Search

Abstract: Aims/hypothesis: MODY (Maturity Onset Diabetes of the Young) is an autosomal dominant inherited type of diabetes with significant genetic heterogeneity. New mutations causing MODY are still being found. A genetically confirmed diagnosis of MODY allows application of individualized treatment based on the underlying concrete genetic dysfunction. Detection of novel MODY mutations helps provide a more complete picture of the possible MODY genotypes. Materials and methods: We tested 43 adult Czech patients with clinical characteristics of MODY, using direct sequencing of HNF1A (hepatocyte nuclear factor 1-alpha), HNF4A (hepatocyte nuclear factor 4-alpha) and GCK (glucokinase) genes. Results: In three Czech families we identified three novel mutations we believe causing MODY—two missense mutations in HNF1A [F268L (c.802T>C) and P291S (c.871C>T)] and one frame shift mutation in GCK V244fsdelG (c.729delG). Some of the novel HNF1A mutation carriers were successfully transferred from insulin to gliclazide, while some of the novel GCK mutation carriers had a good clinical response when switched from insulin or oral antidiabetic drugs to diet. Conclusion: We describe three novel MODY mutations in three Czech families. The identification of MODY mutations had a meaningful impact on therapy on the mutation carriers. [Copyright &y& Elsevier]

The GCKR rs780094 and GCK rs1799884 polymorphisms have been reported to be associated with dyslipidaemia and type 2 diabetes in white Europeans. The aim of this study was to replicate these associations in Han Chinese individuals and to identify the potential mechanisms underlying these associations. The single nucleotide polymorphisms rs780094 and rs1799884 were genotyped in a population-based sample of Han Chinese individuals ( n = 3,210) and tested for association with risk of type 2 diabetes and related phenotypes. The GCKR rs780094 A allele was marginally associated with reduced risk of type 2 diabetes (OR 0.85, 95% CI 0.73–1.00, p value under an additive model [ p(add)] = 0.05) and significantly associated with reduced risk of impaired fasting glucose (IFG) or type 2 diabetes (OR 0.86, 95% CI 0.77–0.96, p[add] = 0.0032). It was also significantly associated with decreased fasting glucose and increased HOMA of beta cell function (HOMA-B) and fasting triacylglycerol levels ( p[add] = 0.0169–5.3 × 10−6), but not with HOMA of insulin sensitivity (HOMA-S). The associations with type 2 diabetes and IFG remained significant after adjustment for BMI, while adjustment for HOMA-B abolished the associations. The GCKR rs780094 was also associated with obesity and BMI, independently of its association with type 2 diabetes. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B ( p[add] = 0.0005), but not with type 2 diabetes or IFG. Individuals with increasing numbers of risk alleles for both variants had significantly lower HOMA-B ( p[add] = 5.8 × 10−5) in the combined analysis. Consistent with observations in white Europeans, the GCKR rs780094 polymorphism contributes to the risk of type 2 diabetes and dyslipidaemia in Han Chinese individuals. In addition, we showed that the effect on type 2 diabetes is probably mediated through impaired beta cell function rather than through obesity. [ABSTRACT FROM AUTHOR]

Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V ( APOA5), lipoprotein lipase ( LPL), and glucokinase ( GCK) genes with fasting glucose or lipid levels. The individuals analysed were participants in the Busselton Health Survey ( n = 4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data ( n = 2,864) used linear mixed-effects models. The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels ( p = 0.0003 and p < 0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels ( p = 0.0004) and raised HDL-C levels ( p = 0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level ( p = 0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age ( p = 0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time ( p = 0.0007). The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time. [ABSTRACT FROM AUTHOR]

The article provides clues for considering monogenic diabetes mellitus (DM) and genetic testing whenever facing a child with DM. DM is a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genes play an important role in the development of DM. Type 1 DM accounts for more than 95% of childhood and adolescence diabetes in most Western countries. Type 2 DM is considered a polygenic disorder with multiple genes located on different chromosomes. Meanwhile, monogenic DM results from the presence of one or more mutations in a single gene. Almost all cases of monogenic DM result from mutations in genes causing Β-cell loss or Β-cell dysfunction.

