Bidirectional regulation of levodopa-induced dyskinesia by a specific neural ensemble in globus pallidus external segment.

Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPeTRAPed in LID) is observed during dyskinesia. Optogenetic inhibition of GPeTRAPed in LID significantly ameliorates LID, whereas reactivation of GPeTRAPed in LID evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPeTRAPed in LID and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPeTRAPed in LID as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future.

Whole-brain Mapping of Inputs and Outputs of Specific Orbitofrontal Cortical Neurons in Mice.

The orbitofrontal cortex (ORB), a region crucial for stimulus-reward association, decision-making, and flexible behaviors, extensively connects with other brain areas. However, brain-wide inputs to projection-defined ORB neurons and the distribution of inhibitory neurons postsynaptic to neurons in specific ORB subregions remain poorly characterized. Here we mapped the inputs of five types of projection-specific ORB neurons and ORB outputs to two types of inhibitory neurons. We found that different projection-defined ORB neurons received inputs from similar cortical and thalamic regions, albeit with quantitative variations, particularly in somatomotor areas and medial groups of the dorsal thalamus. By counting parvalbumin (PV) or somatostatin (SST) interneurons innervated by neurons in specific ORB subregions, we found a higher fraction of PV neurons in sensory cortices and a higher fraction of SST neurons in subcortical regions targeted by medial ORB neurons. These results provide insights into understanding and investigating the function of specific ORB neurons.

Whole-brain spatial organization of hippocampal single-neuron projectomes.

Mapping single-neuron projections is essential for understanding brain-wide connectivity and diverse functions of the hippocampus (HIP). Here, we reconstructed 10,100 single-neuron projectomes of mouse HIP and classified 43 projectome subtypes with distinct projection patterns. The number of projection targets and axon-tip distribution depended on the soma location along HIP longitudinal and transverse axes. Many projectome subtypes were enriched in specific HIP subdomains defined by spatial transcriptomic profiles. Furthermore, we delineated comprehensive wiring diagrams for HIP neurons projecting exclusively within the HIP formation (HPF) and for those projecting to both intra- and extra-HPF targets. Bihemispheric projecting neurons generally projected to one pair of homologous targets with ipsilateral preference. These organization principles of single-neuron projectomes provide a structural basis for understanding the function of HIP neurons.

Interventional metabology: A review of bariatric arterial embolization and endovascular denervation for treating metabolic disorders.

The rising prevalence of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM) poses a major challenge to global health. Existing therapeutic approaches have limitations, and there is a need for new, safe, and less invasive treatments. Interventional metabolic therapy is a new addition to the treatment arsenal for metabolic disorders. This review focuses on two interventional techniques: bariatric arterial embolization (BAE) and endovascular denervation (EDN). BAE involves embolizing specific arteries feeding ghrelin-producing cells to suppress appetite and promote weight loss. EDN targets nerves that regulate metabolic organs to improve glycemic control in T2DM patients. We describe the current state of these techniques, their mechanisms of action, and the available safety and effectiveness data. We also propose a new territory called "Interventional Metabology" to encompass these and other interventional approaches to treating metabolic disorders.

BRSK2 in pancreatic ß cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and ß-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in ß cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible ß-cell-specific Brsk2 knockout (ßKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, ßKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature ß cells reversibly triggers hyperglycemia due to ß-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and ß-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in ß cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between ß cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

The Secondary Motor Cortex-striatum Circuit Contributes to Suppressing Inappropriate Responses in Perceptual Decision Behavior.

The secondary motor cortex (M2) encodes choice-related information and plays an important role in cue-guided actions. M2 neurons innervate the dorsal striatum (DS), which also contributes to decision-making behavior, yet how M2 modulates signals in the DS to influence perceptual decision-making is unclear. Using mice performing a visual Go/No-Go task, we showed that inactivating M2 projections to the DS impaired performance by increasing the false alarm (FA) rate to the reward-irrelevant No-Go stimulus. The choice signal of M2 neurons correlated with behavioral performance, and the inactivation of M2 neurons projecting to the DS reduced the choice signal in the DS. By measuring and manipulating the responses of direct or indirect pathway striatal neurons defined by M2 inputs, we found that the indirect pathway neurons exhibited a shorter response latency to the No-Go stimulus, and inactivating their early responses increased the FA rate. These results demonstrate that the M2-to-DS pathway is crucial for suppressing inappropriate responses in perceptual decision behavior.

