Crosstalk Between Polygonatum kingianum, the miRNA, and Gut Microbiota in the Regulation of Lipid Metabolism

Objectives:Polygonatum kingianum is a medicinal herb used in various traditional Chinese medicine formulations. The polysaccharide fraction of P. kingianum can reduce insulin resistance and restore the gut microbiota in a rat model of aberrant lipid metabolism by down regulating miR-122. The aim of this study was to further elucidate the effect of P. kingianum on lipid metabolism, and the roles of specific miRNAs and the gut microbiota.Key findings:P. kingianum administration significantly altered the abundance of 29 gut microbes and 27 differentially expressed miRNAs (DEMs). Several aberrantly expressed miRNAs closely related to lipid metabolism were identified, of which some were associated with specific gut microbiota. MiR-484 in particular was identified as the core factor involved in the therapeutic effects of P. kingianum. We hypothesize that the miR-484-Bacteroides/Roseburia axis acts as an important bridge hub that connects the entire miRNA-gut microbiota network. In addition, we observed that Parabacteroides and Bacillus correlated significantly with several miRNAs, including miR-484, miR-122-5p, miR-184 and miR-378b.Summary:P. kingianum alleviates lipid metabolism disorder by targeting the network of key miRNAs and the gut microbiota.

Myoinositol plus α-lactalbumin supplementation, insulin resistance and birth outcomes in women with gestational diabetes mellitus: a randomized, controlled study

To verify whether myo-inositol plus α-lactalbumin may reduce insulin resistance and excessive fetal growth in women with gestational diabetes mellitus. In a 12-month period, 120 women with a diagnosis of gestational diabetes mellitus were consecutively enrolled with an allocation of 1:1 in each group and randomly treated with myo-inositol plus α-lactalbumin plus folic acid (treated group) or folic acid (control group) for 2 months. Primary outcome was the variation of insulin resistance through the study evaluated by HOMA-IR. Secondary outcome was the evaluation, through the study, of fetal growth by ultrasound measurements of abdominal circumference centiles and estimated fat thickness. Some clinical outcomes were also considered. After 2 months, in the treated group, a significant reduction in insulin resistance (HOMA values 3.1 ± 1.4 vs 6.1 ± 3.4, p = 0.0002) and fetal growth was shown (Abdominal circumference centiles 54.9 ± 23.5 vs 67.5 ± 22.6, P = 0.006). Among clinical outcomes, a significant decrease in the rate of women who needed insulin (6.7% vs 20.3%, p = 0.03) and of pre-term birth (0 vs 15.2%, p = 0.007) was evidenced. A combination of myo-inositol and α-lactalbumin may reduce insulin resistance and excessive fetal growth.Clinical trial registration: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT 03763669, first posted date 04/12/2018; last posted date December 06/12/2018.

SIRT1 deacetylates mitochondrial trifunctional enzyme α subunit to inhibit ubiquitylation and decrease insulin resistance

Dysregulation of free acid metabolism is a major contributor to the development of insulin resistance and diabetes. Mitochondrial trifunctional enzyme subunit (MTPα) has a critical role in fatty acid β-oxidation. However, the association between MTPα and insulin resistance is not definitively known. Here, we aimed to determine how MTPα affects insulin resistance. We tested how MTPα affected glucose uptake in insulin-resistant 3T3-L1 adipocytes and white adipose tissue (WAT) of db/db diabetic mice. We also measured how acetylation and ubiquitylation modifications regulated MTPα activation and stability, using quantitative real-time polymerase chain reactions, immunoblotting, and immunoprecipitation. We found that MTPα overexpression promoted glucose uptake via Glut4 translocation to the plasma membrane in 3T3-L1 adipocytes. Moreover, MTPα upregulation decreased glycemia in db/db mice. Deacetylation increased MTPα protein stability and its ability to reduce insulin resistance. The activation of SIRT1, a major deacetylase, prevented MTPα degradation by decreasing its acetylation in adipocytes. Our study demonstrates a new role for MTPα in reducing insulin resistance. Acetylation and ubiquitylation modifications of MTPα were crucial to regulating its function in glucose metabolism.

Cajanonic acid A regulates the ratio of Th17/Treg via inhibition of expression of IL-6 and TGF-β in insulin-resistant HepG2 cells

