RESUMO
AIMS: We evaluated the involvement of lncRNAs in the development of pathologies associated with chronic hyperglycaemia in rat models in a model of type 1, type 2 and gestational diabetes. METHODS: Reports were searched in Dialnet, Scielo, HINARI, Springer, ClinicalKey, OTseeker, PubMed and different grey literature databases with any restrictions. Bibliography databases will be searched from their inception to December 2022. RESULTS: Thirty-seven studies met our criteria, and they had the following characteristics: original experimental studies on diabetes, the lncRNAs were extracted or measured from tissues of specific areas and the results were expressed in terms of standard measures by RT-PCR. In most studies, both primary and secondary outcomes were mentioned. On the other hand, we found a total of nine diabetic complications, being retinopathy, nephropathy and neuropathy the most representatives. Additionally, it was found that MALAT1, H19, NEAT1 and TUG1 are the most studied lncRNAs about these complications in rats. On the other hand, the lncRNAs with the highest rate of change were MSTRG.1662 (17.85; 13.78, 21.93), ENSRNOT00000093120_Aox3 (7.13; 5.95, 8.31) and NONRATG013497.2 (-5.55; -7.18, -3.93). CONCLUSIONS: This review found a significant involvement of lncRNAs in the progression of pathologies associated with chronic hyperglycaemia in rat models, and further studies are needed to establish their potential as biomarkers and therapeutic targets for diabetes.
Assuntos
Diabetes Mellitus , Hiperglicemia , RNA Longo não Codificante , Animais , Ratos , RNA Longo não Codificante/genética , Hiperglicemia/genética , BiomarcadoresRESUMO
OBJECTIVE: Intriguingly, hyperinsulinemia, and hyperglycemia can predispose insulin resistance, obesity, and type 2 diabetes, leading to metabolic disturbances. Conversely, physical exercise stimulates skeletal muscle glucose uptake, improving whole-body glucose homeostasis. Therefore, we investigated the impact of short-term physical activity in a mouse model (Slc2a4+/-) that spontaneously develops hyperinsulinemia and hyperglycemia even when fed on a chow diet. METHODS: Slc2a4+/- mice were used, that performed 5 days of endurance or strength exercise training. Further analysis included physiological tests (GTT and ITT), skeletal muscle glucose uptake, skeletal muscle RNA-sequencing, mitochondrial function, and experiments with C2C12 cell line. RESULTS: When Slc2a4+/- mice were submitted to the endurance or strength training protocol, improvements were observed in the skeletal muscle glucose uptake and glucose metabolism, associated with broad transcriptomic modulation, that was, in part, related to mitochondrial adaptations. The endurance training, but not the strength protocol, was effective in improving skeletal muscle mitochondrial activity and unfolded protein response markers (UPRmt). Moreover, experiments with C2C12 cells indicated that insulin or glucose levels could contribute to these mitochondrial adaptations in skeletal muscle. CONCLUSIONS: Both short-term exercise protocols were efficient in whole-body glucose homeostasis and insulin resistance. While endurance exercise plays an important role in transcriptome and mitochondrial activity, strength exercise mostly affects post-translational mechanisms and protein synthesis in skeletal muscle. Thus, the performance of both types of physical exercise proved to be a very effective way to mitigate the impacts of hyperglycemia and hyperinsulinemia in the Slc2a4+/- mouse model.
