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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 diabetes is caused by a combination of impaired insulin secretion and, to a greater extent, resistance of target tissues to insulin action. Phosphoinositide 3-kinase (PI3K) plays a key role in insulin signaling and has been shown to be blunted in tissues of type 2 diabetes subjects. There is emerging biochemical and, particularly, genetic evidence suggesting that insulin resistance can potentially be treated via modulation of PI3K by targeting PI3K itself or its up and down-stream modulators. These potential targets include Src homology 2 domain containing inositol 5-phosphatase 2 (SHIP2), phosphatase and tensin homolog deleted on chromosome ten (PTEN), kappaB kinase beta (IKKbeta), PKC isoforms, and the PI3K p85 subunit. There is evidence suggesting that their inhibition affects PI3K activity and improves insulin sensitivity in vivo. In the current review, we will discuss the role of these molecules in insulin-mediated activation of PI3K, the rational for targeting these molecules for diabetes treatment, and some critical issues in terms of drug development.
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PMID:Pi 3-kinase and its up- and down-stream modulators as potential targets for the treatment of type II diabetes. 1189 56

Phosphoinositides (PIs) play an essential role in diverse cellular functions. Their intracellular level is strictly regulated by specific PI kinases, phosphatases and phospholipases. Recent discoveries indicate that dysfunctions in the control of their level often lead to pathologies. This review will focus on some human diseases whose etiologies involve PI-metabolizing enzymes. The role of PTEN (phosphatase and tensin homolog deleted on chromosome ten) in cancer, the impact of the Src homology 2-containing inositol-5-phosphatase phosphatases in acute myeloid leukemia or diabetes, the involvement of myotubularin family members in genetic diseases and the implication of OCRL1 in Lowe syndrome will be emphasized. We will also review how some bacterial pathogens have evolved strategies to specifically manipulate the host cell PI metabolism to efficiently infect them.
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PMID:Phosphoinositide signaling disorders in human diseases. 1282 32

Vascular insufficiency and retinal ischemia precede many proliferative retinopathies and stimulate secretion of various vasoactive growth factors, including vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). It is unclear, however, how PlGF, which is elevated in proliferative diabetic retinopathy and is a VEGF homolog that binds only to VEGF receptor (VEGFR)-1, promotes pathological angiogenesis. When primary microvascular endothelial cells were grown on collagen gels, PlGF-containing ligands upregulated Bcl-2 expression and stimulated the formation of capillary-like tube networks that were retained for up to 14 days in culture. The inhibition of VEGFR-1 results in a dramatic decrease in the number of capillary connections, indicating that VEGFR-1 ligands promote branching angiogenesis. In contrast, VEGF-induced tube formations and Bcl-2 expression were significantly decreased at the end of this period. Flow cytometry analysis of annexin-V/propidium iodide-stained cells revealed that PlGF and PlGF/VEGF heterodimer inhibited apoptosis in serum-deprived endothelial cells. These two growth factors stimulated a survival signaling pathway phosphatidylinositol 3-kinase (PI3K), as identified by increased Akt phosphorylation and because blocking PI3K signalling by adenovirus-mediated overexpression of wild-type phosphatase and tensin homolog on chromosome 10 (PTEN) disrupted angiogenesis and decreased Bcl-2 expression by PlGF and PlGF/VEGF heterodimer, whereas a dominant-negative PTEN mutant enhanced endothelial sprout formation and Bcl-2 expression. Together, these findings indicate that PlGF-containing ligands contribute to pathological angiogenesis by prolonging cell survival signals and maintaining vascular networks.
Diabetes 2003 Dec
PMID:Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells. 1463 57

Phosphatidyl inositol 3-kinase (PI3-kinase) functions as a lipid kinase to produce PI(3,4,5)P(3) from PI(4,5)P(2) in vivo. PI(3,4,5)P(3) is crucial as a lipid second messenger in various metabolic effects of insulin. Lipid phosphatases, src homology 2 domain containing inositol 5'-phosphatase 2 (SHIP2) and skeletal muscle and kidney-enriched inositol phosphatase (SKIP) hydrolyze PI(3,4,5)P(3) to PI(3,4)P(2) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) hydrolyzes PI(3,4,5)P(3) to PI(4,5)P(2). SHIP2 negatively regulates insulin signaling relatively specifically via its 5'-phosphatase activity. Targeted disruption of the SHIP2 gene in mice resulted in increased insulin sensitivity and conferred protection from obesity induced by a high-fat diet. Polymorphisms in the human SHIP2 gene are associated, at least in part, with the insulin resistance of type 2 diabetes. Importantly, inhibition of endogenous SHIP2 through the liver-specific expression of a dominant-negative SHIP2 improves glucose metabolism and insulin resistance in diabetic db/db mice. Overexpression of PTEN and SKIP also inhibited insulin-induced phosphorylation of Akt and the uptake of glucose in cultured cells. Although a homozygous disruption of the PTEN gene in mice results in embryonic lethality, either skeletal muscle or adipose tissue-specific disruption of PTEN ameliorated glucose metabolism without formation of tumors in animal models of diabetes. The role of SKIP in glucose metabolism remains to be further clarified in vivo. Taken together, inhibition of endogenous SHIP2 in the whole body appears to be effective at improving the insulin resistance associated with type 2 diabetes and/or obesity. Inhibition of PTEN in the tissues specifically targeted, including skeletal muscle and fat, may result in an amelioration of insulin resistance in type 2 diabetes, although caution against the formation of tumors is needed.
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PMID:Lipid phosphatases as a possible therapeutic target in cases of type 2 diabetes and obesity. 1684 57

