Abstract
Endoplasmic reticulum (ER) stress in beta cells induces a signaling network called the unfolded protein response (UPR), which plays a dual role in diabetes. A key regulator of ER-stress and UPR, the orosomucoid 1-like protein 3 (ORMDL3), has been shown to regulate airway remodeling through a major UPR protein, activating transcription factor 6 (ATF6), but the contribution of this regulatory axis to compensatory pancreatic beta cell proliferation in diabetes has not been studied. Here, we detected significantly lower levels of ORMDL3 mRNA in leukocytes of peripheral blood specimens from type 1 diabetes (T1D) children, compared to normal children. Moreover, these ORMDL3 levels in T1D children exhibited further decreases upon follow-up. ORMDL3 levels in islets from NOD mice, a mouse model for T1D in humans, showed a mild increase before diabetes onset, but a gradual decrease subsequently. In high glucose culture, beta cell proliferation, but not apoptosis, was increased by overexpression of ORMDL3 levels, likely mediated by its downstream factor ATF6. Mechanistically, ORMDL3 transcriptionally activated ATF6, which was confirmed in a promoter reporter assay. Together, our data suggest that ORMDL3 may increase beta cell proliferation through ATF6 as an early compensatory change in response to diabetes.
Highlights
Diabetes is a prevalent metabolic disease characterized by high blood sugar caused by either inadequate insulin production by beta cells in the pancreas, or by a defective response to insulin in the liver, muscle and adipose tissue [1]
A key regulator of Endoplasmic reticulum (ER)-stress and unfolded protein response (UPR), the orosomucoid 1-like protein 3 (ORMDL3), has been shown to regulate airway remodeling through a major UPR protein, activating transcription factor 6 (ATF6), but the contribution of this regulatory axis on compensatory pancreatic beta cell proliferation in diabetes has not been studied
Hyperglycemia in diabetes provokes production of mitochondrial reactive oxygen species (ROS) and protein glycation, leading to an exaggerated ER load of misfolded/unfolded and nascent proteins associated with insulin production and release, which impairs ER homeostasis and causes ER stress [26]
Summary
Diabetes is a prevalent metabolic disease characterized by high blood sugar caused by either inadequate insulin production by beta cells in the pancreas, or by a defective response to insulin in the liver, muscle and adipose tissue [1]. There are two types of diabetes, type 1 diabetes (T1D) and type 2 diabetes (T2D), which both result in a loss of functional beta cell mass despite different etiologies and pathological processes [2]. Endoplasmic reticulum (ER) stress is often generated by the expression of mutant proteins that impair normal protein folding in ER, a process which involves a signaling network called the unfolded protein response (UPR) [3]. ER stress plays a pivotal role in the pathogenesis of diabetes, contributing to both the loss of functional beta cells and the development of insulin resistance [5]. UPR, appears to play a dual role in beta cells, being beneficial to cells under physiological conditions or mild stress, but detrimental to cells during pathological stages or chronic stress by triggering beta-cell dysfunction and apoptosis [6]
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