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1.
PLoS Biol ; 18(8): e3000548, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745077

RESUMO

Sleep is vital for survival. Yet under environmentally challenging conditions, such as starvation, animals suppress their need for sleep. Interestingly, starvation-induced sleep loss does not evoke a subsequent sleep rebound. Little is known about how starvation-induced sleep deprivation differs from other types of sleep loss, or why some sleep functions become dispensable during starvation. Here, we demonstrate that down-regulation of the secreted cytokine unpaired 2 (upd2) in Drosophila flies may mimic a starved-like state. We used a genetic knockdown strategy to investigate the consequences of upd2 on visual attention and sleep in otherwise well-fed flies, thereby sidestepping the negative side effects of undernourishment. We find that knockdown of upd2 in the fat body (FB) is sufficient to suppress sleep and promote feeding-related behaviors while also improving selective visual attention. Furthermore, we show that this peripheral signal is integrated in the fly brain via insulin-expressing cells. Together, these findings identify a role for peripheral tissue-to-brain interactions in the simultaneous regulation of sleep quality and attention, to potentially promote adaptive behaviors necessary for survival in hungry animals.


Assuntos
Atenção/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Comportamento Alimentar/fisiologia , Inanição/genética , Percepção Visual/fisiologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Corpo Adiposo/metabolismo , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Insulina/genética , Insulina/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Transdução de Sinais , Sono/fisiologia , Privação do Sono/genética , Privação do Sono/metabolismo , Inanição/metabolismo
2.
PLoS Genet ; 16(7): e1008835, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32644988

RESUMO

In most organisms, dietary restriction (DR) increases lifespan. However, several studies have found that genotypes within the same species vary widely in how they respond to DR. To explore the mechanisms underlying this variation, we exposed 178 inbred Drosophila melanogaster lines to a DR or ad libitum (AL) diet, and measured a panel of 105 metabolites under both diets. Twenty four out of 105 metabolites were associated with the magnitude of the lifespan response. These included proteinogenic amino acids and metabolites involved in α-ketoglutarate (α-KG)/glutamine metabolism. We confirm the role of α-KG/glutamine synthesis pathways in the DR response through genetic manipulations. We used covariance network analysis to investigate diet-dependent interactions between metabolites, identifying the essential amino acids threonine and arginine as "hub" metabolites in the DR response. Finally, we employ a novel metabolic and genetic bipartite network analysis to reveal multiple genes that influence DR lifespan response, some of which have not previously been implicated in DR regulation. One of these is CCHa2R, a gene that encodes a neuropeptide receptor that influences satiety response and insulin signaling. Across the lines, variation in an intronic single nucleotide variant of CCHa2R correlated with variation in levels of five metabolites, all of which in turn were correlated with DR lifespan response. Inhibition of adult CCHa2R expression extended DR lifespan of flies, confirming the role of CCHa2R in lifespan response. These results provide support for the power of combined genomic and metabolomic analysis to identify key pathways underlying variation in this complex quantitative trait.


Assuntos
Envelhecimento/genética , Proteínas de Drosophila/genética , Longevidade/genética , Metaboloma/genética , Receptores Acoplados a Proteínas-G/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Restrição Calórica , Dieta , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Insulina/genética , Metabolômica , Mutação/genética , Transdução de Sinais/genética
3.
PLoS Genet ; 16(7): e1008903, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32678846

RESUMO

Genome wide association studies (GWAS) of human diseases have generally identified many loci associated with risk with relatively small effect sizes. The omnigenic model attempts to explain this observation by suggesting that diseases can be thought of as networks, where genes with direct involvement in disease-relevant biological pathways are named 'core genes', while peripheral genes influence disease risk via their interactions or regulatory effects on core genes. Here, we demonstrate a method for identifying candidate core genes solely from genes in or near disease-associated SNPs (GWAS hits) in conjunction with protein-protein interaction network data. Applied to 1,381 GWAS studies from 5 ancestries, we identify a total of 1,865 candidate core genes in 343 GWAS studies. Our analysis identifies several well-known disease-related genes that are not identified by GWAS, including BRCA1 in Breast Cancer, Amyloid Precursor Protein (APP) in Alzheimer's Disease, INS in A1C measurement and Type 2 Diabetes, and PCSK9 in LDL cholesterol, amongst others. Notably candidate core genes are preferentially enriched for disease relevance over GWAS hits and are enriched for both Clinvar pathogenic variants and known drug targets-consistent with the predictions of the omnigenic model. We subsequently use parent term annotations provided by the GWAS catalog, to merge related GWAS studies and identify candidate core genes in over-arching disease processes such as cancer-where we identify 109 candidate core genes.


