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Sepsis, defined as a life-threatening organ dysfunction, is associated with increased mortality in individuals with diabetes mellitus. In sepsis under diabetic conditions (SUDC), the superimposed inflammatory response and excessive production of reactive oxygen species (ROS) can cause severe damage to the kidney and liver, making it challenging to effectively repair multi-organ injury. In this study, we report the development of a DNA-based bifunctional nanomedicine, termed IL10-rDON, generated by assembling interleukin 10 (IL10) with rectangular DNA origami nanostructures (rDON) to address multi-organ dysfunction in SUDC. IL10-rDON was shown to predominantly accumulate in the kidney and liver of diabetic mice in vivo and effectively alleviate inflammatory responses through its anti-inflammatory IL10 component. In addition, the consumption of rDON itself significantly reduced excessive ROS in the liver and kidney. Serum and histological examinations further confirmed that IL10-rDON treatment could effectively improve liver and kidney function, as well as the survival of mice with SUDC. This study demonstrates an attractive antioxidant and anti-inflammatory nanomedicine for addressing acute liver and renal failure. The integration of rDON with therapeutic agents using DNA nanotechnology is a promising strategy for generating multifunctional nanomedicine to treat multi-organ dysfunction and other complicated diseases. Sepsis under diabetic conditions (SUDC) leads to high mortality due to multiple organ failure such as acute liver and kidney injury. The anti-inflammatory cytokine interleukin 10 (IL10) holds great potential to treat SUDC, while disadvantages of IL-10 such as short half-life, non-specific distribution and lack of antioxidant activities limit its wide clinical applications. In this study, we developed a DNA-based, bifunctional nanomedicine (IL10-rDON) by assembling IL10 with rectangular DNA origami nanostructures (rDON). We found that IL10-rDON preferentially accumulated and sufficiently attenuated the increased levels of ROS and inflammation in the kidney and liver injury sites, and eventually improved the survival rate of mice with SUDC. Our finding provides new insights into the application of DNA-based nanomedicine in treating multi-organ failure. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Background: Many publications have addressed the problem of weight gain and endocrine abnormalities in patients treated with sodium valproate (VPA). However, the presence of metabolic syndrome (MetS) among obese patients with epilepsy on VPA has received little attention. Methods: Thirty-six patients receiving VPA monotherapy were included in this study to evaluate the presence of MetS. All patients were interviewed and clinically examined. Blood samples were obtained after an overnight fast, and an oral glucose-tolerance test was performed. Twenty-eight subjects who were obese but had no epilepsy and were otherwise well were collected as controls (“simple obesity” group). Results: The two study groups were well matched in terms of age, gender and body mass index. Insulin resistance measured via homeostasis model assessment (HOMA) index was more severe among the VPA-treated group (4.91±2.91 vs. 2.00±1.72, P =0.007). The frequency of the MetS was slightly higher in the patients with epilepsy compared to controls (47.2% vs. 32.1%, respectively), but this difference was not statistically significant (P =0.223). Multivariate analysis with stepwise logistic regression revealed low positive correlations between MetS development, HOMA index (P =0.029; r =0.361) and valproic acid dose (P =0.049; r =0.323). These correlations were independent of other clinical parameters. Conclusions: Our preliminary study suggests that obese patients with epilepsy treated with VPA are at higher risk of MetS than individuals who are “simply obese” but otherwise well. Therefore, the HOMA index should be monitored in obese patients who receive VPA therapy, rather than monitoring body weight alone. [Copyright &y& Elsevier]

