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Oxidative stress interferes with blood glucose homeostasis, leading to insulin resistance (IR) and hyperglycemia, which eventually induce type 2 diabetes (T2DM). Fermented noni ( Morinda citrifolia L.) fruit juice (FNJ) is a traditional folk medicine in Polynesia as well as a functional food supplement with a variety of health benefits. In this study, the efficacy and mechanism of FNJ in improving oxidative stress and IR were investigated under the synergistic effect of Nrf2/ARE pathway and gut flora in vivo and in vitro . In vitro , insulin resistant HepG2 cells were established with 50 mM high glucose, and 25 μM rosiglitazone (ROSI) was used as a positive control. In vivo , male C57BLKS mice in the CON group were fed a normal diet and C57BLKS/J-db/db (db/db) mice were treated with 10 mg kg -1 d -1 ROSI and 6.5 and 13 mL kg -1 d -1 FNJ for 8 weeks, respectively. The results showed that 3-5% FNJ markedly improved IR by increasing glucose uptake and consumption and ameliorated oxidative stress via up-regulating the expression of related antioxidant enzymes such as SOD and GPx and attenuating ROS and MDA in IR-HepG2 cells. In vivo , db/db mice exhibited hyperglycemia, hyperinsulinemia, and oxidative stress, whereas FNJ significantly inverted those conditions. Moreover, FNJ supplementation notably increased the gut microbiota diversity of T2DM mice and remodeled the gut microbial composition to suppress microbial disorder. Specifically, FNJ increased the ratio of F/B and lowered the Proteobacteria abundance at the phylum level. The db/db mice were enriched in Enterobacteriaceae, Klebsiella, and Klebsiella-pneumonia, while FNJ feeding significantly up-regulated Rikenellaceae. In addition, western blotting and qPCR experiments showed that FNJ promoted the expression of Nrf2, HO-1, IRS1, PI3K, AKT, and GLUT4 and reduced the JNK level both in vivo and vitro . These results confirmed that FNJ had a protective effect on oxidative stress and IR by activating Nrf2/ARE signaling pathway and regulating gut flora in db/db mice and IR-HepG2 cells.

Background: Insulin resistance (IR) in obesity is associated with the occurrence of metabolic and cardiovascular diseases. Dipepidyl peptidase 4 (DPP4) plays a pivotal role during the development of IR, and was found to be a target gene of microRNA-214 (miR-214) in our study. This study sought to assess the expression and clinical value of miR-214 in obese patients with IR, and investigate its therapeutic potential in obese rats and adipocytes with IR., Methods: Serum expression of miR-214 in obese patients with or without IR was estimated by quantitative real-time-PCR. A receiver operating characteristic curve was plotted to evaluate the diagnostic value of miR-214 in the patients. Obesity-induced IR animal and cell models were constructed, and the therapeutic ability of miR-214 was explored., Results: Serum expression of miR-214 was decreased in obese patients compared with the healthy controls, and the lowest expression was observed in the cases with IR. Downregulation of miR-214 was significantly correlated with the serum DPP4 levels and HOMA-IR of the patients upon IR conditions, and was demonstrated to perform diagnostic accuracy for distinguishing obese patients with IR from those without IR. In obesity-associated IR animal and cell models, the downregulation of miR-214 was also been detected. According to the measurement of glucose and insulin tolerance and glucose uptake abilities, we found that the overexpression of miR-214 could be used to alleviate IR in the IR models, especially when collaboratively used with DPP4 inhibitor vildagliptin., Conclusion: All data revealed that miR-214, as a regulator of DPP4, is decreased in obese patients with IR and may serve as a diagnostic biomarker. The upregulation of miR-214 could improve IR in obese rats and adipocytes, indicating that miR-214 has the therapeutic potential for obesity and IR.

