scholarly journals Direct Effects of D-Chiro-Inositol on Insulin Signaling and Glucagon Secretion of Pancreatic Alpha Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1404
Author(s):  
Agnese Filippello ◽  
Alessandra Scamporrino ◽  
Stefania Di Mauro ◽  
Roberta Malaguarnera ◽  
Antonino Di Pino ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Glucagon Secretion ◽  
Diabetes Treatment ◽  
Pancreatic Alpha Cells ◽  
Induce Insulin Resistance ◽  
Patients With Diabetes ◽  
Resistance State ◽  
Type 2 Diabetes Treatment

The insulin resistance state of pancreatic α-cells seems to be related to glucagon hypersecretion in type 2 diabetes. Treatment that can improve the insulin sensitivity of α-cells could control glucagon levels in patients with diabetes mellitus. The aim of this study was to investigate the preventive role of D-chiro-inositol (DCI), which has insulin receptor-sensitizer effects on insulin signaling pathways and glucagon secretion in pancreatic α-TC1 clone 6 cells. Cells were chronically treated with palmitate to induce insulin resistance in the presence/absence of DCI. DCI treatment improved the insulin signaling pathway and restored insulin-mediated glucagon suppression in α-TC1-6 cells exposed to palmitate. These results indicate that DCI treatment prevents the insulin resistance of α-TC1-6 cells chronically exposed to palmitate. Our data provide evidence that DCI could be useful to improve the insulin sensitivity of pancreatic α-cells in diabetes treatment.

scholarly journals The Impact of Differentiation on Cytotoxicity and Insulin Sensitivity in Streptozotocin Treated SH-SY5Y Cells

2021 ◽  
Vol 46 (6) ◽  
pp. 1350-1358
Author(s):  
Fruzsina Bagaméry ◽  
Kamilla Varga ◽  
Kitti Kecsmár ◽  
István Vincze ◽  
Éva Szökő ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Insulin Metabolism ◽  
Relative Significance ◽  
Differentiated Cells ◽  
Mature Neuron ◽  
The Right ◽  
The Impact

AbstractRecently neuronal insulin resistance was suggested playing a role in Alzheimer’s disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration–response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.

scholarly journals Age and tissue specific differences in the development of acute insulin resistance following injury

2009 ◽  
Vol 203 (3) ◽  
pp. 365-374 ◽  
Author(s):  
Lidong Zhai ◽  
Joseph L Messina
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Signaling ◽  
Intracellular Signaling ◽  
Male Rats ◽  
Hepatic Insulin Resistance ◽  
Surgical Trauma ◽  
Induce Insulin Resistance ◽  
Old Rats ◽  
Effect Of Age

Injuries, hemorrhage, sepsis, burn, and critical illnesses all induce insulin resistance, and insulin resistance is strongly associated with advancing age. However, the effect of age on injury induced insulin resistance is not well studied. We performed surgical trauma in male rats of three different ages (3-, 6-, and 10-weeks old). Rats were either hemorrhaged to a mean arterial pressure of 35–40 mmHg and subsequently maintained at that pressure for up to 90 min, or maintained without hemorrhage as controls. Results indicate that insulin-induced intracellular signaling was diminished in liver and skeletal muscle of 6- and 10-week old rats following trauma and hemorrhage. In even younger rats, immediately post-weaning (∼3 weeks of age), insulin signaling was lost in liver, but not in skeletal muscle. Glucocorticoids can play a role in the chronic development of insulin resistance. Our results demonstrate that corticosterone levels were increased in 6- and 10-week old animals following hemorrhage, but little change was measured in 3-week old animals. Blockade of glucocorticoid synthesis prevented the development of insulin resistance in skeletal muscle, but not in liver of 6- and 10-week old rats. Moreover, skeletal muscle glucocorticoid receptor levels increased dramatically between 3 and 6 weeks of age. These results indicate that trauma and hemorrhage-induced hepatic insulin resistance occurs at all ages tested. However, there is no development of insulin resistance following trauma and hemorrhage in skeletal muscle of post-weaning rats. In skeletal muscle of 6- and 10-week old rats, inhibition of glucocorticoid levels prevents the development of insulin resistance.

scholarly journals PGRN Induces Impaired Insulin Sensitivity and Defective Autophagy in Hepatic Insulin Resistance

2015 ◽  
Vol 29 (4) ◽  
pp. 528-541 ◽  
Author(s):  
Jiali Liu ◽  
Huixia Li ◽  
Bo Zhou ◽  
Lin Xu ◽  
Xiaomin Kang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Nuclear Factor Κb ◽  
Hepatic Insulin Resistance ◽  
Causative Role ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Impaired Insulin

Abstract Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.

scholarly journals Comprehensive functional screening of miRNAs involved in fat cell insulin sensitivity among women

