The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH

Hedjazifar, Shahram; Shahidi, Roxana Khatib; Hammarstedt, Ann; Bonnet, L.; Church, Chris; Boucher, Jérémie; Blüher, Matthias; Smith, Ulf

doi:10.2337/db19-0701

Cited by 50 publications

(67 citation statements)

References 29 publications

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“…Adiponectin and leptin can independently predict the onset of NAFLD that is why they may be taken into consideration as potential predictive biomarkers for NAFLD [ 94 ]. Recently, researchers found that novel adipokine Gremlin 1 can antagonize insulin signaling, is positively correlated with the percentage of body fat and IR in T2DM and NAFLD/NASH subjects, and also could represent a potential biomarker or therapeutic target [ 95 ].…”

Section: Immunopathogenesismentioning

confidence: 99%

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

Tănase

Gosav

Costea

et al. 2020

Journal of Diabetes Research

279

180

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Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) remain as one of the most global problematic metabolic diseases with rapidly increasing prevalence and incidence. Epidemiological studies noted that T2DM patients have by two-fold increase to develop NAFLD, and vice versa. This complex and intricate association is supported and mediated by insulin resistance (IR). In this review, we discuss the NAFLD immunopathogenesis, connection with IR and T2DM, the role of screening and noninvasive tools, and mostly the impact of the current antidiabetic drugs on steatosis liver and new potential therapeutic targets.

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Section: Immunopathogenesismentioning

confidence: 99%

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

Tănase

Gosav

Costea

et al. 2020

Journal of Diabetes Research

279

180

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show abstract

“…201 The novel adipokine gremlin 1 antagonizes insulin action and is increased in type 2 diabetes and NAFLD/NASH. 202 Diet and nutrient intake. Inadequate vitamin and fiber content in the diet, as well as simple carbohydrates, saturated fat, and excessive cholesterol, are associated with NASH development.…”

Section: Microbial Dysbiosis and Intestinal Barrier Functionmentioning

confidence: 99%

Immunological mechanisms and therapeutic targets of fatty liver diseases

et al. 2020

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Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.

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“…A subcutaneous abdominal adipose tissue biopsy was performed. The biopsies (approximately 20-30 mg) were obtained with a needle aspiration technique, from the paraumbilical region after local infiltrative anesthesia with lidocaine (20 ml, 0.5%) 28 .…”

Section: Study Populationmentioning

confidence: 99%

Adipose tissue morphology, imaging and metabolomics predicting cardiometabolic risk and family history of type 2 diabetes in non-obese men

Rawshani

Eliasson

Rawshani

et al. 2020

Sci Rep

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We evaluated the importance of body composition, amount of subcutaneous and visceral fat, liver and heart ectopic fat, adipose tissue distribution and cell size as predictors of cardio-metabolic risk in 53 non-obese male individuals. Known family history of type 2 diabetes was identified in 25 individuals. The participants also underwent extensive phenotyping together with measuring different biomarkers and non-targeted serum metabolomics. We used ensemble learning and other machine learning approaches to identify predictors with considerable relative importance and their intricate interactions. Visceral fat and age were strong individual predictors of ectopic fat accumulation in liver and heart along with markers of lipid oxidation and reduced glucose tolerance. Subcutaneous adipose cell size was the strongest individual predictor of whole-body insulin sensitivity and also a marker of visceral and ectopic fat accumulation. The metabolite 3-MOB along with related branched-chain amino acids demonstrated strong predictability for family history of type 2 diabetes. Overweight, obesity and a sedentary life style are major causes of the current global Type 2 diabetes epidemic. Excess body weight promotes insulin resistance and the expanded adipose tissue plays a critical role for this. The subcutaneous adipose tissue is the largest and preferred site to accumulate excess fat but it is limited in its ability to recruit new cells in adults and, thus, cell expansion is the major way of accommodating excess lipids 1,2. Expanded subcutaneous adipose cells tend to become proinflammatory, insulin resistant and to have increased lipolysis. In addition, visceral fat is increasingly used for lipid storage while ectopic fat accumulates in the liver, heart and other tissues, which also enhances insulin resistance and the dysmetabolic state 2,3. Ability to differentiate new subcutaneous adipose cells is reduced in adults with expanded cells, not because of reduced number of precursor cells but as a consequence of increased cell senescence 4. Importantly, individuals with type 2 diabetes (T2D) 5 , and also non-diabetic individuals with family history for T2D (First-Degree Relatives), have inappropriately expanded adipose cells in relation to their BMI 6,7 due to the reduced subcutaneous adipogenesis in the presence of increased senescent progenitor cells 4. Conceptually, there should be a close interaction between ability to store excess lipids in subcutaneous fat and the accumulation of visceral fat, ectopic fat and development of a dysmetabolic state. The associations and potential regulation exercised by subcutaneous adipose tissue lipid accumulation and cellular morphology on overall metabolic risk profile with imaging and metabolomics data and relation to family history have, to our knowledge, never been examined before in man.

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The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH

Cited by 50 publications

References 29 publications

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

Immunological mechanisms and therapeutic targets of fatty liver diseases

Adipose tissue morphology, imaging and metabolomics predicting cardiometabolic risk and family history of type 2 diabetes in non-obese men

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