Over-expression of insulin-response element binding protein-1 (IRE-BP1) in mouse pancreatic islets increases expression of RACK1 and TCTP: Beta cell markers of high glucose sensitivity.

Background: A targeted analysis of the 50kDa C-terminal fragment of insulin-response element binding protein-1 (IRE-BP1) activation of target genes through the insulin receptor substrate receptor/PI-3 kinase/Akt pathway has been demonstrated for the insulin growth factor-1 receptor. The broader effects of 50kDa C-terminal IRE-BP1 fragment over-expression on protein abundance in pancreatic islet beta cells have not been determined.

Results: Liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses of replicate lysates of pancreatic islets isolated from background strain animals and transgenic animals, overexpressing IRE-BP1 in pancreatic islet beta cells, demonstrated statistically significant increases in the expression of proteins involved in protein synthesis, endoplasmic reticulum (ER) stress and scaffolding proteins important for protein kinase C signaling; some of which were confirmed by immunoblot analyses.

Developmental changes in pituitary adenylate cyclase activating polypeptide expression during the perinatal period: possible role in fetal gonadotroph regulation.

Normal reproductive functioning may require secretion of LH independently of FSH. Variation in GnRH pulse frequency and inhibin negative feedback are mechanisms for differential gonadotropin regulation; however, the first instance of differential regulation in rats is during fetal development, prior to the establishment of GnRH connections, when LH accumulates appreciably 2-4 d prior to FSH. Pituitary adenylate cyclase activating polypeptide (PACAP) can differentially regulate the gonadotropins in vitro by stimulating alpha-subunit transcription, lengthening LHbeta transcripts and decreasing FSHbeta mRNA levels, probably through stimulation of follistatin transcription.

Transgenic expression of insulin-response element binding protein-1 in beta-cells reproduces type 2 diabetes.

Recent evidence supports the idea that insulin signaling through the insulin receptor substrate/phosphatidyl-inositol 3-kinase/Akt pathway is involved in the maintenance of beta-cell mass and function. We previously identified the insulin-response element binding protein-1 (IRE-BP1) as an effector of insulin-induced Akt signaling in the liver, and showed that the 50-kDa carboxyl fragment confers the transcriptional activity of this factor. In this investigation we found that IRE-BP1 is expressed in the alpha, beta, and delta-cells of the islets of Langerhans, and is localized to the cytoplasm in beta-cells in normal rats, but is reduced and redistributed to the islet cell nuclei in obese Zucker rats.

Hot flashes and fatigue relieved by metformin.

Objective: To describe 3 patients with long-standing hot flashes, excessive sweating, and fatigue whose symptoms were ameliorated with metformin.

Methods: In this case series, we report the findings of laboratory evaluations, including assessments for thyroid, gonadal, adrenal, and pancreatic disorders, in 3 patients referred for endocrine evaluation. A 75-g oral glucose tolerance test with measurement of fasting and postprandial glucose and insulin concentrations was conducted.

Regulation of insulin-response element binding protein-1 in obesity and diabetes: potential role in impaired insulin-induced gene transcription.

One of the major mechanisms by which insulin modulates glucose homeostasis is through regulation of gene expression. Therefore, reduced expression of transcription factors that are required for insulin-regulated gene expression may contribute to insulin resistance. We recently identified insulin response element-binding protein-1 (IRE-BP1) as a transcription factor that binds and transactivates multiple insulin-responsive genes, but the regulation of IRE-BP1 in vivo is largely unknown.

An insulin-response element-binding protein that ameliorates hyperglycemia in diabetes.

Insulin modulates glucose homeostasis, but the role of insulin-responsive transcription factors in such actions is not well understood. Recently, we have identified the insulin-response element-binding protein-1 (IRE-BP1) as a transcription factor that appears to mediate insulin action on multiple target genes. To examine the possibility that IRE-BP1 is an insulin-responsive glucoregulatory factor involved in the metabolic actions of insulin, we investigated the effect of adenoviral overexpression of hepatic IRE-BP1 on the glycemic control of insulin-resistant diabetic rats.

Insulin-response element-binding protein 1: a novel Akt substrate involved in transcriptional action of insulin.

Although the cis-acting elements that mediate the actions of insulin on gene transcription have been defined for a significant number of genes, the transcription factors responsible for the transactivation of these target sequences remain unknown. In this report, we identified a novel transcription factor that binds and transactivates the insulin-response elements of the insulin-like growth factor-binding protein-3 and other insulin responsive genes. This factor is a target of insulin signal transduction downstream of the phosphatidylinositol 3'-kinase/protein kinase B (Akt) pathway.