scholarly journals Pathological Hyperinsulinemia and Hyperglycemia in the Impaired Glucose Tolerance Stage Mediate Endothelial Dysfunction Through miR-21, PTEN/AKT/eNOS, and MARK/ET-1 Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Ran Liu ◽  
Shilin Guan ◽  
Zhongai Gao ◽  
Jingyu Wang ◽  
Jie Xu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Relative Concentration ◽  
Inhibitory Effect ◽  
Glomerular Endothelial Cells ◽  
High Insulin ◽  
The Individual

BackgroundImpaired glucose tolerance (IGT) is an important prediabetic stage characterized by elevated concentrations of glucose and insulin in the blood. The pathological hyperglycemia and hyperinsulinemia in IGT may regulate the expression of microRNA-21 (miR-21) and affect the downstream insulin signaling pathways, leading to endothelial cell dysfunction and early renal damage.MethodsThe individual and combined effects of insulin and glucose were investigated using human glomerular endothelial cells (HGECs). The expression levels of miR-21, and PTEN/AKT/eNOS and MAPK/ET-1 pathway proteins in the treated cells were measured. The levels of nitric oxide (NO) and endothelin-1 (ET-1) secreted by the cells were also measured. The role of miR-21 in mediating the regulatory effects of insulin and glucose was assessed by overexpression/inhibition of this miRNA using mimics/inhibitor.ResultsHigh (>16.7 mmol/L) concentration of glucose upregulated the expression of miR-21, leading to the activation and inhibition of the PTEN/AKT/eNOS and MAPK/ET-1 pathways, and upregulation of NO and downregulation of ET-1 secretion, respectively. High (>25 ng/mL) concentration of insulin downregulated the expression of miR-21, and lead to the activation of the MAPK/ET-1 and inhibition of the PTEN/AKT/eNOS pathway, thereby upregulating the expression of ET-1 and downregulating the secretion of NO. MiR-21 was observed to play a key role by directly controlling the activation of the insulin signaling pathways when the cells were cotreated with different concentrations of insulin and glucose. The expression of miR-21 was found to be dependent on the relative concentration of insulin and glucose. Under simulated conditions of the IGT stage (8.3 mmol/L glucose + 50 ng/mL insulin), the inhibitory effect of high insulin concentration on miR-21 expression in the cells attenuated the activation by high glucose concentration, resulting in the downregulation of miR-21, upregulation of ET-1 and downregulation of NO secretion.ConclusionTaken together, these results indicate that high insulin and glucose concentrations regulate the secretory function of glomerular endothelial cells in opposite ways by regulating the expression of miRNA-21. Pathological concentrations of insulin and glucose in the IGT stage may lead to a decrease in miR-21 expression, thereby disordering the secretion of vasoactive factors, resulting in renal tubule ischemia.

ATP stimulates Ca2+ mobilization by a nucleotide receptor in glomerular endothelial cells

1994 ◽  
Vol 266 (2) ◽  
pp. F210-F217 ◽  
Author(s):  
V. A. Briner ◽  
F. Kern
Keyword(s):  
Endothelial Cells ◽  
Receptor Agonist ◽  
Rank Order ◽  
P2y Receptors ◽  
Inhibitory Effect ◽  
P2x Receptor ◽  
Dependent Manner ◽  
Nucleotide Receptor ◽  
Pyrimidine Nucleotide ◽  
Glomerular Endothelial Cells

