A retrospective review of the roles of multifunctional glucose-6-phosphatase in blood glucose homeostasis: Genesis of the tuning/retuning hypothesis

Abstract

In a scientific career spanning from 1955-2000, my research focused on phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Grounded in basic enzymology, and initially pursuing the steady-state rate behavior of isolated preparations of these critically important gluconeogenic enzymes, our key findings were confirmed and extended by in situ enzyme rate experiments exploiting isolated liver perfusions. These efforts culminated in the discovery of the liver cytosolic isozyme of carboxykinase, known today as (GTP)PEPCK-C (EC4.1.1.32) and also revealed a biosynthetic function and multicomponent nature of glucose-6-phosphatase (EC3.1.3.9). Discovery that glucose-6-phosphatase possessed an intrinsically biosynthetic activity, now known as carbamyl-P:glucose phosphotransferase-along with a deeper consideration of the enzyme's hydrolytic activity as well as the action of liver glucokinase resulted in the evolution of Tuning/ Retuning Hypothesis for blood glucose homeostasis in health and disease. This THEN & NOW review shares with the reader the joy and exhilaration of major scientific discovery and also contrasts the methodologies and approaches on which I relied with those currently in use.

Hesperidin prevents hyperglycemia in diabetic rats by activating the insulin receptor pathway

“…Hesperidin induced glucokinase activity, but decreased the activity of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase compared with the model group (Fig. 4), which are vital hepatic glucose regulating enzymes involved in glycolysis and gluconeogenesis (28).…”

Metabolomic Heterogeneity of Pulmonary Arterial Hypertension

“…By gene array and immunostaining, we showed that genes in vascular smooth muscle cells encoding the key enzymes for glycolysis, such as LDH-B, were significantly increased, whereas genetic expression of other key enzymes in the glycolytic pathway, specifically glucose-6-phosphatase subunit C3 (G6PC3) was significantly downregulated. Glucose-6-phosphate (G6P), a key rate-limiting metabolite in normal glycolysis and a substrate for G6PC3, can enter many pathways, including gluconeogenesis to produce glucose [25] , glycogenesis for storing glucose, anaerobic glycolysis [26] to convert to pyruvate, or entrance to the pentose phosphate pathway for generating ribose-5-phsophate (R5P) for the synthesis of nucleotides and erythrose-4-phosphate (E4P) for the biosynthesis of aromatic amino acids. In particular, the enzyme glucose-6-phosphatase plays a major role in the gluconeogenesis process of dephosphorylating glucose-6-phsophate to generate glucose [27] .…”

Elevated Glucose Represses Liver Glucokinase and Induces Its Regulatory Protein to Safeguard Hepatic Phosphate Homeostasis

“…Accordingly, induction of G6pc, which promotes enhanced glucose production, is generally viewed as a paradoxical response to glucose ( 18 ). Various hypotheses have been proposed to explain the possible adaptive advantage of the glucose induction of G6pc in relation to blood glucose homeostasis ( 18 , 19 ). However, overexpression of G6pc causes glucose intolerance ( 20 ), which argues against an adaptive role for G6pc induction in blood glucose homeostasis.…”