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Journal articles on the topic 'Insulin signaling-Resistance'

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Published: 6 September 2023

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1

Beale, Elmus G. "Insulin Signaling and Insulin Resistance." Journal of Investigative Medicine 61, no. 1 (January 1, 2013): 11–14. http://dx.doi.org/10.2310/jim.0b013e3182746f95.

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2

Martz, Lauren. "Signaling insulin resistance in obesity." Science-Business eXchange 2, no. 30 (August 2009): 1166. http://dx.doi.org/10.1038/scibx.2009.1166.

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3

Randriamboavonjy, V., and I. Fleming. "Insulin, Insulin Resistance, and Platelet Signaling in Diabetes." Diabetes Care 32, no. 4 (March 31, 2009): 528–30. http://dx.doi.org/10.2337/dc08-1942.

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4

Zick, Yehiel. "Insulin resistance: a phosphorylation-based uncoupling of insulin signaling." Trends in Cell Biology 11, no. 11 (November 2001): 437–41. http://dx.doi.org/10.1016/s0962-8924(01)02129-8.

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5

Zick, Yehiel. "Insulin resistance: a phosphorylation-based uncoupling of insulin signaling." Trends in Cell Biology 11 (November 2001): 437–41. http://dx.doi.org/10.1016/s0962-8924(01)81297-6.

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6

Horita, Shoko, Motonobu Nakamura, Masashi Suzuki, Nobuhiko Satoh, Atsushi Suzuki, and George Seki. "Selective Insulin Resistance in the Kidney." BioMed Research International 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/5825170.

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Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule.
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7

Chen, Li, Rui Chen, Hua Wang, and Fengxia Liang. "Mechanisms Linking Inflammation to Insulin Resistance." International Journal of Endocrinology 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/508409.

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Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.
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8

Choi, Cheol S., Young-Bum Kim, Felix N. Lee, Janice M. Zabolotny, Barbara B. Kahn, and Jang H. Youn. "Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling." American Journal of Physiology-Endocrinology and Metabolism 283, no. 2 (August 1, 2002): E233—E240. http://dx.doi.org/10.1152/ajpendo.00557.2001.

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Elevation of plasma lactate levels induces peripheral insulin resistance, but the underlying mechanisms are unclear. We examined whether lactate infusion in rats suppresses glycolysis preceding insulin resistance and whether lactate-induced insulin resistance is accompanied by altered insulin signaling and/or insulin-stimulated glucose transport in skeletal muscle. Hyperinsulinemic euglycemic clamps were conducted for 6 h in conscious, overnight-fasted rats with or without lactate infusion (120 μmol · kg−1 · min−1) during the final 3.5 h. Lactate infusion increased plasma lactate levels about fourfold. The elevation of plasma lactate had rapid effects to suppress insulin-stimulated glycolysis, which clearly preceded its effect to decrease insulin-stimulated glucose uptake. Both submaximal and maximal insulin-stimulated glucose transport decreased 25–30% ( P < 0.05) in soleus but not in epitrochlearis muscles of lactate-infused rats. Lactate infusion did not alter insulin's ability to phosphorylate the insulin receptor, the insulin receptor substrate (IRS)-1, or IRS-2 but decreased insulin's ability to stimulate IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activities and Akt/protein kinase B activity by 47, 75, and 55%, respectively ( P < 0.05 for all). In conclusion, elevation of plasma lactate suppressed glycolysis before its effect on insulin-stimulated glucose uptake, consistent with the hypothesis that suppression of glucose metabolism could precede and cause insulin resistance. In addition, lactate-induced insulin resistance was associated with impaired insulin signaling and decreased insulin-stimulated glucose transport in skeletal muscle.
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9

Boura-Halfon, Sigalit, and Yehiel Zick. "Phosphorylation of IRS proteins, insulin action, and insulin resistance." American Journal of Physiology-Endocrinology and Metabolism 296, no. 4 (April 2009): E581—E591. http://dx.doi.org/10.1152/ajpendo.90437.2008.

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Insulin signaling at target tissues is essential for growth and development and for normal homeostasis of glucose, fat, and protein metabolism. Control over this process is therefore tightly regulated. It can be achieved by a negative feedback control mechanism whereby downstream components inhibit upstream elements along the insulin-signaling pathway (autoregulation) or by signals from apparently unrelated pathways that inhibit insulin signaling thus leading to insulin resistance. Phosphorylation of insulin receptor substrate (IRS) proteins on serine residues has emerged as a key step in these control processes under both physiological and pathological conditions. The list of IRS kinases implicated in the development of insulin resistance is growing rapidly, concomitant with the list of potential Ser/Thr phosphorylation sites in IRS proteins. Here, we review a range of conditions that activate IRS kinases to phosphorylate IRS proteins on “hot spot” domains. The flexibility vs. specificity features of this reaction is discussed and its characteristic as an “array” phosphorylation is suggested. Finally, its implications on insulin signaling, insulin resistance and type 2 diabetes, an emerging epidemic of the 21st century are outlined.
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10

Li, Hongliang, Jiyeon Lee, Chaoyong He, Ming-Hui Zou, and Zhonglin Xie. "Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids." American Journal of Physiology-Endocrinology and Metabolism 306, no. 2 (January 15, 2014): E197—E209. http://dx.doi.org/10.1152/ajpendo.00202.2013.

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Nutrient overload is associated with the development of obesity, insulin resistance, and type 2 diabetes. However, the underlying mechanisms for developing insulin resistance in the presence of excess nutrients are incompletely understood. We investigated whether activation of AMP-activated protein kinase (AMPK) prevents the hepatic insulin resistance that is induced by the consumption of a high-protein diet (HPD) and the presence of excess amino acids. Exposure of HepG2 cells to excess amino acids reduced AMPK phosphorylation, upregulated Notch1 expression, and impaired the insulin-stimulated phosphorylation of Akt Ser473 and insulin receptor substrate-1 (IRS-1) Tyr612. Inhibition of Notch1 prevented amino acid-induced insulin resistance, which was accompanied by reduced expression of Rbp-Jk, hairy and enhancer of split-1, and forkhead box O1. Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3). Activation of AMPK by metformin inhibited mTORC1-STAT3 signaling, thereby preventing excess amino acid-impaired insulin signaling. Finally, HPD feeding suppressed AMPK activity, activated mTORC1/STAT3/Notch1 signaling, and induced insulin resistance. Chronic administration of either metformin or rapamycin inhibited the HPD-activated mTORC1/STAT3/Notch1 signaling pathway and prevented hepatic insulin resistance. We conclude that the upregulation of Notch1 expression by hyperactive mTORC1 signaling is an essential event in the development of hepatic insulin resistance in the presence of excess amino acids. Activation of AMPK prevents amino acid-induced insulin resistance through the suppression of the mTORC1/STAT3/Notch1 signaling pathway.
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11

Zand, Hamid, Nava Morshedzadeh, and Farnush Naghashian. "Signaling pathways linking inflammation to insulin resistance." Diabetes & Metabolic Syndrome: Clinical Research & Reviews 11 (November 2017): S307—S309. http://dx.doi.org/10.1016/j.dsx.2017.03.006.

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12

Larner, Joseph, David L. Brautigan, and Michael O. Thorner. "D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance." Molecular Medicine 16, no. 11-12 (November 2010): 543–52. http://dx.doi.org/10.2119/molmed.2010.00107.

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13

Mitev, Vanio, and Lyuben Sirakov. "Recent data about insulin signaling system and insulin resistance states." Biomedical Reviews 5 (July 31, 1996): 47. http://dx.doi.org/10.14748/bmr.v5.182.

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14

Pessin, Jeffrey E., and Alan R. Saltiel. "Signaling pathways in insulin action: molecular targets of insulin resistance." Journal of Clinical Investigation 106, no. 2 (July 15, 2000): 165–69. http://dx.doi.org/10.1172/jci10582.

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15

Pei, Jinli, Baochun Wang, and Dayong Wang. "Current Studies on Molecular Mechanisms of Insulin Resistance." Journal of Diabetes Research 2022 (December 23, 2022): 1–11. http://dx.doi.org/10.1155/2022/1863429.

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Diabetes is a metabolic disease that raises the risk of microvascular and neurological disorders. Insensitivity to insulin is a characteristic of type II diabetes, which accounts for 85-90 percent of all diabetic patients. The fundamental molecular factor of insulin resistance may be impaired cell signal transduction mediated by the insulin receptor (IR). Several cell-signaling proteins, including IR, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase (PI3K), have been recognized as being important in the impaired insulin signaling pathway since they are associated with a large number of proteins that are strictly regulated and interact with other signaling pathways. Many studies have found a correlation between IR alternative splicing, IRS gene polymorphism, the complicated regulatory function of IRS serine/threonine phosphorylation, and the negative regulatory role of p85 in insulin resistance and diabetes mellitus. This review brings up-to-date knowledge of the roles of signaling proteins in insulin resistance in order to aid in the discovery of prospective targets for insulin resistance treatment.
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16

Ning, Jie, Tao Hong, Xuefeng Yang, Shuang Mei, Zhenqi Liu, Hui-Yu Liu, and Wenhong Cao. "Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse." American Journal of Physiology-Endocrinology and Metabolism 301, no. 2 (August 2011): E391—E401. http://dx.doi.org/10.1152/ajpendo.00164.2011.

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The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes.
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17

Mayer, Christopher M., and Denise D. Belsham. "Central Insulin Signaling Is Attenuated by Long-Term Insulin Exposure via Insulin Receptor Substrate-1 Serine Phosphorylation, Proteasomal Degradation, and Lysosomal Insulin Receptor Degradation." Endocrinology 151, no. 1 (January 1, 2010): 75–84. http://dx.doi.org/10.1210/en.2009-0838.

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Abstract Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR.
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18

Zhai, Lidong, Scott W. Ballinger, and Joseph L. Messina. "Role of Reactive Oxygen Species in Injury-Induced Insulin Resistance." Molecular Endocrinology 25, no. 3 (March 1, 2011): 492–502. http://dx.doi.org/10.1210/me.2010-0224.

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Abstract Acute insulin resistance is common after injury, infection, and critical illness. To investigate the role of reactive oxygen species (ROS) in critical illness diabetes, we measured hepatic ROS, which rapidly increased in mouse liver. Overexpression of superoxide dismutase 2, which decreased mitochondrial ROS levels, protected mice from the development of acute hepatic insulin resistance. Insulin-induced intracellular signaling was dramatically decreased, and cellular stress signaling was rapidly increased after injury, resulting in the hyperglycemia of critical illness diabetes. Insulin-induced intracellular signaling, activation of stress (c-Jun N-terminal kinase) signaling, and glucose metabolism were all normalized by superoxide dismutase 2 overexpression or by pretreatment with antioxidants. Thus, ROS play an important role in the development of acute hepatic insulin resistance and activation of stress signaling after injury.
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19

Stafeev, I. S., A. V. Vorotnikov, E. I. Ratner, M. Y. Menshikov, and Ye V. Parfyonova. "Latent Inflammation and Insulin Resistance in Adipose Tissue." International Journal of Endocrinology 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/5076732.

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Obesity is a growing problem in modern society and medicine. It closely associates with metabolic disorders such as type 2 diabetes mellitus (T2DM) and hepatic and cardiovascular diseases such as nonalcoholic fatty liver disease, atherosclerosis, myocarditis, and hypertension. Obesity is often associated with latent inflammation; however, the link between inflammation, obesity, T2DM, and cardiovascular diseases is still poorly understood. Insulin resistance is the earliest feature of metabolic disorders. It mostly develops as a result of dysregulated insulin signaling in insulin-sensitive cells, as compared to inactivating mutations in insulin receptor or signaling proteins that occur relatively rare. Here, we argue that inflammatory signaling provides a link between latent inflammation, obesity, insulin resistance, and metabolic disorders. We further hypothesize that insulin-activated PI3-kinase pathway and inflammatory signaling mediated by several IκB kinases may constitute negative feedback leading to insulin resistance at least in the fat tissue. Finally, we discuss perspectives for anti-inflammatory therapies in treating the metabolic diseases.
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20

Strömmer, Lisa, Johan Permert, Urban Arnelo, Camilla Koehler, Bengt Isaksson, Jörgen Larsson, Inger Lundkvist, et al. "Skeletal muscle insulin resistance after trauma: insulin signaling and glucose transport." American Journal of Physiology-Endocrinology and Metabolism 275, no. 2 (August 1, 1998): E351—E358. http://dx.doi.org/10.1152/ajpendo.1998.275.2.e351.