Association of 3-year change in sleep duration with risk of all-cause mortality in Chinese older population: A national cohort study.

BACKGROUND: Existing evidence on the association of dynamic change in sleep duration with risk of all-cause mortality in Chinese older population is limited. We aimed to explore the association of 3-year change in sleep duration with risk of all-cause mortality in a Chinese older population. MATERIALS AND METHODS: A total of 5772 Chinese older participants (median age 82 years) were enrolled in the current study. Cox proportional-hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of 3-year change in sleep duration with risk of all-cause mortality. Subgroup analyses of the association between 3-year change in sleep duration and risk of all-cause mortality were conducted by age, sex and residence. RESULTS: During a median of 4.08 years of follow-up, death developed in 1762 participants. Compared with -1 to <1 h/day change in sleep duration, the adjusted risk of all-cause mortality with < -3 h/day change in sleep duration may increase 26% (HR = 1.26, 95% CI: 1.05-1.52); the risk of all-cause mortality with 3-year change from short to long sleep duration, or long to short sleep duration versus stable normal sleep duration status was increased about 28% and 52%, respectively (HR = 1.28, 95% CI: 1.00-1.64 and HR = 1.52, 95% CI: 1.21-1.92). Subgroup analyses demonstrated that similar significant associations were observed among participants with 65 to <85 years, men and living in city and town. CONCLUSIONS: Dynamic sleep duration change was significantly associated with risk of all-cause mortality. The current study suggests that sleep duration may be a non-invasive indicator for interventions aiming to reduction risk of all-cause mortality in Chinese older population.

Dose-Response Association of Low and Normal Ankle Brachial Index With the Risk of Cardiovascular Disease Morbidity and Mortality.

We quantitatively evaluated the dose-response association of low and normal ankle brachial index (ABI) with the risk of morbidity and mortality from cardiovascular diseases (CVDs). PubMed, Embase, and Web of Science were systematically searched for cohort studies. Random effects or fixed effects models were used to estimate the pooled relative risks (RRs) and 95% confidence intervals (95% CIs). Generalized least squares regression was used to assess study-specific dose-response associations per 0.1 ABI decrease. Restricted cubic splines were used to evaluate linear or nonlinear trends. Twelve cohort studies (57 031 participants) were included in this meta-analysis. For low vs normal ABI levels, the pooled RRs were 2.03 (95% CI, 1.72-2.41; I2 = 52.9%; pheterogeneity=0.030) and 2.29 (95% CI, 1.98-2.64; I2 = 39.5%; pheterogeneity =0.158) for CVD morbidity and CVD mortality, respectively. For per 0.1 ABI decrease from 1.40 the risk for CVD morbidity and CVD mortality increased by 8% (1.08, 95% CI 1.04-1.11) and 11% (1.11, 95% CI 1.07-1.15), respectively. Restricted cubic splines showed inverse linear associations for CVD morbidity and CVD mortality. As a non-invasive index, lower ABI was significantly associated with the increased risk of morbidity and mortality from CVDs in an inverse linear manner.

The Prevalence and Characteristics of Exocrine Pancreatic Insufficiency in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background: Exocrine pancreatic insufficiency (EPI) is common in patients with type 2 diabetes. However, the prevalence of EPI varies significantly in different studies. Untreated EPI in these patients can adversely affect their nutrition and metabolism. The aim of this study is to estimate the pooled prevalence of EPI in patients with type 2 diabetes and to explore the potential risk factors. Methods: A systematic search was performed in PubMed, Web of Science, and Embase, which included studies meeting inclusion criteria from 1960 to 1 April 2022. Relevant articles were searched using the combination of Medical Subject Heading (MeSH) terms of "Type 2 diabetes" and "pancreatic exocrine insufficiency." The Stata 16.0 software was used for data analyses. The random-effects model was used to estimate the pooled prevalence rates and 95% CI using "metaprop program." Results: The pooled prevalence of EPI was 22% (95% CI: 15%-31%) in patients with type 2 diabetes and 8% (95% CI: 4%-14%) of them developed severe pancreatic insufficiency. In the subgroup analyses, the prevalence of EPI in type 2 diabetes was correlated with geographic location. The prevalence in Asian countries (35%, 95% CI: 22%-49%) is higher than in Europe (18%, 95% CI: 10%-29%) and Australia (9%, 95% CI: 4%-16%). Furthermore, patients with higher insulin requirements, who are more likely to be insulin-deficient, have a higher prevalence of EPI. The pooled prevalence was 27% (95% CI: 17%-37%) in type 2 diabetes with higher insulin requirement (1 group) and 15% (95% CI: 1%-40%) in patients with lower insulin requirement (2 group). In addition, the morbidity of severe EPI in the higher insulin requirement group (12%, 95% CI: 7%-19%) was sextuple as much as the lower insulin requirement group (2%, 95% CI: 0%-13%). EPI was more common in subjects younger than 60 compared with elderlies (25% vs. 19%). Conclusion: The prevalence of EPI in type 2 diabetes may be overestimated. Furthermore, the higher prevalence may be closely related to ß-cell function. Endocrine disease therapy would potentially represent a novel therapeutic approach for patients with type 2 diabetes and EPI.

