[Pancreatic ß-cell Dysfunction and Apoptosis Induced by Elevated Free Fatty Acids Synergize with Hyperglycemia].

OBJECTIVES: To analysis the effects of glucoxicity and lipotoxicity on the function and apoptosis of pancreatic ß-cells. METHODS: The levels of circulating glucose and free fat acids (FFAs) were elevated by infusion dextrose and fat emulsion in high-fat obese rats. The insulin resistance model obese rats were divided into four gourp: obese group with saline infusion (OB-NS group, n=7), obese group with glucose infusion (OB-GS group, n=9), obese group with Lipid emulsion infusion (OB-FFA group, n=8), obese group with glucose and lipid emulsion infusion (OB-FG group, n=9). Five rats fed with general diet were taken as normal group (NC group).Plasma FFAs and ß-hydroxybutyric acid (ß-HBA) concentrations were determined by an enzymatic colorimetric method. An intravenous glucose tolerance test (IVGTT) was performed to examine the glucose-stimulated insulin secretion in vivo and immunohistochemical staining to detect the storage volume of insulin. FFA and ß-HBA concentrations were measured at baseline and post-infusion. The apoptosis of pancreatic ß-cell was detected byin situ end labeling technique (TUNEL). RESULTS: Glucose infusion rate (GIR) of obese rats was significantly lower than that in NC group [(10.82±1.8) mg/(kg·min) vs. (25.21±1.7) mg/(kg·min), P<0.05], confirming insulin resistance rat model successfully established. The insulin secretion peak load time of OB-FG group rats delayed, and the serum insulin level was significantly lower than that of NC group and OB-NS group during IVGTT. The differences were statistically significant ( P<0.05). Compared with OB-NS and NC groups, storage volume of insulin of OB-GS group reduced, and ß cell apoptosis rate elevated significantly. CONCLUSIONS: Glucolipotoxicity could induce ketone overproduction, insulin resistance and defective insulin secretion.

[Association of nt3434A→G Mutation in Mitochondrial DNA ND1 Gene with Diabetes Mellitus].

OBJECTIVES: To study the association of nt3434 A→G mutation in mitochondrial DNA NADH dehydrogenase 1 subunit (ND1) gene with diabetes mellitus. METHODS: PCR-RFLP was used to detect the nt3434 A→G variant of mtDNA ND1 gene in 216 diabetic patients and 203 healthy control individuals. Characteristics of mutation and clinical indicators in nt3434A→G family were analyzed. RESULTS: nt3434A→G mutation was detected in one diabetic patient but not found in NC group. This patient had low insulin secretion, low BMI, and elevated serum lactate acids. No significant difference was found in the mutation frequencies between these two groups. nt3434 A→G mutation was also detected in this patient's sister and daughter, who were normal glucose tolerance and had slightly elevated serum lactate acids levels. CONCLUSIONS: Further investigation would be helpful to answer whether nt3434A→G mutation of mitochondrial DNA ND1 gene is associated with an increased risk of diabetes.

Radix Astragali Improves Dysregulated Triglyceride Metabolism and Attenuates Macrophage Infiltration in Adipose Tissue in High-Fat Diet-Induced Obese Male Rats through Activating mTORC1-PPAR γ Signaling Pathway.

Increased levels of free fatty acids (FFAs) and hypertriglyceridemia are important risk factors for cardiovascular disease. The effective fraction isolated from radix astragali (RA) has been reported to alleviate hypertriglyceridemia. The mechanism of this triglyceride-lowering effect of RA is unclear. Here, we tested whether activation of the mTORC1-PPAR γ signaling pathway is related to the triglyceride-lowering effect of RA. High-fat diet-induced obese (DIO) rats were fed a high-fat diet (40% calories from fat) for 9-10 weeks, and 4 g/kg/d RA was administered by gavage. RA treatment resulted in decreased fasting triglyceride levels, FFA concentrations, and adipocyte size. RA treated rats showed improved triglyceride clearance and fatty acid handling after olive oil overload. RA administration could also decrease macrophage infiltration and expression of MCP-1 and TNF α , but it may also increase the expression of PPAR γ in epididymal adipose tissue from RA treated rats. Consistently, expressions of PPAR γ and phospho-p70S6K were increased in differentiated 3T3-L1 adipocytes treated with RA. Moreover, RA couldnot upregulate the expression of PPAR γ at the presence of rapamycin. In conclusion, the mTORC1-PPAR γ signaling pathway is a potential mechanism through which RA exerts beneficial effects on the disturbance of triglyceride metabolism and dysfunction of adipose tissue in DIO rats.

[The changes of gastrointestinal hormones GLP-1, PYY and ghrelin in patients with newly diagnosed type 2 diabetes mellitus].