Glucokinase deficiency is an unfrequent cause of permanent neonatal diabetes (PND), as only seven patients have been reported, either homozygous for a missense or frameshift mutation or compound heterozygous for both of them. We report here the first known case caused by a homozygous nonsense mutation (Y61X) in the glucokinase gene ( GCK) that introduces a premature stop codon, generating a truncated protein that is predicted to be completely inactive as it lacks both the glucose- and the adenosine triphosphate-binding sites. The proband, born to consanguineous parents, was a full-term, intra-uterine growth-retarded male newborn who presented with a glycaemia of 129 mg/dL (7.16 mmol/L) on his second day of life, increasing thereafter up to 288 mg/dL (15.98 mmol/L) and 530 mg/dL (29.41 mmol/L) over the next 24 h, in the face of low serum insulin (<3 μIU/mL; <20.83 pmol/L). He was put on insulin on the third day of life. Insulin has never been discontinued since then. The patient was tested negative for anti-insulin and islet cell antibodies at age 5 months. His father had non-progressive, impaired fasting glucose for several years. The mother was found to be mildly hyperglycaemic only when her glucose was checked after the child was diagnosed. In conclusion, biallelic GCK loss should be considered as a potential cause of PND in children born to consanguineous parents, even if they are not known to be diabetic at the time of PND presentation. [ABSTRACT FROM AUTHOR]

Mutations in the GCK and HNF1A genes are the most common cause of the monogenic forms of diabetes known as ‘maturity-onset diabetes of the young’. GCK encodes the glucokinase enzyme, which acts as the pancreatic glucose sensor, and mutations result in stable, mild fasting hyperglycaemia. A progressive insulin secretory defect is seen in patients with mutations in the HNF1A and HNF4A genes encoding the transcription factors hepatocyte nuclear factor-1 alpha and -4 alpha. A molecular genetic diagnosis often changes management, since patients with GCK mutations rarely require pharmacological treatment and HNF1A/4A mutation carriers are sensitive to sulfonylureas. These monogenic forms of diabetes are often misdiagnosed as type 1 or 2 diabetes. Best practice guidelines for genetic testing were developed to guide testing and reporting of results. A workshop was held to discuss clinical criteria for testing and the interpretation of molecular genetic test results. The participants included 22 clinicians and scientists from 13 countries. Draft best practice guidelines were formulated and edited using an online tool (). An agreed set of clinical criteria were defined for the testing of babies, children and adults for GCK, HNF1A and HNF4A mutations. Reporting scenarios were discussed and consensus statements produced. Best practice guidelines have been established for monogenic forms of diabetes caused by mutations in the GCK, HNF1A and HNF4A genes. The guidelines include both diagnostic and predictive genetic tests and interpretation of the results. [ABSTRACT FROM AUTHOR]

Heterozygous mutations of glucokinase ( GCK) and hepatocyte nuclear factor-1 alpha ( HNF1A; also known as hepatic transcription factor 1 [ TCF1]) genes are the most common cause of MODY. Genomic deletions of the HNF1B (also known as TCF2) gene have recently been shown to account for one third of mutations causing renal cysts and diabetes syndrome. We investigated the prevalence of partial and whole gene deletions in UK patients meeting clinical criteria for GCK or HNF-1α/-4α MODY and in whom no mutation had been identified by sequence analysis. A multiplex ligation-dependent probe amplification (MLPA) assay was developed using synthetic oligonucleotide probes for 30 exons of the GCK, HNF1A and HNF4A genes. Partial or whole gene deletions were identified in 1/29 (3.5%) probands using the GCK MLPA assay and 4/60 (6.7%) of probands using the HNF1A/-4A MLPA assay. Four different deletions were detected: GCK exon 2, HNF1A exon 1, HNF1A exons 2 to 10 and HNF1A exons 1 to 10. An additional Danish pedigree with evidence of linkage to HNF1A had a deletion of exons 2 to 10. Testing other family members confirmed co-segregation of the deletion mutations with diabetes in the pedigrees. Large deletions encompassing whole exons can cause GCK or HNF-1α MODY and will not be detected by sequencing. Gene dosage assays, such as MLPA, are a useful adjunct to sequence analysis when a diagnosis of MODY is strongly suspected. [ABSTRACT FROM AUTHOR]

