With type 1 diabetes too much glucose and fat circulating in the blood help make cardiovascular disease the leading cause of death and disability in people with the disease. While some patients with diabetes take statins, which help reduce production and enhance elimination of disease-promoting low-density lipoprotein (LDL) most continue to have a significant cardiovascular risk. This is because at least one issue statins don’t address is the abundance of fat-rich, circulating lipoproteins from the intestines. Now, a study from researchers at MCG, the Veterans Affairs Medical Center, and the University of Miami provides new insight into the complex interchange that can raise blood levels of unhealthy fat in type 1 diabetes, and early evidence that a drug under study to block cancer cell growth can restore healthier levels. The team state that their findings expand the therapeutic potential of antagonists of growth hormone-releasing hormone (GHRH) to diabetes, which affects a significant percentage of the world’s population.
Previous studies show that levels of growth hormone, produced by the pituitary, are high in diabetes, which increases insulin resistance and lipid levels, and clearly play a role in the high levels of fat in the blood. In fact, growth hormone therapy to help normalize a child’s growth has been shown to increase the child’s risk of type 2 diabetes. GHRH, which regulates growth hormone production, is also elevated in type 1 diabetes. It’s in the intestines that potentially problematic lipids and cholesterol are taken from food eaten and transformed into lipoproteins that can travel in the blood and linger if levels get too high. Earlier studies from the lab had found increased expression of this GHRH receptor in the small intestines of their rat model of type 1 diabetes. Therefore the group hypothesized that GHRH receptors were a worthy target. The current study shows that by targeting the receptor for GHRH lipid production in diabetes was normalised without reducing normal blood levels of growth hormones, which could be problematic.
The current study shows that even without giving their diabetic models insulin the drug, MIA-602, turned around the typically unhealthy and complicated lipid-producing scenario that occurs in the intestines in diabetes. Results show that when diabetic rats were treated with MIA-602 three times weekly the usually high expression of GHRH receptors was essentially normalized in the intestines, where these super, fat-loaded lipoproteins originate. Data findings show that levels of lipids, LDL, and very low-density cholesterol, the so-called bad cholesterol were also normalized.
Results show that stabilized as well were levels of apolipoprotein B-48, a major lipoprotein used to build triglyceride-rich lipoproteins made out of the food humans eat. Data findings show a reduction in all these lipids just by giving the GHRH antagonist, which indicates that this is an important pathway to controlling the hyperlipidemia that occurs in diabetes and, perhaps, in other diseases. The researchers note that MIA-602 treatment also normalized glucagon-like peptide-1 and glucagon levels to a healthy normal, both of which are elevated in patients with type 1 diabetes.
The team surmise that their data shows 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. They go on to add that MIA-602 also reduced two indicators of diabetes, namely protein in the urine, a sign of kidney damage, and the inability of blood vessels to relax, an indicator of blood vessel damage. For the future, the researchers state that they now plan to perform lab work on human cells.