Effects of acarbose and metformin on the inflammatory state in newly diagnosed type 2 diabetes patients: a one-year randomized clinical study.

OBJECTIVE: This study aimed to investigate the changes in inflammatory biomarkers between newly diagnosed type 2 diabetes (T2DM) patients under one-year acarbose treatments and those under metformin managements. METHODS: Seventy patients with newly diagnosed T2DM and 32 volunteers with normal glucose tolerance (normal controls, NCs) were enrolled. Seventy patients with T2DM were randomly assigned to two subgroups and treated with acarbose (n=34) or metformin (n=36) for 1 year. Blood glucose, insulin, glycosylated hemoglobin (A1C), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and inflammatory biomarker levels (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), and ferritin) were detected at 0, 6 and 12 months. RESULTS: After adjusting for sex, the waist-to-hip ratio (WHR) and body mass index (BMI), higher fasting plasma glucose (FPG), standard meal test 1/2 hr and 2 hr glucose, TG, TC, LDL-C, IL-6, TNF-α, IL-2 and ferritin levels were observed in T2DM group than in NCs (P<0.05). After 6 months of treatment, TNF-α levels were significantly decreased in both subgroups, and IL-6 and ferritin levels were significantly decreased after 12 months (P<0.05). However, no significant differences in the IL-6, TNF-α and ferritin levels were observed between the two subgroups. Moreover, significantly higher IL-6 and TNF-α levels were detected in the T2DM group than in NCs after 12 months of treatment (P<0.05). CONCLUSION: Patients with newly diagnosed T2DM exhibited a marked chronic inflammatory state characterized by increased IL-6, TNF-α, IL-1ß, IL-2 and ferritin levels. After 1 year of treatment with acarbose or metformin, IL-6, TNF-α, IL-1ß and ferritin levels were significantly decreased compared with the baseline. The anti-inflammatory effects of acarbose and metformin were comparable and required a long-term treatment (1 year), but the characteristics were different. Further investigations are needed to determine whether this effect was independent of the hypoglycemic effects.

[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.

Increased Metabolic Disorders and Impaired Insulin Secretory Function in the First-Degree Relatives of Type 2 Diabetic Patients with Normal Glucose Tolerance.

OBJECTIVE: To compare the metabolic status and pancreatic ß-cell function in first-degree relatives (FDRs) of type 2 diabetic patients with normal glucose tolerance (NGT). MATERIALS AND METHODS: Three hundred twelve subjects, who were NGT-FDR of type 2 diabetic patients and 1348 subjects, who were NGT individuals with no family history of diabetes, were defined as NGT-FDRs and NGT-controls (NGT-C), respectively. Blood pressure, body weight, waist circumference, plasma glucose, lipid profile, and insulin levels were measured in all subjects. Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA-ß, insulin sensitivity index (ISI), and disposition index (DI) was used to evaluate insulin resistance and insulin sensitivity. RESULTS: The HOMA-IR and HOMA-ß indices were significantly higher in the NGT-FDR group relative to the NGT-C, while the ISI, DI, and ΔI30/ΔG30 were lower (P < 0.05). The prevalence rate of greater than or equal to three metabolic disorders was higher in the NGT-FDR group compared to the NGT-C (P < 0.05). In the NGT-FDR group, compared to people with normal metabolism, HOMA-ß decreased when there was only one metabolic disorder, increased slightly when there were two to three metabolic abnormalities, and decreased again when there were four or more metabolic abnormalities. The data also indicated that having a family history of type 2 diabetes maybe an independent risk factor of ß-cell dysfunction. CONCLUSIONS: Metabolic disorders developed frequently in the NGT-FDRs of type 2 diabetic patients. As the number of coexisting metabolic disorders increased, pancreatic ß-cell secretory ability and insulin sensitivity decreased. Therefore, it is necessary to provide early preventive interventions and monitoring of metabolic indices for NGT-FDRs of type 2 diabetic patients.

