CCAAT/enhancer binding protein alpha maintains the ability of insulin-stimulated GLUT4 translocation in 3T3-C2 fibroblastic cells.

In 3T3-L1 preadipocytes, hormonal induction causes adipose conversion and facilitates the expression of insulin-sensitive glucose transporter, GLUT4. Evidence has accumulated that, in 3T3-L1 preadipocytes, the formation of GLUT4 storage vesicle and its translocation to plasma membrane precede both lipid accumulation and expression of GLUT4 and C/EBPalpha, a key transcription factor for adipose differentiation. On the other hand, 3T3-C2 fibroblastic cells, a subline of 3T3-L1, follow adipogenic process till mitotic clonal expansion stage (2 days after hormonal induction), but do not proceed to terminal differentiation stage (8 days after the induction), resulting in a lack of adipose conversion and GLUT4 expression. Here we show that, when myc-tagged GLUT4 was retrovirally expressed in 3T3-C2 cells, insulin-stimulated GLUT4 translocation did occur on day 2 after the induction. On day 8 after the induction, however, neither GLUT4 translocation nor the expression of C/EBPalpha was observed. We also created 3T3-C2 cells stably expressing both myc-tagged GLUT4 and C/EBPalpha, demonstrating that co-expressed cells showed insulin-stimulated GLUT4 translocation on day 8 after the induction, as well as adipose conversion coupling with PPARgamma expression. Our results provide evidence that C/EBPalpha has the potential to maintain the ability of insulin-stimulated GLUT4 translocation in C/EBPalpha-deficient 3T3-C2 fibroblastic cells.

The haplotypes of the IRS-2 gene affect insulin sensitivity in Japanese patients with type 2 diabetes.

A commonly occurring nucleotide polymorphism of the insulin-receptor substrate 2 (IRS-2) gene at amino acid 1057 from Glycine to Asparaginic acid (G1057D) was recently shown to be a determinant of insulin sensitivity in both glucose-tolerant individuals and those with type 2 diabetes. With respect to the latter, the IRS-2 D1057 allele increase the risk of insulin resistance among obese individuals. After we reconstructed haplotypes from the G1057D variant and the -769C/T replacement that was newly identified, we investigated the possibility that the IRS-2 gene affects insulin sensitivity in Japanese glucose-tolerant subjects (n = 260) and type 2 diabetic patients (n = 123). We did not find that the D1057 allele and haplotype pairs were associated with the risk of diabetes. However, type 2 diabetic patients, particularly obese patients, carrying the D1057 allele and the CA haplotype were associated with insulin resistance. Furthermore, we suggested that the TG and CG haplotypes might have a protective role against insulin resistance. This observation raises the possibility that both the IRS-2 D1057 allele and the CA haplotype are useful genetic markers for identifying obese individuals who are particularly susceptible to insulin resistance.

An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes.

Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of telmisartan on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of telmisartan effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with telmisartan caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and adiponectin. By contrast, telmisartan attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that telmisartan augmented GLUT4 protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability.