Renal effects of glucagon‐like peptide‐1 receptor knockout in Akita‐diabetic mice

Background Glucagon‐like peptide‐1 (GLP‐1) is a gut‐derived hormone that enhances glucose‐dependent insulin release and has anti‐oxidative and protective effects mediated through GLP‐1 receptor (GLP1R) in various tissues. Here, we determined whether the GLP1R has a pathophysiologic role in the diabetic kidney. Methods GLP1R‐KO mice (C57BL/6J) were backcrossed to DBA2 background for at least 4 generations and crossed with heterozygous Ins2 Akita mice, a genetic model of type 1 diabetes, to generate 4 experimental groups; i) WT (n=7), ii) GLP1R‐KO (n=14), iii) diabetic WT (n=6), and iv) diabetic GLP1R‐KO (n=10). Body weight, blood glucose, urine glucose and albumin to creatinine ratios, GFR (by plasma elimination kinetics of FITC‐sinistrin in conscious mice), and kidney weight were determined at 16 weeks of age. Results In non‐diabetic mice, no significant differences were observed between GLP1R‐KO and WT for bodyweight (26.1±1.0 vs 26±1.3 g), blood glucose (127±4 vs 112±5 mg/dl), urine glucose (2.5±0.3 vs 3.6±0.8 umol/mg), albuminuria (39±7 vs 37±19 μg/mg), and GFR (18±1 vs 22±2 μl/min/g), while kidney weight tended to be reduced in GLP1R‐KO (7.8±0.2 vs 8.5±0.3 mg/g; P=0.064). In GLP1R‐KO and WT mice, diabetes increased to similar levels: blood glucose (515±21 vs 501±32 mg/dl), urine glucose (3504±426 vs 5515±864 umol/mg), albuminuria (117±41 vs 102±22 ug/mg), food and fluid intake (not shown), and GFR (28±2 vs 33±3 ul/min/g), associated with a similar reduction in body weight (23.1±0.9 vs 23.7±0.6 g). While diabetes increased kidney weight in GLP1R‐KO and WT to similar absolute levels (11.8±0.8 vs 10.3±0.4 mg/g), the diabetes‐induced fractional increase was enhanced in GLP1R‐KO vs WT (increase of 51 vs 21%). Conclusion 1) On a predominant DBA2 genetic background, type 1 Akita diabetes increased blood glucose levels, GFR, kidney to body weight ratios, and albuminuria. 2) The effects of diabetes on blood glucose, GFR and albuminuria occurred independent of the GLP1R, whereas the absence of the GLP1R appeared to facilitate the diabetes‐induced increase in kidney to body weight ratios. Support or Funding Information National Institutes of Health (R01DK56248, P30DK079337) and AstraZeneca

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