OBJECTIVE: To study the changes of plasma glucagon-like peptide-1 (GLP-1), serum peptide-YY (PYY) and Ghrelin and their secretion functions in patients with newly diagnosed type 2 diabetes mellitus (T2DM). METHOD: A total of 102 subjects were enrolled, including 32 normal-glucose-tolerance controls (NGT) and 70 patients with newly diagnosed T2DM. Height, body mass, waist circumference (WC) and hip circumference were measured. The plasma lipids and 0 h, 1/2 h, 2 h plasma glucose, insulin (INS), GLP-1, serum PYY and Ghrelin in a standard meal test in each subject were detected, and body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index (ISI), homeostasis model assessment of beta cell function (HOMA-B) and early insulin secretion function index (DeltaI30/DeltaG30) were calculated. All these variables were compared between the two groups. RESULTS: Compared with those in NGT group, the WC, fasting plasma glucose (FPG), postprandial plasma glucose (2 h-PG), triglyceride (TG), HOMA-IR were significantly higher (P 0.05), while INS(30), HOMA-B, ISI, DeltaI30/DeltaG30 were significantly lower in T2DM group (P<0. 05). In addition, in T2DM group, 0 h, 1/2 h, 2 h plasma GLP-1 and serum PYY and the area under the curve (AUC) of GLP-1 (GLP-lAuc ) and PYY (PYYAc) in standard meal test were significantly lower (P<0. 05), but the serum Ghrelin and GhrelinA, were significantly higher (P<0. 05). Meanwhile, the secretory peak of GLP-1 and PYY after standard meal in T2DM patients all disappeared. In T2DM group, PYYAUC and TG were negatively correlated (P<0.05), the fasting serum Ghrelin level was negatively associated with total cholesterol (TC), and GhrelinAuc was positively associated with HOMA-B, but negatively with the low-density lipoprotein cholesterol (LDL-C) and FPG (P(<0. 05). CONCLUSION: Patients with newly diagnosed T2DM have decreased fasting and postprandial GLP-1 and PYY levels, along with changes of their secretion mode and increased levels of Ghrelin.

Short-term glucose metabolism and gut hormone modulations after Billroth II gastrojejunostomy in nonobese gastric cancer patients with type 2 diabetes mellitus, impaired glucose tolerance and normal glucose tolerance.

BACKGROUND AND AIMS: Roux-en-Y gastric bypass (RYGB) is effective in controlling blood glucose in obese patients with type 2 diabetes (T2DM). The alterations of gut hormones involving in glucose metabolism may play an important role. Our aim was to explore the short-term effects of Billroth II gastrojejunostomy (a similar type of RYGB) on glucose metabolism and gut hormone modulations in nonobese patients with different levels of blood glucose tolerance. METHODS: Twenty one nonobese gastric cancer patients with different levels of blood glucose tolerance were submitted to Billroth II gastrojejunostomy. Among them, seven had T2DM, seven with impaired glucose tolerance (IGT) and the other seven had normal glucose tolerance (NGT). Body weight, glucose parameters, responses of plasma glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP) to 75 g glucose were measured at baseline and 3 months after surgery. RESULTS: Similar weight losses were observed in all groups. Blood glucose was reduced in T2DM and IGT patients. Fasting and 30-min plasma glucose were increased significantly in NGT. GLP-1 showed insignificant alterations in all groups. PYY was evaluated in T2DM and IGT but remained unchanged in the NGT group. Decreased fasting and AUC GIP were observed in patients with T2DM; however, fasting and 30-min GIP were increased in NGT patients. CONCLUSIONS: Billroth II gastrojejunostomy is effective in reducing blood glucose in nonobese patients with T2DM and IGT but could deteriorate early blood glucose in nonobese NGT in a 3-month time period. Variations of glucose and gut hormone changes in the three groups suggest a role of proximal intestine in the pathophysiology of T2DM.

[Molecular scanning of mtDNA gene in two early-onset diabetic pedigrees].

OBJECTIVE: To search for new potential diabetogenic mtDNA defects by scanning mtDNA genome in mitochondrial DNA diabetes (MDM) pedigrees. METHODS: Blood samples were collected from the family members in two suspected MDM pedigrees, which were both maternal transmitted and early-onset diabetes. The whole mtDNA genome except D-loop was detected by direct sequencing in probands of these two diabetic pedigrees. Novel mutations displayed by direct sequencing were then screened in 200 normal glucose tolerant controls and 100 early-onset diabetic patients. RESULTS: We found a novel nt14319T --> C mutation in No. 2 pedigree, but no pathogenic mutation was found in No. 1 pedigree. The mutation of nt14319T --> C, which not being reported previously, locate in the region of ND6 subunit, causing amino acid change (asparagine --> aspartic acid). The frequencies of 14319T/C substitution in 100 early-onset diabetic patients and 200 control subjects were 6% and 5%(P > 0.05). CONCLUSION: A novel mutation 14319T --> C was identified in No. 2 pedigree. All three diabetic family members in this pedigree haboured 14319T --> C mutation, indicating that it may be the major pathogenic mutation for this family.

