Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis

Abstract

The pathogeneses of the two major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing β-cells is common to virtually all forms of diabetes. Although the mechanisms underlying β-cell dysfunction remain incompletely characterized, recent years have been witness to major advances in our understanding of the molecular pathways that contribute to the demise of the β-cell. Cellular and environmental factors contribute to β-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and β-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the identification of genes and proteins specifically involved in β-cell dysfunction during diabetes pathogenesis. Here, we review the critical stress response pathways that are activated in β-cells in the context of the animal models.

Protection of β cells against pro-inflammatory cytokine stress by the GDF15-ERBB2 signaling

“…GDF15 mRNA contains an AU-rich element (ARE), which is a binding site for the RNA-binding protein tristetraprolin (TTP, Figure 6A ). TTP targets mRNAs to stress granules [30] and cytokines can induce stress granule formation [31]. Upon cytokine treatment TTP transcript, protein, and phosphorylation were upregulated ( Figure 6B-C ).…”

Vitamin D Alleviates Type 2 Diabetes Mellitus by Mitigating Oxidative Stress-Induced Pancreatic β-Cell Impairment

“…Treatment with 1,25(OH) 2 D 3 effectively suppressed OS in PA-induced MIN6 cells, as the ROS and MDA levels were downregulated along with upregulated GSH and SOD levels. Apart from OS, inflammation and ERS have been demonstrated to be the significant factors for β-cell decline in T2DM 55 . In line with the previous study 29 , upregulated expression of the pro-inflammatory cytokines, TNF-α and IL-6, was observed in PA-induced MIN6 cells compared to normal cells.…”

Senescence: a double-edged sword in beta-cell health and failure?

“…Beta-cell fragility is a shared underlying feature of both type 1- and type 2- diabetes (T1D and T2D), with the activation of unfolded protein response (UPR) and DDR preceding beta-cell failure ( 53 – 57 ). In addition, the immune-mediated islet inflammation is a well-established stress trigger in T1D and is now also recognized to contribute to beta-cell failure in T2D ( 58 , 59 ).…”

“…Besides the immune and metabolic factors as triggers for beta-cell stress ( 57 , 62 , 63 ), the contribution of beta-cell intrinsic changes is becoming increasingly evident ( 64 ). For instance, genetic vulnerability due to mutations in DNA repair genes can trigger beta-cell failure independent of immune defects ( 53 ).…”

“…The link between UPR, DDR, and senescence is especially relevant for beta-cells that produce and process a large amount of protein load, rely on replication for adaptive expansion, and are highly susceptible to oxidative damage ( 79 – 81 ) ( Figure 2C ). While the initial induction of these stress-sensing adaptive mechanisms in response to stress facilitates cellular repair and adaptation, persistent activation of these mechanisms leads to tissue maladaptation, senescence, and even death ( 53 – 57 ). Recent data show that p21 is a temporal stress-sensor that shapes the cellular response by placing cells under immunosurveillance, which either disengages or eliminates damaged cells depending on the duration of p21 persistence ( 82 ).…”