet-induced fatty liver in mice through upregulation of hepatic UCP2. Dietary capsaicin may represent a promising intervention in populations at high risk for fatty liver.

Atorvastatin attenuates TNF-α-induced increase of glucose oxidation through PGC-1α upregulation in cardiomyocytes.

Recent studies have shown that atorvastain has anti-inflammatory effect and can prevent cardiac hypertrophy. The development of cardiac hypertrophy and dysfunction is associated with an increase in cardiac glucose utilization. In this study, we investigated the effect of atorvastatin on glucose oxidation in tumor necrosis factor α (TNF-α)-stimulated cardiomyocytes (H9c2 cells) and the potential role of peroxisome proliferation-activated receptor coactivator 1α (PGC-1α) in this effect. Exposure of H9c2 cells to TNF-α inhibited the expressions of PGC-1α, pyruvate dehydrogenase kinase 4, and carnitine palmityl transferase 1 and induced a significant increase in glucose oxidation rate. However, the effects of TNF-α were significantly reversed by atorvastatin. Selective silence of PGC-1α in H9c2 cells resulted in the downregulation of pyruvate dehydrogenase kinase 4 and carnitine palmityl transferase 1 and further increased the TNF-α-induced glucose oxidation. Interestingly, the effect of atorvastatin on PGC-1α was almost abolished by mevalonate and partially by farnesol but not by geranylgeraniol. In conclusion, atorvastatin inhibits TNF-α-induced glucose oxidation through PGC-1α upregulation in cardiomyocytes, which might be associated with the regulation of isoprenoid metabolites.

Resveratrol Inhibits Insulin-Induced Vascular Smooth Muscle Cell Proliferation and Migration by Activating SIRT1.

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are essential for the development of hypertension. Insulin has been identified to promote VSMC proliferation and migration; resveratrol has been shown to have protective effects against cardiovascular diseases. This study aimed to investigate the effect of resveratrol on insulin-induced VSMC proliferation and migration and its potential mechanism. VSMC proliferation was measured by Cell Counting Kit-8 (CCK-8), cell counting method, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. Cell migration was detected by wound healing assay and transwell method. Expression of silent information regulator of transcription 1 (SIRT1) and phosphorylation levels of signaling molecules, such as phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), in VSMCs were detected by Western blotting. Resveratrol (25-150 µM) was found to inhibit insulin-induced VSMC proliferation. Pretreatment with 100 µM resveratrol reduced insulin (100 nM)-mediated VSMC migration. LY294002, an inhibitor of PI3K, inhibited the stimulatory effect of insulin (100 nM) on the proliferation of VSMCs. Treatment with resveratrol also decreased insulin-induced stimulatory effect on PI3K and Akt phosphorylation levels. Moreover, resveratrol treatment increased SIRT1 protein expression in VSMCs. A SIRT1 inhibitor, EX527, reversed the inhibitory effect of resveratrol on insulin-induced VSMC proliferation and migration and activation of PI3K and Akt phosphorylation levels. In conclusion, our study revealed that treatment with resveratrol inhibited insulin-mediated VSMC proliferation and migration, possibly by activating SIRT1 and downregulating the PI3K/AKT pathway.

Activation of transient receptor potential vanilloid 1 by dietary capsaicin delays the onset of stroke in stroke-prone spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: Previous studies show that endothelial nitric oxide synthase (eNOS) plays a prominent role in maintaining cerebral blood flow and preventing stroke. Capsaicin in hot pepper can increase the phosphorylation of eNOS in endothelial cells. We test the hypothesis that chronic dietary capsaicin can prevent stroke through activation of cerebrovascular transient receptor potential vanilloid 1 (TRPV1) channels in stroke-prone spontaneously hypertensive rats (SHRsp). METHODS: SHRsp were fed dietary capsaicin, and their onset of stroke was examined. TRPV1 knockout and transgenic mice were used for determining the function of TRPV1 channels. Expression of eNOS and cerebrovascular reactivity were examined. RESULTS: Immunofluorescence showed TRPV1 channels and eNOS coexpression in cerebral arterioles. Administration of capsaicin significantly increased phosphorylated eNOS in carotid arteries from wild-type mice but not in TRPV1 knockout mice. Inhibition of eNOS using N(G)-nitro-L-arginine methyl ester, removal of endothelium, or mutant TRPV1 significantly reduced capsaicin-induced endothelium-dependent relaxation of basilar arteries in mice. Chronic dietary capsaicin also remarkably increased eNOS expression in carotid arteries from SHRsp. Compared with Wistar-Kyoto rats, SHRsp had impaired endothelium-dependent relaxation of basilar arteries. Administration of capsaicin or L-arginine significantly improved the endothelium-dependent relaxation of basilar arteries in SHRsp. SHRsp had hypertrophy of cerebral arterioles, which was reversed by dietary capsaicin. Importantly, long-term administration of capsaicin significantly delayed the onset of stroke and increased the survival time in SHRsp. CONCLUSIONS: Activation of TRPV1 channels by dietary capsaicin mediated increases in phosphorylation of eNOS and could represent a novel target for dietary intervention of stroke.