[Prevalence of diabetes and prediabetes mellitus in the first-degree relatives of patients with type 2 diabetes in Chengdu].

OBJECTIVE: To investigate the prevalence of diabetes and prediabetes mellitus in the first-degree relatives (FDR) of patients with type 2 diabetes (T2DM) in Chengdu. METHODS: A cross-sectional study was undertaken in Chengdu. A total of 2306 adults were recruited, including 535 FDR of T2DM patients and 1771 people without a family history of diabetes. All participants received glucose tolerance tests and measurements of waist, blood pressure and blood lipids. RESULTS: (1) The FDR of T2DM patients had greater standardized prevalence of diabetes than those without a family history of diabetes (26.6% vs. 9.2%). The standardized prevalence of prediabetes in these two groups was 15.0% and 14.1%, respretively. (2) Greater standardized prevalence of diabetes were found in both female (25.5%) and male (28.5%) FDR of T2DM patients compared with their counterparts without a family history of diabetes (women 8.7%, men 11.2%). The standardized prevalence of prediabetes between those with and without a family history of diabetes was 15.9% and 13.4% in women, 13.7% and 15.3% in men, respretively. (3) The younger than 40 years old FDR of T2DM patients had greater prevalence of diabetes and prediabetes than their counterpart without a family history of diabetes, while the FDR of T2DM with an age of > or =40 years old had greater prevalence of diabetes than their counterparts only (P > 0.05). The FDR of T2DM patients with <25 kg/m2 body mass index (BMI) had greater prevalence of diabetes and prediabetes than their counterparts without a family history of diabetes (25.1% vs. 7.4%, 13.2% vs. 9.3%, P < 0.05). The FDR of T2DM patients with > or = 25 kg/m2 BMI had greater prevalence of diabetes (33.0% vs. 13.7%, P < 0.05) but less prevalence of prediabetes (19.2% vs. 26.8%, P < 0.05) than their counterparts without a family history of diabetes. (4) The logistic regression showed that triglyceride (TG) was a risk factor for diabetes in those FDR of T2DM patients (OR = 1.363) and those without a family history of diabetes (OR = 1.27), and high density lipoprotein cholesterol (HDL-C) was a protective factor for diabetes in those without a family history of diabetes (OR = 0.546). CONCLUSION: The FDR of T2DM patients have high risk of diabetes and those younger than 40 years or with <25 kg/m2 BMI also have high risk of prediabetes.

[The efficacy and safety of recombinant human insulin injection in the treatment of diabetic patients:a multicenter, randomized, controlled and open-labeled clinical trial].

OBJECTIVE: A multicenter, randomized, controlled and open-labeled clinical trial was performed to compare the efficacy and safety of recombinant human insulin injection (Yousilin R) and Novolin R in diabetic patients. METHODS: A total of 211 cases were randomized into two groups (1:1) treated with Yousilin R versus Novolin R for 12 weeks respectively. RESULTS: Compared with baseline, the levels of glycosylated hemoglobin A1c (HbA1c) at the end of 12 weeks treatment decreased from 10.77% to 7.72%(P < 0.05) in Yousilin R group and from 10.33% to 7.62% (P < 0.05) in Novolin R group, 2-hour postprandial plasma glucose (2hPG) decreased from 15.49 mmol/L to 9.72 mmol/L (P < 0.05) in Yousilin R group and from 15.33 mmol/L to 10.07 mmol/L (P < 0.05) in Novolin R group, and fasting plasma glucose (FPG) decreased from 10.90 mmol/L to 7.31 mmol/L (P < 0.05) in Yousilin R group and from 10.22 mmol/L to 7.21 mmol/L (P < 0.05) in Novolin R group. The changes of HbA1c, 2hPG and FPG from baseline to endpoint in Yousilin R group was similar to those in Novolin R group (P > 0.05). Furthermore, hypoglycemic events (26.42% vs 30.48%), other adverse events (13.21% vs 16.19%), and serious adverse events (1.89% vs 1.90%) were comparable between Yousilin R and Novolin R groups (P > 0.05). CONCLUSIONS: Yousilin R has similar efficacy, safety and compliance profiles to Novolin R group in the treatment of diabetic patients.

[PPARGC1A gene Thr394Thr G/A polymorphism and its association with type 2 diabetes mellitus and insulin resistance in a Chinese population].

