Pancreatic Islet GLUT2 Glucose Transporter mRNA and Protein Expression in Humans With and Without NIDDM

Abstract

GLUT2 glucose transporter mRNA has been shown to be underexpressed in pancreatic islets of numerous animal models of non-insulin-dependent diabetes mellitus (NIDDM). It has been proposed that this molecular defect contributes to the pathogenesis of diabetes, although information concerning the expression of GLUT2 in human pancreatic islet tissue is lacking. In contrast to the high abundance of GLUT2 in rat islets, human islets were found to express distinctly low levels of this glucose transporter mRNA and protein. Thus, a sensitive competitive reverse transcription-polymerase chain reaction assay was developed to quantify human GLUT2 mRNA. We obtained pancreases from 4 human organ donors with previously diagnosed NIDDM and 11 nondiabetic donors and found no significant differences in GLUT2 mRNA between the two groups. GLUT2 mRNA was 0.24 +/- 0.08 amol/micrograms RNA (mean +/- SE) in pancreases from humans with diabetes and 0.27 +/- 0.06 amol/microgram RNA in those without this diagnosis. Similarly, human pancreatic islet GLUT2 protein was measured by immunoblot and found to be present at similar levels in two individuals with diabetes relative to six control samples. These results thus demonstrate the existence of species differences in the abundance of islet GLUT2 mRNA and protein. Furthermore, the analysis of islet GLUT2 in a small sample of human organ donors with and without diabetes raises the possibility that decreased beta-cell GLUT2 may not represent a widespread feature of humans with NIDDM.

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“…The techniques used here are not quantitative so do not permit estimation of relative amounts of GLUT1 and GLUT2 in our tissue samples. Nevertheless, the results do suggest that GLUT1 is the major beta cell glucose transporter in fetal and neonatal life and, although we clearly demonstrate that GLUT2 can be detected in the mature pancreas, other studies show that GLUT1 remains the major isoform in the adult pancreas [5,6].…”

Role of the GLUT 2 Glucose Transporter in the Response of the L-type Pyruvate Kinase Gene to Glucose in Liver-derived Cells

“…In endocrine pancreas ␤ cells, the predominant glucose-sensor has been definitively identified as glucokinase by knock out of the gene in mice (32,33), and the significance of the specific GLUT 2 expression in rodent ␤ cells is still disputed, especially as the amount of the GLUT 2 isoform seems to be very low in human ␤ cells (34,35). German (36) has shown that ␤ cells overexpressing GLUT 1 do not lose their ability to sense changes in glucose concentration within the physiological range and to respond by an appropriate stimulation of the insulin gene promoter.…”

Mechanism underlying resistance of human pancreatic beta cells against toxicity of streptozotocin and alloxan

“…Human beta cells could be more resistant to the toxic action of streptozotocin and alloxan either because they express the GLUT2 glucose transporter only to a very low extent [7,8] (1-2% of the level expression in rat beta cells), or, alternatively, because streptozotocin and alloxan, in contrast to the rat GLUT2 glucose transporter isoform, are not taken up through the human GLUT2 glucose transporter isoform into the intracellular compartment where the toxins exert their cell-death action.…”

“…The results show that it is apparently the very low level of constitutive GLUT2 glucose transporter expression in the human beta cell [7,8] rather than the inability of the human GLUT2 glucose transporter isoform to provide uptake of streptozotocin and alloxan into the intracellular compartment (Table 1) which is responsible for the extraordinarily high resistance of humans against the diabetogenic action of streptozotocin and alloxan. However, even if the human GLUT2 glucose transporter isoform would be more abundant in human pancreatic beta cells, the lower capacity for uptake of the toxins through the human GLUT2 glucose transporter isoform as compared to the rat transporter isoform would limit Therefore it is also not surprising that development of Type 1 diabetes mellitus is not known to be a typical side effect when streptozotocin is used as a chemotherapeutic agent in human cancer treatment and that it is not a particularly efficient anti-cancer drug when used in the treatment of human insulinomas which usually do not express the GLUT2 glucose transporter [4].…”