Hypercholesterolemia Up-Regulates the Expression of Intermedin and Its Receptor Components in the Aorta of Rats via Inducing the Oxidative Stress.

OBJECTIVE: Hypercholesterolemia can cause damage to the artery. Intermedin (IMD) is a novel member of the calcitonin gene-related peptide family. This study aims to investigate the aortic expression of IMD and its receptors in hypercholesterolemia without atherosclerosis. METHODS: Male Wistar rats were fed with high cholesterol diet, with or without simvastatin and vitamin C. Both the malondialdehyde (MDA) and superoxide dismutase (SOD) in plasma and aorta were determined as the oxidative stress biomarkers. The plasma IMD was assessed by radioimmunoassay. Within the aorta, the mRNA expression of IMD along with its receptor components was determined, and the corresponding protein level of the CRLR/RAMPs was also assessed. RESULTS: The hypercholesterolemia rats without atherosclerotic lesion manifested a higher level of MDA and SOD and the plasma IMD elevated. Increased expression of IMD and all its receptor components (CRLR, RAMP1, RAMP2, and RAMP3) were displayed within the aorta. The simvastatin indirectly attenuated oxidative stress by improving lipid profiles, while the vitamin C directly reduced oxidative stress without interfering with the serum lipids. Both simvastatin and vitamin C ameliorated the aortic injury, decreased the plasma IMD level, and recovered the expression of IMD and its receptors within the aorta. CONCLUSIONS: The up-regulated expression of IMD is observed within the aorta of the hypercholesterolemia rats. In addition, the oxidative stress participates in the up-regulation.

The combination of a novel 2 bp deletion mutation and p.D63H in CYP11B1 cause congenital adrenal hyperplasia due to steroid 11ß-hydroxylase deficiency.

Deficiency of steroid 11ß-hydroxylase activity occurs in 5-8% of patients with congenital adrenal hyperplasia (CAH). The aim of the current study was to identify mutations in the CYP11B1 gene of a patient with CAH due to deficiency of steroid 11ß-hydroxylase activity, and to study the functional and structural consequences of these mutations. A molecular genetic analysis of the CYP11B1 gene in this patient and her parents identified a known missense mutation g.5194G>C (p.D63H) and a novel 2 bp deletion mutation (g.9525_9526delCT, corresponding to p.L380V…R420X) in the patient. In vitro expression studies in COS7 cells revealed a decreased 11ß-hydroxylase activity in the p.D63H mutant to 2.0±0.8% and in the p.L380V…R420X mutant to 0.2±2.2% for the conversion of 11-deoxycortisol to cortisol. Three dimensional homology models for the normal and mutant proteins were built by using the recently published x-ray structure of the human CYP11B2 as a template. Presumably, the g.9525_9526delCT mutation in CYP11B1 resulted in a truncated protein with a misfolded C-terminal domain that could not efficiently bind heme iron, substrate, and adrenodoxin and had lost its biochemical function. In summary, CAH due to steroid 11ß-hydroxylase deficiency can be attributed to both the novel deletion mutation (g.9525_9526delCT, corresponding to p.L380V…R420X) and known missense mutation (g.5194G>C corresponding to p.D63H) in CYP11B1.

[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.

Association of Serum Gamma-Glutamyl Transferase and Ferritin with the Metabolic Syndrome.

Aim. To investigate the relationship among GGT, ferritin, and the risk of metabolic syndrome. Methods. A total of 1024 eligible individuals of the Chinese Yi ethnic group were enrolled in this cross-sectional study. The presence of metabolic syndrome was determined using the revised NCEP-ATP III and CDS criteria. Odds ratios for the metabolic syndrome and its components for different groups based on the levels of GGT and ferritin were calculated using multiple logistic regressions. Results. Serum GGT and ferritin concentrations were significantly higher in subjects with metabolic syndrome compared to those without metabolic syndrome in both genders (p < 0.05). Serum GGT was positively correlated with ferritin (p < 0.05). The risk of the metabolic syndrome was significantly higher in female subjects who had elevated GGT and ferritin levels (p < 0.05). Furthermore, the increased risk of having each of the metabolic syndrome components (overweight or obesity, hypertriglyceridemia, hypertension, hyperglycemia, and insulin resistance) was also observed in those subjects after adjustment for possible confounders (p < 0.05). Conclusions. These data indicate that GGT and ferritin synergistically correlate with the risk of the metabolic syndrome, suggesting that they could potentially be used as predictive biomarkers for the metabolic syndrome.