Monogenic diabetes results from one or more mutations in a single gene which might hence be rare but has great impact leading to diabetes at a very young age. It has resulted in great challenges for researchers elucidating the aetiology of diabetes and related features in other organ systems, for clinicians specifying a diagnosis that leads to improved genetic counselling, predicting of clinical course and changes in treatment, and for patients to altered treatment that has lead to coming off insulin and injections with no alternative (Glucokinase mutations), insulin injections being replaced by tablets (e.g. low dose in HNFα or high dose in potassium channel defects -Kir6.2 and SUR1) or with tablets in addition to insulin (e.g. metformin in insulin resistant syndromes). Genetic testing requires guidance to test for what gene especially given limited resources. Monogenic diabetes should be considered in any diabetic patient who has features inconsistent with their current diagnosis (unspecified neonatal diabetes, type 1 or type 2 diabetes) and clinical features of a specific subtype of monogenic diabetes (neonatal diabetes, familial diabetes, mild hyperglycaemia, syndromes). Guidance is given by clinical and physiological features in patient and family and the likelihood of the proposed mutation altering clinical care. In this article, I aimed to provide insight in the genes and mutations involved in insulin synthesis, secretion, and resistance, and to provide guidance for genetic testing by showing the clinical and physiological features and tests for each specified diagnosis as well as the opportunities for treatment. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM. Subjects and methods: We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-α (HNF1A, commonly known as MODY3) and 4-α (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women). Results: The A allele of the GCK -30G→A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06.1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21.3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001.1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08.1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM. Conclusions/interpretation: The -30G→A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women. [ABSTRACT FROM AUTHOR]

Abstract: Nck-interacting kinase-like embryo-specific kinase (NESK) is a protein kinase that is predominantly expressed in skeletal muscle during the late stages of mouse embryogenesis. NESK belongs to the germinal center kinase (GCK) family and selectively activates the c-Jun N-terminal kinase (JNK) pathway when overexpressed in cultured cells. Some members of the GCK family have been shown to be proteolytically cleaved and activated during apoptosis. Here, we report that NESK is also proteolytically cleaved during apoptosis. Treatment of NESK-transfected HeLa cells with TNF-α in the presence of cycloheximide or with staurosporine induced proteolytic cleavage of NESK. The cleavage of NESK occurred at two sites, generating three fragments: an N-terminal fragment containing a kinase domain, an intermediate fragment and a C-terminal fragment containing a regulatory CNH domain. These two cleavages occurred in a stepwise manner and were dependent on a caspase activity. The cleavage sites were identified as aspartic acid residues at 868 and 1091. The N-terminal fragment had less kinase activity than the full-length NESK and did not activate the JNK pathway. In contrast, the C-terminal fragment activated the JNK pathway more strongly than the full-length NESK and promoted TNF-α-induced apoptotic cell death. These results implicate NESK in the JNK pathway-mediated promotion of apoptosis through its C-terminal regulatory domain generated by proteolytic cleavage during apoptosis, in a unique manner different from other GCK family kinases. [Copyright &y& Elsevier]

Aims/hypothesis: C57BL/6J mice exhibit impaired glucose tolerance. The aims of this study were to map the genetic loci underlying this phenotype, to further characterise the physiological defects and to identify candidate genes. Methods: Glucose tolerance was measured in an intraperitoneal glucose tolerance test and genetic determinants mapped in an F2 intercross. Insulin sensitivity was measured by injecting insulin and following glucose disposal from the plasma. To measure beta cell function, insulin secretion and electrophysiological studies were car- ned out on isolated islets. Candidate genes were investigated by sequencing and quantitative RNA analysis. Results: C57BL/6J mice showed normal insulin sensitivity and impaired insulin secretion. In beta cells, glucose did not stimulate a rise in intracellular calcium and its ability to close KATP channels was impaired. We identified three genetic loci responsible for the impaired glucose tolerance. Nicotinamide nucleotide transhydrogenase (Nnt) lies within one locus and is a nuclear-encoded mitochondrial proton pump. Expression of Nnt is more than sevenfold and fivefold lower respectively in C57BL/6J liver and islets. There is a mis sense mutation in exon 1 and a multi-exon deletion in the C57BL/6J gene. Glucokinase lies within the Gluchos2 locus and shows reduced enzyme activity in liver. Conclusions/interpretation: The C57BL/6J mouse strain exhibits plasma glucose intolerance reminiscent of human type 2 diabetes. Our data suggest a defect in beta cell glucose metabolism that results in reduced electrical activity and insulin secretion. We have identified three loci that are responsible for the inherited impaired plasma glucose tolerance and identified a novel candidate gene for contribution to glucose intolerance through reduced beta cell activity. [ABSTRACT FROM AUTHOR]