Integrated analysis of probability of type 2 diabetes mellitus with polymorphisms and methylation of SLC30A8 gene: a nested case-control study.

To estimate the associations between single-nucleotide polymorphisms (SNPs) and methylation of SLC30A8 gene and T2DM risk, and the interactions among SNPs, methylation, and environmental factors on T2DM risk. We genotyped 9 SNPs and tested methylation at 46 CpG loci of SLC30A8 in the baseline DNA of 290 T2DM cases and 290 matched controls nested in the Rural Chinese Cohort Study. A conditional logistic regression model was used to estimate the associations between SNPs and SLC30A8 methylation and T2DM risk. Multifactor Dimensionality Reduction analysis was used to estimate the effect of interactions among SNPs, methylation, and environment on T2DM risk. Probability of T2DM was decreased with rs11558471 (GG vs. AA, OR = 0.55, 95% CI 0.32, 0.96), with rs13266634 (TT vs. CC, OR = 0.55, 95% CI 0.32, 0.94), with rs3802177 (AA vs. GG, OR = 0.54, 95%CI 0.31, 0.94), and its probability was increased with rs2466293 of SLC30A8 (GA vs. AA, OR = 1.63, 95% CI 1.08-2.47). Its probability was also significantly associated with methylation of CG9 and CG45 (OR = 0.56 [95% CI 0.33-0.97] and 1.61 [95%CI 1.03--2.51]). T2DM probability was significantly associated with the interaction effect between rs2466293 and hypertension (p = 0.045). T2DM probability was also significantly associated with the combination effects of rs2466293 with BMI, hypertension, and hypertriglyceridemia, with the combination effects of hypertriglyceridemia with rs11558471, rs13266634, and methylation of CG45.

Association between cardiovascular health metrics and risk of incident type 2 diabetes mellitus: the Rural Chinese Cohort Study.

AIMS: The evidence for association between cardiovascular health (CVH) metrics and type 2 diabetes mellitus (T2DM) in Chinese population is limited. We explored the association between the number of ideal CVH metrics and risk of incident T2DM in a rural Chinese population. MATERIALS AND METHODS: A total of 12,150 rural Chinese participants (median age 51 years) were enrolled. A Cox proportional-hazards model was used to assess the association between the number of ideal CVH metrics and risk of incident T2DM by using hazard ratios (HRs) and 95% confidence intervals (CIs). We another conducted multiplicative and additive interaction effect between the number of ideal CVH metrics and sex or age on incident T2DM, and subgroup analyses of the association were also conducted by sex and age. RESULTS: During a median of 6.01 years of follow-up, 840 incident cases of T2DM occurred. The number of ideal CVH metrics was negatively associated with risk of incident T2DM (per unit increase: HR = 0.76, 95% CI 0.70-0.82). We also observed both multiplicative and additive interaction effect between lower number of ideal CVH metrics and sex on incident T2DM, and multiplicative interaction effect between lower number of ideal CVH metrics and age on incident T2DM was observed. The association remained statistically significant for both men and women, or participants with age < 65 years. CONCLUSIONS: Increasing number of ideal CVH metrics was associated with reduced risk of incident T2DM, which presented age- and sex-related differential associations.

Identification of Inflammation-Related Biomarkers in Diabetes of the Exocrine Pancreas With the Use of Weighted Gene Co-Expression Network Analysis.

