MODIS Research Articles

A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes.

Maturity-onset diabetes of the young (MODY) has about a dozen known causal genes to date, the most common ones being HNF1A, HNF4A, HNF1B and GCK. The phenotype of this clinically and genetically heterogeneous form of diabetes depends on the gene in which the patient has the mutation. We have tested 450 Hungarian index patients with suspected MODY diagnosis with Sanger sequencing and next-generation sequencing and found a roughly 30% positivity rate. More than 70% of disease-causing mutations were found in the GCK gene, about 20% in the HNF1A gene and less than 10% in other MODY-causing genes. We found 8 pathogenic and 9 likely pathogenic mutations in the HNF1A gene in a total of 48 patients and family members. In the case of HNF1A-MODY, the recommended first-line treatment is low dose sulfonylurea but according to our data, the majority of our patients had been on unnecessary insulin therapy at the time of requesting their genetic testing. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of the MODY subtype in order to choose the most appropriate treatment.

Congenital hyperinsulinism in Gran Canaria, Canary Isles

IntroductionCongenital hyperinsulinism (CH) is a severe disorder characterised by the appearance of severe hypoglycaemia. Pathogenic mutations in the ABCC8 and KCNJ11 genes are the most frequent cause, although its appearance also been associated to mutations in other genes (GCK, GLUD1, HADH, HNF1A, HNF4A, SLC16A1, UCP2, HK1), and with different syndromes. Materials and methodsRetrospective review of patients diagnosed with CH in this unit during the last 18 years (2001–2018). Genetic analysis included screening for 11 genes in genomic DNA from peripheral blood (ABCC8, GCK, GLUD1, HADH, HNF1A, HNF4A, INSR, KCNJ11, SLC16A1, UCP2, and SLC25A15). ObjectiveTo carry out a clinical and genetic characterisation of the diagnosed cases of CH in Gran Canaria. ResultsThere have been 10 cases of persistent HC since 2001. Seven of them had mutations in the ABCC8 gene, one in the HNF4α gene, and in two patients, no pathogenic mutations were found in the analysed genes. Four patients presented with previously undescribed mutations. Pancreatectomy was performed in two of the cases. The minimum insulin value detected in hypoglycaemia was 6.81 µIU/mL. The incidence of persistent CH for Gran Canaria and Lanzarote is 1/15,614. ConclusionsFour patients had previously undescribed mutations. The most frequently affected gene was ABCC8. Pancreatectomy was required in 20% of the patients. An insulin value of ≥6.81 µIU/mL was observed in all patients at the time of diagnosis. The incidence of CH in Gran Canaria is high.

Diagnostic utility of the combined use of HNF4A and GATA3 in distinction between primary and metastatic breast and gastric carcinomas.

Sometimes the distinction between gastric adenocarcinomas and breast carcinomas can be challenging. Hepatocyte nuclear factor 4-alpha (HNF4A) has been suggested as a potential marker in these cases. The aim of the present work was to evaluate the role of the combined use of HNF4A and GATA3 as immunohistochemical markers in distinction between primary and metastatic breast and gastric carcinomas. This retrospective study was conducted on (81) cases divided into four groups of cohorts: primary BC (cohort I, n=25), primary GC (cohort II, n=23), and metastases derived from both types of tumors designated as metastasis derived from BC (cohort III-A, n=17) and metastasis derived from GC (cohort III-B, n=16). We performed immunohistochemistry analysis of HNF4A and GATA3 in all (81) cases. HNF4A expression was seen in 22 of 23 primary gastric adenocarcinomas and was absent in all 25 primary breast carcinomas (sensitivity 95.7%, specificity 100%). HNF4A was seen in 15 of 16 metastatic gastric adenocarcinomas and was absent in all 17 metastatic breast carcinomas (sensitivity 93.8%, specificity 100%). GATA3 showed 92 and 88% sensitivity, and 95.7 and 100% specificity for primary breast carcinomas and metastatic breast carcinomas, respectively. Our data confirmed the potential utility of HNF4A as a diagnostic marker and can be used as an adjunct to GATA3 as an immunohistochemical panel to differentiate between breast and gastric carcinomas.