Abstract: Congenital hyperinsulinism (CHI) is a genetically and phenotypically diverse syndrome. Key management issues involve early diagnosis by ensuring that appropriate samples are taken at the point of hypoglycaemia, prevention of recurrent hypoglycaemia, and detailed charcterisation of the clinical, biochemical, and genetic features of each case. Infants with persistent diazoxide resistant CHI require evaluation at specialist referral centres equipped to differentiate those with focal (fo-HI) and diffuse (di-HI) pancreatic disease. Fo-HI is treated with selective pancreatic resection but di-HI is treated by surgery only if intensive medical management regimes are not efficacious. [Copyright &y& Elsevier]

Background: Maturity-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., Methods: Twenty 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., Results: A total of two mutations were revealed among all patients raising the diagnostic rate to 10%. We identified a large novel GCK deletion (c.209-?&#95;1398+?del) by MLPA in one patient and a previously reported missense substitution (c.92G > A) in HNF1A gene., Conclusion: This 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., Competing Interests: The authors declare no conflict of interest., (© 2021 Publishing services provided by Elsevier B.V. on behalf of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.)

The transition from a fasted to a fed state is associated with extensive transcriptional remodeling in hepatocytes facilitated by hormonal- and nutritional-regulated transcription factors. Here, we use a liver-specific glucocorticoid receptor (GR) knockout (L-GRKO) model to investigate the temporal hepatic expression of GR target genes in response to feeding. Interestingly, in addition to the well-described fasting-regulated genes, we identify a subset of hepatic feeding-induced genes that requires GR for full expression. This includes Gck , which is important for hepatic glucose uptake, utilization, and storage. We show that insulin and glucocorticoids cooperatively regulate hepatic Gck expression in a direct GR-dependent manner by a 4.6 kb upstream GR binding site operating as a Gck enhancer. L-GRKO blunts preprandial and early postprandial Gck expression, which ultimately affects early postprandial hepatic glucose uptake, phosphorylation, and glycogen storage. Thus, GR is positively involved in feeding-induced gene expression and important for postprandial glucose metabolism in the liver. [Display omitted] • GR controls the expression of a subset of hepatic feeding-induced genes • Hepatic glucokinase (Gck) gene expression is positively regulated by GR • GR disruption leads to reduced preprandial RNAPII recruitment to the Gck promoter • Liver-specific GRKO impairs hepatic glucose uptake, phosphorylation, and utilization Præstholm et al. show that the glucocorticoid receptor (GR) controls a subset of temporally expressed genes in the liver. This includes many feeding-induced genes, such as Gck , encoding the glucokinase, a key enzyme in glucose metabolism. Acute GR disruption ultimately leads to reduced hepatic glucose uptake and storage. [ABSTRACT FROM AUTHOR]

True random number generators (TRNGs) based on flip‐flop (FF) metastability can suffer from sensitivity to frequency injection attacks. A dedicated attack can interfere with a FF's initial condition and influence the logical state or resolve time. These, in turn might result in significant keyspace reduction. Therefore, a novel TRNG utilising random timing of metastable FF is proposed. In this concept, a programmable delay line driven by a pseudo‐random generator with a random seed, changes continuously the phase between triggering signals (data and clock) and the global system clock. Nevertheless, the relative interval of clock and data active slopes remains constant and violates FF timing to ensure metastable (truly random) operation. [ABSTRACT FROM AUTHOR]

