scholarly journals The Role of GATA3 in Adipogenesis & Insulin Resistance

2020 ◽  
Author(s):  
Hend Sultan Al-Jaber ◽  
Layla Jadea Al-Mansoori ◽  
Mohamed Aghar Elrayess
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Resistant ◽  
Gata3 Expression ◽  
Inflammatory State ◽  
Induced Changes ◽  
The Impact

Background: Impaired adipogenesis plays an important role in the development of obesityassociated insulin resistance and type 2 diabetes. Adipose tissue inflammation is a crucial mediator of this process. In hyperglycemia, immune system is activated partially through upregulation of GATA3, causing exacerbation of the inflammatory state associated with obesity. GATA3 also plays a role as a gatekeeper of terminal adipocyte differentiation. Here we are examining the impact of GATA3 inhibition in adipose tissue on restoring adipogenesis, reversing insulin resistance and potentially lowering the risk of type 2 diabetes. Results: GATA-3 expression was higher in insulin resistant obese individuals compared to their insulin sensitive counterparts. Targeting GATA-3 with GATA-3 specific inhibitors reversed impaired adipogenesis and induced changes in the expression of a number insulin signaling-related genes, including up-regulation of insulin sensitivity-related gene and down-regulation of insulin resistance-related genes. Conclusion: GATA3 expression is higher in differentiating adipocytes from obese insulin resistant. Inhibiting GATA3 improves adipocytes differentiation and rescues insulin sensitivity in insulin resistant cells

scholarly journals Quantification of adipose tissue insulin sensitivity

2016 ◽  
Vol 64 (5) ◽  
pp. 989-991 ◽  
Author(s):  
Esben Søndergaard ◽  
Michael D Jensen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Resistant ◽  
Healthy Humans ◽  
Metabolic Defects ◽  
Tissue Resistance

In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses.

scholarly journals Ethnic distinctions in the pathophysiology of type 2 diabetes: a focus on black African-Caribbean populations

2019 ◽  
Vol 79 (2) ◽  
pp. 184-193 ◽  
Author(s):  
Louise M. Goff ◽  
Meera Ladwa ◽  
Olah Hakim ◽  
Oluwatoyosi Bello
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Global Public Health ◽  
Black African ◽  
African Caribbean ◽  
Black Populations ◽  
The Impact ◽  
Caribbean Populations

Type 2 diabetes (T2D) is a global public health priority, particularly for populations of black African-Caribbean ethnicity, who suffer disproportionately high rates of the disease. While the mechanisms underlying the development of T2D are well documented, there is growing evidence describing distinctions among black African-Caribbean populations. In the present paper, we review the evidence describing the impact of black African-Caribbean ethnicity on T2D pathophysiology. Ethnic differences were first recognised through evidence that metabolic syndrome diagnostic criteria fail to detect T2D risk in black populations due to less central obesity and dyslipidaemia. Subsequently more detailed investigations have recognised other mechanistic differences, particularly lower visceral and hepatic fat accumulation and a distinctly hyperinsulinaemic response to glucose stimulation. While epidemiological studies have reported exaggerated insulin resistance in black populations, more detailed and direct measures of insulin sensitivity have provided evidence that insulin sensitivity is not markedly different to other ethnic groups and does not explain the hyperinsulinaemia that is exhibited. These findings lead us to hypothesise that ectopic fat does not play a pivotal role in driving insulin resistance in black populations. Furthermore, we hypothesise that hyperinsulinaemia is driven by lower rates of hepatic insulin clearance rather than heightened insulin resistance and is a primary defect rather than occurring in compensation for insulin resistance. These hypotheses are being investigated in our ongoing South London Diabetes and Ethnicity Phenotyping study, which will enable a more detailed understanding of ethnic distinctions in the pathophysiology of T2D between men of black African and white European ethnicity.

scholarly journals Metabolic signature of obesity-associated insulin resistance and type 2 diabetes

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Haya Al-Sulaiti ◽  
Ilhame Diboun ◽  
Maha V. Agha ◽  
Fatima F. S. Mohamed ◽  
Stephen Atkin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Serum Samples ◽  
Metabolic Markers ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Novel Biomarkers ◽  
Prospective Cohorts

Abstract Background Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear. Methods In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals. Results Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively. Conclusion This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.

