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Macrovascular

Renal lesions aggravation are prevented by low doses of sitagliptin in a rat model of type 2 diabetes. Cristina Mega, Helena Vala , Jorge Oliveira, Rosa Fernandes, Filipa Mascarenhas-Melo, Belmiro Parada, Rui Pinto, Frederico Teixeira, Flávio Reis, Edite Teixeira de Lemos.

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Macrovascular

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  1. Renal lesions aggravation are prevented by low doses of sitagliptin in a rat model of type 2 diabetes Cristina Mega, Helena Vala, Jorge Oliveira, Rosa Fernandes, Filipa Mascarenhas-Melo, Belmiro Parada, Rui Pinto, Frederico Teixeira, Flávio Reis, Edite Teixeira de Lemos

  2. Major complications of Type 2 Diabetes Mellitus (T2DM) Macrovascular Microvascular Cardiovascular diseases Retinopathy Neuropathy Nephropathy Heine RJ, Spijkerman AM. 2006.

  3. Diabetic Nephropathy – A Major Diabetic Complication • Diabetic nephropathy is a major microvascular complication of T2DM • Incidence of T2DM is rapidly increasing, as well as the prevalence of chronic kidney disease (CKD), resulting from these diabetic complications • In different regions of the World, it accounts for almost one-third of all cases of end-stage renal disease (ESRD) Diabetes remains the single most important cause of kidney failure

  4. Therapeutic Goals in Type 2 Diabetes Mellitus (T2DM) Prevention of Diabetes-Induced dysmetabolism and associated vascular complications Blood Glucose levels Insulin secretion/action

  5. Therapeutic Goals in Type 2 Diabetes Mellitus (T2DM) Until now, anti-diabetic drugs were able to Hyperglycaemia None were able to preserve β-cells Anti-diabetic drugs

  6. Sitagliptin • incretin defect is a major contributor to β-cell dysfunction • incretins stimulate release of insulin by β-cells • incretin inhibits glucagon release by α-cells • and that in T2DM the incretin effect is decreased Knowing that New anti-diabetic drugs, focus on the increase of incretin levels in diabetic patients, like Sitagliptin a dipeptidylpeptidase-4 (DPP-4) inhibitor and one of the best known incretin enhancers

  7. Sitagliptin targets 2 physiologic glucose-lowering actions with a single oral agent Improves 24 h glycaemic control Incretin hormones GLP-1 and GIP are released by the intestine throughout the day Their levels increase in response to a meal and are found to be reduced in Diabetes Glucose dependent B L O O D G L U C O S E  Insulin(GLP-1 and GIP) Beta cells Glucose uptake byperipheral tissues GLP-1 GIP 2 - 4 minutes  Glucagon (GLP-1) DPP-4 enzyme Alpha cells X SITAGLIPTIN allows for a longer circulation life for incretins Glucose productionby liver InactiveGLP-1 InactiveGIP

  8. Inhibition of DPP-4 activity, by incretin enhancers, such as Sitagliptin (Known Effects) Improve glycaemic control, in diabetic patients Preserving pancreatic function by prolonging the actions of incretin hormones but the real impact of low-dose sitagliptin treatment on diabetic nephropathy remains to be elucidated

  9. Assesstheeffects SITAGLIPTIN ? Prevention of Diabetes-Induced dysmetabolism and microvascular complications – Diabetic Nephropathy AIM: Evaluate the effects of chronic (6 weeks) inhibition of DPP-4 by low doses of sitagliptin, in the ZDF rat, an animal model of T2DM, on progression of renal lesions

  10. Animals and experimental design: ♂ Zucker Diabetic Fatty (ZDF fa/fa) (n=16) Age: 20 weeks Divided in 2 subgroups (n = 8 rats) treated with: - Sitagliptin 10 mg/kg/BW/day or - Vehicle (orange juice) SID (6:00 PM), for 6 weeks Controls: their lean littermates (ZDF +/+) (n=8) Age: 20 weeks

  11. Sample Collection and Preparation Blood and tissues -collected at20 weeks (Ti)and at26 weeks(Tf) Renal specimenswere paraffin-embedded and the 3 µm thick sections stained for routine histopathological diagnosis with haematoxylin and eosin (HE) and Periodic Acid of Schiff (PAS) All samples were examined by light microscopy using a Zeiss Axioplan 2 microscope

