195-OR: The P66Shc Protein Mediates Insulin Resistance in Pancreatic β Cells Under Lipotoxic Conditions
Insulin, acting in an autocrine manner, promotes β-cell survival and growth and its own biosynthesis and secretion. Prolonged exposure of β-cells to high levels of saturated fatty acids (SFAs) impairs insulin signaling, reducing the ability of insulin to promote its release. The p66Shc protein is an...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2019-06, Vol.68 |
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| container_title | Diabetes (New York, N.Y.) |
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| creator | Dipaola, Lucia Natalicchio, Annalisa Biondi, Giuseppina Marrano, Nicola Bugliani, Marco Cignarelli, Angelo Perrini, Sebastio Marchetti, Piero Laviola, Luigi Dipaola, Francesco Giorginolucia Giorgino, Francesco |
| description | Insulin, acting in an autocrine manner, promotes β-cell survival and growth and its own biosynthesis and secretion. Prolonged exposure of β-cells to high levels of saturated fatty acids (SFAs) impairs insulin signaling, reducing the ability of insulin to promote its release. The p66Shc protein is an inducer of cellular oxidative stress and apoptosis, and its mRNA levels are increased in pancreatic islets from overweight/obese subjects. Here we evaluated the role of p66Shc in pancreatic β-cell insulin resistance (IR) occurring in obesity and lipotoxic conditions. Insulin effects on its own content and C-peptide secretion were studied in pancreatic islets from overweight/obese (BMI ≥25 kg/m2) compared to lean (BMI |
| doi_str_mv | 10.2337/db19-195-OR |
| format | Article |
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Prolonged exposure of β-cells to high levels of saturated fatty acids (SFAs) impairs insulin signaling, reducing the ability of insulin to promote its release. The p66Shc protein is an inducer of cellular oxidative stress and apoptosis, and its mRNA levels are increased in pancreatic islets from overweight/obese subjects. Here we evaluated the role of p66Shc in pancreatic β-cell insulin resistance (IR) occurring in obesity and lipotoxic conditions. Insulin effects on its own content and C-peptide secretion were studied in pancreatic islets from overweight/obese (BMI ≥25 kg/m2) compared to lean (BMI <25 kg/m2) human donors, and in INS-1E cells, murine pancreatic islets and human pancreatic islets exposed to palmitate. To evaluate the role of p66Shc in lipotoxicity-induced β-cell IR, p66Shc levels were silenced or overexpressed. Pancreatic islets from overweight/obese subjects showed a reduced ability of insulin to increase its own biosynthesis and C-peptide secretion. Similarly, prolonged exposure to palmitate augmented p66Shc levels and induced IR in INS-1E cells, human islets and murine islets. When p66Shc protein levels were reduced, insulin-induced C-peptide secretion was enhanced, and the palmitate-induced reductions of C-peptide levels and insulin content were both reversed. By contrast, p66Shc overexpression resulted in inhibition of insulin-induced C-peptide secretion and increase of insulin content, both in absence and presence of palmitate. These effects of p66Shc were found to require p70S6K (Thr389) and IRS-1 (Ser307) phosphorylation, which inhibited insulin-stimulated Akt phosphorylation. In conclusion, the protein p66Shc exerts an inhibitory effect on β-cell insulin signaling and can mediate the ability of SFAs and excess body fat to cause β-cell IR, which results in both reduced survival and impaired secretory function.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db19-195-OR</identifier><language>eng</language><publisher>New York: American Diabetes Association</publisher><subject>AKT protein ; Apoptosis ; Autocrine signalling ; Beta cells ; Biosynthesis ; Body fat ; Body weight ; Cell survival ; Fatty acids ; Glucose ; Insulin ; Insulin receptor substrate 1 ; Insulin resistance ; mRNA ; Obesity ; Overweight ; Oxidative stress ; Palmitic acid ; Pancreas ; Peptides ; Phosphorylation ; Proteins ; Secretion</subject><ispartof>Diabetes (New York, N.Y.), 2019-06, Vol.68</ispartof><rights>Copyright American Diabetes Association Jun 1, 2019</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Dipaola, Lucia</creatorcontrib><creatorcontrib>Natalicchio, Annalisa</creatorcontrib><creatorcontrib>Biondi, Giuseppina</creatorcontrib><creatorcontrib>Marrano, Nicola</creatorcontrib><creatorcontrib>Bugliani, Marco</creatorcontrib><creatorcontrib>Cignarelli, Angelo</creatorcontrib><creatorcontrib>Perrini, Sebastio</creatorcontrib><creatorcontrib>Marchetti, Piero</creatorcontrib><creatorcontrib>Laviola, Luigi</creatorcontrib><creatorcontrib>Dipaola, Francesco Giorginolucia</creatorcontrib><creatorcontrib>Giorgino, Francesco</creatorcontrib><title>195-OR: The P66Shc Protein Mediates Insulin Resistance in Pancreatic β Cells Under Lipotoxic Conditions</title><title>Diabetes (New York, N.Y.)