Insulin-mediated suppression of lipolysis in adipose tissue and skeletal muscle of obese type 2 diabetic men and men with normal glucose tolerance

Jocken, Johan W. E.; Goossens, Gijs H.; Boon, Hanneke; Mason, Rachael R.; Essers, Yvonne; Havekes, Bas; Watt, Matthew J.; Loon, Luc J. C. van; Blaak, Ellen E.

doi:10.1007/s00125-013-2995-9

Cited by 64 publications

(56 citation statements)

References 49 publications

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“…Furthermore, the degree of saturation of specifically the DAG pool has been reported to be increased in insulin resistant men when compared to control subjects (52). However, we failed to observe any changes in the degree of saturation of the various lipid pools, but actually observed a relative increase in polyunsaturated fatty acids (PUFAs, Supplemental Table 3) in the different lipid pools.…”

Section: Page 23 Of 53 Diabetesmentioning

confidence: 48%

“…By means of comparison, the measured decline in insulin sensitivity (i.e. ~30%) is similar to the difference between a normal glucose tolerant individual and a type 2 diabetes patient (52), and is equivalent to a decline that is observed following ~30-40 years of ageing (23; 61). As the decline in muscle mass, strength, and peripheral insulin sensitivity have been shown to be good proxy markers for patient outcomes following hospitalization (62), our results emphasize the importance of finding practical and effective interventional strategies that can be applied immediately following the onset of muscle disuse.…”

Section: Page 27 Of 53 Diabetesmentioning

confidence: 88%

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One Week of Bed Rest Leads to Substantial Muscle Atrophy and Induces Whole-Body Insulin Resistance in the Absence of Skeletal Muscle Lipid Accumulation

et al. 2016

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Short (<10 days) periods of muscle disuse, often necessary for recovery from illness or injury, lead to various negative health consequences. The current study investigated mechanisms underlying disuse-induced insulin resistance, taking into account muscle atrophy. Ten healthy, young males (age: 23 ± 1 years; BMI: 23.0 ± 0.9 kg · m(-2)) were subjected to 1 week of strict bed rest. Prior to and after bed rest, lean body mass (dual-energy X-ray absorptiometry) and quadriceps cross-sectional area (CSA; computed tomography) were assessed, and peak oxygen uptake (VO2peak) and leg strength were determined. Whole-body insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Additionally, muscle biopsies were collected to assess muscle lipid (fraction) content and various markers of mitochondrial and vascular content. Bed rest resulted in 1.4 ± 0.2 kg lean tissue loss and a 3.2 ± 0.9% decline in quadriceps CSA (both P < 0.01). VO2peak and one-repetition maximum declined by 6.4 ± 2.3 (P < 0.05) and 6.9 ± 1.4% (P < 0.01), respectively. Bed rest induced a 29 ± 5% decrease in whole-body insulin sensitivity (P < 0.01). This was accompanied by a decline in muscle oxidative capacity, without alterations in skeletal muscle lipid content or saturation level, markers of oxidative stress, or capillary density. In conclusion, 1 week of bed rest substantially reduces skeletal muscle mass and lowers whole-body insulin sensitivity, without affecting mechanisms implicated in high-fat diet-induced insulin resistance.

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Section: Page 23 Of 53 Diabetesmentioning

confidence: 48%

Section: Page 27 Of 53 Diabetesmentioning

confidence: 88%

One Week of Bed Rest Leads to Substantial Muscle Atrophy and Induces Whole-Body Insulin Resistance in the Absence of Skeletal Muscle Lipid Accumulation

et al. 2016

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“…Humans who have poorly controlled T2DM (fasting plasma glucose >250 mg dl −1 ) have higher plasma concentrations of NEFA than healthy controls throughout the day, and increased plasma concentrations of NEFA are an independent predictor of incident T2DM 61–67 . Insulin-dependent suppression of glycerol turnover, which is a readout of lipolytic flux, is impaired in individuals who have insulin resistance, with or without diabetes mellitus 68–71 . The rates of glycerol turnover and of gluconeogenesis from glycerol are also increased in overnight fasted humans with T2DM 72,73 .…”

Section: Control Of Hepatic Gluconeogenesismentioning

confidence: 99%

Regulation of hepatic glucose metabolism in health and disease

2017

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The liver is crucial for the maintenance of normal glucose homeostasis — it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis.

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“…Obesity is also associated with increased SM content of ATGL, whereas HSL is decreased, resulting in a substantial decrease in the ratio of DG to TG hydrolase activity (Jocken et al 2010). Finally, in obese type 2 diabetic patients, basal SM lipolysis is elevated and the anti-lipolytic action of insulin is blunted (Jocken et al 2013). Whether this impairment is a result of peripheral insulin resistance or a cause of it is unclear although, and at present, the mechanistic connection between intramyocellular lipolysis and insulin resistance is a matter of intense debate and research.…”

Section: Intracellular Lipolysis In Non-atsmentioning

confidence: 99%

Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease

Nielsen¹,

Jessen²,

Jørgensen³

et al. 2014

Journal of Molecular Endocrinology

300

239

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Lipolysis is the process by which triglycerides (TGs) are hydrolyzed to free fatty acids (FFAs) and glycerol. In adipocytes, this is achieved by sequential action of adipose TG lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase. The activity in the lipolytic pathway is tightly regulated by hormonal and nutritional factors. Under conditions of negative energy balance such as fasting and exercise, stimulation of lipolysis results in a profound increase in FFA release from adipose tissue (AT). This response is crucial in order to provide the organism with a sufficient supply of substrate for oxidative metabolism. However, failure to efficiently suppress lipolysis when FFA demands are low can have serious metabolic consequences and is believed to be a key mechanism in the development of type 2 diabetes in obesity. As the discovery of ATGL in 2004, substantial progress has been made in the delineation of the remarkable complexity of the regulatory network controlling adipocyte lipolysis. Notably, regulatory mechanisms have been identified on multiple levels of the lipolytic pathway, including gene transcription and translation, post-translational modifications, intracellular localization, protein-protein interactions, and protein stability/ degradation. Here, we provide an overview of the recent advances in the field of AT lipolysis with particular focus on the molecular regulation of the two main lipases, ATGL and HSL, and the intracellular and extracellular signals affecting their activity.

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Insulin-mediated suppression of lipolysis in adipose tissue and skeletal muscle of obese type 2 diabetic men and men with normal glucose tolerance

Cited by 64 publications

References 49 publications

One Week of Bed Rest Leads to Substantial Muscle Atrophy and Induces Whole-Body Insulin Resistance in the Absence of Skeletal Muscle Lipid Accumulation

One Week of Bed Rest Leads to Substantial Muscle Atrophy and Induces Whole-Body Insulin Resistance in the Absence of Skeletal Muscle Lipid Accumulation

Regulation of hepatic glucose metabolism in health and disease

Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease

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