In metabolic syndrome, a systemic deregulation of the insulin pathway leads to a combined deregulation of insulin-regulated metabolism and cardiovascular functions. Free fatty acids (FFAs), which are increased in metabolic syndrome, inhibit insulin signaling and induce metabolic insulin resistance. This study was designed to examine FFAs' effects on vascular insulin signaling and endothelial nitric oxide (NO) synthase (eNOS) activation in endothelial cells. We showed that FFAs inhibited insulin signaling and eNOS activation through different mechanisms. While linoleic acid inhibited Akt-mediated eNOS phosphorylation, palmitic acid appeared to affect the upstream signaling. Upregulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) activity and transcription by palmitic acid mediated the inhibitory effects on insulin signaling. We further found that activated stress signaling p38, but not Jun NH(2)-terminal kinase, was involved in PTEN upregulation. The p38 target transcriptional factor activating transcription factor (ATF)-2 bound to the PTEN promoter, which was increased by palmitic acid treatment. In summary, both palmitic acid and linoleic acid exert inhibitory effect on insulin signaling and eNOS activation in endothelial cells. Palmitic acid inhibits insulin signaling by promoting PTEN activity and its transcription through p38 and its downstream transcription factor ATF-2. Our findings suggest that FFA-mediated inhibition of vascular insulin signaling and eNOS activation may contribute to cardiovascular diseases in metabolic syndrome.
Diabetes 2006 Aug
PMID:Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. 1687 94

Adverse events during pregnancy, including prenatal ethanol (EtOH) exposure, are associated with insulin-resistant diabetes in male rat offspring, but it is unclear whether this is true for female offspring. We investigated whether prenatal EtOH exposure alters glucose metabolism in adult female rat offspring and whether this is associated with reduced in vivo insulin signaling in skeletal muscle. Female Sprague-Dawley rats were given EtOH, 4 g.kg(-1).day(-1) by gavage throughout pregnancy. Glucose tolerance test and hyperinsulinemic euglycemic clamp were performed, and insulin signaling was investigated in skeletal muscle, in adult female offspring. We gave insulin intravenously to these rats and determined the association of glucose transporter-4 with plasma membranes, as well as the phosphorylation of phosphoinositide-dependent protein kinase-1 (PDK1), Akt, and PKCzeta. Although EtOH offspring had normal birth weight, they were overweight as adults and had fasting hyperglycemia, hyperinsulinemia, and reduced insulin-stimulated glucose uptake. After insulin treatment, EtOH-exposed rats had decreased membrane glucose transporter-4, PDK1, Akt, and PKCzeta in the gastrocnemius muscle, compared with control rats. Insulin stimulation of PDK1, Akt, and PKCzeta phosphorylation was also reduced. In addition, the expression of the protein tribbles-3 and the phosphatase enzyme activity of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which prevent Akt activation, were increased in muscle from EtOH-exposed rats. Female rat offspring exposed to EtOH in utero develop insulin-resistant diabetes in association with excessive PTEN and tribbles-3 signaling downstream of the phosphatidylinositol 3-kinase pathway in skeletal muscle, which may be a mechanism for the abnormal glucose tolerance.
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PMID:Abnormal glucose homeostasis in adult female rat offspring after intrauterine ethanol exposure. 1721 36

Free fatty acid (FFA) is believed to be a major environmental factor linking obesity to Type II diabetes. We have recently reported that FFA can induce gluconeogenesis in hepatocytes through p38 mitogen-activated protein kinase (p38). In this study, we have investigated the role of p38 in oleate-induced hepatic insulin resistance. Our results show that a prolonged treatment of primary hepatocytes with oleate blunted insulin suppression of hepatic gluconeogenesis, and decreased insulin-induced phosphorylation of Akt in a p38-dependent manner. Reduction of the insulin-induced Akt phosphorylation by oleate correlated with activation of p38. In the presence of p38 inhibition, prolonged exposure of hepatocytes to oleate failed to reduce insulin-stimulated phosphorylation of Akt. An siRNA against p38alpha prevented oleate suppression of the insulin-induced phosphorylation of Akt. Furthermore, a prolonged exposure of hepatocytes to oleate decreased insulin-induced tyrosine phosphorylation of IRS1/2, while slightly increasing serine phosphorylation of IRS. The decrease of insulin-stimulated tyrosine phosphorylation of IRS1/2 in hepatocytes by oleate was reversed by the inhibition of p38. We further show that a prolonged exposure of primary hepatocytes to oleate elevated the protein level of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in a p38-dependent manner, but had no effect on the mRNA level of PTEN. Knocking down the PTEN gene prevented oleate to inhibit insulin activation of Akt and insulin suppression of gluconeogenesis. Together, results from this study demonstrate a critical role for p38 in oleate-induced hepatic insulin resistance.
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PMID:Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase. 1738 40

Phosphoinositide phosphatases dephosphorylate the three positions (D-3, 4 and 5) of the inositol ring of the poly-phosphoinositides. They belong to different families of enzymes. The PtdIns(3,4)P(2) 4-phosphatase family, the tumour suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN), SAC1 domain phosphatases and myotubularins belong to the tyrosine protein phosphatases superfamily. They share the presence of a conserved cysteine residue in the consensus CX(5)RT/S. Another family consists of the inositol polyphosphate 5-phosphatase isoenzymes. The importance of these phosphoinositide phosphatases in cell regulation is illustrated by multiple examples of their implications in human diseases such as Lowe syndrome, X-linked myotubular myopathy, cancer, diabetes or bacterial infection.
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PMID:Phosphoinositide phosphatases in a network of signalling reactions. 1760 38

We investigated the effects of chronic simvastatin treatment on the impaired endothelium-dependent relaxation seen in aortas from type 2 diabetic mice. Starting at 8 weeks of diabetes, simvastatin (10 mg/kg per day) was administered to diabetic mice for 4 weeks. The significantly elevated systolic blood pressure in diabetic mice was normalized by simvastatin. Aortas from diabetic mice, but not those from simvastatin-treated diabetic mice, showed impaired endothelium-dependent relaxation in response to both clonidine and adrenomedullin. After preincubation with an Akt inhibitor, these relaxations were not significantly different among the three Akt inhibitor-treated groups (controls, diabetics, and simvastatin-treated diabetics). Although clonidine-induced NO(x)(-) (NO(2)(-) + NO(3)(-)) production was greatly attenuated in our diabetic model, it was normalized by simvastatin treatment. The expression levels of both total Akt protein and clonidine-induced Ser-473-phosphorylated Akt were significantly decreased in diabetic aortas, while chronic simvastatin administration improved these decreased levels. The expression level of clonidine-induced phosphorylated PTEN (phosphatase and tensin homolog deleted on chromosome ten) was significantly increased in diabetic aortas, but chronic simvastatin did not affect it. These results strongly suggest that simvastatin improves the endothelial dysfunction seen in type 2 diabetic mice via increases in Akt and Akt phosphorylation.
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PMID:Possible involvement of Akt activity in endothelial dysfunction in type 2 diabetic mice. 1839 84

The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt axis is a key signal transduction node that regulates crucial cellular functions, including insulin and other growth factors signaling, lipid and glucose metabolism, as well as cell survival and apoptosis. In this pathway, PTEN acts as a phosphoinositide phosphatase, which terminates PI3K-propagated signaling by dephosphorylating PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3). However, the role of PTEN does not appear to be restricted only to PI3K signaling antagonism, and new functions have been recently discovered for this protein. In addition to the well-established role of PTEN as a tumor suppressor, increasing evidence now suggests that a dysregulated PTEN expression and/or activity is also linked to the development of several hepatic pathologies. Dysregulated PTEN expression/activity is observed with obesity, insulin resistance, diabetes, hepatitis B virus/hepatitis C virus infections, and abusive alcohol consumption, whereas mutations/deletions have also been associated with the occurrence of hepatocellular carcinoma. Thus, it appears that alterations of PTEN expression and activity in hepatocytes are common and recurrent molecular events associated with liver disorders of various etiologies. These recent findings suggest that PTEN might represent a potential common therapeutic target for a number of liver pathologies.
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PMID:PTEN in liver diseases and cancer. 2087 61


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