Altered Immune Regulation in Type 1 Diabetes

Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development

The MTNR1B rs10830963 Variant in Interaction with Pre-Pregnancy BMI is a Pharmacogenetic Marker for the Initiation of Antenatal Insulin Therapy in Gestational Diabetes Mellitus

The rs10830963 variant of the Melatonin Receptor 1B (MTNR1B) gene is associated with the development of gestational diabetes mellitus (GDM). We hypothesized that carrying the rs10830963/G risk allele had effect on antenatal insulin therapy (AIT) initiation in GDM in a body mass index (BMI)-dependent manner. Design: In this post hoc analysis the MTNR1B rs10830963 genotype and the clinical data of 211 Caucasian GDM patients were assessed. As a first step, a pre-pregnancy BMI threshold was determined where the effect of MTNR1B rs10830963/G allele carrying on AIT initiation was the most significant using logistic regression. Maternal age adjusted real-life odds ratios (OR) values were calculated. The chi-square test was also used to calculate the p value and 10.000 bootstrap simulations were performed in each case to re-assess the statistical power and the OR. Carrying the MTNR1B rs10830963/G allele increased the odds of AIT initiation (OR = 5.2, p = 0.02 [χ2 test], statistical power = 0.53) in GDM patients with pre-pregnancy BMI ≥ 29 kg/m2. The statistical power reached 0.77, when the pre-pregnancy BMI cutoff of 27 kg/m2 was used and the genetic effect on AIT initiation was still significant, but only using the logistic regression model. Carrying the MTNR1B rs10830963/G risk allele—in interaction with pre-pregnancy BMI—is likely be considered as a candidate pharmacogenetic marker of antenatal insulin therapy initiation and should be further assessed in precision medicine trials in GDM

Association Study with 77 SNPs Confirms the Robust Role for the rs10830963/G of MTNR1B Variant and Identifies Two Novel Associations in Gestational Diabetes Mellitus Development

CONTEXT: Genetic variation in human maternal DNA contributes to the susceptibility for development of gestational diabetes mellitus (GDM). OBJECTIVE: We assessed 77 maternal single nucleotide gene polymorphisms (SNPs) for associations with GDM or plasma glucose levels at OGTT in pregnancy. METHODS: 960 pregnant women (after dropouts 820: case/control: m99'WHO: 303/517, IADPSG: 287/533) were enrolled in two countries into this case-control study. After genomic DNA isolation the 820 samples were collected in a GDM biobank and assessed using KASP (LGC Genomics) genotyping assay. Logistic regression risk models were used to calculate ORs according to IADPSG/m'99WHO criteria based on standard OGTT values. RESULTS: The most important risk alleles associated with GDM were rs10830963/G of MTNR1B (OR = 1.84/1.64 [IADPSG/m'99WHO], p = 0.0007/0.006), rs7754840/C (OR = 1.51/NS, p = 0.016) of CDKAL1 and rs1799884/T (OR = 1.4/1.56, p = 0.04/0.006) of GCK. The rs13266634/T (SLC30A8, OR = 0.74/0.71, p = 0.05/0.02) and rs7578326/G (LOC646736/IRS1, OR = 0.62/0.60, p = 0.001/0.006) variants were associated with lower risk to develop GDM. Carrying a minor allele of rs10830963 (MTNR1B); rs7903146 (TCF7L2); rs1799884 (GCK) SNPs were associated with increased plasma glucose levels at routine OGTT. CONCLUSIONS: We confirmed the robust association of MTNR1B rs10830963/G variant with GDM binary and glycemic traits in this Caucasian case-control study. As novel associations we report the minor, G allele of the rs7578326 SNP in the LOC646736/IRS1 region as a significant and the rs13266634/T SNP (SLC30A8) as a suggestive protective variant against GDM development. Genetic susceptibility appears to be more preponderant in individuals who meet both the modified 99'WHO and the IADPSG GDM diagnostic criteria