Aims: The study aimed to elucidate the effects of rare genetic variants on the risk of type 2 diabetes (T2D)., Materials and Methods: Weighted burden analysis of rare variants was applied to a sample of 200,000 exome-sequenced participants in the UK Biobank project, of whom over 13,000 were identified as having T2D. Variant weights were allocated based on allele frequency and predicted effect, as informed by a previous analysis of hyperlipidaemia., Results: There was an exome-wide significant increased burden of rare, functional variants in three genes, GCK, HNF4A and GIGYF1. GIGYF1 has not previously been identified as a diabetes risk gene and its product appears to be involved in the modification of insulin signalling. A number of other genes did not attain exome-wide significance but were highly ranked and potentially of interest, including ALAD, PPARG, GYG1 and GHRL. Loss of function (LOF) variants were associated with T2D in GCK and GIGYF1 whereas nonsynonymous variants annotated as probably damaging were associated in GCK and HNF4A. Overall, fewer than 1% of T2D cases carried one of these variants. In HNF1A and HNF1B there was an excess of LOF variants among cases but the small numbers of these fell short of statistical significance., Conclusions: Rare genetic variants make an identifiable contribution to T2D in a small number of cases but these may provide valuable insights into disease mechanisms. As larger samples become available it is likely that additional genetic factors will be identified., (© 2021 John Wiley & Sons Ltd.)

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed. [ABSTRACT FROM AUTHOR]

While the molecular events controlling insulin secretion from β-cells have been documented in detail, the exact mechanisms governing glucagon release by α-cells are understood only partially. This is a critical knowledge gap, as the normal suppression of glucagon secretion by elevated glucose levels fails in type 2 diabetes (T2D) patients, contributing to hyperglycemia through stimulation of hepatic glucose production. A critical role of glycolytic flux in regulating glucagon secretion was supported by recent studies in which manipulation of the activity and expression of the glycolytic enzyme glucokinase altered the setpoint for glucose-suppression of glucagon secretion (GSGS). Given this precedent, we hypothesized that genetic activation of glucokinase specifically in α-cells would enhance GSGS and mitigate T2D hyperglucagonemia. We derived an inducible, α-cell-specific glucokinase activating mutant mouse model (Gck LoxPGck∗/LoxPGck∗; Gcg-CreER T2 ; henceforth referred to as "α-mutGCK") in which the wild-type glucokinase gene (GCK) is conditionally replaced with a glucokinase mutant allele containing the ins454A activating mutation (Gck∗), a mutation that increases the affinity of glucokinase for glucose by almost 7-fold. The effects of α-cell GCK activation on glucose homeostasis, hormone secretion, islet morphology, and islet numbers were assessed using both in vivo and ex vivo assays. Additionally, the effect of α-cell GCK activation on GSGS was investigated under diabetogenic conditions of high-fat diet (HFD) feeding that dysregulate glucagon secretion. Our study shows that α-mutGCK mice have enhanced GSGS in vivo and ex vivo , independent of alterations in insulin levels and secretion, islet hormone content, islet morphology, or islet number. α-mutGCK mice maintained on HFD displayed improvements in glucagonemia compared to controls, which developed the expected obesity, glucose intolerance, elevated fasting blood glucose, hyperinsulinemia, and hyperglucagonemia. Using our novel α-cell specific activation of GCK mouse model, we have provided additional support to demonstrate that the glycolytic enzyme glucokinase is a key determinant in glucose sensing within α-cells to regulate glucagon secretion. Our results contribute to our fundamental understanding of α-cell biology by providing greater insight into the regulation of glucagon secretion through α-cell intrinsic mechanisms via glucokinase. Furthermore, our HFD results underscore the potential of glucokinase as a druggable target which, given the ongoing development of allosteric glucokinase activators (GKAs) for T2D treatment, could help mitigate hyperglucagonemia and potentially improve blood glucose homeostasis. • Inducible and cell type-specific point mutation in glucokinase enables analysis of glucose suppression of glucagon secretion. • Glycolytic flux through glucokinase determines the set-point for glucagon secretion in pancreatic α-cells. • Pancreatic α-cells are a physiologically relevant target of glucokinase activator drugs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Genetic detection for the diagnosis of maturity-onset diabetes of the young (MODY) in China has low sensitivity and specificity. Better gene detection is urgently needed to distinguish testing subjects. We proposed to use numerous and weighted clinical traits as key indicators for reasonable genetic testing to predict the probability of MODY in the Chinese population., Methods: We created a prediction model based on data from 306 patients, including 140 patients with MODY, 84 patients with type 1 diabetes (T1D), and 82 patients with type 2 diabetes (T2D). This model was evaluated using receiver operating characteristic curves., Results: Compared with patients with T1D, patients with MODY had higher C-peptide levels and negative antibodies, and most patients with MODY had a family history of diabetes. Different from T2D, MODY was characterized by lower body mass index and younger diagnostic age. A clinical prediction model was established to define the comprehensive probability of MODY by a weighted consolidation of the most distinguishing features, and the model showed excellent discrimination (areas under the curve of 0.916 in MODY vs T1D and 0.942 in MODY vs T2D). Further, high-sensitivity C-reactive protein, glycated hemoglobin A1c, 2-h postprandial glucose, and triglyceride were used as indicators for glucokinase-MODY, while triglyceride, high-sensitivity C-reactive protein, and hepatocellular adenoma were used as indicators for hepatocyte nuclear factor 1-α MODY., Conclusion: We developed a practical prediction model that could predict the probability of MODY and provide information to identify glucokinase-MODY and hepatocyte nuclear factor 1-α MODY. These results provide an advanced and more reasonable process to identify the most appropriate patients for genetic testing., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Background: Maturity onset diabetes of the young type 2 (MODY) is an inherited disorder due to mutations in glucokinase (GCK) gene, which lead to mild fasting hyperglycemia. Case Presentation: Herein an otherwise healthy 9-year old boy with hyperglycemia is presented in whom the diagnosis of MODY2 was suspected. Genetic studies showed heterozygous inactivating GCK gene mutation in exon 8 (c.1010delA) in this patient. The same mutation was found in his father as well. The patient received some dietary advices without any medication. Conclusion: The identification of GCK mutation and diagnosis of MODY2 helps the clinicians to predict the disease course, prognosis and to exclude other types of diabetes. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of the young type 2 (MODY2) is an autosomal dominant inherited disease caused by heterozygous inactivating mutations in the glucokinase ( GCK) gene and is characterized by mild non-insulin-dependent fasting hyperglycemia. It is treated with diet only, and complications are extremely rare. We present a report of a family with MODY2 caused by a novel NM_000162.3:c.878T>C mutation in exon 8 of the GCK gene. Testing for MODY2 and reporting all novel mutations are important to avoid difficulties in the interpretation of genetic test results and to provide fast and definitive diagnosis for all patients with this disease. [ABSTRACT FROM AUTHOR]