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Surgical trauma induces peripheral insulin resistance; however, the cellular mechanism has not been fully elucidated. We examined the effects of surgical trauma on insulin receptor signaling and glucose transport in skeletal muscle, a tissue that plays a predominant role in maintaining glucose homeostasis. Surgical trauma was induced by intestinal resection in the rat. Receptor phosphorylation was not altered with surgical trauma. Phosphotyrosine-associated phosphatidylinositol (PI) 3-kinase association was increased by 60 and 82% compared with fasted and fed controls, respectively ( P < 0.05). Similar results were observed for insulin receptor substrate-1-associated PI 3-kinase activity. Insulin-stimulated protein kinase B (Akt kinase) phosphorylation was increased by 2.2-fold after surgical trauma ( P < 0.05). The hyperphosphorylation of Akt is likely to reflect amplification of PI 3-kinase after insulin stimulation. Submaximal rates of insulin-stimulated 3- O-methylglucose transport were reduced in trauma vs. fasted rats by 51 and 38% for 100 and 200 μU/ml of insulin, respectively ( P< 0.05). In conclusion, insulin resistance in skeletal muscle after surgical trauma is associated with reduced glucose transport but not with impaired insulin signaling to PI 3-kinase or its downstream target, Akt. The surgical trauma model presented in this report provides a useful tool to further elucidate the molecular mechanism(s) underlying the development of insulin resistance after surgical trauma.
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21

Muniyappa, Ranganath, Monica Montagnani, Kwang Kon Koh, and Michael J. Quon. "Cardiovascular Actions of Insulin." Endocrine Reviews 28, no. 5 (August 1, 2007): 463–91. http://dx.doi.org/10.1210/er.2007-0006.

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Insulin has important vascular actions to stimulate production of nitric oxide from endothelium. This leads to capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in classical insulin target tissues (e.g., skeletal muscle). Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways regulating endothelial production of nitric oxide share striking parallels with metabolic insulin-signaling pathways. Distinct MAPK-dependent insulin-signaling pathways (largely unrelated to metabolic actions of insulin) regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These and other cardiovascular actions of insulin contribute to coupling metabolic and hemodynamic homeostasis under healthy conditions. Cardiovascular diseases are the leading cause of morbidity and mortality in insulin-resistant individuals. Insulin resistance is typically defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin. This cardinal feature of diabetes, obesity, and dyslipidemia is also a prominent component of hypertension, coronary heart disease, and atherosclerosis that are all characterized by endothelial dysfunction. Conversely, endothelial dysfunction is often present in metabolic diseases. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling that in vascular endothelium contributes to a reciprocal relationship between insulin resistance and endothelial dysfunction. The clinical relevance of this coupling is highlighted by the findings that specific therapeutic interventions targeting insulin resistance often also ameliorate endothelial dysfunction (and vice versa). In this review, we discuss molecular mechanisms underlying cardiovascular actions of insulin, the reciprocal relationships between insulin resistance and endothelial dysfunction, and implications for developing beneficial therapeutic strategies that simultaneously target metabolic and cardiovascular diseases.
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22

Zhou, Qiu Gen, Xiao Jing Fu, Guo Yu Xu, Wei Cao, Hong Fa Liu, Jing Nie, Min Liang, and Fan Fan Hou. "Vascular insulin resistance related to endoplasmic reticulum stress in aortas from a rat model of chronic kidney disease." American Journal of Physiology-Heart and Circulatory Physiology 303, no. 9 (November 1, 2012): H1154—H1165. http://dx.doi.org/10.1152/ajpheart.00407.2012.

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Metabolic insulin resistance has been demonstrated in patients with nondiabetic chronic kidney disease (CKD), yet their vascular insulin signaling remains poorly understood. Here we tested the hypothesis that vascular insulin signaling was impaired and related with endoplasmic reticulum (ER) stress in aortas from the reduced renal mass (RRM) model of CKD. The activity of insulin signaling and markers of ER were determined in aortas from rats with RRM and cultured human umbilical vein endothelial cells. Tyrosine phosphorylation of insulin receptor-β and insulin receptor substrate (IRS)-1 and phosphorylation of protein kinase B and endothelial nitric oxide synthase were all decreased in aorta from RRM rats, whereas serine phosphorylation of IRS-1, a marker of insulin resistance, was increased. In addition, nitric oxide generation and insulin-mediated vasorelaxation were decreased in aortas from RRM rats. Insulin signaling in cultured vascular endothelial cells was impaired by induction of ER stress and was restored in aortas of RRM rats by inhibition of ER stress. Taken together, rats with RRM had vascular insulin resistance that was linked to ER stress. This identified vascular insulin resistance and ER stress as a potential therapeutic target for cardiovascular complications in patients with CKD.
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23

Vazirani, Reema P., Akanksha Verma, L. Amanda Sadacca, Melanie S. Buckman, Belen Picatoste, Muheeb Beg, Christopher Torsitano, et al. "Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance." Diabetes 65, no. 6 (March 25, 2016): 1577–89. http://dx.doi.org/10.2337/db15-1128.

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24

Ogihara, Takehide, Tomoichiro Asano, Katsuyuki Ando, Yuko Chiba, Hideyuki Sakoda, Motonobu Anai, Nobuhiro Shojima, et al. "Angiotensin II–Induced Insulin Resistance Is Associated With Enhanced Insulin Signaling." Hypertension 40, no. 6 (December 2002): 872–79. http://dx.doi.org/10.1161/01.hyp.0000040262.48405.a8.

