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

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

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7 Scopus citations

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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    Romero, M. J., Lucas, R., Dou, H., Sridhar, S., Czikora, I., Mosieri, E. M., Rick, F. G., Block, N. L., Sridhar, S., Fulton, D., Weintraub, N. L., & Bagi, Z. (2016). Role of growth hormone-releasing hormone in dyslipidemia associated with experimental type 1 diabetes. Proceedings of the National Academy of Sciences of the United States of America, 113(7), 1895-1900. https://doi.org/10.1073/pnas.1525520113