OBJECTIVE: To examine the association of the Thr394Thr polymorphism of PPARGC1A gene with type 2 diabetes (T2DM), insulin resistance (IR) and other metabolic disorders in a Chinese population. METHODS: Three hundred and seven subjects including 151 T2DM patients and 156 normal glucose tolerant controls (NC) were enrolled in this study. The Thr394Thr G/A polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Glucose, insulin, lipids levels were determined in all subjects. Body mass index (BMI), waist circumferences, index of homeostasis model assessment-insulin resistance (HOMA-IR) and blood pressure were also measured. RESULTS: The diabetic subjects had higher levels of BMI, waist circumferences, blood systolic pressure, triglycerides and lower levels of high density lipoprotein-cholesterol (HDL-C) compared with those of control subjects (P<0.05). About 43.7% (66/151) of the T2DM subjects had the AG genotype, while 37.2% (58/156) in the NC group. The frequency of the A allele was 0.225 in T2DM, and 0.186 in the NC subjects. There were no significant differences either in genotype or allelic distribution of G/A polymorphism between the two groups. In the T2DM group, subjects with AA and GA genotypes had significantly higher levels of HOMA-IR, waist circumferences and lower levels of HDL-C (P<0.05) than those carrying GG genotype. HOMA-IR in subjects with AA and AG were significantly higher than those with GG genotype in both groups. CONCLUSION: The A allele of the Thr394Thr (G-->A) polymorphism of the PPARGC1A gene was associated with insulin resistance, and may be related to central obesity and decreased HDL-C levels in Chinese population. The relationship between this polymorphism and T2DM needs further investigation.

[Protein kinase C activation is required for free fatty acid-induced impairment of endothelial nitric oxide synthase].

OBJECTIVE: To observe whether the impairment of endothelial nitric oxide synthase (eNOS) activity by elevated level of free fatty acid (FFA) is associated with activation of protein kinase C (PKC). METHODS: The cultured human umbilical vein endothelial cells were used for four groups: control group, oleic acid (OA) group (10, 50, 100, 150, 200 micromol/L), GFX group and OA+GFX group. The activity of eNOS in each group was examined, and the activity and expression of PKC were determined in both control and OA groups. The method of immunocytochemistry was performed to detect the expression of p-eNOS(1177) in control, OA (100 micromol/L), GFX and OA+GFX groups respectively. RESULTS: Compared with control group, the eNOS activity of endothelial cells in OA group was significantly reduced in a dose-dependent manner, and the expression of p-eNOS(1177) were also impaired (0.0854 +/- 0.017 vs. 0.0134 +/- 0.023, P < 0.05). PKC transposition from endochylema to cytomembrane was observed by confocal microscopy. The PKC activity was degraded in endochylema, while enhanced in cell membrane inversely, and the gross activity of PKC increased after all. When GFX, an inhibition of PKC, was added to endothelial cells at the present of OA or not, the impaired eNOS activity were partly improved. CONCLUSION: Elevated level of FFA (here is oleic acid) leading to endothelial dysfunction results from a loss of eNOS activity and its serine phosphorylation, and it may be related to activation of PKC.

Mesenchymal stem cells transplantation mildly ameliorates experimental diabetic nephropathy in rats.

BACKGROUND: Diabetic nephropathy is a common complication of diabetes mellitus. This study aimed to explore whether mesenchymal stem cells (MSCs) transplantation could attenuate diabetic nephropathy in experimental diabetic rats. METHODS: Sprague-Dawley rats received a single intraperitoneal injection of streptozotocin (STZ) (60 mg/kg). Diabetic rats were randomized to four groups: diabetes control group (DC), ciclosporin A group (CsA), MSC group, and MSC + CsA group (MSCA). Bone marrow mesenchymal stem cells were cultured, identified and labeled by 5-bromo-2'-deoxyuridine (BrdU) in vitro. Then they were transplanted to diabetic rats via introcardiac infusion. Ciclosporin A was administered daily at 5 mg/kg. At 1, 2, 4, 8 weeks after transplantation, random blood glucose, urine albumin/creatinine ratio (Alb/Cr), endogenous creatinine clearance rate and renal mass index were tested. Renal morphology and labeled cells were examined. RESULTS: Cultured MSCs expressed mesenchymal cell phenotype, and could be multidifferentiated to osteogenic and adipogenic cells. Labeled MSCs could be detected in the kidney of nephropathic rats, mainly in renal interstitium, but they did not propagate after engrafting in kidney. Over the course of the experiment, MSCA group showed a significant decrease in blood glucose compared with MSC group, CsA group and DC group (P < 0.05, respectively). The Alb/Cr in MSCA group and MSC group were significantly lower than CsA group and DC group (P < 0.05). And the Alb/Cr in MSCA group showed a significant decrease compared with MSC group (0.74 vs 0.84, P < 0.05). There was a significant difference in renal mass index between the MSCA group and DC group (5.66 vs 6.37, P < 0.05). No significant difference was found in creatinine clearance rate among 4 groups (P > 0.05). Treatment with MSC + CsA significantly ameliorated the morphology of diabetic kidney. CONCLUSION: MSC could mildly ameliorate diabetic nephropathy by decreasing blood glucose, Alb/Cr ratio and renal mass index.