Activation of protein kinase C (PKC) in vascular tissue is associated with endothelial dysfunction and insulin resistance. However, the effect of vascular PKC activation on insulin-stimulated endothelial nitric oxide (NO) synthase (eNOS) regulation has not been characterized in obesity-associated insulin resistance. Diacylglycerol (DAG) concentration and PKC activity were increased in the aorta of Zucker fatty compared with Zucker lean rats. Insulin-stimulated increases in Akt phosphorylation and cGMP concentration (a measure of NO bioavailability) after euglycemic-hyperinsulinemic clamp were blunted in the aorta of fatty compared with lean rats but were partly normalized after 2 weeks of treatment with the PKCbeta inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKCbeta1 and -beta2, but not PKCalpha, -delta, or -zeta, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKCbeta1 and -beta2, but not PKCalpha or -delta, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKCbeta2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKCbeta in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Akt-dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity-associated insulin resistance.

Objective To investigate the glucose metabolic status in patients with previous gestational diabetes mellitus (GDM) in the 5-6 years after delivery, and to explore the changes in insulin resistance and islet β cell function from postpartum short-term (6-12 weeks) to the long-term (5-6 years) after delivery, as well as the relationship with glucose metabolic status. Methods A total of 72 patients with a history of GDM who delivered in Peking University First Hospital and had complete short-and long-term postpartum follow-up data were included. They were divided into normal glucose metabolism (NGT) and abnormal glucose metabolism (AGT) groups according to their glucose metabolism status in 5-6 years after delivery. Pre-pregnancy, pregnancy, perinatal, short-and long-term postpartum clinical data were collected and compared between the two groups, including demographic indicators, glucose and lipid metabolism indicators [oral glucose tolerance test (OGTT) fasting blood glucose (FPG), 1-hour blood glucose (1hPG), 2-hour blood glucose (2hPG), 3-hour blood glucose (3hPG), total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol], insulin use ratio, fasting insulin (FINS), OGTT 2-hour insulin (2hINS), insulin sensitivity index (ISI), homeostasis model assessment of insulin resistance index (HOMA-IR) and homeostasis model assessment of β cell function index (HOMA-β) were calculated. The comparison between the two groups was conducted using independent sample t-test, rank sum test χ² test or Fisher's exact probability test. Multivariate logistic regression analysis was used to analyze the influence factors of abnormal glucose metabolism. Results There were 38 (52.78%) cases in NGT group and 34 (47.22%) cases in AGT group. Compared with the NGT group, there are differences in related metabolic indicators in AGT group from pregnancy to long-term postpartum period: During pregnancy, 3hPG in 75 g OGTT and the proportion of insulin users were higher in AGT group. As for 6-12 weeks postpartum, OGTT 2hPG and the incidence of blood glucose abnormalities and the proportion of hypertriglyceridemia were higher (all P<0.05). However, there was no statistically significant difference in HOMA-IR and HOMA-β between the two groups(P>0.05). At 5-6 years postpartum, FPG, OGTT 2hPG, and FINS were all higher, with a higher degree of insulin resistance and lower insulin sensitivity (ISI) in AGT group (all P<0.05). Compared with short-term postpartum period (6-12 weeks), FPG, FINS, HOMA-IR, HOMA-β were all significantly increased regardless of glucose metabolic status at 5-6 years postpartum, while OGTT 2hPG and 2hINS increased further in the AGT group (all P<0.05). OGTT 2hPG and insulin use during pregnancy were risk factors for abnormal glucose metabolism 5-6 years postpartum according to multivariate logistic regression analysis, with OR values (95%CI) of 1.646 (1.015-2.671) and 3.570 (1.009-12.624), respectively. Conclusions The incidence of AGT was still high in patients with previous GDM 5-6 years after delivery. Insulin resistance progressed gradually after delivery regardless of glucose metabolism, especially in patients with abnormal glucose metabolism. OGTT 2hPG and insulin use in pregnancy were risk factors for abnormal glucose metabolism in postpartum 5-6 years, suggesting that there is continuity in time and similarity in pathogenesis between GDM and T2DM. [ABSTRACT FROM AUTHOR]

