Protein and glucose metabolic responses to hyperinsulinemia, hyperglycemia, and hyperaminoacidemia in obese men

Chevalier, Stéphanie; Burgos, Sergio A.; Morais, José A.; Gougeon, Réjeanne; Bassil, Maya; Lamarche, Marie; Marliss, Errol B.

doi:10.1002/oby.20943

Cited by 20 publications

(40 citation statements)

References 40 publications

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“…However, again the degree of impairment is markedly less than that observed in insulin-stimulated glucose disposal in the same subjects (75,87), suggesting that these different insulin-regulated processes are differentially sensitive to insulin resistance. Similarly, insulin-dependent phosphorylation of FOXO in muscle was unaffected in common insulin resistance (54).…”

Section: Selective Insulin Resistancementioning

confidence: 83%

Muscle and adipose tissue insulin resistance: malady without mechanism?

Fazakerley

Krycer

Kearney

et al. 2019

Journal of Lipid Research

126

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Insulin resistance is a major risk factor for numerous diseases including Type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of 'common' insulin resistance. Despite considerable effort, the mechanisms that contribute to 'common' insulin resistance are not resolved. There is universal agreement that extracellular perturbations such as nutrient excess, hyperinsulinemia, glucocorticoids or inflammation trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells. Here we present evidence that the impairment in insulin action is independent of proximal elements of the insulin signaling pathway, but rather is likely specific to the glucoregulatory branch of insulin signaling. We propose that many intracellular stress pathways act in concert to increase mitochondrial reactive oxygen species to trigger insulin resistance. We speculate that this may be a physiological pathway to conserve glucose during specific states such as fasting, and that in the presence of chronic nutrient excess this pathway ultimately leads to disease. This review highlights key points in this pathway that require further research effort. Insulin resistance is a pathophysiological state where cells display reduced responsiveness to the glucose-lowering activity of insulin. While there are rare cases where mutations in genes associated with insulin signaling or lipodystrophy cause insulin resistance, for the most part insulin resistance is associated with obesity and thus a state of positive energy balance. This form of insulin resistance is frequently associated with hyperinsulinemia, increased waist circumference or visceral adiposity, metabolic dyslipidemia with high triglycerides and low HDL, and hepatic steatosis, features collectively referred to as the metabolic syndrome. We refer to this as "common insulin resistance". Here, both insulin-dependent glucose disposal and suppression of glucose output are impaired, albeit the relative degree of impairment in each process can vary between individuals (1-3).In this review we focus on the literature surrounding insulin resistance in muscle and adipose tissue, and specifically on insulin-stimulated glucose transport into myocytes and adipocytes within these tissues. Impaired insulin action in other tissues, most notably the liver (4, 5), brain (6, 7) and vasculature (8), also play a key role in whole body insulin resistance, and we direct readers to reviews that explore insulin resistance at these sites in detail. We will examine the evidence that common insulin resistance, in the context of muscle and adipose tissue, results from a defect in 'proximal' insulin signaling, which we define for the purposes of this review as the signaling intermediates that lead to the activation of Akt. We argue that common insulin resistance arises ...

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Section: Selective Insulin Resistancementioning

confidence: 83%

Muscle and adipose tissue insulin resistance: malady without mechanism?

Fazakerley

Krycer

Kearney

et al. 2019

Journal of Lipid Research

126

View full text Add to dashboard Cite

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“…), but not all (Chevalier et al . ; Hector et al . ), we showed that postprandial myofibrillar protein synthesis rates were stimulated in the CON leg of people with obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, several studies have reported a reduced stimulation of the muscle protein synthetic response to amino acid provision in obese adults compared to normal weight controls (Guillet et al 2009;Chevalier et al 2015;Murton et al 2015;Beals et al 2016;Smeuninx et al 2017). Interestingly, it appears that this anabolic resistance of postprandial muscle protein synthesis rates in response to exogenous amino acid administration may be confined to distinct muscle protein subfractions (Guillet et al 2009;Chevalier et al 2015;Murton et al 2015;Beals et al 2016Beals et al , 2017. For example, we have recently demonstrated an impairment in the stimulation of postprandial myofibrillar protein synthesis rates (Beals et al 2016) but not mitochondrial protein synthesis rates ) after ingestion of protein-dense food in sedentary obese vs. normal-weight adults.…”

Section: Introductionmentioning

confidence: 99%

Altered anabolic signalling and reduced stimulation of myofibrillar protein synthesis after feeding and resistance exercise in people with obesity

