The processing, maturation and secretion of insulin are under precise regulation, and dysregulation causes profound defects in glucose handling, leading to diabetes. Tmem30a is the β subunit of the phosphatidylserine (PS) flippase, which maintains the membrane asymmetric distribution of PS. Tmem30a regulates cell survival and the localization of subcellular structures, and is thus critical to the normal function of multiple physiological systems. Here, we show that conditional knockout of Tmem30a specifically in pancreatic islet β cells leads to obesity, hyperglycemia, glucose intolerance, hyperinsulinemia and insulin resistance in mice, due to insufficient insulin release. Moreover, we reveal that Tmem30a plays an essential role in clathrin-mediated vesicle transport between the trans Golgi network (TGN) and the PM, which comprises immature secretory granule (ISG) budding at the TGN. We also find that Tmem30a deficiency impairs clathrin-mediated vesicle budding, and thus blocks both insulin maturation in ISGs and the transport of glucose-sensing Glut2 to the PM. Collectively, these disruptions compromise both insulin secretion and glucose sensitivity, thus contributing to impairments in glucose-stimulated insulin secretion. Taken together, our data demonstrate an important role of Tmem30a in insulin maturation and glucose metabolic homeostasis, and suggest the importance of membrane phospholipid distribution in metabolic disorders.

Introduction: Semaglutide shows significant performance on weight reduction in several clinical trials. However, it is not clear what kind of administration frequency or dosage will achieve better effects. This study aims to explore the different therapeutic effect of semaglutide on weight control under the diverse administration circumstances.Methods: The PubMed, Embase, Web of Science, Cochrane Library, and the Clinical Trials.gov were searched from inception until 6 June, 2022 to include randomized controlled trials evaluating the Efficacy and safety of subcutaneous semaglutide in overweight or obese adults. Random effects or fixed effects model was conducted based on the heterogeneity among trials. Subgroup analysis was performed to identify the detailed effects under different intervention situations.Results and discussion: Our study included 13 RCTs involving 5,838 participants with 3,794 ones in semaglutide group and 2,044 in placebo group. Semaglutide was associated with a significant reduction on weight loss related outcomes, including the absolute value of weight loss (WMD -8·97, 95% CI -10·73 to -7·21), percentage of weight loss (WMD -10·00, 95% CI -11·99 to -8·00), body mass index (WMD-3·19, 95% CI -4·02 to -2·37) and waist circumference (WMD -7·21,95% CI -8·87 to -5·56). Subgroup analyses illustrated participants with high weekly dosage, long-term treatment duration and severe baseline BMI (Class II obesity) had a more remarkably decreasing on the main outcomes of weight loss (P for interaction<0·05). Total adverse reactions occurred more frequently in the daily administration group than that in the weekly group (P for interaction =0·01). During the treatment, the incidence rate of hypoglycemia was higher in the group without lifestyle intervention compared with that with lifestyle intervention (P for interaction =0·04). Interpretation Subcutaneous semaglutide had significant benefits on weight loss with reasonable safety in overweight or obese adults. Moreover, additional benefits on cardiometabolic profiles were also seen. We recommended semaglutide treatment to be coupled with lifestyle interventions, and target dose of 2·0 mg or more subcutaneously once weekly. Clinicians can choose suitable treatment schemes based on diverse individual situations.Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=337099, identifier PROSPERO (CRD42022337099).

Background: The triglyceride-glucose (TyG) index, a simple surrogate marker of insulin resistance, is significantly associated with chronic kidney disease (CKD). However, there is limited research on the longitudinal trajectory of TyG index over time and its relationship with CKD.Objective: To analyse the characteristics of the longitudinal trajectory of the TyG index over time and its association with the development of CKD in a health check-up population.Methods: Participants who underwent at least three annual health check-ups at the Health Management Center of Sichuan Provincial People’s Hospital from 2015 to 2022 were included in this retrospective cohort study. The TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The latent class mixed model (LCMM) was used to identify the TyG index trajectory of the study population. A Cox proportional hazard model was used to estimate the CKD incidence risk in different quartile groups and the association of changes in the TyG index trajectory with the development of CKD.Results: A total of 4,921 participants were included in this study, and they were divided into four groups according to the quartiles of the baseline TyG index: Q1 (5.43-6.66), Q2 (6.67-7.04), Q3 (7.05-7.43), and Q4 (7.43-9.97). There was no difference in the risk of CKD occurrence among the TyG groups. Three different TyG index trajectories were identified in this study: a high-level group, middle-level stable group and low-level stable group, respectively. The incidence rate of CKD in the high-level TyG index trajectory group was 2.399 times greater than that in the low-level stable trajectory group (HR=2.399, 95% CI 1.167-4.935).Conclusion: Individuals with long-term exposure to high TyG index levels had a significantly greater risk of CKD. Routine monitoring of the TyG index and its longitudinal trend will aid in the risk stratification of CKD in the general population and will be helpful for CKD prevention and targeted management.

Objective: The available evidence regarding the association of immune nutrition status with chronic kidney disease (CKD) is limited. Thus, the present study examined whether immunonutrition indices were associated with renal function and mortality among CKD individuals.Research design and methods: This study enrolled 6,099 U.S. adults with CKD from the NHANES 2005–2018 database. Participants were matched with National Death Index records until 31 December 2019 to determine mortality outcomes. The time-dependent receiver operating characteristic was utilized to identify the most effective index among the prognostic nutritional index (PNI), system inflammation score (SIS), Naples prognostic score (NPS), and controlling nutritional status (CONUT) for predicting mortality. Cox regression models were employed to evaluate the associations of immunonutrition indices with mortality in participants with CKD.Results: The PNI exhibited the strongest predictive power among the four indices evaluated and the restricted cubic spline analysis revealed a cutoff value of 51 for the PNI in predicting mortality. During a median follow-up of 72 months (39–115 months), a total of 1,762 (weighted 24.26%) CKD participants died from all causes. The Kaplan–Meier curve demonstrated a reduced risk of death for the subjects with a higher PNI compared to those in the lower group. Besides, after adjusting for multiple potential confounders, a higher PNI remained an independent predictor for lower risks of all-cause mortality (HR 0.80, 95%CI: 0.71–0.91, p < 0.001) and cardiovascular disease (CVD) mortality (HR 0.69, 95%CI: 0.55–0.88, p = 0.002) in individuals with CKD.Conclusion: In CKD, a higher PNI level was significantly associated with lower mortality from all causes and CVD. Thus, the clinical utility of this immunonutrition indicator may facilitate risk stratification and prevent premature death among patients with CKD.

Zhang L, et al. Allergy Asthma Immunol Res. 2023 Nov;15(6):812-824. https://doi.org/10.4168/aair.2023.15.6.812