A Glucose-6-phosphate Hydrolase, Widely Expressed Outside the Liver, Can Explain Age-dependent Resolution of Hypoglycemia in Glycogen Storage Disease Type Ia

Jeng-Jer Shieh,Chi-Jiunn Pan,Brian C Mansfield,Janice Yang Chou

doi:10.1074/jbc.m309472200

Abstract

A fine control of the blood glucose level is essential to avoid hyper- or hypo-glycemic shocks associated with many metabolic disorders, including diabetes mellitus and type I glycogen storage disease. Between meals, the primary source of blood glucose is gluconeogenesis and glycogenolysis. In the final step of both pathways, glucose-6-phosphate (G6P) is hydrolyzed to glucose by the glucose-6-phosphatase (G6Pase) complex. Because G6Pase (renamed G6Pase-alpha) is primarily expressed only in the liver, kidney, and intestine, it has implied that most other tissues cannot contribute to interprandial blood glucose homeostasis. We demonstrate that a novel, widely expressed G6Pase-related protein, PAP2.8/UGRP, renamed here G6Pase-beta, is an acid-labile, vanadate-sensitive, endoplasmic reticulum-associated phosphohydrolase, like G6Pase-alpha. Both enzymes have the same active site structure, exhibit a similar Km toward G6P, but the Vmax of G6Pase-alpha is approximately 6-fold greater than that of G6Pase-beta. Most importantly, G6Pase-beta couples with the G6P transporter to form an active G6Pase complex that can hydrolyze G6P to glucose. Our findings challenge the current dogma that only liver, kidney, and intestine can contribute to blood glucose homeostasis and explain why type Ia glycogen storage disease patients, lacking a functional liver/kidney/intestine G6Pase complex, are still capable of endogenous glucose production.

Highlights

A Glucose-6-phosphate Hydrolase, Widely Expressed Outside the Liver, Can Explain Age-dependent Resolution of Hypoglycemia in Glycogen Storage Disease Type Ia*
Our findings challenge the current dogma that only liver, kidney, and intestine can contribute to blood glucose homeostasis and explain why type Ia glycogen storage disease patients, lacking a functional liver/kidney/intestine G6Pase complex, are still capable of endogenous glucose production
Insulin plays major roles in regulating blood glucose levels [23], blood glucose homeostasis between meals depends on gluconeogenesis and glycogenolysis

Summary

The abbreviations used are

G6P, glucose-6-phosphate; G6Pase, glucose-6-phosphatase; ER, endoplasmic reticulum; G6PT, G6P transporter; UGRP, ubiquitously expressed G6Pase catalytic subunit-related protein; TRITC, tetramethylrhodamine isothiocyanate. G6PT is expressed ubiquitously [8], but G6Pase expression is considered to be restricted to the liver, kidney, and intestine [9, 10]. We identified a theoretical phosphatidic acid phosphatase, PAP2.8, encoded within locus 92579 (accession number XM࿝045901) on chromosome 17q21.31, which, by electronic Northern, is expressed ubiquitously [11]. This protein was described by Martin et al [12] as a ubiquitously expressed G6Pase catalytic subunit-related protein (UGRP) lacking phosphohydrolase activity. We demonstrate that PAP2.8/UGRP is a phosphohydrolase that can couple with G6PT to form an active G6Pase complex. Our results provide new insights into glucose homeostasis and explain why patients genetically deficient in the G6Pase-␣ complex are still capable of endogenous glucose production

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION