scholarly journals miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression

2020 ◽  
Vol 21 (22) ◽  
pp. 8675
Author(s):  
Asier Benito-Vicente ◽  
Kepa B. Uribe ◽  
Noemi Rotllan ◽  
Cristina M. Ramírez ◽  
Shifa Jebari-Benslaiman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Receptor Expression ◽  
Hepatic Insulin Resistance ◽  
Hepatic Tissue ◽  
Special Importance ◽  
The Impact

Insulin resistance (IR) is one of the key contributing factors in the development of type 2 diabetes mellitus (T2DM). However, the molecular mechanisms leading to IR are still unclear. The implication of microRNAs (miRNAs) in the pathophysiology of multiple cardiometabolic pathologies, including obesity, atherosclerotic heart failure and IR, has emerged as a major focus of interest in recent years. Indeed, upregulation of several miRNAs has been associated with obesity and IR. Among them, miR-27b is overexpressed in the liver in patients with obesity, but its role in IR has not yet been thoroughly explored. In this study, we investigated the role of miR-27b in regulating insulin signaling in hepatocytes, both in vitro and in vivo. Therefore, assessment of the impact of miR-27b on insulin resistance through the hepatic tissue is of special importance due to the high expression of miR-27b in the liver together with its known role in regulating lipid metabolism. Notably, we found that miR-27b controls post-transcriptional expression of numerous components of the insulin signaling pathway including the insulin receptor (INSR) and insulin receptor substrate 1 (IRS1) in human hepatoma cells. These results were further confirmed in vivo showing that overexpression and inhibition of hepatic miR-27 enhances and suppresses hepatic INSR expression and insulin sensitivity, respectively. This study identified a novel role for miR-27 in regulating insulin signaling, and this finding suggests that elevated miR-27 levels may contribute to early development of hepatic insulin resistance.

scholarly journals EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance

2021 ◽  
Author(s):  
Kakali Ghoshal ◽  
Xiyue Li ◽  
Dungeng Peng ◽  
John R. Falck ◽  
Raghunath Reddy Anugu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Genetic Model ◽  
Water Soluble ◽  
Hepatic Insulin Resistance ◽  
Epoxyeicosatrienoic Acid ◽  
Genetic Mouse Model ◽  
Hepatic Insulin Signaling ◽  
Underlying Mechanisms

We previously showed that global deletion of the cytochrome P450 epoxygenase <i>Cyp2c44</i>, a major epoxyeicosatrienoic acid (EET) producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water soluble EET analog restores insulin signaling <i>in vivo</i> in <i>Cyp2c44(-/-)</i> mice and investigated the underlying mechanisms by which this effect is exerted. <i>Cyp2c44(-/-)</i> mice treated with the analog EET-A for 4 weeks improved fasting glucose and glucose tolerance compared to <i>Cyp2c44(-/-)</i> mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor β (IRβ) is impaired in primary <i>Cyp2c44(-/-) </i>hepatocytes and this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRβ in membrane rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRβ and potentiating insulin signaling.

scholarly journals Gosha-jinki-gan (a Herbal Complex) Corrects Abnormal Insulin Signaling

2004 ◽  
Vol 1 (3) ◽  
pp. 269-276 ◽  
Author(s):  
Bolin Qin ◽  
Masaru Nagasaki ◽  
Ming Ren ◽  
Gustavo Bajotto ◽  
Yoshiharu Oshida ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Protein Content ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Diabetic Rats ◽  
Metabolic Clearance ◽  
Long Term Effects ◽  
Β Protein

Previous studies have shown that the traditional herbal complex Gosha-jinki-gan (GJG) improves diabetic neuropathy and insulin resistance. The present study was undertaken to elucidate the molecular mechanisms related with the long-term effects of GJG administration on insulin actionin vivoand the early steps of insulin signaling in skeletal muscle in streptozotocin (STZ) diabetes. Rats were randomized into five subgroups: (1) saline treated control, (2) GJG treated control, (3) 2-unit insulin + saline treated diabetic, (4) saline + GJG treated diabetic and (5) 2-unit insulin + GJG treated diabetic groups. After seven days of treatment, euglycemic clamp experiment at an insulin infusion rate of 6 mU/kg/min was performed in overnight fasted rats. Despite the 2-unit insulin treatment, the metabolic clearance rates of glucose (MCR, ml/kg/min) in diabetic rats were significantly lower compared with the controls (11.4 ± 1.0 vs 44.1 ± 1.5;P< 0.001), and were significantly improved by insulin combined with GJG or GJG alone (26 ± 3.2 and 24.6 ± 2.2,P< 0.01, respectively). The increased insulin receptor (IR)-β protein content in skeletal muscle of diabetic rats was not affected by insulin combined with GJG administration. However, the decreased insulin receptor substrate-1 (IRS-1) protein content was significantly improved by treatment with GJG. Additionally, the increased tyrosine phosphorylation levels of IR-β and IRS-1 were significantly inhibited in insulin combined with GJG treated diabetes. The present results suggest that the improvement of the impaired insulin sensitivity in STZ-diabetic rats by administration of GJG may be due, at least in part, to correction in the abnormal early steps of insulin signaling in skeletal muscle.

