195-OR: The P66Shc Protein Mediates Insulin Resistance in Pancreatic ß Cells Under Lipotoxic Conditions

195-OR: The P66Shc Protein Mediates Insulin Resistance in Pancreatic ß 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 (Supplement_1)
Hauptverfasser: DIPAOLA, LUCIA, NATALICCHIO, ANNALISA, BIONDI, GIUSEPPINA, MARRANO, NICOLA, BUGLIANI, MARCO, CIGNARELLI, ANGELO, PERRINI, SEBASTIO, MARCHETTI, PIERO, LAVIOLA, LUIGI, GIORGINO, FRANCESCO
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container_issue Supplement_1
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container_title Diabetes (New York, N.Y.)
container_volume 68
creator DIPAOLA, LUCIA
NATALICCHIO, ANNALISA
BIONDI, GIUSEPPINA
MARRANO, NICOLA
BUGLIANI, MARCO
CIGNARELLI, ANGELO
PERRINI, SEBASTIO
MARCHETTI, PIERO
LAVIOLA, LUIGI
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
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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 &lt;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. 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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. 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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 &lt;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. 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title 195-OR: The P66Shc Protein Mediates Insulin Resistance in Pancreatic ß Cells Under Lipotoxic Conditions
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