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25

Azziz, Ricardo. "Polycystic Ovary Syndrome, Insulin Resistance, and Molecular Defects of Insulin Signaling." Journal of Clinical Endocrinology & Metabolism 87, no. 9 (September 2002): 4085–87. http://dx.doi.org/10.1210/jc.2002-021131.

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26

Bertuzzi, Alessandro, Federica Conte, Geltrude Mingrone, Federico Papa, Serenella Salinari, and Carmela Sinisgalli. "Insulin Signaling in Insulin Resistance States and Cancer: A Modeling Analysis." PLOS ONE 11, no. 5 (May 5, 2016): e0154415. http://dx.doi.org/10.1371/journal.pone.0154415.

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27

Pomytkin, Igor, and Vsevolod Pinelis. "Brain Insulin Resistance: Focus on Insulin Receptor-Mitochondria Interactions." Life 11, no. 3 (March 22, 2021): 262. http://dx.doi.org/10.3390/life11030262.

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Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.
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28

Heo, Yu Jung, Sung-E. Choi, Ja Young Jeon, Seung Jin Han, Dae Jung Kim, Yup Kang, Kwan Woo Lee, and Hae Jin Kim. "Visfatin Induces Inflammation and Insulin Resistance via the NF-κB and STAT3 Signaling Pathways in Hepatocytes." Journal of Diabetes Research 2019 (July 17, 2019): 1–11. http://dx.doi.org/10.1155/2019/4021623.

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Background. It has been suggested that visfatin, which is an adipocytokine, exhibits proinflammatory properties and is associated with insulin resistance. Insulin resistance and inflammation are the principal pathogeneses of nonalcoholic fatty liver disease (NAFLD), but the relationship, if any, between visfatin and NAFLD remains unclear. Here, we evaluated the effects of visfatin on hepatic inflammation and insulin resistance in HepG2 cells and examined the molecular mechanisms involved. Methods. After treatment with visfatin, the inflammatory cytokines IL-6, TNF-α, and IL-1β were assessed by real-time polymerase chain reaction (RT-PCR) and immunocytochemical staining in HepG2 cells. To investigate the effects of visfatin on insulin resistance, we evaluated insulin-signaling pathways, such as IR, IRS-1, GSK, and AKT using immunoblotting. We assessed the intracellular signaling molecules including STAT3, NF-κB, IKK, p38, JNK, and ERK by western blotting. We treated HepG2 cells with both visfatin and either AG490 (a JAK2 inhibitor) or Bay 7082 (an NF-κB inhibitor); we examined proinflammatory cytokine mRNA levels using RT-PCR and insulin signaling using western blotting. Results. In HepG2 cells, visfatin significantly increased the levels of proinflammatory cytokines, reduced the levels of proteins (e.g., phospho-IR, phospho-IRS-1 (Tyr612), phospho-AKT, and phospho-GSK-3α/β) involved in insulin signaling, and increased IRS-1 S307 phosphorylation compared to controls. Interestingly, visfatin increased the activities of the JAK2/STAT3 and IKK/NF-κB signaling pathways but not those of the JNK, p38, and ERK pathways. Visfatin-induced inflammation and insulin resistance were regulated by JAK2/STAT3 and IKK/NF-κB signaling; together with AG490 or Bay 7082, visfatin significantly reduced mRNA levels of IL-6, TNF-α and IL-1β and rescued insulin signaling. Conclusion. Visfatin induced proinflammatory cytokine production and inhibited insulin signaling via the STAT3 and NF-κB pathways in HepG2 cells.
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Zhu, Lin, Melissa N. Martinez, Christopher H. Emfinger, Brian T. Palmisano, and John M. Stafford. "Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity." American Journal of Physiology-Endocrinology and Metabolism 306, no. 10 (May 15, 2014): E1188—E1197. http://dx.doi.org/10.1152/ajpendo.00579.2013.

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The development of insulin resistance in the liver is a key event that drives dyslipidemia and predicts diabetes and cardiovascular risk with obesity. Clinical data show that estrogen signaling in males helps prevent adiposity and insulin resistance, which may be mediated through estrogen receptor-α (ERα). The tissues and pathways that mediate the benefits of estrogen signaling in males with obesity are not well defined. In female mice, ERα signaling in the liver helps to correct pathway-selective insulin resistance with estrogen treatment after ovariectomy. We assessed the importance of liver estrogen signaling in males using liver ERα-knockout (LKO) mice fed a high-fat diet (HFD). We found that the LKO male mice had decreased insulin sensitivity compared with their wild-type floxed (fl/fl) littermates during hyperinsulinemic euglycemic clamps. Insulin failed to suppress endogenous glucose production in LKO mice, indicating liver insulin resistance. Insulin promoted glucose disappearance in LKO and fl/fl mice similarly. In the liver, insulin failed to induce phosphorylation of Akt-Ser473 and exclude FOXO1 from the nucleus in LKO mice, a pathway important for liver glucose and lipid metabolism. Liver triglycerides and diacylglycerides were also increased in LKO mice, which corresponded with dysregulation of insulin-stimulated ACC phosphorylation and DGAT1/2 protein levels. Our studies demonstrate that estrogen signaling through ERα in the liver helps prevent whole body and hepatic insulin resistance associated with HFD feeding in males. Augmenting hepatic estrogen signaling through ERα may lessen the impact of obesity on diabetes and cardiovascular risk in males.
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30

Li, Li, LaWanda H. Thompson, Ling Zhao, and Joseph L. Messina. "Tissue-Specific Difference in the Molecular Mechanisms for the Development of Acute Insulin Resistance after Injury." Endocrinology 150, no. 1 (September 18, 2008): 24–32. http://dx.doi.org/10.1210/en.2008-0742.

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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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31

Polkey, Michael, and Mary J. Morrell. "Could Leptin Mediate Insulin Resistance Through Cytokine Signaling?" Journal of Clinical Sleep Medicine 08, no. 02 (April 15, 2012): 229. http://dx.doi.org/10.5664/jcsm.1796.