[Glycemic excursions in people with normal glucose tolerance in Chengdu].

OBJECTIVE: To investigate the characteristics of glycemic excursions in people with normal glucose tolerance (NGT) in Chengdu. METHODS: A total of 50 non-obese people with normal glucose tolerance (NGT, 23-68 years old), normal blood pressures and lipid profiles participated in the study. The fluctuations of glucose levels in the participants were measured by a continuous glucose monitoring system (CGMS) for three days 72 h. The 48 h mean blood glucose (MBG), mean amplitude of glycemic excursions (MAGE), Largest amplitude of glycemic excursions (LAGE), Postprandial peak glucose (PPG), Postprandial glucose excursion (PPGE), Mean of postprandial glucose excursion (MPPGE), and absolute means of daily differences (MODD) were measured. RESULTS: The number of glucose values detected by CGMS amounted to 861+/-7 with a mean absolute difference (MAD) of 11.3%+/-10.6%. The CGMS values were significantly correlated with the capillary glucose measurements (n=1076, r=0.761, P<0.005). The participants had a MBG of (5.9+/-1.2) mmol/L, a MAGE of (1.7+/-0.7) mmol/L, a LAGE of (4.4+/-1.9) mmol/L, a daily glycemic peak (PPG) of (8.7+/-1.7) mmol/L, a nadir level of (4.3+/-0.7) mmol/L, a MPPGE of (2.3+/-1.6) mmol/L, and a MODD of (0.75+/-0.79) mmol/L. The post-breakfast Postprandial glycemic excursions (PPGE) were lower than those of post-lunch and post-dinner (P=0.01 and P=0.05). The postprandial glucose excursions in the 60-70 year-old participants were the highest (P<0.022). In 95% (77%-100%) of the daytime, the glycose levels fluctuated between 4.1 and 8.8 mmol/L, and 78% of the participants (n=39) had hyperglycemia (BG>7.8 mmol/L) and 10% (n=5) had asymtomatic hypoglycemia (BG<2.8 mmol/L). CONCLUSION: CGMS tests may be important for detecting asymptomatic hyperglycemia and hypoglycemia. The NGT people in Chengdu have exhibited abnormal blood glucose values in CGMS, revealing problems in people with normal range of blood glucose.

[Study on the mechanism of autologous platelet-rich gel to treat the refractory diabetic dermal ulcers].

OBJECTIVE: To investigate the mechanism of autologous platelet-rich gel (APG)in the treatment of refractory diabetic dermal ulcers. METHODS: After the treatment of refractory diabetic dermal ulcers with APG at 0, 3, 6, 9, 15 days, the protein levels of PDGF-BB, VEGF, IGF-1, EGF and TGF-beta1 in the granulation tissue were detected by ELISA, while the dimensions of ulcer area were measured at the same time. RESULTS: The areas of ulcers were obviously reduced at the third and fifteen day after APG treatment (P < 0.05). The concentrations of these 5 growth factors in the granulation tissue were began to increase after 3 days treatment, the peak of PDGF-BB emerged at the third day (P < 0.05), and the peaks of VEGF, IGF-1, TGF-beta1 were found at the ninth day (P < 0.05). The concentration of VEGF increased 2.1-fold, IGF-1 increased 1.95-fold, EGF increased 1.75-fold, PDGF-BB increased 1.89-fold and TGF-beta1 increased 1.67-fold. CONCLUSION: The expression of multiple growth factors are increased in granulation tissue of refractory diabetic dermal ulcers after the treatment of APG,which might be one of the mechanism of APG to treat refractory diabetic dermal ulcer.

[The effect and pathophysiological mechanism of high free fatty acids(FfAs) on the cardiac structure and function].

