Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 10/2018

01-10-2018 | Article

A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes

Authors: Md Abdul Hye Khan, Lauren Kolb, Melissa Skibba, Markus Hartmann, René Blöcher, Ewgenij Proschak, John D. Imig

Published in: Diabetologia | Issue 10/2018

Login to get access

Abstract

Aims/hypothesis

The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes.

Methods

We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) inhibitor and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in rat models of the metabolic syndrome—the obese spontaneously hypertensive (SHROB) rat and the obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat. In SHROB rats we studied the ability of RB394 to prevent metabolic syndrome phenotypes, while in ZSF1 obese diabetic rats we compared RB394 with the ACE inhibitor enalapril in the treatment of type 2 diabetes and associated comorbid conditions. RB394 (10 mg/kg daily) and enalapril (10 mg/kg daily) were administered orally for 8 weeks.

Results

RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA1c, improved glucose tolerance, reduced blood pressure and improved lipid profiles in obese ZSF1 rats. A reduction in liver fibrosis and hepatosteatosis was evident in RB394-treated obese ZSF1 rats. Unlike RB394, enalapril did not demonstrate any positive effects in relation to diabetes, hyperlipidaemia or liver dysfunction in obese ZSF1 rats. RB394 ameliorated diabetic nephropathy by reducing renal interstitial fibrosis and renal tubular and glomerular injury in obese diabetic ZSF1 rats. Intriguingly, enalapril demonstrated a weaker action against diabetic nephropathy in obese ZSF1 rats.

