Consumption of thyroid medications as an indicator of increase of thyroid morbidity in Latvia from 2011 to 2014

Funding Information: EU Horizon 2020 research and innovation programme under grant agreement No 634453; project EUthyroid. The authors thank the EUthyroid project leader Henry Völzke and the work package leader Betina H. Thuesen for designing, planning and managing the project and, in particular, morbidity data collection. Publisher Copyright: © 2019 Ieva Kalere et al., published by Sciendo 2019.The most common autoimmune disorders with clinically opposite manifestations are hypothyroidism in Hashimoto's thyroiditis and hyperthyroidism in Graves' disease. The healthcare burden of thyroid disease is substantial, resulting in substantial health care costs. The aim of the present analysis is to assess the use of thyroid medications in Latvia from 2011 to 2014 by age and gender. Our study used reimbursed medication prescriptions data, collected by the National Health Service of Latvia. The main indicator was the number of prevalent users of thyroid medications each year from 2011 to 2014, stratified by age and gender. From 2011 to 2014, the number of thyroxine users per 100 000 revealed a statistically significant increase in all age and gender groups, except in 0- to 9-year-old girls. The number of Thiamazole users among men increased in the age group from 40 to 89 years and in women age groups above 49 years. Increasing sales of both thyroid hormones and antithyroid medications are also observed in Estonia and Lithuania, indicating that growing thyroid morbidity is an issue in the whole region. The substantial increase in number of patients highlights the necessity for national guidelines on the use of thyroid function tests and standards of medical care.publishersversionPeer reviewe

The efficacy and safety of imeglimin as add-on therapy in patientswith type 2 diabetes inadequately controlled with metformin monotherapy

OBJECTIVE A 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone. RESEARCH DESIGN AND METHODS A total of 156 patients were randomized 1:1 to receive imeglimin (1,500 mg twice a day) or placebo added to a stable dose of metformin (1,500–2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio. RESULTS After 12 weeks, the placebo-subtracted decrease in A1C with metformin-imeglimin was −0.44% (P < 0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (−0.91 mg/dL and −7.5, respectively) compared with metformin-placebo (0.36 mg/dL and 11.81). Metformin-imeglimin therapy was generally well-tolerated with a comparable safety profile to metformin-placebo. CONCLUSIONS Addition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes. Imeglimin is the first in a new tetrahydrotriazine-containing class of oral antidiabetic agents, the glimins. Imeglimin decreases hepatic glucose production, increases muscle glucose uptake, and improves pancreatic glucose-dependent insulin secretion (1). Previous studies have demonstrated imeglimin to be as effective as metformin in improving glycemia (2). Since metformin is the preferred first-line therapy for type 2 diabetes, the current study examined the efficacy, safety, and tolerability of imeglimin in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone

Nitric oxide production and arachidonic acid metabolism in platelet membranes of coronary heart disease patients with and without diabetes

Aim: To evaluate the levels of nitrite (NO2-) and nitrate (NO3-) ions and the incorporation of [3H]arachidonic acid (AA) into phospholipids of platelet membranes from coronary artery disease (CAD) patients with and without diabetes (NIDDM). Subjects and Methods: Eighteen CAD patients (group A), 18 CAD patients with NIDDM (group B), and 20 healthy controls (group C) without dyslipidemia, peripheral vascular disease and hypertension were included in the study. The groups were matched for age, sex and body mass index. The diagnosis of CAD was confirmed by coronary angiography. The nitric oxide end products (NOx), NO2- plus NO3- ions in platelet membranes, were determined using a spectrophotometric method based on the Griess reaction. The turnover of phospholipids was evaluated by incorporation of [3H]AA into platelet membrane phospholipids. Results: A significantly smaller amount of NOx ions was in the platelet membrane of groups A (40 ± 8 μmol/l) and B (29 ± 10 μmol/l) than C (57 ± 6 μmol/l), p < 0.001. Conversely a significantly greater amount of [3H]AA was incorporated into platelet phospholipids of group B patients (5,123 ± 1,637 dpm/mg) than groups A (3,159 ± 1,253 dpm/mg; p < 0.002) and C (1,621 ± 417 dpm/mg). An inverse correlation between [3H]AA incorporation and NOx levels was established: r = -0.76 (p < 0.05, n = 36) in CAD patients. Conclusions: Diabetes in CAD patients decreased the ability to produce platelet-derived NO and affects AA metabolism. This may result in higher platelet sensitivity to aggregating stimuli.publishersversionPeer reviewe