The present study investigates ATP effects on Ca2+ mobilization in bovine glomerular endothelial cells (GEC) and the receptors mediating ATP response. Extracellular ATP stimulated a rise in inositol 1,4,5-trisphosphate and cytosolic free Ca2+ concentration ([Ca2+]i) in a dose-dependent manner. Extracellular Ca2+ depletion did not prevent [Ca2+]i rise. ATP effects were not mediated by P1, P2x, and P2t purinoceptors, since the P1 receptor agonist adenosine and the P2x receptor agonist [alpha,beta-CH2]ATP had no effect on inositol 1-monophosphate (IP) formation and Ca2+ mobilization and ATP does not activate P2t receptors. The P2y receptor antagonist reactive blue (10(-3) M) had little inhibitory effect on ATP (10(-5) M)-stimulated IP formation (15.6 +/- 4.2%) and Ca2+ rise (7.0 +/- 3.0%). According to the classification of purinoceptors, ATP is less potent than 2-methylthioadenosine 5'-triphosphate (2-MeS-ATP) in stimulating P2y receptors. In GEC, however, the rank order of potency in stimulating IP and [Ca2+]i rise was ATP > 2-MeS-ATP > ADP. The pyrimidine nucleotide UTP (10(-3) M) induced maximal IP formation (653 +/- 37%) and Ca2+ mobilization (591 +/- 22 nM) similar to ATP (IP 647 +/- 27%; [Ca2+]i 583 +/- 15 nM). At submaximal (10(-5) M) but not at maximal (10(-3) M) doses ATP and UTP effects were additive. ATP and UTP induced specific cross-desensitization. It is concluded that the purinergic nucleotide ATP and pyrimidine nucleotide UTP mediate their effects by a common nucleotide receptor. This receptor differs from P2z and P2y1 receptors, since by definition UTP does not activate these receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Intrauterine Growth Restriction Increases TNFαand Activates the Unfolded Protein Response in Male Rat Pups

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Emily S. Riddle ◽  
Michael S. Campbell ◽  
Brook Y. Lang ◽  
Ryann Bierer ◽  
Yan Wang ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Insulin Signaling ◽  
Intrauterine Growth Restriction ◽  
Male Rat ◽  
Intrauterine Growth ◽  
Unfolded Protein ◽  
Rat Pups ◽  
The Unfolded Protein Response ◽  
Protein Response

Intrauterine growth restriction (IUGR) programs adult disease, including obesity and insulin resistance. Our group previously demonstrated that IUGR dysregulates adipose deposition in male, but not female, weanling rats. Dysregulated adipose deposition is often accompanied by the release of proinflammatory signaling molecules, such as tumor necrosis factor alpha (TNFα). TNFαcontributes to adipocyte inflammation and impaired insulin signaling. TNFαhas also been implicated in the activation of the unfolded protein response (UPR), which impairs insulin signaling. We hypothesized that, in male rat pups, IUGR would increase TNFα, TNFR1, and components of the UPR (Hspa5, ATF6, p-eIF2α, and Ddit3) prior to the onset of obesity. We further hypothesized that impaired glucose tolerance would occur after the onset of adipose dysfunction in male IUGR rats. To test this hypothesis, we used a well-characterized rat model of uteroplacental insufficiency-induced IUGR. Our primary findings are that, in male rats, IUGR (1) increased circulating and adipose TNFα, (2) increased mRNA levels of UPR components as well as p-eIF2a, and (3) impaired glucose tolerance after observed TNFαincreased and after UPR activation. We speculate that programmed dysregulation of TNFαand UPR contributed to the development of glucose intolerance in male IUGR rats.

scholarly journals Evaluation of a Standardized Extract fromMorus albaagainstα-Glucosidase Inhibitory Effect and Postprandial Antihyperglycemic in Patients with Impaired Glucose Tolerance: A Randomized Double-Blind Clinical Trial

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Seung Hwan Hwang ◽  
Hong Mei Li ◽  
Soon Sung Lim ◽  
Zhiqiang Wang ◽  
Jae-Seung Hong ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Clinical Signs ◽  
Inhibitory Effect ◽  
Postprandial Hyperglycemia ◽  
Dependent Manner ◽  
Double Blind ◽  
Double Blind Clinical Trial

