Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resistin (Rstn) is known as an adipocyte-specific secretory factor that can cause insulin resistance and decrease adipocyte differentiation. Conversely, based on various studies, insulin-like growth factors (IGFs) can improve insulin resistance and stimulate adipocyte adipogenesis. Whether IGFs exert their effects through the control of Rstn's production or modulation of Rstn's action is unknown. This study was designed to examine the influence and the signaling of IGF-I on Rstn gene expression and protein secretion by 3T3-L1 adipocytes. We found that IGF-I suppressed Rstn mRNA expression and protein release in dose- and time-dependent manners. The IC50 of IGF-I was approximately 1 nM for a range of 6-10 h of treatment. Treatment with cycloheximide, but not with actinomycin D, prevented IGF-I-suppressed Rstn mRNA expression, suggesting that IGF-I destabilizes Rstn mRNA and that IGF-I's effect requires new protein, but not mRNA, synthesis. Pretreatment with IGF-I receptor (IGF-IR) antibody blocked IGF-I-altered IGF-IR activity and Rstn mRNA levels. Neither PD-98059, SB-203580, nor LY-294002 changed the IGF-I-decreased levels of Rstn mRNA, but they inhibited IGF-I-stimulated activities of MEK1, p38 MAPK, and phosphoinositide 3-kinase, respectively. However, SB-203580 antagonized the IGF-I-decreased Rstn protein release. These data demonstrate that IGF-I downregulates Rstn gene expression via IGF-IR-dependent and MEK1-, p38 MAPK-, and phosphoinositide 3-kinase-independent pathways and likely modifies the distribution of Rstn protein between the intracellular and extracellular compartments via a p38 MAPK-dependent pathway. Decreases in Rstn production and secretion induced by IGF-I may be related to the mechanism by which IGF-I modulates body weight and diabetes in animals.
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PMID:IGF-I downregulates resistin gene expression and protein secretion. 1558 89

Glucagon-like peptide 1 (GLP-1), a gut incretin hormone that stimulates insulin secretion, also activates antiapoptotic signaling pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinase in pancreatic and insulinoma cells. Since these kinases have been shown to protect against myocardial injury, we hypothesized that GLP-1 could directly protect the heart against such injury via these prosurvival signaling pathways. Both isolated perfused rat heart and whole animal models of ischemia/reperfusion were used, with infarct size measured as the end point of injury. In both studies, GLP-1 added before ischemia demonstrated a significant reduction in infarction compared with the valine pyrrolidide (an inhibitor of its breakdown) or saline groups. This protection was abolished in the in vitro hearts by the GLP-1 receptor antagonist exendin (9-39), the cAMP inhibitor Rp-cAMP, the PI3kinase inhibitor LY294002, and the p42/44 mitogen-activated protein kinase inhibitor UO126. Western blot analysis demonstrated the phosphorylation of the proapoptotic peptide BAD in the GLP-1-treated groups. We show for the first time that GLP-1 protects against myocardial infarction in the isolated and intact rat heart. This protection appears to involve activating multiple prosurvival kinases. This finding may represent a new therapeutic potential for this class of drug currently undergoing clinical trials in the treatment of type 2 diabetes.
Diabetes 2005 Jan
PMID:Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. 1561 22

Pten (phosphatase with tensin homology), a dual-specificity phosphatase, is a negative regulator of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Pten regulates a vast array of biological functions including growth, metabolism, and longevity. Although the PI3K/Akt pathway is a key determinant of the insulin-dependent increase in glucose uptake into muscle and adipose cells, the contribution of this pathway in muscle to whole-body glucose homeostasis is unclear. Here we show that muscle-specific deletion of Pten protected mice from insulin resistance and diabetes caused by high-fat feeding. Deletion of muscle Pten resulted in enhanced insulin-stimulated 2-deoxyglucose uptake and Akt phosphorylation in soleus but, surprisingly, not in extensor digitorum longus muscle compared to littermate controls upon high-fat feeding, and these mice were spared from developing hyperinsulinemia and islet hyperplasia. Muscle Pten may be a potential target for treatment or prevention of insulin resistance and diabetes.
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PMID:Muscle-specific Pten deletion protects against insulin resistance and diabetes. 1565 39