Objective: The aim of this article is to present a summary of the actual diagnostic possibilities and differentiation of MODY (Maturity-Onset Diabetes of the Young) from gestational diabetes (GDM) found during routine screening, and specific aspects of care and treatment of MODY during pregnancy and early postpartum period., Design: Rewiev., Settings: Centre for Research of Diabetes, Metabolism and Nutrition; Second Department of Internal Medicine University Hospital Královské Vinohrady and Third Faculty of Medicine, Prague. Department of Internal Medicine, Second Faculty of Medicine, Charles University, Prague., Methods: Recent publications selected in PubMed with the key words MODY, gestational diabetes., Results: Many patients with MODY, especially the glucokinase MODY, can be first diagnosed during pregnancy. It is estimated that MODY patients account for up to 5% of GDM cases found in routine screening of GDM. MODY should be considered in lean women around 25 years of age, with a positive family history of diabetes in one of the parents. The differentiation of MODY from GDM is of particular importance not only for the different management and goals of antidiabetic therapy and planning ultrasound controls of fetal growth during pregnancy, but also because of the risk of hyperinsulinemic hypoglycemia in newborns., Conclusion: Recognition of MODY during pregnancy and adherence to existing recommendations concerning specific care of these patients is essential for the optimal course of their pregnancy and proper care of the newborn in the early postpartum period.

Aims: Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Many patients with MODY2 in Asia have delayed timely treatment because they did not receive the correct diagnosis. This study aims to analyze the clinical characteristics and GCK mutations in Asian MODY2., Methods: We have collected 110 Asian patients with MODY2 from the PubMed, Embase, Medline, Web of Science, CNKI, and Wanfang with the following search terms: 'maturity-onset diabetes of the young' OR 'MODY' OR 'maturity-onset diabetes of the young type 2' OR 'MODY2' OR 'GCK-DM' OR 'GCK-MODY'. Both mutations of GCK and clinical characteristics of MODY2 were analyzed., Results: There were 96 different mutations that occurred in coding regions and non-coding regions. Exon 5 and 7 were the most common location in coding regions and missense was the primary mutation type. The proportion of probands younger than 25 was 81.8%, and 81.4% of the probands had family history of hyperglycaemia. Ninety percent and 93% of Asian MODY2 probands exhibited mild elevation in FPG (5.4-8.3 mmol/L) and HbA1c (5.6-7.6%), respectively., Conclusions: In most Asian patients, MODY2 occurred due to GCK mutation in coding regions, and exon 5 and 7 were the most common locations. FPG, HbA1c, and familial diabetes were important reference indicators for diagnosing MODY2. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c and family history of hyperglycaemia, molecular genetic testing is suggested in order to differentiate MODY2 from other types of diabetes earlier.