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Li, Zhi-Yong, Jie Song, Si-Li Zheng, Mao-Bing Fan, Yun-Feng Guan, Yi Qu, Jian Xu, Pei Wang, and Chao-Yu Miao. "Adipocyte Metrnl Antagonizes Insulin Resistance Through PPARγ Signaling." Diabetes 64, no. 12 (August 25, 2015): 4011–22. http://dx.doi.org/10.2337/db15-0274.

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33

Sędzikowska, Aleksandra, and Leszek Szablewski. "Insulin and Insulin Resistance in Alzheimer’s Disease." International Journal of Molecular Sciences 22, no. 18 (September 15, 2021): 9987. http://dx.doi.org/10.3390/ijms22189987.

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Insulin plays a range of roles as an anabolic hormone in peripheral tissues. It regulates glucose metabolism, stimulates glucose transport into cells and suppresses hepatic glucose production. Insulin influences cell growth, differentiation and protein synthesis, and inhibits catabolic processes such as glycolysis, lipolysis and proteolysis. Insulin and insulin-like growth factor-1 receptors are expressed on all cell types in the central nervous system. Widespread distribution in the brain confirms that insulin signaling plays important and diverse roles in this organ. Insulin is known to regulate glucose metabolism, support cognition, enhance the outgrowth of neurons, modulate the release and uptake of catecholamine, and regulate the expression and localization of gamma-aminobutyric acid (GABA). Insulin is also able to freely cross the blood–brain barrier from the circulation. In addition, changes in insulin signaling, caused inter alia insulin resistance, may accelerate brain aging, and affect plasticity and possibly neurodegeneration. There are two significant insulin signal transduction pathways: the PBK/AKT pathway which is responsible for metabolic effects, and the MAPK pathway which influences cell growth, survival and gene expression. The aim of this study is to describe the role played by insulin in the CNS, in both healthy people and those with pathologies such as insulin resistance and Alzheimer’s disease.
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Olver, T. Dylan, Zachary I. Grunewald, Thaysa Ghiarone, Robert M. Restaino, Allan R. K. Sales, Lauren K. Park, Pamela K. Thorne, et al. "Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction." American Journal of Physiology-Heart and Circulatory Physiology 317, no. 5 (November 1, 2019): H1166—H1172. http://dx.doi.org/10.1152/ajpheart.00464.2019.

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Insulin modulates vasomotor tone through vasodilator and vasoconstrictor signaling pathways. The purpose of the present work was to determine whether insulin-stimulated vasoconstriction is a pathophysiological phenomenon that can result from a combination of persistent insulin signaling, suppressed phosphatidylinositol-3 kinase (PI3K) activation, and an ensuing relative increase in MAPK/endothelin-1 (ET-1) activity. First, we examined previously published work from our group where we assessed changes in lower-limb blood flow in response to an oral glucose tolerance test (endogenous insulin stimulation) in lean and obese subjects. The new analyses showed that the peak rise in vascular resistance during the postprandial state was greater in obese compared with lean subjects. We next extended on these findings by demonstrating that insulin-induced vasoconstriction in isolated resistance arteries from obese subjects was attenuated with ET-1 receptor antagonism, thus implicating ET-1 signaling in this constriction response. Last, we examined in isolated resistance arteries from pigs the dual roles of persistent insulin signaling and blunted PI3K activation in modulating vasomotor responses to insulin. We found that prolonged insulin stimulation did not alter vasomotor responses to insulin when insulin-signaling pathways remained unrestricted. However, prolonged insulinization along with pharmacological suppression of PI3K activity resulted in insulin-induced vasoconstriction, rather than vasodilation. Notably, such aberrant vascular response was rescued with either MAPK inhibition or ET-1 receptor antagonism. In summary, we demonstrate that insulin-induced vasoconstriction is a pathophysiological phenomenon that can be recapitulated when sustained insulin signaling is coupled with depressed PI3K activation and the concomitant relative increase in MAPK/ET-1 activity. NEW & NOTEWORTHY This study reveals that insulin-induced vasoconstriction is a pathophysiological phenomenon. We also provide evidence that in the setting of persistent insulin signaling, impaired phosphatidylinositol-3 kinase activation appears to be a requisite feature precipitating MAPK/endothelin 1-dependent insulin-induced vasoconstriction.
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Longato, Lisa, Kelsey Ripp, Mashiko Setshedi, Miroslav Dostalek, Fatemeh Akhlaghi, Mark Branda, Jack R. Wands, and Suzanne M. de la Monte. "Insulin Resistance, Ceramide Accumulation, and Endoplasmic Reticulum Stress in Human Chronic Alcohol-Related Liver Disease." Oxidative Medicine and Cellular Longevity 2012 (2012): 1–17. http://dx.doi.org/10.1155/2012/479348.

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Background. Chronic alcohol-related liver disease (ALD) is mediated by insulin resistance, mitochondrial dysfunction, inflammation, oxidative stress, and DNA damage. Recent studies suggest that dysregulated lipid metabolism with accumulation of ceramides, together with ER stress potentiate hepatic insulin resistance and may cause steatohepatitis to progress.Objective. We examined the degree to which hepatic insulin resistance in advanced human ALD is correlated with ER stress, dysregulated lipid metabolism, and ceramide accumulation.Methods. We assessed the integrity of insulin signaling through the Akt pathway and measured proceramide and ER stress gene expression, ER stress signaling proteins, and ceramide profiles in liver tissue.Results. Chronic ALD was associated with increased expression of insulin, IGF-1, and IGF-2 receptors, impaired signaling through IGF-1R and IRS1, increased expression of multiple proceramide and ER stress genes and proteins, and higher levels of the C14, C16, C18, and C20 ceramide species relative to control.Conclusions. In human chronic ALD, persistent hepatic insulin resistance is associated with dysregulated lipid metabolism, ceramide accumulation, and striking upregulation of multiple ER stress signaling molecules. Given the role of ceramides as mediators of ER stress and insulin resistance, treatment with ceramide enzyme inhibitors may help reverse or halt progression of chronic ALD.
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Damanik, Gustiany Nadya, and Hadyanto Lim. "The Effect of Pare (Momordica Charantia L.) Fruit Extract Fraction on Reducing Blood Sugar, Insulin Resistance and Phosphatidyl Inositol 3 Kinase (PI3K) Signalling in Male Rats (Rattus novergicus) Streptozotocin-induced Hyperglycemia." International Journal of Biomedical Herbal Medicine 1, no. 1 (December 12, 2021): 29–35. http://dx.doi.org/10.46880/ijbhm.v1i1.734.