2017 ◽  
Vol 312 (6) ◽  
pp. E482-E494 ◽  
Author(s):  
Ingrid Dahlman ◽  
Yasmina Belarbi ◽  
Jurga Laurencikiene ◽  
Annie M. Pettersson ◽  
Peter Arner ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Differential Expression ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Functional Screening ◽  
Fat Cell ◽  
Subcutaneous White Adipose Tissue ◽  
Micro Rnas

The key pathological link between obesity and type 2 diabetes is insulin resistance, but the molecular mechanisms are not entirely identified. micro-RNAs (miRNA) are dysregulated in obesity and may contribute to insulin resistance. Our objective was to detect and functionally investigate miRNAs linked to insulin sensitivity in human subcutaneous white adipose tissue (scWAT). Subjects were selected based on the insulin-stimulated lipogenesis response of subcutaneous adipocytes. Global miRNA profiling was performed in abdominal scWAT of 18 obese insulin-resistance (OIR), 21 obese insulin-sensitive (OIS), and 9 lean women. miRNAs demonstrating differential expression between OIR and OIS women were overexpressed in human in vitro-differentiated adipocytes followed by assessment of lipogenesis and identification of miRNA targets by measuring mRNA/protein expression and 3′-untranslated region analysis. Eleven miRNAs displayed differential expression between OIR and OIS states. Overexpression of miR-143-3p and miR-652-3p increased insulin-stimulated lipogenesis in human in vitro differentiated adipocytes and directly or indirectly affected several genes/proteins involved in insulin signaling at transcriptional or posttranscriptional levels. Adipose expression of miR-143-3p and miR-652-3p was positively associated with insulin-stimulated lipogenesis in scWAT independent of body mass index. In conclusion, miR-143-3p and miR-652-3p are linked to scWAT insulin resistance independent of obesity and influence insulin-stimulated lipogenesis by interacting at different steps with insulin-signaling pathways.

scholarly journals Probiotics, prebiotics, synbiotics and insulin sensitivity

2017 ◽  
Vol 31 (1) ◽  
pp. 35-51 ◽  
Author(s):  
Y. A. Kim ◽  
J. B. Keogh ◽  
P. M. Clifton
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Intestinal Permeability ◽  
Peptide Yy ◽  
Glucagon Secretion ◽  
Energy Harvest ◽  
Improve Insulin Sensitivity

AbstractAnimal studies indicate that the composition of gut microbiota may be involved in the progression of insulin resistance to type 2 diabetes. Probiotics and/or prebiotics could be a promising approach to improve insulin sensitivity by favourably modifying the composition of the gut microbial community, reducing intestinal endotoxin concentrations and decreasing energy harvest. The aim of the present review was to investigate the effects of probiotics, prebiotics and synbiotics (a combination of probiotics and prebiotics) on insulin resistance in human clinical trials and to discuss the potential mechanisms whereby probiotics and prebiotics improve glucose metabolism. The anti-diabetic effects of probiotics include reducing pro-inflammatory cytokines via a NF-κB pathway, reduced intestinal permeability, and lowered oxidative stress. SCFA play a key role in glucose homeostasis through multiple potential mechanisms of action. Activation of G-protein-coupled receptors on L-cells by SCFA promotes the release of glucagon-like peptide-1 and peptide YY resulting in increased insulin and decreased glucagon secretion, and suppressed appetite. SCFA can decrease intestinal permeability and decrease circulating endotoxins, lowering inflammation and oxidative stress. SCFA may also have anti-lipolytic activities in adipocytes and improve insulin sensitivity via GLUT4 through the up-regulation of 5'-AMP-activated protein kinase signalling in muscle and liver tissues. Resistant starch and synbiotics appear to have favourable anti-diabetic effects. However, there are few human interventions. Further well-designed human clinical studies are required to develop recommendations for the prevention of type 2 diabetes with pro- and prebiotics.

scholarly journals Deletion of EHD2 Attenuated Adipocyte Hypertrophic Expansion and Ameliorated Diet-Induced Obesity and Insulin Resistance

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1633-1633
Author(s):  
Darius Fox ◽  
Ashley Toney ◽  
Mikyoung You ◽  
Hamid Band ◽  
Soonkyu Chung
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Plasma Glucose ◽  
Insulin Signaling ◽  
Adipocyte Differentiation ◽  
Adipocyte Size ◽  
Lipogenic Gene ◽  
Insulin Levels ◽  
Gene And Protein Expression

