Role of Growth Hormone Releasing Hormone (GHRH) receptor in diabetes-associated dyslipidemia

Dyslipidemia frequently accompanies both T1D and T2D and imposes a cardiovascular risk. Apart from low-density lipoprotein (LDL) cholesterol, which is efficiently reduced by statins, also triglyceride-rich lipoproteins (TRL) represent an important additional risk factor for cardiovascular disease, at least partially through the induction of macrophage chemoattractant protein (MCP-1), particularly in subjects with diabetes or the metabolic syndrome. We have made a novel and unexpected discovery that expression of the receptor for Growth Hormone Releasing Hormone (GHRH-R) is increased in the small intestine of T1D diabetic rats without insulin treatment, and that selective blockade of this peripheral receptor with the antagonist MIA-602 significantly reduced TRL fractions in non-fasted diabetic animals. A potential mechanism for this protective action of the GHRH antagonist is the observed improvement of signaling of GLP-1 in intestinal epithelial cells. This incretin hormone is secreted in the small intestine and promotes post-prandial insulin release, reduces postprandial glucagon secretion and significantly blunts chylomicron biogenesis. Given the high incidence of obesity and T2D and its association with dyslipidemia and cardiovascular disease in the context of insulin resistance, the primary objective of this proposal is to improve the understanding of this novel role of the GHRH-R in dyslipidemic states associated with impaired GLP-1 signaling, and to extend these studies in T2D db/db mice, a valid model of human T2D/obesity, and in human small intestine specimens. In T1D and T2D subjects and rodents, impaired GLP-1 signaling in combination with increased GLP-1 plasma levels have been observed. At physiologically relevant doses, GLP-1 triggers receptor signaling and receptor recycling for further activation, which requires activation of protein kinase C (PKC). Our central hypothesis is that GHRH-R activation, which yields a robust activation of protein kinase A (PKA), impairs PKC-mediated GLP-1R signaling and recycling in human and rodent small intestinal epithelial cells, as such elevating intestinal chylomicron output and postprandial TRL levels. The impact of our project is a better understanding of the role of peripheral GHRH-R in dyslipidemic states associated with impaired GLP-1 signaling, which can foster the identification of novel pathways and the development of novel therapies to control dyslipidemia in T2D/obese subjects. (AHA Program: Grant-in-Aid)