The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy

OBJECTIVE: This 12-week study assessed the efficacy and tolerability of imeglimin as add-on therapy to the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy. RESEARCH DESIGN AND METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, imeglimin (1,500 mg b.i.d.) or placebo was added to sitagliptin (100 mg q.d.) over 12weeks in 170 patientswith type 2 diabetes (mean age 56.8 years; BMI 32.2 kg/m2) that was inadequately controlled with sitagliptin alone (A1C ≥7.5%) during a 12-week run-in period. The primary ef ficacy end point was the change in A1C from baseline versus placebo; secondary end points included corresponding changes in fasting plasma glucose (FPG) levels, strati fication by baseline A1C, and percentage of A1C responders. RESULTS: Imeglimin reduced A1C levels (least-squares mean difference) from baseline (8.5%) by 0.60% compared with an increase of 0.12% with placebo (between-group difference 0.72%, P < 0.001). The corresponding changes in FPG were -0.93 mmol/L with imeglimin vs. -0.11 mmol/L with placebo (P = 0.014). With imeglimin, the A1C level decreased by ≥0.5% in 54.3% of subjects vs. 21.6% with placebo (P < 0.001), and 19.8%of subjects receiving imeglimin achieved a decrease in A1C level of ≤7% compared with subjects receiving placebo (1.1%) (P = 0.004). Imeglimin was generally well tolerated, with a safety pro file comparable to placebo and no related treatment-emergent adverse events. CONCLUSIONS: Imeglimin demonstrated incremental efficacy benefits as add-on therapy to sitagliptin, with comparable tolerability to placebo, highlighting the potential for imeglimin to complement other oral antihyperglycemic therapies

Analysis of polymorphisms at the adiponectin gene locus in association with type 2 diabetes, body mass index and cardiovascular traits in Latvian population

Funding Information: The work was supported by the National Research Programme in Medicine 2006–2009 project No. 14, “Creation of the unified and generally accessible data base on the main life expectancy and life quality threatening pathologies and epidemiology of their risk factors in Latvian population”, Latvian Council of Science Grant 01.0023.01. We acknowledge Genome Database of Latvian Population, Latvian Biomedical Research and Study Centre for providing data and DNA samples. Copyright: Copyright 2010 Elsevier B.V., All rights reserved.Despite the number of recently conducted studies seeking to determine the association between genetic variants of adiponectin gene and susceptibility to type 2 diabetes (T2D) and increased body mass index (BMI), the results obtained are often inconsistent. To determine the impact of common polymorphisms in promoter and coding regions of adiponectin gene on these conditions in Latvian population, we selected ten SNPs (rs2241767, rs1501299, rs3777261, rs16861210, rs2241766, rs822396, rs182052, rs17300539, rs16861194, rs266729) based on haploblock structure and previously reported association studies. The selected SNPs were screened in a study group of 835 participants from the Genome Data Base of Latvian Population and mainly consisted of patients with T2D and coronary heart disease. None of the individual polymorphisms were significantly associated with T2D status or BMI when analysed using logistic or linear regression and adjusted for gender, age and other significant covariates. Frequency of rs2241766 T allele homozygotes however was significantly increased in T2D patients compared to controls (uncorrected P = 0.007). When analysed with other traits, the rs182052 G allele was found to be less frequent in patients suffering from myocardial infarction (P = 0.02; OR = 0.76, CI95% [0.61-0.92]) compared to others. Haplotype analysis revealed significant association of one haplotype with atrial fibrillation (uncorrected P = 0.01). In summary, we conclude that SNPs in adiponectin gene are unlikely to represent the risk for T2D, but may be involved in pathogenesis of CHD in the Latvian population.publishersversionPeer reviewe

Novel susceptibility loci identified in a genome-wide association study of type 2 diabetes complications in population of Latvia

