Long-Term Treatment with Empagliflozin Attenuates Renal Damage in Obese Zucker Rat

Abstract

Introduction Empagliflozin, a known inhibitor of sodium-glucose cotransporter type 2 (SGLT2) decreases glucose reabsorption by the renal tubules and promotes glucose excretion into the urine. While the effectiveness of Empagliflozin in the management of hyperglycemia along with associated cardiovascular and all-cause mortality has been demonstrated previously, the therapeutic benefits associated with the long-term use of this drug in obese animals have yet to be investigated.

Methods Male 5-week-old lean and obese Zucker rats were randomly assigned to one of the 4 groups- lean control, lean treated, obese control, obese treated and treated with either Empagliflozin (10 mg/kg BW / day) or placebo for 25 weeks to investigate the therapeutic effect of Empagliflozin.

Results Empagliflozin treatment in the obese animals was associated with decreased body weight, attenuated the loss of F-actin from the renal tubules and improved renal structure and function. These changes in renal function were associated with significant improvements in the glucose tolerance, and decreased non-fasting circulatory levels of glucose, amylase, and other inflammatory markers including NGAL, cystatin C, and clusterin.

Conclusion Long-term use of Empagliflozin in diabetic obese Zucker rats is associated with improvements in glucose tolerance and decreased loss of renal structure and function.