[Evaluation of visceral adipose in abdominal obesity and its clinical application].

OBJECTIVE: To compare the values of measurements of obesity, including body mass index(BMI), waist circumference (WC), waist-to-hip ratio (WHR), bioelectrical impedance analyzer(BIA) (fat mass and FAT%), ultrasonography (US) (subcutaneous fat distance and intraabdominal fat distance), and computed tomography (CT) in predicting the quantification of visceral adipose in abdominal obesity, and to evaluate the best cut-off point, sensitivity and specificity of these methods. METHODS: 4,301 inpatients with hypertension, 2,155 males and 2,146 females, aged (56.4 +/- 13.8) (11 - 89), all with at least 1 risk factor of cardiovascular diseases, underwent simple body fat measurement. 3458 received BIA, 2,553 received B mode ultrasonography, 1039 underwent CT examination, and 659 received all kinds of examination. Abdominal visceral adipose area (VA) measured with CT >or= 100 cm(2) was the diagnostic criteria of visceral fat obesity (VFO). Receiver operating characteristic (ROC) curve was used to analyze the body fat indexes to determine the best cut-off point. RESULTS: (1) It was accurate for WC, fat mass, BMI, intraabdominal fat distance, FAT%, and WHR were all accurate in diagnosis of VFO with the values of area under ROC of 0.730 - 0.867. WC was the most effective measurement. (2) The best cut-off points of these methods in predicting abdominal visceral obesity in males and females were as follows: WC: 89.5 cm and 85.5 cm for WC. 25 kg/m(2) and 26 kg/m(2) for BMI, 0.97 and 0.95 for WHR, 29% and 38% for fat composition, 18.6 kg, and 20.4 kg for fat mass, and 38.5 mm and 34.7 mm for intraabdominal fat distance. CONCLUSIONS: WC, fat mass, BMI, intraabdominal fat distance, simple fat parameters, and WHR all can predict visceral adipose in abdominal obesity, in which WC is the best. For a given WC, the type of obesity can be determined by BIA and US.

[Relationship of different types of abdominal obesity to risk of metabolic syndrome].

OBJECTIVE: To explore the relationship of different types of abdominal obesity to risk of metabolic syndrome (MS). METHODS: Visceral fat area (VA) and substantial fat area (SA) were assessed by CT in 846 patients, 470 males and 376 females, aged 55 +/- 12, who suffered from at least one cardiometabolic risk factor and divided into 4 groups according to their VA and waist circumference (WC): non-obesity, masked visceral fat obesity (VFO), pseudo-VFO, and VFO groups. Blood pressure, fasting blood glucose, fasting serum insulin, and lipid profile were also measured. The MS risks of different types of abdominal obesity were compared. RESULTS: The prevalence rate of masked VFO of males was 10.9% (51/470), significantly higher than that of female (4.8%, 18/376). The prevalence rate of MS of the male patients with masked VFO was 43.1%, significantly higher than that of those in non-obesity group (25.0%), and lower than those of the males in the pseudo-VFO group (78.7%) and in the VFO group (88.6%), whereas the MS prevalence rate of the males in the pseudo-VFO group was significantly higher than those in the non-obesity and masked VFO groups. On the other hand, the MS prevalence rate of the female patients with masked VFO was 33.3%, not significantly different from that of the female patients in the non-obesity group (31.2%), but significantly lower than those of the pseudo-VFO and VFO groups (78.7% and 90.9% respectively). The MS prevalence rate of the female pseudo-VFO patients was also significantly higher than those in the non-obesity and masked VFO groups. Logistic regression analysis showed that WC and VA were independent risk factors for MS [OR (95% CI) = 1.13 (1.10-1.17), 1.01 (1.01-1.02), respectively, P < 0.01). CONCLUSION: Different types of abdominal obesity have important impacts on the risk of metabolic syndrome. Masked VFO, even though with normal WC, and pseudo-VFO have considerably higher cardiometabolic risks.