Abstract: Aims: To investigate alterations of insulin resistance (IR), chronic inflammation and urine albumin-to-creatinine ratio (ACR) in Chinese community-based prediabetic population. Materials and methods: 252 prediabetics [prediabetes (PD), including impaired fasting glucose (IFG), 91; impaired glucose tolerance (IGT), 123; IFG+IGT, 38] and 38 newly diagnosed-diabetics (NDDM) aged over 35 years older were screened from 2336 community individuals. 123 age and gender matched individuals with normal glucose tolerance (NGT) were selected as controls. Serum adiponectin, interleukin-6 (IL-6) levels and urine ACR were determined, HOMA-IR and Gutt''s index were calculated to evaluate IR and insulin sensitivity, respectively. Results: The data displayed significant difference of serum adiponectin, IL-6, ACR and Gutt''s index among PD, NDDM and NGT groups. Adiponectin level and Gutt''s index decreased, but IL-6 level and ACR increased gradually among NGT, PD and NDDM groups (P <0.01). Unlike adiponectin and IL-6, ACR analysis indicates a gradual increase from NGT, IFG, IGT, IFG+IGT to NDDM individuals (P <0.01). Gutt''s index showed significant difference between IFG and NDDM, IFG+IGT and NDDM (P <0.01), but HOMA-IR index did not. Conclusions: IR, chronic inflammation and endothelial dysfunction dose exist in prediabetic individuals, especially in IFG+IGT population. Gutt''s index and ACR might seem to be more sensitive than adiponectin and HOMA-IR index as IR and chronic inflammation maker in prediabetic population. [Copyright &y& Elsevier]

Delayed regeneration of alveolar bone defects because of prolonged inflammation under diabetic conditions remains a challenge for dental rehabilitation in clinic, and effective therapies are required. Cytokines-based immuotherapies might be a potential strategy to regulate inflammation and bone regeneration. Here, we report that local delivery of interleukin-10 (IL-10) by injectable self-assembling peptide (SAP) hydrogel is efficient to promote proinflammatory (M1)-to-anti-inflammatory (M2) phenotype conversion, thereby enhancing bone regeneration in diabetic alveolar bone defects. Characteristics of SAP hydrogel were evaluated by morphology, injectable and rheological properties. The loading and release of IL-10 from the SAP hydrogel were evaluated over time in culture. The local inflammatory response and bone repair efficacy of the SAP/IL-10 hydrogel was evaluated in vivo using an alveolar bone defect model of diabetic mice. Finally, the direct effects of M2 macrophage on M1 phenotype and mineralization of MSCs were investigated. In vitro , encapsulated IL-10 could be sustainedly released by SAP hydrogel with preserved bioactivities. In vivo , SAP/IL-10 hydrogel showed significantly higher efficacy to attenuate M1 polarization and proinflammatory factors levels, and enhance expressions of osteogenic factors. As a result, diabetic bone regeneration induced by SAP/IL-10 hydrogel was significantly faster. Mechanistically, M2 macrophages induced by sustained IL-10 delivery might promote diabetic bone regeneration by reprogramming M1 phenotype, suppressing local inflammation and enhancing the osteogenic differentiation of mesenchymal stem cells (MSCs). This study highlights that the SAP hydrogel is a promising drug delivery platform for treatment of alveolar bone defects, which might have translational potential in future clinical applications. [Display omitted] • The KLD1R hydrogel enables a sustained release of IL-10 with preserved biofunction. • Sustained IL-10 delivery attenuates M1 polarization and local inflammation. • IL-10 induced M2 macrophage polarization promotes osteogenic differentiation. • The SAP hydrogel is a promising drug delivery platform for various oral diseases. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is closely associated with type 2 diabetes (T2D). Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element binding protein (CREB) family whose levels are increased upon stress in pancreatic islets from mice. Intriguingly, ATF5 deficiency has been shown to contribute to increased ER stress and apoptosis in mouse islet micro-organs. We hypothesized that either deficiency or overexpression of ATF5 is equally deleterious for pancreatic islets in terms of ER stress and apoptosis. To test this, we used a number of in vitro and in vivo models whereby ATF5 levels were overexpressed. We also determined the regulation of ATF5 in the context of metabolic derangements by using various mouse models of obesity and T2D. Our in vitro results show that ATF5 overexpression promoted palmitic acid (PA)-induced lipotoxic apoptosis. In vivo , global ATF5 overexpression in mice was lethal and pancreas-specific ATF5 overexpressing mice exhibit increased β-cell apoptosis. Interestingly, ATF5 is downregulated in all mouse models of severe obesity and T2D used in the current study. In conclusion, a tight control on ATF5 levels might be considered when developing novel agents targeting ATF5 for prevention and treatment of metabolic diseases. • ATF5 overexpression promoted palmitic acid (PA)-induced lipotoxic apoptosis. • Overexpression of ATF5 in the mouse islets increased β-cell apoptosis. • ATF5, but not ATF4, is a key regulator of the response to ER stress in the islets of obese and T2D mice. • A tight control on ATF5 levels might be considered when developing novel agents targeting ATF5 for prevention and treatment of metabolic diseases. [ABSTRACT FROM AUTHOR]

