Interaction of Islet α-Cell and β-Cell in the Regulation of Glucose Homeostasis in HI/HA Syndrome Patients With the GDHH454Y Mutation

The hyperinsulinemia/hyperammonemia (HI/HA) syndrome—the secondmost common form of congenital hyperinsulinism—is a rare autosomal dominant disease manifested by hypoglycemic symptoms and elevated serum ammonia triggered by fasting or high-protein meals (1). In 1955, Cochrane et al. described a child and her father, both with hypoglycemia that was aggravated by consumption of a low-carbohydrate, high-protein diet (2). Subsequently, another group identified the gene GLUD1. This gene, located on chromosome 10q23.3, is composed of 13 exons and regulates mitochondrial enzyme glutamate dehydrogenase (GDH) (3). The GDH enzyme catalyzes glutamate metabolism and plays important roles in the regulation of amino acid2stimulated insulin secretion in b-cells, modulation of amino acid catabolism in hepatocytes, and ammoniagenesis in the brain (4). A total of 14 amino acid residues affected by GDH-activating mutations has been identified in patients with the HI/HA syndrome (5). GDH activity also is subject to complex regulation by GTP, ADP, and leucine (6). For example, the flux of glutamate into the tricarboxylic acid cycle for energy generation is modulated by the mitochondrial energy potential, which, in turn, is controlled by the ratio of GTP to ADP. When the energy potential is high, amino acid oxidation is not required, and GDH enzyme activity shuts down. When energy potential is low, GDH is activated to sustain energy generation through oxidation of amino acids (4). Interestingly, epigallocatechin gallate, a component of green tea, has been shown to be a potent allosteric inhibitor of GDH enzyme activity (7). Insulin secretion is upregulated through increased cellular phosphate energy potential, which is manifested as an increase in the ATP/ADP ratio. Elevated ATP/ADP concentrations promote closing of plasma membrane KATP channels, resulting in pancreatic b-cell membrane depolarization. This voltage change across the cell membrane opens voltage-gated calcium (Ca) channels, which promote insulin granule exocytosis (8). For example, in pancreatic b-cells, the elevated levels of ATP promoted by high intracellular a-ketoglutarate lead to hyperinsulinemia and an increased propensity for hypoglycemia. Similarly, a decrease in intracellular N-acetylglutamate leads to inactivity of carbamoyl phosphate synthetase—a ligase mitochondrial enzyme involved in the production of urea—which can cause an overproduction of ammonia (9). Thus in patients with HI/HA syndrome, enhanced insulin secretion by pancreatic b-cells is driven by increased GDH activity in conjunction with available glucose and amino acids (Fig. 1). The importance of enhanced GDH activity is underscored by features of HI/HA syndrome, where a dominant mutation causes loss of inhibition of GDH enzyme activity that is normally exerted by GTP and ATP (10). Indeed, H454Y transgene pancreatic expression was confirmed by increased GDH enzyme activity and decreased sensitivity to GTP inhibition in islets (11). Leucine levels serve as an indicator of increases in amino acid supply following a highprotein feeding in mice with the H454Y mutation of GDH. The activation of oxidation of amino acids through transamination to glutamate and then into the tricarboxylic acid cycle via GDH causes an increase in the ATP/ADP ratio and ultimately triggers insulin release (1) (Fig. 1). This pathway can be activated in the absence of glucose when the phosphate potential is low. This is because a low ATP/ADP ratio