CN1 over-expression aggravates disease progression and mitigates the beneficial effect of carnosine in type 2 diabetic mice

Introduction:

Carnosine supplementation in diabetic BTBR^ob/ob mice significantly lowers fasting blood glucose and HbA1c levels and reduces renal function deterioration. Since mice lack serum carnosinase the translational value of these findings is limited.

Methods:

We therefore generated human CN-1 transgenic (TG) mice in the BTBR^ob/ob background, over-expressing human CN-1 protein in liver and blood. Human CN-1 was also expressed to lesser extend in the kidney. Serum carnosinase activity and concentration widely varied amongst the TG mice, even though they all expressed the (CTG)₆ genetic variant.

Results:

TG BTBR^ob/ob mice displayed an increased HbA1c and more severe renal impairment (albumin to creatinine ratio). This was much stronger in female compared to male mice.

Carnosine supplementation in non-diabetic TG BTBR^ob/wt mice neither increased plasma carnosine concentrations nor was carnosine increased in renal tissue.

In 18 weeks supplemented TG BTBR^ob/ob mice hyperglycemia was slightly improved without affecting renal function deterioration.

By making use of genome wide gene expression profiling of renal tissue we could show that the effect on gene expression was much larger between diabetic vs. non-diabetic compared to CN-1 TG vs. non-TG mice. Histidine decarboxylase (HCD) was the most affected gene (˜ 32 fold decrease in diabetic mice), this was neither affected by the TG nor by carnosine supplementation.

Conclusion:

In conclusion, a high serum carnosinase activity aggravates hyperglycemia and renal impairment in type 2 diabetic mice. The beneficial of carnosine supplementation is completely lost in these mice. Therapeutic inhibition of carnosinase with or without carnosine supplementation is currently studied.