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J. Biol. Chem., Vol. 275, Issue 31, 23751-23758, August 4, 2000
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From the Institute of Pharmacology and Toxicology, 27, rue du
Bugnon, CH-1005 Lausanne and § Swiss Institute for
Experimental Research on Cancer, Ch. des Boveresses, 1066 Epalinges, Switzerland
GLUT2-null mice are hyperglycemic,
hypoinsulinemic, hyperglucagonemic, and glycosuric and die within the
first 3 weeks of life. Their endocrine pancreas shows a loss of first
phase glucose-stimulated insulin secretion (GSIS) and inverse
Transgenic Reexpression of GLUT1 or GLUT2 in Pancreatic
Cells
Rescues GLUT2-null Mice from Early Death and Restores Normal
Glucose-stimulated Insulin Secretion*
,
to
cell ratio. Here we show that reexpression by transgenesis of
either GLUT1 or GLUT2 in the pancreatic cells of these mice allowed
mouse survival and breeding. The rescued mice had normal-fed glycemia
but fasted hypoglycemia, glycosuria, and an elevated glucagon to
insulin ratio. Glucose tolerance was, however, normal. In
vivo, insulin secretion assessed following hyperglycemic clamps
was normal. In vitro, islet perifusion studies revealed
that first phase of insulin secretion was restored as well by GLUT1 or
GLUT2, and this was accompanied by normalization of the glucose
utilization rate. The ratio of pancreatic insulin to glucagon and
volume densities of to cells were, however, not corrected.
These data demonstrate that 1) reexpression of GLUT1 or GLUT2 in cells is sufficient to rescue GLUT2-null mice from lethality, 2) GLUT1
as well as GLUT2 can restore normal GSIS, 3) restoration of GSIS does
not correct the abnormal composition of the endocrine pancreas. Thus, normal GSIS does not depend on transporter affinity but on the rate of
uptake at stimulatory glucose concentrations.
*
This work was supported by Swiss National Science Foundation
Grant 31-46958.96 and Juvenile Diabetes Foundation International Grant
198243.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 41 21 692 53 90;
Fax: 41 21 692 53 55; E-mail: Bernard.Thorens@ipharm.unil.ch.
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