Backgrounds: Clopidogrel resistance (CR), which was manifested as the failure of platelet inhibition in clopidogrel treatment, was likely to lead to cardiovascular events. Our study was aimed to explore the contribution of DNA methylation in glucokinase (GCK) to the CR risk., Methods: Among 36 CR and 36 non-CR acute coronary syndrome (ACS) patients, the platelet functions were evaluated by VerifyNow P2Y12 assay (turbidimetric-based optical detection) and DNA methylation levels on two fragments of the CGI from the GCK were investigated through bisulfite pyrosequencing methods. In addition, the GCK mRNA expression was analyzed via quantitative real-time PCR. Lastly, the logistic regression was employed to test the interaction between GCK methylation and nongenetic variables in CR patients., Results: Subunit analysis showed that in male patients without DM but suffering from dyslipidemia, the increased methylation of cg18492943 indicated a risk of poor clopidogrel response (male, NCR vs CR(%): 84.86 ± 6.29 vs 88.16 ± 4.32, P = .032; without DM, NCR vs CR (%): 84.66 ± 6.18 vs 88.16 ± 4.17, P = .029; and dyslipidemia, NCR vs CR (%): 83.81 ± 6.96 vs 88.39 ± 4.74, P = .042).In addition, GCK mRNA expression was reduced in CR patients without DM. Moreover, regression analysis indicated that the values of platelet distribution width (PDW), total cholesterol (TC), and uric acid (UA) were correlated with the incidence of CR, and hypertension lowered the CR risk., Conclusions: A higher methylation of cg18492943 in GCK gene would lower the expression of GCK mRNA, which might contribute to CR in patients without DM. Meanwhile, PDW and TC might be risk factors in CR., (© 2019 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Background: Neonatal diabetes mellitus (NDM) is a rare condition that occurs within the first six months of life. Permanent NDM (PNDM) is caused by mutations in specific genes that are known for their expression at early and/or late stages of pancreatic beta‐ cell development, and are either involved in beta‐cell survival, insulin processing, regulation, and release. The native population in Qatar continues to practice consanguineous marriages that lead to a high level of homozygosity. To our knowledge, there is no previous report on the genomics of NDM among the Qatari population. The aims of the current study are to identify patients with NDM diagnosed between 2001 and 2016, and examine their clinical and genetic characteristics. Methods: To calculate the incidence of PNDM, all patients with PNDM diagnosed between 2001 and 2016 were compared to the total number of live births over the 16‐year‐period. Whole Genome Sequencing (WGS) was used to investigate the genetic etiology in the PNDM cohort. Results: PNDM was diagnosed in nine (n = 9) patients with an estimated incidence rate of 1:22,938 live births among the indigenous Qatari. Seven different mutations in six genes (PTF1A, GCK, SLC2A2, EIF2AK3, INS, and HNF1B) were identified. In the majority of cases, the genetic etiology was part of a previously identified autosomal recessive disorder. Two novel de novo mutations were identified in INS and HNF1B. Conclusion: Qatar has the second highest reported incidence of PNDM worldwide. A majority of PNDM cases present as rare familial autosomal recessive disorders. Pancreas associated transcription factor 1a (PTF1A) enhancer deletions are the most common cause of PNDM in Qatar, with only a few previous cases reported in the literature. [ABSTRACT FROM AUTHOR]

Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is an autosomal dominant disorder caused by heterozygous inactivating GCK gene mutations. GCK-MODY is one the most common MODY subtypes, affecting 0.1% of the population and 0.4-1% of women with gestational diabetes mellitus. Glucokinase is predominantly expressed in pancreatic beta cells and catalyzes the phosphorylation of glucose to glucose-6-phosphate. The unique kinetics of glucokinase enable it to change the rate of glucose phosphorylation according to the glucose concentration, thereby regulating insulin secretion. Individuals with GCK-MODY have mildly elevated fasting blood glucose levels (5.5-8.0 mmol/L) and regulate glucose perturbations to a higher set-point, resulting in a relatively flat glucose profile on a 75 g oral glucose tolerance test. The hyperglycemia is usually subclinical and may only be detected on incidental glucose testing. It is important to correctly identify GCK-MODY as the clinical course and management differs substantially from other types of diabetes. Diabetes-related complications are relatively uncommon, so glucose-lowering treatment is not usually required. The exception is pregnancy, where fetal growth and therefore glucose-lowering treatment are predominantly determined by whether or not the fetus inherits the GCK mutation. The fetal genotype is not usually known but can be inferred from serial fetal ultrasound measurements. If there is evidence of accelerating fetal abdominal circumference on serial ultrasounds, the fetus is assumed to not have the GCK mutation and treatment of maternal hyperglycemia is indicated to reduce the risk of macrosomia, Caesarean section and neonatal hypoglycemia. If there is no evidence of accelerating fetal growth, the fetus is assumed to have inherited the GCK mutation and will have a similarly elevated glucose set-point as their mother, so maternal hyperglycemia is not treated. With recent advances in genetic technology, such as next-generation sequencing and noninvasive fetal genotyping, the detection and management of GCK-MODY in pregnancy should continue to improve., Competing Interests: The author reports no conflicts of interest in this work.

Background: GCK gene variants have been reported to be associated with gestational diabetes mellitus (GDM) in the Caucasian population. There are no reports exploring this association in the Indian population. Methods: This cross-sectional study included subjects from Max Super Speciality Hospital, New Delhi, India, over a span of 6 months. Females diagnosed with GDM as per the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria were enrolled. Direct gene sequencing was performed to screen all 10 exons and promoter region of GCK gene. Results: Out of the total 1000 females screened, 154 subjects had any degree of hyperglycemia. GCK gene screening was done and we observed 11 variants in 80.4% (41/51) of the GDM subset and 89.6% (43/48) of the controls. Allele frequencies of observed variants were not different between the control subjects (12.5%) and those diagnosed with GDM (8.4%). Conclusion: To the best of our knowledge, this is the first report from north India exploring association of GCK variants with GDM and we do not observe any association of GCK variants with GDM in our study population. CTRI Registration No: CTRI/2017/07/008964 [ABSTRACT FROM AUTHOR]

Aims and Hypothesis: A significant amount of pregnant women develop gestational diabetes mellitus (GDM) during their pregnancies and the prevalence has increased considerably during the last decade. GDM is a heterogeneous disorder characterized by intolerance to carbohydrates and hyperglycemia in varied degrees of intensity, with onset of first diagnosis during pregnancy. This work is focusing on genes, common to both type 2 diabetes and gestational diabetes. Methods: DNA was extracted from peripheral blood leukocyte using salting out method. Genotyping of 30G>A in GCK, Ala 98 Val in HNF1A and Glu 23 Lys in KCNJ11 genes were performed in 77 non diabetic control pregnant women and 58 GDM subjects using PCR coupled restriction fragment length polymorphism analysis. Results: GCK-30G>A allele frequency in GDM (18.1%) was increased compare to non-diabetic control pregnant women (14.8%) (odds ratio [OR] 1.28 [95% CI 1.02-1.35]), where HNF1A Ala 98 Val polymorphism was not associated with GDM but Leu 27 polymorphism in GDM (36.3%) compare with non-diabetic control pregnant women (33.01%) shows borderline significance (odds ratio [OR] 1.16 [95% CI 1.001-1.34]). In case of KCNJ11 gene Glu 23 Lys polymorphism is associated with GDM (42.2%) compare to normal pregnancy (38.3%) (odds ratio [OR] 1.17[95% CI 1.02-1.35]). Conclusion: The 30G>A polymorphism in GCK, Leu 27 polymorphism in HNF1A and Glu 23 Lys polymorphism in KCNJ11 gene are seems to increase the risk of GDM in Eastern Indian Population. [ABSTRACT FROM AUTHOR]