Species-Specific Glucose-6-Phosphatase Activity in the Small Intestine-Studies in Three Different Mammalian Models.

Zsófia Murányi,Angelo Benedetti,Paola Marcolongo,Viola Varga,Gábor Bánhegyi,Anita Kurucz,Éva Margittai

doi:10.3390/ijms20205039

Abstract

Besides the liver, which has always been considered the major source of endogenous glucose production in all post-absorptive situations, kidneys and intestines can also produce glucose in blood, particularly during fasting and under protein feeding. However, observations gained in different experimental animals have given ambiguous results concerning the presence of the glucose-6-phosphatase system in the small intestine. The aim of this study was to better define the species-related differences of this putative gluconeogenic organ in glucose homeostasis. The components of the glucose-6-phosphatase system (i.e., glucose-6-phosphate transporter and glucose-6-phosphatase itself) were analyzed in homogenates or microsomal fractions prepared from the small intestine mucosae and liver of rats, guinea pigs, and humans. Protein and mRNA levels, as well as glucose-6-phosphatase activities, were detected. The results showed that the glucose-6-phosphatase system is poorly represented in the small intestine of rats; on the other hand, significant expressions of glucose-6-phosphate transporter and of the glucose-6-phosphatase were found in the small intestine of guinea pigs and homo sapiens. The activity of the recently described fructose-6-phosphate transporter–intraluminal hexose isomerase pathway was also present in intestinal microsomes from these two species. The results demonstrate that the gluconeogenic role of the small intestine is highly species-specific and presumably dependent on feeding behavior (e.g., fructose consumption) and the actual state of metabolism.

Highlights

The glucose-6-phosphatase enzyme (G6Pase, EC 3.1.3.9) catalyzes the common terminal reaction of gluconeogenesis and glycogenolysis, i.e., the hydrolysis of glucose-6-phosphate (G6P) to glucose and inorganic phosphate (Pi)
The G6Pase system is located in the endoplasmic reticulum (ER) and is composed of the phosphohydrolase G6Pase with an intraluminal active site, a G6P transporter (G6PT), and two other putative translocases for the reaction products, i.e., glucose and Pi
Three glucose-6-phosphatase isoforms have been identified in humans: Glucose-6-phosphatase-α, encoded by G6PC; pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP), encoded by G6PC2; and glucose-6-phosphatase-β, encoded by the G6PC3 gene

Summary

Introduction

The glucose-6-phosphatase enzyme (G6Pase, EC 3.1.3.9) catalyzes the common terminal reaction of gluconeogenesis and glycogenolysis, i.e., the hydrolysis of glucose-6-phosphate (G6P) to glucose and inorganic phosphate (Pi). The G6Pase system is located in the endoplasmic reticulum (ER) and is composed of the phosphohydrolase G6Pase with an intraluminal active site, a G6P transporter (G6PT), and two other putative translocases for the reaction products, i.e., glucose and Pi. While G6Pase and the G6PT are well characterized at the molecular level, the transporters responsible for phosphate and glucose transport have not been unequivocally identified [1,2]. It is generally accepted that only G6PC, expressed in the liver and kidney, significantly contributes to the maintenance of the blood glucose level [3]. The liver G6PC regulates whole-body glucose homeostasis, constantly maintaining the blood glucose level, even during starvation. The kidney G6PC can contribute to whole-body glucose turnover, up to 25% in a deep fasting status and diabetes, conditions under which the kidney works as a major gluconeogenetic site. G6PC3 presumably hydrolyzes sugar phosphates other than G6P; a recent paper demonstrated that 1,5-anhydroglucitol-6-phosphate can be a substrate for the enzyme [4]

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