Assuntos
Doença de Alzheimer/genética , Neoplasias da Mama/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Mapas de Interação de Proteínas/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Proteína BRCA1/genética , Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Insulina/genética , Polimorfismo de Nucleotídeo Único/genética , Pró-Proteína Convertase 9/genética , Fatores de Risco
4.
Mol Genet Genomics ; 295(5): 1253-1262, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32556999

RESUMO

Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic Caucasian girl with diabetes onset at 2½ years who was negative for autoantibodies. The lean father had diabetes from age 11 years. A novel heterozygous mutation in EDEM2, c.1271G > A; p.Arg424His, was found in the proband and father. Downregulation of Edem2 in rat RIN-m ß-cells resulted in a decrease in insulin genes Ins1 to 67.9% (p = 0.006) and Ins2 to 16.8% (p < 0.001) and reduced insulin secretion by 60.4% (p = 0.0003). Real-time PCR revealed a major disruption of endocrine pancreas-specific genes, including Glut2 and Pxd1, with mRNA suppression to 54% (p < 0.001) and 85.7% (p = 0.01), respectively. No other expression changes related to stress or apoptotic genes were observed. Extended clinical follow-up involving ten family members showed that two healthy individuals carried the same mutation with no sign of diabetes in the clinical screen except for a slight increase in IA-2 antibody in one of them, suggesting incomplete penetrance. In conclusion, we describe EDEM2 as a likely/potential novel diabetes gene, in which inhibition in vitro reduces the expression of ß-cell genes involved in the glucose-stimulated insulin secretion (GSIS) pathway, leading to an overall suppression of insulin secretion but not apoptosis.


Assuntos
Diabetes Mellitus/genética , Regulação para Baixo , Transportador de Glucose Tipo 2/genética , Glicoproteínas/genética , Proteínas de Homeodomínio/genética , Mutação Puntual , Transativadores/genética , alfa-Manosidase/genética , Idade de Início , Idoso , Animais , Linhagem Celular , Diabetes Mellitus/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Inativação Gênica , Humanos , Insulina/genética , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Ratos , Sequenciamento Completo do Exoma , Adulto Jovem
5.
Gene ; 754: 144861, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32531454

RESUMO

Alu sequences are the most abundant repetitive elements in the human genome, and have proliferated to more than one million copies in the human genome. Primate-specific Alu sequences account for ~10% of the human genome, and their spread within the genome has the potential to generate new exons. The new exons produced by Alu elements appear in various primate genes, and their functions have been elucidated. Here, we identified a new exon in the insulin-like 3 gene (INSL3), which evolved ~50 million years ago, and led to a splicing variant with 31 extra amino acid residues in addition to the original 95 nucleotides (NTs) of INSL3. The Alu-INSL3 isoform underwent diverse changes during primate evolution; we identified that human Alu-INSL3 might be on its way to functionality and has potential to antagonize LGR8-INSL3 function. Therefore, the present study is designed to provide an example of the evolutionary trajectory of a variant peptide hormone antagonist that caused by the insertion of an Alu element in primates.


