Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans

Nowotny, Bettina; Zahiragic, Lejla; Krog, Dorothea; Nowotny, Peter; Herder, Christian; Carstensen, Maren; Yoshimura, Toru; Szendroedi, Julia; Phielix, Esther; Schadewaldt, Peter; Schloot, Nanette C.; Shulman, Gerald I.; Roden, Michael

doi:10.2337/db12-1179

Cited by 101 publications

(128 citation statements)

References 51 publications

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“…Although it is possible that the low content of saturated FAs in the lipid infusion used in the current study might explain this discrepancy, a recent study found that saturated fat-induced insulin resistance can occur independently of TLR4 activation and increased in tissue ceramide content (35). Finally, markers of systemic inflammation, IL-6, adiponectin, RBP4, and sICAM-1, which have all been implicated in causing insulin resistance in obese and T2D (14) individuals, remained unchanged during the lipid infusion, thus dissociating these factors from lipid-induced muscle insulin resistance in this study (24).…”

Section: Discussionmentioning

confidence: 54%

“…Previous studies in rodent models have implicated increases in myocellular lipid metabolites, such as ceramides and DAGs, with subsequent inhibition of insulin signaling as causal factors in the pathogenesis of lipid-induced muscle insulin resistance (5,6,10,11,23). Studies in humans have been less conclusive because of conflicting results of studies with different experimental protocols, resulting in varying plasma FA concentrations and compositions (15,16,24). By performing serial muscle biopsies before and during a lipid infusion, we found that total muscle DAG content increased transiently within 2.5 h and subsequently declined 4 h after starting the lipid infusion.…”

Section: Discussionmentioning

confidence: 93%

“…Thirteen CON had muscle biopsies at baseline and after 4.5 h of lipid and glycerol infusion after 30 min of the high-insulin clamp to examine insulin signaling during short-term insulin resistance. The region above the musculus vastus lateralis was anesthetized with local anesthetics (Xylocain 2%) (24), a muscle biopsy of ∼70-400 mg was obtained using a Bergstrom needle. Samples were immediately stored in liquid nitrogen and then frozen at −80°C.…”

Section: Methodsmentioning

confidence: 99%

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Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans

Szendroedi

Yoshimura

Phielix

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Muscle insulin resistance is a key feature of obesity and type 2 diabetes and is strongly associated with increased intramyocellular lipid content and inflammation. However, the cellular and molecular mechanisms responsible for causing muscle insulin resistance in humans are still unclear. To address this question, we performed serial muscle biopsies in healthy, lean subjects before and during a lipid infusion to induce acute muscle insulin resistance and assessed lipid and inflammatory parameters that have been previously implicated in causing muscle insulin resistance. We found that acute induction of muscle insulin resistance was associated with a transient increase in total and cytosolic diacylglycerol (DAG) content that was temporally associated with protein kinase (PKC)θ activation, increased insulin receptor substrate (IRS)-1 serine 1101 phosphorylation, and inhibition of insulin-stimulated IRS-1 tyrosine phosphorylation and AKT2 phosphorylation. In contrast, there were no associations between insulin resistance and alterations in muscle ceramide, acylcarnitine content, or adipocytokines (interleukin-6, adiponectin, retinol-binding protein 4) or soluble intercellular adhesion molecule-1. Similar associations between muscle DAG content, PKCθ activation, and muscle insulin resistance were observed in healthy insulin-resistant obese subjects and obese type 2 diabetic subjects. Taken together, these data support a key role for DAG activation of PKCθ in the pathogenesis of lipid-induced muscle insulin resistance in obese and type 2 diabetic individuals.lipotoxicity | insulin signaling

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans

Szendroedi

Yoshimura

Phielix

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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346

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“…VO 2 and VCO 2 were measured, and substrate oxidation rates were calculated as previously described (23). Nonoxidative glucose disposal was calculated as the difference between R d and oxidative glucose utilization.…”

