4 research outputs found
Role of the ENPP1 K121Q Polymorphism in Glucose Homeostasis
OBJECTIVE— To study the role of the ENPP1 Q121 variant on glucose homeostasis in whites from Italy
ENPP1 Affects Insulin Action and Secretion: Evidences from In Vitro Studies
The aim of this study was to deeper investigate the mechanisms through which
ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on
insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1
cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6
skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation
(HepG2, L6, INS1E), Akt-Ser473,
ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9
phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and
2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA
(L6), insulin secretion and caspase-3 activation (INS1E) were also investigated.
Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K
(20%, 52% and 11% reduction vs. untransfected cells) and
twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%).
Similar data were obtained with Akt-Ser473,
ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 in
HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in
untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%).
Insulin-induced glucose uptake in untransfected L6 (60% increase over
basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly
reduced in L6-K and twice as much in L6-Q (13% and 25% reduction
vs. untransfected cells). Glucose-induced insulin secretion was 60%
reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated
caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and
INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in
isolated human islets from homozygous QQ donors as compared to those from KK and
KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121
variant is operating, affects insulin signaling and glucose metabolism in
skeletal muscle- and liver-cells and both function and survival of insulin
secreting beta-cells, thus representing a strong pathogenic factor predisposing
to insulin resistance, defective insulin secretion and glucose metabolism
abnormalities
Measurement invariance of the Functional Assessment of Cancer Therapy—Colorectal quality-of-life instrument among modes of administration
Endothelial Ca2+-activated K+ channels in normal and impaired EDHF–dilator responses – relevance to cardiovascular pathologies and drug discovery
The arterial endothelium critically contributes to blood pressure control by releasing vasodilating autacoids such as nitric oxide, prostacyclin and a third factor or pathway termed ‘endothelium-derived hyperpolarizing factor’ (EDHF). The nature of EDHF and EDHF-signalling pathways is not fully understood yet. However, endothelial hyperpolarization mediated by the Ca2+-activated K+ channels (KCa) has been suggested to play a critical role in initializing EDHF–dilator responses in conduit and resistance-sized arteries of many species including humans. Endothelial KCa currents are mediated by the two KCa subtypes, intermediate-conductance KCa (KCa3.1) (also known as, a.k.a. IKCa) and small-conductance KCa type 3 (KCa2.3) (a.k.a. SKCa). In this review, we summarize current knowledge about endothelial KCa3.1 and KCa2.3 channels, their molecular and pharmacological properties and their specific roles in endothelial function and, particularly, in the EDHF–dilator response. In addition we focus on recent experimental evidences derived from KCa3.1- and/or KCa2.3-deficient mice that exhibit severe defects in EDHF signalling and elevated blood pressures, thus highlighting the importance of the KCa3.1/KCa2.3-EDHF–dilator system for blood pressure control. Moreover, we outline differential and overlapping roles of KCa3.1 and KCa2.3 for EDHF signalling as well as for nitric oxide synthesis and discuss recent evidence for a heterogeneous (sub) cellular distribution of KCa3.1 (at endothelial projections towards the smooth muscle) and KCa2.3 (at inter-endothelial borders and caveolae), which may explain their distinct roles for endothelial function. Finally, we summarize the interrelations of altered KCa3.1/KCa2.3 and EDHF system impairments with cardiovascular disease states such as hypertension, diabetes, dyslipidemia and atherosclerosis and discuss the therapeutic potential of KCa3.1/KCa2.3 openers as novel types of blood pressure-lowering drugs