Abstract: TH-PO711

Renal Inflammation, Insulin Resistance, and Enhanced Renal Gluconeogenesis in Type 2 Diabetic Nephropathy: The Missing Links

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Liu, Qianling, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences & Peking Union Medical College, Beijing, China
  • Zhang, Liangyan, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences & Peking Union Medical College, Beijing, China
  • Qiu, Wei, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences & Peking Union Medical College, Beijing, China
  • Zhang, Wei, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences & Peking Union Medical College, Beijing, China
  • Wen, Yubing, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences & Peking Union Medical College, Beijing, China
  • Wang, Haiyun, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences & Peking Union Medical College, Beijing, China
  • Li, Xuemei, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences & Peking Union Medical College, Beijing, China
Background

Renal gluconeogenesis is substantially stimulated in patients with type 2 diabetes, but the mechanism remains unknown. Renal gluconeogenesis is negatively regulated by insulin. Since inflammation is activated in diabetic nephropathy (DN), however, inflammation is well known to induce insulin resistance, we wondered whether enhanced renal gluconeogenesis in DN was partially resulted from renal inflammation-mediated insulin resistance. If so, whether inflammation inhibitor could partially reverse this change.

Methods

Eight-week-old male diabetic db/db (C57BLKS/J-LepRdb/LepRdb) mice and their non-diabetic littermates db/m (C57BLKS/J-LepRdb/+) mice were used in this study. Diabetic db/db mice were treated with 1 mg/kg NF-κB inhibitor parthenolide (PTN) or saline as control intraperitoneal every other day. After 12 weeks of treatment, blood, urine and kidney samples were collected for measurement.

Results

Expression of inflammatory factors and the gluconeogenic rate-limiting enzyme phosphoenolpyruvate carboxykinase (PEPCK) were increased in the renal cortex of both type 2 DN human patients and db/db mice. Moreover, reduced insulin signaling as demonstrated by downregulated phosphorylation of AKT and increased expression of downstream gene FOXO1 were detected in db/db+saline mice compaired with db/m mice. Consistant with our hypothesis, NF-κB inhibitor PTN significantly reduced renal expression of NF-κB, TNF-a, ICAM-1, MIP-1α and macrophage infiltration in db/db+PTN mice compaired with db/db+saline mice. Moreover, it partially alleviated renal insulin resistance and reduced the expression of gluconeogenic enzyme PEPCK (1.62±0.47 VS 0.89 ±0.14, p<0.05), indicating that inflammation could be one of the triggers for insulin resistance and enhanced renal gluconeogenesis.

Conclusion

Our study demonstrated for the first time that renal gluconeogenesis is upregulated in db/db mice, and this was associated with renal inflammation-mediated insulin resistance. PTN partially reversed this change by promoting renal insulin sensitivity. This work shed light on the role of inflammation in enhanced renal gluconeogenesis and may yield a novel target for hyperglycemia.