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: 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, Andrew V Schally
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 7 Pg. 1895-900 (Feb 16 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 26831066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Receptors, Neuropeptide
• Receptors, Pituitary Hormone-Regulating Hormone
• Streptozocin
• Growth Hormone-Releasing Hormone
• somatotropin releasing hormone receptor

Topics

• Animals
• Diabetes Mellitus, Type 1 (physiopathology)
• Disease Models, Animal
• Dyslipidemias (physiopathology, therapy)
• Growth Hormone-Releasing Hormone (antagonists & inhibitors, physiology)
• Intestine, Small (metabolism)
• Male
• Rats
• Rats, Wistar
• Receptors, Neuropeptide (metabolism)
• Receptors, Pituitary Hormone-Regulating Hormone (metabolism)
• Streptozocin