Endotēlija disfunkcija un ar insulīna rezistenci saistītie biomarķieri pacientiem ar metabolisko sindromu

Abstract

Par insulīna rezistences un endotelija disfunkcijas korelāciju pacientiem ar metabola sindromu līdz šim tika veikts maz pētījumu. Šī pētījuma mērķis bija noskaidrot insulīna rezistenci (ar metodi NOMA-IR) un endoteliālās disfunkcijas biomarķierus (ICAM-1, VCAM-1, E-selektīns, adiponektīns, TNF-alfa un IL-6) pacientiem ar metabolo sindromu ar un bez 2.tipa cukura diabētu, un izvērtēt endotēlija atkarīgu vazodilatāciju (vazomotoro disfunkciju) pacientiem ar metabolo sindromu un noskaidrot sakarību starp insulīna rezistenci un endotēlija disfunkciju. Pētījums tika veikts Paula Stradiņa klīniskās universitātes slimnīcas endokrinoloģijas centrā. Pacienti bija sadalīti grupās pēc dzimuma un vecuma: piedalījās 66 pacienti ar metabolu sindromu (MS). Pacienti bija sadalīti 3 grupās: 43 pacienti ar 2.tipa diabētu (insulīnneatkarīgie un bez acīmredzamam diabēta izraisītajām komplikācijām(MD)), 23 pacienti bez DM (MS), 19 veseli pacienti kā kontroles grupa (C). Lai novērtēt mikrovaskulāru un endoteliālu funkciju katrai no pacientu grupām tika izmantota LDI (laser doppler perfusion imaging). Paula Stradiņa klīniskās universitātes slimnīcā pacientiem tika noteikts lipīdu līmenis, glikozes līmenis tukšā dūšā, glikozilēts hemoglobīns, insulīna līmenis plazmā un insulīna rezistences tests (HOMA-IR). Tika veikti šādi klīniskie mērījumi: asinsspiediens, svars, augums, vēdera apkārtmērs un ķermeņa masas indekss. Pētījumu gaitā tika atklāts, ka slimniekiem ar metabolu sindromu un ar 2. tipa cukura diabētu(MD) insulīna rezistence ir 5.833.47, metabola sindroma slimniekiem bez 2. tipa diabēta (MS) zemāka insulīna rezistence bija 4.073.24. Tika ievērota nozīmīga (p0.05) korelācija starp insulīna rezistenci (HOMA-IR) un ķermeņa masas indeksu (r=0.44), jostas apkārtmēru (r=0.41), adiponektīnu (r=0.42), E-selektīnu (r=0.41), VCAM (r=0.23). Kā arī ievērojamas bija korelācijas atarp insulīna rezistenci un adiponektīnu ar E-selektīnu (r=0.55), ICAM (r=0.44), IL-8 (r=0.40), LDI (r=0.38). Noslēgumā, mēs konstatējām, ka MS pacientiem, neatkarīgi no T2DM esamības, ievērojami pieauga insulīna rezistence (HOMA-IR) salīdzinājumā ar kontroles grupu, kā arī ĶMI un jostas apkārtmērs korelēja ar HOMA-IR. Endotēlija disfunkcijas biomarķieri- adhēzijas molekulu līmeņi: ICAM-1, VCAM-1 un E-selektīns statistiski bija ievērojami augstāki tikai MS pacientiem ar T2DM salīdzinājumā ar kontroles grupu, kā arī tikai E-selektīns un VCAM-1 korelēja ar insulīna rezistenci (HOMA-IR). Neskatoties uz to ka Kraskela- Vollisa tests parādija statistiski nozīmīgu starpību (p0.05) starp endoteliālās disfunkcijas biomarķieriem ( iekaisuma citokīnu TNF-alfa un IL-6 līmeņiem), one-way ANOVA (izmantojot Fišera multiplu salīdzinājumu) tests neapstiprināja starpību starp grupām, izņemot TNF-alfa līmeņu pieaugumu MS pacientiem bez T2DM salīdzinot ar citām pētamām grupām. Adipocīna, anti-iekaisuma adipokīna līmeņi bija ievērojami pieauguši MS pacientiem neatkarīgi no T2DM esamības, un adipocīns korelēja ar HOMA-IR. Endotēlija disfunkcijas funkcionāls rādītājs- endotēlija atkarīga vazodilatācija (LDI) statistiski samazinājās MS pacientiem ar T2Dm salīdzinot ar citām grupām. Lineārās regresijas analīzes rezultāti rāda, ka insulīna rezistence (HOMA-IR) statistiski ievērojami ietekmēja vienlaicīgi divus rādītājus: a) adiponektīnu un LDI; b) E-selektīnu un LDI; c) E-selektīnu un adiponektīnu; d) ICAM-1 un adiponektīnu; e) VCAM-1 un adiponektīnu; f) E-IL-6 un adiponektīnu; g) TNF-alfa un adiponektīnu.

