Glucokinase (GCK) mainly exists in pancreatic β-cell, hepatocytes and brain, and is the first-rate limiting enzyme in glucose metabolism pathway. The heterozygous inactivation mutation of GCK leads to Maturity-onset diabetes of the young (MODY2) , an autosomal dominant mild fasting hyperglycemia. In the monogenic diabetes registration project initiated by our research group, we found a novel inactivation mutation site of GCK gene, c.77A>T (p.Q26L) . We sought to explore the pathogenic mechanism with a newly constructed mouse model.The proband was first diagnosed with diabetes at 11. Her father was diagnosed with diabetes at 32, and his mother was healthy. Genetic testing showed there was a novel heterozygous missense mutation site c.77A >T in exon 1 of the GCK of the proband, which resulted in the change of the 26th amino acid from glutamine to leucine. The pedigree indicated the mutation of proband was inherited from her father, not her mother. A global knock-in GCK (Q26L) mice (GCKKI/-) model was successfully established. From 3-16 weeks, substantial group differences in fasting blood glucose, other than body weight, was observed in GCKKI/-. At 3-week, impaired glucose tolerance and lower serum insulin level of GCKKI/- mice were detected. There was no difference in insulin sensitivity and content of proinsulin and insulin in the islet of GCKKI/-. In vitro experiment, decreased glucose-stimulated insulin secretion was observed in the GCKKI/-, but no significant changes in KCl stimulated insulin secretion. Furthermore, the results of different glucose concentration stimulated insulin secretion and islet perfusion showed the insulin secretion threshold increased and the insulin secretion ability decreased in the GCKKI/-. In the GCKKI/- liver, there were no changes in the morphology, but glycogen content was reduced. The level of plasma HDL significantly increased, plasma TC and LDL levels decreased, and TG levels did not change.
S.Ji: None. H.Shu: None. W.Feng: None. J.Zhen: None. J.Qiao: None. Y.Huang: None. S.Chen: None. M.Liu: None.
National Natural ScienceFoundation of China (81830025,81620108004,81800733,and 81900720) , the Ministry of Science and Technologyof China (2019YFA0802502) , the Tianjin Municipal Science andTechnology Bureau (17ZXMFSY00150)