OBJECTIVE: To study the pathophysiological links between elevated circulating FFAs concentration and the cardiac structure, and their function in obese insulin resistance rat model. METHODS: 4 weeks age male SD rats were fed with high-fat chow (OB) or standard laboratory chow (NC) respectively. Whole-body insulin sensitivity, the maximum velocity of myocardial contraction (+dp/dt(max)) and the maximum velocity of myocardial diastole (-dp/dt(max)) of intracardiac pressure, and myocardiac cell diameter (MCD) were measured. The concentrations of triglyceride (TG), FFAs and angiotensin II (Ang II) both in blood and in left ventricular portions of heart and the expressions of NF-kappaB, I-kappaB and iNOS in myocardium were analyzed. RESULTS: OB group developed obesity and left ventricular hypertrophy, and their insulin sensitivity was much lower than that of control group. Obese rats had higher plasma concentrations of TG, FFAs and Ang II. Accordingly, dramatic lipid deposition occurred within cardiomyocytes of obese rats, and the value of myocardiac Ang II was also increased. High-fat diet also induced a progressive decrease in values of +dp/dt(max) and -dp/dt(max). The higher expressions of NF-kappaB and iNOS in myocardium were observed in OB group, while IkappaB lower. Intramyocardial lipid deposition was associated with plasma FFAs concentrations (r = 0.80, P < 0.01). Intramyocardial FFAs concentration was associated with myocardial Ang II concentration (r = 0.74, P < 0.05) and changes in expressions of NF-kappaB (r = 0.86, P < 0.01), iNOS (r = 0.66, P < 0.05). The contractile dysfunction was associated with intramyocardial lipid deposition (r = -0.87, P < 0.01), Ang II (r = -0.52, P < 0.05) and expressions of NF-kappaB (r = -0.57, P < 0. 01), iNOS (r = -0.70, P < 0. 01). The diastolic dysfunction was associated with intramyocardial lipid deposition ( r = -0.85, P < 0.01), Ang II (r = -0.82, P<0.01) and expressions of NF-kappaB (r = -0.75, P < 0.01), iNOS (r = -0.78, P < 0.01). CONCLUSION: In obese/insulin resistance, state ectopic lipid accumulation in myocardium as the results of elevated circulating FFAs and TG concentration impairs cardiac systolic and diastolic functions. It is logical to deduce that ectopic lipid accumulation in myocardium may increase RAS activity and expressions of NF-kappaB, iNOS in myocardium, all of them have important roles to increase the risk of congestive heart failure in obese subjects.

[Epidemiological study on metabolic syndrome in Chengdu adult in 2007].

OBJECTIVE: To investigate the prevalence of metabolic syndrome (MS) and associated factors in the adults in Chengdu. METHODS: A cross-sectional survey was undertaken in 2242 residents over 20 years of age. The cluster sampling method was employed to recruit participants from Yulin and Longquan communities in Chengdu. The metabolic syndrome was defined by IDF 2005. RESULTS: The prevalence of MS was 17.2%, with 15.0% and 18.6% for male and female, respectively. The age-adjusted rate of MS was 13.47%, with 17.71% and 11.09% for male and female, respectively. The difference in prevalence of MS between male and female was significant. The prevalence of central obesity, hypertension, hyperglycemia, high triglycerides, low HDL-C were 31.6%, 32.0%, 16.5%, 30.4%, and 31.2% respectively, which became 26.3%, 26.0%, 12.9%, 26.9%, and 30.5% respectively after age-adjustment. Gender differences appeared in all of the components of MS except for low HDL-C (P < 0.05). The multivariable stepwise analysis extracted age, history of hypertension, blood pressure, waist circumference, fasting glycaemia level and triglyceride as major risk factors for MS and blood HDL-C level as a protective factor of MS. CONCLUSION: The prevalence of MS is considerably high in Chengdu. It will continue to rise thanks to the social economic development and population ageing. There is an urgent need to take actions to reduce the burden of MS.

[Role of apoptosis and mitochondrial apoptotic pathway in glucolipotoxicity-induced islet beta-cell dysfunction].

OBJECTIVE: To investigate the mechanism of beta-cell dysfunction induced by glucolipotoxicity in high fat-fed obese rats. METHODS: Eighteen high-fat obese male Wistar rats were assigned into 3 groups and underwent 48-hour infusion through the jugular vein with normal saline (n=6), 20% intralipid + heparin (FFA group, n=6), or 25%glucose +20% intralipid + heparin (GS-FFA group, n=6). The plasma beta-hydroxybutyric acid (beta-HBA) was measured before and at the end of the infusion. After the infusion, the rats were sacrificed following an intravenous glucose tolerance test (IVGTT) to remove the tail of the pancreas for detection of apoptotic islet cells using TUNEL method. Immunohistochemical staining was performed to detect the expression of cytochrome c (cyt c), apoptosis-inducing factor (AIF), caspase-9 and caspase-3 in the islet cells. RESULTS: At the end of the infusion, all the rats exhibited increased plasma beta-HBA levels, which was the highest in the GS-FFA group (P<0.05). IVGTT performed after the infusion showed a significantly lower insulinogenic index in GS-FFA group than that in NS and FFA groups. Greater number of apoptotic islet cells was found in the GS-FFA group than in the FFA and NS groups (P<0.05), and the islets had significantly higher levels of cyt c, AIF, caspase-9 and caspase-3 in the former group than in the latter two groups (P<0.05). CONCLUSIONS: Hyperglycemia and high free fatty acid level synergistically impair insulin secretions to cause ketone overproduction in high fat-fed obese rats. The beta-cell dysfunction due to glucolipotoxicity is associated with increased beta-cell apoptosis and activation of mitochondrial apoptotic pathway.