A case of digenic maturity onset diabetes of the young with heterozygous variants in both HNF1Α and HNF1Β genes

BackgroundMaturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now. Case reportA female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant. ConclusionDigenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.

774-P: Hereditary Renal Glycosuria, Diabetes, and Responses to SGLT2 Inhibitor

Aims: To present the clinical features of two rare cases with hereditary renal glycosuria and diabetes, and summarize the previously reported SLC5A2 mutations and the related phenotypes. Methods: The two patients were followed up for 7 and 3 years respectively, and detailed clinical characteristics were collected. SLC5A2 and HNF1A gene were sequenced. We used flash glucose monitoring system to record the variation of glucose with and without SGLT2 inhibitor treatment. Then we retrieved all the literature from Pubmed and analyzed SLC5A2 gene mutations and the phenotypes. Results: During regular long-time follow up, the two patients both had frequent un-proportional renal glycosuria in the morning even when their fasting serum glucose was only slightly increased above the normal range. A novel rare mutation V359G and a pathogenic rare mutation ivs7+5G>A in SLC5A2 gene were found in Case 1 and Case 2 respectively. In Case 1, the 24h glycosuria was 2.2g/d, and increased to 103g/day after dapaglifozin treatment. The average glucose (6.33±1.56 vs. 6.28±1.74mmol/L, P=0.663), and Time in Range (TIR) (95% vs. 93%) were not significantly different in metformin and dapaglifozin treatment respectively. In Case 2, the 24h glycosuria was 121.4g/d and increased to 185.8g/day after dapaglifozin add-on treatment, with a further reduction of average glucose (9.11±2.63 vs. 7.54±2.39mmol/L, P<0.001), and better TIR 70% vs. 84%. We reviewed 139 cases with hereditary renal glycosuria and SLC5A2 gene mutation. The quantity of urine glucose was highest in patients with homozygous mutation (64.0(36.6-89.6)g/24h) compared with compound heterozygous (25.9(14.4-41.2)g/24h) and heterozygous(3.45(1.41-7.50)g/24h) (P<0.001). Conclusions: Genetic renal glycosuria could not be translated into protecting individuals completely from developing diabetes. The response of these patients suggested that even in diabetic patients with decreased renal glucose threshold, SGLT2 inhibitor could also be effective. Disclosure Q. Ren: None. S. Gong: None. X. Han: None. L. Ji: None. Funding National Key Research and Development Program of China (2016YFC1304901); Beijing Municipal Commission of Science and Technology (Z141100007414002, D131100005313008)

Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant \u03b2 cells

Heterozygous HNF1A gene mutations can cause maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. However, specific mechanisms of MODY3 in humans remain unclear due to lack of access to diseased human pancreatic cells. Here, we utilize MODY3 patient-derived human induced pluripotent stem cells (hiPSCs) to study the effect(s) of a causal HNF1A+/H126D mutation on pancreatic function. Molecular dynamics simulations predict that the H126D mutation could compromise DNA binding and gene target transcription. Genome-wide RNA-Seq and ChIP-Seq analyses on MODY3 hiPSC-derived endocrine progenitors reveal numerous HNF1A gene targets affected by the mutation. We find decreased glucose transporter GLUT2 expression, which is associated with reduced glucose uptake and ATP production in the MODY3 hiPSC-derived β-like cells. Overall, our findings reveal the importance of HNF1A in regulating GLUT2 and several genes involved in insulin secretion that can account for the insulin secretory defect clinically observed in MODY3 patients.

Glucokinase activating mutation causing hypoglycaemia diagnosed late in adult who fasts for Ramadhan.

