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1.
Hum Genomics ; 14(1): 35, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008459

RESUMO

Precision medicine aims to empower clinicians to predict the most appropriate course of action for patients with complex diseases like cancer, diabetes, cardiomyopathy, and COVID-19. With a progressive interpretation of the clinical, molecular, and genomic factors at play in diseases, more effective and personalized medical treatments are anticipated for many disorders. Understanding patient's metabolomics and genetic make-up in conjunction with clinical data will significantly lead to determining predisposition, diagnostic, prognostic, and predictive biomarkers and paths ultimately providing optimal and personalized care for diverse, and targeted chronic and acute diseases. In clinical settings, we need to timely model clinical and multi-omics data to find statistical patterns across millions of features to identify underlying biologic pathways, modifiable risk factors, and actionable information that support early detection and prevention of complex disorders, and development of new therapies for better patient care. It is important to calculate quantitative phenotype measurements, evaluate variants in unique genes and interpret using ACMG guidelines, find frequency of pathogenic and likely pathogenic variants without disease indicators, and observe autosomal recessive carriers with a phenotype manifestation in metabolome. Next, ensuring security to reconcile noise, we need to build and train machine-learning prognostic models to meaningfully process multisource heterogeneous data to identify high-risk rare variants and make medically relevant predictions. The goal, today, is to facilitate implementation of mainstream precision medicine to improve the traditional symptom-driven practice of medicine, and allow earlier interventions using predictive diagnostics and tailoring better-personalized treatments. We strongly recommend automated implementation of cutting-edge technologies, utilizing machine learning (ML) and artificial intelligence (AI) approaches for the multimodal data aggregation, multifactor examination, development of knowledgebase of clinical predictors for decision support, and best strategies for dealing with relevant ethical issues.


Assuntos
Infecções por Coronavirus/genética , Diabetes Mellitus/genética , Neoplasias/genética , Pneumonia Viral/genética , Medicina de Precisão/tendências , Cardiomiopatias , Infecções por Coronavirus/epidemiologia , Análise de Dados , Diabetes Mellitus/epidemiologia , Genômica/tendências , Humanos , Metabolômica/tendências , Neoplasias/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Proteômica/tendências
2.
In Vivo ; 34(5): 3029-3032, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32871848

RESUMO

BACKGROUND/AIM: Reports indicate that coronaviridae may inhibit insulin secretion. In this report we aimed to describe the course of glycemia in critically ill patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. PATIENTS AND METHODS: We studied 36 SARS-CoV-2 patients (with no history of diabetes) in one intensive care unit (ICU). All the patients were admitted for hypoxemic respiratory failure; all but four required mechanical ventilation. The mean (±SD) age of the patients was 64.7 (9.7) years; 27 were men; the mean (±SD) duration of ICU stay was 12.9 (8.3 days). RESULTS: Twenty of 36 patients presented with hyperglycemia; brief intravenous infusions of short-acting insulin were administered in six patients. As of May 29 2020, 11 patients had died (seven with hyperglycemia). In 17 patients the Hyperglycemia Index [HGI; defined as the area under the curve of (hyper)glycemia level*time (h) divided by the total time in the ICU] was <16.21 mg/dl (0.90 mmol/l), whereas in three patients the HGI was ≥16.21 mg/dl (0.90 mol/l) and <32.25 mg/dl (1.79 mmol/l). CONCLUSION: In our series of ICU patients with SARS-CoV-2 infection, and no history of diabetes, a substantial number of patients had hyperglycemia, to a higher degree than would be expected by the stress of critical illness, lending credence to reports that speculated a tentative association between SARS-CoV-2 and hyperglycemia. This finding is important, since hyperglycemia can lead to further infectious complications.