[Effects of free fatty acids on nitric oxide synthase activity and mRNA expression in endothelial cell of SD rat aorta].

OBJECTIVE: To test the hypothesis that free fatty acids (FFA) induced endothelial dysfunction might relate with the inhibitions of endothelial nitric oxide synthase (eNOS) mRNA expression and activity, and to explore the possible pathogenic mechanisms. METHODS: Male SD rats underwent 6 h infusion in two groups: Normal control (NC, n=20) infused with saline; FFA group (n=20) infused with 20% intralipid + heparin. Blood samples were collected at the end of infusion so as to measure the concentrations of FFA, nitrogen oxides (NOx), reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH) and high sensitivity C-reactive protein (hs-CRP). The eNOS activity and mRNA expression were analyzed with aortic endothelial homogenate. RESULTS: In FFA group, the plasma FFA concentration was higher [(1146.4+/-336.6) micromol/L vs (345.5+/-113.6) micromol/L, P<0.01] while the NOx level was lower [(14.3+/-1.9) micromol/L vs (19.3+/-2.9) micromol/L, P<0.01]. The serum concentrations of ROS, MDA, hs-CRP were elevated in FFA group when compared with controls [ROS: (864.3+/-135.4) mmol/L vs (452.4+/-90.5) mmol/L, P<0.05; MDA: (8.05+/-1.69) nmol/L vs (5.53+/-0.43) noml/L, P<0. 05; hs-CRP: (0.35+/-0.04) mg/L vs (0.21+/-0.03) mg/L, P<0.053] while GSH level was significantly declined in FFA group [(153.1+/-55.9) mg/L vs (171.9+/-60.5) mg/L, P<0.05]. Both the eNOS mRNA level and eNOS activity in endothelial homogenate were decreased in FFA group [eNOS mRNA/beta-actin: 1.42 vs 2.12, P<0.01; eNOS activity: (1.15+/-0.42) pmol/(min x mg) vs (2.43+/-0.56) pmol/(min x mg), P<0.01]. CONCLUSION: The eNOS mRNA expression and activity may be inhibited by elevated circulating FFAs concentration, of which mechanisms may be related to the increased oxidative stress and moderate inflammation.

[A study on the mechanism of islet cell insulin resistance in high-fat-diet obese rats].

OBJECTIVE: To study the changes of insulin signal transduction in islet cells of high-fat-diet rats with peripheral insulin resistance (IR). METHODS: Thirty male Wistar rats were randomly divided into 2 equal groups: high-fat-diet group and control group to be fed with high-fat food and normal food respectively. Twenty weeks after the rats were sacrificed. The contents of insulin and glucagon in homogenate of pancreas were detected during islet cell perifusion, and insulin receptor (IRc) and insulin receptor substrates (IRS-1 and IRS-2) were detected by immunohistochemistry. RESULTS: (1) The insulin sensitive index (ISI) was significantly decreased in the high-fat-diet rats in comparison with the normal rats, while the contents of glucagon in blood and in homogenate of pancreas were both significantly increased in the high-fat-diet rats (362 pg/ml +/- 58 pg/ml vs 291 pg/ml +/- 35 pg/ml; 442 pg/ml +/- 56 pg/ml vs 287 pg/ml +/- 48 pg/ml, both P < 0.05). (2) The glucose stimulated insulin secretion (GSIS) was impaired in the high-fat-diet rats. 16.7 nmol/L glucose could inhibit the glucagon secretion by the alpha cells of the normal rats, but not of the high-fat-diet rats. (3) The expression of IRc, IRS-1 and IRS-2 in islets was stronger in the peripheral cells (non-insulin secretion cells) than in the center cells (insulin secretion cells). The expression of IRc and IRS-2 was significantly decreased by 28% and 22% respectively in the high-fat-diet rats compared with the normal controls (both P < 0.01). CONCLUSION: High-fat-diet rats have impairment of insulin signal transduction in islet cells, which may contribute to the insulin resistance of islet alpha and beta cells and explain, at least in part, the dysfunction of the islet cells under peripheral IR.

[The protective effects of Radix Astragali and Rhizoma Ligustici chuanxiong on endothelial dysfunction in type 2 diabetic patients with microalbuminuria].