  12. Histomorphological Evaluation R E N A L L E S I O N S Mesangial expansion GBM thickening Capsule of Bowman thickening Nodular sclerosis Glomerulosclerosis Atrophy Hyalinosis of the vascular pole Arteriolar hyalinosis Arteriosclerosis. Inflammation Hyaline cylinders Tubular basement membrane irregularity Tubular calcification Interstitial fibrosis/tubular atrophy (IFTA)

  13. Semi-quantitative scoring of lesions 0 = absent 1 = mild 2 = moderate 3 = severe Severity (Except IFTA) + 0 = < 25% 1 = 25 - 50% 2 = 50 - 75% 3 = > 75 % Extension All lesions were evaluated on the total tissue on the slide. Scored in single blind fashion

  14. Scoring of lesions VASCULAR Arteriolar hyalinosis 0 = absent 1 = one arteriole with hyalinosis was present 2 = more than one arteriole was observed Arteriosclerosis 0 = no intimal thickening was present 1 = intimal thickening was < than media thickness 2 = intimal thickening > than media thickness IFTA 0 = absent 1 = < 25%, 2 = 25 - 50% 3 = > 50% (of affected area)

  15. RESULTS

  16. Sitagliptin Reduced Kidney Oxidative Stress (Positive Impact on Lipid Peroxidation Levels in renal tissues) TreatedDiabetic Rats Ti (20 wks) Tf (26 wks)

  17. Sitagliptin Reduced Kidney Dysfunction (Decrease of Blood Urea Nitrogen – BUN)

  18. Effect of Sitagliptin on Glomerular Lesions Diabetic ZDF (Sita-treated vs Untreated) UNTREATED SITA-TREATED RATS 50µm 50µm 25µm 25µm

  19. Effect of Sitagliptin on Glomerular Lesions Diabetic ZDF (Sita-treated vs Untreated) UNTREATED SITAGLIPTIN-TREATED 50µm 50µm 25µm 25µm mnng

  20. Effect of Sitagliptin on Glomerular Lesions Diabetic ZDF (Sita-treatedvs Untreated)

  21. Effect of Sitagliptin on Tubulointersticial Lesions Diabetic ZDF (Sita-treatedvs Untreated) UNTREATED SITAGLIPTIN-TREATED 50µm 50µm 25µm 50µm

  22. All Tubulointerstitial Lesions improved Diabetic ZDF (Sita-treatedvs Untreated)

  23. The Improvement of Glomerular & Tubulointerstitial Lesions Diabetic ZDF (Sita-treatedvs Untreated) 25µm 25µm

  24. Effect of Sitagliptin on Vascular Lesions Diabetic ZDF (Sita-treatedvs Untreated) UNTREATED SITA-TREATED ANIMALS 25µm 25µm

  25. Effect of Sitagliptin on Vascular Lesions Diabetic ZDF (Sita-treatedvs Untreated) UNTREATED SITAGLIPTIN-TREATED 25µm 25µm

  26. Effect of Sitagliptin on Vascular Lesions Diabetic ZDF (Sita-treatedvs Untreated) UNTREATED SITAGLIPTIN-TREATED 25µm 25µm

  27. Effect of Sitagliptin on Vascular Lesions Diabetic ZDF (Sita-treatedvs Untreated) UNTREATED SITAGLIPTIN-TREATED 25µm 25µm

  28. Effect of Sitagliptin on Vascular Lesions Diabetic ZDF (Sita-treated vs Untreated)

  29. Conclusions In an animal model of T2DM, a 6 week once daily treatment with a low dose of Sitagliptin promoted: REGULATION OF DIABETICDISMETABOLISM IMPROVEMENT OF DIABETIC NEPHROPATHY Hyperglycaemia Hypertriglyceridaemia Has the effect in - Glomerulosclerosis - Tubulointerstitial lesions - Vascular lesions RENAL FUNCTION Oxidative stress Blood Urea Nitrogen

  30. Conclusions Sitagliptin was able to delay the development of diabetic nephropathy in this model of T2DM, viewed by reduction of renal lesions This effect might be, at least, partially due, to its benefits on correction of diabetes dysmetabolism (hyperglicaemia, dyslipidaemia and insulin production/sensitivity), as well as due to a favorable impact on kidney lipid peroxidation The prevention of diabetic nephropathy evolution might represent a key step forward in the management of T2DM and these serious complications

  31. Muito obrigada! Paljonkiitoksia Thank you very much! Cristina Mega, Helena Vala, Jorge Oliveira, Rosa Fernandes, Filipa Mascarenhas-Melo, Belmiro Parada, Rui Pinto, Frederico Teixeira, Flávio Reis, Edite Teixeira de Lemos This presentation was supported by the Polytechnic Institute of Viseu, Portugal

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