Funding Information: The study was supported by European Regional Development Fund (ERDF) On Implementation of Activity 1.1.1.2 “Post-doctoral Research Aid” of the Specific Aid Objective 1.1.1 “To increase the research and innovative capacity of scientific institutions of Latvia and the ability to attract external financing, investing in human resources and infrastructure” of the Operational Programme “Growth and Employment”. Project No 1.1.1.2/VIAA/2/18/287 “Identification of clinical subgroups of Type 2 diabetes mellitus and application of pharmacogenetics in the development of personalized antidiabetic therapy”. The funding body was not involved in the design of the study, collection, analysis or interpretation of data, or writing the manuscript. Publisher Copyright: © 2021, The Author(s).Background: Type 2 diabetes complications cause a serious emotional and economical burden to patients and healthcare systems globally. Management of both acute and chronic complications of diabetes, which dramatically impair the quality of patients' life, is still an unsolved issue in diabetes care, suggesting a need for early identification of individuals with high risk for developing diabetes complications. Methods: We performed a genome-wide association study in 601 type 2 diabetes patients after stratifying them according to the presence or absence of four types of diabetes complications: diabetic neuropathy, diabetic nephropathy, macrovascular complications, and ophthalmic complications. Results: The analysis revealed ten novel associations showing genome-wide significance, including rs1132787 (GYPA, OR = 2.71; 95% CI = 2.02–3.64) and diabetic neuropathy, rs2477088 (PDE4DIP, OR = 2.50; 95% CI = 1.87–3.34), rs4852954 (NAT8, OR = 2.27; 95% CI = 2.71–3.01), rs6032 (F5, OR = 2.12; 95% CI = 1.63–2.77), rs6935464 (RPS6KA2, OR = 2.25; 95% CI = 6.69–3.01) and macrovascular complications, rs3095447 (CCDC146, OR = 2.18; 95% CI = 1.66–2.87) and ophthalmic complications. By applying the targeted approach of previously reported susceptibility loci we managed to replicate three associations: MAPK14 (rs3761980, rs80028505) and diabetic neuropathy, APOL1 (rs136161) and diabetic nephropathy. Conclusions: Together these results provide further evidence for the implication of genetic factors in the development of type 2 diabetes complications and highlight several potential key loci, able to modify the risk of developing these conditions. Moreover, the candidate variant approach proves a strong and consistent effect for multiple variants across different populations.publishersversionPeer reviewe

Polymorphisms in MEN1 and DRD2 genes are associated with the occurrence and characteristics of pituitary adenomas

Publisher Copyright: © 2016 European Society of Endocrinology Published by Bioscientifica Ltd. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.Objective: Although pituitary adenomas (PAs) affect a significant proportion of the population, only a fraction have the potential to become clinically relevant during an individual's lifetime, causing hormonal imbalance or complications due to mass effect. The overwhelming majority of cases are sporadic and without a clear familial history, and the genotype-phenotype correlation in PA patients is poorly understood. Our aim was to investigate the involvement of genes known for their role in familial cases on drug response and tumor suppression in the development and pathology of PAs in a patient group from Latvia. Design: The study included 143 cases and 354 controls, we investigated the role of single-nucleotide polymorphisms (SNPs) in seven genes (SSTR2, SSTR5, DRD2, MEN1, AIP, GNAS, and PRKAR1A) associated with pituitary tumor occurrence, phenotype, and clinical symptoms. Methods: Genotyping of 96 tag and nonsynonymous SNPs was performed in the genomic regions of interest. Results: We discovered a significant association (OR = 17.8, CI 0.95 = 2.18-145.5, P = 0.0002) between a rare MEN1 mutation (rs2959656) and clinically active adenoma in our patients. Additionally, rs7131056 at DRD2 was associated with a higher occurrence of extrasellar growth in patients with prolactinoma and somatotropinoma (OR = 2.79, CI 0.95 = 1.58-4.95, P = 0.0004). Conclusions: rs2959656, a nonsynonymous variant in MEN1, is associated with the development of clinically active PA. Furthermore, rs7131056 in DRD2 contributes to either faster growth of the adenoma or reduced symptomatic presentation, allowing PAs to become larger before detection.publishersversionPeer reviewe

Whole exome sequencing reveals novel risk genes of pituitary neuroendocrine tumors

Funding Information: This research was supported by the European Regional Development Fund (ERDF), Measure 1.1.1.1 “Industry-Driven Research” project „Molecular markers of pituitary tumour development, progression and therapy response” (Project No. 1.1.1.1/16/A/066, 2017). The authors acknowledge the Latvian Biomedical Research and Study Centre and the Genome Database of the Latvian Population for providing infrastructure, biological material and data. Publisher Copyright: © 2022 Peculis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Somatic genetic alterations in pituitary neuroendocrine tumors (PitNET) tissues have been identified in several studies, but detection of overlapping somatic PitNET candidate genes is rare. We sequenced and by employing multiple data analysis methods studied the exomes of 15 PitNET patients to improve discovery of novel factors involved in PitNET development. PitNET patients were recruited to the study before PitNET removal surgery. For each patient, two samples for DNA extraction were acquired: venous blood and PitNET tissue. Exome sequencing was performed using Illumina NexSeq 500 sequencer and data analyzed using two separate workflows and variant calling algorithms: GATK and Strelka2. A combination of two data analysis pipelines discovered 144 PitNET specific somatic variants (mean = 9.6, range 0–19 per PitNET) of which all were SNVs. Also, we detected previously known GNAS PitNET mutation and identified somatic variants in 11 genes, which have contained somatic variants in previous WES and WGS studies of PitNETs. Noteworthy, this is the third study detecting somatic variants in gene RYR1 in the exomes of PitNETs. In conclusion, we have identified two novel PitNET candidate genes (AC002519.6 and AHNAK) with recurrent somatic variants in our PitNET cohort and found 13 genes overlapping from previous PitNET studies that contain somatic variants. Our study demonstrated that the use of multiple sequencing data analysis pipelines can provide more accurate identification of somatic variants in PitNETs.publishersversionPeer reviewe