High-sensitivity C-reactive protein predicts target organ damage in Chinese patients with metabolic syndrome.

Observational studies established high-sensitivity C-reactive protein as a risk factor for cardiovascular events in the general population. The goal of this study was to determine the relationship between target organ damage and high-sensitivity C-reactive protein in a cohort of Chinese patients with metabolic syndrome. A total of 1082 consecutive patients of Chinese origin were screened for the presence of metabolic syndrome according to the National Cholesterol Education Program's Adult Treatment Panel III. High-sensitivity C-reactive protein and target organ damage, including cardiac hypertrophy, carotid intima-media thickness, and renal impairment, were investigated. The median (25th and 75th percentiles) of high-sensitivity C-reactive protein in 619 patients with metabolic syndrome was 2.42 mg/L (0.75 and 3.66 mg/L) compared with 1.13 mg/L (0.51 and 2.46 mg/L) among 463 control subjects (P < .01). There was a progressive increase in high-sensitivity C-reactive protein level with the number of components of the metabolic syndrome. Stratification of patients with metabolic syndrome into 3 groups according to their high-sensitivity C-reactive protein concentrations (<1.0, 1.0-3.0, and >3.0 mg/L) showed that the subjects with the elevated high-sensitivity C-reactive protein had a higher percentage of target organ damage than those with lower high-sensitivity C-reactive protein. Stepwise multiple logistic regression confirmed that high-sensitivity C-reactive protein was significantly associated with cardiac hypertrophy, carotid intima-media thickness, and renal impairment. The study shows a strong independent association between inflammation and target organ damage in a large cohort of patients of Chinese origin with metabolic syndrome.

[Relationship between abdominal obesity and left ventricular weight/function].

OBJECTIVE: To observe the relationship between abdominal obesity and left ventricular weight/function. METHODS: A total of 495 patients [265 males, mean age (55 +/- 12) years] with hypertension (139), diabetes (65), metabolic syndrome (285), diabetes complicated with hypertension (11) were enrolled in this study. Visceral adipose area (VA), the subcutaneous adipose (SA), the total abdominal adipose (TA) were measured by computerized tomography (CT) and left ventricular weight and function were obtained by echocardiography. Patients were divided into three groups according to the VA (I. VA<75 cm(2), n=173, II. VA>75 and < 110 cm(2), n=153, III. VA >or= 110 cm(2), n=169). RESULTS: Left ventricular mass (LVM) and LVM index (LVMI) increased and LVEF and E/A decreased in proportion to increasing VA. Left ventricular hypertrophy (LVH) rate was significantly higher in group II and III compared to group I and LVEF was significantly reduced in group III compared to group I and II. There are significant correlation between LVMI and VA, SA, TA as well as between LVEF and VA after adjusting gender, age and blood pressure. Logistic regression analysis showed that VA is an independent predictor for LVH. CONCLUSION: The abdominal adipose accumulation is closely related to the left ventricular weight and function.

[Relationship between visceral adipose tissue and prevalence of metabolic syndrome MS in patients with MS, and hypertension and/or diabetes].