A novel small molecule A2A adenosine receptor agonist, indirubin-3′-monoxime, alleviates lipid-induced inflammation and insulin resistance in 3T3-L1 adipocytes

2019 ◽  
Vol 476 (16) ◽  
pp. 2371-2391 ◽  
Author(s):  
Saynaz A. Choudhary ◽  
Nikita Bora ◽  
Dipanjan Banerjee ◽  
Leena Arora ◽  
Anindhya Sundar Das ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adenosine Receptor ◽  
In Vitro Study ◽  
A2a Adenosine Receptor ◽  
Insulin Resistant ◽  
Adenosine Receptor Agonist ◽  
Inflammatory State

Abstract Saturated free fatty acid-induced adipocyte inflammation plays a pivotal role in implementing insulin resistance and type 2 diabetes. Recent reports suggest A2A adenosine receptor (A2AAR) could be an attractive choice to counteract adipocyte inflammation and insulin resistance. Thus, an effective A2AAR agonist devoid of any toxicity is highly appealing. Here, we report that indirubin-3′-monoxime (I3M), a derivative of the bisindole alkaloid indirubin, efficiently binds and activates A2AAR which leads to the attenuation of lipid-induced adipocyte inflammation and insulin resistance. Using a combination of in silico virtual screening of potential anti-diabetic candidates and in vitro study on insulin-resistant model of 3T3-L1 adipocytes, we determined I3M through A2AAR activation markedly prevents lipid-induced impairment of the insulin signaling pathway in adipocytes without any toxic effects. While I3M restrains lipid-induced adipocyte inflammation by inhibiting NF-κB dependent pro-inflammatory cytokines expression, it also augments cAMP-mediated CREB activation and anti-inflammatory state in adipocytes. However, these attributes were compromised when cells were pretreated with the A2AAR antagonist, SCH 58261 or siRNA mediated knockdown of A2AAR. I3M, therefore, could be a valuable option to intervene adipocyte inflammation and thus showing promise for the management of insulin resistance and type 2 diabetes.

scholarly journals Inhibition of Protein Tyrosine Phosphatase-1B with Antisense Oligonucleotides Improves Insulin Sensitivity and Increases Adiponectin Concentrations in Monkeys

Endocrinology ◽  
2009 ◽  
Vol 150 (4) ◽  
pp. 1670-1679 ◽  
Author(s):  
Michael M. Swarbrick ◽  
Peter J. Havel ◽  
Arthur A. Levin ◽  
Andrew A. Bremer ◽  
Kimber L. Stanhope ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Protein Tyrosine Phosphatase ◽  
Antisense Oligonucleotides ◽  
Tyrosine Phosphatase ◽  
Ptp 1B ◽  
Insulin Responses

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40–50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1–10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = −0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.

Normal Akt/PKB with reduced PI3K activation in insulin-resistant mice

2001 ◽  
Vol 281 (6) ◽  
pp. E1249-E1254 ◽  
Author(s):  
Samuel T. Nadler ◽  
Jonathan P. Stoehr ◽  
Mary E. Rabaglia ◽  
Kathryn L. Schueler ◽  
Morris J. Birnbaum ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Resistant ◽  
Experimental Systems ◽  
Pi3k Activity ◽  
Pi3k Activation

Insulin stimulates muscle and adipose tissue to absorb glucose through a signaling cascade that is incompletely understood. Insulin resistance, the inability of insulin to appropriately stimulate glucose uptake, is a hallmark of type 2 diabetes mellitus. The development of experimental systems that model human insulin resistance is important in elucidating the defects responsible for the development of type 2 diabetes. When two strains of mice, BTBR and C57BL/6J (B6), are crossed, the resultant male offspring (BtB6) demonstrate insulin resistance in muscle tissue. Here, we report an insulin resistance phenotype in adipose tissue from lean, nondiabetic BtB6 mice similar to that observed in human muscle. Adipocytes isolated from insulin-resistant male mice display 65% less insulin-stimulated glucose uptake compared with insulin-sensitive female mice. Similarly, adipocytes from insulin-resistant mice have diminished insulin-stimulated IRS-1 phosphorylation and phosphatidylinositol 3-kinase (PI3K) activation. However, normal activation of protein kinase B (Akt/PKB) by insulin is observed. Thus BtB6 mice demonstrate the dissociation of insulin-stimulated PI3K activity and Akt/PKB activation and represent a useful model to investigate the causes of insulin resistance in humans.

scholarly journals Intramuscular triglyceride synthesis: importance in muscle lipid partitioning in humans

2018 ◽  
Vol 314 (2) ◽  
pp. E152-E164 ◽  
Author(s):  
Bryan C. Bergman ◽  
Leigh Perreault ◽  
Allison Strauss ◽  
Samantha Bacon ◽  
Anna Kerege ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Acute Exercise ◽  
Insulin Resistant ◽  
Lipid Desaturation ◽  
Intramuscular Triglyceride ◽  
Athlete’S Paradox

Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type 2 diabetes, and have very low risk of diabetes, termed the “athlete’s paradox.” We now know that IMTG synthesis is positively related to insulin sensitivity, but the exact mechanisms for this are unclear. To understand the relationship between IMTG synthesis and insulin sensitivity, we measured IMTG synthesis in obese control subjects, endurance-trained athletes, and individuals with type 2 diabetes during rest, exercise, and recovery. IMTG synthesis rates were positively related to insulin sensitivity, cytosolic accumulation of DAG, and decreased accumulation of C18:0 ceramide and glucosylceramide. Greater rates of IMTG synthesis in athletes were not explained by alterations in FFA concentration, DGAT1 mRNA expression, or protein content. IMTG synthesis during exercise in Ob and T2D indicate utilization as a fuel despite unchanged content, whereas IMTG concentration decreased during exercise in athletes. mRNA expression for genes involved in lipid desaturation and IMTG synthesis were increased after exercise and recovery. Further, in a subset of individuals, exercise decreased cytosolic and membrane di-saturated DAG content, which may help explain insulin sensitization after acute exercise. These data suggest IMTG synthesis rates may influence insulin sensitivity by altering intracellular lipid localization, and decreasing specific ceramide species that promote insulin resistance.

scholarly journals Fatty Acid Synthase: Association with Insulin Resistance, Type 2 Diabetes, and Cancer

2009 ◽  
Vol 55 (3) ◽  
pp. 425-438 ◽  
Author(s):  
Javier A Menendez ◽  
Alejandro Vazquez-Martin ◽  
Francisco Jose Ortega ◽  
Jose Manuel Fernandez-Real
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Synthase ◽  
Metabolic Diseases ◽  
De Novo ◽  
Genetic Alterations ◽  
Insulin Resistant

Abstract Background: An emerging paradigm supports the notion that deregulation of fatty acid synthase (FASN)-catalyzed de novo FA biogenesis could play a central role in the pathogenesis of metabolic diseases sharing the hallmark of insulin-resistance. Content: We reviewed pharmacological and genetic alterations of FASN activity that have been shown to significantly influence energy expenditure rates, fat mass, insulin sensitivity, and cancer risk. This new paradigm proposes that insulin-resistant conditions such as obesity, type 2 diabetes, and cancer arise from a common FASN-driven “lipogenic state”. An important question then is whether the development or the progression of insulin-related metabolic disorders can be prevented or reversed by the modulation of FASN status. If we accept the paradigm of FASN dysfunction as a previously unrecognized link between insulin resistance, type 2 diabetes, and cancer, the use of insulin sensitizers in parallel with forthcoming FASN inhibitors should be a valuable therapeutic approach that, in association with lifestyle interventions, would concurrently improve energy-flux status, ameliorate insulin sensitivity, and alleviate the risk of lipogenic carcinomas. Conclusions: Although the picture is currently incomplete and researchers in the field have plenty of work ahead, the latest clinical and experimental evidence that we discuss illuminates a functional and drug-modifiable link that connects FASN-driven endogenous FA biosynthesis, insulin action, and glucose homeostasis in the natural history of insulin-resistant pathologies.

scholarly journals Inflammation during obesity is not all bad: evidence from animal and human studies

2013 ◽  
Vol 304 (5) ◽  
pp. E466-E477 ◽  
Author(s):  
Jianping Ye ◽  
Owen P. McGuinness
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Proinflammatory Cytokines ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Anti Inflammatory ◽  
The Impact

Chronic inflammation is a characteristic of obesity and is associated with accompanying insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Although proinflammatory cytokines are known for their detrimental effects on adipose tissue function and insulin sensitivity, their beneficial effects in the regulation of metabolism have not drawn sufficient attention. In obesity, inflammation is initiated by a local hypoxia to augment angiogenesis and improve adipose tissue blood supply. A growing body of evidence suggests that macrophages and proinflammatory cytokines are essential for adipose remodeling and adipocyte differentiation. Phenotypes of multiple lines of transgenic mice consistently suggest that proinflammatory cytokines increase energy expenditure and act to prevent obesity. Removal of proinflammatory cytokines by gene knockout decreases energy expenditure and induces adult-onset obesity. In contrast, elevation of proinflammatory cytokines augments energy expenditure and decreases the risk for obesity. Anti-inflammatory therapies have been tested in more than a dozen clinical trials to improve insulin sensitivity and glucose homeostasis in patients with T2DM, and the results are not encouraging. One possible explanation is that anti-inflammatory therapies also attenuate the beneficial effects of inflammation in stimulating energy expenditure, which may have limited the efficacy of the treatment by promoting energy accumulation. Thus, the positive effects of proinflammatory events should be considered in evaluating the impact of inflammation in obesity and type 2 diabetes.

scholarly journals Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng

2009 ◽  
Vol 203 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Yun Wang ◽  
Patsy M Nishina ◽  
Jürgen K Naggert
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Insulin Resistant

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.

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