Evaluation of the Possibility to Detect Circulating Tumor DNA From Pituitary Adenoma

Funding Information: The authors acknowledge the Latvian Biomedical Research and Study Center and the Genome Database of the Latvian Population for providing infrastructure, biological material, and data. Funding. This research was supported by the European Regional Development Fund (ERDF), Measure 1.1.1.1 Industry-Driven Research project Molecular markers of pituitary tumor development, progression and therapy response (Project No. 1.1.1.1/16/A/066, 2017), and Roche Academy project Immunohistochemical analysis of pituitary adenoma tissue. Publisher Copyright: © Copyright © 2019 Megnis, Peculis, Rovite, Laksa, Niedra, Balcere, Caune, Breiksa, Nazarovs, Stukens, Konrade, Pirags and Klovins.Objective: Circulating free DNA (cfDNA) in general and circulating tumor DNA (ctDNA) in particular is becoming an increasingly used form of liquid biopsy biomarkers. In this study, we are investigating the ability to detect ctDNA from the plasma of pituitary adenoma (PA) patients. Design: Tumor tissue samples were obtained from planed PA resections, before which blood plasma samples were taken. Somatic variants found in PA tissue samples were evaluated in related cfDNA, isolated from plasma samples. Methods: Sanger sequencing, as well as previously obtained whole-exome sequencing data, were used to evaluate somatic variants composition in tumor tissue samples. cfDNA was isolated from the same PA patients and competitive allele-specific TaqMan PCR and amplicon-based next-generation sequencing (NGS) approach were used for targeted detection of variants found in corresponding tumor tissue samples. Results: Using NGS-based analysis, we detected five out of 17 somatic variants in 40 to 60% of total reads, three variants in 0.50–5.00% of total read count, including GNAS c.601C>T, which was detected using ultra-deep NGS (1.78 million X) in 0.77% of amplicons reads. Nine variants were not detected. We also detected We were not able to detect variant found in PA tissue in cfDNA using cast-PCR, indicating that the portion of variant-containing ctDNA in total isolated cfDNA is too small to be detected with this method. Conclusions: For the first time, we demonstrate the possibility to detect somatic variants of PA in cfDNA isolated from patients' blood plasma. Whether the source of variant detected in cfDNA is PA should be further tested.publishersversionPeer reviewe

Iodine deficiency in Latvia : Current status and need for national recommendations

Publisher Copyright: © 2017 De Gruyter Open Ltd. All rights reserved. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.In the absence of a mandatory salt iodisation programme, two nationwide cross-sectional cluster surveys revealed persisting iodine deficiency among Latvian schoolchildren during the spring season and a noteworthy iodine deficiency in pregnant women in Latvia; these deficiencies warrant intervention. The consequences of mild-to-moderate iodine deficiency during pregnancy and lactation can adversely affect foetal brain development. Data from a Latvian population survey revealed the consumption of approximately 100 μg of iodine per day through foods and iodised salt. Therefore, strategies to increase the consumption of iodine-containing products should be implemented, particularly for children. In addition, to meet the increased iodine requirement during pregnancy, pregnant women should take daily supplements containing 150 μg iodine from the earliest time possible. All women of childbearing age should be advised to increase their dietary iodine intake by using iodised table salt and iodine-rich products: seafood, milk and milk products. For women with pre-existing thyroid pathologies, the medical decision should be considered on a case-by-case basis. Urinary iodine concentration monitoring among schoolchildren and pregnant women and neonatal thyrotropin registry analysis every five years would be an appropriate strategy for maintaining iodine intake within the interval that prevents iodine deficiency disorders.Peer reviewe