Assuntos
Infecções por Coronavirus/terapia , Diabetes Mellitus/terapia , Hiperglicemia/terapia , Insulina/metabolismo , Pneumonia Viral/terapia , Betacoronavirus/patogenicidade , Glicemia/metabolismo , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Diabetes Mellitus/genética , Diabetes Mellitus/virologia , Feminino , Hospitalização , Humanos , Hiperglicemia/complicações , Hiperglicemia/virologia , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Respiração Artificial , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/terapia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/terapia , Síndrome Respiratória Aguda Grave/virologia
3.
PLoS One ; 15(8): e0237004, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756589

RESUMO

Dysregulated expression of MicroRNAs (miRNAs) plays substantial role in the initiation and progression of both diabetes and periodontitis. The aim of the present study was to validate four miRNAs in saliva as potential predictive biomarkers of periodontal disease among patients with and without diabetes mellitus (DM). MiRNAs were extracted from the saliva of 24 adult subjects with DM and 29 healthy controls. Each group was subdivided into periodontally healthy or having periodontitis. In silico analysis identified 4 miRNAs (miRNA 155, 146 a/b and 203) as immune modulators. The expression of miRNAs-146a/b, 155, and 203 was tested using quantitative PCR. The expression levels in the study groups were compared to explore the effect of diabetes on periodontal status and vice versa. In our cohort, the four miRNAs expression were higher in patients with periodontitis and/or diabetes. miRNA-155 was the most reliable predictors of periodontitis among non-diabetics with an optimum cut-off value of < 8.97 with accuracy = 82.6%. MiRNA 146a, on the other hand, was the only reliable predictor of periodontitis among subjects with diabetes with optimum cut-off value of ≥11.04 with accuracy = 86.1%. The results of the present study concluded that MiRNA-146a and miRNA155 in saliva provide reliable, non-invasive, diagnostic and prognostic biomarkers that can be used to monitor periodontal health status among diabetic and non-diabetic patients.


Assuntos
Diabetes Mellitus/diagnóstico , MicroRNAs/metabolismo , Periodontite/diagnóstico , Adolescente , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Complicações do Diabetes/diagnóstico , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Análise Discriminante , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Periodontite/genética , Periodontite/metabolismo , Projetos Piloto , Saliva/metabolismo , Regulação para Cima , Adulto Jovem
4.
Life Sci ; 258: 118202, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758625

RESUMO

Pandemic coronavirus disease-2019, commonly known as COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious disease with a high mortality rate. Various comorbidities and their associated symptoms accompany SARS-CoV-2 infection. Among the various comorbidities like hypertension, cardiovascular disease and chronic obstructive pulmonary disease, diabetes considered as one of the critical comorbidity, which could affect the survival of infected patients. The severity of COVID-19 disease intensifies in patients with elevated glucose level probably via amplified pro-inflammatory cytokine response, poor innate immunity and downregulated angiotensin-converting enzyme 2. Thus, the use of ACE inhibitors or angiotensin receptor blockers could worsen the glucose level in patients suffering from novel coronavirus infection. It also observed that the direct ß-cell damage caused by virus, hypokalemia and cytokine and fetuin-A mediated increase in insulin resistance could also deteriorate the diabetic condition in COVID-19 patients. This review highlights the current scenario of coronavirus disease in pre-existing diabetic patients, epidemiology, molecular perception, investigations, treatment and management of COVID-19 disease in patients with pre-existing diabetes. Along with this, we have also discussed unexplored therapies and future perspectives for coronavirus infection.


Assuntos
Infecções por Coronavirus/epidemiologia , Diabetes Mellitus/epidemiologia , Pneumonia Viral/epidemiologia , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Gerenciamento Clínico , Humanos , Hipoglicemiantes/uso terapêutico , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Polimorfismo Genético
5.
Am J Gastroenterol ; 115(7): 1103-1109, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32618661

