β-cell dynamics in type 2 diabetes and in dietary and exercise interventions

Abstract

Pancreatic β-cell dysfunction and insulin resistance are two of the major causes of type 2 diabetes (T2D). Recent clinical and experimental studies have suggested that the functional capacity of β-cells, particularly in the first phase of insulin secretion, is a primary contributor to the progression of T2D and its associated complications. Pancreatic β-cells undergo dynamic compensation and decompensation processes during the development of T2D, in which metabolic stresses such as endoplasmic reticulum stress, oxidative stress, and inflammatory signals are key regulators of β-cell dynamics. Dietary and exercise interventions have been shown to be effective approaches for the treatment of obesity and T2D, especially in the early stages. Whilst the targeted tissues and underlying mechanisms of dietary and exercise interventions remain somewhat vague, accumulating evidence has implicated the improvement of β-cell functional capacity. In this review, we summarize recent advances in the understanding of the dynamic adaptations of β-cell function in T2D progression and clarify the effects and mechanisms of dietary and exercise interventions on β-cell dysfunction in T2D. This review provides molecular insights into the therapeutic effects of dietary and exercise interventions on T2D, and more importantly, it paves the way for future research on the related underlying mechanisms for developing precision prevention and treatment of T2D.

Keywords: dietary intervention; exercise intervention; pancreatic β-cell; type 2 diabetes.

Figure 1

Schematic diagram of the regulation of insulin secretion in β-cells. Glycolysis- and mitochondrial oxidative phosphorylation-mediated elevation of ATP level induces first-phase insulin secretion through inactivation of the K^ATP channel, membrane depolarization, opening of the voltage-dependent Ca²⁺ channel, influx of Ca²⁺ from the extracellular space, and the final triggering of the docking of insulin granules on the plasma membrane and insulin secretion. The first phase of insulin secretion is followed by the second phase of insulin secretion that is controlled by the amplifying pathways, in which the ER regulation of intercellular Ca²⁺ homeostasis plays an important role. Incretins, such as GIP, GLP-1, and FFA, can induce insulin secretion through modulating the above glucose-stimulated insulin secretion pathway, such as sensitizing the K^ATP channel, adjusting the intracellular Ca²⁺ concentration, and promoting the fusion of insulin granules and the plasma membrane.

Figure 2

Schematic diagram of β-cell functional alternations under metabolic stress. Metabolic stress first stimulates β-cells to initiate compensatory responses, including hyperplasia, hypertrophy, upregulation of insulin synthesis and secretion, etc. These compensatory responses do not cause irreversible damage to β-cells and can be reversed upon reduction of metabolic stress. However, under prolonged and intense metabolic stress, a cluster of genes critical for β-cell function, such as FOXO1, PDX1, MAFA, and NKX6-1, are downregulated, resulting in functional impairment and decompensation of β-cells. During this process, β-cells also undergo dedifferentiation, transdifferentiation, and eventually apoptosis, leading to the gradual onset of T2D.

Figure 3

Schematic diagram of dietary intervention-mediated regulation of insulin secretion in β-cells. Three widely established dietary intervention strategies for sustaining β-cell function and enhancing glycemic control are restricting calorie intake, following a fasting-like diet, and altering the intake of specific dietary components. Alleviating metabolic stress, maintaining β-cell mass, promoting insulin secretion, and preserving β-cell identity are all possible mechanisms for dietary interventions to protect β-cell function.

Figure 4

Schematic diagram of physical exercise-medicated regulation of insulin secretion in β-cells. β-cells Cells are primarily affected by exercise via the alternation of the metabolic state of peripheral tissues. On the one hand, exercise improves overnutrition by increasing peripheral tissue (e.g. the skeletal muscle, adipose tissue, and liver) glucose uptake and ameliorating insulin resistance; on the other hand, peripheral tissues under the effect of exercise modulate the secretion of a range of exerkines, which have a variety of protective effects on β-cells.