To evaluate the antihyperglycemic effect of a standardized extract of the leaves ofMorus alba(SEMA), the present study was designed to investigate theα-glucosidase inhibitory effect and acute single oral toxicity as well as evaluate blood glucose reduction in animals and in patients with impaired glucose tolerance in a randomized double-blind clinical trial. SEMA was found to inhibitα-glucosidase at a fourfold higher level than the positive control (acarbose), in a concentration-dependent manner. Moreover, blood glucose concentration was suppressed by SEMAin vivo. Clinical signs and weight changes were observed when conducting an evaluation of the acute toxicity of SEMA through a single-time administration, with clinical observation conducted more than once each day. After administration of the SEMA, observation was for 14 days; all of the animals did not die and did not show any abnormal symptoms. In addition, the inhibitory effects of rice coated with SEMA were evaluated in a group of impaired glucose tolerance patients on postprandial glucose and a group of normal persons, and results showed that SEMA had a clear inhibitory effect on postprandial hyperglycemia in both groups. Overall, SEMA showed excellent potential in the present study as a material for improving postprandial hyperglycemia.

scholarly journals Roles for Insulin Receptor, PI3-Kinase, andAktin Insulin-Signaling Pathways Related to Production of Nitric Oxide in Human Vascular Endothelial Cells

Circulation ◽  
2000 ◽  
Vol 101 (13) ◽  
pp. 1539-1545 ◽  
Author(s):  
Guangyuan Zeng ◽  
Frederick H. Nystrom ◽  
Lingamanaidu V. Ravichandran ◽  
Li-Na Cong ◽  
Martha Kirby ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Insulin Receptor ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Vascular Endothelial Cells ◽  
Pi3 Kinase ◽  
Vascular Endothelial

scholarly journals Diet-induced impaired glucose tolerance and gestational diabetes in the dog

2011 ◽  
Vol 110 (2) ◽  
pp. 458-467 ◽  
Author(s):  
Mary Courtney Moore ◽  
Renuka Menon ◽  
Katie C. Coate ◽  
Maureen Gannon ◽  
Marta S. Smith ◽  
...  
Keyword(s):  
Gestational Diabetes ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Late Pregnancy ◽  
Canine Model ◽  
Tolerance Test ◽  
Oral Glucose ◽  
High Insulin ◽  
Gestational Week ◽  
Glucose Output

Glucose metabolism was compared in dogs consuming a chow/meat diet throughout pregnancy (P group, n = 6) and dogs switched to a high-fat/high-fructose (HFF) diet during the 4th–5th gestational week (gestation ≃9 wk; P-HFF group; n = 6). An oral glucose tolerance test (OGTT; 0.9 g/kg) was administered in the 6th–7th gestational week, and a hyperinsulinemic [0–120 min: 1.8 pmol·kg−1·min−1 (low insulin); 120–240 min: 9 pmol·kg−1·min−1 (high insulin)] euglycemic clamp was performed the following week. Nonpregnant (NP) female dogs underwent OGTTs but not clamp studies. All P-HFF dogs exhibited impaired glucose tolerance (IGT) or gestational diabetes (GDM), but only one P dog had IGT. Insulin concentrations in P and P-HFF dogs were significantly lower than in NP dogs 30 and 60 min after the OGTT. Therefore, mean islet size and area were evaluated in P and NP dogs. These values did not differ between groups, and proliferating endocrine cells were rare in pregnancy. During exposure to high insulin, glucose infusion rate and hindlimb glucose uptake were ∼30% greater ( P < 0.05) and net hepatic glucose output was more suppressed (−5.5 ± 6.1 vs. 7.8 ± 2.8 mg·100 g liver−1·min−1, P < 0.05) in P than in P-HFF dogs. In conclusion, in the 2nd trimester the canine pancreas does not exhibit islet hypertrophy, hyperplasia, or neogenesis. Combined with the lack of pancreatic adaptation, a HFF diet during late pregnancy produces a canine model of IGT and GDM without hyperinsulinemia but exhibiting liver and muscle insulin resistance.

Classical PKC is not associated with defective insulin signaling in patients with impaired glucose tolerance

2009 ◽  
Vol 83 (3) ◽  
pp. 334-340 ◽  
Author(s):  
Do Min Kim ◽  
Hyun Ju Jang ◽  
Seung Jin Han ◽  
Eun Suk Ha ◽  
Yun Kyung Kim ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Insulin Signaling
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