Abstract Objectives Obesity induces adipocyte hypertrophy, which promotes metabolic dysfunction. The EPS15-Homology Domain-Containing (EHD) 2 is an endocytic traffic-regulatory protein regulating caveolae stability, thereby participating cell size expansion. Although EHD2 is abundantly expressed in adipocytes, very little information is available on its role on adipose metabolism. This study aimed to define the role of EHD2 on governing adipocyte size, lipid metabolism and insulin sensitivity. Methods To prepare the EHD2-deficient adipocytes, primary ear mesenchymal stem cells were isolate from wildtype (WT) and EHD2 KO mice and induced differentiation into adipocytes. To induce obesity and insulin resistance, EHD2 KO and WT male mice were fed a high-fat diet (50% calorie from lard) for 8 weeks. The changes in body weight was monitored weekly. Fasting plasma glucose and insulin levels were determined by glucometer and ELISA respectively. Glucose tolerance test (GTT) was conducted after HF diet feeding. To investigate insulin signaling, human recombinant insulin (1 U/kg BW) was injected peritoneally and epididymal fat was collected immediately for measuring the phosphorylation levels of AKT (p-AKT), a downstream target for insulin. To determine the lipogenic gene and protein expression, qPCR and Western blot analysis were conducted. Results Deletion of EHD2 markedly upregulated EHD1 expression in primary adipocytes. Also, deletion of EHD2 significantly attenuated adipocyte differentiation and maintained smaller lipid droplets. Consistently, absence of EHD2 was linked with reduced lipogenic gene expression. In vivo study, EHD2 KO mice exhibited slightly lower total body weight, but fat mass was markedly reduced. After 8 weeks of HF diet, EHD2 KO mice had lower levels of plasma glucose and insulin levels compared with WT. EHD2 KO mice were more glucose tolerant during GTT. Insulin signaling study revealed that EHD2 KO mice showed higher levels of insulin-stimulated p-AKT compared to WT mice, indicating EHD2 deletion promotes insulin sensitivity. Conclusions This study suggests that EHD2 is required for maximal adipocyte differentiation and hypertrophic expansion. The absence of EHD2 was linked with improved insulin and glucose sensitivity, presumably due to reduced adiposity and adipocyte size. Funding Sources Nebraska EPSCoR (Food for Health 2017) Seed Grant.

scholarly journals Placental Restriction Reduces Insulin Sensitivity and Expression of Insulin Signaling and Glucose Transporter Genes in Skeletal Muscle, But Not Liver, in Young Sheep

Endocrinology ◽  
2012 ◽  
Vol 153 (5) ◽  
pp. 2142-2151 ◽  
Author(s):  
Miles J. De Blasio ◽  
Kathryn L. Gatford ◽  
M. Lyn Harland ◽  
Jeffrey S. Robinson ◽  
Julie A. Owens
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Postnatal Growth ◽  
Whole Body ◽  
Poor Growth ◽  
Hepatic Expression ◽  
Metabolic Genes

Poor growth before birth is associated with impaired insulin sensitivity later in life, increasing the risk of type 2 diabetes. The tissue sites at which insulin resistance first develops after intrauterine growth restriction (IUGR), and its molecular basis, are unclear. We have therefore characterized the effects of placental restriction (PR), a major cause of IUGR, on whole-body insulin sensitivity and expression of molecular determinants of insulin signaling and glucose uptake in skeletal muscle and liver of young lambs. Whole-body insulin sensitivity was measured at 30 d by hyperinsulinaemic euglycaemic clamp and expression of insulin signaling genes (receptors, pathways, and targets) at 43 d in muscle and liver of control (n = 15) and PR (n = 13) lambs. PR reduced size at birth and increased postnatal growth, fasting plasma glucose (+15%, P = 0.004), and insulin (+115%, P = 0.009). PR reduced whole-body insulin sensitivity (−43%, P < 0.001) and skeletal muscle expression of INSR (−36%), IRS1 (−28%), AKT2 (−44%), GLUT4 (−88%), GSK3α (−35%), and GYS1 (−31%) overall (each P < 0.05) and decreased AMPKγ3 expression in females (P = 0.030). PR did not alter hepatic expression of insulin signaling and related genes but increased GLUT2 expression (P = 0.047) in males. Whole-body insulin sensitivity correlated positively with skeletal muscle expression of IRS1, AKT2, HK, AMPKγ2, and AMPKγ3 in PR lambs only (each P < 0.05) but not with hepatic gene expression in control or PR lambs. Onset of insulin resistance after PR and IUGR is accompanied by, and can be accounted for by, reduced expression of insulin signaling and metabolic genes in skeletal muscle but not liver.

