Interorgan Crosstalk Contributing to β-Cell Dysfunction

Abstract

Type 2 diabetes mellitus (T2DM) results from pancreatic β-cell failure in the setting of insulin resistance. In the early stages of this disease, pancreatic β-cells meet increased insulin demand by both enhancing insulin-secretory capacity and increasing β-cell mass. As the disease progresses, β-cells fail to maintain these compensatory responses. This involves both extrinsic signals and mediators intrinsic to β-cells, which adversely affect β-cells by impairing insulin secretion, decreasing proliferative capacities, and ultimately causing apoptosis. In recent years, it has increasingly been recognized that changes in circulating levels of various factors from other organs play roles in β-cell dysfunction and cellular loss. In this review, we discuss current knowledge of interorgan communications underlying β-cell failure during the progression of T2DM.

Figure 1

The interorgan crosstalk involved in β-cell failure. Representative pathways from metabolic organs involved in a reduction of functional β-cell mass are illustrated. Although adiponectin, preferentially secreted from lean adipose tissue, may have protective effects on β-cells, leptin, which is secreted more from obese adipose tissue, negatively impacts β-cell function and mass via direct and indirect pathways. Leptin suppresses the bioactivity of osteocalcin, which is essential for β-cell function and expansion, through the modulation of sympathetic tone signals delivered to osteoblasts, creating a feed-forward interplay among adipose tissue, the brain, bone, and β-cells. Conversely, insulin enhances osteocalcin bioactivity through the activation of osteoclastic bone resorption. Meanwhile, excess FFA spillover from obese adipose tissue induces insulin resistance in insulin sensitive organs such as muscle and liver, resulting in overload of β-cells by excess insulin demand. Additionally, skeletal muscle and liver might exert detrimental effects of β-cell function by secreting proinflammatory cytokines and chemokines in this setting. Glucagon promotes Kisspeptin 1 production in hepatocyte, which mediates an alternative pathway from liver to β-cells. Furthermore, FFA induces the production of chemokines in β-cells, recruiting M1 macrophages into islets. In the diabetic milieu, hyperglycemia and IAPP derived from β-cells synergistically promote inflammatory responses through the promotion of IL-1β biosynthesis in M1 macrophages.