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 PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling

2018 ◽  
Vol 115 (38) ◽  
pp. E8996-E9005 ◽  
Author(s):  
Brandon M. Gassaway ◽  
Max C. Petersen ◽  
Yulia V. Surovtseva ◽  
Karl W. Barber ◽  
Joshua B. Sheetz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphorylation ◽  
Cross Talk ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Large Scale ◽  
Kinase Assay ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
The Impact

Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat–fed, and high-fat–fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.

scholarly journals Interleukin-6 Depletion Selectively Improves Hepatic Insulin Action in Obesity

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3417-3427 ◽  
Author(s):  
Peter J. Klover ◽  
Alicia H. Clementi ◽  
Robert A. Mooney
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Receptor ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Stat3 Phosphorylation ◽  
Insulin Dependent ◽  
Significant Change

Abstract Obesity and insulin resistance are considered chronic inflammatory states, in part because circulating IL-6 is elevated. Exogenous IL-6 can induce hepatic insulin resistance in vitro and in vivo. The importance of endogenous IL-6, however, to insulin resistance of obesity is unresolved. To test the hypothesis that IL-6 contributes to the inflammation and insulin resistance of obesity, IL-6 was depleted in Lepob mice by injection of IL-6-neutralizing antibody. In untreated Lepob mice, signal transducer and activator of transcription-3 (STAT3) activation was increased compared with that in lean controls, consistent with an inflammatory state. With IL-6 depletion, activation of STAT3 in liver and adipose tissue and expression of haptoglobin were reduced. Expression of the IL-6-dependent, hepatic acute phase protein fibrinogen was also decreased. Using the hyperinsulinemic-euglycemic clamp technique, insulin-dependent suppression of endogenous glucose production was 89% in IL-6-depleted Lepob mice, in contrast to only 32% in Lepob controls, indicating a marked increase in hepatic insulin sensitivity. A significant change in glucose uptake in skeletal muscle after IL-6 neutralization was not observed. In a direct comparison of hepatic insulin signaling in Lepob mice treated with anti-IL-6 vs. IgG-treated controls, insulin-dependent insulin receptor autophosphorylation and activation of Akt (pSer473) were increased by nearly 50% with IL-6 depletion. In adipose tissue, insulin receptor signaling showed no significant change despite major reductions in STAT3 phosphorylation and haptoglobin expression. In diet-induced obese mice, depletion of IL-6 improved insulin responsiveness in 2-h insulin tolerance tests. In conclusion, these results indicate that IL-6 plays an important and selective role in hepatic insulin resistance of obesity.

scholarly journals Role of inhibitory κB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes

2011 ◽  
Vol 301 (3) ◽  
pp. G454-G463 ◽  
Author(s):  
Shaoning Jiang ◽  
Joseph L. Messina
Keyword(s):  
Insulin Resistance ◽  
Critical Illness ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Adenovirus Vector ◽  
Dominant Negative ◽  
Serine Phosphorylation ◽  
Hepatic Insulin Resistance ◽  
Mortality And Morbidity ◽  
Hepatic Insulin Signaling

Hyperglycemia and insulin resistance induced by acute injuries or critical illness are associated with increased mortality and morbidity, as well as later development of type 2 diabetes. The molecular mechanisms underlying the acute onset of insulin resistance following critical illness remain poorly understood. In the present studies, the roles of serine kinases, inhibitory κB kinase (IKK) and c-Jun NH2-terminal kinase (JNK), in the acute development of hepatic insulin resistance were investigated. In our animal model of critical illness diabetes, activation of hepatic IKK and JNK was observed as early as 15 min, concomitant with the rapid impairment of hepatic insulin signaling and increased serine phosphorylation of insulin receptor substrate 1. Inhibition of IKKα or IKKβ, or both, by adenovirus vector-mediated expression of dominant-negative IKKα or IKKβ in liver partially restored insulin signaling. Similarly, inhibition of JNK1 kinase by expression of dominant-negative JNK1 also resulted in improved hepatic insulin signaling, indicating that IKK and JNK1 kinases contribute to critical illness-induced insulin resistance in liver.

