We measured the insulin-stimulated amount of Akt1, Akt2, and Akt3 enzymatic activities in four breast cancer cell lines and three prostate cancer cell lines. In the estrogen receptor-deficient breast cancer cells and the androgen-insensitive prostate cells, the amount of Akt3 enzymatic activity was approximately 20 -60-fold higher than in the cells that were estrogen-or androgen-responsive. In contrast, the levels of Akt1 and -2 were not increased in these cells. The increase in Akt3 enzyme activity correlated with an increase in both Akt3 mRNA and protein. In a prostate cancer cell line lacking the tumor suppressor PTEN (a lipid and protein phosphatase), the basal enzymatic activity of Akt3 was constitutively elevated and represented the major active Akt in these cells. Finally, reverse transcription-PCR was used to examine the Akt3 expression in 27 primary breast carcinomas. The expression levels of Akt3 were significantly higher in the estrogen receptor-negative tumors in comparison to the estrogen receptor-positive tumors. To see if the increase in Akt3 could be due to chromosomal abnormalities, the Akt3 gene was assigned to human chromosome 1q44 by fluorescence in situ hybridization and radiation hybrid cell panel analyses. These results indicate that Akt3 may contribute to the more aggressive clinical phenotype of the estrogen receptornegative breast cancers and androgen-insensitive prostate carcinomas.
To investigate the direct relationship of oxidative stress with obesity and insulin resistance in men, we measured the plasma levels of 8-epi-prostaglandin F2alpha (PGF2alpha) in 14 obese and 17 nonobese men and evaluated their relationship with body mass index; body fat weight; visceral, sc, and total fat areas, measured by computed tomography; and glucose infusion rate during a euglycemic hyperinsulinemic clamp study. Obese men had significantly higher plasma concentrations of 8-epi-PGF2alpha than nonobese men (P < 0.05). The plasma levels of 8-epi-PGF2alpha were significantly correlated with body mass index (r = 0.408; P < 0.05), body fat weight (r = 0.467; P < 0.05), visceral (r = 0.387; P < 0.05) and total fat area (r = 0.359; P < 0.05) in all (obese and nonobese) men. There was also a significant correlation between the plasma levels of 8-epi-PGF2alpha and glucose infusion rate in obese men (r = -0.552; P < 0.05) and all men (r = -0.668; P < 0.01). In all subjects, the plasma levels of 8-epi-PGF2alpha were significantly correlated with fasting serum levels of insulin (r = 0.487; P < 0.01). In brief, these findings showed that the circulating levels of 8-epi-PGF2alpha are related to adiposity and insulin resistance in men. Although correlation does not prove causation, the results of this study suggest that obesity is an important factor for enhanced oxidative stress and that this oxidative stress triggers the development of insulin resistance in men.
We used mouse hepatoma (Hepa1c1c7) cells to study the role of the serine/threonine kinase Akt in the induction of GLUT1 gene expression. In order to selectively turn on the Akt kinase cascade, we expressed a hydroxytamoxifen-regulatable form of Akt (myristoylated Akt1 estrogen receptor chimera (MER-Akt1)) in the Hepa1c1c7 cells; we verified that hydroxytamoxifen stimulates MER-Akt1 activity to a similar extent as the activation of endogenous Akt by insulin. Our studies reveal that stimulation of MER-Akt1 by hydroxytamoxifen induces GLUT1 mRNA and protein accumulation to levels comparable to that induced by insulin; therefore, activation of the Akt cascade suffices to induce GLUT1 gene expression in this cell system. Furthermore, expression of a kinase-inactive Akt mutant partially inhibits the response of the GLUT1 gene to insulin. Additional studies reveal that the induction of GLUT1 mRNA by Akt and by insulin reflects increased mRNA synthesis and not decreased mRNA degradation. Our findings imply that the GLUT1 gene responds to insulin at the transcriptional level and that Akt mediates a step in the activation of GLUT1 gene expression in this system.
OBJECTIVE -The purpose of this study was to investigate the association between visceral adiposity or triglyceride (TG) metabolism and insulin resistance in metabolically obese, normal weight (MONW) Japanese individuals with normal glucose tolerance.RESEARCH DESIGN AND METHODS -We evaluated body fat areas, lipid profiles, and the glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp study in 20 MONW subjects (BMI Ͻ25 kg/m 2 and visceral fat areas 100 cm 2 ) with normal glucose tolerance. Body fat areas were measured by computed tomography scans. Control data were obtained from 20 normal subjects (BMI Ͻ25 kg/m 2 and visceral fat areas Ͻ100 cm 2 ).RESULTS -MONW subjects showed a significant increase in fasting serum levels of TG (P Ͻ 0.01) and a decrease in GIR (P Ͻ 0.01) compared with normal subjects. There were significant correlations between visceral fat areas (r ϭ Ϫ0.563, P Ͻ 0.01) or serum levels of TG (r ϭ Ϫ0.474, P Ͻ 0.05) and GIR in MONW subjects. Multiple regression analyses showed that visceral fat areas (F ϭ 7.702, P Ͻ 0.02) and serum levels of TG (F ϭ 7.114, P Ͻ 0.05) were significantly associated with GIR in all (MONW and normal) subjects.CONCLUSIONS -Increased visceral fat and serum levels of TG are associated with insulin resistance in Japanese MONW subjects with normal glucose tolerance. Excess visceral fat and elevated TG levels may play important roles in the development of insulin resistance in Japanese MONW subjects with normal glucose tolerance. Diabetes Care 26:2341-2344, 2003R ecent reports described the existence of individuals with normal body weight but with a cluster of obesity-related characteristics (1,2). They are characterized by excess visceral fat, insulin resistance, and hyperinsulinemia and have been called metabolically obese, normal weight (MONW) subjects. Ethnic differences should be considered for identifying MONW subjects. In the Japanese population, nonobese (BMI Ͻ25 kg/ m 2 ) subjects with increased visceral fat areas (100 cm 2 ) fulfill the criteria for categorizing them in the MONW group (2-6). Regarding the association of the MONW state with diabetes, higher prevalence of hyperglycemia has been observed in MONW subjects than in normal individuals (3,4).Previous studies have demonstrated that visceral fat areas are associated with insulin resistance in Japanese subjects with normal glucose tolerance and impaired glucose tolerance and in nonobese Japanese patients with type 2 diabetes (7-9). Visceral fat accumulation is also associated with serum triglyceride (TG) levels, and the disturbance of TG metabolism precedes the development of insulin resistance in nonobese Japanese type 2 diabetic patients (9,10). However, the relationships of visceral adiposity and TG metabolism with insulin resistance in Japanese MONW subjects with normal glucose tolerance have not been evaluated. To clarify these points, in the present study, we investigated the relationship between visceral fat areas or serum levels of TG and insulin resistance in Japanese MONW subjects wit...
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