Beals

Skinner

McKenna

et al. 2018

The Journal of Physiology

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We aimed to determine whether obesity alters muscle anabolic and inflammatory signalling phosphorylation and also muscle protein synthesis within the myofibrillar (MYO) and sarcoplasmic (SARC) protein fractions after resistance exercise. Nine normal weight (NW) (21 ± 1 years, body mass index 22 ± 1 kg m ) and nine obese (OB) (22 ± 1 years, body mass index 36 ± 2 kg m ) adults received l-[ring- C ]phenylalanine infusions with blood and muscle sampling at basal and fed-state of the exercise (EX) and non-exercise (CON) legs. Participants performed unilateral leg extensions and consumed pork (36 g of protein) immediately after exercise. Basal muscle Toll-like receptor 4 (TLR4) protein was similar between OB and NW groups (P > 0.05) but increased at 300 min after pork ingestion only in the OB group (P = 0.03). Resistance exercise reduced TLR4 protein in the OB group at 300 min (EX vs. CON leg in OB: P = 0.04). Pork ingestion increased p70S6K phosphorylation at 300 min in CON and EX of the OB and NW groups (P > 0.05), although the response was lower in the EX leg of OB vs. NW at 300 min (P = 0.05). Basal MYO was similar between the NW and OB groups (P > 0.05) and was stimulated by pork ingestion in the EX and CON legs in both groups (Δ from basal NW: CON 0.04 ± 0.01% h ; EX 0.10 ± 0.02% h ; OB: CON 0.06 ± 0.01% h ; EX 0.06 ± 0.01% h ; P < 0.05). MYO was more strongly stimulated in the EX vs. CON legs in NW (P = 0.02) but not OB (P = 0.26). SARC was feeding sensitive but not further potentiated by resistance exercise in both groups. Our results suggest that obesity may attenuate the effectiveness of resistance exercise to augment fed-state MYO.

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“…Obese individuals undergoing a hyperinsulinemic-hyperaminoacidemic-hyperglycemic clamp demonstrated normal protein synthesis and less suppression of breakdown compared with lean subjects, which was associated with lower IRS-1, Akt, and S6K1 phosphorylation (9). It has been proposed that hyperactivation of mTORC1 through S6K1 negatively feeds back to IRS-1, downregulating insulin signaling (73).…”

Section: R859mentioning

confidence: 99%

“…Reduced translation initiation, stemming from dephosphorylated 4E-BP1, reduces protein synthesis (36). Findings ranging from reduced to no difference in skeletal muscle protein synthesis have been reported in obese (9,11,43) and T2D (59, 71) individuals compared with lean individuals. In most cases, individuals diagnosed with T2D are slightly older, which can exacerbate skeletal muscle protein synthesis (10,52) and mass (70).…”

Section: R859mentioning

confidence: 99%

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

Williamson

Dungan

Mahmoud

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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-The objective of this study was to establish whether alterations in the REDD1-mTOR axis underlie skeletal muscle insensitivity to insulin in Type 2 diabetic (T2D), obese individuals. Vastus lateralis muscle biopsies were obtained from lean, control and obese, T2D subjects under basal and after a 2-h hyperinsulinemic (40 mU·m Ϫ2 ·min Ϫ1 )-euglycemic (5 mM) clamp. Muscle lysates were examined for total REDD1, and phosphorylated Akt, S6 kinase 1 (S6K1), 4E-BP1, ERK1/2, and MEK1/2 via Western blot analysis. Under basal conditions [(-) insulin], T2D muscle exhibited higher S6K1 and ERK1/2 and lower 4E-BP1 phosphorylation (P Ͻ 0.05), as well as elevations in blood cortisol, glucose, insulin, glycosylated hemoglobin (P Ͻ 0.05) vs. lean controls. Following insulin infusion, whole body glucose disposal rates (GDR; mg/kg/ min) were lower (P Ͻ 0.05) in the T2D vs. the control group. The basal-to-insulin percent change in REDD1 expression was higher (P Ͻ 0.05) in muscle from the T2D vs. the control group. Whereas, the basal-to-insulin percent change in muscle Akt, S6K1, ERK1/2, and MEK1/2 phosphorylation was significantly lower (P Ͻ 0.05) in the T2D vs. the control group. Findings from this study propose a REDD1-regulated mechanism in T2D skeletal muscle that may contribute to whole body insulin resistance and may be a target to improve insulin action in insulin-resistant individuals.glucocorticoid; insulin resistance; mTOR; signaling TWO-THIRDS OF THE UNITED STATES has a 25% or greater prevalence of obesity (54), which places increased demand and cost on the health care system. Of the numerous comorbidities associated with obesity, the development of insulin resistance and Type 2 diabetes (T2D) are major concern for obese individuals, leading to overall reductions in metabolic flexibility (50). This becomes more of a concern, since the population of obese individuals is expanding in all age groups. Findings from the National Health and Nutrition Examination Survey data (68,69) show that skeletal muscle mass is fundamental for insulin sensitivity. Skeletal muscle mass is lower in the obese when expressed relative to total body mass vs. a lean individual and has a high pervasiveness of ectopic lipid within skeletal muscle that contributes to reduced insulin action (27,50). Among other factors, elevated endogenous glucocorticoid concentrations contribute to insulin resistance in the obese and T2D (58, 74).Insulin activation of the insulin receptor substrate 1 (IRS-1), phosphatidyl-inositol-3 kinase (PI3K), Ak strain transforming (Akt), and the ERK 1/2 pathways are essential for the regulation of cellular glucose uptake, proliferation, and growth. Akt and ERK1/2 activation increases GTPase function of the Ras homolog enriched in brain (Rheb) protein toward the mechanistic target of rapamycin (mTOR; also known as mammalian target of rapamycin) by inactivating the repressive effects of the tuberous sclerosis complex (TSC). The TSC complex remains central to the integration of signaling inputs from Akt, ERK1/2, and AMPK (32, 44,...

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Protein and glucose metabolic responses to hyperinsulinemia, hyperglycemia, and hyperaminoacidemia in obese men

Cited by 20 publications

References 40 publications

Muscle and adipose tissue insulin resistance: malady without mechanism?

Muscle and adipose tissue insulin resistance: malady without mechanism?

Altered anabolic signalling and reduced stimulation of myofibrillar protein synthesis after feeding and resistance exercise in people with obesity

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

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