Glucotoxicity, reduced β-cell function and mass are key events in the pathogenesis and progression of diabetes. We previously generated an insulin secretory-deficient mouse model of human KATP-induced diabetes. As predicted, KATP-GOF (gain-of-function) mice demonstrate severe diabetes due to low circulating insulin levels, reiterating the human disease. However, as diabetes progresses, KATP-GOF mice show reduction of insulin content and β-cell mass, consequences of glucotoxicity. Islets from diabetic mice also show increased glucose metabolism (NAD(P)H autofluorescence) and oxygen consumption rate (Seahorse analysis), and augmented mitochondrial membrane potential. Strikingly, they also demonstrate increased glucokinase (GK, first enzyme in glucose metabolism) and GLUT2 gene transcripts and proteins. We hypothesized that augmented glucose metabolism in diabetic mice will contribute to the glucotoxic reduction in in insulin content, β-cell function and mass; and that these consequences will be alleviated by reducing glucose metabolism. To test this in vivo, we crossed KATP-GOF mice with mildly glucose-intolerant heterozygous GK+/- knockout mice (with reduced glucose metabolism), to generate double-transgenic GK+/-/KATP-GOF mice. Progression of diabetes, assessed by blood glucose levels overtime, is slower in GK+/-/KATP-GOF mice, compared with KATP-GOF mice. Importantly also, glucose tolerance is enhanced in GK+/-/KATP-GOF mice 12 days after disease onset, with respect to KATP-GOF mice, without significant changes in insulin sensitivity. Insulin gene expression, insulin content and β-cell mass are partially preserved in GK+/-/KATP-GOF mice. Together, these results demonstrate that hyperglycemia induce accelerated metabolism in KATP-GOF mice damaging the islets, and that deceleration of metabolism by reducing GK activity delays/prevent hypermetabolism induced-glucotoxicity in KATP-GOF mice.


M. Fortunato: None. Z. Yan: None. Z.A. Shyr: None. H.E. Conway: None. M.S. Remedi: None.

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