PPARγ-mediated differences in energy substrate among T2DM patients differing in the stage of diabetic retinopathy
S.O. Rykov,1 Dr Sc (Med), Prof; L.V. Natrus,2 Dr Sc (Med), Prof; M.Iu. Bykhovets,1 Post-graduate Student
1 Shupik National Medical Academy of Postgraduate Education; Kyiv (Ukraine)
2 Bohomolets National Medical University; Kyiv (Ukraine)
Background: Because fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptor (PPAR) γ physically interact, the ability of FABPs to modulate lipid signaling could be exploited for developing medications, improving therapeutic or prophylactic measures for the control of metabolic disorders, and for controlling the activity of their therapeutic targets such as PPARs.
Purpose: To examine PPARγ-mediated differences in energy substrate among type 2 diabetes mellitus (T2DM) patients differing in the stage of diabetic retinopathy.
Material and Methods: This study involved 101 T2DM patients (101 eyes) with different stages of diabetic retinopathy (DR) and 40 non-diabetics (controls) who were comparable in age, gender and body mass index. DR was graded using the ETDRS scale. The polymorphism was detected by real-time PCR on a Real-Time Gene Amp® PCR System 7500 (Applied Biosystems). ELISA was used to determine serum L-FABP levels with Human L-FABP ELISA kit (Hycult Biotech).
Conclusion: We found a significant variation in fatty acid (FA) concentrations in red blood cell membranes in T2DM patients differing in PPARγ-gene mediated phenotypes. Among wild-type carriers, arachidonic acid concentration increased 1.4-fold in those with the early stage of DR (р < 0.05) compared to controls and decreased 7.5-fold in those with DR progression (р < 0.05). Among carriers of the 12Ala allele, arachidonic acid concentration decreased twofold in those with the early stage of DR (р < 0.05) compared to controls, and further gradually decreased with DR progression. There was a gradual and not significant increase in L-FABP concentration with DR progression in T2DM patients carrying the wild genotype. Among carriers of the 12Ala allele, concentration of the chaperone increased fourfold in those with the early stage of DR compared to controls (р < 0.05), and gradually decreased with DR progression.
Keywords: diabetic retinopathy, type 2 diabetes mellitus, L-FABP, fatty acids, RBC membrane, lipid metabolism
1.Balashevich LI, Izmailov AS. [Diabetic ophthalmopathy]. St. Petersburg: Chelovek; 2012. Russian.
2.Pasyechnikova NV. [Diabetic maculopathy: current aspects of the pathogenesis, clinical manifestations, diagnosis and treatment]. Kyiv: Karbon LTD; 2010. Russian.
3.Hammer SS, Busik JV. The role of dyslipidemia in diabetic retinopathy. Vision Res. 2017 Oct; 139: 228–36.
4.Sacks FM, Hermans MP, Fioretto P, et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation. 2014 Mar 4;129(9):999-1008.
5.Persistent Effects of Intensive Glycemic Control on Retinopathy in Type 2 Diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Follow-On Study. Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Eye Study Group and the Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Study Group. Diabetes Care. 2016 Jul;39(7):1089-100.
6.Shiomi Y, Yamauchi T, Iwabu M, et al. A Novel Peroxisome Proliferator-activated Receptor (PPAR)α Agonist and PPARγ Antagonist, Z-551, Ameliorates High-fat Diet-induced Obesity and Metabolic Disorders in Mice. J Biol Chem. 2015 Jun 5;290(23):14567-81.
7.Cock T-A, Houten SM, Auwerx J. Peroxisome proliferator-activated receptor-γ: too much of a good thing causes harm. EMBO Rep. 2004 Feb; 5(2): 142–7.
8.Saremi L, Lotfipanah S, Mohammadi M, et al. The Pro12Ala polymorphism in the PPARγ2 gene is not associated with an increased risk of NAFLD in Iranian patients with type 2 diabetes mellitus. Cell Mol Biol Lett. 2019; 24:12.
9.Grimaldi PA. Peroxisome proliferator-activated receptors as sensors of fatty acids and derivatives. Cell Mol Life Sci. 2007 Oct;64(19-20):2459-64.
10.Lee YK, Park JE, Lee M, Hardwicka J.P. Hepatic lipid homeostasis by peroxisome proliferator-activated receptor gamma 2. Liver Res. 2018 Dec; 2(4): 209–15.
11.Ma X, Wang D, Zhao W, and Xu L. Deciphering the Roles of PPARγ in Adipocytes via Dynamic Change of Transcription Complex. Front Endocrinol (Lausanne). 2018; 9: 473.
12.Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution in the human PPARγ2 is associated with decreased receptor activity, improved insulin sensitivity, and lowered body mass index. Nat Genet. 1998 Nov;20(3):284-7.
13.Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000 Sep;26(1):76-80.
14.Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP-kinase mediated phosphorylation of PPARγ. Science. 1996 Dec 20;274(5295):2100-3.
15.Esteves A, Ehrlich R. Invertebrate intracellular fatty acid binding proteins. Comp Biochem Physiol C Toxicol Pharmacol. 2006 Mar-Apr;142(3-4):262-74.
16.Choromańska B, Myśliwiec P, Dadan J, Hady HR, Chabowski A. The clinical significance of fatty acid binding proteins. Postepy Hig Med Dosw (Online).2011 Nov 24;65:759-63.
17.Boden G, Laakso M. Lipids and Glucose in Type 2 Diabetes. What is the cause and effect? Diabetes Care. 2004 Sep;27(9): 2253-9.
18.Rykov SO, Bykhovets MY, Natrus LV. [Features of the lifestyle as a risk factor for the development and progression of diabetic retinopathy in patients with type 2 diabetes mellitus]. Arkhiv Oftal'mologii Ukrainy. 2019. 7(1), 54-61. Ukrainian.
19.Rykov SO, Bykhovets MY, Natrus LV. [The role of metabolic disorders and genotype in the diabetic retinopathy development (review)]. Arkhiv Oftal'mologii Ukrainy. 2018. 6(3), 54-60. doi: http://dx.doi.org/10.22141/2309-8184.108.40.2068.165211. Ukrainian.
20.Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 2008 Jun;7(6):489-503.
21.Kaydashev IP, Rasin AM, Shlykova OA, et al. Frequency of the Pro12Ala-polymorphism of the gene PPARγ2 in the Ukrainian population and its possible relation to the development of the metabolic syndrome. Cytol Genet. 2007; 41(5):43-7.
22.Ziablytsev SV, Mokrii VI. [Association of the 12Pro allele of PPARγ2 (rs1801282) and type 2 diabetes mellitus]. Klinichna endocrynologiia i endocrinna khirurgiia. 2016;55(3):34-8. Ukrainian.
23.Petrenko OV, Natrus LV, Tavartkiladze К. [Concentrations of fatty acids in blood cells of patients with diabetic retinopathy]. Arkhiv Oftal'mologii Ukrainy. 2017;3(19): 54-60. Ukrainian.
24.Auwerx J. PPARgamma, the ultimate thrifty gene. Diabetologia. 1999 Sep;42(9):1033-49.
The authors certify that they have no conflicts of interest in the subject matter or materials discussed in this manuscript.