Downregulation of mapk/mak/mrk overlapping kinase 1 in peripheral blood mononuclear cells of pediatric patients with type 1 diabetes mellitus.

Miron Sopić,Marija Mihajlović,Jelena Vekić,Jelena Munjas,Tatjana Milenković,Vesna Spasojević-Kalimanovska,Dragana Bojanin,Barbara Ostanek,Ana Ninić,Janja Marc

doi:10.5937/jomb0-33220

Miron Sopić, Marija Mihajlović + Show 8 more

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https://doi.org/10.5937/jomb0-33220

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Abstract

BackgroundType 1 diabetes mellitus (T1DM) is one of the most common endocrine diseases in children. T-cell autoreactivity toward b-cells is controlled by significant changes in metabolism of T cells. Mammalian target of rapamycin (mTOR) is an important intracellular regulator of metabolism and cell growth. MAPK/MAK/MRK overlapping kinase 1 (MOK1) is one of the less known regulators of mTOR. We sought to investigate if MOK1 and mTOR mRNA levels in peripheral blood mononuclear cells (PBMCs) of T1DM pediatric patients are different compared to healthy subjects.MethodsThis study included 172 adolescents with T1DM and 36 healthy adolescent volunteers designated for control group (CG). MOK1 and mTOR mRNA levels were determined in PBMCs by qPCR.ResultsT1DM patients have significant downregulation of MOK1 mRNA levels in PBMCs compared CG (P=0.018), while there was no significant difference in mTOR mRNA levels (P=0.891). Furthermore, in T1DM patients, MOK1 significantly correlated with age, triglycerides and mTOR, while mTOR correlated significantly with BMI and systolic blood pressure. Overweight T1DM subjects had significantly lower MOK1 (P=0.034) and mTOR (P=0.017) mRNA levels, together with significantly higher levels of systolic blood pressure (P<0.001), total cholesterol (P=0.001), LDL-cholesterol (P=0.001) and CRP (P<0.001). Multi - variate analysis showed that MOK1 was independently negatively associated with T1DM when adjusted for sex, age, HDL-C and CRP (OR=0.417 (95%CI: 0.175-0.997), p=0.049).ConclusionsOur study demonstrated for the first time that T1DM is associated with MOK1 downregulation. In addition, downregulation of both mTOR and MOK1 gene expressions was associated with cardiovascular risk factors in overweight T1DM patients.

Highlights

Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by dysfunction of pancreatic islet b-cells and concomitant insulin deficiency and hyperglycemia
Downregulation of both Mammalian target of rapamycin (mTOR) and MRK overlapping kinase 1 (MOK1) gene expressions was associated with cardiovascular risk factors in overweight T1DM patients
Normalized MOK1 mRNA levels were significantly downregulated in T1DM patients compared to control group (CG) (P=0.018) (Figure 1A), while there were no significant differences in normalized mTOR mRNA levels between observed groups (P=0.891) (Figure 1B)

Summary

Introduction

Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by dysfunction of pancreatic islet b-cells and concomitant insulin deficiency and hyperglycemia It is considered as one of the most common endocrine and metabolic diseases in children, and over 500,000 children are currently living with this condition worldwide [1, 2]. The analysis of Langerhans islets in post mortem samples obtained close to T1DM diagnosis showed rare cellular infiltrates dominated by CD4+ and CD8+ T lymphocytes [4] It seems that T cell autoreactivity in b-cells autoimmunity is controlled by significant changes in metabolic pathways [5]. Relatively little is known about MOK1 functions or its upstream and

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