Glucokinase and glucose homeostasis: proven concepts and new ideas

2005 ◽  
Vol 33 (1) ◽  
pp. 306-310 ◽  
Author(s):  
D. Zelent ◽  
H. Najafi ◽  
S. Odili ◽  
C. Buettger ◽  
H. Weik-Collins ◽  
...  

The enzyme GK (glucokinase), which phosphorylates glucose to form glucose 6-phosphate, serves as the glucose sensor of insulin-producing β-cells. GK has thermodynamic, kinetic, regulatory and molecular genetic characteristics that are ideal for its glucose sensor function and allow it to control glycolytic flux of the β-cells as indicated by control-, elasticity- and response-coefficients close to or larger than 1.0. GK operates in tandem with the K+ and Ca2+ channels of the β-cell membrane, resulting in a threshold for glucose-stimulated insulin release of approx. 5 mM, which is the set point of glucose homoeostasis for most laboratory animals and humans. Point mutations of GK cause ‘glucokinase disease’ in humans, which includes hypo- and hyper-glycaemia syndromes resulting from activating or inactivating mutations respectively. GK is allosterically activated by pharmacological agents (called GK activators), which lower blood glucose in normal animals and animal models of T2DM. On the basis of crystallographic studies that identified a ligand-free ‘super-open’ and a liganded closed structure of GK [Grimsby, Sarabu, Corbett and others (2003) Science 301, 370–373; Kamata, Mitsuya, Nishimura, Eiki and Nagata (2004) Structure 12, 429–438], on thermostability studies using glucose or mannoheptulose as ligands and studies showing that mannoheptulose alone or combined with GK activators induces expression of GK in pancreatic islets and partially preserves insulin secretory competency, a new hypothesis was developed that GK may function as a metabolic switch per se without involvement of enhanced glucose metabolism. Current research has the goal to find molecular targets of this putative ‘GK-switch’. The case of GK research illustrates how basic science may culminate in therapeutic advances of human medicine.