It now seems clear that aPKC (atypical protein kinase C) isoforms are required for insulin-stimulated glucose transport in muscle and adipocytes. Moreover, there are marked defects in the activation of aPKCs under a variety of insulin-resistant conditions in humans, monkeys and rodents. In humans, defects in aPKC in muscle are seen in Type II diabetes and its precursors, obesity, the obesity-associated polycystic ovary syndrome and impaired glucose tolerance. These defects in muscle aPKC activation are due to both impaired activation of insulin receptor substrate-1-dependent PI3K (phosphoinositide 3-kinase) and the direct activation of aPKCs by the lipid product of PI3K, PI-3,4,5-(PO4)3. Although it is still uncertain which underlying defect comes first, the resultant defect in aPKC activation in muscle most certainly contributes significantly to the development of skeletal muscle insulin resistance. Of further note, unlike the seemingly ubiquitous presence of defective aPKC activation in skeletal muscle in insulin-resistant states, the activation of aPKC is normal or increased in livers of Type II diabetic and obese rodents. The maintenance of aPKC activation in the liver may explain how insulin-dependent lipid synthesis is maintained in these states, as aPKCs function mainly in the activation of enzymes important for lipid synthesis. Thus increased activation of liver aPKC in hyperinsulinaemic states may contribute significantly to the development of hyperlipidaemia in insulin-resistant states.
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PMID:Atypical protein kinase C in insulin action and insulin resistance. 1578 4

An accumulating body of evidence indicates that an increased endothelin-1 level is related to endothelial dysfunction in cardiovascular diseases. In this study, we tested whether prolonged treatment of aortas with endothelin-1 induces endothelial dysfunction. When isolated aortas from control rats were cultured with endothelin-1, at levels above the plasma concentration, the acetylcholine-induced endothelium-dependent relaxation was significantly decreased (as compared with endothelin-1-nontreatment). This endothelin-1-induced endothelial dysfunction was more marked in aortas obtained from rats with streptozotocin-induced diabetes than in those from the controls. The endothelin-1- induced attenuation was very strongly suppressed by co-incubation with J-104132, endothelin receptor A/B antagonist, or polyethylene-glycolated superoxide dismutase, a cell-permeant superoxide anion scavenger or LY294002, phosphoinositide 3-kinase inhibitor. These results indicate that endothelin-1 can induce endothelial dysfunction, and that this may be related to superoxide generation and to PI3-kinase activity.
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PMID:Endothelin-1-induced impairment of endothelium-dependent relaxation in aortas isolated from controls and diabetic rats. 1583 75

The lipid products of phosphoinositide 3-kinase (PI3K) are involved in many cellular responses such as proliferation, migration, and survival. Disregulation of PI3K-activated pathways is implicated in different diseases including cancer and diabetes. Among the three classes of PI3Ks, class I is the best characterized, whereas class II has received increasing attention only recently and the precise role of these isoforms is unclear. Similarly, the role of phosphatidylinositol-3-phosphate (PtdIns-3-P) as an intracellular second messenger is only just beginning to be appreciated. Here, we show that lysophosphatidic acid (LPA) stimulates the production of PtdIns-3-P through activation of a class II PI3K (PI3K-C2beta). Both PtdIns-3-P and PI3K-C2beta are involved in LPA-mediated cell migration. This study is the first identification of PtdIns-3-P and PI3K-C2beta as downstream effectors in LPA signaling and demonstration of an intracellular role for a class II PI3K. Defining this novel PI3K-C2beta-PtdIns-3-P signaling pathway may help clarify the process of cell migration and may shed new light on PI3K-mediated intracellular events.
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PMID:Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration. 1592 2

Activated platelets participate in arterial thrombosis by forming aggregates and potentiating the coagulation through exposure of procoagulant phosphatidylserine. The function of the two receptors for ADP, P2Y(1) and P2Y(12), is well-established in aggregation, but is incompletely understood in the platelet procoagulant response. We established that, in PRP from healthy subjects, ADP accelerated and potentiated tissue factor induced thrombin generation exclusively via stimulation of P2Y(12) and not via P2Y(1) receptors. The P2Y(12) receptors also mediated the potentiating effect of PAR-1 stimulation on thrombin generation. Furthermore, ADP enhanced in a P2Y(12)-dependent manner the Ca(2+) response induced by thrombin, which was either added externally or generated in-situ. This ADP effect was in part dependent of phosphoinositide 3-kinase and was paralleled by increased phosphatidylserine exposure. In PRP from (young) patients with either stroke or type-II diabetes, platelet-dependent thrombin generation was similarly enhanced byADP or SFLLRN as in healthy subjects. In PRP from stroke patients of older age, the P2Y(12)-mediated contribution to thrombin generation was variably reduced by two weeks of clopidogrel medication. Remaining P2Y(12) activity after medication correlated with remaining P2Y(12)-dependent P-selectin exposure, i.e. Ca(2+)-dependent secretion, likely due to incomplete antagonism of P2Y(12) receptors. Together, these results indicate that physiological platelet agonists amplify phosphatidylserine exposure and subsequent thrombin generation by release of ADP and P2Y(12)-receptor stimulation. This P2Y(12) response is accomplished by a novel Ca(2+) signalling pathway. It is similarly active in platelets from control subjects and patients at thrombotic risk. Finally, the thrombogram method is useful for measuring incomplete P2Y(12) inhibition with clopidogrel.
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PMID:Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk. 1596 99