Assuntos
Evolução Molecular , Insulina/genética , Primatas/genética , Proteínas/genética , Processamento de RNA/genética , Elementos Alu , Sequência de Aminoácidos , Animais , Sequência de Bases , Humanos , Isoformas de Proteínas , Homologia de Sequência
6.
Ecotoxicol Environ Saf ; 201: 110802, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32531573

RESUMO

Extended exposure to inorganic arsenic through contaminated drinking water has been linked with increased incidence of diabetes mellitus. The most common exposure occurs through the consumption of contaminated drinking water mainly through geogenic sources of inorganic arsenic. Epigenetic modifications are important mechanisms through which environmental pollutants could exert their toxic effects. Bisulfite sequencing polymerase chain reaction method followed by Sanger sequencing was performed for DNA methylation analysis. Our results showed that sodium arsenite treatment significantly reduced insulin secretion in pancreatic islets. It was revealed that the methylation of glucose transporter 2 (Glut2) gene was changed at two cytosine-phosphate-guanine (CpG) sites (-1743, -1734) in the promoter region of the sodium arsenite-treated group comparing to the control. No changes were observed in the methylation status of peroxisome proliferator-activated receptor-gamma (PPARγ), pancreatic and duodenal homeobox 1 (Pdx1) and insulin 2 (Ins2) CpG sites in the targeted regions. Measuring the gene expression level showed increase in Glut2 expression, while the expression of insulin (INS) and Pdx1 were significantly affected by sodium arsenite treatment. This study revealed that exposure to sodium arsenite changed the DNA methylation pattern of Glut2, a key transporter of glucose entry into the pancreatic beta cells (ß-cells). Our data suggested possible epigenetic-mediated toxicity mechanism for arsenite-induced ß-cells dysfunction. Further studies are needed to dissect the precise epigenetic modulatory activity of sodium arsenite that affect the biogenesis of insulin.


Assuntos
Arsenitos/toxicidade , Metilação de DNA/efeitos dos fármacos , Transportador de Glucose Tipo 2/genética , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Compostos de Sódio/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Epigênese Genética/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Técnicas In Vitro , Insulina/genética , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Transativadores/genética
7.
BMC Med Genet ; 21(1): 91, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375679

RESUMO

BACKGROUND: Renal hypouricemia (RHUC) is a hereditary disorder where mutations in SLC22A12 gene and SLC2A9 gene cause RHUC type 1 (RHUC1) and RHUC type 2 (RHUC2), respectively. These genes regulate renal tubular reabsorption of urates while there exist other genes counterbalancing the net excretion of urates including ABCG2 and SLC17A1. Urate metabolism is tightly interconnected with glucose metabolism, and SLC2A9 gene may be involved in insulin secretion from pancreatic ß-cells. On the other hand, a myriad of genes are responsible for the impaired insulin secretion independently of urate metabolism. CASE PRESENTATION: We describe a 67 year-old Japanese man who manifested severe hypouricemia (0.7 mg/dl (3.8-7.0 mg/dl), 41.6 µmol/l (226-416 µmol/l)) and diabetes with impaired insulin secretion. His high urinary fractional excretion of urate (65.5%) and low urinary C-peptide excretion (25.7 µg/day) were compatible with the diagnosis of RHUC and impaired insulin secretion, respectively. Considering the fact that metabolic pathways regulating urates and glucose are closely interconnected, we attempted to delineate the genetic basis of the hypouricemia and the insulin secretion defect observed in this patient using whole exome sequencing. Intriguingly, we found homozygous Trp258* mutations in SLC22A12 gene causing RHUC1 while concurrent mutations reported to be associated with hyperuricemia were also discovered including ABCG2 (Gln141Lys) and SLC17A1 (Thr269Ile). SLC2A9, that also facilitates glucose transport, has been implicated to enhance insulin secretion, however, the non-synonymous mutations found in SLC2A9 gene of this patient were not dysfunctional variants. Therefore, we embarked on a search for causal mutations for his impaired insulin secretion, resulting in identification of multiple mutations in HNF1A gene (MODY3) as well as other genes that play roles in pancreatic ß-cells. Among them, the Leu80fs in the homeobox gene NKX6.1 was an unreported mutation. CONCLUSION: We found a case of RHUC1 carrying mutations in SLC22A12 gene accompanied with compensatory mutations associated with hyperuricemia, representing the first report showing coexistence of the mutations with opposed potential to regulate urate concentrations. On the other hand, independent gene mutations may be responsible for his impaired insulin secretion, which contains novel mutations in key genes in the pancreatic ß-cell functions that deserve further scrutiny.


