scholarly journals Inhibition of Insulin Sensitivity by Free Fatty Acids Requires Activation of Multiple Serine Kinases in 3T3-L1 Adipocytes

2004 ◽  
Vol 18 (8) ◽  
pp. 2024-2034 ◽  
Author(s):  
Zhanguo Gao ◽  
Xiaoying Zhang ◽  
Aamir Zuberi ◽  
Daniel Hwang ◽  
Michael J. Quon ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Free Fatty Acids ◽  
Serine Kinases

scholarly journals Serum secreted frizzled-related protein 5 in relation to insulin sensitivity and its regulation by insulin and free fatty acids

Endocrine ◽  
2021 ◽  
Author(s):  
Marta Rydzewska ◽  
Agnieszka Nikołajuk ◽  
Natalia Matulewicz ◽  
Magdalena Stefanowicz ◽  
Monika Karczewska-Kupczewska
Keyword(s):  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Free Fatty Acids ◽  
Wnt Signaling Pathway ◽  
Normal Weight ◽  
Healthy Population ◽  
Related Protein ◽  
Heparin Infusion ◽  
Male Subjects ◽  
Contradictory Data

Abstract Purpose Secreted frizzled-related protein 5 (SFRP5) is an adipokine, which acts as an inhibitor of noncanonical WNT signaling pathway. It has been suggested to exert anti-inflammatory and insulin-sensitizing effects, however, contradictory data has also been reported. The aim of this study was to assess serum SFRP5 concentration in a young healthy population in relation to insulin sensitivity and its regulation by hyperinsulinemia and/or serum free fatty acids (FFA) elevation. Methods We examined 150 healthy subjects (83 normal-weight and 67 overweight/obese). Insulin sensitivity (M) was measured with hyperinsulinemic-euglycemic clamp. In 20 male subjects, clamp was prolonged to 6 h and after 1 week another clamp with the concurrent Intralipid/heparin infusion was performed. Independent group of 10 male subjects received infusions of Intralipid/heparin or saline in 1-week interval. Results Baseline SFRP5 was lower in the overweight/obese group (p = 0.01) and was positively associated with M (r = 0.23, p = 0.006) and serum adiponectin (r = 0.55, p < 0.001) and negatively with BMI (r = −0.18, p = 0.03). In multiple regression analysis, adiponectin was independently associated with SFRP5. Insulin infusion resulted in a decrease in serum SFRP5, both at 120′ (p = 0.02) and 360′ (p = 0.031). This effect was not observed during the clamp with Intralipid/heparin as well as during Intralipid/heparin alone or saline infusions. Conclusions The relation between SFRP5 and insulin sensitivity is mainly dependent on adiponectin. FFA abolish a decrease in circulating SFRP5 caused by insulin, but Intralipid/heparin infusion alone does not regulate SFRP5 concentration. Insulin seems to be more important factor in the regulation of circulating SFRP5 levels than FFA.

scholarly journals Impact of Growth Hormone Receptor Blockade on Substrate Metabolism during Fasting in Healthy Subjects

2009 ◽  
Vol 94 (11) ◽  
pp. 4524-4532 ◽  
Author(s):  
Louise Moller ◽  
Helene Norrelund ◽  
Niels Jessen ◽  
Allan Flyvbjerg ◽  
Steen B. Pedersen ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Free Fatty Acids ◽  
Protein Metabolism ◽  
Healthy Subjects ◽  
Receptor Blockade ◽  
Substrate Metabolism ◽  
Gh Receptor ◽  
Basal Period ◽  
Igf I

