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
N1 - Funding Information:
We thank Dr. Ronald Goldberg (Division of Endocrinology, Diabetes and Metabolism, Diabetes Research Institute, University of Miami Miller School of Medicine) and Dr. Monty Krieger (Department of Biology, Massachusetts Institute of Technology) for critically reading the manuscript. This work was supported by a Pilot Study Research Program Intramural Grant from the Office of the Vice President for Research at the Medical College of Georgia, Augusta University (to M.J.R.), as well as by the Medical Research Service of Veterans Affairs Department (A.V.S.), Departments of Pathology and Medicine, Division of Hematology/Oncology, University of Miami, Miller School of Medicine (A.V.S.), the South Florida Veterans Affairs Foundation for Research and Education (A.V.S.), and the L. Austin Weeks Family Endowment for Research (N.L.B.).
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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U2 - 10.1073/pnas.1525520113
DO - 10.1073/pnas.1525520113
M3 - Article
C2 - 26831066
AN - SCOPUS:84958818463
SN - 0027-8424
VL - 113
SP - 1895
EP - 1900
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -