Arginine regulation of alpha cell proliferation and function

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PROJECT SUMMARY Traditionally, diabetes is defined as decreased insulin action resulting in impaired glucose homeostasis. However, inappropriate secretion of glucagon also contributes to the hyperglycemia in diabetes. Blocking glucagon action lowers blood glucose, but also leads to hyperglucagonemia with α cell proliferation and hyperplasia. We demonstrated that this is due to high blood levels of amino acids resulting from impaired amino acid catabolism in liver (gluconeogenesis). These studies demonstrated a classical endocrine feedback loop, the liver-islet α cell axis. As part of our K01 funded investigations, we discovered that high levels of arginine are required for the effects of high amino acid levels on α cell proliferation and function. We identified SLC7A2 (CAT2) is the major arginine transporter in pancreatic islet α cells. Using global CAT2 knockout mice, we found that loss of CAT2 results in protection from α cell hyperplasia and a complete loss of glucagon secretion even in response to strong depolarizing agents. This suggests that CAT2 is playing an important role in α cells beyond affecting membrane polarization as had been previously proposed as a mechanism for arginine-stimulated secretion. Our current objective is to define the mechanisms of arginine-stimulated α cell proliferation and secretion. Under the support of this R01 in Aim 1, we will characterize changes in the α cell when CAT2 expression is lost using α cell specific targeted deletion, including α cell proliferation and mass, glucagon secretion, Ca2+ dynamics, and gene and protein expression. We will also test if the heterodimeric amino acid exchanger LAT2 (SLC7A8/SLC3A2) is required for α cell proliferation and function. In Aim 2, we will examine a novel putative arginine cell surface binding protein called TM4SF4 that is selectively and robustly expressed on pancreatic α cells. We will fully characterize TM4SF4 arginine binding kinetics, protein binding partners in α cells, effects on arginine transport, and regulation of α cell proliferation and function. An important feature of our work is that we will translate our discoveries made in mouse islets using human islets. These studies will provide new insights into normal α cell function and how α cells could be targeted to repair dysregulated glucagon secretion in diabetes.