Assuntos
Diabetes Mellitus Tipo 2 , Hiperglicemia , Resistência à Insulina , Camundongos , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Músculo Esquelético/metabolismo , Hiperglicemia/genética , Hiperglicemia/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismoRESUMO
BACKGROUND: Diabetes mellitus is the most common metabolic alteration in gestation. Monogenic diabetes or Maturity-Onset Diabetes of the Young (MODY) is a subtype caused by a primary defect in insulin secretion determined by autosomal dominant inheritance. OBJECTIVES: This study aimed to analyze molecular changes of the Glucokinase gene (GCK) in pregnant women with hyperglycemia during gestation and in their neonates. Case Study and Methods: We collected 201 blood samples, 128 from pregnant patients diagnosed with hyperglycemia and 73 from umbilical cord blood from neonates of the respective patients. DNA extraction and polymerase chain reaction (PCR) were performed to identify molecular changes in the GCK gene. RESULTS: In a total of 201 samples (128 from mothers and 73 from neonates), we found changes in 21 (10.6%), among which 12 were maternal samples (6.0%) and 9 were neonatal samples (4.5%). DNA sequencing identified two polymorphisms and one deleterious MODY GCK-diagnostic mutation. CONCLUSION: The prevalence of molecular changes in the Glucokinase gene (GCK) and the deleterious MODY GCK-diagnostic mutation were 9.3% and 0.7%, respectively, in women with hyperglycemia during gestation and 12.5% and 1.3%, respectively, in their neonates. The deleterious MODY GCK mutation identified is associated with a reduction in GCK activity and hyperglycemia. In the other molecular changes identified, it was impossible to exclude phenotypic change despite not having clinical significance. Therefore, these changes may interfere with the management and clinical outcome of the patients.
Assuntos
Diabetes Mellitus Tipo 2 , Hiperglicemia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Glucoquinase/genética , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/genética , Recém-Nascido , Mutação , Gravidez , GestantesRESUMO
Propolis is a honeybee product with various biological activities, including antidiabetic effects. We previously reported that artepillin C, a prenylated cinnamic acid derivative isolated from Brazilian green propolis, acts as a peroxisome proliferator-activated receptor γ (PPARγ) ligand and promotes adipocyte differentiation. In this study, we examined the effect of baccharin, another major component of Brazilian green propolis, on adipocyte differentiation. The treatment of mouse 3T3-L1 preadipocytes with baccharin resulted in increased lipid accumulation, cellular triglyceride levels, glycerol-3-phosphate dehydrogenase activity, and glucose uptake. The mRNA expression levels of PPARγ and its target genes were also increased by baccharin treatment. Furthermore, baccharin enhanced PPARγ-dependent luciferase activity, suggesting that baccharin promotes adipocyte differentiation via PPARγ activation. In diabetic ob/ob mice, intraperitoneal administration of 50 mg/kg baccharin significantly improved blood glucose levels. Our results suggest that baccharin has a hypoglycemic effect on glucose metabolic disorders, such as type 2 diabetes mellitus.
Assuntos
Adipócitos/metabolismo , Hiperglicemia/metabolismo , Própole/química , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Glicerolfosfato Desidrogenase/genética , Glicerolfosfato Desidrogenase/metabolismo , Hiperglicemia/genética , CamundongosRESUMO
AIMS: Maturity-Onset Diabetes of the Young (MODY) caused by glucokinase (GCK) mutations is characterized by lifelong mild non-progressive hyperglycemia, with low frequency of coronary artery disease (CAD) compared to other types of diabetes. The aim of this study is to estimate cardiovascular risk by coronary artery calcification (CAC) score in this group. MATERIALS AND METHODS: Twenty-nine GCK-MODY cases, 26 normoglycemic controls (recruited among non-affected relatives/spouses of GCK mutation carriers), and 24 unrelated individuals with type 2 diabetes were studied. Patients underwent CAC score evaluation by computed tomography and were classified by Agatston score ≥ or < 10. Framingham Risk scores of CAD in 10 years were calculated. RESULTS: Median [interquartile range] CAC score in GCK-MODY was 0 [0,0], similar to controls (0 [0,0], P = 0.49), but lower than type 2 diabetes (39 [0, 126], P = 2.6 × 10-5). A CAC score ≥ 10 was seen in 6.9% of the GCK group, 7.7% of Controls (P = 1.0), and 54.2% of individuals with type 2 diabetes (P = 0.0006). Median Framingham risk score was lower in GCK than type 2 diabetes (3% vs. 13%, P = 4 × 10-6), but similar to controls (3% vs. 4%, P = 0.66). CONCLUSIONS: CAC score in GCK-MODY is similar to control individuals from the same family and/or household and is significantly lower than type 2 diabetes. Besides demonstrating low risk of CAD in GCK-MODY, these findings may contribute to understanding the specific effect of hyperglycemia in CAD.