2019 ◽  
pp. 282-288
Author(s):  
Viktor Klimenko

Проведен обзор научно-исследовательских работ по методологии клоновой селекции винограда. Анализируются различные определения термина «клон винограда». Рассмотрены возможные причины возникновения клонов: точковые мутации, поликлональное происхождение, модификации. Поддерживающий отбор, используемый для сохранения чистоты, типичности сорта и его хозяйственно ценных свойств, способствует очищению сорта от отрицательных клонов и созданию выровненных насаждений. Для улучшения существующих сортов винограда используется направленный отбор и размножение нетипичных, ценных в биолого-хозяйственном отношении форм растений. Также одной из задач отбора должна быть задача восстановления сортов. Идентификация отличий нового клона нуждается в индивидуальном подходе в зависимости от свойства: мутации и полиплоидия, качественные и количественные признаки . У винограда химерность тканей и клеток является распространенным явлением, многие сорта виноградной лозы являются периклинальными химерами. Приведены варианты отличий маточного куста от исходного сорта, необходимых и достаточных для выделения клона в первом вегетативном поколении. С генетической точки зрения, к основным признакам для клонового отбора винограда обоснованно следует отнести признаки, наследование которых установлено и существенно. Поскольку при работе с клонами приходится принимать во внимание большое количество признаков, представляется эффективным использование многомерных моделей изменчивости. Отмечена перспективность развития методов молекулярной генетики, позволяющих идентифицировать плоидность и генетические различия между растениями, но изучение клонов такими методами пока не получило широкого распространения. Рассматриваются возможности использования в клоновой селекции винограда биотехнологических методов. Недостатком клонового отбора является однородность виноградников и продукции в дополнение к генетической эрозии. Поэтому изменчивость в пределах отдельных сортов должна поддерживаться путем отбора различных клонов, и в виноградарстве, наряду с клоновой селекцией, обязательно должна иметь место генеративная селекция. Таким образом, клон в виноградарстве - это идентичное по генотипу и фенотипу вегетативное потомство растения, выделенного в насаждениях какого-либо сорта винограда и отличающегося от типичных кустов исходного сорта по характеристикам, сохраняющимся при вегетативном размножении. Клоновая селекция винограда перспективна, чему способствуют генетические особенности этой культуры: большая частота спонтанных мутантов, наличие сортов с достаточно широкой генетической изменчивостью, вегетативное размножение, позволяющее сохранять каждое отклонение на неограниченное время.A review of research work on the methodology of clone selection of grapes was carried out. Various definitions of the term ‘grape clone’ are analyzed. Possible causes for the emergence of clones are discussed: point mutations, polyclonal origin, modifications. Recurrent selection used to preserve the purity and typicality of a variety and its economically valuable traits promotes cleansing the variety from negative clones and creating uniform plantings. To improve existing grape varieties, directional selection and propagation of atypical, biologically and economically valuable plant forms are used. Also, restoration of varieties should be one of selection tasks. The identification of different features of a new clone needs an individual approach depending on the properties: mutations and polyploidy, qualitative and quantitative traits. Chimerism of tissues and cells is common in grapes; many varieties of grapevines are periclinal chimeras. Variants of differences between the clone mother vine and the initial variety which are necessary and sufficient for clone selection in the first vegetative generation are presented. From the genetic point of view, main traits for clone selection of grapes should reasonably include traits whose inheritance is essential and has been established. Since a large number of traits have to be taken into account when working with clones, it seems efficient to use multidimensional models of variability. It is noted that development of molecular genetic methods has good prospects since they make it possible to identify ploidy and genetic differences between plants, but the study of clones by such methods has not yet become widespread. The possibilities of using biotechnological methods in clone selection of grapes are discussed. In addition to genetic erosion, the uniformity of vineyards and products enters as a weak point of clone selection. Therefore, the variability within individual varieties should be maintained by selection of various clones, and, along with clone selection, generative breeding must necessarily take place in viticulture. Thus, a clone in viticulture is a vegetative offspring of a plant selected in the plantings of any grape variety and differing from typical vines of the initial variety in terms of characteristics preserved during vegetative propagation. Plants of a clone are identical in genotype and phenotype. Clone selection of grapes is promising, which is facilitated by genetic characteristics of this crop: a high frequency of spontaneous mutants, existence of varieties with a fairly wide genetic variability, vegetative propagation which allows to preserve each deviation for an unlimited time.


2019 ◽  
Vol 65 (4) ◽  
pp. 268-272
Author(s):  
Natalia Yu. Kalinchenko ◽  
Anna A. Kolodkina ◽  
Vasiliy M. Petrov ◽  
Evgeniy V. Vasiliev ◽  
Anatoly N. Tiulpakov

Androgen insensitivity syndrome is an X-linked disorder characterized by either complete or partial insensitivity of target tissues to androgens. This disease is caused by mutations in the AR gene located on the Х chromosome. Currently, there are no distinct clinical, biochemical, or hormonal markers that would allow one to differentiate androgen insensitivity syndrome from a number of other forms of 46,XY disorders of sex development. Therefore, final verification of this condition is based on the results of molecular genetic tests. Although more than 1,000 point mutations in the AR gene have been reported, somatic mutations in this gene have been described rather rarely. However, this very type of mutations makes the course of this disease difficult to predict, since various cells in the human body contain both normal and mutant receptors. Somatic mosaicism can cause spontaneous masculization during puberty in individuals born with a completely normal female phenotype. In this case report, we describe the phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene.


2009 ◽  
Vol 55 (3) ◽  
pp. 3-7 ◽  
Author(s):  
I I Dedov ◽  
Natal'ya Anatol'evna Zubkova ◽  
N Yu Arbatskaya ◽  
A G Akopova ◽  
A N Tyul'pakov

Maturity-onset diabetes of the young (MODY) is a clinically heterogenic group of diseases, with an autosomal dominant mode of inheritance and gene mutations resulting in dysfunction of pancreatic β cells. The type of diabetes and further treatment policy can be reliably determined on the basis of the data of a molecular genetic study that confirms gene mutations. Today there are known mutations of 8 genes, of which glucokinase (GCK) gene mutation that leads to the development of MODY2 and occurs most frequently. The spread of this mutation among DM patients in our country has not been studied. The diagnosis of MODY2 was established in 13 members of 5 families with the clinical picture typical of this type. The molecular genetic study revealed 4 new and 1 earlier described mutations. The findings extend ideas on the molecular bases of MODY, which creates conditions for improving the diagnosis of this disease, genetic counseling and the development of pathogenetically founded approaches to treatment.


2017 ◽  
pp. 132-138
Author(s):  
O.V. Paliychuk ◽  
◽  
L.Z. Polishchuk ◽  
Z.I. Rossokha ◽  
◽  
...  

The objective: determining gene polymorphism features ERS1, CYP2D6 in patients with breast cancer (RHZ) and endometrial cancer (EC) and the impact assessment studied genetic characteristics compared to receptor status (immunohistochemical determination of expression levels of ER, PR) tumors and the results of the treatment. Patients and methods. article presents the results of complex clinical, morphological, clinical-genealogical, and molecular-genetic examination of 28 females: 19 patients with breast cancer (BC), 9 patients with endometrial cancer (EC), including 5 patients with primary-multiple tumors (PMT) with and without tumor pathology aggregation in families. Results. The It was determined that in patients’ families malignant tumors of breast, uterine body and/or ovaries prevail that corresponds to Lynch type II syndrome (family cancer syndrome). Molecular-genetic examination of genomic DNA of peripheral blood and histological sections for the presence of SNPs of ESR and CYP2D6*4 genes comparing with the results of immunohistochemical study of tumors for receptors ER and PR status have not found associations between these characteristics; although among EC patients the occurrence of genotypes 397ТТ and 351АА was significantly higher comparing with BC patients (55.55% and 10.5% for genotype 397ТТ,and 15.8% for genotype 351АА, respectively). At the same time the patients with BC and primary-multiple tumors (PMT) of female reproductive system organs (FRSO) that carried mutations in BRCA1 in all the cases demonstrated positive ER and PR receptor status and adverse combinations of polymorphous variants of the genes ESR1 (397СС, 397ТС) and CYP2D6*4 (1846G, 1846GA), suggesting combined effect of these factors on the development of malignant neoplasias of FRSO in families with positive family cancer history. In BC patients, receiving standard hormone therapy with tamoxifen, those, who had genotype 1846GG of the gene CYP2D6*4, in 3 patients (15.8%) of 19 (100%) patients disease recurrence was diagnosed. Conclusion. The obtained results allow clinical use of the assessment of polymorphism frequency of the genes ESR1 and CYP2D6*4 for selection of individual hormone therapy regimens schemes for BC patients, to increase efficacy of dispensary observation after finishing of special therapy for such patients, and also personalization of complex and combined treatment regimens. Key words: breast cancer, endometrial cancer, family cancer syndrome, single nucleotide polymorphisms (SNPs) of the genes ESR1, CYP2D6*4.


GYNECOLOGY ◽  
2018 ◽  
Vol 20 (1) ◽  
pp. 113-116
Author(s):  
L A Bagdasaryan ◽  
I E Korneyeva

The aim of the study is to systematically analyze the data available in the modern literature on the relationship between endometrial thickness and the frequency of pregnancy in the program of assisted reproductive technologies (ART). Materials and methods. The review includes data from foreign and domestic articles found in PubMed on this topic. Results. The article presents data on the relationship between the thickness of the endometrium and the frequency of pregnancy in ART programs. The greatest number of studies is devoted to the evaluation of the relationship between the thickness of the endometrium and the frequency of pregnancy on the day of the ovulation trigger. Data are presented on the existence of a correlation between the thickness of the endometrium measured on the day of the ovulation trigger and the frequency of clinical pregnancy, as well as data on the need to evaluate the structure of the endometrium and the state of subendometric blood flow. The importance of multilayered (three-layered) endometrium as a prognostic marker of success in in vitro fertilization/intracytoplasmic sperm injection programs in the ovum is emphasized. The conclusion. The thickness of the endometrium can not be used as an argument for canceling the cycle or abolishing embryo transfer to the uterine cavity. Further studies in this direction are needed with a study of the morphological and molecular genetic characteristics of the endometrium, which in the future will allow us to evaluate the relationship between the thickness of the endometrium and the probability of pregnancy.