OBJECTIVE: To investigate the relationship between the visceral adipose (VA) accumulation and the prevalence of metabolic syndrome (MS) in patients with MS, and hypertension and/or diabetes. METHODS: VA area was measured by computed tomography (CT) in 564 patients with with MS, and hypertension and/or diabetes, 308 males and 256 females. Body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) were assessed. Receiver operating characteristic (ROC) curve was used as index for analysis. RESULTS: (1) The VA of the patients with MS was 116 cm(2) +/- 38 cm(2), significantly higher than those of the patients with hypertension and diabetes (72 cm(2) +/- 34 cm(2) and 64 cm(2) +/- 34 cm(2) respectively, both P < 0.01). ROC curve analysis showed that the optimal cut-off points of VA for hypertriglyceridemia, hypo-high density lipoproteinemia, abdominal obesity and MS was 91 - 107 cm(2) for men; and 70 - 72 cm(2) for women. (2) The anthropometric parameters to the corresponding optimal cut-off points of VA were as follow: BMI, WC, and WHP were 25 kg/m(2), 89 cm, and 0.95 - 0.96 for men; and 24 - 25 kg/m(2), 82 - 84 cm, and 0.91 for women. Both the cut-off points of VA in assessing hyperglycemia and in assessing hypertension could not be found out. (3) The prevalence of MS was significantly increased when VA >or= 55 cm(2) in women and when VA >or= 70 cm(2) in men respectively. CONCLUSION: There is a gender difference in the accumulation of the VA tissue. Even in the subjects with overweight, abdominal obesity and dyesmetabolism have appeared in patients. The prevalence of MS is significantly increased with the intra-abdominal fat accumulation.

[PPARdelta + 294T/C gene polymorphism related to plasma lipid, obesity and left ventricular hypertrophy in subjects with metabolic syndrome].

OBJECTIVE: To investigate the relationship between PPARdelta + 294T/C gene polymorphism and lipid profile, obesity and left ventricular hypertrophy (LVH) in patients with metabolic syndrome (MS). METHODS: This study was conducted in 300 patients with MS and 174 patients with essential hypertension (EH) and 143 patients with type 2 diabetes mellitus (T2DM). MS was diagnosed according to 1999 WHO criteria. Fasting insulin (FINS), fasting blood glucose (FBG), plasma lipids levels were measured, LVH was examined by Doppler echocardiography. The PPARdelta + 294T/C gene polymorphism were analyzed using polymerase chain reaction and subsequently digested by BSLI restriction endonuclease. RESULTS: The frequencies of the PPARdelta + 294T/C genotypes were not different among three groups. Compared with T2DM and EH, MS patients had significantly higher body mass index (BMI), plasma total cholesterol, TG and LDL-C levels (P < 0.01 or P < 0.05). LVM, LVMI and incidence rate of LVH were significantly higher in MS and EH patients than that in T2DM (P < 0.01). MS patients with CC genotype had significantly higher total cholesterol and LDL-C levels than those with TT and TC genotypes (total cholesterol in CC genotype: 6.13 +/- 1.86 mmol/L vs in TC genotype: 5.14 +/- 1.10 mmol/L, P < 0.05, and CC genotype: 6.13 +/- 1.86 mmol/L vs TT genotype: 4.99 +/- 1.42 mmol/L, P < 0.01; LDL-C in CC genotype: 3.82 +/- 1.52 mmol/L vs in TC genotype: 3.14 +/- 0.88 mmol/L, P < 0.05, and in CC genotype: 3.82 +/- 1.52 mmol/L vs in TT genotype: 2.90 +/- 0.87 mmol/L, P < 0.01). BMI and LVMI in MS patients with C allele carriers (CC + TC) were significantly higher than that of TT genotype (LVMI in CC + TC: 46 +/- 10 g/m(2.7) vs in TT: 44 +/- 10 g/m(2.7); BMI in CC + TC: 26 +/- 3 kg/m(2) vs in TT: 25 +/- 3 kg/m(2), P < 0.05). CONCLUSIONS: It is indicated that PPARdelta + 294T/C gene polymorphism in subjects with MS may be involved in the occurrence of obesity and dyslipidemia. MS patients with C allele had a predominant LVH than subjects with TT genotype.

Polymorphism of the leptin gene promoter in pedigrees of type 2 diabetes mellitus in Chongqing, China.