Conclusions/interpretation

These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.
Appendix
Available only for authorised users
Literature
1.
Potenza MV, Mechanick JI (2009) The metabolic syndrome: definition, global impact, and pathophysiology. Nutr Clin Pract 24:560–577CrossRefPubMed
2.
Isomaa B, Almgren P, Tuomi T et al (2001) Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24:683–689CrossRefPubMed
3.
Grundy SM (2006) Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 5:295–309CrossRefPubMed
4.
5.
Luria A, Bettaieb A, Xi Y et al (2011) Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance. Proc Natl Acad Sci U S A 108:9038–9043CrossRefPubMedPubMedCentral
6.
Iyer A, Kauter K, Alam MA et al (2012) Pharmacological inhibition of soluble epoxide hydrolase ameliorates diet-induced metabolic syndrome in rats. Exp Diabetes Res 2012:758614CrossRefPubMed
7.
Roche C, Guerrot D, Harouki N et al (2015) Impact of soluble epoxide hydrolase inhibition on early kidney damage in hyperglycemic overweight mice. Prostaglandins Other Lipid Mediat 120:148–154CrossRefPubMedPubMedCentral
8.
Hye Khan MA, Neckář J, Cummens B, Wahl GM, Imig JD (2014) Azilsartan decreases renal and cardiovascular injury in the spontaneously hypertensive obese rat. Cardiovasc Drugs Ther 28:313–322CrossRefPubMed
9.
Molinar-Toribio E, Pérez-Jiménez J, Ramos-Romero S et al (2015) Effect of n-3 PUFA supplementation at different EPA:DHA ratios on the spontaneously hypertensive obese rat model of the metabolic syndrome. Br J Nutr 113:878–887CrossRefPubMed
10.
Tofovic SP, Kost CK Jr, Jackson EK, Bastacky SI (2002) Long-term caffeine consumption exacerbates renal failure in obese, diabetic, ZSF1 (fa-facp) rats. Kidney Int 61:1433–1444CrossRefPubMed
11.
Prabhakar S, Starnes J, Shi S, Lonis B, Tran R (2007) Diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production. J Am Soc Nephrol 18:2945–2952CrossRefPubMed
12.
Blöcher R, Lamers C, Wittmann SK et al (2016) N-Benzylbenzamides: a novel merged scaffold for orally available dual soluble epoxide hydrolase/peroxisome proliferator-activated receptor γ modulators. J Med Chem 59:61–81CrossRefPubMed
13.
Imig JD, Walsh KA, Hye Khan MA et al (2012) Soluble epoxide hydrolase inhibition and peroxisome proliferator activated receptor γ agonist improve vascular function and decrease renal injury in hypertensive obese rats. Exp Biol Med (Maywood) 237:1402–1412CrossRef
14.
Rollason V, Vogt N (2003) Reduction of polypharmacy in the elderly: a systematic review of the role of the pharmacist. Drugs Aging 20:817–832CrossRefPubMed
15.
Henriksen EJ, Jacob S (2003) Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition. J Cell Physiol 196:171–179CrossRefPubMed
16.
Hunsicker LG (2004) Emerging trends for prevention and treatment of diabetic nephropathy: blockade of the RAAS and BP control. J Manag Care Pharm (5 Suppl A):S12–S17
17.
Batlle D, Wysocki J, Soler MJ (2012) Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy. Kidney Int 81:520–528CrossRefPubMed
18.
Sarafidis PA, Lasaridis AN (2006) Actions of peroxisome proliferator-activated receptors-gamma agonists explaining a possible blood pressure-lowering effect. Am J Hypertens 19:646–653CrossRefPubMed
19.
Fogo AB (2008) Potential for peroxisome proliferator-activated receptor-gamma agonists in progression: beyond metabolism. Curr Opin Nephrol Hypertens 17:282–285CrossRefPubMed
20.
Eckel RH, Grundy SM, Zimmet PZ (2005) The metabolic syndrome: epidemiology, mechanisms, and therapy. Lancet 365:1415–1428CrossRefPubMed
21.
Carmona MC, Louche K, Nibbelink M et al (2005) Fenofibrate prevents rosiglitazone-induced body weight gain in ob/ob mice. Int J Obes 29:864–871CrossRef
22.
Shah P, Mudaliar S (2010) Pioglitazone: side effect and safety profile. Expert Opin Drug Saf 9:347–354CrossRefPubMed
23.
Guan Y, Hao C, Cha DR et al (2005) Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption. Nat Med 11:861–866CrossRefPubMed
24.
Hye Khan MA, Pavlov TS, Christain SV et al (2014) Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition. Clin Sci (Lond) 127:463–474CrossRef
25.
Pavlov TS, Ilatovskaya DV, Levchenko V (2011) Effects of cytochrome P-450 metabolites of arachidonic acid on the epithelial sodium channel (ENaC). Am J Physiol Ren Physiol 301:F672–F681CrossRef
26.
Pidkovka N, Rao R, Mei S et al (2013) Epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel activity by extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated phosphorylation. J Biol Chem 288:5223–5231CrossRefPubMedPubMedCentral
27.
Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC (2013) The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care 36:2271–2279CrossRefPubMedPubMedCentral
28.
de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J (2011) Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 305:2532–2539CrossRefPubMedPubMedCentral
29.
30.
Brenneman J, Hill J, Pullen S (2016) Emerging therapeutics for the treatment of diabetic nephropathy. Bioorg Med Chem Lett 26:4394–4402CrossRefPubMed
31.
32.
Singh DK, Winocour P, Farrington K (2011) Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol 7:176–184CrossRefPubMed
33.
Dronavalli S, Duka I, Bakris GL (2008) The pathogenesis of diabetic nephropathy. Nat Clin Pract Endocrinol Metab 4:444–452CrossRefPubMed
34.
Groop PH, Forsblom C, Thomas MC (2005) Mechanisms of disease: pathway-selective insulin resistance and microvascular complications of diabetes. Nat Clin Pract Endocrinol Metab 1:100–110CrossRefPubMed
35.
36.
