title: Overexpression of a glucokinase point mutant in the treatment of diabetes mellitus.
abstract: Glucokinase (GCK) is an important enzyme critical for glucose metabolism, and has been targeted as such in the pursuit of a cure for diabetes mellitus. We show that streptozotocin (STZ)-induced diabetic murine model exhibits low GCK expression with high blood glucose levels; moreover, aggravated glomerulonephritis is observed in the model when there is IL10 deficiency. Although T cells infiltrate into the liver and pancreas in STZ-induced diabetes mice, T helper 1 (Th1) and T helper 17 (Th17) cells decrease significantly with STZ addition in in vitro polarization. Using a mutant GCK gene (GCK 262) with a knocked out cytosine at position 2643 results in lower protein expression and more ubiquitination-led protein degradation compared with wild-type GCK (GCK 261). We further observed that hsa-mir-1302 can bind to 3'-untranslated region of mutant GCK, which can decrease GCK mRNA translation. Finally, delivery of mutant GCK by subcutaneous injection is more effective at decreasing blood glucose in the STZ-treated (STZ) murine diabetes model than insulin treatment alone. Similarly, mutant GCK consistently and moderately decreases blood glucose levels in GK rats over a period of 12 and 70 days without inducing hypoglycemia, whereas insulin is only effective over 12 h. These results suggest that mutant GCK may be a future cure for diabetes.
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lu
authors.affiliation: Hangzhou Yiyuan Biotechnology Co. Ltd, Hangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Teng
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Peng
authors.affiliation: Organ Transplant Institute, Fuzhou General Hospital, Xiamen University, Fuzhou, China.
authors.forename: F
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Hangzhou Yiyuan Biotechnology Co. Ltd, Hangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xiong
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005941:Glucokinase / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D051381:Rats; D011919:Rats, Inbred Strains; D013311:Streptozocin / Q000494:pharmacology; D018417:Th1 Cells / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D001786:Blood Glucose; D007328:Insulin; D035683:MicroRNAs; D013311:Streptozocin; D005941:Glucokinase