RESUMO

INTRODUCTION: Diabetes mellitus (DM) and colorectal cancer (CRC) share some risk factors, including lifestyle and metabolic disturbances. We aimed to provide in-depth information on the association of CRC risk, especially early-onset CRC, with DM, family history of CRC, and age at DM diagnosis. METHODS: A nationwide cohort study was conducted using Swedish family cancer data sets, inpatient, and outpatient registers (follow-up: 1964-2015), including all individuals born after 1931 and their parents (12,614,256 individuals; 559,375 diabetic patients; 162,226 CRC patients). RESULTS: DM diagnosis before the age of 50 years was associated with a 1.9-fold increased risk of CRC before the age of 50 years (95% CI for standardized incidence ratio: 1.6-2.3) vs 1.3-fold risk of CRC at/after the age of 50 years (1.2-1.4). DM diagnosis before the age of 50 years in those with a family history of CRC was associated with 6.9-fold risk of CRC before the age of 50 years (4.1-12) and 1.9-fold risk of CRC at/after the age of 50 years (1.4-2.5). Diabetic patients had a similar lifetime risk of CRC before the age of 50 years (0.4%, 95% CI: 0.3%-0.4%) to those with only a family history of CRC (0.5%, 0.5%-0.5%), double that of the population (0.2%, 0.2%-0.2%). DISCUSSION: Our large cohort with valid information on DM and family history of cancer showed that DM is associated with increased risk of CRC in a magnitude close to having family history of CRC. Associations of DM and CRC family history with increased CRC risk were most prominent in young adults. These findings warrant further studies on harms, benefits, and cost-effectiveness of CRC screening in patients with diabetes, especially type 2, at earlier ages than in the general population.


Assuntos
Neoplasias Colorretais/genética , Diabetes Mellitus/genética , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Medição de Risco , Fatores de Risco , Suécia/epidemiologia
6.
Biochem Biophys Res Commun ; 528(3): 413-419, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: covidwho-436643

RESUMO

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.


Assuntos
Betacoronavirus/metabolismo , Isquemia Encefálica/virologia , Encéfalo/irrigação sanguínea , Diabetes Mellitus , Peptidil Dipeptidase A/biossíntese , Receptores Virais/biossíntese , Fumantes , Acidente Vascular Cerebral/virologia , Regulação para Cima , Animais , Betacoronavirus/patogenicidade , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ratos , Ratos Sprague-Dawley , Receptores Virais/genética , Fumaça/efeitos adversos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Regulação para Cima/efeitos dos fármacos
7.
Biochem Biophys Res Commun ; 528(3): 413-419, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32513532

RESUMO

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.


Assuntos
Betacoronavirus/metabolismo , Isquemia Encefálica/virologia , Encéfalo/irrigação sanguínea , Diabetes Mellitus , Peptidil Dipeptidase A/biossíntese , Receptores Virais/biossíntese , Fumantes , Acidente Vascular Cerebral/virologia , Regulação para Cima , Animais , Betacoronavirus/patogenicidade , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ratos , Ratos Sprague-Dawley , Receptores Virais/genética , Fumaça/efeitos adversos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
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
9.
Ann Endocrinol (Paris) ; 81(2-3): 68-77, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32409007

RESUMO

OBJECTIVE: While the most frequent mutation responsible for mitochondrial diabetes is the point mutation m.3243 A>G of mitochondrial DNA (mtDNA), few data are available about the role of rare mtDNA mutations in the pathophysiology of diabetes. The main objective of our study was to describe the phenotypic characteristics of patients suffering from diabetes linked to rare mtDNA mutations. RESEARCH DESIGN AND METHODS: We performed a post-hoc analysis of a prospective multicenter cohort of 743 patients with mitochondrial disorder (previously published by the French Network of Mitochondrial Diseases), associated to a literature review of the PubMed database from 1992 to May 2016. We extracted all reported patients with diabetes and identified rare mtDNA mutations and described their clinical and metabolic phenotypes. RESULTS: The 50 identified patients (10 from the princeps study; 40 from the review of the literature) showed a heterogeneous metabolic phenotype in terms of age, symptoms prior to diagnosis, treatments, and associated clinical and biological signs. However, neurological symptoms were more frequent in case of rare mtDNA mutations compared to the classical m.3243 A>G mutation (P=0.024). In contrast, deafness (65% vs. 95%, P=3.7E-5), macular pattern dystrophy (20% vs. 86%, P=1.6E-10) and nephropathy (8% vs. 28%, P=0.018) were significantly less frequent than in case of the classical m.3243 A>G mutation. CONCLUSION: Although no specific metabolic phenotype could be identified suggesting or eliminating implication of rare mtDNA mutations in diabetes, clinical phenotypes featured more frequent neurological signs.