Petrie JR, Morris AD, Ueda S et al (2000) Trandolapril does not improve insulin sensitivity in patients with hypertension and type 2 diabetes: a double-blind, placebo-controlled crossover trial. J Clin Endocrinol Metab 85:1882–1889PubMed
37.
Heise T, Heinemann L, Kristahn K et al (1999) Insulin sensitivity in patients with essential hypertension: no influence of the ACE inhibitor enalapril. Horm Metab Res 31:418–423CrossRefPubMed
38.
Bilan VP, Salah EM, Bastacky S et al (2011) Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats. J Endocrinol 210:293–308CrossRefPubMed
39.
Steigerwalt S (2008) Management of hypertension in diabetic patients with chronic kidney disease. Diabetes Spectrum 21:30–36CrossRef
40.
41.
Muntner P, Coresh J, Smith JC, Eckfeldt J, Klag MJ (2000) Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study. Kidney Int 58:293–301CrossRefPubMed
42.
Cases A, Coll E (2005) Dyslipidemia and the progression of renal disease in chronic renal failure patients. Kidney Int Suppl 99:S87–S93CrossRef
43.
Zhang LN, Vincelette J, Cheng Y et al (2009) Inhibition of soluble epoxide hydrolase attenuated atherosclerosis, abdominal aortic aneurysm formation, and dyslipidemia. Arterioscler Thromb Vasc Biol 29:1265–1270CrossRefPubMed
44.
He J, Wang C, Zhu Y, Ai D (2016) Soluble epoxide hydrolase: a potential target for metabolic diseases. J Diabetes 8:305–313CrossRefPubMed
45.
46.
Ma S, Zhu XY, Eirin A et al (2016) Perirenal fat promotes renal arterial endothelial dysfunction in obese swine 508 through tumor necrosis factor-alpha. J Urol 195:1152–1259CrossRefPubMed
47.
Liu Y, Webb HK, Fukushima H et al (2012) Attenuation of cisplatin-induced renal injury by inhibition of soluble epoxide hydrolase involves nuclear factor κB signaling. J Pharmacol Exp Ther 341:725–734CrossRefPubMedPubMedCentral
48.
Kim J, Yoon SP, Toews ML et al (2015) Pharmacological inhibition of soluble epoxide hydrolase prevents renal interstitial fibrogenesis in obstructive nephropathy. Am J Physiol Ren Physiol 308:F131–F139CrossRef
49.
Lee S, Kim W, Moon SO et al (2006) Rosiglitazone ameliorates cisplatin-induced renal injury in mice. Nephrol Dial Transplant 21:2096–2105CrossRefPubMed
50.
Kawai T, Masaki T, Doi S et al (2009) PPAR-γ agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-β. Lab Investig 89:47–58CrossRefPubMed
51.
Rafiq N, Younossi ZM (2008) Effects of weight loss on nonalcoholic fatty liver disease. Semin. Liver Dis 28:427–433CrossRefPubMed
52.
Wong RJ, Aguilar M, Cheung R et al (2015) Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 148:547–555CrossRefPubMed
53.
Tilg H, Moschen AR, Roden M (2017) NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol 14:32–42CrossRefPubMed
54.
Younossi ZM, Blissett D, Blissett R et al (2016) The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 64:1577–1586CrossRefPubMed
55.
Schattner A, Kozak N, Friedman J (2001) Captopril-induced jaundice: report of 2 cases and a review of 13 additional reports in the literature. Am J Med Sci 322:236–240CrossRefPubMed
56.
Douros A, Kauffmann W, Bronder E, Klimpel A, Garbe E (2013) Kreutz R (2013) Ramipril-induced liver injury: case report and review of the literature. Am J Hypertens 26:1070–1075CrossRefPubMed
57.
Yeung E, Wong FS, Wanless IR et al (2003) Ramipril-associated hepatotoxicity. Arch Pathol Lab Med 127:1493–1497PubMed
58.
Inoue M, Ohtake T, Motomura W et al (2005) Increased expression of PPARγ in high fat diet-induced liver steatosis in mice. Biochem Biophys Res Commun 336:215–222CrossRefPubMed
59.
Pettinelli P, Videla LA (2011) Up-regulation of PPAR-γ mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab 96:1424–1430CrossRefPubMed
60.
Liu Y, Dang H, Li D, Pang W, Hammock BD, Zhu Y (2012) Inhibition of soluble epoxide hydrolase attenuates high-fat-diet–induced hepatic steatosis by reduced systemic inflammatory status in mice. PLoS One 7:e39165CrossRefPubMedPubMedCentral
61.
Harris TR, Bettaieb A, Kodani S et al (2015) Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice. Toxicol Appl Pharmacol 286:102–111CrossRefPubMedPubMedCentral
62.
Sumida Y, Seko Y, Yoneda M (2016) Japan Study Group of NAFLD (JSG-NAFLD). Novel antidiabetic medications for nonalcoholic fatty liver disease with type 2 diabetes. Hepatol Res 47:266–280CrossRef
63.
Qiang G, Zhang L, Yang X et al (2012) Effect of valsartan on the pathological progression of hepatic fibrosis in rats with type 2 diabetes. Eur J Pharmacol 685:156–164CrossRefPubMed
Metadata
Title
A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes
Authors
Md Abdul Hye Khan
Lauren Kolb
Melissa Skibba
Markus Hartmann
René Blöcher
Ewgenij Proschak
John D. Imig
Publication date
01-10-2018
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 10/2018
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-018-4685-0

Other articles of this Issue 10/2018

Diabetologia 10/2018 Go to the issue

Editorial

The bark giving diabetes therapy some bite: the SGLT inhibitors

Article

Gluten intake and risk of type 2 diabetes in three large prospective cohort studies of US men and women

Article

Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in hIAPP transgenic mice

Article

Programming of central and peripheral insulin resistance by low birthweight and postnatal catch-up growth in male mice

Review

SGLT inhibitor adjunct therapy in type 1 diabetes

Short Communication

Genome-wide association study of coronary artery disease among individuals with diabetes: the UK Biobank

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits