SUMMARYA hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells1–3. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mechanisms has been challenging4–6. To identify early disease-driving events, we performed single cell spatial proteomics, sorted cell transcriptomics, and assessed islet physiology on pancreatic tissue from short-duration T2D and control donors. Here, through integrative analyses of these diverse modalities, we show that multiple gene regulatory modules are associated with early-stage T2D β cell-intrinsic defects. One notable example is the transcription factor RFX6, which we show is a highly connected β cell hub gene that is reduced in T2D and governs a gene regulatory network associated with insulin secretion defects and T2D GWAS variants. We validated the critical role of RFX6 in β cells through direct perturbation in primary human islets followed by physiological and single nucleus multiome profiling, which showed reduced dynamic insulin secretion and large-scale changes in the β cell transcriptome and chromatin accessibility landscape. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals and thus we anticipate this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits with GWAS data.

Background: Previous studies have shown inconsistent outcomes in the efficacy of angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) on insulin resistance (IR). Hence, we aim to compare the efficacy of ACE inhibitors with ARBs on IR in hypertensive patients. Methods: Five electronic databases (included The Cochrane Library, MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials) will be searched. Randomized controlled trials (RCTs) will be included if they recruited hypertensive participants for assessing the effect of ACE inhibitors on IR versus ARBs. The primary outcome will be IR (using recognized methods such as homeostasis model assessment of insulin resistance), secondary outcomes will be blood pressure, fasting plasma glucose, fasting plasma insulin. Relevant literature search, data extraction, and quality assessment will be performed by 2 researchers independently, and the third researcher will be involved in a discussion for any disagreements. All analyses will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Stata 12.0 software will be used for statistical analysis. The effect size of dichotomous data will be measured using the odds ratio (OR), and the effect size of continuous data will be measured using the standardized mean difference. And 95% confidence intervals will be calculated. Heterogeneity will be tested by χ 2-based Cochran Q statistic and I2 statistic. Sensitivity analysis and subgroup analysis will be used to observe changes in the pooled effect size and heterogeneity between included studies, to assess the reliability and stability of the pooled results. The funnel plot and Egger's and Begg's tests will be used to judge publication bias, and the trim and fill method will be used to correct the funnel asymmetry caused by publication bias. P < 0.05 will be considered to indicate a statistically significant result. Results: This systematic review and meta-analysis will assess the efficacy of ACE inhibitors versus ARBs on IR in hypertensive patients. Conclusions: Our study will show the efficacy of ACE inhibitors versus ARBs on IR in hypertensive patients. And it may find a more beneficial therapeutic option to assist clinicians in making clinical decisions. Ethics and dissemination: This study is a protocol for systematic review and meta-analysis of the efficacy of ACE inhibitors and ARBs on IR in hypertensive patients. This systematic review and meta-analysis will be published in a journal and disseminated in print by peer-review. INPLASY registration number: INPLASY202050032.

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Background: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in reproductive-aged women. In addition to the reproductive consequences, PCOS is also characterized by a metabolic disorder, which may play a part in the etiology of anovulation and has important implications for long-term health as well. Vitamin D deficiency is prevalent in PCOS and there is a close relationship between metabolic dysfunction and vitamin D status in women with PCOS. The purpose of this systematic analysis is to evaluate the effect of vitamin D supplementation on serum lipid profiles in patients with PCOS. Methods: We will search five databases for relative studies: Medline, the Cochrane Library, EMBASE, Web of Science, and ClinicalTrials.gov and identified all reports of randomized controlled trials published prior to July 2020. Two authors will independently scan the articles searched, extract the data from articles included, and assess the risk of bias by Cochrane tool of risk of bias. Disagreements will be resolved by discussion among authors. All analysis will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Fixed-effects model or random-effects model was used to calculate pooled estimates of weighted mean difference (WMD) with 95% confidence intervals. Results: This review will be to assess the effect of vitamin D supplementation on serum lipid profiles in patients with PCOS. The results of the study will be published in a scientific journal after peer-review. Conclusions: These findings will provide guidance to clinicians and patients on the use of vitamin D for PCOS with dyslipidemia. Ethics and dissemination: This study is a protocol for a systematic review of vitamin D as a treatment of dyslipidemia in PCOS patients. Systematic review registration: INPLASY202050007.

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