Diabetes of the exocrine pancreas (DEP), also commonly described as pancreatogenic diabetes mellitus, is a type of diabetes secondary to abnormalities in pancreatic or exocrine secretion of the pancreas. However, its pathogenesis is not yet known. The aim of this article was to explore the biomarkers of DEP and their potential molecular mechanisms. Based on GSE76896 dataset, which was acquired from Gene Expression Omnibus (GEO), we identified 373 genes by weighted gene co-expression network analysis (WGCNA) and differential expression analysis. In addition, protein-protein interaction (PPI) network analysis and cytoHubba were used to screen potential hub genes. Five hub genes were determined, comprising Toll-like receptor 4 (TLR4), ITGAM, ITGB2, PTPRC, and CSF1R. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways suggested macrophage activation and Toll-like receptor signaling pathway as important pathophysiological features of DEP. CIBERSORT suggested that TLR4 may regulate the immune pathway via macrophages. Next, we validated the expression and receiver operating characteristic curve (ROC) of the hub genes using the GSE164416 dataset. In addition, we used miRNet to predict the target miRNAs of hub genes and intersected them with common miRNAs in diabetes from the Human MicroRNA Disease Database (HMDD), which was used to propose a possible mechanistic model for DEP. The miRNA-mRNA network showed that has-miR-155-5p/has-miR-27a-3p/has-miR-21-5p-TLR4 might lead to TLR4 signaling pathway activation in DEP. In conclusion, we identified five hub genes, namely, TLR4, ITGAM, ITGB2, PTPRC, and CSF1R, as biomarkers to aid in the diagnosis of DEP and conducted an in-depth study of the pathogenesis of DEP at the genetic level.

Exosomal miR-140-3p and miR-143-3p from TGF-ß1-treated pancreatic stellate cells target BCL2 mRNA to increase ß-cell apoptosis.

BACKGROUND: People with chronic pancreatitis (CP) normally develop a fibrotic pancreas with reduced ß-cell mass. Limited studies have focused on the development and pathogenesis of CP-related diabetes. MiRNAs packaged as exosomes are the key regulators of ß-cell dysfunction. This study aimed to define the effect of exosomal miRNA from activated pancreatic stellate cells (PSCs) on ß-cells. METHODS: Exosomes in the supernatants of mouse PSCs lines were extracted via ultracentrifugation and then identified. The role of exosomes secreted by transforming growth factor-ß1 (TGF-ß1)-treated PSCs in ß-cell function was assessed. MiRNAs were prepared from exosomes extracted from TGF-ß1-treated and untreated PSCs (T-Exo or C-Exo), and the miRNA expression profiles were compared by microarray. Then, miR-140-3p and miR-143-3p were overexpressed or inhibited in MIN6 cells and islets to determine their molecular and functional effects. RESULTS: Exosomes were the predominant extracellular vesicles secreted by PSCs into the culture medium. The MIN6 cells incubated with T-Exo had less insulin secretion and lower viability than the MIN6 cells incubated with PBS or C-Exo. MiR-140-3p and miR-143-3p were notably upregulated in T-Exo. Enhancing the expression of miR-140-3p and miR-143-3p in ß-cells decreased the cell count and viability and increased the cleaved caspase-3 levels. Mechanistically, T-Exo mediated the intercellular transfer of miR-140-3p and miR-143-3p by targeting the B-cell lymphoma 2 gene in recipient ß-cells to induce cell death. CONCLUSIONS: Exosomal miRNA transfer as a communication mode between PSCs and ß-cells, which may be explored for its therapeutic utility.

Joint effect of physical activity and blood lipid levels on all-cause and cardiovascular disease mortality: The Rural Chinese Cohort Study.

