Joslin Diabetes Center scientists have recently indentified biological mechanisms through glucagon-like peptide-1 (GLP-1), which is known as a gut hormone that protects against kidney disease also has the same mechanisms that slow down the same actions in diabetes. These findings will possibly lead to new therapeutic agents which can help to prevent hyperglycemia on renal endothelial cells.
Diabetic complications come in many different forms but one of those is through renal complications known as diabetic nephropathy. Diabetic nephropathy is one of the most life threatening complications from diabetes that most often leads to end-stage renal disease (ESRD). About 44 percent of people who have been diagnosed with diabetes in the United States have ESRD, which requires either a kidney transplant or dialysis.
George King, M.D., lead author of the study and chief scientific officer, head of the Dianne Nunnally Hoppes Laboratory for Diabetes Complications and a professor of medicine at Harvard Medical School said, “We are very eager to develop new treatments for diabetic kidney disease.”
GLP-1 is an incretion hormone that is produced in the intestine upon the intake of food. It increases the insulin within the pancreas and slows down the absorption of glucose from the gut which reduces the action of glucagon. This all has a huge impact on lowering glucose levels in the blood. It also reduces appetite as well.
Different studies have shown that GLP-1 also improves renal endothelial cells. These cells regulate blood clotting, blood vessel activity and immune response and other issues that are damaged through insulin resistance. GLP-1 receptors are abundant in the intestine and can also be found in the kidneys and endothelium as well.
Through the Joslin study, the effects of GLP-1 in non-diabetic and diabetic mice were investigated. These mice has and over expression of the enzyme PKCB (protein kinase C-beta). This is produced in excess when the glucose in the blood is high. Excessive amounts of PKCB can lead to diabetic complications, which includes kidney disease. Through PKCB, Ang II, a peptide hormone that affects renal filtration and blood flow and regulates blood pressure, increases and accelerates the progression of kidney disease.
Dr. King says, “We’ve been interested in diabetic kidney disease for a long time, particularly the role of PKCβ and Ang II in promoting kidney damage. We were interested in investigating how GLP-1 could protect against the effects of hyperglycemia on renal function.”
“Two major findings were discovered through the Joslin study, mechanisms were identified by which GLP-1 can induce protective actions on the glomerular (renal) endothelial cells by inhibiting the signaling pathway of Ang II and its pro-inflammatory effect and also demonstrated a dual signaling mechanism by which hyperglycemia through PKCB activation can increase the Ang II action and inhibit GLP-1’s protective effects by reducing the expression with diabetes are more sensitive to Ang II; our data suggests one reason why,” says Dr. King.
“We now know that increased PKCβ decreases GLP-1R which makes the kidney less responsive to treatment with GLP-1-based drugs. Possible new treatments could combine PKCβ inhibitors with higher doses of GLP-1 agonists. GLP-1 is one potential pharmaceutical that could both lower glucose and minimize the toxic effects of Ang II to lower the risk of kidney diseases,” says Dr. King.