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Background: Diabetes mellitus (DM) is a metabolic disease characterized by symptoms of hyperglycemia as a result of impaired insulin secretion. The main cause of type 2 diabetes mellitus is a metabolic disorder characterized by insulin receptor resistance, reduced ability of pancreatic -cells to secrete insulin, and abnormal insulin secretion from cells of the pancreatic islets of Langerhans. In insulin resistance, the signaling defect in Phosphatidylinositol 3-kinase (PI3K) causes impaired glucose regulation in the body. The purpose of this study was to determine the effect of bitter melon extract (Momordica charantia L.) on lowering blood sugar, insulin resistance, and phosphatidylinositol 3kinase (PI3K) signaling. Method: Literature review studies from related journals. Results: Based on research conducted, it is known that bitter melon extract has an effect on blood sugar, insulin resistance, and PI3K signaling. Conclusion: Bitter gourd extract has potential as an herbal antidiuretic drug.
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37

Ghoshal, Kakali, Xiyue Li, Dungeng Peng, John R. Falck, Raghunath Reddy Anugu, Manuel Chiusa, John M. Stafford, et al. "EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance." Diabetes 71, no. 1 (October 21, 2021): 83–92. http://dx.doi.org/10.2337/db21-0298.

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We previously showed that global deletion of the cytochrome P450 epoxygenase Cyp2c44, 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 in vivo in Cyp2c44−/− mice and investigated the underlying mechanisms by which this effect is exerted. Cyp2c44−/− mice treated with the analog disodium 13-(3-pentylureido)tridec-8(Z)-enoyl)-LL-aspartate2 (EET-A) for 4 weeks improved fasting glucose and glucose tolerance compared with Cyp2c44−/− 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 Cyp2c44−/− hepatocytes and that 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.
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38

Kothmann, Kadden H., Victoria Jacobsen, Emily Laffitte, Corinne Bromfield, Matthew Grizzaffi, Monica Jarboe, Andrea G. Braundmeier-Fleming, Janice M. Bahr, Romana A. Nowak, and Annie E. Newell-Fugate. "Virilizing doses of testosterone decrease circulating insulin levels and differentially regulate insulin signaling in liver and adipose tissue of females." American Journal of Physiology-Endocrinology and Metabolism 320, no. 6 (June 1, 2021): E1107—E1118. http://dx.doi.org/10.1152/ajpendo.00281.2020.

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Acute virilizing doses of testosterone administered to females suppress circulating insulin levels, upregulate components of the insulin-signaling pathway in liver, and suppress insulin signaling in white adipose tissue. These results suggest that insulin resistance in transgender men may be due to suppression of the insulin-signaling pathway and decreased insulin sensitivity in white adipose tissue.
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39

Petersen, Max C., and Gerald I. Shulman. "Mechanisms of Insulin Action and Insulin Resistance." Physiological Reviews 98, no. 4 (October 1, 2018): 2133–223. http://dx.doi.org/10.1152/physrev.00063.2017.

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The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.
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40

Chen, Yang, Lili Huang, Xinzhou Qi, and Chen Chen. "Insulin Receptor Trafficking: Consequences for Insulin Sensitivity and Diabetes." International Journal of Molecular Sciences 20, no. 20 (October 10, 2019): 5007. http://dx.doi.org/10.3390/ijms20205007.

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Insulin receptor (INSR) has been extensively studied in the area of cell proliferation and energy metabolism. Impaired INSR activities lead to insulin resistance, the key factor in the pathology of metabolic disorders including type 2 diabetes mellitus (T2DM). The mainstream opinion is that insulin resistance begins at a post-receptor level. The role of INSR activities and trafficking in insulin resistance pathogenesis has been largely ignored. Ligand-activated INSR is internalized and trafficked to early endosome (EE), where INSR is dephosphorylated and sorted. INSR can be subsequently conducted to lysosome for degradation or recycled back to the plasma membrane. The metabolic fate of INSR in cellular events implies the profound influence of INSR on insulin signaling pathways. Disruption of INSR-coupled activities has been identified in a wide range of insulin resistance-related diseases such as T2DM. Accumulating evidence suggests that alterations in INSR trafficking may lead to severe insulin resistance. However, there is very little understanding of how altered INSR activities undermine complex signaling pathways to the development of insulin resistance and T2DM. Here, we focus this review on summarizing previous findings on the molecular pathways of INSR trafficking in normal and diseased states. Through this review, we provide insights into the mechanistic role of INSR intracellular processes and activities in the development of insulin resistance and diabetes.
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41

Leng, Sanhua, Wenshuo Zhang, Yanbin Zheng, Ziva Liberman, Christopher J. Rhodes, Hagit Eldar-Finkelman, and Xiao Jian Sun. "Glycogen synthase kinase 3β mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1." Journal of Endocrinology 206, no. 2 (May 12, 2010): 171–81. http://dx.doi.org/10.1677/joe-09-0456.

