Relationship between serum tumor necrosis factor-α and insulin resistance in obese men with Type 2 diabetes mellitus

Mishima, Yasuo; Kuyama, Ayako; Tada, Atsuhiko; Takahashi, Kiyoshi; Ishioka, Tatsuji; Kibata, Masayoshi

doi:10.1016/s0168-8227(00)00247-3

Cited by 155 publications

(117 citation statements)

References 15 publications

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“…Systemic inflammation is also a feature of obesity and type 2 diabetes, raising the hypothesis that elevated cytokine levels may contribute to peripheral insulin resistance as well as decreased beta cell function and mass. Correlative studies provide evidence that type 2 diabetes is associated with elevated levels of the proinflammatory cytokine tumor necrosis factor-␣ (TNF-␣) 2 in adipose tissue (1), skeletal muscle (2), and plasma (3)(4)(5). In beta cells, TNF-␣ has been shown to induce insulin resistance mediated by nitric oxide (6) and a reduction of glucose-stimulated calcium influx (7).…”

mentioning

confidence: 99%

Silencing Mitogen-activated Protein 4 Kinase 4 (MAP4K4) Protects Beta Cells from Tumor Necrosis Factor-α-induced Decrease of IRS-2 and Inhibition of Glucose-stimulated Insulin Secretion

Bouzakri

Ribaux

Halban

2009

Journal of Biological Chemistry

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Obesity and type 2 diabetes present partially overlapping phenotypes with systemic inflammation as a common feature, raising the hypothesis that elevated cytokine levels may contribute to peripheral insulin resistance as well as the decreased beta cell functional mass observed in type 2 diabetes. In healthy humans, TNF-␣ infusion induces skeletal muscle insulin resistance. We now explore the impact of TNF-␣ on primary beta cell function and the underlying signaling pathways. Human and rat primary beta cells were sorted by FACS and cultured for 24 h ؎ 20 ng/ml TNF-␣ to explore the impact on apoptosis, proliferation, and short-term insulin secretion (1 h, 2.8 mM glucose followed by 1 h, 16.7 mM glucose at the end of the 24-h culture period) as well as key signaling protein phosphorylation and expression. Prior exposure to TNF-␣ for 24 h inhibits glucose-stimulated insulin secretion from primary beta cells. This is associated with a decrease in glucose-stimulated phosphorylation of key proteins in the insulin signaling pathway including Akt, AS160, and other Akt substrates, ERK as well as the insulin receptor. Strikingly, TNF-␣ treatment decreased IRS-2 protein level by 46 ؎ 7% versus control, although mRNA expression was unchanged. While TNF-␣ treatment increased MAP4K4 mRNA expression by 33 ؎ 5%, knockdown of MAP4K4 by siRNA-protected beta cells against the detrimental effects of TNF-␣ on both insulin secretion and signaling. We thus identify MAP4K4 as a key upstream mediator of TNF-␣ action on the beta cell, making it a potential therapeutic target for preservation of beta cell function in type 2 diabetes.

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mentioning

confidence: 99%

Silencing Mitogen-activated Protein 4 Kinase 4 (MAP4K4) Protects Beta Cells from Tumor Necrosis Factor-α-induced Decrease of IRS-2 and Inhibition of Glucose-stimulated Insulin Secretion

Bouzakri

Ribaux

Halban

2009

Journal of Biological Chemistry

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“…Introduction Low-grade inflammation is associated with the metabolic syndrome and type 2 diabetes [1,2]. Several studies have demonstrated association between circulating TNF-α, obesity and type 2 diabetes [3][4][5], whereas other studies have failed to do so [6,7]. A direct effect of TNF-α on insulin sensitivity in skeletal muscle has been demonstrated in vitro [8], in vivo in animals [9] and in vivo in humans [10].…”

mentioning

confidence: 99%

Associations between insulin resistance and TNF-α in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes

et al. 2007

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Aims/hypothesis Clear evidence exists that TNF-α inhibits insulin signalling and thereby glucose uptake in myocytes and adipocytes. However, conflicting results exist with regard to the role of TNF-α in type 2 diabetes. Methods We obtained blood and biopsy samples from skeletal muscle and subcutaneous adipose tissue in patients with type 2 diabetes (n=96) and healthy controls matched for age, sex and BMI (n=103). Results Patients with type 2 diabetes had higher plasma levels of fasting insulin (p<0.0001) and glucose (p<0.0001) compared with controls, but there was no difference between groups with regard to fat mass. Plasma levels of TNF-α (p=0.0009) and soluble TNF receptor 2 (sTNFR2; p = 0.002) were elevated in diabetic patients. Insulin sensitivity was correlated with quartiles of plasma TNF-α after adjustment for age, sex, obesity, WHR, neutrophils,

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“…Trandolapril was found to be decreasing resistin levels alone or in combination with verapamil [23]. TNF-alpha levels were reported to be higher in obese type 2 diabetic patients with IR compared to ones without IR and controls [25]. It's known that TNF-alpha increases resistin production and has inverse relation with adiponectin [23].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Trandolapril on Insulin Resistance is Determined by the Degree of Baseline Resistance Level

Ersoy¹,

Elbüken²,

Tuncel

2014

Med-Science

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Relationship between serum tumor necrosis factor-α and insulin resistance in obese men with Type 2 diabetes mellitus

Cited by 155 publications

References 15 publications

Silencing Mitogen-activated Protein 4 Kinase 4 (MAP4K4) Protects Beta Cells from Tumor Necrosis Factor-α-induced Decrease of IRS-2 and Inhibition of Glucose-stimulated Insulin Secretion

Silencing Mitogen-activated Protein 4 Kinase 4 (MAP4K4) Protects Beta Cells from Tumor Necrosis Factor-α-induced Decrease of IRS-2 and Inhibition of Glucose-stimulated Insulin Secretion

Associations between insulin resistance and TNF-α in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes

The Effect of Trandolapril on Insulin Resistance is Determined by the Degree of Baseline Resistance Level

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