Regulation of beta-cell glucose transporter gene expression.

Abstract

It has been postulated that a glucose transporter of (3 cells (GLUT-2) may be important In glucosestimulated insulin secretion. To determine whether this transporter is constitutively expressed or regulated, we subjected conscious unrestrained Wistar rats to perturbations in glucose homeostasis and qmntitated (-cell GLUT-2 mRNA by in situ hybridization. After 3 hr of hypoglycemia (glucose at 29 ± 5 mg/dl), GLUT-2 and proinsulin mRNA signal deities were reduced by 25% of the level in control rats. After 4 days (blood glucose at 57 ± 7 mg/dl vs. 120 ± 10 mg/dl in saline-infused control rats), GLUT-2 and proinsulin mRNA densities were reduced by 85% and 65%, respectively (P = 0.001). After 12 days (glucose at 54 ± 8 mg/dl), GLUT-2 mRNA signal density was undetectable whereas proinsulin mRNA was reduced by 51%. After 12 days of hypoglycemia, the K. for 3-0-methyl-D-glucose transport in isolated rat islets, normally 18-20 mM, was 2.5 mM. This provides functional evidence of a profound reduction of high K. glucose transporter in P cells. In contrast, GLUT-2 was only slightly reduced by hypoglycemia in liver. To determine the effect of prolonged hyperglycemia, we also infused animal with 50% (wt/vol) glucose for 5 days (glucose at 200 ± 50 mg/dl). Hyperglycemic clamping increased GLUT-2 mRNA by 46% (P = 0.001) whereas proinsulin mRNA doubled (P = 0.001). We conclude that GLUT.2 expression in (3 cells, but not liver, is subject to regulation by certain perturbations in blood glucose homeostasis.In recent years biochemical and molecular studies have revealed the existence of a family of glucose transporters with distinct functional properties but with related primary sequences (1, 2). Glucose uptake into hepatocytes (3) and pancreatic .8 cells (4) occurs with a Km of 17-20 mM and is likely mediated by the so-called glucose transporter 2 (GLUT-2) (5) or L type (6) glucose transporter that has identical primary sequence in the two tissues (4, 7). In most other tissues the Km for glucose uptake is in the 1-2 mM range (8) and is mediated by the low Km transporter that is termed glucose transporter 1 (GLUT-1) (5) or the E type (6). Normal 13cells express GLUT-2 but not GLUT-1 (1, 4, 7) whereas in clonal insulinoma cell lines such as RINm5F, GLUT-1 mRNA predominates (1). The lack of responsiveness to glucose exhibited by such insulinoma lines has been attributed to a reduction in glucose transport that in normal P cells is believed not to be rate-limiting (9). Replacement of GLUT-2 with GLUT-1 in insulinoma cells may render glucose transport rate-limiting, thereby contributing to their glucose insensitivity. Expression of the high Km GLUT-2 transporter may thus be required for the normal insulin response to glucose, which in turn is essential for normal blood glucose homeostasis. Indeed, loss of glucose-stimulated insulin secretion is the earliest known defect in both autoimmune and nonautoimmune forms of diabetes (10-12).It is not known at present if the GLUT-2 gene is constitutively expressed or if it is regulated b...

Endocrine pancreas in insulin receptor-deficient mouse pups.

“…In contrast, the RNA levels of GLUT2 were slightly increased in 3-to 4-day-old pups lacking IR (Fig. 2B), thereby confirming studies showing that hyperglycemia increases GLUT2 gene expression in ␤-cells (22).…”

Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter.

“…Currently, insulin secretion is known to be stimulated by glucose or its metabolites. In this pathway, GLUT2 may play a role as a glucose sensor (37). Based on these observations and our results, troglitazone is thought not only to protect ␤-cells from lipoapoptosis, but also to improve the glucose sensitivity of ␤-cells.…”

Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion

“…Because the GLUT-2 loss coincides temporally with impairment of glucose-stimulated insulin secretion and the onset of hyperglycemia (7,9), it seemed possible that the reduction in GLUT-2 might be the cause of the ␤-cell dysfunction and diabetes (5); however, subsequent studies have indicated that the loss of GLUT-2 is secondary to one or more of the metabolic abnormalities of diabetes, and not their cause (8). Of these metabolic abnormalities, hyperglycemia had been exculpated as the down-regulator of GLUT-2 because it increases, rather than decreases, GLUT-2 expression in normal islets (10). Interest has therefore shifted to a second metabolic abnormality of diabetes, high plasma free fatty acid (FFA) levels (11)(12)(13)(14)(15).…”