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 of which 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.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912; Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912; andrew.schally@va.gov mromerolucas@gru.edu.
authors.forename: Maritza J
authors.initials: MJ
authors.lastname: Romero
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912; Section of Gastroenterology and Hepatology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912;
authors.forename: Rudolf
authors.initials: R
authors.lastname: Lucas
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
authors.forename: Huijuan
authors.initials: H
authors.lastname: Dou
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
authors.forename: Supriya
authors.initials: S
authors.lastname: Sridhar
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
authors.forename: Istvan
authors.initials: I
authors.lastname: Czikora
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912;
authors.forename: Eby M
authors.initials: EM
authors.lastname: Mosieri
authors.affiliation: Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125; Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33174;
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
authors.affiliation: Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136;
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.affiliation: Section of Gastroenterology and Hepatology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912;
authors.forename: Subbaramiah
authors.initials: S
authors.lastname: Sridhar
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912;
authors.forename: David
authors.initials: D
authors.lastname: Fulton
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912; Section of Gastroenterology and Hepatology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912;
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912; Section of Gastroenterology and Hepatology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912;
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
authors.affiliation: Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125; Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136; Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136; Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136 andrew.schally@va.gov mromerolucas@gru.edu.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000503:physiopathology* / Q000628:therapy; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018013:Receptors, Neuropeptide / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000378:metabolism; D013311:Streptozocin
chemical_list: D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D013311:Streptozocin; D013007:Growth Hormone-Releasing Hormone; C048250:somatotropin releasing hormone receptor
keywords: GHRH; GLP-1 signaling; dyslipidemia; kidney damage; type 1 diabetes
references.citation: Int J Vasc Med. 2012;2012:947417
references.pmid: 21961070
references.citation: N Engl J Med. 1984 Mar 29;310(13):810-5
references.pmid: 6700669
references.citation: Regul Pept. 2006 Sep 11;136(1-3):105-8
references.pmid: 16781787
references.citation: Int J Oncol. 2011 Oct;39(4):1025-32
references.pmid: 21701777
references.citation: Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):13651-6
references.pmid: 26474831
references.citation: Diabetes Metab J. 2015 Oct;39(5):353-62
references.pmid: 26566492
references.citation: Diabetes. 2013 Feb;62(2):373-81
references.pmid: 23028139
references.citation: Diabetologia. 2015 Dec;58(12):2774-80
references.pmid: 26409460
references.citation: Eur Heart J. 2011 Jun;32(11):1345-61
references.pmid: 21531743
references.citation: Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1143-8
references.pmid: 25564660
references.citation: Diabetes. 2014 Nov;63(11):3960-73
references.pmid: 24760139
references.citation: J Lipid Res. 1985 Jan;26(1):70-81
references.pmid: 3973514
references.citation: Diabetes. 1979 Dec;28(12):1141-2
references.pmid: 510813
references.citation: Diabetes Metab J. 2015 Apr;39(2):87-94
references.pmid: 25922802
references.citation: Endocrinology. 2002 Apr;143(4):1213-7
references.pmid: 11897675
references.citation: N Engl J Med. 1985 Jun 6;312(23):1473-9
references.pmid: 2859524
references.citation: Metabolism. 2005 May;54(5):689-97
references.pmid: 15877301
references.citation: Diabetologia. 2015 Apr;58(4):828-34
references.pmid: 25541633
references.citation: Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):644-53
references.pmid: 24407032
references.citation: Arterioscler Thromb Vasc Biol. 2015 May;35(5):1092-100
references.pmid: 25675997
references.citation: Diabetes. 2006 May;55(5):1316-26
references.pmid: 16644688
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):2084-9
references.pmid: 22308467
references.citation: Am J Cardiol. 2011 Aug 2;108(3 Suppl):52B-8B
references.pmid: 21802581
references.citation: Curr Opin Lipidol. 1997 Jun;8(3):146-53
references.pmid: 9211062
references.citation: Atherosclerosis. 2014 Apr;233(2):608-15
references.pmid: 24534456
references.citation: Curr Diab Rep. 2015 Dec;15(12):119
references.pmid: 26520142
references.citation: Atherosclerosis. 2009 May;204(1):105-11
references.pmid: 18834984
references.citation: Nat Rev Cardiol. 2012 Apr;9(4):209-22
references.pmid: 22290234
references.citation: Diabetes. 1986 Mar;35(3):278-81
references.pmid: 3512338
references.citation: Recent Prog Horm Res. 1995;50:35-73
references.pmid: 7740167
references.citation: Prog Lipid Res. 2013 Oct;52(4):446-64
references.pmid: 23774609
references.citation: Diabetologia. 2003 Sep;46(9):1203-10
references.pmid: 12898010
references.citation: Diabetes. 1997 May;46(5):824-8
references.pmid: 9133550
references.citation: J Clin Endocrinol Metab. 2004 Dec;89(12):5972-80
references.pmid: 15579746
references.citation: Lancet. 2006 Sep 9;368(9539):919-28
references.pmid: 16962881
references.citation: PLoS One. 2013;8(2):e55852
references.pmid: 23457483
references.citation: N Engl J Med. 2008 Jan 17;358(3):293-7
references.pmid: 18199869
references.citation: Arterioscler Thromb Vasc Biol. 2010 Jan;30(1):9-19
references.pmid: 20018941
references.citation: Diabetes Care. 2009 Apr;32(4):658-63
references.pmid: 19171721
references.citation: Clin Endocrinol (Oxf). 1996 May;44(5):547-53
references.pmid: 8762731
references.citation: J Clin Endocrinol Metab. 1998 Oct;83(10):3663-7
references.pmid: 9768681
references.citation: Front Physiol. 2013 Jan 03;3:485
references.pmid: 23316165
references.citation: Diabetes Care. 2014 Oct;37(10):2864-83
references.pmid: 25249672
references.citation: Am J Pathol. 2013 Mar;182(3):727-41
references.pmid: 23318573
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18611-5
references.pmid: 20937882
references.citation: Lancet. 2005 Oct 8;366(9493):1267-78
references.pmid: 16214597
references.citation: Hypertension. 2012 Sep;60(3):833-41
references.pmid: 22868389
references.citation: Curr Diab Rep. 2015 Nov;15(11):86
references.pmid: 26370697
references.citation: Am J Cardiol. 2015 Feb 15;115(4):441-6
references.pmid: 25554536
references.citation: J Endocrinol Invest. 2012 Dec;35(11):1021-9
references.pmid: 23143695
references.citation: Diabetes. 2013 Feb;62(2):336-8
references.pmid: 23349538
references.citation: Atherosclerosis. 2003 Dec;171(2):193-200
references.pmid: 14644387
references.citation: J Am Coll Cardiol. 2008 Feb 19;51(7):724-30
references.pmid: 18279736
references.citation: Clin Endocrinol (Oxf). 1990 Feb;32(2):177-83
references.pmid: 1971774
references.citation: J Clin Lipidol. 2014 Nov-Dec;8(6):576-83
references.pmid: 25499940
references.citation: Biochem J. 1990 May 15;268(1):1-13
references.pmid: 2188646
references.citation: Diabetologia. 1970 Feb;6(1):27-33
references.pmid: 5434734