Assuntos
Complicações do Diabetes/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Erros Inatos do Transporte Tubular Renal/genética , Cálculos Urinários/genética , Idoso , Complicações do Diabetes/complicações , Complicações do Diabetes/patologia , Glucose/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Heterozigoto , Proteínas de Homeodomínio/genética , Homozigoto , Humanos , Insulina/biossíntese , Insulina/genética , Secreção de Insulina/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Mutação/genética , Erros Inatos do Transporte Tubular Renal/complicações , Erros Inatos do Transporte Tubular Renal/patologia , Ácido Úrico/metabolismo , Cálculos Urinários/complicações , Cálculos Urinários/patologia , Sequenciamento Completo do Exoma
8.
Nat Commun ; 11(1): 1822, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286278

RESUMO

B cell dysfunction due to obesity can be associated with alterations in the levels of micro-RNAs (miRNAs). However, the role of miRNAs in these processes remains elusive. Here, we show that miR-802 is increased in the pancreatic islets of obese mouse models and demonstrate that inducible transgenic overexpression of miR-802 in mice causes impaired insulin transcription and secretion. We identify Foxo1 as a transcription factor of miR-802 promoting its transcription, and NeuroD1 and Fzd5 as targets of miR-802-dependent silencing. Repression of NeuroD1 in ß cell and primary islets impairs insulin transcription and reduction of Fzd5 in ß cell, which, in turn, impairs Ca2+ signaling, thereby repressing calcium influx and decreasing insulin secretion. We functionally create a novel network between obesity and ß cell dysfunction via miR-802 regulation. Elucidation of the impact of obesity on microRNA expression can broaden our understanding of pathophysiological development of diabetes.


Assuntos
Secreção de Insulina/genética , Insulina/genética , MicroRNAs/metabolismo , Obesidade/genética , Transcrição Genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Dieta Hiperlipídica , Modelos Animais de Doenças , Proteína Forkhead Box O1/metabolismo , Receptores Frizzled/metabolismo , Deleção de Genes , Inativação Gênica , Insulina/metabolismo , Resistência à Insulina/genética , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , MicroRNAs/genética , Modelos Biológicos , Proteínas do Tecido Nervoso/metabolismo , Regulação para Cima/genética
9.
Gen Comp Endocrinol ; 293: 113478, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32243957

RESUMO

This study identified an insulin-like peptide (ILP) in Macrobrachium rosenbergii termed Mr-ILP and further investigated its function through glucose injection and RNAi. With the analysis of five other glucose metabolism related genes, this study shed light on the molecular mechanism of carbohydrate metabolism in crustaceans. Mr-ILP shared the typical skeleton with six conserved cysteine and mainly expressed in neuroendocrine system. In M. rosenbergii, the elevated hemolymph glucose concentration after glucose injection returned to basal levels in short time, implying an efficient regulatory system in carbohydrate metabolism. Hyperglycemic related genes answered the elevated hemolymph glucose concentration quickly with significant decreased expression level, while Mr-ILP showed delayed response. Instead, glycolysis increased after glucose injection, which indicated glycolysis might play an important role in lowering the abnormally high glucose level. In vivo silencing of Mr-ILP, by injecting the prawns with double-stranded RNA (dsRNA) for 21 days reduced its expression by approximately 75%. Accordingly, glycogen synthase decreased and the trehalose and glycogen level in the hepatopancreas were significantly reduced, indicating the function of Mr-ILP in oligosaccharide and polysaccharide accumulation. When Mr-ILP was silenced, the expression of hyperglycemic related genes were enhanced, but the hemolymph glucose level was not elevated significantly, which might attribute to the increased glycolysis to keep a balanced glucose level in hemolymph.


Assuntos
Metabolismo dos Carboidratos , Insulina/metabolismo , Palaemonidae/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Metabolismo dos Carboidratos/genética , DNA Complementar/genética , Feminino , Regulação da Expressão Gênica , Glucose/administração & dosagem , Hemolinfa/metabolismo , Insulina/química , Insulina/genética , Masculino , Palaemonidae/genética , Filogenia
10.
Proc Natl Acad Sci U S A ; 117(14): 7990-8000, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32198206

RESUMO

Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+ current (INa) and repolarizing K+ current (IK) carried by voltage gated K+ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na+ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.


Assuntos
Fibrilação Atrial/metabolismo , Remodelamento Atrial/fisiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Insulina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/imunologia , Células Cultivadas , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Eletrocardiografia , Átrios do Coração/citologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Humanos , Insulina/administração & dosagem , Insulina/genética , Canal de Potássio Kv1.5/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Técnicas de Patch-Clamp , Potássio/metabolismo , Cultura Primária de Células , Sódio/metabolismo , Estreptozocina/toxicidade
11.
Diabetes ; 69(6): 1248-1263, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32169892

RESUMO

Conceivably, upregulation of myo-inositol oxygenase (MIOX) is associated with altered cellular redox. Its promoter includes oxidant-response elements, and we also discovered binding sites for XBP1, a transcription factor of endoplasmic reticulum (ER) stress response. Previous studies indicate that MIOX's upregulation in acute tubular injury is mediated by oxidant and ER stress. Here, we investigated whether hyperglycemia leads to accentuation of oxidant and ER stress while these boost each other's activities, thereby augmenting tubulointerstitial injury/fibrosis. We generated MIOX-overexpressing transgenic (MIOX-TG) and MIOX knockout (MIOX-KO) mice. A diabetic state was induced by streptozotocin administration. Also, MIOX-KO were crossbred with Ins2 Akita to generate Ins2 Akita/KO mice. MIOX-TG mice had worsening renal functions with kidneys having increased oxidant/ER stress, as reflected by DCF/dihydroethidium staining, perturbed NAD-to-NADH and glutathione-to-glutathione disulfide ratios, increased NOX4 expression, apoptosis and its executionary molecules, accentuation of TGF-ß signaling, Smads and XBP1 nuclear translocation, expression of GRP78 and XBP1 (ER stress markers), and accelerated tubulointerstitial fibrosis. These changes were not seen in MIOX-KO mice. Interestingly, such changes were remarkably reduced in Ins2 Akita/KO mice and, likewise, in vitro experiments with XBP1 siRNA. These findings suggest that MIOX expression accentuates, while its deficiency shields kidneys from, tubulointerstitial injury by dampening oxidant and ER stress, which mutually enhance each other's activity.


Assuntos
Nefropatias Diabéticas/metabolismo , Regulação Enzimológica da Expressão Gênica/fisiologia , Inositol Oxigenase/metabolismo , Animais , Apoptose , Glicemia , Linhagem Celular , Diabetes Mellitus Experimental , Humanos , Hiperglicemia , Inositol Oxigenase/genética , Insulina/genética , Insulina/metabolismo , Rim/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutação , Espécies Reativas de Oxigênio
12.
BMC Med Genet ; 21(1): 24, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028929

RESUMO

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of hereditary diabetes, generally caused by one abnormal gene. MODY5 is caused by mutations of the hepatocyte nuclear factor 1 homeobox ß gene (HNF1ß), always as a part of Chr17q12 deletion, whereas heterozygous mutation in B lymphocyte kinase (BLK) gene is responsible for MODY11. CASE PRESENTATION: We report a patient who developed diabetes with a 1.58-Mb Chr17q12 microdeletion and BLK gene c.211G > A mutation using the cytoscan high-density array and whole-exome sequencing analysis. The patient received the surgery at five days after birth for the duodenal atresia and had normal growth postoperatively. Mild elevated liver enzymes were found along with the normal renal function. Quantitative analysis of ß-cell function markers, including fasting insulin (< 0.2 mIU/L), fasting C-peptide (0.02 µg/L), postprandial-2 h insulin (< 0.2 mIU/L), and postprandial-2 h C-peptide (0.03 µg/L) suggested a severe loss of insulin secreting capacity. Meanwhile, islet autoantibodies (GADA, IA-2, ICA, and IAA) in the patient's blood appeared negative. Neither dysplasia in other tissues nor abnormality in development and behavior was found. CONCLUSION: To date, gastrointestinal malformations were extremely rarely reported in patients with MODY. Our clinical report further expands the clinical presentation and variability of MODY5.