</title><description>Insulin, acting in an autocrine manner, promotes β-cell survival and growth and its own biosynthesis and secretion. Prolonged exposure of β-cells to high levels of saturated fatty acids (SFAs) impairs insulin signaling, reducing the ability of insulin to promote its release. The p66Shc protein is an inducer of cellular oxidative stress and apoptosis, and its mRNA levels are increased in pancreatic islets from overweight/obese subjects. Here we evaluated the role of p66Shc in pancreatic β-cell insulin resistance (IR) occurring in obesity and lipotoxic conditions. Insulin effects on its own content and C-peptide secretion were studied in pancreatic islets from overweight/obese (BMI ≥25 kg/m2) compared to lean (BMI <25 kg/m2) human donors, and in INS-1E cells, murine pancreatic islets and human pancreatic islets exposed to palmitate. To evaluate the role of p66Shc in lipotoxicity-induced β-cell IR, p66Shc levels were silenced or overexpressed. Pancreatic islets from overweight/obese subjects showed a reduced ability of insulin to increase its own biosynthesis and C-peptide secretion. Similarly, prolonged exposure to palmitate augmented p66Shc levels and induced IR in INS-1E cells, human islets and murine islets. When p66Shc protein levels were reduced, insulin-induced C-peptide secretion was enhanced, and the palmitate-induced reductions of C-peptide levels and insulin content were both reversed. By contrast, p66Shc overexpression resulted in inhibition of insulin-induced C-peptide secretion and increase of insulin content, both in absence and presence of palmitate. These effects of p66Shc were found to require p70S6K (Thr389) and IRS-1 (Ser307) phosphorylation, which inhibited insulin-stimulated Akt phosphorylation. In conclusion, the protein p66Shc exerts an inhibitory effect on β-cell insulin signaling and can mediate the ability of SFAs and excess body fat to cause β-cell IR, which results in both reduced survival and impaired secretory function.</description><subject>AKT protein</subject><subject>Apoptosis</subject><subject>Autocrine signalling</subject><subject>Beta cells</subject><subject>Biosynthesis</subject><subject>Body fat</subject><subject>Body weight</subject><subject>Cell survival</subject><subject>Fatty acids</subject><subject>Glucose</subject><subject>Insulin</subject><subject>Insulin receptor substrate 1</subject><subject>Insulin resistance</subject><subject>mRNA</subject><subject>Obesity</subject><subject>Overweight</subject><subject>Oxidative stress</subject><subject>Palmitic acid</subject><subject>Pancreas</subject><subject>Peptides</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Secretion</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNqNistKAzEUhoO04Ni68gUOuI7mohPjdqgoKB16AXdlnDkyKUPS5mTA5_JBfCYD-gDlX_yX72fsSoobpbW57T6k5dLe8-XqjBXSasu1Mu8TVgghFZfGmnN2QbQXQpRZBev_3o-w6RHqslz3LdQxJHQe3rBzTUKCF0_jkIcVkqPU-BYhtzqHiE1yLfx8Q4XDQLD1HUZ4dYeQwlcGVfCdSy54mrPpZzMQXv77jF0_LTbVMz_EcByR0m4fxugz2il196CtsaXSp71-AbUtTHk</recordid><startdate>20190601</startdate><enddate>20190601</enddate><creator>Dipaola, Lucia</creator><creator>Natalicchio, Annalisa</creator><creator>Biondi, Giuseppina</creator><creator>Marrano, Nicola</creator><creator>Bugliani, Marco</creator><creator>Cignarelli, Angelo</creator><creator>Perrini, Sebastio</creator><creator>Marchetti, Piero</creator><creator>Laviola, Luigi</creator><creator>Dipaola, Francesco Giorginolucia</creator><creator>Giorgino, Francesco</creator><general>American Diabetes Association</general><scope>K9.