Assuntos
Cálcio/sangue , Vasos Coronários/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Fatores de Risco de Doenças Cardíacas , Adulto , Idoso , Cálcio/análise , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Vasos Coronários/química , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/diagnóstico , Feminino , Glucoquinase/genética , Humanos , Hiperglicemia/genética , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Medição de Risco , Fatores de RiscoRESUMO
Because the liver plays a major role in metabolic homeostasis and secretion of clotting factors and inflammatory innate immune proteins, there is interest in understanding the mechanisms of hepatic cell activation under hyperglycaemia and whether this can be attenuated pharmacologically. We have previously shown that hyperglycaemia stimulates major changes in chromatin organization and metabolism in hepatocytes, and that the histone deacetylase inhibitor valproic acid (VPA) is able to reverse some of these metabolic changes. In this study, we have used RNA-sequencing (RNA-seq) to investigate how VPA influences gene expression in hepatocytes. Interesting, we observed that VPA attenuates hyperglycaemia-induced activation of complement and coagulation cascade genes. We also observe that many of the gene activation events coincide with changes to histone acetylation at the promoter of these genes indicating that epigenetic regulation is involved in VPA action.
Assuntos
Coagulação Sanguínea/genética , Proteínas do Sistema Complemento/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/genética , Ácido Valproico/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Proteínas do Sistema Complemento/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Histonas/metabolismo , Humanos , Regiões Promotoras Genéticas/genética , Reprodutibilidade dos TestesRESUMO
La diabetes MODY 2 es un tipo de diabetes monogénica producida por una mutación en la enzima glucoquinasa, generando un fenotipo hiperglicémico. Para posibles fines terapéuticos o de diagnóstico, se debe conocer esta proteína, una enzima monomérica de la familia de las hexoquinasas, encargadas de convertir glucosa en glucosa-6-fosfato, el primer paso de la glicolisis. La glucoquinasa se caracteriza por sus propiedades cinéticas únicas: tiene una afinidad mucho menor por el sustrato que las demás hexoquinasas y no es inhibida por su producto. Se encuentra principalmente en páncreas e hígado (ßGK y LGK, respectivamente), donde como sensor regula los distintos estados metabólicos de estos tejidos, y controla la glicemia a nivel sistémico. Las formas ßGK y LGK se diferencian a nivel transcripcional, pues el gen posee dos promotores distintos, específicos para cada tejido. A nivel hormonal, la actividad de esta enzima es regulada selectivamente de manera tejido-específica por glucosa, insulina y otras proteínas reguladoras. La isoforma hepática puede ser secuestrada hacia el núcleo por la proteína reguladora de glucoquinasa (GKRP, por su sigla en inglés). La principal característica de la enzima glucoquinasa es su inusual regulación alostérica, propiedad que le permite adoptar dos conformaciones principales, una cerrada (activa) y otra súper-abierta (inactiva). Se han desarrollado distintas drogas activadoras de glucoquinasa, las cuales se unen al sitio alostérico de la enzima y estabilizan a la proteína en su estado cerrado. En esta revisión se describen las características estructurales y propiedades regulatorias que posee la enzima glucoquinasa, relacionándolas con su rol en el desarrollo de la diabetes MODY 2. También se profundiza en las implicancias moleculares de algunas mutaciones descritas que originan MODY 2, y se abordan los efectos de moléculas activadoras de glucoquinasa.