In vivo insulin signaling through PI3-kinase is impaired in skeletal muscle of adult rat offspring exposed to ethanol in utero

2005 ◽  
Vol 99 (2) ◽  
pp. 528-534 ◽  
Author(s):  
Li Chen ◽  
Xing-Hai Yao ◽  
B. L. G. Nyomba
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
In Utero ◽  
Pi3 Kinase ◽  
Adult Rat ◽  
Rat Offspring ◽  
Significant Difference

It is now known that prenatal ethanol (EtOH) exposure is associated with impaired glucose tolerance and insulin resistance in rat offspring, but the underlying mechanism(s) is not known. To test the hypothesis that in vivo insulin signaling through phosphatidylinositol 3 (PI3)-kinase is reduced in skeletal muscle of adult rat offspring exposed to EtOH in utero, we gave insulin intravenously to these rats and probed steps in the PI3-kinase insulin signaling pathway. After insulin treatment, EtOH-exposed rats had decreased tyrosine phosphorylation of the insulin receptor β-subunit and of insulin receptor substrate-1 (IRS-1), as well as reduced IRS-1-associated PI3-kinase in the gastrocnemius muscle compared with control rats. There was no significant difference in basal or insulin-stimulated Akt activity between EtOH-exposed rats and controls. Insulin-stimulated PKC isoform ζ phosphorylation and membrane association were reduced in EtOH-exposed rats compared with controls. Muscle insulin binding and peptide contents of insulin receptor, IRS-1, p85 subunit of PI3-kinase, Akt/PKB, and atypical PKC isoform ζ were not different between EtOH-exposed rats and controls. Thus insulin resistance in rat offspring exposed to EtOH in utero may be explained, at least in part, by impaired insulin signaling through the PI3-kinase pathway in skeletal muscle.

scholarly journals The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance

2020 ◽  
Vol 11 ◽  
Author(s):  
Han Cheng ◽  
Xiaokun Gang ◽  
Guangyu He ◽  
Yujia Liu ◽  
Yingxuan Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Insulin Signaling ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Glucose Sensing ◽  
Hepatic Insulin Resistance ◽  
Endoplasmic Reticulum Membrane ◽  
Hepatic Insulin Signaling

Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.

scholarly journals Insulin Receptor and its Relationship with Different Forms of Insulin Resistance

2010 ◽  
Vol 2 (2) ◽  
pp. 59-90 ◽  
Author(s):  
Aleksandra Rojek ◽  
Marek Niedziela
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Molecular Mechanisms ◽  
Receptor Gene ◽  
Insulin Receptors ◽  
Receptor Expression ◽  
Insulin Receptor Gene ◽  
Efficient Treatment ◽  
Regulatory Processes ◽  
Stage Of Development

SummaryInsulin plays an important role in maintaining the whole organism’s homeostasis. The presence of insulin receptors in all vertebrates and invertebrates cells reflects the diversity of regulatory processes in which this hormone is involved. Furthermore, many different factors may influence the level of insulin receptor expression. These factors include e.g. the sole insulin or stage of development. Mutations in the receptor may lead to the development of insulin resistance. These mutations differ in the level of severity and are frequently associated with diabetes mellitus, hypertension, cardiovascular disorders, heart failure, metabolic syndrome and infertility in women. More than 50 mutations in insulin receptor gene have already been characterized. These mutations are associated with rare forms of insulin resistance like leprechaunism, insulin resistance type A or Rabson-Mendenhall syndrome. Molecular analysis of insulin receptor gene may lead to a better understanding of molecular mechanisms underlying various types of insulin resistance and help to develop more efficient treatment.

scholarly journals Tissue-Specific Difference in the Molecular Mechanisms for the Development of Acute Insulin Resistance after Injury

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 24-32 ◽  
Author(s):  
Li Li ◽  
LaWanda H. Thompson ◽  
Ling Zhao ◽  
Joseph L. Messina
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Rapid Development ◽  
Serine Phosphorylation ◽  
Synthesis Inhibitor ◽  
Adult Rats ◽  
Counterregulatory Hormones

Acute insulin resistance occurs after injury, hemorrhage, infection, and critical illness. However, little is known about the development of this acute insulin-resistant state. In the current study, we found that insulin resistance develops rapidly in skeletal muscle, with the earliest insulin signaling defects at 60 min. However, defects in insulin signaling were measurable even earlier in liver, by as soon as 15 min after hemorrhage. To begin to understand the mechanisms for the development of acute insulin resistance, serine phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun N-terminal kinase phosphorylation/activation was investigated. These markers (and possible contributors) of insulin resistance were increased in the liver after hemorrhage but not measurable in skeletal muscle. Because glucocorticoids are important counterregulatory hormones responsible for glucose homeostasis, a glucocorticoid synthesis inhibitor, metyrapone, and a glucocorticoid receptor antagonist, RU486, were administered to adult rats prior to hemorrhage. In the liver, the defects of insulin signaling after hemorrhage, including reduced tyrosine phosphorylation of the insulin receptor and IRS-1, association between IRS-1 and phosphatidylinositol 3-kinase and serine phosphorylation of Akt in response to insulin were not altered by pretreatment of rats with metyrapone or RU486. In contrast, hemorrhage-induced defects in insulin signaling were dramatically reversed in skeletal muscle, indicating a prevention of insulin resistance in muscle. These results suggest that distinct mechanisms for hemorrhage-induced acute insulin resistance are present in these two tissues and that glucocorticoids are involved in the rapid development of insulin resistance in skeletal muscle, but not in the liver, after hemorrhage. Glucocorticoids play a major role in the development of acute insulin resistance following hemorrhage in skeletal muscle, but not in the liver.

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