Contribution of Liver and Pancreatic Islet Crosstalk to β-Cell Function/Dysfunction in the Presence of Fatty Liver

Abstract

Tissue-to-tissue crosstalk regulates organ function, according to growing data. This phenomenon is relevant for pancreatic β-cells and the liver, as both tissues are involved in glucose homeostasis and lipid metabolism. The ability to fine-tune regulation and adaptive responses is enabled through communication between pancreatic β-cells and the liver. However, the crosstalk between both tissues changes when metabolic dysregulation is present. Factors and cargo from extracellular vesicles (EVs) released by liver and pancreatic β-cells that reach the circulation form the words of this interaction. The molecules released by the liver are called hepatokines and are usually secreted in response to the metabolic state. When hepatokines reach the pancreatic islets several mechanisms are initiated for their protection or damage. In the case of the crosstalk between pancreatic β-cells and the liver, only one factor has been found to date. This protein, pancreatic derived factor (PANDER) has been proposed as a novel linker between insulin resistance (IR) and type 2 diabetes mellitus (T2D) and could be considered a biomarker for non-alcoholic fatty liver disease (NAFLD) and T2D. Furthermore, the cargo released by EVs, mainly miRNAs, plays a significant role in this crosstalk. A better knowledge of the crosstalk between liver and pancreatic β-cells is essential to understand both diseases and it could lead to better prevention and new therapeutic options.

Pump‐Less, Recirculating Organ‐on‐Chip (rOoC) Platform to Model the Metabolic Crosstalk between Islets and Liver

“…In this function, it fine-tunes the regulation and adaptive responses to metabolic and nutritional states through an integrated communication using protein hormones, peptides, factors, metabolites, and the cargo of extracellular vesicles, mainly miRNAs. [9] Under physiological conditions, in response to increased blood glucose levels, beta cells in the pancreatic islets secrete insulin, which promotes glucose uptake and processing in hepatocytes. When the glucose level is reduced, alpha cells in the pancreatic islets secrete glucagon, which triggers hepatic glucose production by increased glycogenolysis and gluconeogenesis, and by decreased glycogenesis and glycolysis.…”

“…[12] The metabolism-regulating cross-talk mediated by insulin and glucagon is complemented by a plethora of proteins secreted by the liver (hepatokines), including angiopoietin-like 8, [13] Fetuin-A, [14] follistatin, [15] insulinlike growth factor binding proteins, [16,17] sex hormone-binding globulin, fibroblast growth factor 21, Hepatic Growth Factor, Kisspeptins, Serpin B1, selenoprotein and others. [9] In MASLD, the above-described cross-talk between the liver and the pancreas is disturbed and patients show a high prevalence of insulin resistance (IR), a condition in which the body's cells become less responsive to the effects of insulin leading to increased levels of blood glucose. [18] In addition, an insufficient compensatory beta cell function in the pancreatic islets has been associated with MASLD, causing reduced levels of insulin release upon glucose stimulation.…”

“…In this function, it fine‐tunes the regulation and adaptive responses to metabolic and nutritional states through an integrated communication using protein hormones, peptides, factors, metabolites, and the cargo of extracellular vesicles, mainly miRNAs. [ 9 ]…”

“…[ 12 ] The metabolism‐regulating cross‐talk mediated by insulin and glucagon is complemented by a plethora of proteins secreted by the liver (hepatokines), including angiopoietin‐like 8, [ 13 ] Fetuin‐A, [ 14 ] follistatin, [ 15 ] insulin‐like growth factor binding proteins, [ 16,17 ] sex hormone‐binding globulin, fibroblast growth factor 21, Hepatic Growth Factor, Kisspeptins, Serpin B1, selenoprotein and others. [ 9 ]…”

Islet cilia and glucose homeostasis

“…Locally within the islets, these hormones along with somatostatin act as paracrine cues to influence neighboring cell behavior ( Figure 1 ). A classically defined β-cell disease, diabetes is increasingly seen as a collective dysregulation of all islet endocrine cells, as well as disrupted communication between the pancreas and other metabolic organs ( Bouzakri et al, 2011 ; Dunmore and Brown, 2013 ; Watt et al, 2019 ; López-Bermudo et al, 2022 ).…”