A data integration approach unveils a transcriptional signature of type 2 diabetes progression in rat and human islets.

Pancreatic islet failure is a key characteristic of type 2 diabetes besides insulin resistance. To get molecular insights into the pathology of islets in type 2 diabetes, we developed a computational approach to integrating expression profiles of Goto-Kakizaki and Wistar rat islets from a designed experiment with those of the human islets from an observational study. A principal gene-eigenvector in the expression profiles characterized by up-regulated angiogenesis and down-regulated oxidative phosphorylation was identified conserved across the two species.

A Novel Dual Eigen-Analysis of Mouse Multi-Tissues' Expression Profiles Unveils New Perspectives into Type 2 Diabetes.

Type 2 diabetes (T2D) is a complex and polygenic disease yet in need of a complete picture of its development mechanisms. To better understand the mechanisms, we examined gene expression profiles of multi-tissues from outbred mice fed with a high-fat diet (HFD) or regular chow at weeks 1, 9, and 18. To analyze such complex data, we proposed a novel dual eigen-analysis, in which the sample- and gene-eigenvectors correspond respectively to the macro- and micro-biology information.

Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover.

Vascular permeability regulated by the vascular endothelial growth factor (VEGF) through endothelial-barrier junctions is essential for inflammation. Mechanisms regulating vascular permeability remain elusive. Although 'Akt' and 'Src' have been implicated in the endothelial-barrier regulation, it is puzzling how both agents that protect and disrupt the endothelial-barrier activate these kinases to reciprocally regulate vascular permeability.

Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms.

Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoform inhibition were not fully explored. We showed that while combined Akt1 and Akt3 deletion in adult mice is tolerated, combined Akt1 and Akt2 deletion induced rapid mortality.

Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium.

The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. Here we show that unlike neovascularization, endothelial Akt signalling in established vasculature is crucial not for endothelial cell (EC) survival, but for sustained interactions with pericytes and vascular smooth muscle cells (VSMCs) regulating vascular stability and function. Inducible endothelial-specific Akt1 deletion in adult global Akt2KO mice triggers progressive VSMC apoptosis.

Akt-dependent Skp2 mRNA translation is required for exiting contact inhibition, oncogenesis, and adipogenesis.

The requirement of Akt for cell proliferation and oncogenesis is mammalian target of rapamycin complex 1 (mTORC1) dependent. SV40 large T expression in Akt-deficient cells restores cell proliferation rate, but is insufficient for exiting contact inhibition and oncogene-induced anchorage-independent growth, because of a failure to promote Skp2 mRNA translation. Skp2 mRNA and protein are induced upon exiting contact inhibition, which enables entry into mitosis.

[Serum adiponectin, leptin level, and bone mineral density in postmenopausal women].

Objective: To determine whether serum adipocytokines and leptin level are associated with bone mineral density (BMD) in postmenopausal women.

Methods: Serum adiponectin and leptin level were measured by ELISA in 336 postmenopausal women. BMD was measured by dual energy X-ray absorptiometry (DXA) at the whole body, lumbar spine, hip, and forearm.

Use of the metallothionein promoter-human growth hormone-releasing hormone (GHRH) mouse to identify regulatory pathways that suppress pituitary somatotrope hyperplasia and adenoma formation due to GHRH-receptor hyperactivation.

Hyperactivation of the GHRH receptor or downstream signaling components is associated with hyperplasia of the pituitary somatotrope population, in which adenomas form relatively late in life, with less than 100% penetrance. Hyperplastic and adenomatous pituitaries of metallothionein promoter-human GHRH transgenic (Tg) mice (4 and > 10 months, respectively) were used to identify mechanisms that may prevent or delay adenoma formation in the presence of excess GHRH. In hyperplastic pituitaries, expression of the late G(1)/G(2) marker Ki67 increased, whereas the proportion of 5-bromo-2'-deoxyuridine-labeled cells (S phase marker) did not differ from age-matched controls.

Leptin deficiency and beta-cell dysfunction underlie type 2 diabetes in compound Akt knockout mice.

Phenotypic analyses of mice null for the individual Akt isoforms suggested that they are functionally distinct and that only Akt2 plays a role in diabetes. We show here that Akt isoforms play compensatory and complementary roles in glucose homeostasis and diabetes. Insulin resistance in Akt2(-/-) mice was inhibited by haplodeficiency of Pten, suggesting that other Akt isoforms can compensate for Akt2 function.