Aims. The objective of the present study was to explore the long-term postpartum glucose metabolism in women with previous GDM, and study the mechanism of hyperglycemia from gestation to postpartum by investigating the postpartum insulin resistance and insulin secretion. Methods. A total of 321 females with previous GDM were followed up once during 1- to 6-years postpartum. Characteristics during pregnancy, perinatal period, and postpartum were compared between postpartum NGT and hyperglycemic women. HOMA-IR and HOMA-β were used to assess insulin resistance and insulin secretion levels with different glucose statuses. Results. The prevalence of postpartum hyperglycemia had a fluctuant increase from 25.9% at 1 year, to 53.7% at 5 year. 75 g OGTT 2 hPG during pregnancy was an independent predictor of postpartum hyperglycemia with an OR of 2.15 (95% CI 1.245, 3.722) (P = 0.006). After ROC analysis, the best equilibrium between sensitivity (70.3%) and specificity (60.4%) for 2 hPG was 9.03 mmol/L. HOMA-IR was increased in postpartum normal glucose tolerance (NGT), prediabetes, and T2DM (1.64 vs. 2.14 vs. 4.27, P < 0.001), while HOMA-β was decreased (1.19 vs. 1.11 vs. 0.71, P = 0.011). In pairwise comparison, except for HOMA-IR between prediabetes and T2DM, and HOMA-β between NGT and prediabetes, other differences showed significance. Conclusions. 75 g OGTT 2h PG during pregnancy higher than 9.03 mmol/L is regarded as an independent risk factor of postpartum hyperglycemia. Insulin resistance with insufficient insulin secretion compensation is still common phenomenon during long-term postpartum. Women with heavier insulin resistance in the postpartum period are more likely develop prediabetes, while decreased β-cell function contributes more to T2DM development. [ABSTRACT FROM AUTHOR]

Purpose: Dipeptidyl peptidase 4 (DPP4) is one of the newly identified adipokines, which acts as paracrine in adipose tissue and as endocrine hormones in the liver, muscles and central nervous system. Expression of DPP4 was significantly upregulated in obese patients upon insulin resistance (IR) conditions, but the mechanism underlying the dysregulation of DPP4 remains unclear. This study aimed to investigate the DPP4 expression in adipose tissue and adipocytes under IR conditions or with liraglutide intervention, and explore the potential molecular mechanisms. Methods: Obesity-associated IR animal and cell models were, respectively, constructed by using high-fat diet and palmitic acid (PA) stimulation. Expression of DPP4 in adipose tissues and adipocytes was estimated by quantitative real-time RT-PCR and Western-blot. Effects of the AMPK/JAK2/STAT3 pathway on DPP4 were examined by regulating the activity of AMPK and the JAK2/STAT signaling. The therapeutic efficacy of liraglutide in the IR models was evaluated, and its regulatory effects on DPP4 expression and the underlying molecular mechanisms were explored. Results: The expression of DPP4 was markedly upregulated in both the animal and cell IR models. In the adipocyte, DPP4 expression was found to be suppressed by the activation of AMPK, and this inhibition effect was mediated by the JAK2/STAT3 signaling. Moreover, liraglutide could alleviate the obesity-induced IR, and led to the downregulation of DPP4 in IR animal and cell models. Liraglutide intervention resulted in the activation of AMPK and deactivation of the JAK2/STAT3 signaling in the adipocytes. Conclusion: Taken together, the expression of DPP4 is upregulated in adipose tissues and adipocytes upon IR conditions, but is reduced after liraglutide intervention. The dysregulation of DPP4 in the adipocytes may be performed by the AMPK/JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the role of MTP on lipid metabolism disorders in insulin-resistant rats and the potential mechanism through which metformin can improve lipid