Recent studies have implicated endoplasmic reticulum (ER) stress in insulin resistance associated with caloric excess. In mice placed on a 3-day high fat diet, we find augmented eIF2α signaling, ...together with hepatic lipid accumulation and insulin resistance. To clarify the role of the liver ER stress-dependent phospho-eIF2α (eIF2α-P) pathway in response to acute caloric excess on liver and muscle glucose and lipid metabolism, we studied transgenic mice in which the hepatic ER stress-dependent eIF2α-P pathway was inhibited by overexpressing a constitutively active C-terminal fragment of GADD34/PPP1R15a, a regulatory subunit of phosphatase that terminates ER stress signaling by phospho-eIF2α. Inhibition of the eIF2α-P signaling in liver led to a decrease in hepatic glucose production in the basal and clamped state, which could be attributed to reduced gluconeogenic gene expression, resulting in reduced basal plasma glucose concentrations. Surprisingly, hepatic eIF2α inhibition also impaired insulin-stimulated muscle and adipose tissue insulin sensitivity. This latter effect could be attributed at least in part by an increase in circulating IGFBP-3 levels in the transgenic animals. In addition, infusion of insulin during a hyperinsulinemic-euglycemic clamp induced conspicuous ER stress in the 3-day high fat diet-fed mice, which was aggravated through continuous dephosphorylation of eIF2α. Together, these data imply that the hepatic ER stress eIF2α signaling pathway affects hepatic glucose production without altering hepatic insulin sensitivity. Moreover, hepatic ER stress-dependent eIF2α-P signaling is implicated in an unanticipated cross-talk between the liver and peripheral organs to influence insulin sensitivity, probably via IGFBP-3. Finally, eIF2α is crucial for proper resolution of insulin-induced ER stress.
A administração de deidroepiandrosterona (DHEA) tem resultado em efeitos anti-diabetogênicos em animais de experimentação e no homem. Assim, o objetivo desse trabalho foi avaliar o efeito do DHEA ...sobre a função vascular em aorta e resistência periférica à insulina em roedores fêmeas ovariectomizadas (modelo experimental de menopausa - OVX). O tratamento com DHEA em ratas OVX, embora não levou a nenhuma alteração da composição corporal, induziu a uma redução na pressão arterial sistólica e disatólica, além de uma melhora na função vascular, aumentando a resposta à ACh e reduzindo a resposta à fenilefrina. Isso foi associado a uma redução do estresse oxidativo e inflação na aorta das ratos OVX. Para estudo da resistência à insulina foram utilizadas camundongos fêmeas OVX alimentadas com dieta hiperlipídica. O tratamento com DHEA nesses animais levou a uma redução do percentual de gordura corporal, provavelmente devido a uma redução da ingestão calórica. Também foi observado um aumento da sensibilidade à insulina nos animais tratados com DHEA, associado a uma redução do acúmulo ectópico de lipídios (fígado e músculo). Concluímos que o DHEA pode ser uma possível altenativa de tratamento, ao invés de estradiol, em mulheres na menopausa, já que ele é capaz de melhorar a função vascular e perfil metabólico em modelo experimental de menopausa.
Dehydroepiandrosterone (DHEA) treatment has resulted in anti-diabetogenic effects in both animals and humans. The aim of this study was to evaluate the effect of DHEA on vascular function in the aorta and peripheral insulin resistance in ovariectomized female rodents (experimental model of menopause - OVX). Although DHEA treatment in OVX rats did not lead to any change in body composition, it induced a decrease in blood pressure, and an improvement in vascular function, increasing the ACh response and reduces the response to phenylephrine. This was associated with a reduction in oxidative stress and inflammation in the aorta of OVX rats. For the study of insulin resistance it was used OVX female mice fed with high fat diet. DHEA treatment in these animals led to a reduction in body fat percentage, probably due to a reduction in caloric intake. It was also observed an increase in insulin sensitivity in animals treated with DHEA, associated with a reduction in ectopic fat (liver and muscle) accumulation. We conclude that DHEA may be a possible alternative treatment instead of estradiol, in postmenopausal women, since he is able to improve vascular function and metabolic profile in an experimental model of menopause.
A administração de deidroepiandrosterona (DHEA) tem resultado em efeitos anti-diabetogênicos em animais de experimentação e no homem. Assim, o objetivo desse trabalho é avaliar o efeito do DHEA in ...vitro na expressão protéica do IR, do IRS-1, IRS-2, PI3-K, Akt, ERK-1/2; na expressão gênica do PDX-1, do PGC-1, da insulina, do GLUT-2 e da glicocinase; e avaliar a secreção estática de insulina de ilhotas pancreáticas de ratos. O cultivo das ilhotas por 24 horas com DHEA, não induziu nenhuma alteração tanto na expressão das proteínas quanto na secreção estática de insulina estimulada por glicose. Ocorreu aumento da fosforilação de ERK-1/2 e na expressão gênica do PGC-1. As células RINm5F, cultivadas por 72 horas com DHEA, apresentaram aumento da expressão total de IRS-1 e IRS-2. Concluímos, que 24 horas de cultura com ilhotas não é tempo suficiente para observar nenhuma alteração induzida pelo DHEA, na secreção de insulina, e na expressão das proteínas da via IRS/PI3-K/Akt. Células RINm5F podem ser um modelo alternativo para investigar os efeitos diretos do DHEA.
The dehydroepiandrosterone (DHEA) administration has resulted in reduction of abdominal fat and protection against insulin resistance from experimental animals and humans. So, the purpose of this project is measure the in vitro effects from DHEA: on protein expression of insulin receptor, the proteins IRS-1, IRS-2, PI3-K, Akt, and ERK-1/2; on gene expression of transcriptional factors PDX-1 and PGC-1, insulin, glucose transport GLUT-2 and glicocinase; and to measure the static insulin secretion, on cultured pancreatic islets of the rat. The culture of pancreatic islet for 24 hours with DHEA, did not induce nothing alteration on protein expression of the IR, IRS-1, IRS-2, PI3-K, Akt-1 and ERK-1/2, and static insulin secretion induced by glucose. However, happened increase ERK-1/2 phosphorylation and PGC-1 gene expression. The RINm5F cells, cultured by 72 hours, showed increase of the IRS-1 and IRS-2 expression. We conclude that 24 hours of the pancreatic islets culture are not sufficient time to look any alteration induced by DHEA, on insulin secretion, and on protein expression involved on IRS/PI3-K/Akt pathway. RINm5F cells can be an alternative model to research the direct effects from DHEA.
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