Expression of yeast hexokinase in pancreatic beta cells of transgenic mice reduces blood glucose, enhances insulin secretion, and decreases diabetes.
It has been proposed that endogenous hexokinases of the pancreatic beta cell control the rate of glucose-stimulated insulin secretion and that genetic defects that reduce beta-cell hexokinase activity may lead to diabetes. To test these hypotheses, we have produced transgenic mice that have a 2-fold increase in hexokinase activity specific to the pancreatic beta cell. This increase was sufficient to significantly augment glucose-stimulated insulin secretion of isolated pancreatic islets, increase serum insulin levels in vivo, and lower the blood glucose levels of transgenic mice by 20-50% below control levels. Elevation of hexokinase activity also significantly reduced blood glucose levels of diabetic mice. These results confirm the role of beta-cell hexokinase activity in the regulation of insulin secretion and glucose homeostasis. They also provide strong support for the proposal that reductions in beta-cell hexokinase activity can produce diabetes.
Epstein
P N
PN
Department of Pharmacology and Toxicology, University of North Dakota, Grand Forks 58203.
Boschero
A C
AC
Atwater
I
I
Cai
X
X
Overbeek
P A
PA
D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D015870:Gene Expression; D006593:Hexokinase / Q000502:physiology*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology
D001786:Blood Glucose; D007328:Insulin; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D006593:Hexokinase