</scope><scope>NAPCQ</scope></search><sort><creationdate>20190601</creationdate><title>195-OR: The P66Shc Protein Mediates Insulin Resistance in Pancreatic β Cells Under Lipotoxic Conditions</title><author>Dipaola, Lucia ; Natalicchio, Annalisa ; Biondi, Giuseppina ; Marrano, Nicola ; Bugliani, Marco ; Cignarelli, Angelo ; Perrini, Sebastio ; Marchetti, Piero ; Laviola, Luigi ; Dipaola, Francesco Giorginolucia ; Giorgino, Francesco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_22483979623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>AKT protein</topic><topic>Apoptosis</topic><topic>Autocrine signalling</topic><topic>Beta cells</topic><topic>Biosynthesis</topic><topic>Body fat</topic><topic>Body weight</topic><topic>Cell survival</topic><topic>Fatty acids</topic><topic>Glucose</topic><topic>Insulin</topic><topic>Insulin receptor substrate 1</topic><topic>Insulin resistance</topic><topic>mRNA</topic><topic>Obesity</topic><topic>Overweight</topic><topic>Oxidative stress</topic><topic>Palmitic acid</topic><topic>Pancreas</topic><topic>Peptides</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Secretion</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dipaola, Lucia</creatorcontrib><creatorcontrib>Natalicchio, Annalisa</creatorcontrib><creatorcontrib>Biondi, Giuseppina</creatorcontrib><creatorcontrib>Marrano, Nicola</creatorcontrib><creatorcontrib>Bugliani, Marco</creatorcontrib><creatorcontrib>Cignarelli, Angelo</creatorcontrib><creatorcontrib>Perrini, Sebastio</creatorcontrib><creatorcontrib>Marchetti, Piero</creatorcontrib><creatorcontrib>Laviola, Luigi</creatorcontrib><creatorcontrib>Dipaola, Francesco Giorginolucia</creatorcontrib><creatorcontrib>Giorgino, Francesco</creatorcontrib><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dipaola, Lucia</au><au>Natalicchio, Annalisa</au><au>Biondi, Giuseppina</au><au>Marrano, Nicola</au><au>Bugliani, Marco</au><au>Cignarelli, Angelo</au><au>Perrini, Sebastio</au><au>Marchetti, Piero</au><au>Laviola, Luigi</au><au>Dipaola, Francesco Giorginolucia</au><au>Giorgino, Francesco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>195-OR: The P66Shc Protein Mediates Insulin Resistance in Pancreatic β Cells Under Lipotoxic Conditions</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><date>2019-06-01</date><risdate>2019</risdate><volume>68</volume><issn>0012-1797</issn><eissn>1939-327X</eissn><abstract>Insulin, acting in an autocrine manner, promotes β-cell survival and growth and its own biosynthesis and secretion. Prolonged exposure of β-cells to high levels of saturated fatty acids (SFAs) impairs insulin signaling, reducing the ability of insulin to promote its release. The p66Shc protein is an inducer of cellular oxidative stress and apoptosis, and its mRNA levels are increased in pancreatic islets from overweight/obese subjects. Here we evaluated the role of p66Shc in pancreatic β-cell insulin resistance (IR) occurring in obesity and lipotoxic conditions. Insulin effects on its own content and C-peptide secretion were studied in pancreatic islets from overweight/obese (BMI ≥25 kg/m2) compared to lean (BMI <25 kg/m2) human donors, and in INS-1E cells, murine pancreatic islets and human pancreatic islets exposed to palmitate. To evaluate the role of p66Shc in lipotoxicity-induced β-cell IR, p66Shc levels were silenced or overexpressed. Pancreatic islets from overweight/obese subjects showed a reduced ability of insulin to increase its own biosynthesis and C-peptide secretion. Similarly, prolonged exposure to palmitate augmented p66Shc levels and induced IR in INS-1E cells, human islets and murine islets. When p66Shc protein levels were reduced, insulin-induced C-peptide secretion was enhanced, and the palmitate-induced reductions of C-peptide levels and insulin content were both reversed. By contrast, p66Shc overexpression resulted in inhibition of insulin-induced C-peptide secretion and increase of insulin content, both in absence and presence of palmitate. These effects of p66Shc were found to require p70S6K (Thr389) and IRS-1 (Ser307) phosphorylation, which inhibited insulin-stimulated Akt phosphorylation. In conclusion, the protein p66Shc exerts an inhibitory effect on β-cell insulin signaling and can mediate the ability of SFAs and excess body fat to cause β-cell IR, which results in both reduced survival and impaired secretory function.</abstract><cop>New York</cop><pub>American Diabetes Association</pub><doi>10.2337/db19-195-OR</doi></addata></record> |
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| subjects | AKT protein Apoptosis Autocrine signalling Beta cells Biosynthesis Body fat Body weight Cell survival Fatty acids Glucose Insulin Insulin receptor substrate 1 Insulin resistance mRNA Obesity Overweight Oxidative stress Palmitic acid Pancreas Peptides Phosphorylation Proteins Secretion |
| title | 195-OR: The P66Shc Protein Mediates Insulin Resistance in Pancreatic β Cells Under Lipotoxic Conditions |
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