Altered glucose metabolism and insulin resistance in cancer-induced cachexia: a sweet poison
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REVIEW
Altered glucose metabolism and insulin resistance in cancer‑induced cachexia: a sweet poison Tamhida Masi1 · Bhoomika M. Patel1 Received: 6 August 2020 / Revised: 19 October 2020 / Accepted: 20 October 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Cancer cachexia is a wasting disorder characterised by specific skeletal muscle and adipose tissue loss. Cancer cachexia is also driven by inflammation, altered metabolic changes such as increased energy expenditure, elevated plasma glucose, insulin resistance and excess catabolism. In cachexia, host-tumor interaction causes release of the lactate and inflammatory cytokines. Lactate released by tumor cells takes part in hepatic glucose production with the help of gluconeogenic enzymes. Thus, Cori cycle between organs and cancerous cells contributes to increased glucose production and energy expenditure. A high amount of blood glucose leads to increased production of insulin. Overproduction of insulin causes inactivation of PI3K/Akt/m-TOR pathway and finally results in insulin resistance. Insulin is involved in maintaining the vitality of organs and regulate the metabolism of glucose, protein and lipids. Insulin insensitivity decreases the uptake of glucose in the organs and results in loss of skeletal muscles and adipose tissues. However, looking into the complexity of this metabolic syndrome, it is impossible to rely on a single variable to treat patients having cancer cachexia. Hence, it becomes greater a challenge to produce a clinically effective treatment for this metabolic syndrome. Thus, the present paper aims to provide an understanding of pathogenesis and mechanism underlining the altered glucose metabolism and insulin resistance and its contribution to the progression of skeletal muscle wasting and lipolysis, providing future direction of research to develop new pharmacological treatment in cancer cachexia. Keywords Cancer cachexia · Gluconeogenesis · Insulin resistance · Futile cycle · Muscle wasting Abbreviations ActRIIB Activin receptor type IIB AgRP Agouti related protein Akt Protein kinase B AMPK AMP-activated protein kinase ARC Arcuate nuclei ATGL Adipose triglyceride lipase ATP Adenosine triphosphate BAT Brown adipose tissue BMR Basal metabolic rate CRF Corticotropin-releasing factor CRP C-reactive protein EDL Extensor digitorum longus * Bhoomika M. Patel [email protected]; [email protected] 1
Institute of Pharmacy, Nirma University, Sarkhej‑Gandhinagar Highway, Ahmedabad, Gujarat 382 481, India
EIF4E3/4E-BP-1 Eukaryotic translation initiation factor 4E type 3 FBPase Fructose bisphosphatase FOXO3 Forkhead box protein O3 G6P Glucose-6-phosphate G6Pase Glucose-6-phosphatase GDP Glutamine dipeptide GDP Guanosine diphosphate GLUT 1, GLUT 2, GLUT 4 and GLUT 5 Glucose transporter 1, 2, 4 and 5 GSK3-β Glycogen synthase kinase-3 β GTP Guanosine triphosphate HFD High-fat diet HIF-1 Hypoxia inducing factor-1 HSL Hormone-sensitive lipase IFN-γ Interferon γ IGF-1 Insulin like gro
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