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: G Lu, X Teng, Z Zheng, R Zhang, L Peng, F Zheng, J Liu, H Huang, H Xiong
• Journal: Gene therapy (Gene Ther) Vol. 23 Issue 4 Pg. 323-9 (Apr 2016) ISSN: 1476-5462 [Electronic] England
• PMID: 26752353 (Publication Type: Journal Article)

Chemical References

• 3' Untranslated Regions
• Blood Glucose
• Insulin
• MicroRNAs
• Streptozocin
• Glucokinase

Topics

• 3' Untranslated Regions
• Animals
• Blood Glucose (metabolism)
• Diabetes Mellitus, Experimental (blood, enzymology, genetics, therapy)
• Female
• Genetic Therapy (methods)
• Glucokinase (administration & dosage, biosynthesis, genetics)
• Insulin (pharmacology)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (administration & dosage, genetics, metabolism)
• Point Mutation
• Rats
• Rats, Inbred Strains
• Streptozocin (pharmacology)
• Th1 Cells (metabolism)
• Th17 Cells (metabolism)