OBJECTIVE: To evaluate the effects of traditional Chinese complex prescription of Radix Astragali and Rhizoma Ligustici Chuanxiong on urinary albumin excretion (UAE) and vascular endothelial dysfunction in type 2 diabetic patients with microalbuminuria. METHODS: Twenty-one type 2 diabetic patients with microalbuminuria were involved in this before-after study by individual informed consent. Each of the eligible subjects was given the decoction of Radix Astragali and Rhizoma Ligustici Chuanxiong per os 150 ml q.d. for six months. The following examinations were performed at baseline and after treatment: (1) high-resolution ultrasonography to measure the diameter changes of brachial artery in response to reactive hyperemia (endothelium-dependent) and on administration of glyceryl trinitrate (endothelium-independent); (2) high resolution ultrasonography to measure combined intima-media thickness (IMT) of common carotid arteries (CCA); (3) fasting plasma plasminogen activator inhibitor type 1 (PAI-1) activity, C reactive protein (CRP) and malonic aldehyde(MDA) concentration. RESULTS: The patients had impaired endothelial dependent vasodilation (EDV), elevated plasma PAI-1 activity and increased CRP and MDA concentration at baseline. After six months treatment with Radix Astragali and Rhizoma Ligustici Chuanxiong, their urinary albumin-to- creatinine ratio decreased from (86.5 +/- 53.9) microg/mg to (55.05 +/- 51.67) microg/mg (P=0.002). The EDV was improved at the end of the treatment (baseline: 7.49 +/- 2.98%, after treatment: 12.73 +/- 5.36%, P=0.001). Meanwhile, the activity of PAI-1 and the levels of MDA and CRP were significantly decreased CPAI-1: (83.49 +/- 5.11) X 10(-2) AU/ml vs. (79.7 +/- 7.8) x 10(-2) AU/ml, P=0.015; MDA: (3.20 +/- 1.13) nmol/L vs. (2.09 +/- 0.71) nmol/L, P=0.000; CRP: (7.04 +/- 2.64) mg/ L vs. (1.58 +/- 0.69) mg/L, P=0.000]. But no significant changes of the CCA IMT and endothelial independent vasodilation (EIV) were observed. Partial correlated analysis showed that MDA concentration was negatively correlated with EDV (r=-0.3736, P = 0.018). Correlated analysis also showed that CRP was negatively correlated with EDV (r=-0.348, P=0.028). CONCLUSION: Radix Astragali and Rhizoma Ligustici Chuanxiong compound medication may decrease urinary albumin excretion and improve endothelial dysfunction in type 2 diabetic patients with microalbuminuria. The mechanism may relate with the therapeutic effects of Radix Astragali and Rhizoma Ligustici Chuanxiong on anti-inflammation, anti-oxidation and alleviation of the hypo-fibrinolytic/pro-thrombotic state.

[Relationship between peripheral insulin resistance and beta-cell function in obese subjects].

OBJECTIVE: To detect the relationship between peripheral insulin resistance and beta-cell function in obese subjects with normal blood glucose, and to explore the role of free fatty acids (FFAs) in the pathogenesis of type 2 DM. METHODS: Ten simple obesity male subjects (OB) with normal blood glucose and 10 lean male persons (NC) matched on age and living style were included. None of them was smoker, and their blood pressure, serum cholesterol levels were all normal. All subjects underwent the following tests: (1) Fasting serum lipids profile and FFA; (2) Baseline immunoreactive insulin (IRI), pro-insulin (PI) and true-insulin (TI); (3) Acute insulin response (AIR) to an intravenous bonus of glucose; (4) Euglycemic hyperinsulinemia clamp study to assess the peripheral glucose disposal rate (GDR). RESULTS: In obesity subjects, the baseline IRI, PI and TI were elevated and the ratio of PI/(PI + TI) was higher than controls (P < 0.01). The AIR was enhanced in OB and the area under the curve was larger (P < 0.05), but in obesity subjects the plasma glucose levels at 3, 5 and 10 minutes were much higher than controls (P < 0.05). The GDRs obtained during steady state were markedly decreased in OB (P < 0.05). The serum lipids profiles were normal except that triglyceride was higher in OB (P < 0.05) and the FFAs concentration was also elevated in OB (P < 0.05). There was a negative correlation between FFAs concentration and GDR in OB groups (r = -0.767, P < 0.01). CONCLUSION: The present data showed that in obese subjects with normal blood glucose, there were severe peripheral insulin resistance, relative deficiency of beta-cell first-phase insulin release and increased ratio of pro-insulin to insulin. It is logical to deduce that both insulin resistance and the beta-cell changes could be, at least partially, secondary to high levels of serum FFAs. Elevated circulating FFAs may paly a role in the pathogenesis of type 2 DM.