Ca2+ signaling and metabolic stress-induced pancreatic β-cell failure

Abstract

Early in the development of Type 2 diabetes (T2D), metabolic stress brought on by insulin resistance and nutrient overload causes β-cell hyperstimulation. Herein we summarize recent studies that have explored the premise that an increase in the intracellular Ca²⁺ concentration ([Ca²⁺]_i), brought on by persistent metabolic stimulation of β-cells, causes β-cell dysfunction and failure by adversely affecting β-cell function, structure, and identity. This mini-review builds on several recent reviews that also describe how excess [Ca²⁺]_i impairs β-cell function.

Keywords: Ca2+ signaling; dedifferentiation; gene expression; metabolic stress; pancreatic β-cells; type 2 diabetes.

Figure 1

A multifaceted role for [Ca²⁺]_i in β-cell function. Hyperglycemia and other insulin secretagogues cause [Ca²⁺]_i in β-cells to increase. (A) Metabolism-stimulated insulin secretion. Glucose and amino acid metabolism lead to an increase in the ATP/ADP ratio, causing K_ATP (ATP-sensitive) potassium channel closure, plasma membrane depolarization, and the opening of voltage‐gated Ca²⁺ channels (VDCC) triggering transient increases in intracellular Ca²⁺ concentrations ([Ca²⁺]_i). The transient spikes in [Ca²⁺]_i stimulate docking and exocytosis of insulin vesicles. The activity of K_ATP and VDCC channels can be blocked with tolbutamide (a sulfonylurea) and verapamil, respectively. (B) Adaptive regulation. Hormones, cytokines, neurotransmitters, and certain fatty acids and metabolites that signal through G protein-coupled receptors (GPCRs) activate intracellular signal transduction pathways that cause Ca²⁺ efflux/influx from intracellular stores/extracellular space. GPCR-induced alterations in [Ca²⁺]_i modify other metabolism-based insulin secretory responses. In addition, Ca²⁺ signaling to the nucleus alters the expression Ca²⁺-dependent transcription factors that control many cellular functions.

Figure 2

A model for the development of T2D that considers the role of metabolic-stress and [Ca²⁺]_i. This model illustrates the stepwise failure of β-cells in response to metabolic stress. 1) In healthy individuals β-cells have normal [Ca²⁺]_i levels. 2) In pre-diabetes, environmental factors such as age, sex, genetic makeup, obesity, and overnutrition cause insulin resistance and an increase in insulin demand resulting in mild metabolic stress. Transient elevations of the blood glucose and other insulin secretagogues cause the hyperstimulation of β-cells and small increases in [Ca²⁺]_i. Initially, the increase in Ca²⁺-signaling stimulate insulin secretion, β-cell proliferation and other adaptive responses that continue to maintain glycemia and compensate for increased insulin demand. 3) The limited ability of β-cells to compensate together with a continuing rise in metabolic stress cause further increases in [Ca²⁺]_i. A tipping point occurs where a network of Ca²⁺-regulated genes crucial for maintaining Ca²⁺ homeostasis and β-cell function becomes maladaptive. 4) The maladaptive changes brought on by chronically elevated [Ca²⁺]_i cause the loss of β-cell identity and function, with β-cells entering a decompensation stage where they can no longer secrete enough insulin to maintain normal blood glucose. Glucolipotoxicity further accelerates the loss of β-cell function, identity and viability, therefore resulting in overt T2D. The increased gray shading of β-cells from left to right indicates increasing loss of β-cell identity and function. The * indicates a tipping point.