Mechanisms for skeletal muscle insulin resistance in patients with pancreatic ductal adenocarcinoma
2011
Agustsson, Thorhallur | D’souza, Melroy A. | Nowak, Greg | Isaksson, Bengt
OBJECTIVE: Weight loss, glucose intolerance, and insulin resistance are seen in patients with pancreatic ductal adenocarcinoma (PDAC). Peripheral insulin resistance is decreased after tumor resection in patients with PDAC, which is consistent with the hypothesis that factors from the tumor may induce skeletal muscle insulin resistance. Our aim was to investigate the possible mechanisms for their skeletal muscle insulin resistance. Accordingly, the action of insulin on glucose metabolism and content of energy metabolites in muscle of patients with PDAC were investigated. To explore whether PDAC cells could influence muscle glucose uptake, myotubes were exposed to media conditioned by PDAC cells. METHODS: Muscle biopsies from patients with PDAC (n = 13), cancer of other sites (n = 8), chronic pancreatitis (n = 8), and controls with benign diseases (n = 8) were assessed for glycogen, adenosine triphosphate, and phosphocreatine content. Basal and insulin-stimulated glucose transport and incorporation into glycogen were also assessed. Myotubes were treated with media conditioned by PDAC (MiaPaca 2) cells and glucose transport was monitored. RESULTS: Insulin-stimulated glucose transport, muscle glycogen, and adenosine triphosphate content were decreased in patients with PDAC compared with controls, and insulin stimulation did not significantly increase glucose incorporation into glycogen in vitro in patients with PDAC. Adenosine triphosphate content correlated with glycogen content but not with glucose transport in skeletal muscle. Media conditioned with human PDAC cells did not affect basal or insulin-stimulated glucose transport in L6 myotubes. CONCLUSION: In patients with PDAC, muscle insulin resistance is an early and specific finding unrelated to weight loss, plasma free fatty acid levels, and energy status of the cell. PDAC cell-derived factors did not directly induce insulin resistance in myotubes, suggesting a lack of direct tumor-related effects.
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