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Obesity, Diabetes, and Increased Cancer Progression
Dae-Seok Kim, Philipp E. Scherer
Diabetes Metab J. 2021;45(6):799-812.   Published online November 22, 2021
DOI: https://doi.org/10.4093/dmj.2021.0077
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Graphical AbstractGraphical Abstract AbstractAbstract PDFPubReader   ePub   
Rates of obesity and diabetes have increased significantly over the past decades and the prevalence is expected to continue to rise further in the coming years. Many observations suggest that obesity and diabetes are associated with an increased risk of developing several types of cancers, including liver, pancreatic, endometrial, colorectal, and post-menopausal breast cancer. The path towards developing obesity and diabetes is affected by multiple factors, including adipokines, inflammatory cytokines, growth hormones, insulin resistance, and hyperlipidemia. The metabolic abnormalities associated with changes in the levels of these factors in obesity and diabetes have the potential to significantly contribute to the development and progression of cancer through the regulation of distinct signaling pathways. Here, we highlight the cellular and molecular pathways that constitute the links between obesity, diabetes, cancer risk and mortality. This includes a description of the existing evidence supporting the obesity-driven morphological and functional alternations of cancer cells and adipocytes through complex interactions within the tumor microenvironment.

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Pathophysiology
Regulation of Systemic Glucose Homeostasis by T Helper Type 2 Cytokines
Yea Eun Kang, Hyun Jin Kim, Minho Shong
Diabetes Metab J. 2019;43(5):549-559.   Published online October 24, 2019
DOI: https://doi.org/10.4093/dmj.2019.0157
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AbstractAbstract PDFPubReader   

Obesity results in an inflammatory microenvironment in adipose tissue, leading to the deterioration of tissue protective mechanisms. Although recent studies suggested the importance of type 2 immunity in an anti-inflammatory microenvironment in adipose tissue, the regulatory effects of T helper 2 (Th2) cytokines on systemic metabolic regulation are not fully understood. Recently, we identified the roles of the Th2 cytokine (interleukin 4 [IL-4] and IL-13)-induced adipokine, growth differentiation factor 15 (GDF15), in adipose tissue in regulating systemic glucose metabolism via signal transducer and activator of transcription 6 (STAT6) activation. Moreover, we showed that mitochondrial oxidative phosphorylation is required to maintain these macrophage-regulating autocrine and paracrine signaling pathways via Th2 cytokine-induced secretion of GDF15. In this review, we discuss how the type 2 immune response and Th2 cytokines regulate metabolism in adipose tissue. Specifically, we review the systemic regulatory roles of Th2 cytokines in metabolic disease and the role of mitochondria in maintenance of type 2 responses in adipose tissue homeostasis.

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Clinical Diabetes & Therapeutics
Effects of Omega-3 Supplementation on Adipocytokines in Prediabetes and Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis of Randomized Controlled Trials
Tarik Becic, Christian Studenik
Diabetes Metab J. 2018;42(2):101-116.   Published online April 19, 2018
DOI: https://doi.org/10.4093/dmj.2018.42.2.101
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AbstractAbstract PDFPubReader   
Background

The objective of this systematic review and meta-analysis was to determine the effects of omega-3 supplementation on adipocytokine levels in adult prediabetic and diabetic individuals.

Methods

We searched PubMed, Medline, EMBASE, Scopus, Web of Science, Google Scholar, Cochrane Trial Register, World Health Organization Clinical Trial Registry Platform, and Clinicaltrial.gov Registry from inception to August 1, 2017 for randomized controlled trials. Pooled effects of interventions were assessed as mean difference using random effects model. We conducted a sensitivity, publication bias and subgroup analysis.

Results

Fourteen studies individuals (n=685) were included in the meta-analysis. Omega-3 supplementation increased levels of adiponectin (0.48 µg/mL; 95% confidence interval [CI], 0.27 to 0.68; P<0.00001, n=10 trials), but effects disappeared after sensitivity analysis. Tumor necrosis factor α (TNF-α) levels were reduced (−1.71; 95% CI, −3.38 to −0.14; P=0.03, n=8 trials). Treatment duration shorter than 12 weeks was associated with greater reduction than longer treatment duration. Levels of other adipocytokines were not significantly affected. Publication bias could generally not be excluded.

Conclusion

Eicosapentaenoic acid and docosahexaenoic acid supplementation may increase adiponectin and reduce TNF-α levels in this population group. However, due to overall study heterogeneity and potential publication bias, a cautious interpretation is needed.

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Original Article
Clinical Diabetes & Therapeutics
Adipokines and Insulin Resistance According to Characteristics of Pregnant Women with Gestational Diabetes Mellitus
Eon Ju Jeon, Seong Yeon Hong, Ji Hyun Lee
Diabetes Metab J. 2017;41(6):457-465.   Published online November 15, 2017
DOI: https://doi.org/10.4093/dmj.2017.41.6.457
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AbstractAbstract PDFPubReader   
Background

The aim of this study was to evaluate adipokines concentration and insulin resistance according to maternal age or obesity at pregnancy and weight change at diagnosed gestational diabetes mellitus (GDM) in pregnant women with GDM.