Background: The objectives of the present study are to investigate whether cajanonic acid A (CAA) can reduce insulin resistance (IR) in HepG2 cells and to gain a preliminary understanding of the mechanisms underlying this effect. Methods: Following induction of IR in HepG2 cells, we tested the regulatory effect of CAA on glucose consumption and evaluated hepatocyte production of IL-6, TGF-β, and key molecules in the insulin transduction pathway. A transwell co-culturing system was used to assess the effect of CAA on IR in HepG2 cells during the differentiation of CD4+ T cells by calculating the ratio of (Th17)/regulatory T cell (Treg). We evaluated the effect of CAA on the expression of IL-17RC cells and HepG2 cell apoptosis by immunofluorescence and flow cytometry assay. Results: CAA improved dexamethasone-induced reduction in glucose consumption in HepG2 cells, inhibited hepatocyte production of IL-6 and TGF-β, increased the expression of IL-17RC cell, and increased cellular apoptosis in insulin-resistant HepG2 cells. When co-cultured with CD4+ T cells, insulin-resistant HepG2 cells induced a decrease in the ratio of Th17/Treg, but CAA dampened the effect. Application of IL-6 and TGF-β, together with CAA, reversed the effect of CAA on insulin-resistant HepG2 cells. Overexpression of IL17R, however, counteracted the effect of IL-6 neutralizing antibody within the culture system. Conclusion: CAA can regulate the ratio of Th17/Treg by mediating the expression of IL-6 and TGF-β in insulin-resistant HepG2 cells.

Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT

Background Combination antiretroviral therapy (cART) is the standard for human immunodeficiency virus (HIV) infection treatment but can result in metabolic abnormalities, such as insulin resistance, dyslipidaemia and lipodystrophy, which can increase the risk of cardiovascular disease. Objective The objective of the trial was to evaluate whether or not telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor-γ partial agonist, could reduce insulin resistance in HIV-positive individuals on cART, and affect blood and imaging biomarkers of cardiometabolic disease. Design A Phase II, multicentre, randomised, open-labelled, dose-ranging trial of telmisartan over a period of 48 weeks with an adaptive design comprising two stages was used to identify the optimal dose of telmisartan. Participants were randomised to receive one of the three doses of telmisartan (20, 40 and 80 mg) or no intervention (control). Setting Recruitment was from 19 HIV specialist centres in the UK. Participants A total of 377 patients infected with HIV who met the prespecified inclusion/exclusion criteria. Interventions 20-, 40- and 80-mg tablets of telmisartan. Main outcome measures The primary outcome measure was reduction in the homeostatic model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, at 24 weeks. Secondary outcome measures were changes in plasma lipid profile; Quantitative Insulin Sensitivity Check Index (QUICKI) and revised QUICKI, alternative markers of insulin resistance, plasma adipokines (adiponectin, leptin, interleukin 8, tumour necrosis factor alpha, resistin); high-sensitivity C-reactive protein (hs-CRP); body fat redistribution, as measured by magnetic resonance imaging/proton magnetic resonance spectroscopy; changes in renal markers (albumin-to-creatinine ratio, neutrophil gelatinase-associated lipocalin); and tolerability to telmisartan. Results At the interim analysis, 80 mg of telmisartan was taken forward into the second stage of the study. Baseline characteristics were balanced across treatment arms. There were no differences in HOMA-IR [0.007, standard error (SE) 0.106], QUICKI (0.001, SE 0.001) and revised QUICKI (0.002, SE 0.002) at 24 weeks between the telmisartan (80 mg; n = 106) and non-intervention (n = 105) arms. Longitudinal analysis over 48 weeks showed that there was no change in HOMA-IR, lipid or adipokine levels; however, but there were significant, but marginal, improvements in revised QUICKI [0.004, 95% confidence interval (CI) 0.000 to 0.008] and plasma hs-CRP (–0.222, 95% CI –0.433 to –0.011) over 48 weeks. Substudies also showed a significant reduction in the liver fat content at 24 weeks (1.714, 95% CI –2.787 to –0.642; p = 0.005) and urinary albumin excretion at 48 weeks (–0.665, 95% CI –1.31 to –0.019; p = 0.04). There were no differences in serious adverse events between the telmisartan and control arms. Limitations The patients had modest elevations of HOMA-IR at baseline, and our trial could have been under-powered to detect smaller improvements in insulin resistance over time. Conclusions Using a novel adaptive design, we demonstrated that there was no significant effect of telmisartan (80 mg) on the primary outcome measure of HOMA-IR and some secondary outcomes (plasma lipids and adipokines). Telmisartan did lead to favourable, and biologically plausible, changes of the secondary longitudinal outcome measures: revised QUICKI, hs-CRP, hepatic fat accumulation and urinary albumin excretion. Taken collectively, our findings showed that telmisartan did not reduce insulin resistance in patients infected with HIV on antiretrovirals. Future work The mechanistic basis of adipocyte regulation will be studied to allow for development of biomarkers and interventions. Trial registration Current Controlled Trials ISRCTN51069819. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.

At A Glance On Kothala himbutu

Kothala himbutu (Salacia reticulate; SR) is a very useful medicinal plant in Sri Lanka and the southern region of India. SR contains salacinol and kotalanol neosalacinol and neokotalanol which can isolated from the Salacia species by using iron pair chromatography [1& 2]. It is a woody climber and widely used in Ayurvedic medicine for diabetes and obesity treatment. Previously, the action of SR for diabetes is not described properly. Researchers tried to explore the effect of SR and found that it has an alpha glucosidase inhibitor activity in invitro study. Moreover, SR may increase lipolysis and reduce insulin resistance by enhancing mRNA expression for hormone sensitive lipase (HSL) and adiponectin [3].