Key words

SGLT2 inhibitor - type 2 diabetes - glucose tolerance - inflammation

Publikationsverlauf

Eingereicht: 20. Juli 2018
Eingereicht: 15. November 2018

Angenommen: 04. Dezember 2018

Artikel online veröffentlicht:
07. Januar 2019

• References

• 1 Weyer C, Bogardus C, Mott DM. et al. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999; 104: 787-794
• 2 Boyle JP, Thompson TJ, Gregg EW. et al. Projection of the year 2050 burden of diabetes in the US adult population: Dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr 2010; 8: 29
• 3 Kishore P, Kim SH, Crandall JP. Glycemic control and cardiovascular disease: What's a doctor to do?. Curr Diab Rep 2012; 12: 255-264
• 4 Kojima N, Williams JM, Takahashi T. et al. Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J Pharmacol Exp Ther 2013; 345: 464-472
• 5 Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: The pleiotropic effects of SGLT2 inhibition. Diabetologia 2017; 60: 215-225
• 6 Chao EC. SGLT-2 Inhibitors: A new mechanism for glycemic control. Clin Diabetes 2014; 32: 4-11
• 7 List JF, Woo V, Morales E. et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009; 32: 650-657
• 8 Seidu S, Kunutsor SK, Cos X. et al. SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis. Prim Care Diabetes 2018; 12: 265-283
• 9 Grandy S, Hashemi M, Langkilde AM. et al. Changes in weight loss-related quality of life among type 2 diabetes mellitus patients treated with dapagliflozin. Diabetes Obes Metab 2014; 16: 645-650
• 10 Zinman B, Wanner C, Lachin JM. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-2128
• 11 Abdul-Ghani M, Del Prato S, Chilton R. et al. SGLT2 Inhibitors and cardiovascular risk: Lessons learned from the empa-reg outcome study. Diabetes Care 2016; 39: 717-725
• 12 Skrtic M, Yang GK, Perkins BA. et al. Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. Diabetologia 2014; 57: 2599-2602
• 13 Tonneijck L, Muskiet MH, Smits MM. et al. Glomerular hyperfiltration in diabetes: Mechanisms, clinical significance, and treatment. J Am Soc Nephrol 2017; 28: 1023-1039
• 14 Cherney DZI, Zinman B, Inzucchi SE. et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: An exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2017; 5: 610-621
• 15 Abbas NAT, El Salem A, Awad MM. Empagliflozin, SGLT2 inhibitor, attenuates renal fibrosis in rats exposed to unilateral ureteric obstruction: Potential role of klotho expression. Naunyn Schmiedebergs Arch Pharmacol 2018; 391: 1347-1360
• 16 Wang XX, Levi J, Luo Y. et al. SGLT2 protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation, and the development of nephropathy in diabetic mice. J Biol Chem 2017; 292: 5335-5348
• 17 Grempler R, Thomas L, Eckhardt M. et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: Characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 2012; 14: 83-90
• 18 Nalabotu SK, Kolli MB, Triest WE. et al. Intratracheal instillation of cerium oxide nanoparticles induces hepatic toxicity in male sprague-dawley rats. Int J Nanomedicine 2011; 6: 2327-2335
• 19 Manne ND, Arvapalli R, Nepal N. et al. Cerium oxide nanoparticles attenuate acute kidney injury induced by intra-abdominal infection in Sprague-Dawley rats. Journal of nanobiotechnology 2015; 13: 75
• 20 Leon BM, Maddox TM. Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes 2015; 6: 1246-1258
• 21 Ndefo UA, Anidiobi NO, Basheer E. et al. Empagliflozin (Jardiance): A novel SGLT2 Inhibitor for the treatment of type-2 diabetes. P T 2015; 40: 364-368
• 22 Cheng ST, Chen L, Li SY. et al. The effects of empagliflozin, an SGLT2 Inhibitor, on Pancreatic beta-cell mass and glucose homeostasis in type 1 diabetes. PLoS One 2016; 11: e0147391.
• 23 Oelze M, Kroller-Schon S, Welschof P. et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS One 2014; 9: e112394.
• 24 Vallon V, Gerasimova M, Rose MA. et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 2014; 306: F194-F204
• 25 Sengupta P. The laboratory rat: Relating its age with human's. Int J Prev Med 2013; 4: 624-630
• 26 Steven S, Oelze M, Hanf A. et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol 2017; 13: 370-385
• 27 Neeland IJ, McGuire DK, Chilton R. et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2016; 13: 119-126
• 28 Young JA, Hwang SJ, Sarnak MJ. et al. Association of visceral and subcutaneous adiposity with kidney function. Clin J Am Soc Nephrol 2008; 3: 1786-1791
• 29 Chaudhury A, Duvoor C, Reddy Dendi VS. et al. Clinical review of antidiabetic drugs: Implications for type 2 diabetes mellitus management. Front Endocrinol (Lausanne) 2017; 8: 6
• 30 Hansen HH, Jelsing J, Hansen CF. et al. The sodium glucose cotransporter type 2 inhibitor empagliflozin preserves beta-cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat. J Pharmacol Exp Ther 2014; 350: 657-664
• 31 Grundy SM, Benjamin IJ, Burke GL. et al. Diabetes and cardiovascular disease: A statement for healthcare professionals from the american heart association. Circulation 1999; 100: 1134-1146
• 32 Apelqvist J, Larsson J. What is the most effective way to reduce incidence of amputation in the diabetic foot?. Diabetes/Metabolism Research and Reviews 2000; 16: S75-S83
• 33 Narres M, Claessen H, Droste S. et al. The incidence of end-stage renal disease in the diabetic (compared to the non-diabetic) population: A systematic review. PLoS One 2016; 11: e0147329.
• 34 Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 1983; 32 (Suppl. 02) 64-78
• 35 Gallo LA, Ward MS, Fotheringham AK. et al. Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice. Sci Rep 2016; 6: 26428
• 36 Alter ML, Kretschmer A, Von Websky K. et al. Early urinary and plasma biomarkers for experimental diabetic nephropathy. Clin Lab 2012; 58: 659-671
• 37 Ascic-Buturovic B, Cavaljuga S. Cystatin C as a marker for detection of early renal failure in diabetes type 2 patients. Bosn J Basic Med Sci 2005; 5: 68-71
• 38 Kim SS, Song SH, Kim JH. et al. Urine clusterin/apolipoprotein J is linked to tubular damage and renal outcomes in patients with type 2 diabetes mellitus. Clin Endocrinol (Oxf) 2017; 87: 156-164
• 39 Togashi Y, Miyamoto Y. Urinary cystatin C as a biomarker for diabetic nephropathy and its immunohistochemical localization in kidney in Zucker diabetic fatty (ZDF) rats. Exp Toxicol Pathol 2013; 65: 615-622
• 40 Wanner C, Inzucchi SE, Lachin JM. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323-334