hypothesis that elevated free fatty acids are causally implicated in pancreatic B-cell insensitivity to glucose by down-regulating the enzymatic activity and the expression of genes

encoding

key

regulatory enzymes

involved in the

^pathway

of malonyl-CoA

and long-chain acyl-CoA production from glucose, we have begun

to

study the effects

of

prolonged exposure

of INS-I

cells

to fatty

acids on glucose-induced

ACC mRNA

accumulation. Our pretiminary data show that

fatty

free acids antagonize the action

of

glucose on

ACC

gene expression. To our knowledge,

it

is the

first

time that an action

of

fatty acids on metabolic gene expression

in

the

B-cell is

described. These observations

could

have implications

in type 2

diabetes and obesity where circulatory lipids and free fatty acids are abundant.

It

is becoming apparent that glucose and

fatty

acids are involved

in insulin

resistance, diabetes

and obesity. Indeed,

nutrients

and specially the fatty acids affect

important

physiological and

pathological processes such

as thrombotic,

atherosclerotic, immune, inflammatory and proliferative processes. Therefore, defining the genes whose expression

are

modulated

by

nutrients

and the

mechanism(s)

involved should have

considerable biological and

clinical

implications.

4.

5.

6.

8

9 7

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