SummaryActivating mutation of glucokinase gene (GCK) causes resetting of insulin inhibition at a lower glucose threshold causing hyperinsulinaemic hypoglycaemia (GCK-HH). This is the first reported case who tolerated years of regular fasting during Ramadhan, presenting only with seizure and syncope now. We describe a case with GCK gene variant p.T65I diagnosed in a 51-year-old woman with hypoglycaemia unawareness even at glucose level of 1.6 mmol/L. Insulin and C-peptide levels during hypoglycaemia were suggestive of hyperinsulinism, but at a day after intravenous glucagon, hypoglycaemia occurred with low insulin and C-peptide levels, pointing against insulinoma as the underlying aetiology. Imaging studies of the pancreas and calcium arterial stimulation venous sampling were unremarkable. A review of old medical records revealed asymptomatic hypoglycaemia years ago. Genetic testing confirmed activating mutation of GCK. Hypoglycaemia was successfully controlled with a somatostatin analogue. This case highlights the importance of consideration of genetic causes of hypoglycaemia in adulthood, especially when imaging is uninformative.Learning pointsConsider genetic causes of endogenous hyperinsulinism hypoglycaemia in adulthood, especially when imaging is uninformative.Late presentation of activating mutation of GCK can occur because of hypoglycaemia unawareness.Long-acting somatostatin analogue may be useful for the treatment of activating mutation of GCK causing hypoglycaemia.Depending on the glucose level when the blood was taken, and the threshold of glucose-stimulated insulin release (GSIR), the serum insulin and C-peptide levels may be raised (hyperinsulinaemic) or low (hypoinsulinaemic) in patients with activating mutation of GCK.Glucagon may be useful to hasten the process of unmasking the low insulin level during hypoglycaemia below the GSIR level of which insulin released is suppressed.

Effect of moderate exercises and curcumin on hepatic transcriptional factors associated with lipid metabolism and steatosis in elderly male rat.

Background and purpose:The specific molecular mediators involved in dyslipidemia in older people are not yet clearly understood. The current study was, thus, an attempt to investigate whether moderate aerobic exercises and curcumin administration alleviates the abnormalities caused by aging in the rats’ liver.Experimental approach:Thirty-two eight-year-old young rats were classified into five groups, namely, young control, aged control, aged-curcumin, aged-exercise, and aged-curcumin-exercise co-treatment. The rats in the exercise groups were trained on an animal treadmill for 60 min/day five times per week for eight weeks.Findings/Results:The results revealed a significant increase in FAT/CD36, PTP1B, significantly decreased HNF4α genes expression, increase in LDL and cholesterol in the aged group compared to the young control. Compared to those in the young control group, no significant changes in HDL and TG amounts in the aged control were observed. Moreover, compared to the young control, the aged group showed liver histological changes such as fibrosis and mild or grade 1 steatohepatitis. Moderate aerobic exercise and curcumin alone or in combination completely masked this effect.Conclusion and implications:The findings revealed dyslipidemia and liver steatosis related to aging might be partly associated with changes in hepatic transcriptional factors which can be mitigated via moderate aerobic exercise and curcumin.

A Review of Functional Characterization of Single Amino Acid Change Mutations in HNF Transcription Factors in MODY Pathogenesis.

Mutations in HNF transcription factor genes cause the most common subtypes of maturity-onset of diabetes of youth (MODY), a monogenic form of diabetes mellitus. Mutations in the HNF1-α, HNF4-α, and HNF1-β genes are primarily considered as the cause of MODY3, MODY1, and MODY5 subtypes, respectively. Although patients with different subtypes display similar symptoms, they may develop distinct diabetes-related complications and require different treatments depending on the type of the mutation. Genetic analysis of MODY patients revealed more than 400 missense/nonsense mutations in HNF1-α, HNF4-α, and HNF1-β genes, however only a small portion of them are functionally characterized. Evaluation of nonsense mutations are more direct as they lead to premature stop codons and mostly in mRNA decay or nonfunctional truncated proteins. However, interpretation of the single amino acid change (missense) mutation is not such definite, as effect of the variant may vary depending on the location and also the substituted amino acid. Mutations with benign effect on the protein function may not be the pathologic variant and further genetic testing may be required. Here, we discuss the functional characterization analysis of single amino acid change mutations identified in HNF1-α, HNF4-α, and HNF1-β genes and evaluate their roles in MODY pathogenesis. This review will contribute to comprehend HNF nuclear family-related molecular mechanisms and to develop more accurate diagnosis and treatment based on correct evaluation of pathologic effects of the variants.