Assuntos
Diabetes Mellitus Tipo 2/genética , Obstrução Duodenal/genética , Fator 1-beta Nuclear de Hepatócito/genética , Atresia Intestinal/genética , Quinases da Família src/genética , Diabetes Mellitus Tipo 2/patologia , Obstrução Duodenal/patologia , Feminino , Humanos , Recém-Nascido , Insulina/genética , Atresia Intestinal/patologia , Masculino , Mutação/genética , Fenótipo
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 159-161, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034745

RESUMO

OBJECTIVE: To analyze INS gene variant in a patient with maturity-onset diabetes of the young type 10. METHODS: High-throughput sequencing was used to screen for the variants. Suspected variant was verified by Sanger sequencing. RESULTS: Genetic testing indicated that the patient and his mother have both carried a heterozygous c.130G>A (p.Gly44Arg) variant in exon 1 of the INS gene. Prediction of protein structure suggested the variant to be pathogenic. CONCLUSION: The c.130G>A (p.Gly44Arg) variant of the INS gene probably underlies the disease in this patient.


Assuntos
Diabetes Mellitus Tipo 2 , Insulina/genética , Adolescente , Feminino , Testes Genéticos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação
14.
Nat Commun ; 11(1): 484, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980627

RESUMO

ß-Cell dysfunction and reduction in ß-cell mass are hallmark events of diabetes mellitus. Here we show that ß-cells express abundant Kindlin-2 and deleting its expression causes severe diabetes-like phenotypes without markedly causing peripheral insulin resistance. Kindlin-2, through its C-terminal region, binds to and stabilizes MafA, which activates insulin expression. Kindlin-2 loss impairs insulin secretion in primary human and mouse islets in vitro and in mice by reducing, at least in part, Ca2+ release in ß-cells. Kindlin-2 loss activates GSK-3ß and downregulates ß-catenin, leading to reduced ß-cell proliferation and mass. Kindlin-2 loss reduces the percentage of ß-cells and concomitantly increases that of α-cells during early pancreatic development. Genetic activation of ß-catenin in ß-cells restores the diabetes-like phenotypes induced by Kindlin-2 loss. Finally, the inducible deletion of ß-cell Kindlin-2 causes diabetic phenotypes in adult mice. Collectively, our results establish an important function of Kindlin-2 and provide a potential therapeutic target for diabetes.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Fatores de Transcrição Maf Maior/metabolismo , Proteínas Musculares/metabolismo , beta Catenina/metabolismo , Animais , Proliferação de Células , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Insulina/genética , Resistência à Insulina , Ilhotas Pancreáticas/crescimento & desenvolvimento , Ilhotas Pancreáticas/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fenótipo , Estabilidade Proteica , beta Catenina/genética
15.
J Biol Chem ; 295(7): 1769-1780, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31915252

RESUMO

Sestrins represent a family of stress-inducible proteins that prevent the progression of many age- and obesity-associated disorders. Endogenous Sestrins maintain insulin-dependent AKT Ser/Thr kinase (AKT) activation during high-fat diet-induced obesity, and overexpressed Sestrins activate AKT in various cell types, including liver and skeletal muscle cells. Although Sestrin-mediated AKT activation improves metabolic parameters, the mechanistic details underlying such improvement remain elusive. Here, we investigated how Sestrin2, the Sestrin homolog highly expressed in liver, induces strong AKT activation. We found that two known targets of Sestrin2, mTOR complex (mTORC) 1 and AMP-activated protein kinase, are not required for Sestrin2-induced AKT activation. Rather, phosphoinositol 3-kinase and mTORC2, kinases upstream of AKT, were essential for Sestrin2-induced AKT activation. Among these kinases, mTORC2 catalytic activity was strongly up-regulated upon Sestrin2 overexpression in an in vitro kinase assay, indicating that mTORC2 may represent the major link between Sestrin2 and AKT. As reported previously, Sestrin2 interacted with mTORC2; however, we found here that this interaction occurs indirectly through GATOR2, a pentameric protein complex that directly interacts with Sestrin2. Deleting or silencing WDR24 (WD repeat domain 24), the GATOR2 component essential for the Sestrin2-GATOR2 interaction, or WDR59, the GATOR2 component essential for the GATOR2-mTORC2 interaction, completely ablated Sestrin2-induced AKT activation. We also noted that Sestrin2 also directly binds to the pleckstrin homology domain of AKT and induces AKT translocation to the plasma membrane. These results uncover a signaling mechanism whereby Sestrin2 activates AKT through GATOR2 and mTORC2.


