Impaired insulin action on phosphatidylinositol 3-kinase activity and glucose transport in skeletal muscle of pancreatic cancer patients.
BACKGROUND
Glucose intolerance or overt diabetes occurs in 80% of patients with pancreatic cancer (PC). This associated metabolic disorder includes peripheral insulin resistance, which may be caused by factors produced by the PC. The mechanism underlying PC-associated insulin resistance has not been clearly defined.


OBJECTIVE
To characterize basal and insulin-stimulated glucose transport, phosphatidylinositol (PI) 3-kinase activity, and glucose transporter 4 (GLUT4) in skeletal muscles of PC patients.


METHODS
Skeletal muscle samples were obtained from the abdominal wall of 17 PC patients during surgery. Control muscles were sampled in the same way from 11 donors undergoing abdominal surgery for benign diseases. PI 3-kinase activity, glucose transport, and GLUT4 were assessed in vitro in these muscles.


RESULTS
In the presence of physiologic concentrations of insulin, glucose transport and PI 3-kinase activity were significantly decreased in the PC group compared with controls. At supraphysiologic insulin concentrations, glucose transport was significantly decreased but PI 3-kinase activity was normalized. In the absence of insulin, these parameters were not significantly different between PC and control groups. Muscle GLUT4 contents were similar between PC and control groups.


CONCLUSIONS
Defects in insulin-mediated PI 3-kinase activity and glucose transport contribute to the insulin resistance in patients with PC.
Isaksson
Bengt
B
Arvid Wretlind Laboratory for Metabolic and Nutritional Research, Department of Surgery, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden. bengt.isaksson@gastro.hs.sll.se
Strömmer
Lisa
L
Friess
Helmut
H
Büchler
Markus W
MW
Herrington
Margery K
MK
Wang
Feng
F
Zierath
Juleen R
JR
Wallberg-Henriksson
Harriet
H
Larsson
Jörgen
J
Permert
Johan
J
D019325:3-O-Methylglucose / Q000378:metabolism; D000368:Aged; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; D019325:3-O-Methylglucose; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose