Glucose homeostasis describes the body's balance of insulin and glucagon that maintains blood glucose levels and is crucial in maintaining appropriate energy and metabolic state. The inability to maintain glucose homeostasis in both chronic hyperglycemia and hyperlipidemia, known as important causative factors of type 2 diabetes, has been found to disrupt homeostasis of the endoplasmic reticulum (ER) in insulin producing β cells of the pancreatic islets. Given the functional importance of the ER, an organelle that performs folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, the maintenance of ER homeostasis in β cells is very important.
Research suggests that ER stress and resulting loss of ER homeostasis is intrinsic to the pathogenesis of diabetes by mechanisms that involve the unfolded protein response. When ER homeostasis is disrupted, the ER generates adaptive signaling pathways, called the unfolded protein response, in an attempt to restore homeostasis. However, if homeostasis fails to be restored, as can occur in chronic ER stress conditions found in diabetes, the ER initiates death signaling pathways (apoptosis). Evidence is growing that the single branches of the unfolded protein response work in concert in β cells to supply insulin in response to acute glucose availability. ER stress due to chronic glucose stimulation disrupts these primarily adaptive changes into an overwhelming unfolded protein response, which leads to reduced insulin supply and loss of β-cell mass due to apoptosis. Accordingly, alleviation of the pro-apoptotic activity of ER stress during diabetes emerges as a strategy of choice in treatment.
It has previously been reported that deregulation of p53/p21 activity occurs during ER stress and is associated with the cytotoxic effects of the unfolded protein response. p21 is a potent cyclin-dependent kinase inhibitor that binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G1 and S phase. The expression of p21 is tightly controlled by the tumor suppressor protein p53. In the context of diabetes it has been found that stimulation of p53/p21 activity by nutlin-3a (a cis-imidazoline analog activator of p53 stability) is beneficial for diabetes in mice. The specific suppression of p21 during ER stress and its pro-survival activity during DNA damage-induced apoptosis have also been suggested.
Unfortunately, p53 stabilization by nutlin-3a also elicits pro-apoptotic effects that may likely compromise its beneficial activities for diabetes management. This suggests that bypassing the death-inducing function of p53 while inducing the activity of p21 may bear significant anti-diabetic value. Consistent with this notion, p21-deficient diabetic mice have been found to be unresponsive to nutlin-3a and more sensitive to diet-induced diabetes than their wild type counterparts. This is in line with the concept that in the absence of p21, the pro-apoptotic effects of p53 persist, reducing islets' survival and function during treatment of diabetic mice with nutlin-3a.
What are needed in the art are compounds that can encourage pancreatic islet health and survival of β cells in high ER stress conditions such as chronic loss of glucose homeostasis common in diabetes. For instance, a compound that can modulate the unfolded protein response in conditions of high ER stress and thus modulate glucose homeostasis could be of great benefit.