Cardiovascular Comorbidity Associated With Albuminuria in Youth-Onset Type 2 Diabetes: Analyses From the iCARE Study

ObjectivesLittle is known about the relationship between albuminuria in youth with type 2 diabetes (T2D) and cardiovascular risk. We aimed to determine whether youth with T2D and albuminuria have evidence of increased cardiovascular risk and/or early cardiovascular dysfunction compared with youth with T2D without albuminuria. MethodsYouth with T2D were stratified by albuminuria status. Cardiovascular risk factors, including body mass index (BMI), 24-hour blood pressure, lipid profile, smoking and smoking exposure, habitual physical activity and screen time, were compared between groups. Left ventricular structure and function and carotid intima-media thickness (cIMT) were evaluated in participants who underwent cardiac imaging. ResultsTwo hundred sixty-five youth participated, 83 (31.3%) of whom had albuminuria. Ethnicity, sex, BMI z score, age at diagnosis, duration of diabetes and hepatocyte nuclear factor-1alpha status did not differ between youth stratified by albuminuria. Smoking, exposure to second-hand smoke and low physical activity levels did not differ between groups. Youth with albuminuria were more likely to have hypertension, dyslipidemia and poor glycemic control. Left ventricular structure and carotid cIMT did not differ between groups, but youth with albuminuria had evidence of early left ventricular diastolic dysfunction. ConclusionsWe found evidence of increased cardiovascular disease risk factors and left ventricular diastolic dysfunction in youth with T2D and albuminuria compared with those without albuminuria, despite a relatively short duration of disease. Thus, albuminuria may serve as a marker of early cardiovascular disease risk in youth with T2D.

Clinical and genetic characteristics of patients with congenital hyperinsulinism in 21 non-consanguineous families from Serbia.

Persistent hypoglycaemia in newborns and infants is most commonly caused by congenital hyperinsulinism (CHI). Most CHI studies report outcomes in children from both consanguineous and non-consanguineous families which can affect the phenotype-genotype analysis. The aim of this study was to analyze characteristics of patients with CHI in 21 non-consanguineous families from Serbia. This retrospective cohort study included a total of 21 patients with CHI treated in the Mother and Child Healthcare Institute of Serbia during the past 20 years. The prevalence of macrosomia at birth was very low in our cohort (4.8%). Median age at presentation was 6 days, with seizures as the presenting symptom in 76% of patients. Only four patients (19%) were diazoxide unresponsive, and eventually underwent pancreatectomy. Genetic testing was performed in 15 patients and genetic diagnosis was confirmed in 60%, with all patients being heterozygous for detected mutations. The ABCC8 gene mutations were detected in 55.6%, GLUD1 in three patients (33.3%) with HIHA syndrome and one patient had HNF4A gene mutation and unusual prolonged hyperglycaemia lasting 6 days after diazoxide cessation. Neurodevelopmental deficits persisted in 33% of patients.Conclusion: This is the first study regarding CHI patients in Serbia. It suggests that in countries with low consanguinity rate, majority of CHI patients are diazoxide responsive. The most common mutations were heterozygous ABCC8, followed by GLUD1 and HNF4A mutations, suggesting the potential benefit of population-tailored genetic analysis approach, targeting the mutations causing CHI via dominant inheritance model in regions with low consanguinity rates. What is Known: • Persistent hypoglycaemia during infancy and early childhood is most commonly caused by congenital hyperinsulinism (CHI). • Consanguinity is a very important factor regarding the genetics and phenotype of CHI, increasing the risk of autosomal recessive genetic disorders, including the severe, diazoxide-unresponsive forms caused by recessive inactivating mutations in ABCC8 and KCNJ11. What is New: • Results of the present study which included CHI patients from 21 non-consanguineous families suggest that in countries with low consanguinity rates, majority of CHI patients can be diazoxide responsive, with most common mutations being heterozygous ABCC8, followed by GLUD1 and HNF4A mutations. • Unusually prolonged hyperglycaemic reaction to diazoxide treatment in a patient with HNF4A mutation was also described in the present study.

Interlaboratory evaluation of plasma N-glycan antennary fucosylation as a clinical biomarker for HNF1A-MODY using liquid chromatography methods

Antennary fucosylation alterations in plasma glycoproteins have been previously proposed and tested as a biomarker for differentiation of maturity onset diabetes of the young (MODY) patients carrying a functional mutation in the HNF1A gene. Here, we developed a novel LC-based workflow to analyze blood plasma N-glycan fucosylation in 320 diabetes cases with clinical features matching those at risk of HNF1A-MODY. Fucosylation levels measured in two independent research centers by using similar LC-based methods were correlated to evaluate the interlaboratory performance of the biomarker. The interlaboratory study showed good correlation between fucosylation levels measured for the 320 cases in the two centers with the correlation coefficient (r) of up to 0.88 for a single trait A3FG3S2. The improved chromatographic separation allowed the identification of six single glycan traits and a derived antennary fucosylation trait that were able to differentiate individuals carrying pathogenic mutations from benign or no HNF1A mutation cases, as determined by the area under the curve (AUC) of up to 0.94. The excellent (r = 0.88) interlaboratory performance of the glycan biomarker for HNF1A-MODY further supports the development of a clinically relevant diagnostic test measuring antennary fucosylation levels.

The HNF1A-AS1/miR-92a-3p axis affects the radiosensitivity of non-small cell lung cancer by competitively regulating the JNK pathway.

It has been widely reported that long non-coding RNAs (lncRNAs) could affect the varieties of tumor response to radiotherapy. LncRNA HNF1A-AS1 is transcribed from HNF1A gene cluster's antisense strand. This work focused on the mechanism of how HNF1A-AS1 participated in the radiosensitivity of non-small cell lung cancer (NSCLC). The mRNA or protein expression of HNF1A-AS1, miR-92a-3p MAP2K4, and JNK in NSCLC cells and tissues was detected by qRT-PCR or western blotting. RNA immunoprecipitation (RIP) detection and luciferase reporting system were used to evaluate the relationship between HNFA-AS1 and miR-92a-3p or between miR-92a-3p and MAP2K4. Flow cytometry assays, colony formation, and MTT were performed to analyze the function changes in A549 and Calu-1 cells. The rescue experiment was also conducted to explore the underlying mechanisms. HNF1A-AS1 was investigated in NSCLC cells and tissues and highly related to the advanced pathological stage. HNF1A-AS1 bound with miR-92a-3p, which was downregulated in NSCLC. It showed that miR-92a-3p was negatively related to HNF1A-AS1. Knockdown of HNF1A-AS1 impacted most cell biological behaviors in NSCLC cells, including restricting the proliferation and aggravating apoptosis. Furthermore, knockdown of HNF1A-AS1 dramatically enhanced radiotherapy sensitivity of NSCLC. Moreover, miR-92a-3p was found to target MAP2K4 and could reduce MAP2K4 expression. Inhibition of HNF1A-AS1 elevated radiotherapy sensitivity and retarded the progression of NSCLC cells, followed by decreasing expression levels of MAP2K4. Besides, MAP2K4 mimic rescued the si-HNF1A-AS1 effects on the biological behavior of NSCLC cells. HNF1A-AS1 is highly expressed in NSCLC. MiR-92a-3p is the target gene of HNF1A-AS1 and involved in tumor progression by regulating the MAP2K4/JNK pathway. HNF1AS1/miR-92a-3p/MAP2K4 axis plays important roles in radiotherapy resistance of NSCLC.