Aims Polymorphism of rs2016520 in gene PPARD has been associated with lipid metabolism, obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). We aimed to study the association of rs2016520 with common metabolic traits in a large population of Han Chinese adults. Methods The polymorphism was genotyped in 1409 subjects using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS); all participants underwent standard clinical examination and a 75 g oral glucose tolerance test (OGTT); associations between the polymorphism and metabolic traits and indices of insulin resistance and insulin sensitivity were analyzed. Results There was no significant difference in genotypes between the normal glucose tolerance (NGT) and the prediabetes group (χ 2 = 3.17, P = 0.2), except a nominal difference of allele frequency (χ 2 = 3.07, P = 0.07). The G carrier presented lower fasting plasma glucose (FPG, P = 0.03), lower 2 h plasma glucose (P dom = 0.04) and lower fasting insulin (P = 0.02), lower systolic blood pressure (SBP, P = 0.03), lower HOMA-IR (P = 0.02) and higher QUICKI (P = 0.01). Moreover, rs2016520 polymorphism was associated with FPG (β = − 0.09, P = 0.05), it was also associated with indices of insulin resistance (HOMA-IR, β = − 0.06, P dom = 0.02; fasting insulin, β = − 0.04, P = 0.02) and indices of insulin sensitivity (QUICKI, β = − 0.01, P = 0.004). In addition, we observed that the allele G was also associated with lower SBP (β = − 1.29, P = 0.04) and diastolic blood pressure (DBP, β = − 0.09, P = 0.01). However, the minor allele G was not associated with risk of metabolic disorders including prediabetes, overweight, hypertension and metabolic syndrome. Conclusions Polymorphism of rs2016520 in gene PPARD was associated with benign metabolic traits in a large cohort of Chinese adults. The G allele may confer protection from type 2 diabetes and hypertension in Han Chinese. [ABSTRACT FROM AUTHOR]

Purpose Acarbose is effective in delaying or preventing the progression of prediabetes to type 2 diabetes mellitus (T2DM). The aim of this study was to assess differences in the preventive effects of acarbose in Eastern and Western populations with prediabetes. Methods We performed a systematic search of databases and reference lists of clinical trials conducted through August 2013. Randomized controlled trials of acarbose alone, with a minimum intervention duration of 3 years and which provided data on T2DM incidence, were included for analysis. Analyses were conducted by using Review Manager version 5.1 software. Findings Eight randomized controlled trials with 2628 participants were included. Acarbose decreased the occurrence of T2DM (number needed to treat [NNT], 6.7). Compared with the control (placebo and/or lifestyle intervention), the incidence of T2DM was significantly lower in the Eastern group (NNT, 5.9) than in the Western group (NNT, 11.1) ( P < 0.0001, I 2 = 94.7%). At the end of follow-up, reversal of prediabetes to normal glucose tolerance was more likely in the Eastern group (NNT, 4.3) than in the Western group (NNT, 25) ( P = 0.004, I 2 = 92%). Among those remaining prediabetic, there was no significant difference between the subtotal estimates for the subgroups ( P = 0.17, I 2 = 46.5%). There was no positive correlation between preventive effect and dose, and no difference in studies with varying follow-up durations within and across either ethnic group. Implications The preventive effect of acarbose on the development of diabetes seems superior in Eastern populations with prediabetes compared with Western populations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The aim is to identify new long noncoding RNAs (lncRNAs) involved in adipocyte differentiation. High-throughput RNA sequencing of 3T3-L1 preadipocytes was carried out before and after differentiation to identify the target lncRNAs and miRNAs. The effects of lncRNA, miRNA and the network mechanism on adipocyte differentiation were evaluated in vitro and in vivo. Visceral adipose tissue (VAT) was collected from Chinese subjects with obesity or a