Diabetes MODY 2 or GCK-MODY is a type of monogenic diabetes produced by a mutation in the glucokinase enzyme, generating a hyperglycemic phenotype. This protein, a monomeric enzyme of the hexokinase family, is responsible for converting glucose into glucose-6-phosphate, the first step of glycolysis. Glucokinase is characterized by its unique kinetic properties: it has a much lower affinity for its substrate than other hexokinases and is not inhibited by its product. It is found mainly in pancreas (ßGK) and liver (LGK), where it acts as a sensor regulating the different metabolic states of these tissues, and ultimately, controlling systemic glycemia. The two forms ßGK and LGK differ at a transcriptional level, because the gene presents two different tissue-specific promoters. The activity of glucokinase in liver and pancreas is regulated by glucose, insulin and other regulatory proteins. The liver isoform can be sequestered to the nucleus by the glucokinase regulatory protein (GKRP). The main characteristic of the enzyme is its unusual allosteric regulation, a property that allows the protein to adopt a closed (active) conformation, and a super-open (inactive) conformation. Different glucokinase activating drugs have been developed, which bind to the allosteric site of the enzyme and stabilize glucokinase in its closed state. This review describes the structural and regulatory properties of the glucokinase enzyme, and its role in the development of MODY 2 diabetes. The molecular implications of some mutations that originate MODY 2 are also described, and the effects of glucokinase activating molecules are addressed.
Assuntos
Humanos , Diabetes Mellitus Tipo 2/genética , Glucoquinase/genética , Hiperglicemia/genética , MutaçãoRESUMO
To evaluate Interleukin 1-beta (IL-1ß) serum and mononuclear leucocyte mRNA levels, also rs16944 (-511C/T) genotype, in relation to hyperglycemic normalization in Type 2 diabetes (T2D) patients, we recruited 30 individuals recently T2D diagnosed with hyperglycemia studied at basal time and after 6 and 12 months of the normalization treatment. At basal time, the T polymorphic allele of the rs16944 was associated with lower IL-1ß mRNA expression (p = 0.006); and higher glucose level was positive correlated to IL-1ß protein levels (p = 0.015). After treatment, the individuals showed a significant decrease in glucose level (p = 0.003), but they did not express significant changes in the IL-1ß serum levels. Surprisingly, we observed that the greater decreases in glucose level were associated to increased IL-1ß serum levels (p = 0.040). This is the first follow-up study evaluating IL-1ß mRNA expression and serum levels in hyperglycemic T2D individuals and after glycemic normalization treatment. The current results contribute to the knowledge of the relationship between inflammation and glucose metabolism in T2D.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Genótipo , Hiperglicemia/sangue , Interleucina-1beta/sangue , Adulto , Idoso , Alelos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hipoglicemiantes/uso terapêutico , Interleucina-1beta/genética , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
The consumption of fructose during pregnancy can cause hyperglycaemia and may stimulate production of reactive oxygen species; however, there are only a few studies reporting whether fructose consumption during pregnancy causes DNA damage. Therefore, the aim of this study was to evaluate the effects of fructose consumption on genetic and biochemical parameters in Swiss mice treated during pregnancy and lactation. For this, 15 couples of 60-day-old Swiss mice were divided into three groups of five couples: negative control (water) and two fructose groups (fructose dose of 10%/l and 20%/l). During this period, we evaluated food consumption, energy efficiency and body weight. Samples of blood were collected from the females before copulation, after the 15th day of conception and on the 21st day after the lactation period, for the glycaemic and lipid profiles as well as comet assay and micronucleus (MN) test. Comet assay and MN test evaluate DNA damage and clastogenicity, respectively. In the gestation and lactation period, the two fructose doses tested showed DNA damage as observed in the comet assay, which is associated with an increase in dietary intake, body weight, lipid profile and fasting glycaemia in females. Thus, it can be suggested that the high consumption of fructose during these periods is harmful for pregnancy and lactation.
Assuntos
Dano ao DNA/efeitos dos fármacos , Frutose/efeitos adversos , Hiperglicemia/genética , Complicações na Gravidez/genética , Animais , Dano ao DNA/genética , Modelos Animais de Doenças , Feminino , Frutose/farmacologia , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Lactação/efeitos dos fármacos , Camundongos , Testes para Micronúcleos , Gravidez , Complicações na Gravidez/induzido quimicamente , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
ABSTRACT Objective To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. Subjects and methods We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. Results We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. Conclusion The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).