Assuntos
Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Obesidade/genética , Peroxidases/genética , Proteínas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/genética , Células Hep G2 , Humanos , Insulina/genética , Resistência à Insulina/genética , Camundongos , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Fosfatidilinositol 3-Quinases/genética , Fosforilação/genética , Ligação Proteica/genética , Proteínas/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética
16.
FASEB J ; 34(2): 2376-2391, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908002

RESUMO

Recent studies have demonstrated an essential role for insulin signaling in folliculogenesis as conditional ablation of Igf1r in primary follicles elicits defective follicle-stimulating hormone responsiveness blocking development at the preantral stage. Thus the potential role of insulin action in the periovulatory window and in the corpus luteum is unknown. To examine this, we generated conditional Insr,Igf1r, and double receptor knockout mice driven by Pgr-Cre. These models escape the preantral follicle block and in response to superovulatory gonadotropins exhibit normal distribution of ovarian follicles and corpora lutea. However, single ablation of Igf1r leads to subfertility and mice lacking both receptors are infertile. Double knockout mice have impaired oocyte development and ovulation. While some oocytes are released and fertilized, subsequent embryo development is retarded, and the embryos potentially fail to thrive due to lack of luteal support. In support of this, we found reduced expression of key enzymes in the steroid synthesis pathway and reduced serum progesterone. In addition to metabolic and steroidogenic pathways, RNA-sequencing analysis revealed transcription factor-3 as an important transcription factor downstream of insulin signaling. Collectively, these results highlight the importance of growth factors of the insulin family during two distinct windows of follicular development, ovulation, and luteinization.


Assuntos
Diferenciação Celular/fisiologia , Fertilidade/fisiologia , Células da Granulosa/metabolismo , Insulina/metabolismo , Ovulação/fisiologia , Animais , Feminino , Células da Granulosa/citologia , Insulina/genética , Masculino , Camundongos , Camundongos Knockout
17.
Diabetes ; 69(4): 661-669, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31896551

RESUMO

Autoimmunity against pancreatic ß-cell autoantigens is a characteristic of childhood type 1 diabetes (T1D). Autoimmunity usually appears in genetically susceptible children with the development of autoantibodies against (pro)insulin in early childhood. The offspring of mothers with T1D are protected from this process. The aim of this study was to determine whether the protection conferred by maternal T1D is associated with improved neonatal tolerance against (pro)insulin. Consistent with improved neonatal tolerance, the offspring of mothers with T1D had reduced cord blood CD4+ T-cell responses to proinsulin and insulin, a reduction in the inflammatory profile of their proinsulin-responsive CD4+ T cells, and improved regulation of CD4+ T cell responses to proinsulin at 9 months of age, as compared with offspring with a father or sibling with T1D. Maternal T1D was also associated with a modest reduction in CpG methylation of the INS gene in cord blood mononuclear cells from offspring with a susceptible INS genotype. Our findings support the concept that a maternal T1D environment improves neonatal immune tolerance against the autoantigen (pro)insulin.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Metilação de DNA , Feminino , Humanos , Lactente , Inflamação/imunologia , Insulina/genética , Insulina/farmacologia , Proinsulina/farmacologia
18.
Postgrad Med ; 132(2): 109-125, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31615302