Context: Experimental studies in GH-deficient patients and in healthy subjects receiving somatostatin-infusion suggest that GH is an important regulator of substrate metabolism during fasting. These models may not adequately reflect the selective effects of GH, and GH receptor (GHR) blockade offers a new model to define the metabolic role of GH. Objective: The aim of this study was to investigate the impact of GHR blockade on substrate metabolism and insulin sensitivity during fasting. Design: We conducted a randomized, placebo-controlled, crossover study in 10 healthy young men. Intervention: After 36 h of fasting with saline or pegvisomant (GHR blockade), the subjects were studied during a 4-h basal period and 2.5-h hyperinsulinemic euglycemic clamp. Main Outcome: We measured whole-body and forearm glucose, lipid, and protein metabolism, peripheral insulin sensitivity, and acyl and desacyl ghrelin. Results: GHR blockade significantly suppressed circulating free fatty acids (1226 ± 83 vs. 1074 ± 65 μmol/liter; P = 0.03) and ketone bodies (3080 ± 271 vs. 2015 ± 235 μmol/liter; P ≤ 0.01), as well as forearm uptake of free fatty acids (0.341 ± 0.150 vs. 0.004 ± 0.119 μmol/100 ml · min; P &lt; 0.01) and lipid oxidation (1.3 ± 0.1 vs. 1.2 ± 0.1 mg/kg · min; P = 0.03) in the basal period. By contrast, IGF-I levels in either serum or peripheral tissues were not impacted by GHR blockade, and protein metabolism was also unaffected. Basal glucose levels were elevated by GHR blockade, but insulin sensitivity was similar; this was associated with an increased acyl/desacyl ghrelin ratio. Conclusion: GHR blockade, without changes in circulating or tissue IGF-I levels, selectively suppresses lipid mobilization and oxidation after short-term fasting. This supports the notion that stimulation of lipolysis is a primary and important effect of GH. GH receptor blockade during fasting in healthy subjects suppresses lipid metabolism without a change in insulin sensitivity or protein metabolism.

From Obesity to Diabetes

2006 ◽  
Vol 76 (4) ◽  
pp. 172-177 ◽  
Author(s):  
Keller
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Free Fatty Acids ◽  
Vegetable Consumption ◽  
Prediabetic State ◽  
The Metabolic Syndrome ◽  
Life Style Changes

The prevalence of obesity has been increasing dramatically in the last decades in the whole world, not only in industrialized countries but also in developing areas. A major complication of obesity is insulin resistance and type 2 diabetes. Diabetes is also rapidly increasing world-wide – reaching a prevalence in adults of approx. 5–6% in Central Europe and in the US, and more than 50% in specific, genetically prone populations. This article reviews pathogenetic mechanisms linking obesity and type 2 diabetes. Emphasis is placed on the observation that excessive amounts of adipocytes are associated with an impairment of insulin sensitivity, a key feature of the "metabolic syndrome". This is a cluster of metabolic abnormalities such as type 2 diabetes, hypertension and dyslipidemia; all of them are enhanced by the presence of visceral (abdominal) obesity and all contribute to the increased cardiovascular risk observed in these patients. Besides release of free fatty acids, adipocytes secrete substances that contribute to peripheral insulin resistance, including adiponectin, resistin, TNF-α and interleukin 6. Increased turnover of free fatty acids interferes with intracellular metabolism of glucose in the muscle, and they exert lipotoxic effect on pancreatic β-cells. The pre-receptor metabolism of cortisol is enhanced in visceral adipose tissue by activation of 11 β-hydroxysteroid dehydrogenase type 1. A new class of anti-diabetic drugs (thiazolidinediones, or glitazones) bind to peroxisome proliferator activated receptor (PPAR-γ) and lower thereby plasma free fatty acids and cytokine production in adipocytes, in addition to a decrease of resistin and an increase in adiponectin observed in animals, resulting in an overall increase in insulin sensitivity and in an improvement of glucose homeostasis. However, the first step to avoid insulin resistance and prevent the development of diabetes should be a reduction in body weight in overweight subjecs, and an increase in physical activity. There are now three published randomized controlled trials demonstrating that in high risk individuals, life style changes with modest weight lost, associated with diminished fat intake and an increase in fruit and vegetable consumption result in marked inhibition of the transition from the prediabetic state to manifest type 2 diabetes.

scholarly journals Acipimox stimulates leptin production from isolated rat adipocytes

