Augmentation of insulin secretion by leucine supplementation in malnourished rats: possible involvement of the phosphatidylinositol 3-phosphate kinase/mammalian target protein of rapamycin pathway

Filiputti, Eliane; Rafacho, Alex; Araújo, Eliana P.; Silveira, Leonardo R.; Trevisan, Amon; Batista, Thiago M.; Curi, Rui; Velloso, Lı́cio A.; Quesada, Iván; Boschero, Antônio Carlos; Carneiro, Everardo M.

doi:10.1016/j.metabol.2009.09.007

Cited by 48 publications

(40 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Here, we examined the role of mTOR signaling in the regulation of NT peptide secretion and gene expression. Support of this notion is provided by findings that leucine supplementation augments pancreatic ␤-cell function and insulin secretion in malnourished rats, which is associated with increased PI3K and mTOR protein contents, suggesting that activation of the PI3K/mTOR pathway may play a role in this process (25). mTORC1 is known to increase mRNA translation and protein synthesis via the two downstream substrates p70S6K and 4E-BP1 (46).…”

Section: Discussionmentioning

confidence: 95%

mTORC1 inhibition increases neurotensin secretion and gene expression through activation of the MEK/ERK/c-Jun pathway in the human endocrine cell line BON

Liu

Song

et al. 2011

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR) signaling exists in two complexes: mTORC1 and mTORC2. Neurotensin (NT), an intestinal hormone secreted by enteroendocrine (N) cells in the small bowel, has important physiological effects in the gastrointestinal tract. The human endocrine cell line BON abundantly expresses the NT gene and synthesizes and secretes NT in a manner analogous to that of N cells. Here, we demonstrate that the inhibition of mTORC1 by rapamycin (mTORC1 inhibitor), torin1 (both mTORC1 and mTORC2 inhibitor) or short hairpin RNA-mediated knockdown of mTOR, regulatory associated protein of mTOR (RAPTOR), and p70 S6 kinase (p70S6K) increased basal NT release via upregulating NT gene expression in BON cells. c-Jun activity was increased by rapamycin or torin1 or p70S6K knockdown. c-Jun overexpression dramatically increased NT promoter activity, which was blocked by PD98059, an mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, overexpression of MEK1 or extracellular signal-regulated kinase 1 (ERK1) increased c-Jun expression and NT promoter activity. More importantly, PD98059 blocked rapamycin- or torin1-enhanced NT secretion. Consistently, rapamycin and torin1 also increased NT gene expression in Hep3B cells, a human hepatoma cell line that, similar to BON, expresses high levels of NT. Phosphorylation of c-Jun and ERK1/2 was also increased by rapamycin and torin1 in Hep3B cells. Finally, we showed activation of mTOR in BON cells treated with amino acids, high glucose, or serum and, concurrently, the attenuation of ERK1/2 and c-Jun phosphorylation and NT secretion. Together, mTORC1, as a nutrient sensor, negatively regulates NT secretion via the MEK/ERK/c-Jun signaling pathway. Our results identify a physiological link between mTORC1 and MEK/ERK signaling in controlling intestinal hormone gene expression and secretion.

show abstract

Section: Discussionmentioning

confidence: 95%

mTORC1 inhibition increases neurotensin secretion and gene expression through activation of the MEK/ERK/c-Jun pathway in the human endocrine cell line BON

Liu

Song

et al. 2011

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

show abstract

“…However, leucine, the major component of the mixture, has been demonstrated to increase insulin secretion in malnourished rats [16] and modulate contractionand insulin-stimulated glucose transport in rat's skeletal muscle [17]. Whether other amino acids in the study supplement may contribute to enhance glucose metabolism remains a question which must be addressed by specifically designed clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Metabolic and Clinical Effects of the Supplementation of a Functional Mixture of Amino Acids in Cerebral Hemorrhage

et al. 2010

View full text Add to dashboard Cite

show abstract

“…On the other hand, reduced levels of plasma amino acids in response to a low protein diet might be responsible for this rapid alteration, because certain amino acids, such as leucine and arginine, have been reported to stimulate insulin secretion from β cells directly. [15][16][17] Fig. 5.…”

Section: Discussionmentioning

confidence: 99%

Insulin injection restored increased insulin receptor substrate (IRS)-2 protein during short-term protein restriction but did not affect reduced insulin-like growth factor (IGF)-I mRNA or increased triglyceride accumulation in the liver of rats

Ozaki

Takeda

Akanishi

et al. 2014

Bioscience, Biotechnology, and Biochemistry

View full text Add to dashboard Cite

Dietary protein restriction reduces insulin-like growth factor (IGF)-I synthesis and impairs growth. Moreover, insulin secretion is impaired and hepatic insulin signaling is activated presumably through upregulation of insulin receptor substrate (IRS)-2, which can stimulate lipogenesis thereby resulting in steatosis. In order to determine whether impaired insulin secretion is the primary cause of these changes, we injected insulin into protein-restricted rats and compensated for the reduction in insulin secretion for 1 and 7 d. Insulin infusion did not overcome the reduction in liver IGF-I mRNA nor the hepatic triglyceride accumulation. In contrast, it clearly suppressed the upregulation of hepatic IRS-2 on day 1, but not on day 7. Furthermore, insulin elimination increased IRS-2 in H4IIE-C3 cells. In summary, we found that reduced insulin secretion during protein restriction directly increased hepatic IRS-2 as a rapid response on day 1, while additional mechanisms contributed to the upregulation of IRS-2 on day 7.

show abstract

Augmentation of insulin secretion by leucine supplementation in malnourished rats: possible involvement of the phosphatidylinositol 3-phosphate kinase/mammalian target protein of rapamycin pathway

Cited by 48 publications

References 54 publications

mTORC1 inhibition increases neurotensin secretion and gene expression through activation of the MEK/ERK/c-Jun pathway in the human endocrine cell line BON

mTORC1 inhibition increases neurotensin secretion and gene expression through activation of the MEK/ERK/c-Jun pathway in the human endocrine cell line BON

Metabolic and Clinical Effects of the Supplementation of a Functional Mixture of Amino Acids in Cerebral Hemorrhage

Insulin injection restored increased insulin receptor substrate (IRS)-2 protein during short-term protein restriction but did not affect reduced insulin-like growth factor (IGF)-I mRNA or increased triglyceride accumulation in the liver of rats

Contact Info

Product

Resources

About