Impaired insulin action in adipocytes of New Zealand obese mice: a role for postbinding defects in pyruvate dehydrogenase and insulin mediator activity.
This study investigated possible mechanisms underlying insulin resistance in the New Zealand Obese (NZO) mouse, an animal model for obese, non-insulin-dependent diabetes. Insulin binding, mediator generation, and action both at the level of glucose utilization and enzyme modulation were compared in adipocytes from lean control New Zealand Chocolate (NZC) mice and NZO mice during the development of the syndrome. Abnormalities of insulin stimulation of glucose transport and utilization in NZO mouse adipocytes were found which involved both decreased sensitivity and responsiveness to insulin. The defects were evident at an early age (4 weeks) and could not be attributed to differences in nonstimulated glucose metabolism, which was similar in the control NZC and obese NZO strains of mouse. Insulin binding to its receptor was only moderately decreased in adipocytes of NZO mice. Pyruvate dehydrogenase (PDH) activity of NZO mouse adipocytes was totally unresponsive to insulin in contrast to the impaired but still significant insulin stimulation of glucose transport and utilization, suggesting a postreceptor defect at the level of insulin stimulation of this enzyme. Insulin stimulated the production of a low molecular weight factor which activated pyruvate dehydrogenase in NZC mouse adipocytes (insulin mediator) but, paradoxically, caused a decrease in mediator production or activity in adipocytes from NZO mice. Thus, insulin either inhibited mediator production or stimulated generation of an inhibitory mediator in adipocytes from this strain. No evidence for the latter mechanism was found. This study demonstrates in adipocytes of NZO mice: (1) a receptor defect and (2) a postreceptor defect of insulin action at the level of pyruvate dehydrogenase activation.(ABSTRACT TRUNCATED AT 250 WORDS)
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D003920:Diabetes Mellitus / Q000201:enzymology / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage / Q000502:physiology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism
D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; D011972:Receptor, Insulin; D005947:Glucose