2002 ◽  
Vol 174 (2) ◽  
pp. 267-272 ◽  
Author(s):  
YL Wang-Fisher ◽  
J Han ◽  
W Guo
Keyword(s):  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Side Effects ◽  
Nicotinic Acid ◽  
Free Fatty Acids ◽  
Dibutyryl Camp ◽  
Similar Extent ◽  
Rat Adipocytes ◽  
Impaired Insulin ◽  
Isolated Rat

Acipimox is a nicotinic acid-derived antilipolytic drug devoid of major side effects, and has been used in a number of human trials. This work reports the effects of Acipimox on leptin production from isolated rat adipocytes, in comparison with nicotinic acid and insulin. For cells isolated from normal animals, all these three reagents stimulated leptin release to a similar extent. Acipimox and nicotinic acid were more potent than insulin in stimulating leptin release from cells isolated from diabetic animals, probably because of impaired insulin sensitivity in cells from these diseased animals. Co-incubation of Acipimox with norepinephrine or dibutyryl cAMP diminished its stimulatory effects on leptin release, in parallel with increased lipolysis, suggesting that intracellular free fatty acids play an important role in mediating leptin production in adipocytes.

scholarly journals Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial

2016 ◽  
Vol 101 (3) ◽  
pp. 1123-1133 ◽  
Author(s):  
Hideo Makimura ◽  
Takara L. Stanley ◽  
Caroline Suresh ◽  
Ana Luisa De Sousa-Coelho ◽  
Walter R. Frontera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Free Fatty Acids ◽  
Glucose Homeostasis ◽  
Mitochondrial Function ◽  
Effect Size ◽  
Metabolic Effects ◽  
Mitochondrial Density

Abstract Context: Increased circulating free fatty acids (FFAs) have been proposed to contribute to insulin resistance in obesity. Short-term studies have investigated the effects of acipimox, an inhibitor of hormone-sensitive lipase, on glucose homeostasis, but longer-term studies have not been performed. Objective: To test the hypothesis that long-term treatment with acipimox would reduce FFA and improve insulin sensitivity among nondiabetic, insulin-resistant, obese subjects. Design, Setting, Patients, and Intervention: At an academic medical center, 39 obese men and women were randomized to acipimox 250 mg thrice-daily vs identical placebo for 6 months. Main Outcome Measures: Plasma lipids, insulin sensitivity, adiponectin, and mitochondrial function via assessment of the rate of post-exercise phosphocreatine recovery on 31P-magnetic resonance spectroscopy as well as muscle mitochondrial density and relevant muscle gene expression. Results: Fasting glucose decreased significantly in acipimox-treated individuals (effect size, −6 mg/dL; P = .02), in parallel with trends for reduced fasting insulin (effect size, −6.8 μU/mL; P = .07) and HOMA-IR (effect size, −1.96; P = .06), and significantly increased adiponectin (effect size, +668 ng/mL; P = .02). Acipimox did not affect insulin-stimulated glucose uptake, as assessed by euglycemic, hyperinsulinemic clamp. Effects on muscle mitochondrial function and density and on relevant gene expression were not seen. Conclusion: These data shed light on the long-term effects of FFA reduction on insulin sensitivity, other metabolic parameters, and muscle mitochondrial function in obesity. Reduced FFA achieved by acipimox improved fasting measures of glucose homeostasis, lipids, and adiponectin but had no effect on mitochondrial function, mitochondrial density, or muscle insulin sensitivity.

scholarly journals Improved insulin sensitivity after gastric bypass correlates with decreased total body fat, but not with changes in free fatty acids

2013 ◽  
Vol 28 (5) ◽  
pp. 1489-1493 ◽  
Author(s):  
Alessandro Mor ◽  
Lawrence Tabone ◽  
Philip Omotosho ◽  
Alfonso Torquati
Keyword(s):  
Fatty Acids ◽  
Gastric Bypass ◽  
Insulin Sensitivity ◽  
Free Fatty Acids ◽  
Body Fat ◽  
Total Body Fat ◽  
Total Body
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