Targeting macrophage polarization for therapy of diabesity–the feasibility of early improvement of insulin sensitivity and insulin resistance-a comprehensive systematic review

Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.

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Telmisartan Improves Insulin Resistance and Modulates Adipose Tissue Macrophage Polarization in High-Fat-Fed Mice

Endocrinology ◽

10.1210/en.2010-1312 ◽

2011 ◽

Vol 152 (5) ◽

pp. 1789-1799 ◽

Cited By ~ 66

Author(s):

Shiho Fujisaka ◽

Isao Usui ◽

Yukiko Kanatani ◽

Masashi Ikutani ◽

Ichiro Takasaki ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Macrophage Polarization ◽

High Fat ◽

Adipose Tissues ◽

Tissue Macrophage ◽

Adipose Tissue Macrophage ◽

Visceral Adipose

Diet-induced obesity is reported to induce a phenotypic switch in adipose tissue macrophages from an antiinflammatory M2 state to a proinflammatory M1 state. Telmisartan, an angiotensin II type 1 receptor blocker and a peroxisome proliferator-activated receptor-γ agonist, reportedly has more beneficial effects on insulin sensitivity than other angiotensin II type 1 receptor blockers. In this study, we studied the effects of telmisartan on the adipose tissue macrophage phenotype in high-fat-fed mice. Telmisartan was administered for 5 wk to high-fat-fed C57BL/6 mice. Insulin sensitivity, macrophage infiltration, and the gene expressions of M1 and M2 markers in visceral adipose tissues were then examined. An insulin- or a glucose-tolerance test showed that telmisartan treatment improved insulin resistance, decreasing the body weight gain, visceral fat weight, and adipocyte size without affecting the amount of energy intake. Telmisartan reduced the mRNA expression of CD11c and TNF-α, M1 macrophage markers, and significantly increased the expressions of M2 markers, such as CD163, CD209, and macrophage galactose N-acetyl-galactosamine specific lectin (Mgl2), in a quantitative RT-PCR analysis. A flow cytometry analysis showed that telmisartan decreased the number of M1 macrophages in visceral adipose tissues. In conclusion, telmisartan improves insulin sensitivity and modulates adipose tissue macrophage polarization to an antiinflammatory M2 state in high-fat-fed mice.

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Systematic review of the effect of telmisartan on insulin sensitivity in hypertensive patients with insulin resistance or diabetes

Journal of Clinical Pharmacy and Therapeutics ◽

10.1111/j.1365-2710.2011.01295.x ◽

2011 ◽

Vol 37 (3) ◽

pp. 319-327 ◽

Cited By ~ 24

Author(s):

N. Suksomboon ◽

N. Poolsup ◽

T. Prasit

Keyword(s):

Systematic Review ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Hypertensive Patients

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TLR4/AP-1-Targeted Anti-Inflammatory Intervention Attenuates Insulin Sensitivity and Liver Steatosis

Mediators of Inflammation ◽

10.1155/2020/2960517 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Xiang Hu ◽

Jing Zhou ◽

Sha-sha Song ◽

Wen Kong ◽

Yan-Chuan Shi ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Signaling Pathway ◽

High Fat Diet ◽

Macrophage Polarization ◽

Liver Steatosis ◽

Lipid Deposition ◽

Sirna Transfection ◽

High Fat ◽

Metabolic Inflammation

Insulin resistance has been shown to be the common pathogenesis of many metabolic diseases. Metainflammation is one of the important characteristics of insulin resistance. Macrophage polarization mediates the production and development of metainflammation. Toll-like receptor 4 (TLR4) mediates macrophage activity and is probably the intersection of immunity and metabolism, but the detailed mechanism is probably not fully understood. Activated protein 1 (AP1) signaling pathway is very important in macrophage activation-mediated inflammation. However, it is unclear whether AP1 signaling pathway mediates metabolic inflammation in the liver. We aimed to investigate the effects of macrophage TLR4-AP1 signaling pathway on hepatocyte metabolic inflammation, insulin sensitivity, and lipid deposition, as well as to explore the potential of TLR4-AP1 as new intervention targets of insulin resistance and liver steatosis. TLR4 and AP1 were silenced in the RAW264.7 cells by lentiviral siRNA transfection. In vivo transduction of lentivirus was administered in mice fed with high-fat diet. Insulin sensitivity and inflammation were evaluated in the treated cells or animals. Our results indicated that TLR4/AP-1 siRNA transfection alleviated high-fat diet-induced systemic and hepatic inflammation, obesity, and insulin resistance in mice. Additionally, TLR4/AP-1 siRNA transfection mitigated palmitic acid- (PA-) induced inflammation in RAW264.7 cells and metabolic abnormalities in cocultured AML hepatocytes. Herein, we propose that TLR4-AP1 signaling pathway activation plays a crucial role in high fat- or PA-induced metabolic inflammation and insulin resistance in hepatocytes. Intervention of the TLR4 expression regulates macrophage polarization and metabolic inflammation and further alleviates insulin resistance and lipid deposition in hepatocytes.

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Scavenging dicarbonyls with 5’-O-pentyl-pyridoxamine improves insulin sensitivity and reduces atherosclerosis through modulating inflammatory Ly6Chi monocytosis and macrophage polarization

10.1101/529339 ◽

2019 ◽

Author(s):

Jiansheng Huang ◽

Patricia G. Yancey ◽

Linda S. May-Zhang ◽

Huan Tao ◽

Youmin Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Cholesterol Efflux ◽

Macrophage Polarization ◽

Atherosclerotic Cardiovascular Disease ◽

Aortic Lesion ◽

Cholesterol Efflux Capacity ◽

Atherosclerotic Lesions ◽

Hdl Function

BackgroundLipid peroxidation products impair HDL function and contribute to the development of atherosclerosis. Ours and other studies have shown that reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA), crosslink apoAI and impair the ability of HDL to promote cholesterol efflux. We examined whether scavenging of reactive dicarbonyls protects against the development of insulin resistance and atherosclerosis.Methods and ResultsHere, we found that 5’-O-pentyl-pyridoxamine (PPM), a potent scavenger of reactive dicarbonyls, abolished MDA-mediated crosslinking of apoAI in HDL by 80 % (P<0.05). In addition, PPM prevented the reduction in cholesterol efflux capacity of MDA treated HDL and preserved the cholesterol efflux capacity of MPO-modified HDL in Apoe−/− macrophages. Furthermore, PPM significantly improved the cholesterol efflux capacity and PON1 activity of HDL in Ldlr−/− mice (P<0.05), indicating that PPM protects HDL from modifications by reactive dicarbonyls and maintains HDL function in vivo. Importantly, PPM improved hyperglycemia and insulin sensitivity in male Ldlr−/− mice. Administration of 1 mg/mL of PPM, versus 1 mg/mL of the nonreactive analogue PPO, to Ldlr−/− mice consuming a western diet (WD) for 16 weeks reduced the extent of proximal aortic atherosclerosis by 48% and by 46% (P<0.05) in female and male Ldlr−/− mice. PPM also reduced the extent of en face aortic lesion by 52% in male Ldlr−/− mice. In addition, PPM reduced pro-inflammatory enzyme MPO expression by 57.5% and the number of TUNEL positive cells by 52% (P<0.01) in atherosclerotic lesions of Ldlr−/− mice. Immunohistochemistry studies revealed that PPM reduced the lesion macrophage content by 55% (P<0.05). Importantly, PPM increased M2 marker Arg1+ in macrophages of lesions and reduced the number of blood pro-inflammatory Ly6Chi monocytes and the ratio between Ly6Chi and Ly6Clow, but not the numbers of Ly6Clow, neutrophils in Ldlr−/− mice. Similarly, treatment of Apoe−/− mice on a WD for 16 weeks with PPM significantly reduced the extent of atherosclerotic lesions and also enhanced plaque stability as evidenced by a 47% increase in fibrous cap thickness and a 64.7% reduction in necrotic core area.ConclusionsReactive dicarbonyl scavenging with PPM in vivo preserves HDL function which improves insulin sensitivity and decreases atherosclerosis development. These results support the therapeutic potential of reactive dicarbonyl scavenging in the treatment of insulin resistance and atherosclerotic cardiovascular disease.

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Effects of Melatonin Supplementation on Insulin Levels and Insulin Resistance: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Hormone and Metabolic Research ◽

10.1055/a-1544-8181 ◽

2021 ◽

Vol 53 (09) ◽

pp. 616-624

Author(s):

Yan Li ◽

Zhenbin Xu

Keyword(s):

Systematic Review ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Controlled Trials ◽