Assuntos
DNA Mitocondrial/genética , Diabetes Mellitus/genética , Doenças Mitocondriais/genética , Mutação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , DNA Mitocondrial/análise , Surdez/epidemiologia , Surdez/genética , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , França/epidemiologia , Frequência do Gene , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Síndrome MERRF/epidemiologia , Síndrome MERRF/genética , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Fenótipo , Estudos Prospectivos
10.
Nat Rev Endocrinol ; 16(7): 378-393, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376986

RESUMO

The ATP-sensitive potassium channel (KATP channel) couples blood levels of glucose to insulin secretion from pancreatic ß-cells. KATP channel closure triggers a cascade of events that results in insulin release. Metabolically generated changes in the intracellular concentrations of adenosine nucleotides are integral to this regulation, with ATP and ADP closing the channel and MgATP and MgADP increasing channel activity. Activating mutations in the genes encoding either of the two types of KATP channel subunit (Kir6.2 and SUR1) result in neonatal diabetes mellitus, whereas loss-of-function mutations cause hyperinsulinaemic hypoglycaemia of infancy. Sulfonylurea and glinide drugs, which bind to SUR1, close the channel through a pathway independent of ATP and are now the primary therapy for neonatal diabetes mellitus caused by mutations in the genes encoding KATP channel subunits. Insight into the molecular details of drug and nucleotide regulation of channel activity has been illuminated by cryo-electron microscopy structures that reveal the atomic-level organization of the KATP channel complex. Here we review how these structures aid our understanding of how the various mutations in the genes encoding Kir6.2 (KCNJ11) and SUR1 (ABCC8) lead to a reduction in ATP inhibition and thereby neonatal diabetes mellitus. We also provide an update on known mutations and sulfonylurea therapy in neonatal diabetes mellitus.


Assuntos
Diabetes Mellitus/congênito , Diabetes Mellitus/genética , Doenças do Recém-Nascido/genética , Canais KATP/genética , Mutação , Animais , Diabetes Mellitus/tratamento farmacológico , Humanos , Recém-Nascido , Doenças do Recém-Nascido/tratamento farmacológico , Secreção de Insulina/genética , Mutação/fisiologia , Compostos de Sulfonilureia/uso terapêutico
11.
Nat Commun ; 11(1): 2538, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439909

RESUMO

Compromised ß-cell identity is emerging as an important contributor to ß-cell failure in diabetes; however, the precise mechanism independent of hyperglycemia is under investigation. We have previously reported that mTORC1/Raptor regulates functional maturation in ß-cells. In the present study, we find that diabetic ß-cell specific Raptor-deficient mice (ßRapKOGFP) show reduced ß-cell mass, loss of ß-cell identity and acquisition of α-cell features; which are not reversible upon glucose normalization. Deletion of Raptor directly impairs ß-cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to ß-cell failure. Moreover, loss of Raptor activates α-cell transcription factor MafB (via modulating C/EBPß isoform ratio) and several α-cell enriched genes i.e. Etv1 and Tspan12, thus initiates ß- to α-cell reprograming. The present findings highlight mTORC1 as a metabolic rheostat for stabilizing ß-cell identity and repressing α-cell program at normoglycemic level, which might present therapeutic opportunities for treatment of diabetes.


Assuntos
Diferenciação Celular , Plasticidade Celular , Diabetes Mellitus/patologia , Células Secretoras de Insulina/patologia , Proteína Regulatória Associada a mTOR/metabolismo , Animais , Glicemia/metabolismo , Diferenciação Celular/genética , Plasticidade Celular/genética , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Regulação da Expressão Gênica , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Fator de Transcrição MafB/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout , Proteína Regulatória Associada a mTOR/genética , Transdução de Sinais
12.
Am J Hum Genet ; 106(6): 846-858, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32470372

RESUMO

The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2, and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes for obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.