normal body mass index (BMI), and the levels of lncRNAs, adipogenic genes and miRNAs were measured. MIR99AHG, miR-29b-3p were selected as the target lncRNA and miRNA. Short hairpin RNA against MIR99AHG inhibited the differentiation of 3T3-L1 preadipocytes, reduced the expression of the peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer-binding protein alpha (C/EBPα) and fatty acid binding protein 4 (FABP4) genes, upregulated the expression of miR-29b-3p. Overexpression of MIR99AHG showed the opposite effects. Overexpression of miR-29b-3p inhibited the differentiation of 3T3-L1 preadipocytes and decreased the PPARγ level, while inhibition of miR-29b-3p showed the opposite effects. MIR99AHG and PPARγ competed for binding to miR-29b-3p. In mice with high-fat diet-induced obesity, MIR99AHG and miR-29b-3p mRNA level were increased and decreased, respectively. Tail vein injection of adeno-associated virus 9-MIR99AHG-RNA interference (AAV9-MIR99AHG-RNAi) reduced the body weight, epididymal fat mass, MIR99AHG level and increased the expression of miR-29b-3p. The expression levels of MIR99AHG, PPARγ, C/EBPα and FABP4 in human visceral adipose tissue were higher in the obese group than in the normal weight group. MIR99AHG enhances adipogenesis by regulating miR-29b-3p and PPARγ, providing a new target for therapeutic intervention in obesity. • MIR99AHG and miR-29b-3p are selected as the target lncRNA and miRNA during 3T3-L1 preadipocytes differentiation. • Inhibition of MIR99AHG prevents obesity in mice. • MIR99AHG sponges miR-29p-3p to promote PPARγ-mediated regulation of preadipocyte differentiation. [ABSTRACT FROM AUTHOR]

Abstract: We previously showed that activated peroxisome proliferator-activated receptor (PPAR)β/δ can protect pancreatic β cells against lipotoxic apoptosis. However, the molecular mechanism remained unclear. Glucagon-like peptide-1 receptor (GLP-1R) has been reported to exhibit a protective effect against lipotoxic apoptosis in pancreatic β cells. In the present study, we aimed to investigate the underlying molecular mechanisms that PPARβ/δ activation suppressed apoptosis and improved β cell function impaired by fatty acids, focusing on contribution of GLP-1R. Isolated rat islets and rat insulin-secreting INS-1 cells were treated with the PPARβ/δ agonist GW501516 (GW) in the presence or absence of palmitate (PA) and transfected with siRNA for PPARβ/δ or treated with the PPARβ/δ antagonist GSK0660. Apoptosis was assessed by DNA fragmentation, Hoechst 33342 staining and flow cytometry. GLP-1R expression in INS-1 cells and islets was assayed by immunoblotting, quantitative PCR (qPCR) and immunofluorescence staining. SREBP-1c, Caveolin-1, Akt, Bcl-2, Bcl-xl and caspase-3 expression was measured using immunoblotting and qPCR. Our results showed that PPARβ/δ activation decreased apoptosis in β cells and robustly stimulated GLP-1R expression under lipotoxic conditions. GW enhanced glucose-stimulated insulin secretion (GSIS) impaired by PA through stimulation of GLP-1R expression in β cells. Moreover, SREBP-1c/Caveolin-1 signaling was involved in PPARβ/δ-regulated GLP-1R expression. Finally, GW exerted anti-apoptotic effects via interfering with GLP-1R-dependent Akt/Bcl-2 and Bcl-xl/caspase-3 signaling pathways. Our study suggested that the anti-apoptotic action of GW may involve its transcriptional regulation of GLP-1R, and PPARβ/δ activation may represent a new therapeutic method for protecting pancreatic β cells from lipotoxicity. [Copyright &y& Elsevier]

Abstract: Background: Phosphatase and tensin homolog on chromosome 10 gene (PTEN) is known as a tumor-suppressor gene. Previous studies demonstrated that PTEN dysfunction affects the function of insulin. However, investigations of PTEN single nucleotide polymorphisms (SNPs) and IR-related disease associations are limited. The aim of the present study was to investigate whether its polymorphism could be involved in the risk of metabolic syndrome (MetS). Methods: The genotype frequency of PTEN −9C>G polymorphism was determined by using a Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) method in 530 subjects with MetS and 202 healthy control subjects of the Han Ethnic Chinese population in a case–control analysis. Results: The PTEN −9C>G polymorphism was not associated with MetS or its hyperglycemia, hypertension and hypertriglyceridemia components. In the control individuals aged <60years or ≥60years, the CG genotype individuals had lower insulin sensitivity than CC individuals (P <0.05). In the <60-year-old MetS group and