Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets

Derek K. Hagman, Martin G. Latour, Swarup K. Chakrabarti, Ghislaine Fontes, Julie Amyot, Caroline Tremblay, Meriem Semache, James A. Lausier, Violet Roskens, Raghu Mirmira, Thomas L. Jetton, Vincent Poitout

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE-Prolonged exposure of isolated islets of Langer-hans to elevated levels of fatty acids, in the presence of high glucose, impairs insulin gene expression via a transcriptional mechanism involving nuclear exclusion of pancreas-duodenum homeobox-1 (Pdx-1) and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown. Our objective was therefore to ascertain whether chronic nutrient oversupply inhibits insulin gene expression in vivo. RESEARCH DESIGN AND METHODS-Wistar rats received alternating 4-h infusions of glucose and Intralipid for a total of 72 h. Control groups received alternating infusions of glucose and saline, saline and Intralipid, or saline only. Insulin and C-peptide secretion were measured under hyperglycemic clamps. Insulin secretion and gene expression were assessed in isolated islets, and β-cell mass was quantified by morphometric analysis. RESULTS-Neither C-peptide secretion nor insulin sensitivity was different among infusion regimens. Insulin content and insulin mRNA levels were lower in islets isolated from rats infused with glucose plus Intralipid. This was associated with reduced Pdx-1 binding to the endogenous insulin promoter, and an increased proportion of Pdx-1 localized in the cytoplasm versus the nucleus. In contrast, MafA mRNA and protein levels and B-cell mass and proliferation were unchanged. CONCLUSIONS-Cyclical and alternating infusions of glucose and Intralipid in normal rats inhibit insulin gene expression without affecting insulin secretion or β-cell mass. We conclude that fatty acid inhibition of insulin gene expression, in the presence of high glucose, is an early functional defect that may contribute to β-cell failure in type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)424-431
Number of pages8
JournalDiabetes
Volume57
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

Fingerprint

Homeobox Genes
Duodenum
Pancreas
Insulin
Gene Expression
Glucose
C-Peptide
Fatty Acids
phospholipid emulsion soybean oil
Messenger RNA
Islets of Langerhans
Type 2 Diabetes Mellitus
Insulin Resistance
Wistar Rats
Cytoplasm
B-Lymphocytes
Research Design
Cell Proliferation
Food
Control Groups

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Hagman, D. K., Latour, M. G., Chakrabarti, S. K., Fontes, G., Amyot, J., Tremblay, C., ... Poitout, V. (2008). Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets. Diabetes, 57(2), 424-431. https://doi.org/10.2337/db07-1285

Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets. / Hagman, Derek K.; Latour, Martin G.; Chakrabarti, Swarup K.; Fontes, Ghislaine; Amyot, Julie; Tremblay, Caroline; Semache, Meriem; Lausier, James A.; Roskens, Violet; Mirmira, Raghu; Jetton, Thomas L.; Poitout, Vincent.

In: Diabetes, Vol. 57, No. 2, 02.2008, p. 424-431.

Research output: Contribution to journalArticle

Hagman, DK, Latour, MG, Chakrabarti, SK, Fontes, G, Amyot, J, Tremblay, C, Semache, M, Lausier, JA, Roskens, V, Mirmira, R, Jetton, TL & Poitout, V 2008, 'Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets', Diabetes, vol. 57, no. 2, pp. 424-431. https://doi.org/10.2337/db07-1285
Hagman, Derek K. ; Latour, Martin G. ; Chakrabarti, Swarup K. ; Fontes, Ghislaine ; Amyot, Julie ; Tremblay, Caroline ; Semache, Meriem ; Lausier, James A. ; Roskens, Violet ; Mirmira, Raghu ; Jetton, Thomas L. ; Poitout, Vincent. / Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets. In: Diabetes. 2008 ; Vol. 57, No. 2. pp. 424-431.
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abstract = "OBJECTIVE-Prolonged exposure of isolated islets of Langer-hans to elevated levels of fatty acids, in the presence of high glucose, impairs insulin gene expression via a transcriptional mechanism involving nuclear exclusion of pancreas-duodenum homeobox-1 (Pdx-1) and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown. Our objective was therefore to ascertain whether chronic nutrient oversupply inhibits insulin gene expression in vivo. RESEARCH DESIGN AND METHODS-Wistar rats received alternating 4-h infusions of glucose and Intralipid for a total of 72 h. Control groups received alternating infusions of glucose and saline, saline and Intralipid, or saline only. Insulin and C-peptide secretion were measured under hyperglycemic clamps. Insulin secretion and gene expression were assessed in isolated islets, and β-cell mass was quantified by morphometric analysis. RESULTS-Neither C-peptide secretion nor insulin sensitivity was different among infusion regimens. Insulin content and insulin mRNA levels were lower in islets isolated from rats infused with glucose plus Intralipid. This was associated with reduced Pdx-1 binding to the endogenous insulin promoter, and an increased proportion of Pdx-1 localized in the cytoplasm versus the nucleus. In contrast, MafA mRNA and protein levels and B-cell mass and proliferation were unchanged. CONCLUSIONS-Cyclical and alternating infusions of glucose and Intralipid in normal rats inhibit insulin gene expression without affecting insulin secretion or β-cell mass. We conclude that fatty acid inhibition of insulin gene expression, in the presence of high glucose, is an early functional defect that may contribute to β-cell failure in type 2 diabetes.",
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T1 - Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets

AU - Hagman, Derek K.

AU - Latour, Martin G.

AU - Chakrabarti, Swarup K.

AU - Fontes, Ghislaine

AU - Amyot, Julie

AU - Tremblay, Caroline

AU - Semache, Meriem

AU - Lausier, James A.

AU - Roskens, Violet

AU - Mirmira, Raghu

AU - Jetton, Thomas L.

AU - Poitout, Vincent

PY - 2008/2

Y1 - 2008/2

N2 - OBJECTIVE-Prolonged exposure of isolated islets of Langer-hans to elevated levels of fatty acids, in the presence of high glucose, impairs insulin gene expression via a transcriptional mechanism involving nuclear exclusion of pancreas-duodenum homeobox-1 (Pdx-1) and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown. Our objective was therefore to ascertain whether chronic nutrient oversupply inhibits insulin gene expression in vivo. RESEARCH DESIGN AND METHODS-Wistar rats received alternating 4-h infusions of glucose and Intralipid for a total of 72 h. Control groups received alternating infusions of glucose and saline, saline and Intralipid, or saline only. Insulin and C-peptide secretion were measured under hyperglycemic clamps. Insulin secretion and gene expression were assessed in isolated islets, and β-cell mass was quantified by morphometric analysis. RESULTS-Neither C-peptide secretion nor insulin sensitivity was different among infusion regimens. Insulin content and insulin mRNA levels were lower in islets isolated from rats infused with glucose plus Intralipid. This was associated with reduced Pdx-1 binding to the endogenous insulin promoter, and an increased proportion of Pdx-1 localized in the cytoplasm versus the nucleus. In contrast, MafA mRNA and protein levels and B-cell mass and proliferation were unchanged. CONCLUSIONS-Cyclical and alternating infusions of glucose and Intralipid in normal rats inhibit insulin gene expression without affecting insulin secretion or β-cell mass. We conclude that fatty acid inhibition of insulin gene expression, in the presence of high glucose, is an early functional defect that may contribute to β-cell failure in type 2 diabetes.

AB - OBJECTIVE-Prolonged exposure of isolated islets of Langer-hans to elevated levels of fatty acids, in the presence of high glucose, impairs insulin gene expression via a transcriptional mechanism involving nuclear exclusion of pancreas-duodenum homeobox-1 (Pdx-1) and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown. Our objective was therefore to ascertain whether chronic nutrient oversupply inhibits insulin gene expression in vivo. RESEARCH DESIGN AND METHODS-Wistar rats received alternating 4-h infusions of glucose and Intralipid for a total of 72 h. Control groups received alternating infusions of glucose and saline, saline and Intralipid, or saline only. Insulin and C-peptide secretion were measured under hyperglycemic clamps. Insulin secretion and gene expression were assessed in isolated islets, and β-cell mass was quantified by morphometric analysis. RESULTS-Neither C-peptide secretion nor insulin sensitivity was different among infusion regimens. Insulin content and insulin mRNA levels were lower in islets isolated from rats infused with glucose plus Intralipid. This was associated with reduced Pdx-1 binding to the endogenous insulin promoter, and an increased proportion of Pdx-1 localized in the cytoplasm versus the nucleus. In contrast, MafA mRNA and protein levels and B-cell mass and proliferation were unchanged. CONCLUSIONS-Cyclical and alternating infusions of glucose and Intralipid in normal rats inhibit insulin gene expression without affecting insulin secretion or β-cell mass. We conclude that fatty acid inhibition of insulin gene expression, in the presence of high glucose, is an early functional defect that may contribute to β-cell failure in type 2 diabetes.

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