Comparison of Short- and Mid-term Efficacy and the Mechanisms of Gastric Bypass Surgeries on Managing Obese and Nonobese Type 2 Diabetes Mellitus: A Prospective Study.

BACKGROUND AND AIMS: We targeted to investigate the efficacy and the mechanisms of two gastric bypass surgeries, Roux-en-y Gastric Bypass (RYGB) and Billroth II gastrojejunostomy on managing obese patients with T2DM and nonobese T2DM patients, respectively. METHODS: Seven nonobese T2DM patients with gastric cancer submitted to Billroth II gastrojejunostomy were compared with nine obese T2DM patients undergoing RYGB about their baseline characteristics, weight loss and glycemic control, 3 months and 2 years after surgery. Meanwhile, ß-cell function, glucagon-like peptide 1 (GLP-1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP) levels were also investigated. RESULTS: Significant weight loss and improvement of glycemic control were observed in both groups and in the two follow-up periods. Reduction of body mass index was greater in obese patients with T2DM. The efficacy of Billroth II gastrojejunostomy on controlling blood glucose of nonobese T2DM was similar to that of RYGB on managing obese T2DM. Insulin levels and HOMA-IR were decreased in obese T2DM patients, whereas they remained unchanged in nonobese T2DM patients. Generally, levels of GLP-1 and PYY were increased, whereas GIP levels were decreased in both groups. CONCLUSIONS: Glycemic control efficacy of Billroth II gastrojejunostomy on managing nonobese T2DM is similar to that of RYGB on treating obese T2DM in the short- and mid-term. The underlying mechanisms of both surgeries may be related to weight loss and gut hormone modulations.

Increased acyl ghrelin but decreased total ghrelin and unacyl ghrelin in Chinese Han people with impaired fasting glucose combined with impaired glucose tolerance.

We assessed the plasma acyl ghrelin (AG), unacyl ghrelin (UAG), and total ghrelin (TGhr) levels in Chinese adults with pre-diabetes and newly diagnosed diabetes mellitus (NDDM) after an oral glucose tolerance test (OGTT), and abdominal subcutaneous fat area and visceral fat area (VFA) were measured. Fasting AG level was increased in the impaired fasting glucose (IFG) combined with impaired glucose tolerance (IFG+IGT) and NDDM groups. AG, UAG, and TGhr levels were significantly decreased post-OGTT, and the decrements of 30-min AG, UAG, and TGhr post-OGTT were not significantly different among groups. UAG and TGhr levels did not differ significantly among the normal glucose tolerance (NGT), IFG and NDDM groups, but they decreased obviously in the IFG+IGT and impaired glucose tolerance (IGT) groups. The NDDM group had larger VFA than the NGT, IGT, and IFG+IGT groups, even after adjustment for height, it was still larger than the NGT group. The factors such as dyslipidemia and obesity which are prone to develop insulin resistance (IR) and decrease insulin sensitivity (IS) were negatively correlated with UAG and TGhr, positively with AG/UAG, while no correlations with AG. In terms of evaluating IS and IR, AG/UAG ratio may be superior in AG concentration. Our findings suggest that relative sufficiency of AG, the deficiency of TGhr and UAG are already present in IFG+IGT patients. We speculate that there is UAG resistance in severe hyperglycemia (diabetic state), which could produce elevated TGhr and UAG compared to IFG+IGT group. In the development of T2D, increase of VFA could be the initiating factor, leading elevated AG, reduced UAG, IR, decreased IS, and finally hyperglycemia.