Few studies have been performed to elucidate the relationship between insulin resistance and endothelium dysfunction in patients with metabolic syndrome. The aim of the study was to evaluate insulin resistance (by HOMA-IR method) and endothelial dysfunction related biomarkers (ICAM-1, VCAM-1, E-selectin, adiponectin, TNF-alpha and IL-6) in patients with metabolic syndrome with and without type 2 diabetes mellitus and to evaluate endothelial-dependent vasodilatation (vasomotor dysfunction) in patients with metabolic syndrome and to clarify the relationship between insulin resistance and endothelial dysfunction related indexes. The study was performed at the Centre of Endocrinology at the Pauls Stradiņš Clinical University Hospital Patients were divided into age and sex matched groups: 66 metabolic syndrome (MS) patients were included in the study. The patients were divided into three groups:43 patients with type-2 diabetes mellitus (without insulin therapy and pronounced diabetic complications) (MD), 23 patients without DM (MS), 19 healthy subjects were used as a control group (C). Laser Doppler perfusion imaging (LDI) were used to evaluate microvascular and endothelial function in study groups. Clinical tests, which included lipid profile, fasting blood glucose, glycosylated hemoglobin, plasma insulin level and insulin resistance (HOMA IR), were carried out at the Pauls Stradiņš Clinical University Hospital. The following clinical measurements were taken: blood pressure, weight, height abdominal circumference, and body mass index. We found that metabolic syndrome with type 2 diabetes(MD) group men value of insulin resistance was 5.83±3.47, metabolic syndrome without type 2 diabetes (MS) mean insulin resistance was 4.07±3.24.We found significant (p<0.05) correlation between insulin resistance (HOMA-IR) and body mass index (r = 0.44), waist circumference (r= 0.41), adiponection r = 0.42), E-selectin( r=-0.41), VCAM (r=0.23).We found significant correlation of insulin resistance and adiponectin with E-selectin (r= 0.55), ICAM (r = 0.44), VCAM ( r = 0.45), IL-8 (r = 0.43), TNF-alpha (r = 0.40), LDiAch ( r = 0.38 ).

In conclusion, we found MS patients, independently of the presence of T2DM, had very significantly increased insulin resistance (HOMA-IR) in comparison with healthy subjects, besides BMI and waist circumference were correlated with HOMA-IR (in total clinical material). Endothelial dysfunction biomarkers – the levels of adhesion molecules: ICAM-1, VCAM-1 and E-selectin were statistically significantly higher only in MS patients with T2DM in comparison with healthy subjects, besides only E-selectin and VCAM-1 were correlated with insulin resistance (HOMA-IR). Although analysis of Kruskal-Wallis test showed a statistically significant difference (p<0,05) between endothelial dysfunction related biomarkers – the levels of inflammatory cytokines TNF-alpha and IL-6, the one-way ANOVA (using Fisher’s multiple comparison) test did not confirm the difference between the groups, except for increased levels of TNF-alpha in MS patients without T2DM in comparison to other study groups. The levels of adiponectin, anti-inflammatory adipokine, were significantly decreased in MS patients independently of the presence of T2DM, and adiponectin was correlated with HOMA-IR. The functional index of endothelial dysfunction – endothelial-dependent vasodilatation (LDI-Ach) was statistically decreased only in MS patients with T2DM in comparison to other study groups. The results of linear regression analysis show that insulin resistance (HOMA-IR) has a statistically significant effect on two indexes simultaneously: a) adiponectin and LDI-Ach; b) E-selectin and LDI-Ach; c) E-selectin and adiponectin; d) ICAM-1 and adiponectin; e) VCAM-1 and adiponectin; f) E-IL-6 and adiponectin; and g) TNF-alpha and adiponectin.