Cochrane Central Register ◽

Model Assessment ◽

Insulin Levels ◽

Randomized Controlled

AbstractInsulin resistance (IR) is a pivotal process in various metabolic diseases. The well-known treatment is lifestyle modification and medication therapy, which may result in poor compliance and side effects. Melatonin has been suggested to have a role in glucose metabolism, yet the results across studies have been inconsistent. Therefore, we performed a systematic review to evaluate the effects of melatonin supplementation on insulin levels and IR. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov, and identified randomized controlled trials (RCTs) published prior to August 2020. Articles were reviewed, selected and extracted by two reviewers independently. In total, 8 RCTs of 376 participants were included. Data were pooled using a random-effects model, with mean differences (MDs) and 95% confidence intervals (CIs). Our results showed that melatonin administration significantly reduced insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR), and increased the quantitative insulin sensitivity check index (QUICKI). We conclude that melatonin ameliorated hyperinsulinemia, insulin resistance, and insulin sensitivity, and the results are an update of a previous meta-analysis. Although more investigations are required, we clearly provide evidence for the use of melatonin as an adjuvant treatment for metabolic disorders involving IR.

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Insulin resistance in patients with type 1 diabetes assessed by glucose clamp studies: systematic review and meta-analysis

Acta Endocrinologica ◽

10.1530/eje-14-0911 ◽

2015 ◽

Vol 173 (1) ◽

pp. 101-109 ◽

Cited By ~ 33

Author(s):

Esther Donga ◽

Olaf M Dekkers ◽

Eleonora P M Corssmit ◽

Johannes A Romijn

Keyword(s):

Diabetes Mellitus ◽

Systematic Review ◽

Insulin Resistance ◽

Type 1 Diabetes ◽

Insulin Sensitivity ◽

Type 1 Diabetes Mellitus ◽

Meta Analysis ◽

Healthy Controls ◽

Mean Differences

ObjectiveThe aim of this study was to perform a systematic review and meta-analysis on insulin resistance in adult patients with type 1 diabetes mellitus compared to healthy controls, assessed by hyperinsulinemic euglycemic clamp studies.Design and methodsWe conducted a systematic search of publications using PubMed, EMBASE, Web of Science and COCHRANE Library. Hyperinsulinemic euglycemic clamp studies comparing adult patients with type 1 diabetes mellitus to healthy controls were eligible. Primary outcome measures were pooled mean differences of insulin sensitivity of endogenous glucose production (EGP), of glucose uptake and of lipolysis. We estimated mean (standardized) differences and 95% CIs using random effects meta-analysis.ResultsWe included 38 publications in this meta-analysis. The weighed mean differences in EGP during hyperinsulinemia between patients and controls was 0.88 (95% CI: 0.47, 1.29) in the basal state and 0.52 (95% CI: 0.09, 0.95) in insulin stimulated conditions, indicating decreased hepatic insulin sensitivity in patients. Insulin sensitivity of glucose uptake was either reported as M value (M), glucose infusion rate (GIR), glucose disposal rate (GDR) or metabolic clearance rate (MCR). Weighed mean differences were similar for M −3.98 (95% CI: −4.68, −3.29) and GIR −4.61 (95% CI: −5.86, −3.53). Weighed mean difference for GDR was −2.43 (95% CI: −3.03, −1.83) and −3.29 (95% CI: −5.37, −1.22) for MCR, indicating decreased peripheral insulin sensitivity in patients. Insulin mediated inhibition of lipolysis was decreased in patients, reflected by increased non-esterified fatty acid levels.ConclusionsInsulin resistance is a prominent feature of patients with type 1 diabetes mellitus and involves hepatic, peripheral and adipose tissues.

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Magnesium intake, insulin resistance and markers of endothelial function among women

Public Health Nutrition ◽

10.1017/s1368980021001063 ◽

2021 ◽

pp. 1-9

Author(s):

Narges Ghorbani Bavani ◽

Parvane Saneei ◽

Ammar Hassanzadeh Keshteli ◽

Ahmadreza Yazdannik ◽

Ebrahim Falahi ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Adhesion Molecule ◽

