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.

Lipid-Induced Insulin Resistance Mechanisms: The Link to Inflammation and Type 2 Diabetes.

2021 ◽  
pp. 1-9
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Laboratory Data ◽  
Phosphatidyl Inositol ◽  
Resistance Mechanisms ◽  
Cellular Mechanisms ◽  
Insulin Resistant

1. Abstract Insulin Resistance is the leading cause of Type 2 diabetes mellitus [T2DM] onset. It occurs as a result of disturbances in lipid metabolism and increased levels of circulating free fatty acids [FFAs]. FFAs accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues exacerbating different molecular mechanisms. Increased fatty acid flux has been documented to be strongly associated with insulin resistant states and obesity causing inflammation that eventually causes type 2-diabetes development. FFAs appear to cause this defect in glucose transport by inhibiting insulin –stimulated tyrosine phosphorylation of insulin receptor substrate-1 [IRS-1] and IRS-1 associated phosphatidyl-inositol 3-kinase activity. A number of different metabolic abnormalities may increase intramyocellular or intrahepatic fatty acid metabolites that induce insulin resistance through different cellular mechanisms. The current review point out the link between enhanced FFAs flux and activation of PKC and how it impacts on both the insulin signaling in muscle and liver as shown from our laboratory data and highlighting the involvement of the inflammatory pathways importance. This embarks the importance of measuring the inflammatory biomarkers in clinical settings.

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.

scholarly journals Type 2 Diabetes Mouse Model: Insights into the Contribution of Metabolic Defects to Neurocognitive Decline

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Alexa Loncharich ◽  
Austin Reilly ◽  
Shijun Yan ◽  
Hongxia Ren
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Transporter ◽  
Metabolic Diseases ◽  
Neurocognitive Deficits ◽  
Treatment Needs ◽  
Resistant Mouse ◽  
Insulin Resistant ◽  
Metabolic Defects

Background and Hypothesis: Metabolic diseases, including type 2 diabetes (T2D), have become increasingly prevalent and their associated medical costs have skyrocketed. Furthermore, recent epidemiological evidence suggests links between metabolic defects and neurodegenerative diseases, such as Alzheimer’s Disease (AD). The increasing coincidence of AD and T2D, and unmet treatment needs, necessitates research investigating potential shared mechanisms. To study glucose and lipid metabolism defects and neurocognitive deficits, we have generated non-obese insulin resistant mouse models, named GLUT4-mediated Insulin Receptor KnockOut (GIRKO). Insulin-responsive glucose transporter, Glut4, is expressed in muscle, fat, and a subset of neurons in the brain. Our previous publications show that GIRKO mice are highly insulin resistant and insulin sensitive GLUT4 neurons are critical mediators for glucose metabolism. We hypothesize that central insulin resistance in GIRKO mice instigates neurocognitive defects.  Experimental Design: We will measure the neurocognitive function of 3- to 4-month old GIRKO mice using Morris water maze (MWM) test.   Results: GIRKO mice exhibited increased escape latency. Additionally, they spent less time in the target quadrant in the probe trial, in which the platform is removed. GIRKO performed equally compared to control mice in raised platform tests, which demonstrates that motor competencies do not confound our findings.  Conclusion and Potential Impact: GIRKO mice have learning and memory deficits, which illustrates a possible link between neurocognition and metabolism.  Our results support the notion that insulin resistance precedes cognitive decline and necessitates early intervention therapy to treat insulin resistance and protect cognitive function. 

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 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 Astrocyte Clocks and Glucose Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Olga Barca-Mayo ◽  
Miguel López
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Circadian Clock ◽  
Glucose Homeostasis ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Whole Body

The endogenous timekeeping system evolved to anticipate the time of the day through the 24 hours cycle of the Earth’s rotation. In mammals, the circadian clock governs rhythmic physiological and behavioral processes, including the daily oscillation in glucose metabolism, food intake, energy expenditure, and whole-body insulin sensitivity. The results from a series of studies have demonstrated that environmental or genetic alterations of the circadian cycle in humans and rodents are strongly associated with metabolic diseases such as obesity and type 2 diabetes. Emerging evidence suggests that astrocyte clocks have a crucial role in regulating molecular, physiological, and behavioral circadian rhythms such as glucose metabolism and insulin sensitivity. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying glucose homeostasis regulation by the circadian clock and its dysregulation may improve glycemic control. In this review, we summarize the current knowledge on the tight interconnection between the timekeeping system, glucose homeostasis, and insulin sensitivity. We focus specifically on the involvement of astrocyte clocks, at the organism, cellular, and molecular levels, in the regulation of glucose metabolism.

