Transgenic knockouts reveal a critical requirement for pancreatic β cell glucokinase in maintaining glucose homeostasis

• Published in: Cell 1995-10, Vol.83 (1), p.69-78
• Main Authors: Grupe, Andrew, Hultgren, Bruce, Ryan, Anne, Ma, Yan Hui, Bauer, Michele, Stewart, Timothy A.
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Blood Glucose - analysis; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Disease Models, Animal; Enzyme Induction; Female; Genes, Lethal; Glucokinase - deficiency; Glucokinase - genetics; Glucokinase - physiology; Glucose - metabolism; Homeostasis; Hyperglycemia - enzymology; Hyperglycemia - genetics; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - enzymology; Liver - enzymology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mice, Transgenic
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/0092-8674(95)90235-X

The secretion of insulin is controlled by the rate of glucose metabolism in the pancreatic β cells. As phosphorylation by glucokinase (GLK) appears to be the rate-limiting step for glucose catabolism in β cells, this enzyme may be the glucose sensor. To test this possibility and to resolve the relative roles of liver and β cell GLK in maintaining glucose levels, we have generated mice completely deficient in GLK and transgenic mice in which GLK is expressed only in β cells. In mice with only one GLK allele, blood glucose levels are elevated and insulin secretion is reduced. GLK-deficient mice die perinatally with severe hyperglycemia. Expression of GLK in β cells in the absence of expression in the liver is sufficient for survival. These mice demonstrate the critical need for β cell GLK in maintaining normal glucose levels and provide a novel model for one form of noninsulin-dependent diabetes.