BACKGROUND AND AIMS: We aimed to evaluate the joint effect of physical activity (PA) and blood lipid levels on all-cause and cardiovascular disease (CVD) mortality. METHODS AND RESULTS: We analyzed 17,236 participants from the Rural Chinese Cohort Study. Cox's proportional-hazards regression models were used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) between the joint effect of PA and blood lipid levels and risk of all-cause and CVD mortality. Restricted cubic splines were used to estimate the dose-response relationship of PA with risk of all-cause and CVD mortality. During a median follow-up of 6.01 years there were 1106 deaths (484 from CVD) among participants. For all-cause mortality, compared with the group with dyslipidemia and extremely light PA (ELPA), the HRs with dyslipidemia and light PA (LPA), moderate PA (MPA), and heavy PA (HPA) were 0.56 (95% CI 0.45-0.70), 0.59 (0.46-0.75), and 0.59 (0.45-0.78), respectively, while the HRs of groups with normal lipid levels and ELPA, LPA, MPA, and HPA were 0.88 (0.72-1.04), 0.59 (0.48-0.73), 0.53 (0.41-0.67), and 0.38 (0.29-0.50), respectively. We observed similar effects on CVD mortality. Restricted cubic splines showed a curvilinear relationship between PA and risk of all-cause and CVD mortality with normal lipid levels and with dyslipidemia. CONCLUSION: Higher PA reduces the risk of all-cause and CVD mortality. Higher levels of PA are needed in the population.

Single-neuron projectome of mouse prefrontal cortex.

Prefrontal cortex (PFC) is the cognitive center that integrates and regulates global brain activity. However, the whole-brain organization of PFC axon projections remains poorly understood. Using single-neuron reconstruction of 6,357 mouse PFC projection neurons, we identified 64 projectome-defined subtypes. Each of four previously known major cortico-cortical subnetworks was targeted by a distinct group of PFC subtypes defined by their first-order axon collaterals. Further analysis unraveled topographic rules of soma distribution within PFC, first-order collateral branch point-dependent target selection and terminal arbor distribution-dependent target subdivision. Furthermore, we obtained a high-precision hierarchical map within PFC and three distinct functionally related PFC modules, each enriched with internal recurrent connectivity. Finally, we showed that each transcriptome subtype corresponds to multiple projectome subtypes found in different PFC subregions. Thus, whole-brain single-neuron projectome analysis reveals organization principles of axon projections within and outside PFC and provides the essential basis for elucidating neuronal connectivity underlying diverse PFC functions.

Pancreatic cancer-associated diabetes mellitus is characterized by reduced ß-cell secretory capacity, rather than insulin resistance.

AIMS: The early distinction of pancreatic cancer associated diabetes (PaCDM) in patients with elderly diabetes is critical. However, PaCDM and type 2 diabetes mellitus (T2DM) remain indistinguishable. We aim to address the differences between the pancreatic and gut endocrine hormones of patients with PaCDM and T2DM. METHODS: A total of 44 participants underwent mixed meal tolerance test (MMTT). Fasting and postprandial concentrations of insulin, C-peptide, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide (GIP) were measured. Insulin sensitivity and secretion indices were calculated. One-way ANOVA with post-hoc analysis was used for statistical analysis. RESULTS: Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared with T2DM. Baseline concentrations and AUCs differed. PaCDM patients showed lower insulin secretion capacity but better insulin sensitivity than T2DM patients. The peak concentration and AUC of PP in T2DM group were higher than healthy controls, but in accordance with PaCDM. PaCDM patients presented lower baseline GLP-1 concentration than T2DM patients. No between-group differences were found for glucagon and GIP. CONCLUSIONS: PaCDM patients had a lower baseline and postprandial insulin and C-peptide secretion than T2DM patients. Reduced insulin secretion and improved peripheral sensitivity were found in PaCDM patients compared with T2DM.

Independent and joint associations of non-exercise cardiorespiratory fitness and obesity with risk of type 2 diabetes mellitus in the Rural Chinese Cohort Study.

BACKGROUND AND AIMS: An association between cardiorespiratory fitness (CRF) and type 2 diabetes mellitus (T2DM) has not been established in the Chinese population. This study aimed to estimate the independent and joint associations of CRF and obesity with T2DM incidence in the rural Chinese population. METHODS AND RESULTS: We conducted a prospective study of 11,825 non-T2DM subjects among rural Chinese adults. Cox regression models were used to estimate the independent and joint associations between CRF and obesity exposure on T2DM. Restricted cubic splines were used to model the dose-response association. During a median follow-up of 6.01 years, 835 participants developed T2DM. In comparison to quartile 1 of CRF, the multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) of quartiles 2, 3, 4 were 0.75 (0.61-0.91), 0.54 (0.43-0.68), and 0.42 (0.32-0.55), respectively. When stratified by sex, the results were similar. Joint analyses showed that overweight/obesity-unfit individuals had a 2.28 times higher risk of developing T2DM than the normal weight-fit referent (HR 2.28, 95% CI 1.84-2.83; Pinteraction <0.001). The risk for the overweight/obesity-fit category (HR 1.61, 95% CI 1.21-2.15) was larger than for the normal weight-unfit category (HR 1.38, 95% CI 0.97-1.95) versus the normal weight-fit referent. Similar joint associations for waist circumference and CRF with T2DM were also observed. CONCLUSION: A negative association was observed between CRF and risk of T2DM. Overweight/obese or abdominal obesity and unfit participants showed the highest risks of T2DM. It is therefore strongly recommended that fitness-enhancing be encouraged for the prevention of T2DM, especially among obesity participants.

Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic ß-Cell Proliferation Through the CPEB1/CDKN1B Pathway.

Pancreatic ß-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in ß-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed that miR-455 overexpression facilitated ß-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory ß-cell expansion. Mechanistically, our results revealed that increased miR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly(A) tail and the subsequent translation of Cdkn1b mRNA, reducing the CDKN1B expression level and finally promoting ß-cell proliferation. Taken together, our results show that the miR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of ß-cells to meet metabolic demand during obesity.

Metabolic Score for Visceral Fat: a novel predictor for the risk of type 2 diabetes mellitus.

To investigate the association between the Metabolic Score for Visceral Fat (METS-VF) and risk of type 2 diabetes mellitus (T2DM) and compare the predictive value of the METS-VF for T2DM incidence with other obesity indices in Chinese people. A total of 12 237 non-T2DM participants aged over 18 years from the Rural Chinese Cohort Study of 2007-2008 were included at baseline and followed up during 2013-2014. The cox proportional hazards regression was used to calculate hazard ratios (HR) and 95 % CI for the association between baseline METS-VF and T2DM risk. Restricted cubic splines were used to model the association between METS-VF and T2DM risk. Area under the receiver operating characteristic curve (AUC) analysis was used to evaluate the ability of METS-VF to predict T2DM incidence. During a median follow-up of 6·01 (95 % CI 5·09, 6·06) years, 837 cases developed T2DM. After adjusting for potential confounding factors, the adjusted HR for the highest v. lowest METS-VF quartile was 5·97 (95 % CI 4·28, 8·32), with a per 1-sd increase in METS-VF positively associated with T2DM risk. Positive associations were also found in the sensitivity and subgroup analyses, respectively. A significant nonlinear dose-response association was observed between METS-VF and T2DM risk for all participants (Pnonlinearity = 0·0347). Finally, the AUC value of METS-VF for predicting T2DM was largest among six indices. The METS-VF may be a reliable and applicable predictor of T2DM incidence in Chinese people regardless of sex, age or BMI.

Metabolic Score for Visceral Fat: A reliable indicator of visceral obesity for predicting risk for hypertension.

OBJECTIVES: The aim of this study was to investigate the association of the Metabolic Score for Visceral Fat (METS-VF) with the risk for hypertension and to compare the ability of the METS-VF, the metabolic score for insulin resistance, visceral adiposity index, waist-to-height ratio, waist circumference, and body mass index to predict hypertension incidence based on a large prospective study of rural Chinese individuals. METHODS: In all, 10 297 non-hypertensive adults (≥18 y of age) from a rural Chinese cohort study in 2007 and 2008 were included at baseline and followed up in 2013 and 2014. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between baseline METS-VF and hypertension risk. Area under the receiver operating characteristic curve (AUC) analysis was used to evaluate the ability of METS-VF to predict hypertension incidence. RESULTS: We identified 2071 hypertension cases during follow-up. After adjusting for multivariable confounding factors, the adjusted ORs (95% CIs) for the highest versus lowest METS-VF quartile overall and for men and women were 3.84 (3.23-4.56), 3.25 (2.48-4.24), and 4.14 (3.30-5.20), respectively. Also, per-SD increase in METS-VF was positively associated with hypertension risk overall and for men and women. Similar results were found in the sensitivity and subgroup analyses. Finally, the AUC value for hypertension was higher for METS-VF than the other five indices overall and for men and women. CONCLUSIONS: The present study indicated that METS-VF was positively associated with hypertension incidence and performed better in predicting hypertension risk than five other indices, which suggests that METS-VF is a reliable predictor of hypertension in the Chinese population.