Methods of Measuring Insulin Sensitivity

2007 ◽  
Vol 8 (4) ◽  
pp. 305-318 ◽  
Author(s):  
Kimberly K. Trout ◽  
Carol Homko ◽  
Nancy C. Tkacs
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Biological Response ◽  
Insulin Resistant ◽  
Advantages And Disadvantages ◽  
Health Disorders

Insulin resistance is a component of several health disorders, most notably impaired glucose tolerance and type 2 diabetes mellitus. Insulin-resistant individuals have an impaired biological response to the usual action of insulin; that is, they have reduced insulin sensitivity. Various methods are used to assess insulin sensitivity both in individuals and in study populations. Validity, reproducibility, cost, and degree of subject burden are important factors for both clinicians and researchers to consider when weighing the merits of a particular method. This article describes several in vivo methods used to assess insulin sensitivity and presents the advantages and disadvantages of each.

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

Fatty acid binding protein-2 gene variants and insulin resistance: gene and gene-environment interaction effects

2002 ◽  
Vol 10 (3) ◽  
pp. 145-157 ◽  
Author(s):  
Edward P. Weiss ◽  
Michael D. Brown ◽  
Alan R. Shuldiner ◽  
James M. Hagberg
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Body Composition ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Binding Protein ◽  
Gene Variants ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

The intestinal fatty acid binding protein (FABP2) gene is proposed as a candidate gene for diabetes because the protein it codes is involved in fatty acid (FA) absorption and metabolism and may, therefore, affect insulin sensitivity and glucose metabolism. Numerous studies have assessed FABP2 gene variants and their association with insulin resistance and type 2 diabetes. Some weak evidence indicates that the silent variants and those in the noncoding regions of the gene (codon 118, 3′ noncoding region, intron 2 trinucleotide repeat) might be associated with insulin resistance/type 2 diabetes. The most extensively studied variant is the missense Ala54Thr variation, which is common in diverse populations and results in increased FA absorption in vivo. Some evidence indicates that this variant may be associated with insulin sensitivity/type 2 diabetes. However, the large majority of studies assessing the potential association between the Ala54Thr FABP2 variant and insulin resistance/type 2 diabetes did not account for the independent and substantial effects of body composition, habitual physical activity (PA) levels, and diet on insulin resistance. We recently reported that there was an association between Ala54Thr FABP2 genotypes and insulin sensitivity after accounting for the independent effects of body composition and habitual PA levels on insulin sensitivity. Furthermore, others have demonstrated that Ala54Thr FABP2 may associate with insulin sensitivity, but only if individuals are consuming a high-fat diet. These results highlight the importance of including behavioral and environmental factors in the design of studies seeking to assess the impact of genes on physiological and clinical outcome phenotypes.

Abstract 040: The Effects of Coffee Consumption on Insulin Sensitivity and Other Risk Factors for Type 2 Diabetes

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Derrick Johnston Alperet ◽  
Salome Antonette Rebello ◽  
Eric Yin-Hao Khoo ◽  
Zoey Tay ◽  
Sharna Si-Ying Seah ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Controlled Trial ◽  
Coffee Consumption ◽  
Small Sample ◽  
Insulin Resistant

Background: In observational studies, coffee consumption has been consistently associated with a lower risk of type 2 diabetes mellitus. Trials examining the effect of coffee consumption on glucose metabolism have been limited by the use of surrogate insulin sensitivity indices, small sample sizes, lack of blinding, and short follow-up duration. We aimed to overcome these limitations in a randomized placebo-controlled trial examining the effects of coffee consumption on insulin sensitivity. Methodology: We conducted a 24-week randomized placebo-controlled trial in 126 overweight, insulin-resistant (HOMA-IR ≥ 1.30), Chinese, Malay and Asian-Indian males and females aged 35-69 years. Participants were randomly assigned to receive 4 cups of instant regular coffee (n=62) or 4 cups of a coffee-like placebo beverage (n=64) per day. The primary outcome was bodyweight-standardized M-value (M bw ) assessed with a hyperinsulinemic euglycemic clamp. Secondary outcomes included other clamp-based insulin sensitivity measures, biological mediators of insulin sensitivity, and measures of fasting glucose metabolism, body weight and composition. Results: Coffee consumption did not significantly change insulin sensitivity as compared with placebo [% mean difference in M bw : 0.3% (95% CI: -12.0% to 14.2%), P =0.97]. Furthermore, no significant differences in fasting plasma glucose [3.0% (-1.1% to 7.3%), P =0.16] or biological mediators of insulin resistance, such as plasma adiponectin [1.5% (-3.4% to 6.6%), P =0.55], were observed between coffee and placebo groups after 24 weeks of intervention. Coffee consumption led to a loss of body weight as compared with placebo [-1.2% (-2.3% to -0.1%), P =0.03] resulting from a decrease in fat mass [-3.7% (-7.1% to -0.2%), P =0.04] . Conclusions: Consuming 4 cups per day of caffeinated coffee for 24 weeks had no significant effect on insulin sensitivity or biological mediators of insulin resistance. Coffee consumption led to a modest decrease in body fat as compared with coffee abstinence. Trial Registration: ClinicalTrials.gov identifier: NCT01738399. Registered on 28 November 2012. Trial Sponsor: Nestlé Research Center, Lausanne, Switzerland. Trial Site: National University of Singapore.

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