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.

Episodes of paralysis in Chinese men with thyrotoxic periodic paralysis are associated with elevated serum testosterone.

BACKGROUND: The strong predilection for thyrotoxic periodic paralysis (TPP) to occur in males suggests androgen may contribute to its pathogenesis. We therefore sought to determine if serum total and free testosterone (TT and FT) concentrations differed among patients with TPP during episodes of paralysis, patients with TPP between episodes of paralysis, and patients with Graves' disease (GD) not having TPP. METHODS: A total of 105 Chinese men were included in the study, and were divided into three groups. Group 1 consisted of men with TPP who were studied during episodes of paralysis; group 2 consisted of men with TPP who were studied between episodes of paralysis; group 3 consisted of men with GD not having TPP. Patients in each were different persons. Serum electrolytes, free triiodothyronine (FT3), free thyroxine (FT4), TT, and FT were measured. Multiple regression analyses and analysis of covariance were performed to analyze the relationship of serum parameters, group status, and age. RESULTS: One multiple regression analysis was used to determine if serum TT concentrations were associated with age, FT3, FT4, or group status. This analysis indicated that age, FT4 level, and group status were significantly and independently associated with serum TT concentrations. With regard to group status, patients in group 1 had serum TT concentrations 0.92 ng/mL higher than patients in group 3 (p=0.033). As to FT4 level, TT concentrations increased by 0.016 ng/mL for each additional pmol/L of FT4 (p=0.002). Another multiple regression analysis was used to determine if serum FT concentrations were associated with age, FT3, FT4, group status, or serum TT concentrations. This analysis revealed that serum TT concentrations and group status were significantly and independently associated with serum FT concentrations. In terms of group status, patients in group 1 had serum FT concentrations of 2.11 pg/mL greater on average than patients in group 3 (p=0.006). CONCLUSIONS: We infer that episodes of paralysis in Chinese men with TPP are associated with elevated serum testosterone. We also found serum TT and FT concentrations of men with GD are both affected by group status; serum TT rather than FT concentrations are associated with thyroid function.

Impaired secretion of total glucagon-like peptide-1 in people with impaired fasting glucose combined impaired glucose tolerance.

OBJECTIVE: We assessed the serum glucagon-like peptide-1 (GLP-1) levels for Chinese adults with pre-diabetes (PD) and newly-diagnosed diabetes mellitus (NDDM) during oral glucose tolerance test (OGTT). The relationships between total GLP-1 level and islet ß cell function, insulin resistance (IR) and insulin sensitivity (IS) were also investigated. METHODS: A 75g glucose OGTT was given to 531 subjects. Based on the results, they were divided into groups of normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), IFG combined IGT (IFG+IGT) and NDDM. Total GLP-1 levels were measured at 0- and 2-hour during OGTT. Homeostasis model assessment of ß cell function (HOMA-ß), HOMA of insulin resistance (HOMA-IR), Gutt and Matsuda indexes were calculated. The relationships between GLP-1 level and ß cell function, IR and IS were analyzed. RESULTS: The levels of total fasting GLP-1 (FGLP-1), 2h GLP-1 (2hGLP-1) and 2hGLP-1 increments (∆GLP-1) following OGTT reduced significantly in IFG+IGT and NDDM groups (P<0.005). HOMA-ß , HOMA-IR, Gutt and Matsuda indexes demonstrated various patterns among NGT, isolated IFG, isolated IGT, IFG+IGT and NDDM groups (P<0.05). Spearman rank correlation analysis and multivariable linear regression model suggested that some levels of correlation between GLP-1 levels, ∆GLP-1 and ß cell function, IR (P<0.05). CONCLUSIONS: The total GLP-1 levels and its response to glucose load decreased significantly in IFG+IGT group, compared to isolated IFG or IGT group. They were even similar to that of NDDM group. Moreover, there were observable correlations between impaired GLP-1 secretion and ß cell function, IR and IS.

