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    • Regulation of pancreatic and cell mass has been

    2021-12-30

    Regulation of pancreatic α and β cell mass has been extensively studied and hotly debated, due to potential therapeutic implications. Early claims of Angptl8 as “betatrophin” and Angptl4 as a regulator of glucagon secretion and α cell proliferation (Yi et al., 2013, Ben-Zvi et al., 2015) have not stood up to further examination (Gusarova et al., 2014, Yi et al., 2017, Okamoto et al., 2017). Thus, it is very encouraging that we have been able to independently confirm the role of hyperaminoacidemia and an mTOR-dependent pathway in triggering α cell hyperplasia, as proposed by Solloway et al., (2015) and in the accompanying paper by Dean et al. (2017), and further extend this realization by discovering the key cell surface protein on α cells that is required for the response to increased plasma amino acids. Glucagon has a well-defined role in glucose homeostasis, as the hormone responding to low blood glucose levels to promote liver gluconeogenesis via GCGR-Gsα-cAMP-PKA-CREB signaling. Tcf7l2- and Foxo-dependent transcriptional regulation may also contribute directly or via crosstalk with CREB to expression of gluconeogenic genes following GCGR activation (Altarejos and Montminy, 2011, Mihaylova et al., 2011). In addition, glucagon plays an important role during states of protein abundance, facilitating uptake and utilization of amino acids by converting them to glucose in the liver. This is possible since amino acids are potent stimulators of glucagon secretion (Rocha et al., 1972). However, amino acids also stimulate insulin release. Thus, the enhanced hepatic glucose output in settings of protein abundance prevents hypoglycemia resulting from the concomitant insulin release. Here we provide evidence that amino acids are important signaling molecules for α cells in settings of reduced hepatic glucagon action. This results from reduced uptake and conversion of amino acids into gluconeogenic precursors, thereby increasing circulating plasma amino Anti-cancer Compound Library levels, which trigger glucagon secretion and α cell hyperplasia. We have recently reported that plasma amino acids are also increased in humans following administration of the GCGR-blocking antibody (Okamoto et al., 2017). We did not observe changes in plasma insulin levels. This is consistent with the fact that glucagon receptor inhibition lowers blood glucose and that amino acids generally potentiate rather than initiate insulin secretion (Rideau and Simon, 1989, Gadhia et al., 2013). β cell mass remained unchanged and has been shown to only increase in settings of chronic high demand for insulin. We found that α cells express many amino acid transporters and that inhibition of glucagon signaling selectively increased the expression of Slc38a5. The expression of Slc38a5 was largely observed in proliferating α cells and was only rarely detected in the other islet cell types. The increase in α cell mass following GCGR inhibition is mTOR dependent measured as an increase in pS6 staining and was blocked by rapamycin. This is consistent with recent reports (Solloway et al., 2015, Dean et al., 2017) demonstrating that the expansion of α cell mass following glucagon receptor inhibition was mTOR dependent. Interestingly, the expression of Slc38a5 was blocked by rapamycin. This suggests that mTOR regulates expression of Slc38a5 to facilitate uptake of key amino acids, e.g., glutamine to provide the energy and building blocks for cell division (Figure 7F). It is important to note that rapamycin did not block the GCGR inhibition-induced increase in plasma glucagon. This is consistent with the observation that GCGR inhibition induced hyperglucagonemia in Slc38a5−/− mice. We found that GCGR inhibition slightly increased α cell size, an effect that was not affected by Slc38a5 deficiency and only contributes about 10% of the total 400%–500% increase in α cell mass. Future studies are needed to elucidate the mechanism by which mTOR activates the expression of Slc38a5 and which amino acid transporter(s) are responsible for the uptake of amino acids to trigger glucagon release. It also remains to be established why α cells express so many amino acid transporters and why elevated plasma amino acid levels selectively increase expression of Slc38a5. Human α cells express 25 amino acid transporters. Importantly, the overlap of expressed amino acids between mouse and human α cells is low (56% show <1.5-fold difference in expression) (Xin et al., 2016). It was therefore less surprising that SLC38A5 expression was not detected even in proliferating human α cells following implantation in GCGR antibody-treated mice for up to 3 months. Human α cells from type 2 diabetes donors also do not express SLC38A5. Since expression of Slc38a5 is mTOR dependent in mice, it will be interesting to explore whether GCGR inhibition-induced hyperaminoacidemia promotes mTOR activity in human α cells. Further studies are also needed to investigate which (if any) amino acid transporter expression is induced under these conditions.