We examined the gene and protein expression of IRS 1 (insulin receptor subs
trate 1) in adipocytes from two groups of healthy individuals with an incre
ased propensity for non-insulin-dependent diabetes mellitus (NIDDM): those
with two first-degree relatives with diabetes and another group with massiv
e obesity. A low expression of IRS 1 (less than or equal to 50% of the matc
hed control group) was seen in approximate to 30% of both groups and these
individuals were characterized by insulin resistance and its hallmarks: hig
her levels of insulin, glucose, and triglycerides. Two individuals with pre
viously unknown NIDDM were diagnosed and both had low IRS 1 expression. Low
TRS I protein expression was associated with low mRNA levels but not with
the common Gly972Arg polymorphism of the IRS I gene. Taken together, our pr
esent and previous findings show that a low expression of IRS 1 in fat cell
s predicts insulin resistance and NIDDM. Furthermore, they support the like
lihood that an impaired transcriptional activation may play a key role in t
he pathogenesis of NIDDM.