To examine the molecular mechanisms by which plasma amino acid elevation impairs insulin action, we studied seven healthy men twice in random order during infusion of an amino acid mixture or saline (total plasma amino acid approximately 6 vs. approximately 2 mmol/l). Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia ( approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia ( approximately 430 pmol/l, 180-360 min). At low peripheral hyperinsulinemia, endogenous glucose production (EGP) did not change during amino acid infusion but decreased by approximately 70% during saline infusion (EGP(150-180 min) 11 +/- 1 vs. 3 +/- 1 mumol . kg(-1) . min(-1), P = 0.001). Prandial-like peripheral hyperinsulinemia completely suppressed EGP during both protocols, whereas whole-body rate of glucose disappearance (R(d)) was approximately 33% lower during amino acid infusion (R(d) (330-360 min) 50 +/- 4 vs. 75 +/- 6 mumol . kg(-1) . min(-1), P = 0.002) indicating insulin resistance. In skeletal muscle biopsies taken before and after prandial-like peripheral hyperinsulinemia, plasma amino acid elevation markedly increased the ability of insulin to activate S6 kinase 1 compared with saline infusion ( approximately 3.7- vs. approximately 1.9-fold over baseline). Furthermore, amino acid infusion increased the inhibitory insulin receptor substrate-1 phosphorylation at Ser312 and Ser636/639 and decreased insulin-induced phosphoinositide 3-kinase activity. However, plasma amino acid elevation failed to reduce insulin-induced Akt/protein kinase B and glycogen synthase kinase 3alpha phosphorylation. In conclusion, amino acids impair 1) insulin-mediated suppression of glucose production and 2) insulin-stimulated glucose disposal in skeletal muscle. Our results suggest that overactivation of the mammalian target of rapamycin/S6 kinase 1 pathway and inhibitory serine phosphorylation of insulin receptor substrate-1 underlie the impairment of insulin action in amino acid-infused humans.
Diabetes 2005 Sep
PMID:Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. 1612 57

Insulin and cholesterol play important roles in basic metabolic processes in peripheral tissues. Both insulin and cholesterol can also act as signalling molecules in the central nervous system that participate in neuronal function, memory and neurodegenerative diseases. A high-cholesterol diet improves spatial memory in experimental animals. beta-Amyloid, the toxic peptide in neurons of AD (Alzheimer's disease) patients, binds cholesterol and catalyses its oxidation to 7beta-hydroxycholesterol, a highly toxic oxysterol that is a potent inhibitor of alpha-PKC (alpha-protein kinase C), an enzyme critical in memory consolidation and synaptic plasticity and implicated in AD. Oxidized cholesterol also can act as a second messenger for insulin. Oxidized low-density lipoprotein inhibits insulin-dependent phosphorylation of the signalling kinases ERK (extracellular-signal-regulated kinase) and PKB/Akt. In sporadic AD patients, insulin levels are decreased, suggesting links between AD and diabetes. Insulin signalling is also important in synaptic plasticity. Insulin receptors are up-regulated and undergo translocation after spatial learning. Insulin modulates the activity of excitatory and inhibitory receptors including the glutamate and gamma-aminobutyric acid receptors and activates two biochemical pathways: the shc-ras-mitogen-activated protein kinase pathway and the PI3K (phosphoinositide 3-kinase)/PKC pathway, both of which are involved in memory processing. These findings point to a convergence at the biochemical level between pathways involved in AD and those important for normal memory.
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PMID:Insulin and cholesterol pathways in neuronal function, memory and neurodegeneration. 1624 39

Proliferation is the major component for maintenance of beta-cell mass in adult animals. Activation of phosphoinositide 3-kinase/Akt-kinase pathway is a critical regulator of beta-cell mass. Pancreatic beta-cell overexpression of constitutively active Akt in mice (caAkt(Tg)) resulted in marked expansion of beta-cell mass by increase in beta-cell proliferation and size. The current studies provide new insights into the molecular mechanisms involved in beta-cell proliferation by Akt. Proliferation of beta-cells in caAkt(Tg) was associated with increased cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 (cdk4) activity. To determine the role of cdk4 in beta-cell proliferation induced by Akt, we generated caAkt(Tg) mice that were homozygous, heterozygous, or nullizygous for cdk4. The results of these studies showed that deletion of one cdk4 allele significantly reduced beta-cell expansion in caAkt(Tg) mice by decreased proliferation. CaAkt(Tg) mice deficient in cdk4 developed beta-cell failure and diabetes. These experiments suggest that Akt induces beta-cell proliferation in a cdk4-dependent manner by regulation of cyclin D1, cyclin D2, and p21 levels. These data also indicate that alteration in levels of these cell cycle components could affect the maintenance of beta-cell mass in basal states and the adaptation of beta-cells to pathological states resulting in diabetes.
Diabetes 2006 Feb
PMID:Akt induces beta-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity. 1644 63


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