RESUMO

Diabetes mellitus and cardiovascular diseases are part of the metabolic syndrome and share similar risk factors, including obesity, arterial hypertension, and dyslipidemia. Atherosclerosis and insulin resistance contribute to the development of the diseases, and subclinical inflammation is observed in both conditions. There are many proofs about the connection between epigenetic factors and different diseases, including diabetes and cardiovascular diseases. Interestingly, recent studies show that at least some anti-diabetic drugs, as well as blockers of the renin-angiotensin-aldosterone system (RAAS), exert epigenetic effects aside from their hypoglycemic and antihypertensive functions, respectively. More studies are needed to discover other positive effects of the medications established through epigenetic mechanisms and to find out more about the epigenetic role in the development of diabetes mellitus and cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Alarminas/metabolismo , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Cromatina/metabolismo , Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/epidemiologia , Endotélio Vascular/metabolismo , Armadilhas Extracelulares/metabolismo , Microbioma Gastrointestinal/genética , Histonas/metabolismo , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/epidemiologia , Hiper-Homocisteinemia/metabolismo , Hipertensão/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/genética , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , RNA não Traduzido , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco
19.
Arch Physiol Biochem ; 126(2): 129-138, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30270668

RESUMO

Insulin resistance is caused by various environmental and genetic factors leading to a number of serious health issues. Due to its multifactorial origin, molecular characterization may provide better tools for its effective treatment. On molecular level, dysregulation of signaling pathway by insulin receptor substrates (IRSs) is one of the most common reasons of this disease. IRSs are regulated by >50 serine/threonine kinases, which may have positive or negative effects on insulin sensitivity. Among these serine/threonine kinases, PIM kinases have garnered much attention as they not only affect insulin sensitivity by phosphorylating IRSs directly and/or indirectly but also alter the activities of their downstream molecules like PI3K, AKT, and mTOR. In this review, interactions of PIM kinases with IRSs and their downstream proteins and their action mechanism in the regulation of insulin resistance are elaborated. Furthermore, this review offers fundamental understandings of the role of PIM kinases in this signaling pathway.


Assuntos
Antígenos CD/genética , Glucose/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina , Proteínas Proto-Oncogênicas c-pim-1/genética , Receptor de Insulina/genética , Animais , Antígenos CD/metabolismo , Regulação da Expressão Gênica , Humanos , Insulina/genética , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
20.
Gene ; 728: 144296, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31866555

RESUMO

Insulin and glucagon are important hormones for regulating blood glucose levels. Rodents are useful models for understanding human physiology, however, differences exist between rodents and humans. Here I examined the evolution of the genes encoding insulin (Ins) and glucagon (Gcg, which also encodes GLP-1 and GLP-2) and the receptors for these hormones (Insr, Gcgr, Glp1r, and Glp2r). Our results show that the insulin 1 gene (Ins1) that originated by retroposition in some rodents such as mice, experienced selective constraints that are as strong as those acting upon the Ins2 gene found in the locus-of-origin. Previous studies had shown that the insulin hormones and genes in hystricomorph rodents, such as the guinea pig, have altered function and selective constraints, respectively. Here I show that the insulin receptor genes in hystricomorph rodents also experienced changes in evolutionary rates, but that these changes did not alter sites involved in hormone binding. While glucagon, but not GLP-1 and GLP-2, in hystricomorph rodents also show increased rates of sequence evolution, no changes in the evolution of the glucagon receptor gene (Gcgr) was seen. Intriguingly, the GLP2 receptor gene (Glp2r) in mice-like rodents evolved more rapidly than those in hystricomorph rodents. When the rates of evolution of the genes encoding the receptors for proglucagon-derived peptides, which are all G-protein coupled receptors, were compared, the GLP-1 receptor gene (Glp1r) was found to display increased levels of sequence constraint compared to the Gcgr and Glp2r genes.


Assuntos
Evolução Molecular , Glucagon/genética , Insulina/genética , Receptor de Insulina/genética , Receptores de Glucagon/genética , Roedores/genética , Animais , Genoma , Filogenia
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