Glutamate dehydrogenase: role in regulating metabolism and insulin release in pancreatic β-cells

Abstract

Regulation of insulin release and glucose homeostasis by pancreatic β-cells is dependent on the metabolism of glucose by glucokinase (GK) and the influence of that activity on oxidative phosphorylation. Genetic alterations that result in hyperactivity of mitochondrial glutamate dehydrogenase (GDH-1) can cause hypoglycemia-hyperammonemia following high protein meals, but the role of GDH-1 remains poorly understood. GDH-1 activity is strongly inhibited by GTP, to near zero in the absence of ADP, and cooperatively activated ( n = 2.3) by ADP. The dissociation constant for ADP is near 200 µM in vivo, but leucine and its nonmetabolized analog 2-amino-2-norbornane-carboxylic acid (BCH) can activate GDH-1 by increasing the affinity for ADP. Under physiological conditions, as [ADP] increases GDH-1 activity remains very low until ~35 µM (threshold) and then increases rapidly. A model for GDH-1 and its regulation has been combined with a previously published model for glucose sensing that coupled GK activity and oxidative phosphorylation. The combined model (GK-GDH-core) shows that GK activity determines the energy state ([ATP]/[ADP][Pi]) in β-cells for glucose concentrations > 5 mM ([ADP] < 35 µM). As glucose falls < 5 mM the [ADP]-dependent increase in GDH-1 activity prevents [ADP] from rising above ~70 µM. Thus, GDH-1 dynamically buffers β-cell energy metabolism during hypoglycemia, maintaining the energy state and the basal rate of insulin release. GDH-1 hyperactivity suppresses the normal increase in [ADP] in hypoglycemia. This leads to hypoglycemia following a high protein meal by increasing the basal rate of insulin release (β-cells) and decreasing glucagon release (α-cells). NEW & NOTEWORTHY A model of β-cell metabolism and regulation of insulin release is presented. The model integrates regulation of oxidative phosphorylation, glucokinase (GK), and glutamate dehydrogenase (GDH-1). GDH-1 is near equilibrium under physiological conditions, but the activity is inhibited by GTP. In hypoglycemia, however, GK activity is low and [ADP], a potent activator of GDH-1, increases. Reducing equivalents from GDH dynamically buffers the intramitochondrial [NADH]/[NAD], and thereby the energy state, preventing hypoglycemia-induced substrate deprivation.

Branched Chain Amino Acids

“…When glucose drops below 5 mM, adenosine 5 -diphosphate (ADP) levels rise and can activate GDH, thereby providing reducing equivalents and promoting αKG entry into the TCA cycle. Both of these promote adenosine 5 -triphosphate (ATP) production, subsequent inhibition of KATP channels, depolarization of plasma membrane, and vesicular release of insulin (59)(60)(61). Leucine allosterically activates GDH under these conditions by increasing its affinity for ADP, thus further increasing the ATP energy charge, and consequently, insulin secretion.…”

The Central Role of Glucokinase in Glucose Homeostasis: A Perspective 50 Years After Demonstrating the Presence of the Enzyme in Islets of Langerhans

“…The potential of GKAs has since been vigorously explored both by industry and academia (Matschinsky, 2009, 2013). A minimal computational model for GCK based β-cell glucose sensing has been recently developed that emphasizes the essential roles of 5’-AMP and MgADP as metabolic coupling factors in glucose stimulation of insulin release (Wilson et al., 2017, 2018).…”

“…Evidence supporting the hypothesis that GCK is responsible for coupling glucose concentration to insulin release of β-cells, and that it acts by altering cellular energy state, is now extensive (see Matschinsky and Ellerman, 1968; Trus et al., 1980; Meglasson et al., 1983; Ghosh et al., 1991; Liang et al., 1992, 1996; Matschinsky et al., 1993; Sweet and Matschinsky, 1995; Terauchi et al., 1995; Ferre et al., 1996; Sweet et al., 1996; Schuit et al., 1997; Detimary et al., 1998; Pino et al., 2007; Osbak et al., 2009; Sayed et al., 2009; Doliba et al., 2012; Prentki et al., 2013; Nicholls, 2016; Morishita et al., 2017; Wilson et al., 2017, 2018; Affourtit et al., 2018; Zhu et al., 2018). A computational model has been developed that is consistent with regulation of oxidative phosphorylation in vivo (Ox-Phos model) and its role in metabolic homeostasis (Wilson and Vinogradov, 2014, 2015; Wilson, 2015a,b, 2016, 2017a,b).…”

“…This Ox-Phos model has been shown to predict behavior consistent with experimental measurement over a wide range of conditions, including those during the rest-to-work (Wilson, 2015b) and work-to-rest (Wilson, 2016) transitions in skeletal muscle. A model for glucose sensing was then constructed by adding a computational model for GCK and glycolysis in pancreatic β-cells, including coupling to oxidative phosphorylation through the glycerol phosphate shuttle and pyruvate dehydrogenase, to the Ox-Phos model (Wilson et al., 2017, 2018). The combined models quantify how increasing glucose concentration, through increased synthesis of glucose-6-phosphate by GCK, increases the energy state and decreases [Mg 2+ ADP] and [AMP].…”

Independent and Opposite Associations Between Branched-Chain Amino Acids and Lysophosphatidylcholines With Incident Diabetes in Thais

“…Many mechanisms have been proposed for BCAA-medicated insulin resistance, but none have been proven to date. Some of the suggested mechanisms include activation of the mTORC1 complex, which is sensitive to metabolic clues, including amino acids [2], increase in insulin secretion and compensatory insulin resistance [3], and competition for fatty acid oxidation [4]. Most studies on the role of BCAAs in diabetes have been performed in Caucasians.…”