A melatoninreceptor 1B rs10830963 génvariáns szerepe a terhességi cukorbetegség kialakulásában és kezelésében [The role of melatonin receptor 1B rs10830963 gene variant in the development and therapy of gestational diabetes mellitus]

A szerzők ismertetik az MTNR1B gén egy gyakori variánsának (rs10830963) és a G kockázati allél hordozásának hatását a 2-es típusú cukorbetegség, valamint a gestatiós diabetes mellitus (GDM) kialakulására. A két kórképben az MTNR1B rs10830963 variánshoz asszociált kockázatok fennállása minden valószínűséggel a béta-sejt-diszfunkcióval és a korai inzulinválasz romlásával magyarázható. Az MTNR1B rs10830963-hez kapcsolt genetikai kockázat mértéke azonban a két kórformában különböző: a GDM kialakulása szempontjából ugyanannak a G allélnak a hordozása – mind a magyar-osztrák, mind a nemzetközi irodalmi adatok szerint – lényegesen magasabb kockázatot jelent, mint a 2-es típusú cukorbetegség kialakulására nézve. A fokozott genetikai hatás hátterében több magyarázat is állhat, amelyeket részletesen ismertetnek a szerzők. A G kockázati allél gyakorisága (hazánkban a G allélt közel minden második nő hordozza) és GDM-ben az antenatalis inzulinkezelésre vonatkozó genetikai hatás nagysága (OR >5 – terhesség előtti BMI ≥29 kg/m2 esetén) alapján az MTNR1B rs10830963 génvariáns a precíziós medicina alapú terápiás döntéstámogató rendszerek tényleges jelöltjévé válhat a jövőben. | The authors review the effect of a common variant (rs10830963) of MTNR1B gene and the G risk allele carrying on the development of type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM). The risks associated to the MTNR1B rs10830963variant for the two diseases could likely be explained by the beta-cell dysfunction and the worsening early phase insulin response. However, the MTNR1B rs10830963 associated odds of the disease development are different: the risks posed by carrying the same G-allele are significantly higher of GDM compared to T2DM development both according to the Hungarian-Austrian study and also to the international literature. The increased genetic effect could be explained by a number of factors that are discussed in detail by the authors. Due to the genetic effect size on antenatal insulin therapy in GDM (OR >5 in pregnant women with pre-pregnancy BMI ≥29 kg/m2) and to the risk allele frequency (in Hungary nearly every second woman carries the G allele) the MTNR1B rs10830963 gene variant might be a suggested candidate for precision medicine based therapeutic decision support system in the future

A terhességi cukorbetegség rövid története, kockázati tényezői és diagnosztikája napjainkban [A brief of gestational diabetes mellitus, risk factors and current criteria of diagnosis]

Diabetes is one of the most common metabolic disorders that may cause pathological pregnancy. Treating diabetes recognized during pregnancy results in lowering maternal and fetal complications. These patients present higher risk for excessive weight gain, preeclampsia, delivery with cesarean sections, high risk of developing type 2 diabetes and cardiovascular disease in the future. Fetuses of mothers with gestational diabetes are at higher risk for macrosomia and birth trauma, after delivery they present higher risk of developing neonatal hypoglycemia, hyperbilirubinemia, and respiratory distress syndrome. There is still no consensus in the recommendations for the diagnosis of gestational diabetes mellitus by expert committees. Orv. Hetil., 2017, 158(8), 283-290

Clinical characteristics of the pregnant population studied.

<p>Clinical characteristics of the pregnant population studied.</p

Association of common gene variants with pre-pregnancy body mass index.

<p>Association of common gene variants with pre-pregnancy body mass index.</p

Association of common gene variants with fasting and 120 minute plasma glucose values at oral glucose tolerance test (OGTT) in pregnant population.

<p>Association of common gene variants with fasting and 120 minute plasma glucose values at oral glucose tolerance test (OGTT) in pregnant population.</p