2021 ◽  
Vol 100 (2) ◽  
pp. 40-48
Author(s):  
A.G. Rumyantsev ◽  
◽  
A.G. Rumyantsev ◽  
O.M. Demina ◽  
◽  
...  

It has been shown that the inflammatory response in acne develops at the early subclinical stages of the disease, sometimes before the formation of comedones. It is known that an important component of the innate immune system is the complement system, which includes more than 60 components, including 9 basic proteins (C1-C9), a variety of activation products (C3a, C3b, iC3b, C3d and C3dg), regulatory and inhibitory molecules [factor H, fH-like protein 1 (FHL1), CR1 (CD35), C4b-binding protein (C4BP), C1inh and vitronectin], proteases and secreted enzymes (factor B, factor D, C3bBb and C4bC2b), as well as receptors for effector molecules [C3aR, C5aR, C5L2 and C1q receptor (C1qR)]. The compliment is the central part of innate immunity, which is the first line of protection against alien and altered host cells. The objectives of this study were to determine and analyze the variants of the nucleotide sequence of the genes of the complement system C1QA, C1S, C2, C3, C5, C6, C7, C8A, C8B, C8G, C9 in patients with severe acne. Materials and methods of research: To achieve the target a prospective open non-randomized one-center study was carried out in 2017–2020. Under our supervision in the clinical setting at the Department of Skin Diseases and Cosmetology of the Pirogov Russian National Research Medical University, there were 50 patients in the main group and 20 participants in the comparison group (70 people in total) (42/60% men and 28/40% women) aged 15 to 46 years (median – 22,1 years). Molecular genetic diagnostics was performed in all 70 patients of the main and control groups by the method of high-throughput DNA sequencing – next-generation sequencing (NGS). Results: when analyzing the nucleotide sequence variants of the complement system genes identified in our study, it is shown that the severe form of acne probably has an association (4 SNPs of the C8A gene, 1 SNPs of the C8B gene, 2 SNPs of the C1S gene, 3 SNPs of the C3 gene, 2 SNPs of the C9 gene, 1 SNPs of the C7 gene, 1 SNPs of the C6 gene, 1 SNPs of the C2 gene, 2 SNPs of the C5 gene, 2 SNPs of the C8G gene), 13 SNPs of the complement system genes in introns (1 SNPs of the C8A gene, 1 SNPs of the C8B gene, 2 SNPs of the C1S gene, 1 SNPs of the C3 gene, 1 SNPs of the C7 gene, 2 SNPs of the C6 gene, 4 SNPs of the C5 gene, 1 SNPs of C8G gene), 6 SNPs of the complement system genes (2 SNPs of the C8B gene: one SNPs each in the 3'UTR and 5'UTR zones; 3 SNPs of the C3 gene in the 5'UTR zone, 1 SNPs of the C7 gene in the 3'UTR zone). Two mutations of the frame shift of the C2 gene (frameshift deletion) and the C9 gene (rs748464075, frameshift insertion) seem to have a protective effect in the development of acne. Conclusion: the obtained variants of the nucleotide sequence of the genes of the complement system C1QA, C1S, C2, C3, C5, C6, C7, C8A, C8B, C8G, C9, apparently, are associated with the formation of severe acne and cause an imbalance of the components of the complement system. It can cause a defect in chemotactic and phagocytic reactions, and as a result a disturbance of the regulation of the inflammatory reaction with chronization of the skin process occures. Thus, results of studies carried out, revealed – for the first time – polymorphic loci of genes of components of the complement system, the imbalance of which is the pathophysiological mechanism of acne.


2021 ◽  
Vol 31 (2) ◽  
pp. 148-158
Author(s):  
A. Yu. Voronkova ◽  
Yu. L. Melyanovskaya ◽  
N. V. Petrova ◽  
T. A. Adyan ◽  
E. K. Zhekaite ◽  
...  

