Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes

2014 ◽  
Vol 306 (7) ◽  
pp. E769-E778 ◽  
Author(s):  
N. M. Harder-Lauridsen ◽  
R. Krogh-Madsen ◽  
J. J. Holst ◽  
P. Plomgaard ◽  
L. Leick ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Whole Body ◽  
Cytokine Signaling ◽  
Contributing Factors ◽  
Stat3 Phosphorylation ◽  
Socs3 Expression ◽  
Body Energy

Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin [ n = 9, age 54.9 ± 9.7 (mean ± SD) yr, body mass index 34.8 ± 6.1 kg/m2, HbA1c7.0 ± 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h with placebo or rhIL-6, a 3-h hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope-labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 ( P < 0.001), neutrophils ( P < 0.001), and cortisol ( P < 0.001) increased while lymphocytes decreased ( P < 0.01). However, IL-6 infusion did not change glucose infusion rate, rate of appearance, or rate of disappearance during the clamp. While IL-6 enhanced phosphorylation of STAT3 in skeletal muscle ( P = 0.041), the expression of SOCS3 remained unchanged. Whole body oxygen uptake ( P < 0.01) and expired carbon dioxide ( P < 0.01) increased during rhIL-6 infusion. In summary, although IL-6 induced local and systemic responses, the insulin-stimulated glucose uptake was not affected. While different contributing factors may be involved, our results are in contrast to our hypothesis and previous findings in young, healthy men.

scholarly journals Resting Whole Body Energy Metabolism in Class 3 Obesity; from Preserved Insulin Sensitivity to Overt Type 2 Diabetes

2020 ◽  
Vol Volume 13 ◽  
pp. 489-497 ◽  
Author(s):  
Giuseppina Manzoni ◽  
Alice Oltolini ◽  
Silvia Perra ◽  
Emanuele Muraca ◽  
Stefano Ciardullo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Whole Body ◽  
Body Energy

Loss of HIF-1α impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells

2014 ◽  
Vol 306 (9) ◽  
pp. E1065-E1076 ◽  
Author(s):  
Hidemitsu Sakagami ◽  
Yuichi Makino ◽  
Katsutoshi Mizumoto ◽  
Tsubasa Isoe ◽  
Yasutaka Takeda ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Intracellular Signaling ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Glut4 Translocation

Defects in glucose uptake by the skeletal muscle cause diseases linked to metabolic disturbance such as type 2 diabetes. The molecular mechanism determining glucose disposal in the skeletal muscle in response to cellular stimuli including insulin, however, remains largely unknown. The hypoxia-inducible factor-1α (HIF-1α) is a transcription factor operating in the cellular adaptive response to hypoxic conditions. Recent studies have uncovered pleiotropic actions of HIF-1α in the homeostatic response to various cellular stimuli, including insulin under normoxic conditions. Thus we hypothesized HIF-1α is involved in the regulation of glucose metabolism stimulated by insulin in the skeletal muscle. To this end, we generated C2C12myocytes in which HIF-1α is knocked down by short-hairpin RNA and examined the intracellular signaling cascade and glucose uptake subsequent to insulin stimulation. Knockdown of HIF-1α expression in the skeletal muscle cells resulted in abrogation of insulin-stimulated glucose uptake associated with impaired mobilization of glucose transporter 4 (GLUT4) to the plasma membrane. Such defect seemed to be caused by reduced phosphorylation of the protein kinase B substrate of 160 kDa (AS160). AS160 phosphorylation and GLUT4 translocation by AMP-activated protein kinase activation were abrogated as well. In addition, expression of the constitutively active mutant of HIF-1α (CA-HIF-1α) or upregulation of endogenous HIF-1α in C2C12cells shows AS160 phosphorylation comparable to the insulin-stimulated level even in the absence of insulin. Accordingly GLUT4 translocation was increased in the cells expressing CA-HIF1α. Taken together, HIF-1α is a determinant for GLUT4-mediated glucose uptake in the skeletal muscle cells thus as a possible target to alleviate impaired glucose metabolism in, e.g., type 2 diabetes.

scholarly journals Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle

2014 ◽  
Vol 38 (4) ◽  
pp. 308-314 ◽  
Author(s):  
Kristin I. Stanford ◽  
Laurie J. Goodyear
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Whole Body ◽  
Metabolic Genes ◽  
Increase Glucose Uptake ◽  
Glucose Transporter Proteins

Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle glucose uptake, while chronic exercise training improves mitochondrial function, increases mitochondrial biogenesis, and increases the expression of glucose transporter proteins and numerous metabolic genes. This review focuses on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle.

scholarly journals Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng

2009 ◽  
Vol 203 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Yun Wang ◽  
Patsy M Nishina ◽  
Jürgen K Naggert
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Insulin Resistant

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.

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.

scholarly journals Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance

2020 ◽  
Vol 218 (3) ◽  
Author(s):  
Feng He ◽  
Yanrui Huang ◽  
Zhi Song ◽  
Huanjiao Jenny Zhou ◽  
Haifeng Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Energy Homeostasis ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Ros Generation ◽  
Polyubiquitin Chains ◽  
Adipose Inflammation ◽  
Body Energy

White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB–dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.

Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Strongly Predict Whole-Body Insulin Resistance in the Development of Type 2 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1790-P ◽  
Author(s):  
GRETHA J. BOERSMA ◽  
KERSTIN HEURLING ◽  
MARIA J. PEREIRA ◽  
EMIL JOHANSSON ◽  
MARK LUBBERINK ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Visceral Adipose Tissue ◽  
Whole Body ◽  
Visceral Adipose
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