normal glucose tolerance (NGT) subgroup, the CG individuals had lower insulin sensitivity and higher waist circumference (WC) and waist-height-ratio (WHtR) than CC individuals (P <0.05). Multiple linear regression analysis showed that the PTEN polymorphism (P =0.001) contributed independently to 4.2% (adjusted R2) of insulin sensitivity variance (estimated by Matsuda ISI), while age (P =0.004), gender (P =0.000) and the PTEN polymorphism (P =0.032) contributed independently to 5.6% (adjusted R2) of WHtR variance. Conclusions: The CG genotype of PTEN −9C>G polymorphism was not associated with MetS and some of its components as well. However, it may not only decrease insulin sensitivity in the healthy control and MetS in pre-elderly or NGT subjects, but may also increase the risk of central obesity among these MetS individuals. [Copyright &y& Elsevier]

The beneficial effects of empagliflozin (EMPA) on cardiac functions during ischemia and reperfusion were characterized. The contractile functions of isolated cardiomyocytes from adult C57BL/6J mice were determined with IonOptix SoftEdgeMyoCam system. The mitochondrial superoxide production was measured by MitoSOX fluorescent probe. The ex vivo isolated heart perfusion system was used to determine the pharmacological effects of EMPA on heart's contractile functions under both physiological and pathological conditions. The in vivo regional myocardial ischemia and reperfusion by ligation of left artery coronary artery descending (LAD) was used to measure the myocardial infarction caused by ischemia and reperfusion with or without EMPA treatment. The results demonstrated that EMPA treatment significantly improves cardiomyocyte contractility under hypoxia conditions and augments the post-ischemic recovery in the ex vivo heart perfusion system. Furthermore, the in vivo myocardial infarction measurement shows that EMPA treatment significantly reduce myocardial infarct size caused by ischemia and reperfusion. The biochemical analysis demonstrated that EMPA can trigger cardiac AMPK signaling pathway and attenuate mitochondrial superoxide production under hypoxia and reoxygenation conditions. In conclusion, EMPA can trigger AMPK signaling pathways and modulate myocardial contractility and reduce myocardial infarct size caused by ischemia and reperfusion independent of hypoglycemic effect. The results for the first time demonstrate that the activation of AMPK by EMPA could one reason about EMPA's beneficial effects on heart disease. Image 1 • AMPK mediates the cardioprotection of Empagliflozin against ischemic insult. • Empagliflozin treatment augments cardiomyocytes contractile functions during ischemic insults. • The inflammatory response modulation by Empagliflozin is a critical factor. [ABSTRACT FROM AUTHOR]

Purpose We performed a meta-analysis to investigate the legacy effect of >5 years of intensive blood glucose lowering on cardiovascular outcomes in patients with type 2 diabetes and very high risk or secondary prevention of cardiovascular disease (CVD). Methods We mainly searched PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials. Patients in the included studies had intensive glucose lowering for >5 years and posttrial follow-up for at least 5 years. Primary end points were all-cause mortality and cardiovascular death. Secondary end points were major macrovascular events, myocardial infarction, and stroke. We used risk ratios (RRs) with 95% CIs as summary statistics. Findings We included 3 trials that involved 13,684 patients, of whom 6805 received intensive glucose-lowering treatment and 6879 received standard treatment. The mean total follow-up duration was 10.3 years, which included 5.4 years of in-trial intervention and 5.5 years of posttrial follow-up. Intensive glucose control treatment did not significantly reduce all-cause mortality (RR = 0.98; 95% CI, 0.87–1.10) or cardiovascular death (RR = 0.97; 95% CI, 0.87–1.09). No significant risk reduction was found for stroke (RR = 1.02; 95% CI, 0.92–1.14), myocardial infarction (RR = 0.91; 95% CI, 0.75–1.09), or major macrovascular events (RR = 0.99; 95% CI, 0.93–1.06). Implications A legacy effect of >5-year intensive blood glucose control on cardiovascular outcomes in patients with type 2 diabetes and very high risk or secondary prevention of CVD was not detected, although this effect might be applicable in patients with diabetes and primary prevention of CVD. Further investigation of the legacy effect in different CVD risk populations should therefore be performed. [ABSTRACT FROM AUTHOR]