Interorgan crosstalk in pancreatic islet function and pathology

Abstract

Pancreatic β cells secrete insulin in response to glucose, a process that is regulated at multiple levels, including a network of input signals from other organ systems. Impaired islet function contributes to the pathogenesis of type 2 diabetes mellitus (T2DM), and targeting inter-organ communications, such as GLP-1 signalling, to enhance β-cell function has been proven to be a successful therapeutic strategy in the last decade. In this review, we will discuss recent advances in inter-organ communication from the metabolic, immune and neural system to pancreatic islets, their biological implication in normal pancreas endocrine function and their role in the (mal)adaptive responses of islet to nutrition-induced stress.

Keywords: GLP-1; inter-organ crosstalk; pancreatic β cells; type 2 diabetes mellitus.

Figure 1.. Inter-organ crosstalk regulating pancreatic islet function.

Multiple distal metabolic organs, such as liver, adipose, intestine, bone, and skeletal muscle, modulate islet function through a variety of circulating factors. The specific mediators for the inter-organ crosstalk include intestine-released incretin/decretin (GLP-1, GIP, Ghrelin, Galanin, and NMU) and metabolites from microbiome such as SCFA; adipose secreted leptin, adiponectin, adipsin, and free fatty acids (FFA); liver-secreted HGF, Kisspeptin, SerpinB1, IGFBP1 and FGF21; skeletal muscle secreted IL-6 and miR-16; and bone secreted Osteocalcin. Multiple components in the pancreatic microenvironment, such as sympathetic/parasympathetic nerves, infiltrating immune cells, and exocrine compartment, also crosstalk with islet in both normal physiological and pathological settings, such as pro-inflammatory cytokines (IL-1β, etc) from immune cells and neuropeptides (VIP, etc.) from sympathetic/parasympathetic nerves. The inter-organ signaling converge at islet to promote or impair glucose stimulated insulin response in both homeostatic and dysfunctional setting. Red: signaling molecules which cause islet dysfunction. Green: signaling molecules which enhance islet function. Created with Biorender.com.