Assuntos
Inversão Cromossômica/genética , Diabetes Mellitus/genética , Predisposição Genética para Doença , Hipertensão/genética , Obesidade/complicações , Obesidade/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Conjuntos de Dados como Assunto/normas , Diabetes Mellitus/patologia , Europa (Continente)/etnologia , Feminino , Perfilação da Expressão Gênica , Haplótipos , Humanos , Hipertensão/complicações , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Adulto Jovem
13.
Proc Natl Acad Sci U S A ; 117(16): 8912-8923, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32253320

RESUMO

Pancreatic islets regulate glucose homeostasis through coordinated actions of hormone-secreting cells. What underlies the function of the islet as a unit is the close approximation and communication among heterogeneous cell populations, but the structural mediators of islet cellular cross talk remain incompletely characterized. We generated mice specifically lacking ß-cell primary cilia, a cellular organelle that has been implicated in regulating insulin secretion, and found that the ß-cell cilia are required for glucose sensing, calcium influx, insulin secretion, and cross regulation of α- and δ-cells. Protein expression profiling in islets confirms perturbation in these cellular processes and reveals additional targets of cilia-dependent signaling. At the organism level, the deletion of ß-cell cilia disrupts circulating hormone levels, impairs glucose homeostasis and fuel usage, and leads to the development of diabetes. Together, these findings demonstrate that primary cilia not only orchestrate ß-cell-intrinsic activity but also mediate cross talk both within the islet and from islets to other metabolic tissues, thus providing a unique role of cilia in nutrient metabolism and insight into the pathophysiology of diabetes.


Assuntos
Cílios/metabolismo , Diabetes Mellitus/patologia , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Animais , Cálcio/metabolismo , Comunicação Celular/fisiologia , Cílios/genética , Cílios/patologia , Diabetes Mellitus/genética , Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Feminino , Células Secretoras de Glucagon/metabolismo , Humanos , Secreção de Insulina , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/fisiologia
14.
PLoS One ; 15(4): e0231285, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302349

RESUMO

Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted Gene Correlation Network Analysis (WGCNA). Interestingly, lung function, body mass index, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze-omic datasets in rare genetic diseases as patient cohorts are inevitably small.


Assuntos
Fibrose Cística/epidemiologia , Fibrose Cística/genética , Diabetes Mellitus/genética , Genes Modificadores , Adulto , Comorbidade , Fibrose Cística/sangue , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Diabetes Mellitus/sangue , Feminino , Humanos , Pulmão/metabolismo , Masculino , Mutação , Infecções por Pseudomonas/patologia , Transcriptoma
15.
Clin Sci (Lond) ; 134(8): 1031-1048, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32337536

RESUMO

Global trends in the prevalence of overweight and obesity put the adipocyte in the focus of huge medical interest. This review highlights a new topic in adipose tissue biology, namely the emerging pathogenic role of fat accumulation in bone marrow (BM). Specifically, we summarize current knowledge about the origin and function of BM adipose tissue (BMAT), provide evidence for the association of excess BMAT with diabetes and related cardiovascular complications, and discuss potential therapeutic approaches to correct BMAT dysfunction. There is still a significant uncertainty about the origins and function of BMAT, although several subpopulations of stromal cells have been suggested to have an adipogenic propensity. BM adipocytes are higly plastic and have a distinctive capacity to secrete adipokines that exert local and endocrine functions. BM adiposity is abundant in elderly people and has therefore been interpreted as a component of the whole-body ageing process. BM senescence and BMAT accumulation has been also reported in patients and animal models with Type 2 diabetes, being more pronounced in those with ischaemic complications. Understanding the mechanisms responsible for excess and altered function of BMAT could lead to new treatments able to preserve whole-body homeostasis.


Assuntos
Medula Óssea/metabolismo , Diabetes Mellitus/metabolismo , Gorduras/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Diabetes Mellitus/genética , Humanos
16.
Diab Vasc Dis Res ; 17(3): 1479164120907971, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32223319