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High glucose (HG) has been shown to induce insulin resistance in both type 1 and type 2 diabetes. However, the molecular mechanism behind this phenomenon is unknown. Insulin receptor substrate (IRS) proteins are the key signaling molecules that mediate insulin's intracellular actions. Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. We have identified glycogen synthase kinase 3β (GSK3β or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine332 phosphorylation, ubiquitination, and degradation of IRS1. Overexpression of IRS1 with mutation of serine332 to alanine partially prevents HG-induced IRS1 degradation. Furthermore, overexpression of constitutively active GSK3β was sufficient to induce IRS1 degradation. Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3β contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1.
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42

Haider, Nida, Jasmin Lebastchi, Ashok K. Jayavelu, Thiago M. Batista, Hui Pan, Jonathan M. Dreyfuss, Ivan Carcamo-Orive, Joshua W. Knowles, Matthias Mann, and Carl Ronald Kahn. "Insulin Resistance and Gender Define a Cell Autonomous Supernetworkof Protein Phosphorylation." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A446. http://dx.doi.org/10.1210/jendso/bvab048.912.

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Abstract Many hormones and growth factors, including insulin, act through networks of protein phosphorylation. Insulin resistance is an important factor in the pathophysiology of many metabolic disorders. The aim of this study was to uncover the cell autonomous determinants of insulin action and protein phosphorylation using induced pluripotent stem cell (iPSC)-derived myoblasts (iMyos) in vitro. Here, we show that iMyos from non-diabetic individuals in the highest quintile of insulin resistance show impaired insulin signaling, defective insulin-stimulated glucose uptake and decreased glycogen synthase activity compared to iMyos from the insulin sensitive individuals, indicating these cells mirror in vitro the alterations seen in vivo. Global phosphoproteomic analysis uncovered a large network of proteins whose phosphorylation was altered in association with insulin resistance, most outside the canonical insulin-signaling cascade. More surprisingly, we also observed striking differences in the phosphoproteomic signature of iMyos derived from male versus female subjects, involving multiple pathways regulating diverse cellular functions, including DNA and RNA processing, GTPase signaling, and SUMOylation/ubiquitination. These findings provide new insights into the cell autonomous mechanisms underlying insulin resistance in the non-diabetic population and provide evidence of a major, previously unrecognized, supernetwork of cell signaling differences in males and females that must be considered in understanding the molecular basis of sex-based differences in normal physiology and disease.
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Nguyen, Mai Thi, Kyung-Ho Min, and Wan Lee. "MiR-183-5p Induced by Saturated Fatty Acids Hinders Insulin Signaling by Downregulating IRS-1 in Hepatocytes." International Journal of Molecular Sciences 23, no. 6 (March 10, 2022): 2979. http://dx.doi.org/10.3390/ijms23062979.

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Excessive saturated fatty acids (SFA) uptake is known to be a primary cause of obesity, a widely acknowledged risk factor of insulin resistance and type 2 diabetes. Although specific microRNAs (miRNAs) targeting insulin signaling intermediates are dysregulated by SFA, their effects on insulin signaling and sensitivity are largely unknown. Here, we investigated the role of SFA-induced miR-183-5p in the regulation of proximal insulin signaling molecules and the development of hepatic insulin resistance. HepG2 hepatocytes treated with palmitate and the livers of high-fat diet (HFD)-fed mice exhibited impaired insulin signaling resulting from dramatic reductions in the protein expressions of insulin receptor (INSR) and insulin receptor substrate-1 (IRS-1). Differential expression analysis showed the level of miR-183-5p, which tentatively targets the 3′UTR of IRS-1, was significantly elevated in palmitate-treated HepG2 hepatocytes and the livers of HFD-fed mice. Dual-luciferase analysis showed miR-183-5p bound directly to the 3′UTR of IRS-1 and reduced IRS-1 expression at the post-transcriptional stage. Moreover, transfection of HepG2 hepatocytes with miR-183-5p mimic significantly inhibited IRS-1 expression and hindered insulin signaling, consequently inhibiting insulin-stimulated glycogen synthesis. Collectively, this study reveals a novel mechanism whereby miR-183-5p induction by SFA impairs insulin signaling and suggests miR-183-5p plays a crucial role in the pathogenesis of hepatic insulin resistance in the background of obesity.
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44

Lee, Warren L., and Amira Klip. "Endothelial Transcytosis of Insulin: Does It Contribute to Insulin Resistance?" Physiology 31, no. 5 (September 2016): 336–45. http://dx.doi.org/10.1152/physiol.00010.2016.

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Most research on insulin resistance has focused on impaired signaling at the level of target tissues like skeletal muscle. Insulin delivery is also important and includes recruitment and perfusion of capillaries bearing insulin, but also the transit of insulin across the capillary endothelium. The mechanisms of this second stage (insulin transcytosis) and whether it contributes to insulin resistance remain uncertain.
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45

Ma, Yuchen, Ping Wang, Joachim F. Kuebler, Irshad H. Chaudry, and Joseph L. Messina. "Hemorrhage induces the rapid development of hepatic insulin resistance." American Journal of Physiology-Gastrointestinal and Liver Physiology 284, no. 1 (January 1, 2003): G107—G115. http://dx.doi.org/10.1152/ajpgi.00217.2002.

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Hyperglycemia is an early metabolic response to trauma and hemorrhage. The role of hepatic insulin resistance to the development of this hyperglycemia is not well understood. The aim of this study was to determine whether the liver becomes insulin resistant and to identify the particular hepatic insulin signaling pathways that may be compromised following trauma and hemorrhage. Male adult rats were bled to a mean arterial pressure of 40 mmHg and maintained at that pressure for 90 min followed by resuscitation with Ringer lactate. Data showed that trauma and hemorrhage rapidly induced profound hyperinsulinemia in combination with significant hyperglycemia, suggesting the development of insulin resistance. After trauma and hemorrhage, hepatic insulin signaling via the insulin-induced phosphatidylinositol 3 (PI3)-kinase-Akt pathway was abolished, whereas ERK1/2 signaling was relatively normal. The regulation (inhibition) of a hepatic-, insulin-, and the PI3-kinase-dependent gene, IGF binding protein-1, was also lost. The present study provides convincing evidence of a rapid onset hepatic insulin resistance following a combination of trauma and hemorrhage.
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46

Jiang, Shaoning, and Joseph L. Messina. "Role of inhibitory κB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes." American Journal of Physiology-Gastrointestinal and Liver Physiology 301, no. 3 (September 2011): G454—G463. http://dx.doi.org/10.1152/ajpgi.00148.2011.

