Role of growth hormone-releasing hormone in dyslipidemia associated with experimental type 1 diabetes

Maritza Josefina Romero Lucas, Rudolf Lucas, Huijuan Dou, Supriya Sridhar, Istvan Czikora, Eby M. Mosieri, Ferenc G. Rick, Norman L. Block, Subbaramiah Sridhar, David J Fulton, Neal Lee Weintraub, Zsolt Bagi

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Abstract

Dyslipidemia associated with triglyceride-rich lipoproteins (TRLs) represents an important residual risk factor for cardiovascular and chronic kidney disease in patients with type 1 diabetes (T1D). Levels of growth hormone (GH) are elevated in T1D, which aggravates both hyperglycemia and dyslipidemia. The hypothalamic growth hormone- releasing hormone (GHRH) regulates the release of GH by the pituitary but also exerts separate actions on peripheral GHRH receptors, the functional role ofwhich remains elusive in T1D. In a rat model of streptozotocin (STZ)-induced T1D, GHRH receptor expression was found to be up-regulated in the distal small intestine, a tissue involved in chylomicron synthesis. Treatment of T1D rats with a GHRH antagonist,MIA-602, at a dose that did not affect plasma GH levels, significantly reduced TRL, as well as markers of renal injury, and improved endothelial-dependent vasorelaxation. Glucagon-like peptide 1 (GLP-1) reduces hyperglucagonemia and postprandial TRL, the latter in part through a decreased synthesis of apolipoprotein B-48 (ApoB-48) by intestinal cells. Although plasma GLP-1 levels were elevated in diabetic animals, this was accompanied by increased rather than reduced glucagon levels, suggesting impaired GLP-1 signaling. Treatment with MIA-602 normalized GLP-1 and glucagon to control levels in T1D rats. MIA-602 also decreased secretion of ApoB-48 from rat intestinal epithelial cells in response to oleic acid stimulation in vitro, in part through a GLP-1-dependent mechanism. Our findings support the hypothesis that antagonizing the signaling of GHRH in T1D may improve GLP-1 function in the small intestine, which, in turn, diminishes TRL and reduces renal and vascular complications.

Original languageEnglish (US)
Pages (from-to)1895-1900
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number7
DOIs
StatePublished - Feb 16 2016

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Growth Hormone-Releasing Hormone
Dyslipidemias
Glucagon-Like Peptide 1
Type 1 Diabetes Mellitus
Lipoproteins
Triglycerides
Apolipoprotein B-48
Growth Hormone
Glucagon
Small Intestine
Hypothalamic Hormones
Hormone Antagonists
Kidney
Chylomicrons
Oleic Acid
Streptozocin
Chronic Renal Insufficiency
Vasodilation
Hyperglycemia
Blood Vessels

ASJC Scopus subject areas

  • General

Cite this

@article{e750bbe74f29482c9669c80ce42d436d,
title = "Role of growth hormone-releasing hormone in dyslipidemia associated with experimental type 1 diabetes",
abstract = "Dyslipidemia associated with triglyceride-rich lipoproteins (TRLs) represents an important residual risk factor for cardiovascular and chronic kidney disease in patients with type 1 diabetes (T1D). Levels of growth hormone (GH) are elevated in T1D, which aggravates both hyperglycemia and dyslipidemia. The hypothalamic growth hormone- releasing hormone (GHRH) regulates the release of GH by the pituitary but also exerts separate actions on peripheral GHRH receptors, the functional role ofwhich remains elusive in T1D. In a rat model of streptozotocin (STZ)-induced T1D, GHRH receptor expression was found to be up-regulated in the distal small intestine, a tissue involved in chylomicron synthesis. Treatment of T1D rats with a GHRH antagonist,MIA-602, at a dose that did not affect plasma GH levels, significantly reduced TRL, as well as markers of renal injury, and improved endothelial-dependent vasorelaxation. Glucagon-like peptide 1 (GLP-1) reduces hyperglucagonemia and postprandial TRL, the latter in part through a decreased synthesis of apolipoprotein B-48 (ApoB-48) by intestinal cells. Although plasma GLP-1 levels were elevated in diabetic animals, this was accompanied by increased rather than reduced glucagon levels, suggesting impaired GLP-1 signaling. Treatment with MIA-602 normalized GLP-1 and glucagon to control levels in T1D rats. MIA-602 also decreased secretion of ApoB-48 from rat intestinal epithelial cells in response to oleic acid stimulation in vitro, in part through a GLP-1-dependent mechanism. Our findings support the hypothesis that antagonizing the signaling of GHRH in T1D may improve GLP-1 function in the small intestine, which, in turn, diminishes TRL and reduces renal and vascular complications.",
author = "{Romero Lucas}, {Maritza Josefina} and Rudolf Lucas and Huijuan Dou and Supriya Sridhar and Istvan Czikora and Mosieri, {Eby M.} and Rick, {Ferenc G.} and Block, {Norman L.} and Subbaramiah Sridhar and Fulton, {David J} and Weintraub, {Neal Lee} and Zsolt Bagi",
year = "2016",
month = "2",
day = "16",
doi = "10.1073/pnas.1525520113",
language = "English (US)",
volume = "113",
pages = "1895--1900",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
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TY - JOUR

T1 - Role of growth hormone-releasing hormone in dyslipidemia associated with experimental type 1 diabetes

AU - Romero Lucas, Maritza Josefina

AU - Lucas, Rudolf

AU - Dou, Huijuan

AU - Sridhar, Supriya

AU - Czikora, Istvan

AU - Mosieri, Eby M.

AU - Rick, Ferenc G.

AU - Block, Norman L.

AU - Sridhar, Subbaramiah

AU - Fulton, David J

AU - Weintraub, Neal Lee

AU - Bagi, Zsolt

PY - 2016/2/16

Y1 - 2016/2/16

N2 - Dyslipidemia associated with triglyceride-rich lipoproteins (TRLs) represents an important residual risk factor for cardiovascular and chronic kidney disease in patients with type 1 diabetes (T1D). Levels of growth hormone (GH) are elevated in T1D, which aggravates both hyperglycemia and dyslipidemia. The hypothalamic growth hormone- releasing hormone (GHRH) regulates the release of GH by the pituitary but also exerts separate actions on peripheral GHRH receptors, the functional role ofwhich remains elusive in T1D. In a rat model of streptozotocin (STZ)-induced T1D, GHRH receptor expression was found to be up-regulated in the distal small intestine, a tissue involved in chylomicron synthesis. Treatment of T1D rats with a GHRH antagonist,MIA-602, at a dose that did not affect plasma GH levels, significantly reduced TRL, as well as markers of renal injury, and improved endothelial-dependent vasorelaxation. Glucagon-like peptide 1 (GLP-1) reduces hyperglucagonemia and postprandial TRL, the latter in part through a decreased synthesis of apolipoprotein B-48 (ApoB-48) by intestinal cells. Although plasma GLP-1 levels were elevated in diabetic animals, this was accompanied by increased rather than reduced glucagon levels, suggesting impaired GLP-1 signaling. Treatment with MIA-602 normalized GLP-1 and glucagon to control levels in T1D rats. MIA-602 also decreased secretion of ApoB-48 from rat intestinal epithelial cells in response to oleic acid stimulation in vitro, in part through a GLP-1-dependent mechanism. Our findings support the hypothesis that antagonizing the signaling of GHRH in T1D may improve GLP-1 function in the small intestine, which, in turn, diminishes TRL and reduces renal and vascular complications.

AB - Dyslipidemia associated with triglyceride-rich lipoproteins (TRLs) represents an important residual risk factor for cardiovascular and chronic kidney disease in patients with type 1 diabetes (T1D). Levels of growth hormone (GH) are elevated in T1D, which aggravates both hyperglycemia and dyslipidemia. The hypothalamic growth hormone- releasing hormone (GHRH) regulates the release of GH by the pituitary but also exerts separate actions on peripheral GHRH receptors, the functional role ofwhich remains elusive in T1D. In a rat model of streptozotocin (STZ)-induced T1D, GHRH receptor expression was found to be up-regulated in the distal small intestine, a tissue involved in chylomicron synthesis. Treatment of T1D rats with a GHRH antagonist,MIA-602, at a dose that did not affect plasma GH levels, significantly reduced TRL, as well as markers of renal injury, and improved endothelial-dependent vasorelaxation. Glucagon-like peptide 1 (GLP-1) reduces hyperglucagonemia and postprandial TRL, the latter in part through a decreased synthesis of apolipoprotein B-48 (ApoB-48) by intestinal cells. Although plasma GLP-1 levels were elevated in diabetic animals, this was accompanied by increased rather than reduced glucagon levels, suggesting impaired GLP-1 signaling. Treatment with MIA-602 normalized GLP-1 and glucagon to control levels in T1D rats. MIA-602 also decreased secretion of ApoB-48 from rat intestinal epithelial cells in response to oleic acid stimulation in vitro, in part through a GLP-1-dependent mechanism. Our findings support the hypothesis that antagonizing the signaling of GHRH in T1D may improve GLP-1 function in the small intestine, which, in turn, diminishes TRL and reduces renal and vascular complications.

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