Molecular and clinical assessment of maturity-onset diabetes of the young revealed low mutational rate in Moroccan families

BackgroundMaturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance. To offer an adequate patient management and therapeutic treatment for MODY patients, in addition to an early efficient diagnosis of their asymptomatic relatives, it is crucial to set an accurate molecular diagnosis. Hence, our aim was to determine the frequency of HNF1A and GCK genes among Moroccan-suspected MODY patients.MethodsTwenty suspected MODY patients were screened for HNF1A and GCK mutations using Sanger sequencing and MLPA methods. Segregation analysis of identified mutations was performed among family members. The pathogenic nature of missense variants was predicted using bioinformatic tools.ResultsA total of two mutations were revealed among all patients raising the diagnostic rate to 10%. We identified a large novel GCK deletion (c.209-?_1398+?del) by MLPA in one patient and a previously reported missense substitution (c.92G > A) in HNF1A gene.ConclusionThis is the first investigation to perform the molecular diagnosis of MODY suspected patients. Our findings constitute a primary contribution towards unraveling the genetic landscape involved in the pathogenesis of MODY disease in Morocco.

Hepatoprotective effect of Qushihuayu formula on non-alcoholic steatohepatitis induced by MCD diet in rat

BackgroundNon-alcoholic steatohepatitis (NASH) is an advanced form of non-alcoholic fatty liver disease (NAFLD) for which there is yet any standard pharmacotherapy. Traditional Chinese medicine formula such as Qushihuayu (QSHY) composing of multiple bioactive compounds has been used to treat NAFLD and NASH and shows beneficial effects over single compound treatment. This study aimed to investigate the mechanism of hepatoprotective effect of QSHY formula using a rat model.MethodsSix-weeks old male Wistar rats were given methionine/choline supplemented (MCS) diet for 8 weeks and used as the blank control. Another 7 rats, which received methionine/choline deficient (MCD) diet in the first 6 weeks and a MCS&MCD (1:1) mixture diet in the last 2 weeks, were used as the model group. The groups of QSHY pre-treatment, low dosage, medium dosage and high dosage were given the same diet as the model group. Except for pre-treatment group (1 week in advanced of other groups), all QSHY treatment groups received QSHY formula by gavage every day since the MCD diet started.ResultsIn the MCD diet group, the QSHY formula decreased the serum ALT and AST levels, lipid droplets, inflammation foci, FAS and α-SMA protein expression than MCD diet group. MAPK pathways phospharylation were markedly depressed by the QSHY formula. Moreover, QSHY formula enhanced PPAR-γ and p-p65 translocating into nucleus. The administration of QSHY increased hepatic mRNA levels of Transcription Factor 1 alpha (HNF1A), Hepatocyte Nuclear Factor 4 alpha (HNF4A) and Forkhead box protein A3 (FOXA3) which play a pivotal role in Hepatic stellate cell (HSCs) reprogramming.ConclusionThese findings suggest that QSHY formula exerts a hepatoprotective effect against steatosis and fibrosis presumably via depressed MAPK pathways phosphorylation, reinforcement of PPAR-γ and p-p65 translocating into nucleus and enhanced HSCs reprogramming.