BACKGROUND: It has been shown that the presence of leptin is associated with deabefes, glucose wefabolism and insulin metablism. In this research, we evaluated the presence of the leptin C-2549-A polymorphism in the Chinese population in Chongqing and verified its association with plasma leptin levels and anthropometric, metabolic, and clinical parameters. METHODS: Two hundred and sixty-nine patients with diabetes, 135 non-diabetic first-degree relatives of the patients, and 85 healthy controls were screened for the presence of C-2549-A polymorphism using a PCR-RFLP assay. Body mass index, fasting leptin, fasting insulin, fasting glucose and homeostatic model assessment for insulin resistance (HOMA)-IR were also determined. RESULTS: In the type 2 diabetes group, AA genotype frequency (6.32%) and A allele frequency (34.94%) was higher than in normal controls (1.18% and 25.29%, respectively). Diabetic patients with the AA genotype had lower fasting leptin and insulin levels than those with other genotypes. Carriers with the AC genotype had decreased fasting leptin and insulin levels and longer duration of disease as compared with those with CC genotype. The HOMA-IR of patients with AA or AC genotypes was lower than those with the CC genotype. In non-diabetic relatives group, individuals with the AA genotype had a lower fasting leptin level than those with the AC genotype. The fasting insulin and HOMA-IR level of carriers of the AA or AC genotype were lower than those of the CC genotype. CONCLUSION: The C-2549-A polymorphism in the leptin gene is associated with fasting leptin in patients with type 2 diabetes. The distribution of the genotypes in diabetic subjects from diabetic pedigrees differs from those in normal controls. The A allele frequency in diabetic patients is higher than that in normal controls. The haplotypes defined by genotypes are different in the familial subjects.

[Peroxisome proliferator-activated receptor gamma C-161T polymorphism and carotid artery atherosclerosis in metabolic syndrome].

OBJECTIVE: To assess the relationship between PPAR gamma C161-T polymorphism and Carotid Atherosclerosis in metabolic Syndrome (MS). METHODS: Polymerase chain reaction-restricted fragments length polymorphism was used to study the distribution of the PPAR gamma C161-T polymorphism in 248 metabolism syndrome, 163 essential hypertension (EH) and 115 type 2 diabetes mellitus (DM) patients and 121 normal controls. Fasting insulin (FINS), fasting blood glucose (FBG), uric Acid (UA), plasma lipids and ultrasonography for carotid artery were examined. RESULTS: Waistline and BMI were significantly higher in MS compared with those in control, EH and DM (P < 0.01). systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were markedly higher in MS and EH compared with those in DM and control (P < 0.01). The frequencies of the CC, CT and TT were 74.6%, 21.8% and 3.6% in MS respectively, The frequencies of the CC was significantly higher in MS compared with that in control, but T allele carrier (CT + TT) was significantly lower compared with control, DM and EH (P < 0.05 or P < 0.01). In MS, CC genotype had significantly increased the intima-media thickness (IMT) of common carotid artery and plaque index compared with CT + TT (IMT: 0.84 mm +/- 0.3 mm vs 0.66 mm +/- 0.19 mm; plaque index: 2.19 +/- 1.21 vs 1.66 +/- 1.36, P < 0.05), CC genotype had significantly increased plaque index compared with CT + TT in EH and DM (plaque index: EH: 1.55 +/- 1.23 vs 1.29 +/- 0.92; DM: 1.57 +/- 1.2 vs 1.18 +/- 0.85, P < 0.05); CC genotype had significantly higher SBP compared with CT + TT in EH (P < 0.05), CC genotype had significantly increased plaque index in MS than that in DM and EH (P < 0.01), CC genotype had significantly increased IMT in MS compared with DM. CC genotype had significantly higher SBP and PP compared with CT + TT in MS (SBP: 155 mm Hg +/- 23 mm Hg vs 145 mm Hg +/- 21 mm Hg; PP: 69 mm Hg +/- 8 mm Hg vs 58 mm Hg +/- 8 mm Hg, 1 mm Hg = 0.133 kPa, P < 0.05). CONCLUSION: In MS, CC genotype was prone to lesion of carotid artery, but CT + TT may reduce lesion of carotid artery, which implicates that PPAR gamma C161-T may play a important role in carotid artery arteriosclerosis.

[The clinical characteristics and its relationship with metabolic syndrome in elderly subjects with impaired glucose regulation].