Association between serum soluble membrane type matrix metalloproteinase-1 (MT1-MMP) levels and bone mineral density, and biochemical markers in postmenopausal women.

Background: Recently, membrane type matrix metalloproteinase-1 (MT1-MMP) was found to participate in bone metabolism. We investigated the relationship between serum MT1-MMP and bone mineral density (BMD) as well as bone metabolic markers in 206 Chinese postmenopausal women aged 43-80 years.

Methods: Western analysis and ELISA were performed to detect serum soluble MT1-MMP levels.

Relationships between serum adiponectin, leptin, resistin, visfatin levels and bone mineral density, and bone biochemical markers in Chinese men.

Background: Adiponectin, leptin, resistin, and visfatin, as the main circulating peptides secreted by adipose tissue, are potential contributors to bone metabolism. We investigated whether these serum adipocytokines levels are associated with BMD and bone turnover biochemical markers in 232 Chinese men (20-80 y).

Methods: Serum adiponectin, leptin, resistin, and visfatin levels were determined by ELISA.

Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner.

Akt contributes to tumorigenesis by inhibiting apoptosis. Here we establish that Akt is required for normal cell proliferation and susceptibility to oncogenesis independently of its antiapoptotic activity. Partial ablation of Akt activity by deleting Akt1 inhibits cell proliferation and oncogenesis.

The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice.

The tumor suppressor PTEN is frequently inactivated in human cancers. A major downstream effector of PTEN is Akt, which is hyperactivated via PTEN inactivation. It is not known, however, whether diminished Akt activity is sufficient to inhibit tumorigenesis initiated by Pten deficiency.

A phosphoinositide 3-kinase-AKT-nitric oxide-cGMP signaling pathway in stimulating platelet secretion and aggregation.

Phosphoinositide 3-kinase (PI3K) and Akt play important roles in platelet activation. However, the downstream mechanisms mediating their functions are unclear. We have recently shown that nitric-oxide (NO) synthase 3 and cGMP-dependent protein kinase stimulate platelet secretion and aggregation.

Expression analysis of hypothalamic and pituitary components of the growth hormone axis in fasted and streptozotocin-treated neuropeptide Y (NPY)-intact (NPY+/+) and NPY-knockout (NPY-/-) mice.

In the fasted and the streptozotocin (STZ)-induced diabetic male rat, hypothalamic growth hormone (GH)-releasing hormone (GHRH) mRNA levels, and pulsatile GH release are decreased. These changes are believed to be due to a rise in hypothalamic neuropeptide Y (NPY) that inhibits GHRH expression. To directly test if NPY is required for metabolic regulation of hypothalamic neuropeptides important in GH secretion, NPY, GHRH and somatostatin (SRIH) mRNA levels were determined in fasted (48 h) and STZ-treated wild-type (NPY(+/+)) and NPY-knockout (NPY(-/-)) mice by ribonuclease protection assay.

Homologous and heterologous regulation of pituitary receptors for ghrelin and growth hormone-releasing hormone.

Secretion of GH by pituitary somatotropes is primarily stimulated by the hypothalamic GHRH through the activation of a specific G protein-coupled receptor, GHRH receptor (GHRH-R). GH is also released in response to ghrelin, a peptide produced in the stomach, hypothalamus, and pituitary that activates somatotropes via a distinct G protein-coupled receptor, referred to as the GH secretagogue receptor (GHS-R). Here, we have analyzed the expression of both GHRH-R and GHS-R (by multiplex RT-PCR) in porcine pituitary cell cultures, after acute (4 h) treatment with GHRH or ghrelin as well as with other regulators of somatotropes (somatostatin, dexamethasone).

Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2.

To elucidate the functions of the serine/threonine kinase Akt/PKB in vivo, we generated mice lacking both akt1 and akt2 genes. Akt1/Akt2 double-knockout (DKO) mice exhibit severe growth deficiency and die shortly after birth. These mice display impaired skin development because of a proliferation defect, severe skeletal muscle atrophy because of a marked decrease in individual muscle cell size, and impaired bone development.