Genetic characterization of suspected MODY patients in Pakistan by next generation sequencing—a pilot study

Maturity onset diabetes of the young (MODY) is the genetic form of diabetes inherited in autosomal dominant pattern. The diagnosis of MODY is challenging and confirmed by genetic testing. The objective of this study was to investigate MODY in Pakistani patients using next-generation sequencing. The next-generation sequencing was performed to know the cause of disease in 07 patients phenotypically suspected for MODY from Pakistan. These patients were selected based on the high probability score through MODY probability calculator. Only those genetic variants were retained which were having low frequency as per available data bases and their potential effects on protein as assessed by bioinformatics prediction tools. Four heterozygous variants were found among patients. This includes mutation in HNF1a gene (c.526+1G>A) that is already reported for causative for MODY type 3 which is most prevalent among all MODY sub-types. Other variants were identified in GCK (c.-45G>A), KLF11 (c.*96dupA), and CEL (c.1235C>T). This study was the first in Pakistan to investigate the MODY using next-generation sequencing for clinical applications. There is huge public health burden of diabetes in the country. The study identified mutation in one known MODY gene. More extensive studies involving large sample size are required in future.

Association between GCK gene polymorphism and gestational diabetes mellitus and its pregnancy outcomes

Gestational diabetes mellitus is defined as glucose intolerance which is first recognized during the pregnancy. The prevalence of gestational diabetes mellitus (GDM), one of the most common pregnant complications, has increased by more than 30% within one or two decades in a number of countries including developing countries. Glucokinase enzyme plays a key role in the regulation of glucose homeostasis. Our study is aimed to explore the association of GCK gene polymorphism and its pregnancy outcomes in GDM. Methodology: 210 pregnant women with GDM and 209 pregnant women without GDM were selected for study based on The Diabetes In Pregnancy Study group India criteria (DIPSI). DNA extraction was done using kit (Helini Biomolecule SNP) and was analyzed by Polymerase Chain Reaction (PCR). Pregnancy and fetal outcomes were collected from patient case sheet. Result: AA genotype and A allele are found to have higher risk of developing GDM. Pregnancy outcomes of respiratory syndrome were significant with GCK gene polymorphism. There was no association between cardio metabolic risk factor and GCK gene polymorphism.Conclusion: Pregnancy outcomes of respiratory syndrome were associated with GCK gene polymorphism and the polymorphism of GCK gene is associated with GDM. AA genotype and A allele were at higher risk of developing GDM. Cardio metabolic risk factor was not associated with GCK gene polymorphism.

Spatial and temporal distributions of forest fires in Heilongjiang Province from 2001 to 2018 based on MODIS data

Spatial and temporal distributions of forest fires in Heilongjiang Province from 2001 to 2018 based on MODIS data

The Mutation Spectrum of Maturity Onset Diabetes of the Young (MODY)-Associated Genes among Western Siberia Patients.

Maturity onset diabetes of the young (MODY) is a congenital form of diabetes characterized by onset at a young age and a primary defect in pancreatic-β-cell function. Currently, 14 subtypes of MODY are known, and each is associated with mutations in a specific gene: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1. The most common subtypes of MODY are associated with mutations in the genes GCK, HNF1A, HNF4A, and HNF1B. Among them, up to 70% of cases are caused by mutations in GCK and HNF1A. Here, an analysis of 14 MODY genes was performed in 178 patients with a MODY phenotype in Western Siberia. Multiplex ligation-dependent probe amplification analysis of DNA samples from 50 randomly selected patients without detectable mutations did not reveal large rearrangements in the MODY genes. In 38 patients (37% males) among the 178 subjects, mutations were identified in HNF4A, GCK, HNF1A, and ABCC8. We identified novel potentially causative mutations p.Lys142*, Leu146Val, Ala173Glnfs*30, Val181Asp, Gly261Ala, IVS7 c.864 −1G>T, Cys371*, and Glu443Lys in GCK and Ser6Arg, IVS 2 c.526 +1 G>T, IVS3 c.713 +2 T>A, and Arg238Lys in HNF1A.

Spatial-temporal variability of snow cover over the Amur River Basin inferred from MODIS daily snow products in recent decades

Spatial-temporal variability of snow cover over the Amur River Basin inferred from MODIS daily snow products in recent decades