OBJECTIVE: To study the clinical characteristics of impaired glucose regulation (IGR) in elderly subjects and its relationship with metabolic syndrome (MS). METHODS: The exploration of IGR in 2 810 Chongqing citizens over 40 years old was done by OGTT in a cross-section study. Normal glucose tolerance (NGT), IGR and diabetes (DM) were grouped based on the1999 diagnosis standard of WHO. IGR was composed of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and both of which. RESULTS: The prevalence of IGR was 18.11%, among which IGT (85.27%). Compared with the NGT group, the IGR group had higher age, body mass index (BMI), blood pressure, triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-c) and HOMA-IR, lower high density lipoprotein cholesterol (HDL-c) and HOMA-B. The IGR group had lower blood pressure, TG and HOMA-IR, and higher HOMA-B than the DM group. When each subgroup of IGR was compared with each other, both IFG plus IGT subgroup and IFG subgroup had higher BMI and HOMA-IR, and lower HOMA-B than IGT subgroup. The prevalences of hypertension, lipid disorder, obesity/overweight, and microalbuminuria in each subgroup of IGR were statistically higher than that of the NGT group. The prevalence of MS in the IFG plus IGT subgroup was higher than that of the IGT subgroup. CONCLUSIONS: The incidence of IGR was high in elderly people over 40 years old in local district of Chongqing city. There were various metabolic disorders in the subgroups of IGR. The IFG plus IGT and IFG group had higher BMI, hypertension, microalbuminuria and HOMA-IR, but lower HOMA-B than the IGT group.

[Cell biological mechanism involved in the effect of sodium selenite on improving insulin sensitivity].

OBJECTIVE: To study the cell biological mechanism of sodium selenite improving insulin sensitivity in pubertal rats with insulin resistance. METHODS: The content of inositol 1,4,5-trisphosphate (IP3) was examined by anion resin chromatography, and mRNA levels of phosphatidylinositol 3-kinase regulatory subunits (PI3Kp85 alpha) and Se-P were detected by RT-PCR in hepatocyte isolated from pubertal rats with insulin resistance. RESULTS: The mRNA levels of Se-P and PI3Kp85 alpha and content of IP3 in isolated hepatocyte decreased in pubertal male rats with insulin resistance. The above indices increased and reached normal level in rats supplied with selenium. The response to insulin stimulation in isolated hepatocyte in rats with selenium supply was similar to that in the control group, and both groups had higher response than those with high-fat diet. Alone when inhibited by wortmannin, the concentration of IP3 increased slightly in rats with selenium supply, but still was lower than that in the control group. CONCLUSIONS: These results indicate that the effect of selenium improving insulin sensitivity may be related to phosphatidylinositol PI3K signalling pathway. The effect of regulation of IP3 by selenium is not as effective as that by insulin, which may explain the difference of effect between selenium and insulin.

Peroxisome proliferator-activated receptor delta protects against obesity-related glomerulopathy through the P38 MAPK pathway.

OBJECTIVE: Obesity is a prominent component of metabolic syndrome and a major risk factor for renal disease. The aim of this study was to explore the effect of cross-talk between peroxisome proliferator-activated receptor (PPAR)δ and p38 mitogen-activated protein kinase (p38 MAPK) on obesity-related glomerulopathy. DESIGN AND METHODS: Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet for 32 weeks. Glomerular mesangial cells HBZY-1 and mature differentiation 3T3-L1 cells were cocultured and were transfected with PPARδ-expressing vectors or treated with agonist or inhibitor of PPARδ or p38 MAPK. RESULTS: Rats on a high-fat diet showed typical characteristics of metabolic syndrome including obesity, dyslipidemia, insulin resistance, and hypertension. Rats on a high-fat diet also had significant glomerular hypertrophy and extracellular matrix accumulation, which were accompanied by increased p38 MAPK phosphorylation and decreased PPARδ expression in the kidney tissue. The roles of p38 MAPK and PPARδ in a coculture system of mesangial cells and mature differentiation 3T3-L1 cells were further explored. PPARδ suppression promoted laminin and type IV collagen secretion through p38 MAPK phosphorylation in mesangial cells, whereas PPARδ overexpression or PPARδ agonist attenuated phosphorylation of p38 MAPK and laminin and type IV collagen secretion. CONCLUSIONS: The characteristics of obesity-related glomerulopathy, which might be partly caused by PPARδ suppression-induced p38 MAPK activation and laminin and type IV collagen secretion was demonstrated.