Abstract: FR-PO153

Metabolic Reprogramming in Diabetic Kidney Disease Can Be Restored via SGLT2 Inhibition

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Darshi, Manjula, University of California, San Diego, Irvine, California, United States
  • Onishi, Akira, Veterans Affairs, San Diego, La Jolla, California, United States
  • Kim, Jiwan John, University of California, San Diego, Irvine, California, United States
  • Pham, Jessica, University of California, San Diego, Irvine, California, United States
  • Van espen, Benjamin Fj, University of California, San Diego, Irvine, California, United States
  • Murphy, Anne, UCSD, La Jolla, California, United States
  • Lambers Heerspink, Hiddo Jan, University of Groningen, University Medical Center, , Groningen, Netherlands
  • Vallon, Volker, Veterans Affairs, San Diego, La Jolla, California, United States
  • Sharma, Kumar, University of California, San Diego, Irvine, California, United States
Background

Recent studies indicate mitochondrial dysfunction as a dominant pathway in diabetic kidney disease (DKD), however underlying mechanisms are unclear. In this study we used metabolomic and biochemical assays in the type 1 Akita DKD mouse model and in patients with DKD to decipher the consequences of high glucose on metabolic reprogramming leading to proximal tubule damage. Furthermore, we analyzed a therapeutic potential of the proximal tubule glucose transporter, SGLT2, responsible for reabsorption of the majority of the filtered glucose.

Methods

Metabolomic analysis was performed by GC-MS/MS from control and type 1 diabetic mice (Akita, n=6 each) in the presence and absence of SGLT2 inhibitor empagliflozin (~45mg kg-1 day-1). Urinary lactate and pyruvate concentrations were measured using biochemical assays in patients with type 2 diabetes and albumin:creatinine ratio>100mg/g, enrolled in a cross-over study with the SGLT2 inhibitor dapagliflozin or placebo (6 weeks, 10mg/day, n=33 total). Mitochondrial functional changes in human kidney proximal tubule (HK2) cells were analyzed using Seahorse XF technology.

Results

Metabolomic analysis in Akita mice indicated a marked increase in glycolysis with an increase in the lactate/pyruvate ratio in urine (p=0.0002, 95% CI), plasma (p=0.02) and kidney tissue (p=0.06) as compared with non-diabetic controls. The urinary lactate/pyruvate levels in Akita mice were reduced upon treatment with empagliflozin (p=0.002) and in the urine of SGLT2 knockout mice vs wild type controls despite similar blood glucose levels (p=0.03). Furthermore, in T2D patients, dapagliflozin decreased the urine lactate /pyruvate ratio by 34% (p=0.03) compared to placebo and this decrease correlated with the decline in eGFR (r-0.042, p=0.04). Studies in HK2 cells further identified that acute glucose treatment can significantly inhibit rate of oxygen consumption and enhance lactate production suggesting a ‘Crabtree’ effect indicative of glucose suppression of mitochondrial respiration.

Conclusion

High glucose suppresses mitochondrial function with a shift to glycolysis and may be linked to proximal tubule injury. Our studies suggest ta protective role of SGLT2 inhibition, may be via reduction of the lactate/pyruvate ratio resulting in improved mitochondrial function.

Funding

  • NIDDK Support