Section: Indirect Calorimetrymentioning

confidence: 99%

Effect of Low-Energy Diets Differing in Fiber, Red Meat, and Coffee Intake on Cardiac Autonomic Function in Obese Individuals With Type 2 Diabetes

et al. 2015

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OBJECTIVEThe autonomic nervous system (ANS) regulates both the cardiovascular system and energy balance and is disturbed in diabetes and obesity. The effect of different approaches of caloric restriction on ANS function has not been assessed in individuals with diabetes. Thus, we sought to determine whether low-energy diets differing in fiber, red meat, and coffee intake exert differential effects on cardiac autonomic function. RESEARCH DESIGN AND METHODSIn this randomized parallel-group pilot trial, obese patients with type 2 diabetes were randomly allocated to consume either a diet high in cereal fiber, free of red meat, and high in coffee (n = 13) or a diet low in fiber, high in red meat, and coffee free (n = 15) over 8 weeks. Eight measures of heart rate variability (HRV) indicating vagal and/or sympathetic modulation over 3 h and inflammatory markers were determined during a hyperinsulinemic-euglycemic clamp. RESULTSAfter 8 weeks, both dietary interventions resulted in a mean weight loss of 5-6 kg, a mean decline in heart rate of 4-6 bpm, and improvement in vagally mediated HRV. However, the changes in HRV parameters from baseline to 8 weeks did not differ between the groups. In the entire study cohort, incremental HRV from baseline to 8 weeks was associated with enhanced oxidative glucose utilization (P < 0.05), but not with insulin sensitivity and inflammatory markers. CONCLUSIONSIn obese patients with type 2 diabetes, energy restriction per se over 8 weeks contributed to improved cardiac vagal function in relation to improved oxidative glucose utilization. This preliminary finding should be verified in a confirmatory trial. Cardiovascular autonomic neuropathy detected by reduced heart rate variability (HRV) affects ;20% of individuals with diabetes (1). HRV measures the fluctuations in autonomic inputs to the heart (2) and is considered a prognostic marker in various conditions including diabetes (1), metabolic syndrome (3), and cardiovascular disease (2). Spectral analysis of HRV indicates that efferent vagal activity is a major contributor to the high-frequency component, while the low-frequency component

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“…Studies using parenteral administration of unsaturated lipids (18) or high-calorie mixed meals yielded conflicting results with regard to hepatic energy metabolism. One mixed-meal study found greater de novo lipogenesis without affecting hepatic glycogen metabolism (12), while an intravenous lipid infusion study failed to detect any effect on hepatic insulin sensitivity (19). Another study com-BACKGROUND.…”

Section: Introductionmentioning

confidence: 99%

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

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H and ex vivo2 H magnetic resonance spectroscopy before and during hyperinsulinemiceuglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses.RESULTS. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION.Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD. PO results in increased circulating TG, glucagon, and incretins. After PO administration, TG in plasma rose by 59% (area under the time curve [AUC], P < 0.001) and by 156% in chylomicrons (AUC, P = 0.009) (Figure 2A). The AUC for plasma free fatty acids (FFA) ( Figure 2B) and insulin concentrations ( Figure 2C) was unchanged, while the AUC for plasma C-peptide was 28% higher after PO ingestion versus VCL (P < 0.005, Figure 2D). Of note, FFA were increased at 300, 420, and 480 minutes. Blood glucose levels were not different between PO-and VCL-treated groups ( Figure 2E). Plasma glucagon rose by 41% (AUC, P < 0.0001) only after PO ingestion ( Figure 2F). Also, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels were markedly increased and remained elevated after PO ingestion (both P < 0.005) (Supplemental Figure 2; supplemental material available online with this article; https://doi.org/10.1172/ JCI89444DS1). Circulating levels of TNF-α, IL-6, fetuin-A, chemerin, omentin, and cortisol were not different between PO and VCL groups (P > 0.5 for all) (Supplemental Table 1). REGISTRATION. The Journal of Clinical Investigation C L I N I C A L M E D I C I N EPO induces insulin resistance at whole-body, liver, and adipose tissue levels. Insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp tests in healthy humans. Steady state was reached (Supplemental Figure 1), and pertinent parameters were analyzed during this time. PO ingestion reduced WBIS by 25% compared with VCL treatment (P = 0.0005, Figure 3A). Furthermore, after PO, volunteers also showed a decrease of 22% (P = 0.002) in the rate of glucose disappearance (Rd), mostly due to a 33% (P = 0.01) reduction in glucose oxidation (GOX), while the rate of nonoxidative glucose disposal remained unchanged

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Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans

Cited by 101 publications

References 51 publications

Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans

Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans

Effect of Low-Energy Diets Differing in Fiber, Red Meat, and Coffee Intake on Cardiac Autonomic Function in Obese Individuals With Type 2 Diabetes

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

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