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Abstract: FR-PO374

Insulin and Glucose Tolerance Assessment in Guanylyl Cyclase/Natriuretic Peptide Receptor-A Gene-Targeted Mutant Mice

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Neelamegam, Kandasamy, Tulane University School of Medicine, New Orleans, Louisiana, United States
  • Pandey, Kailash Nath, Tulane University School of Medicine, New Orleans, Louisiana, United States
Background

Atrial natriuretic peptide (ANP), acting through the guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), is pivotal in regulating blood pressure and cardiac homeostasis. Ablation of Npr1 (encoding NPRA) in mice exhibits hypertension and provokes congestive heart failure; however, the underlying mechanisms are not yet precisely determined. The objective of this study was to investigate whether Npr1 plays a critical role in regulating glucose homeostasis.

Methods

The adult male (14-18 wk) Npr1 gene-knockout haplotype (Npr1+/-, 1-copy), wild-type (Npr1+/+, 2-copy), and gene-duplicated (Npr1+ +/+ +, 4-copy) mice were fasted overnight (16 h) and given free access to water. The mice were administrated with glucose both orally and intraperitoneally (2 g/kg body weight) to determine the oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). For the insulin tolerance test (ITT), mice were also fasted for 16 h and then received an ip-injection of 1.0 UI/kg of insulin. Blood glucose levels were determined by performing tail bleeds at 0, 15, 30, 60, 90, and 120 min using AlphaTRAK. The non-invasive tail-cuff method determined systolic blood pressure (SBP).

Results

The results showed that administration of glucose resulted in a greater increase in blood glucose levels at 120 mins in 1-copy male mice (OGTT: 237 ± 5 mg/dL, IPGT: 246 ± 6 mg/dL, ITT; 239 ± 7 mg/dL) than 2-copy male (OGTT: 131 ± 3 mg/dL, IPGT: 126 ± 6 mg/dL, ITT; 127 ± 6 mg/dL), respectively. The blood glucose was also significantly lower in 4-copy mice (OGTT: 113 ± 5 mg/dL, IPGT: 108 ± 7 mg/dL, ITT; 107 ± 3 mg/dL) than in 2-copy mice. SBP was significantly greater in 1-copy mice (130 ± 4 mmHg) than in 2-copy mice (100 ± 3 mmHg) and significantly lower in 4-copy mice (90 ± 2) in 2-copy mice. The increase in plasma glucose levels were significantly lower in OGTT than in IPGTT.

Conclusion

NPRA markedly prevented a steep rise in blood glucose levels after glucose challenge and ameliorated glucose intolerance and insulin resistance in 2-copy and 4-copy mice than 1-copy mice. The results suggest that NPRA signaling predisposes to arterial pressure, hyperglycemia, and insulin resistance, thus Npr1 gene might regulate blood glucose homeostasis. Supported by NIH grant DK133833.

Funding

  • NIDDK Support