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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.
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47

Gupta, Amit, and Chinmoy Sankar Dey. "PTEN, a widely known negative regulator of insulin/PI3K signaling, positively regulates neuronal insulin resistance." Molecular Biology of the Cell 23, no. 19 (October 2012): 3882–98. http://dx.doi.org/10.1091/mbc.e12-05-0337.

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Lipid and protein tyrosine phosphatase, phosphatase and tension homologue (PTEN), is a widely known negative regulator of insulin/phosphoinositide 3-kinase signaling. Down-regulation of PTEN is thus widely documented to ameliorate insulin resistance in peripheral tissues such as skeletal muscle and adipose. However, not much is known about its exact role in neuronal insulin signaling and insulin resistance. Moreover, alterations of PTEN in neuronal systems have led to discovery of several unexpected outcomes, including in the neurodegenerative disorder Alzheimer's disease (AD), which is increasingly being recognized as a brain-specific form of diabetes. In addition, contrary to expectations, its neuron-specific deletion in mice resulted in development of diet-sensitive obesity. The present study shows that PTEN, paradoxically, positively regulates neuronal insulin signaling and glucose uptake. Its down-regulation exacerbates neuronal insulin resistance. The positive role of PTEN in neuronal insulin signaling is likely due to its protein phosphatase actions, which prevents the activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), the kinases critically involved in neuronal energy impairment and neurodegeneration. Results suggest that PTEN acting through FAK, the direct protein substrate of PTEN, prevents ERK activation. Our findings provide an explanation for unexpected outcomes reported earlier with PTEN alterations in neuronal systems and also suggest a novel molecular pathway linking neuronal insulin resistance and AD, the two pathophysiological states demonstrated to be closely linked.
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48

Peng, Jinghua, and Ling He. "IRS posttranslational modifications in regulating insulin signaling." Journal of Molecular Endocrinology 60, no. 1 (January 2018): R1—R8. http://dx.doi.org/10.1530/jme-17-0151.

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Insulin resistance is the hallmark of type 2 diabetes; however, the mechanism underlying the development of insulin resistance is still not completely understood. Previous reports showed that posttranslational modifications of IRS play a critical role in insulin signaling, especially the phosphorylation of IRS by distinct kinases. While it is known that increasing Sirtuin1 deacetylase activity improves insulin sensitivity in the liver, the identity of its counterpart, an acetyl-transferase, remains unknown. Our recent study shows that elevated endotoxin (LPS) levels in the liver of obese mice lead to the induction of the acetyl-transferase P300 through the IRE1-XBP1s pathway. Subsequently, induced P300 impairs insulin signaling by acetylating IRS1 and IRS2 in the insulin signaling pathway. Therefore, the P300 acetyl-transferase activity appears to be a promising therapeutic target for the treatment of diabetes.
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Gray, Sarah L., Christine Donald, Arif Jetha, Scott D. Covey, and Timothy J. Kieffer. "Hyperinsulinemia Precedes Insulin Resistance in Mice Lacking Pancreatic β-Cell Leptin Signaling." Endocrinology 151, no. 9 (July 14, 2010): 4178–86. http://dx.doi.org/10.1210/en.2010-0102.

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The adipocyte hormone leptin acts centrally and peripherally to regulate body weight and glucose homeostasis. The pancreatic β-cell has been shown to be a key peripheral target of leptin, with leptin suppressing insulin synthesis and secretion from β-cells both in vitro and in vivo. Mice with disrupted leptin signaling in β-cells (leprflox/flox RIPcre tg+ mice) display hyperinsulinemia, insulin resistance, glucose intolerance, obesity, and reduced fasting blood glucose. We hypothesized that hyperinsulinemia precedes the development of insulin resistance and increased adiposity in these mice with a defective adipoinsular axis. To determine the primary defect after impaired β-cell leptin signaling, we treated leprflox/flox RIPcre tg+ mice with the insulin sensitizer metformin or the insulin-lowering agent diazoxide with the rationale that pharmacological improvement of the primary defect would alleviate the secondary symptoms. We show that improving insulin sensitivity with metformin does not normalize hyperinsulinemia, whereas lowering insulin levels with diazoxide improves insulin sensitivity. Taken together, these results suggest that hyperinsulinemia precedes insulin resistance in β-cell leptin receptor-deficient mice, with insulin resistance developing as a secondary consequence of excessive insulin secretion. Therefore, pancreatic β-cell leptin receptor-deficient mice may represent a model of obesity-associated insulin resistance that is initiated by hyperinsulinemia.
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Yang, Xueping, Lingli Li, Ke Fang, Ruolan Dong, Jingbin Li, Yan Zhao, Hui Dong, et al. "Wu-Mei-Wan Reduces Insulin Resistance via Inhibition of NLRP3 Inflammasome Activation in HepG2 Cells." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/7283241.

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Wu-Mei-Wan (WMW) is a Chinese herbal formula used to treat type 2 diabetes. In this study, we aimed to explore the effects and mechanisms of WMW on insulin resistance in HepG2 cells. HepG2 cells were pretreated with palmitate (0.25 mM) to impair the insulin signaling pathway. Then, they were treated with different doses of WMW-containing medicated serum and stimulated with 100 nM insulin. Results showed that palmitate could reduce the glucose consumption rate in HepG2 cells and impair insulin signaling related to phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), thereby regulating the downstream signaling pathways. However, medicated serum of WMW restored impaired insulin signaling, upregulated the expression of phospho-IR (pIR), phosphatidylinositol 3-kinase p85 subunit, phosphoprotein kinase B, and glucose transporter 4, and decreased IRS serine phosphorylation. In addition, it decreased the expression of interleukin-1β and tumor necrosis factor-α, which are the key proinflammatory cytokines involved in insulin resistance; besides, it reduced the expression of NLRP3 inflammasome. These results suggested that WMW could alleviate palmitate-induced insulin resistance in HepG2 cells via inhibition of NLRP3 inflammasome and reduction of proinflammatory cytokine production.
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