[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.

Free fatty acids induce endothelial dysfunction and activate protein kinase C and nuclear factor-κB pathway in rat aorta.

BACKGROUND: Insulin resistance is associated with an inappropriate elevation of plasma free fatty acids (FFAs) and endothelial dysfunction. In this study, we asked if elevated circulating FFA levels led to impaired insulin signaling and endothelial dysfunction in-vivo via activation of PKC-mediated inflammatory pathways. METHODS: Sprague-Dawley (S-D) rats were infused with 1) 20% intralipid+heparin (FFA group) or 2) saline alone (Control group) for 6h. The intact aorta thoracica and aorta abdominalis were then removed. Aortic rings were isolated and evaluated for endothelial-dependent and non-dependent relaxation in an organ bath. The activities of eNOS and PKC were measured in endothelial homogenates prepared from endothelial cells harvested from the aorta. The expression levels of insulin signaling molecules IRS-1, Akt, eNOS, ERK1/ERK2, PKC-α, NFκB-p65 subunit and IκB-α in rat aortic endothelium were determined by immunohistochemistry and Western blot. RESULTS: Elevation of FFAs resulted in a 35.9% reduction in the response to acetylcholine (p < 0.01), a 26% decline in plasma NOx levels (p < 0.05), a 53% decrease in eNOS activity and a 34 ± 9% inhibition in IRS-1 tyrosine phosphorylation (p < 0.05). We also found a 46% decrease in Akt phosphorylation and a 36% decrease in eNOS phosphorylation. FFA-induced endothelial insulin resistance was associated with 82% increase in total membrane-associated PKC activity, a 1.7-fold increase in total PKC-α protein, 1.29-fold decrease in IκB-α expression levels and 1.47-fold increase in NF-κB p65 subunit expression in rat aortic endothelium. CONCLUSION: The molecular mechanisms underlying FFA-induced endothelial insulin resistance and eNOS inhibition may provide an important link implicating the PKC and IκB-α/NF-κB pathways in FFA-mediated inhibition of vascular insulin signaling.

Impairment of insulin action in non-obese, normal-glucose tolerant, first-degree relatives of Chinese type 2 diabetic patients.

AIMS: To investigate first-phase insulin release and peripheral insulin sensitivity of non-obese, normal-glucose tolerant, first-degree relatives of Chinese type 2 diabetic patients. METHODS: 12 euglycemic first-degree relatives of type 2 diabetic patients (ERDM), 12 newly diagnosed type 2 diabetic patients (DM-2) and 12 healthy individuals (control) participated in the study. All subjects were non-obese (BMI< 25 kg/m(2)). Intravenous glucose tolerance test and euglycemic hyperinsulinemic clamp test were performed to evaluate first-phase insulin release and quantify insulin sensitivity, respectively. RESULTS: the first-phase insulin release did not differ between the ERDM and control subjects (p=0.532), while the acute insulin response was absent in the DM-2 patients (p=0.001). Peripheral glucose deposit rate (GDR) was significantly lower in the ERDM (10.6 ± 2.1mg/kg·min, p=0.000) and DM-2 (9.6 ± 1.1mg/kg·min, p=0.000) groups than that in the control group (13.2 ± 1.2mg/kg·min). There was no statistical difference in GDR between the ERDM and DM-2 groups (p=0.110). Fasting FFA levels of the ERDM (p=0.007) and DM-2 (p=0.000) subjects were significantly higher than those of the controls. CONCLUSIONS: non-obese, first-degree relatives of type 2 diabetic patients with normal glucose tolerance (NGT) exhibit remarkable impairment of insulin sensitivity and increased FFA levels. Insulin resistance is independent of obesity and blood glucose level. Progression from NGT to type 2 diabetes may mainly be attributed to deterioration of early insulin secretion.