Immunobiological consequence of regulation of insulin receptor on alloactivated lymphocytes in normal and obese subjects

Background Given the major role of obesity and insulin resistance (IR) in colorectal cancer (CRC), we investigated whether genetic variants in ghrelin ( GHRL), resistin ( RETN) and insulin receptor substrate 1 ( IRS1) were associated with CRC risk. Methods This study was conducted as a case-control study, and 750 subjects, including 438 controls and 312 patients with CRC, were enrolled and genotyped using the PCR-RFLP method. Results No significant differences were observed for GHRL (rs696217), RETN (rs3745367) and IRS1 (rs1801278, Gly972Arg or G972R) gene variants between the cases and controls. However, the IRS1 G972R R allele compared with the G allele and the G972R RR+GR genotype compared with the GG genotype appeared to be markers of decreased CRC susceptibility in the overweight/obese subjects (p = 0.024; odds ratio [OR] = 0.42, 95% confidence interval [95% CI], 0.20-0.91; and p = 0.048; OR = 0.42, 95% CI, 0.17-0.99, respectively). Furthermore, the R allele and RR+GR genotype were also associated with decreased risks for obesity in the patients with CRC (p = 0.007; OR = 0.35, 95% CI, 0.15-0.77; and p = 0.015; OR = 0.35, 95% CI, 0.15-0.72, respectively). Conclusions In accordance with previous studies, our findings suggest that the IRS1 G972R R allele and RR+GR genotype have protective effects for CRC in overweight/obese patients and for obesity in patients with CRC. Nevertheless, further studies are required to confirm these findings.

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The G972R variant of the insulin receptor substrate-1 (IRS-1) gene is associated with insulin resistance in “uncomplicated” obese subjects evaluated by hyperinsulinemic-euglycemic clamp

Journal of Endocrinological Investigation ◽

10.1007/bf03347518 ◽

2004 ◽

Vol 27 (8) ◽

pp. 754-759 ◽

Cited By ~ 7

Author(s):

M. G. Baroni ◽

F. Leonetti ◽

F. Sentinelli ◽

S. Romeo ◽

E. Filippi ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Insulin Receptor Substrate ◽

Insulin Receptor Substrate 1 ◽

Euglycemic Clamp ◽

Hyperinsulinemic Euglycemic Clamp ◽

Obese Subjects

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Analysis of insulin-stimulated insulin receptor activation and glucose transport in cultured skeletal muscle cells from obese subjects

Metabolism ◽

10.1016/j.metabol.2004.11.018 ◽

2005 ◽

Vol 54 (5) ◽

pp. 598-603 ◽

Cited By ~ 13

Author(s):

Celia Pender ◽

Ira D. Goldfine ◽

Jennifer L. Kulp ◽

Charles J. Tanner ◽

Betty A. Maddux ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Receptor ◽

Glucose Transport ◽

Muscle Cells ◽

Receptor Activation ◽

Skeletal Muscle Cells ◽

Obese Subjects

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Mechanisms of Muscle Insulin Resistance in Obese Individuals

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.11.s1.s64 ◽

2001 ◽

Vol 11 (s1) ◽

pp. S64-S70 ◽

Cited By ~ 4

Author(s):

G. Lynis Dohm

Keyword(s):

Insulin Resistance ◽

Tyrosine Kinase ◽

Insulin Receptor ◽

Kinase Activity ◽

Insulin Receptors ◽

Published Data ◽

Tyrosine Kinase Activity ◽

Insulin Signal Transduction ◽

Insulin Resistant ◽

Obese Subjects

We previously reported that insulin resistance in skeletal muscle of obese individuals was associated with decreases in insulin signal transduction and tyrosine kinase activity of the insulin receptor. Herein is reviewed the recently published data supporting the hypothesis that protein kinase C (PKC) phosphorylates the insulin receptor on serine/threonine residues to decrease tyrosine kinase activity and cause insulin resistance. Treatment of insulin receptors from obese subjects with alkaline phosphatase restored tyrosine kinase activity, suggesting that the reduced activity was a result of hyperphosphorylation of the receptor. Incubating human muscle fiber strips with PKC inhibitors restored insulin action in muscle of obese patients, while activating PKC with a phorbol ester caused insulin resistance in muscle from lean control patients. The beta isoform of PKC was elevated in muscle of obese, insulin-resistant patients. These data are consistent with the hypothesis that elevated PKC activity may cause insulin resistance by phosphorylating the insulin receptor to decrease tyrosine kinase activity.

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Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects.

Journal of Clinical Investigation ◽

10.1172/jci117909 ◽

1995 ◽

Vol 95 (5) ◽

pp. 2195-2204 ◽

Cited By ~ 343

Author(s):

L J Goodyear ◽

F Giorgino ◽

L A Sherman ◽

J Carey ◽

R J Smith ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Receptor ◽

Kinase Activity ◽

Insulin Receptor Substrate ◽

Phosphatidylinositol 3 Kinase ◽

Insulin Receptor Substrate 1 ◽

Receptor Phosphorylation ◽

Obese Subjects ◽

Phosphatidylinositol 3

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A reduced number of insulin receptors in patients with Prader-Willi syndrome

Acta Endocrinologica ◽

10.1530/acta.0.1040345 ◽

1983 ◽

Vol 104 (3) ◽

pp. 345-351 ◽

Cited By ~ 13

Author(s):

Arne M. Kousholt ◽

Henning Beck-Nielsen ◽

Hans T. Lund

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Insulin Response ◽

Insulin Receptors ◽

Normal Subjects ◽

Normal Weight ◽

Target Cells ◽

Prader Willi Syndrome ◽

Plasma Insulin Concentration ◽

Obese Subjects

Abstract. The Prader-Willi syndrome is among other features characterized by obesity and a high prevalence of glucose intolerance. The fasting plasma insulin concentration and the insulin response to glucose are often increased, indicating some insulin resistance in this disease. To investigate whether this could be due to an insulin receptor defect 7 patients with Prader-Willi syndrome, 10 normal weight subjects and 8 obese subjects were tested for the binding of [125I]insulin to monocytes. Monocytes from patients with Prader-Willi syndrome bound significantly less insulin than cells from normal subjects (P < 0.01). However, no difference was found between Prader-Willi patients and the obese controls (P > 0.1). It is concluded that the insulin resistance found in Prader-Willi patients, similar to that found in obese subjects, in part, may be explained by an insulin receptor defect on target cells for insulin action.

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