metabolism disorders.Methods: 30 OLETF rats served as research subjects and 18 LETO rats of the same strain served as the control group (LETO group). After the first oral glucose tolerance test (at 8-week-old), 6 rats were randomly killed from each group. The remaining 24 OLETF rats were randomly divided into untreated group (OLETF group) and treated group (OLETF/M group, cured with metformin). By the end of the 10th and 20th week of treatment, MTP in the liver was measured for all rats in the study.Results: All OLETF rats exhibited diabetic phenotypes at 18-week-old, with their triglyceride level higher than in LETO rats at the same age. In OLETF rats, MTP level in the liver was higher than in LETO rats at 18-week-old, and the difference was significant at 28-week-old [(13.79±1.47) vs. (8.20±1.14), p<0.05]. Treatment with metformin for 20weeks decreased triglyceride [(1.06±0.23) vs. (2.20±0.62) mmol/L, p<0.05] and total cholesterol [(1.90±0.19) vs. (2.36±0.14) mmol/L, p<0.05] in OLETF rats. Metformin also decreased MTP level in the liver [(7.65±1.31) vs. (13.79±1.47), p<0.01].Conclusions: MTP may be associated with the lipid metabolism disorder in OLETF rats and metformin could improve lipid metabolism through reducing the expression of MTP. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is one of the contributing factors to the development of β-cell failure in type 2 diabetes. ER stress response through ATF6 has been shown to play an important role in insulin resistance and pancreatic β-cell function. We investigated whether genetic polymorphisms in ATF6 were associated with the risk of pre-diabetes in a Chinese Han population, and whether they had a synergistic effect with obesity. Our samples included 828 individuals who were diagnosed as pre-diabetic, and 620 controls. The minor allele A at rs2340721 was associated with increased risk for pre-diabetes(p = 0.013), and this association was still significant after adjusting for gender, age, body mass index (BMI), and waist-hip ratio(p′ = 0.011). BMI, treated as a continuous variable, and rs2340721 had an interactive effect on pre-diabetic risk(p for interaction = 0.003, β = 0.106). Carriers of GG at rs7522210 were also at a higher risk compared to non-carriers (OR = 1.390, 95%CI:1.206–1.818, p = 0.013, adjusted OR′ = 1.516, 95%CI:1.101–2.006, p′ = 0.006). GG homozygotes had increased fasting blood glucose (FBG) levels(GG vs CX: 5.6±0.52 vs 5.5±0.57 mmol/L, p = 0.016), lower insulin levels (0,30,120 minutes after glucose load) (p<0.05), and reduced areas under the insulin curve than non-carriers(GG vs CX:67.3(44.2–102.3) vs 73.1(49.4–111.4), p = 0.014). rs10918270 was associated with FBG, and rs4657103 with 2 hour glucose levels after a 75 g glucose load. We also identified a haplotype of TTAG composed of rs4657103, rs2134697, rs2340721, and rs12079579, which was associated with pre-diabetes. The genetic variation in ATF6 is associated with pre-diabetes and has interactive effects with BMI on pre-diabetes in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Activation of protein kinase C (PKC) in vascular tissue is associated with endothelial dysfunction and insulin resistance. However, the effect of vascular PKC activation on insulin-stimulated endothelial nitric oxide (NO) synthase (eNOS) regulation has not been characterized in obesity-associated insulin resistance. Diacylglycerol (DAG) concentration and PKC activity were increased in the aorta of Zucker fatty compared with Zucker lean rats. Insulin-stimulated increases in Akt phosphorylation and cGMP concentration (a measure of NO bioavailability) after euglycemic-hyperinsulinemic clamp were blunted in the aorta of fatty compared with lean rats but were partly normalized after 2 weeks of treatment with the PKCβ inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKCβ1 and -β2, but not PKCα, δ, or -ζ, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKCβ1 and -β2, but not PKCα or -δ, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKCβ2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKCβ in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Akt-dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity-associated insulin resistance. [ABSTRACT FROM AUTHOR]