Bd. Rodgers et al., Endocrine regulation of G-protein subunit production in an animal model oftype 2 diabetes mellitus, J ENDOCR, 168(3), 2001, pp. 509-515
Adipocyte beta -adrenergic sensitivity is compromised in animal models of o
besity and type 2 diabetes. Although changes in the membrane concentrations
of G-protein alpha subunits (G alpha) have been implicated, it remains to
be determined how these changes are affected by insulin resistance in the d
ifferent animal models. Because previous studies used young animals, we mea
sured the concentrations of G alpha and G beta subunits in epididymal fat f
rom aged (48 weeks old) db/db mice and from their lean littermates to more
closely reproduce the model of type 2 diabetes mellitus. Levels of immunore
active G alphas, G alphai(1/2), G alphao and G alphaq/11 were all significa
ntly greater in adipocyte membranes from the db/db mice than in membranes f
rom their lean non-diabetic littermate controls. Levels of G alphai(1) and
G alphai(2) were also individually determined and although they appeared to
be slightly higher in db/db membranes, these differences were not signific
ant. Although the levels of both G alphas isoforms were elevated, levels of
the 42 and 46 kDa proteins rose by approximately 42% and 20% respectively,
indicating differential protein processing of G alphas. By contrast, level
s of G alpha i3 were similar in the two groups. The levels of common G beta
and G beta2 were also elevated in db/db mice, whereas G beta1 and G beta4
levels were not different. To determine whether these changes were due to i
nsulin resistance per se or to elevated glucocorticoid production, G-protei
n subunit levels were quantified in whole cell lysates from 3T3-L1 adipocyt
es that were stimulated with different concentrations of either insulin or
corticosterone. Although none of the subunit levels was affected by insulin
, the levels of both G alphas isoforms were increased equally by corticoste
rone in a concentration-dependent manner. Since glucocorticoids are known r
egulators of G alphas gene expression in many cell types and in adipocytes
from diabetic rodents, the results presented herein appear to more accurate
ly reflect diabetic pathophysiology than do those of previous studies which
report a decrease in G alphas levels. Taken together, these results indica
te that most of the selective changes in G-protein subunit production in ad
ipocytes from this animal model of type 2 diabetes may not be due to dimini
shed insulin sensitivity, but may be due to other endocrine or metabolic ab
normalities associated with the diabetic phenotype.