Serum tumour necrosis factor alpha and insulin resistance in gastrointestinal cancer

Abstract

Cancer cachexia may be mediated by endogenous peptides such as tumour necrosis factor alpha (TNF-alpha). Insulin resistance occurs in these patients, and is also seen experimentally with TNF-alpha administration. In this study, insulin sensitivity and energy metabolism were measured in 11 patients with gastrointestinal cancer and ten controls, using the euglycaemic glucose clamp and indirect calorimetry. Patients with cancer were significantly more insulin resistant than controls (P < 0.01) and in such patients insulin resistance correlated with serum TNF-alpha level (rs = 0.74, P < 0.01). Fasting insulin levels also correlated inversely with insulin sensitivity (rs = -0.62, P = 0.003). These results suggest a possible association between endogenous TNF-alpha production and insulin resistance in patients with gastrointestinal cancer.

IGF-1 is downregulated in experimental cancer cachexia

“…This may be modulated by different conditions such as malnutrition, alterations of the hormonal homeostasis, and increased levels of proinflammatory cytokines (1), not necessarily via downregulation of insulin/IGF-1 expression. TNF-␣, in particular, has been proposed to be involved in the development of the insulin resistance that often complicates the management of neoplastic patients (43,46), whereas the peripheral insulin resistance that develops in diet-induced obesity is less severe in TNF-␣ knockout mice than in their normal counterparts (60). In addition, reduced IGF-1 release has been demonstrated in C 2 C 12 murine myocyte cultures exposed to TNF-␣ (31).…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…Weiner et al (1991) found insulin and recombinant TNF to produce potent and opposing physiological signals in adipocytes. This paved the way for groups interested in various non-AD diseases, including examples caused by infectious agents known to induce TNF, to demonstrate that this cytokine was a potent cause of insulin resistance (Lang et al, 1992;McCall et al, 1992;Davis et al, 1993;Feinstein et al, 1993;Hotamisligil et al, 1993Hotamisligil et al, , 1996Li et al, 2007;Qin et al, 2007;Lorenzo et al, 2008). Feinstein et al (1993) seem to have been the first to argue that TNF exerts a major part of its antiinsulin effect by interrupting insulin-stimulated tyrosine phosphorylation, a key observation that was confirmed in cells from knockout mice by Nieto-Vazquez et al (2007).…”

Tumor necrosis factor alpha inhibits signaling from the insulin receptor.

“…A role has been suggested for cytokines, especially for tumor necrosis factor (TNF) a, as potential mediators of abnormalities in glucose homeostasis in infection, cancer, and trauma (7)(8)(9)(10)(11)(12). Evidence from both whole-animal and cell-culture studies suggests that TNF-a and other cytokines alter glucose metabolism in adipose and skeletal muscle cells and in liver (7,(13)(14)(15).…”