Cell Function ◽

Intercellular Adhesion Molecule ◽

Model Assessment ◽

Serum Concentrations ◽

Homeostasis Model Assessment

Abstract Objective: We investigated the association of dietary Mg intake with insulin resistance and markers of endothelial function among Iranian women. Design: A cross-sectional study. Setting: Usual dietary intakes were assessed using a validated FFQ. Dietary Mg intake was calculated by summing up the amount of Mg in all foods. A fasting blood sample was taken to measure serum concentrations of glycemic indices (fasting plasma glucose and insulin) and endothelial function markers (E-selectin, soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1). Insulin resistance and sensitivity were estimated using the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR), Homeostasis Model Assessment β-cell function (HOMA-β) and quantitative insulin sensitivity check index (QUICKI). Participants: Iranian female nurses (n 345) selected by a multistage cluster random sampling method. Results: The Mg intake across energy-adjusted quartiles was 205 (se 7), 221·4 (se 8), 254·3 (se 7) and 355·2 (se 9) mg/d, respectively. After adjustments for potential confounders, QUICKI level was significantly different across quartiles of Mg intake (Q1: 0·34 (se 0·02), Q2: 0·36 (se 0·01), Q3: 0·40 (se 0·01), and Q4: 0·39 (se 0·02), P = 0·02); however, this association disappeared after considering markers of endothelial function, indicating that this relation might be mediated through endothelial dysfunction. After controlling for all potential confounders, Mg intake was inversely, but not significantly, associated with serum concentrations of sICAM (Q1: 239 (se 17), Q2: 214 (se 12), Q3: 196 (se 12), and Q4: 195 (se 17), P = 0·29). There was no other significant association between dietary Mg intake and other indicators of glucose homoeostasis or endothelial markers. Conclusions: Higher dietary Mg intake was associated with better insulin sensitivity in Iranian females. This linkage was mediated through reduced endothelial dysfunction.

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Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus

Cell Death and Differentiation ◽

10.1038/s41418-020-00714-7 ◽

2021 ◽

Author(s):

Longmin Chen ◽

Jing Zhang ◽

Yuan Zou ◽

Faxi Wang ◽

Jingyi Li ◽

...

Keyword(s):

Insulin Resistance ◽

High Fat Diet ◽

Macrophage Polarization ◽

Fatty Acid Uptake ◽

Chromatin Accessibility ◽

Acid Uptake ◽

High Fat ◽

M2 Polarization ◽

Adipose Tissue Macrophages ◽

Cold Challenge

AbstractKdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of Kdm2a (LysM-Cre-Kdm2af/f, Kdm2a−/−) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. Kdm2a−/− increased H3K36me2 levels at the Pparg locus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the Kdm2a−/− mice were highly protected from high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis, and featured by the reduced accumulation of adipose tissue macrophages and repressed chronic inflammation following HFD challenge. Particularly, Kdm2a−/− macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the Kdm2a−/− mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.

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γ-PGA-Rich Chungkookjang, Short-Term Fermented Soybeans: Prevents Memory Impairment by Modulating Brain Insulin Sensitivity, Neuro-Inflammation, and the Gut–Microbiome–Brain Axis

Foods ◽

10.3390/foods10020221 ◽

2021 ◽

Vol 10 (2) ◽

pp. 221

Author(s):

Do-Youn Jeong ◽

Myeong Seon Ryu ◽

Hee-Jong Yang ◽

Sunmin Park

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Gut Microbiome ◽

Memory Impairment ◽

Memory Function ◽

Bacillus Species ◽

Fermented Foods ◽

Short Term ◽

Brain Insulin ◽

Brain Insulin Resistance

Fermented soybean paste is an indigenous food for use in cooking in East and Southeast Asia. Korea developed and used its traditional fermented foods two thousand years ago. Chungkookjang has unique characteristics such as short-term fermentation (24–72 h) without salt, and fermentation mostly with Bacilli. Traditionally fermented chungkookjang (TFC) is whole cooked soybeans that are fermented predominantly by Bacillus species. However, Bacillus species are different in the environment according to the regions and seasons due to the specific bacteria. Bacillus species differently contribute to the bioactive components of chungkookjang, resulting in different functionalities. In this review, we evaluated the production process of poly-γ-glutamic acid (γ-PGA)-rich chungkookjang fermented with specific Bacillus species and their effects on memory function through the modulation of brain insulin resistance, neuroinflammation, and the gut–microbiome–brain axis. Bacillus species were isolated from the TFC made in Sunchang, Korea, and they included Bacillus (B.) subtilis, B. licheniformis, and B. amyloliquefaciens. Chungkookjang contains isoflavone aglycans, peptides, dietary fiber, γ-PGA, and Bacillus species. Chungkookjangs made with B. licheniformis and B. amyloliquefaciens have higher contents of γ-PGA, and they are more effective for improving glucose metabolism and memory function. Chungkookjang has better efficacy for reducing inflammation and oxidative stress than other fermented soy foods. Insulin sensitivity is improved, not only in systemic organs such as the liver and adipose tissues, but also in the brain. Chungkookjang intake prevents and alleviates memory impairment induced by Alzheimer’s disease and cerebral ischemia. This review suggests that the intake of chungkookjang (20–30 g/day) rich in γ-PGA acts as a synbiotic in humans and promotes memory function by suppressing brain insulin resistance and neuroinflammation and by modulating the gut–microbiome–brain axis.

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