Methods

This study included 57 pregnant women who were diagnosed with GDM at 24 to 28 weeks of gestation. The subjects were classified into two or three groups according to pre-pregnancy body mass index (BMI, <25 kg/m2 vs. ≥25 kg/m2), maternal age at pregnancy (<35 years old vs. ≥35 years old), and weight change during pregnancy at screening for GDM (weight change below, within, and in excess of the recommended range). They were respectively compared in each group.

Results

Leptin, homeostasis model assessment of insulin resistance (HOMA-IR), and HOMA2-%B were increased in the group with pre-pregnancy BMI ≥25 kg/m2. Leptin and HOMA-IR were positively correlated with BMI both before pregnancy and at screening for GDM. There were no significant correlations between HOMA-IR and adipokines. HOMA-IR showed positive correlation with HOMA2-%B and negative correlation with HOMA2-%S.

Conclusion

Leptin and HOMA-IR at diagnosed GDM were increased in the GDM patients with obesity before pregnancy. They were positively correlated with BMI both before pregnancy and at screening for GDM. The effect of maternal age at pregnancy and weight change during pregnancy at GDM screening on adipokines and insulin resistance might be less pronounced than the effect of maternal obesity.

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Reviews
Chemokine Systems Link Obesity to Insulin Resistance
Tsuguhito Ota
Diabetes Metab J. 2013;37(3):165-172.   Published online June 14, 2013
DOI: https://doi.org/10.4093/dmj.2013.37.3.165
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AbstractAbstract PDFPubReader   

Obesity is a state of chronic low-grade systemic inflammation. This chronic inflammation is deeply involved in insulin resistance, which is the underlying condition of type 2 diabetes and metabolic syndrome. A significant advance in our understanding of obesity-associated inflammation and insulin resistance has been recognition of the critical role of adipose tissue macrophages (ATMs). Chemokines are small proteins that direct the trafficking of immune cells to sites of inflammation. In addition, chemokines activate the production and secretion of inflammatory cytokines through specific G protein-coupled receptors. ATM accumulation through C-C motif chemokine receptor 2 and its ligand monocyte chemoattractant protein-1 is considered pivotal in the development of insulin resistance. However, chemokine systems appear to exhibit a high degree of functional redundancy. Currently, more than 50 chemokines and 18 chemokine receptors exhibiting various physiological and pathological properties have been discovered. Therefore, additional, unidentified chemokine/chemokine receptor pathways that may play significant roles in ATM recruitment and insulin sensitivity remain to be fully identified. This review focuses on some of the latest findings on chemokine systems linking obesity to inflammation and subsequent development of insulin resistance.

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Clinical Relevance of Adipokines
Matthias Blüher
Diabetes Metab J. 2012;36(5):317-327.   Published online October 18, 2012
DOI: https://doi.org/10.4093/dmj.2012.36.5.317
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AbstractAbstract PDFPubReader   

The incidence of obesity has increased dramatically during recent decades. Obesity increases the risk for metabolic and cardiovascular diseases and may therefore contribute to premature death. With increasing fat mass, secretion of adipose tissue derived bioactive molecules (adipokines) changes towards a pro-inflammatory, diabetogenic and atherogenic pattern. Adipokines are involved in the regulation of appetite and satiety, energy expenditure, activity, endothelial function, hemostasis, blood pressure, insulin sensitivity, energy metabolism in insulin sensitive tissues, adipogenesis, fat distribution and insulin secretion in pancreatic β-cells. Therefore, adipokines are clinically relevant as biomarkers for fat distribution, adipose tissue function, liver fat content, insulin sensitivity, chronic inflammation and have the potential for future pharmacological treatment strategies for obesity and its related diseases. This review focuses on the clinical relevance of selected adipokines as markers or predictors of obesity related diseases and as potential therapeutic tools or targets in metabolic and cardiovascular diseases.

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Diabetes and Osteoporosis.
Ki Won Oh
Korean Diabetes J. 2009;33(3):169-177.   Published online June 1, 2009
DOI: https://doi.org/10.4093/kdj.2009.33.3.169
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AbstractAbstract PDF
Increased life expectancy and increased obesity have contributed to an increasing incidence of osteoporosis and diabetes mellitus. Recent meta-analyses and cohort studies confirm that diabetes is associated with a higher risk of fracture. Patients with type 2 diabetes exhibit increased fracture risks despite a higher bone mass, which are mainly attributable to non-skeletal risk factors. Patients with type 1 diabetes may have impaired bone formation because of absence of the anabolic effects of insulin and insulin-like growth factor I (IGF-I) system. Several clinical studies have reported adverse skeletal actions of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist in humans. Obesity regulates bone metabolism not only by increasing weight loading but also by modulating adipokines that are known to affect bone remodeling.

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