Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling
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Fatty acid-induced insulin resistance : role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling. / Le Marchand-Brustel, Y; Gual, P; Grémeaux, T; Gonzalez, T; Barres, Romain; Tanti, J-F.
In: Biochemical Society Transactions, Vol. 31, No. Pt 6, 12.2003, p. 1152-6.Research output: Contribution to journal › Journal article › Communication
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TY - JOUR
T1 - Fatty acid-induced insulin resistance
T2 - role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling
AU - Le Marchand-Brustel, Y
AU - Gual, P
AU - Grémeaux, T
AU - Gonzalez, T
AU - Barres, Romain
AU - Tanti, J-F
PY - 2003/12
Y1 - 2003/12
N2 - Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor alpha, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser(307) as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser(307) phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.
AB - Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor alpha, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser(307) as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser(307) phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.
KW - Animals
KW - Fatty Acids
KW - Glucose
KW - Insulin
KW - Insulin Receptor Substrate Proteins
KW - Insulin Resistance
KW - Osmotic Pressure
KW - Phosphoproteins
KW - Serine
KW - Signal Transduction
KW - Tumor Necrosis Factor-alpha
U2 - 10.1042/
DO - 10.1042/
M3 - Journal article
C2 - 14641015
VL - 31
SP - 1152
EP - 1156
JO - Biochemical Society Transactions
JF - Biochemical Society Transactions
SN - 0300-5127
IS - Pt 6
ER -
ID: 45577474