Abstract 15225: Post-ischemic Myocardial Insulin Resistance Induced by Tnf-α Overproduction Precipitates the Development of Heart Failure After Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Feng Fu ◽  
Jia Li ◽  
Jie Xu ◽  
Yuan Zhang ◽  
Chao Gao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Left Ventricular ◽  
Separate Experiment ◽  
Tnf Α ◽  
Lv Remodeling ◽  
Myocardial Insulin Resistance

Objectives: Clinical evidence has demonstrated a decreased myocardial insulin response in HF patients. However, the role of myocardial insulin resistance and the underlying mechanisms in HF are largely unclear. Methods and Results: Sprague Dawley rats subjected to myocardial infarction (MI) resulted in a progressive left ventricular (LV) remodeling and dysfunction. Echocardiographic assessment showed preserved LV end-systolic dimension (LVESD 0.453 ± 0.027 cm) and ejection fraction (EF 57.03 ± 2.35%) at 1 wk after MI, and evident LV dilation (LVESD 0.612 ± 0.026 cm) and dysfunction (EF 40.21 ± 3.09%) at 4 wk after MI. Myocardial insulin sensitivity decreased significantly at 1 wk after MI as evidenced by reduced insulin-stimulated myocardial fluorodeoxyglucose uptake (Standardized Uptake Value: 2.71 ± 0.42 vs. 5.13 ± 0.51 of sham+insulin, n=6, P <0.01) and GLUT-4 translocation and altered insulin signaling, whereas systemic insulin sensitivity remained unchanged. Mechanistically, myocardial TNF-α production was increased following MI. Treatment with etanercept (a TNF-α inhibitor) post-MI improved myocardial insulin sensitivity, while adenovirus-mediated overexpression of TNF-α resulted in myocardial insulin resistance in non-MI hearts. In addition, TNF-α overexpressed rat hearts exhibited LV dysfunction (EF 41.32 ± 4.21%) and LV dilation as early as 1 wk after MI. Moreover, insulin treatment during the first week following MI suppressed myocardial TNF-α production and increased myocardial insulin sensitivity, resulting in alleviated cardiac dysfunction and remodeling at 4 wk after MI. Importantly, in a separate experiment, cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic LV remodeling and dysfunction compared with littermate controls. Conclusions: Our data provide novel insights that myocardial insulin resistance, independently of systemic insulin resistance, precipitates the development of post-ischemic HF. Myocardial insulin resistance is an early event partly attributed to myocardial TNF-α overproduction following MI. This finding indicates the essential role of myocardial insulin signaling in protection against ischemic HF.

Abstract 308: Rgs2 Is An Endogenous Inhibitor Of Insulin Signaling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Prem Sharma ◽  
Jennie Bever ◽  
Scott Heximer ◽  
Carmen Dessauer ◽  
Jerrold M Olefsky
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Regulatory System ◽  
Heart Association ◽  
Glut4 Translocation ◽  
Wild Type ◽  
Akt Phosphorylation ◽  
Insulin Resistant

Background: Insulin resistance is the hallmark of type 2 diabetes and is a known risk factor for the development of cardiovascular diseases. We have determined that overexpression of a GTPase-activating protein, RGS2 decreases insulin sensitivity. This study describes RGS2 regulation of insulin signaling pathways in order to assess whether this information can be used to reverse insulin insensitivity in diabetes. Hypothesis, Methods and Results: RGS2 protein levels were elevated 3 to 5-fold in white adipose tissues from ob/ob and high fat diet induced Insulin Resistant mice. Further, RGS2 protein is elevated in insulin resistant 3T3-L1 adipocytes treated chronically with either insulin, ET-1, or TNF-aplha. Further, SiRNA knockdown of endogenous RGS2 protein increases basal, insulin independent and insulin-dependent GLUT4 translocation. We hypothesized that the RGS2 regulatory system is defective/overactive in insulin resistance, and that a modulation of this regulatory system by RGS2 inhibition would improve insulin sensitivity. Thus, we determined the mechanisms whereby RGS2 modulates insulin sensitivity in 3T3-L1 adipocytes; focusing on insulin-regulated G-protein/PI3-K pathways leading to GLUT4 translocation and glucose uptake; utilizing adenoviruses over-expressing wild-type and mutants RGS2, as well as by siRNA-mediated knock down of endogenous RGS2. We overexpressed the Wild-Type (WT), GTPase defective (GD), and plasma membrane translocation defective (TD) RGS2 proteins in 3T3-L1 adipocytes. Overexpression of WT RGS2 leads to ~ 50% inhibition of insulin induced 2-DOG uptake, without affecting IR Tyr phosphorylation. RGS2 constitutively associates with Galpha/q11, and prevent its Tyr phosphorylation and activation by insulin. Interestingly, insulin-stimulated PKClambda phosphorylation was completely blocked by RGS2, whereas, AKT phosphorylation was minimally inhibited. Neither the insulin receptor tyrosine phosphorylation nor insulin-stimulated MAPK phosphorylation was affected by RGS2. Conclusion: This study identifies a novel role of RGS2 in cellular insulin resistance by negatively regulating signaling through the Galpha/q11 pathway to glucose uptake. This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).

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