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  • In Solloway and colleagues reported that

    2022-06-14

    In 2015, Solloway and colleagues reported that mice with alpha cell hyperplasia due to inactive hepatic glucagon receptor signaling may most likely be caused by amino Y-27632 dependent mechanisms [11]. The authors then showed these adaptations are regulated by ‘mechanistic target of rapamycin’ (mTOR)-dependent signaling pathways as rapamycin eliminated the amino acid induced alpha cell proliferation. Previous literature have linked glucagon receptor signaling to amino acid metabolism through ureagenesis (formation of urea) and gluconeogenesis (formation of glucose) [63], [64], [65]. Interestingly, glucagon receptor knockout animals have indeed increased plasma levels of amino acids (hyperaminoacidemia) [66] but it was only recently that such metabolites have been linked to the physiological target of glucagon via a liver-alpha cell axis [67]. Glucagon stimulates the expression of enzymes controlling gluconeogenesis and glycogenolysis (up to several mg/kg/min) [59]. However, the ability of glucagon to elevate blood glucose seems to be dependent on the fasting status given animals that were fasted for more than 12h did not benefit from administration of glucagon but in contrast a compensatory spike in cortisol levels were observed [68], [69], [70], [71], [72]. Protein levels of the two key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and Glucose 6-phosphatase (G6P), are controlled by glucagon in a hourly dependent-manner since the glucagon-stimulating effects rely on transcriptional changes in messenger RNA (mRNA). It may therefore be less likely that such transcriptional-dependent effects of glucagon constitute the molecular underlying mechanism(s) for a liver-alpha cell axis by which glucagon regulates amino acid metabolism and plasma levels of amino acids control the secretory rates of glucagon [67] given that the changes in plasma levels of amino acids occur within minutes after disruption of hepatic glucagon receptor signaling [37]. Two studies published earlier this year in Cell Metabolism [10], [13] independently demonstrated potential paths on how amino acids may mitigate their proliferative effects on the alpha cells (through one of the amino acids transporters). The ‘down side’ of these studies is the (still) lack of explanation on how glucagon and amino acid acutely merge into an endocrine feedback cycle which when disrupted by liver damage (for example steatosis) results in glucagon receptor resistance and thereby hyperaminoacidemia, and finally hyperglucagonemia (Fig. 2). Delineating the basis of glucagon receptor signaling in metabolic diseases may led to new pharmaceutical drug targets such as biased receptor signaling and or combined with co-agonism with incretins hormone Y-27632 or hepatokines (FGF21), but least and not to forget, improved medical care. The clinical impact of such compounds may include improved glycemic control and weight loss.
    Declaration of interest
    Acknowledgements
    NNF Center for Basic Metabolic Research, University of Copenhagen, NNF application number: 13563 (Novo Nordisk Foundation, Denmark), EliteForsk Rejsestipendiat (2016), The Danish Council for Independent Research (DFF − 1333-00206A), Augustinus Foundation, Aase og Ejnar Danielsens Fond, Mærsk Fonden, Holger Rabitz fond, Læge Johannes Nicolaj Krogsgaard og hustru Else Krogsgaards minde-legat for medicinsk forskning og medicinske studenter ved Københavns Universitet, European Molecular Biology Organization (EMBO) and the European Foundation for the Study of Diabetes (EFSD).
    Introduction Diabetes is a worldwide epidemic metabolic disease, which is typically characterized by chronic hyperglycemia and insufficient insulin secretion from pancreatic β-cells. Recent studies revealed that excess secretion of glucagon from pancreatic α-cells is also responsible for hyperglycemia both in type 1 diabetes (T1D) and type 2 diabetes (T2D) [1]. Disorders of pancreatic islet structure and function play a critical role in the development and progression of diabetes. Pancreatic islets are composed of five subtypes of endocrine cells, including glucagon-secreting α-cells, insulin-secreting β-cells, somatostatin-producing δ-cells, ghrelin-producing ε-cells and pancreatic polypeptide (PP)-producing PP-cells. The hormone secretion of δ-cells, α-cells and β-cells closely interacts with each other through the paracrine mechanism and ultimately affects islet homeostasis [[2], [3], [4]]. For instance, somatostatin secreted from δ-cells inhibits glucagon and insulin secretion. Notably, recent studies have demonstrated that pancreatic δ-cells can be converted into functional β-cells after near-total β-cell loss in juvenile mice [5] or by ectopic expression of Pax4 (a critical transcription factor for β-cell fate decision) [6]. It is interesting to find some clinical potential ways to promote β-cell regeneration through δ-to-β-cell trans-differentiation.