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.


2021 ◽  
Vol 29 (1) ◽  
pp. 5-12
Author(s):  
Grigorii I. Yakubovskii ◽  
Olga B. Serebriakova ◽  
Alina G. Yakubovskaya ◽  
Nadezhda V. Ruban ◽  
Angelina A. Lyakhovets

Aim. This investigation seeks to determine the incidence of phenylketonuria in the Ryazan region, assess the spectrum of mutations in the PAH gene (phenylalanine hydroxylase), investigate the interrelationship between the diseases clinical course, the phenylalanine blood level, and the patients genotype. Materials and Methods. The incidence of phenylketonuria was studied based on the data of massive neonatal screening for the period from 2000 to 2019. Molecular genetic examination of mutations was conducted in 39 patients using the allele-specific multiplex ligation method. The interrelationship between the phenylalanine blood level on the fifth day of life and retest, the diseases clinical course, and the patients genotype was assessed according to the medical record data of 33 patients under dispensary observation in a medico-genetic clinic. The patients were divided into two groups. The first group (n=21) had two severe mutations (residual activity of phenylalanine hydroxylase 10%). The second group (n=12) had one severe and one mild mutation (the residual activity of the enzyme 10%). Results. The incidence of phenylketonuria in the Ryazan region was one in 5054 newborns, exceeding the Russian Federations average parameters. Eighteen mutations were discovered in the PAH gene. The most frequent was the R408W mutation (56.4% alleles). The second most frequent mutations were the IVS10-11GA (6.4%) and P281L (5.1%). The R158Q and Y418C mutations occurred with a frequency of 4.1% and Е280К mutation of 2.7%. All the rest of the mutations occurred as single cases. Investigation of the interrelationship between the phenylalanine blood level, the diseases clinical course, and the patients genotype revealed a reliably higher content of amino acid in the first group on retest (32.11.7 mg/% vs. 17.71.5 mg/% in the second group, р0.001) and predomination of more severe forms of phenylketonuria (90.5% vs. 41.7%, respectively, р0.001). Disorders in neuropsychic and speech development were present in 28.6% of patients in the first group but were absent in the second group. Conclusion. By conducting the study, the incidence of phenylketonuria was determined in the Ryazan region. The spectrum of mutations in the PAH gene was defined. The interrelationship between the diseases clinical portrait, the phenylalanine blood level, and the patients PAH genotype was revealed.


2004 ◽  
Vol 40 (1) ◽  
pp. 1-9 ◽  
Author(s):  
E. E. Kulikov ◽  
A. P. Buzhilova ◽  
A. B. Poltaraus

Author(s):  
E.A. Bazykina ◽  
V.B. Turkutyukov ◽  
O.E. Trotsenko ◽  
V.O. Kotova ◽  
L.A. Balakhonsteva ◽  
...  

We conducted a comparative analysis of the parenteral viral hepatitis B and C (HBV and HCV) prevalence and their molecular genetic characteristics among prisoners of persons diagnosed with HIV infection (41 samples), HIV-positive free citizens (187 samples) and «conditionally healthy population» with the lack of information about the presence of a diagnosis of chronic viral hepatitis of any etiology and HIV infection (231 samples). Immunological and molecular biological research methods were used. Obtained data analysis showed that the prevalence of infection markers with viruses of parenteral hepatitis was significantly higher in the groups of HIV-positive individuals (imprisoned and freemen). The HBsAg-negative form of the disease was determined among the HIV-positive free population and in the «conditionally healthy population». Over the past 10 years (2009–2018), the proportion of HIV-positive prisoners in custody of people with HCV monoinfection doubled, HBV was increased in 8.7 times. Significant decrease in the combined infection of HBV and HCV of this contingent was found. Given this decrease in the penitentiary system in HIV-positive individuals, the overall burden of HBV infection (both in mono form and coinfection with HCV) significantly (5.3 times) decreased , which can be attributed to successful widespread vaccination against hepatitis B in Russia. The most common HCV genotypes among HIV-positive individuals were 1b and 3a, genotypic structure of HBV prevailed genotype D.


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