RESUMO

OBJECTIVE: Diabetes mellitus is a significant risk factor for peripheral artery disease. Diabetes mellitus induces chronic states of oxidative stress and vascular inflammation that increase neutrophil activation and release of myeloperoxidase. The goal of this study is to determine whether inhibiting myeloperoxidase reduces oxidative stress and neutrophil infiltration, increases vascularization, and improves blood flow in a diabetic murine model of hindlimb ischaemia. METHODS: Leptin receptor-deficient (db/db) mice were subjected to hindlimb ischaemia. Ischaemic mice were treated with N-acetyl-lysyltyrosylcysteine-amide (KYC) to inhibit myeloperoxidase. After ligating the femoral artery, effects of treatments were determined with respect to hindlimb blood flow, neutrophil infiltration, oxidative damage, and the capability of hindlimb extracellular matrix to support human endothelial cell proliferation and migration. RESULTS: KYC treatment improved hindlimb blood flow at 7 and 14 days in db/db mice; decreased the formation of advanced glycation end products, 4-hydroxynonenal, and 3-chlorotyrosine; reduced neutrophil infiltration into the hindlimbs; and improved the ability of hindlimb extracellular matrix from db/db mice to support endothelial cell proliferation and migration. CONCLUSION: These results demonstrate that inhibiting myeloperoxidase reduces oxidative stress in ischaemic hindlimbs of db/db mice, which improves blood flow and reduces neutrophil infiltration such that hindlimb extracellular matrix from db/db mice supports endothelial cell proliferation and migration.


Assuntos
Indutores da Angiogênese/farmacologia , Diabetes Mellitus/metabolismo , Inibidores Enzimáticos/farmacologia , Isquemia/tratamento farmacológico , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Peroxidase/antagonistas & inibidores , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Membro Posterior , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Isquemia/enzimologia , Isquemia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Fluxo Sanguíneo Regional , Transdução de Sinais
17.
Curr Diab Rep ; 20(6): 16, 2020 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-32221727

RESUMO

PURPOSE OF REVIEW: The aim was to review evidence about diabetes secondary to hereditary pancreatitis, seeking novel diagnostic and treatment features. RECENT FINDINGS: Hereditary pancreatitis (HP) is an autosomal dominant condition, characterized by recurrent episodes of acute pancreatitis, progression to fibrosis, and chronic pancreatitis. Clinical presentation includes diabetes of the exocrine pancreas (DEP). HP prevalence ranges from 0.3 to 0.57 per 100,000 people, with up to 80% of these develop DEP. This condition often requires specific interventions: with regard to metabolic control, metformin is the first choice for those with mild DEP, and for those in advanced disease, insulin is considered the first-line therapy. Insulin analogues and insulin pump therapy are preferred due to the brittle glycemic pattern and risk of hypoglycemia. In case of exocrine insufficiency, pancreatic enzyme replacement therapy is recommended. Pancreatic polypeptide administration is a promising novel treatment feature. DEP due to HP appears to be a misdiagnosed condition. The requirement of specific management demonstrates the importance of this matter; therefore, appropriate recognition and classification are important.


Assuntos
Diabetes Mellitus/genética , Pâncreas Exócrino/patologia , Pancreatite Crônica/genética , Tripsina/genética , Doença Aguda , Carcinoma Ductal Pancreático/etiologia , Quimotripsina/genética , Complicações do Diabetes/complicações , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/terapia , Insuficiência Pancreática Exócrina/genética , Insuficiência Pancreática Exócrina/fisiopatologia , Insuficiência Pancreática Exócrina/terapia , Fibrose/etiologia , Humanos , Pâncreas Exócrino/fisiopatologia , Neoplasias Pancreáticas/etiologia , Pancreatite Crônica/complicações , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/fisiopatologia , Recidiva , Fatores de Risco , Inibidor da Tripsina Pancreática de Kazal/genética
18.
Gene ; 738: 144476, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061761

RESUMO

BACKGROUND: Metabolic syndrome (MetS) contributes to increased risk of morbidity and mortality. The United Arab Emirates (UAE) has a high prevalence of MetS which may be linked to modifiable and genetic risk factors in the local population. The association between MetS as a phenotype and key genetic variants in the UAE has not been investigated. This study reports on the clinical, biochemical and genetic associations of MetS and its risk factors to improve individualized medicine outcomes. METHODS: There were 471 subjects included in this cross-sectional study, 367 with MetS and 104 without MetS. Along with clinical and laboratory parameters, multiple risk genetic variants were tested for their association with MetS, which include 49 variants that have previously been shown to be linked with MetS development as a phenotype, 116 variants for association with waist-hip ratio (WHR), 398 variants with body-mass index (BMI), 213 variants with T2DM and insulin resistance, 307 variants with different lipid traits, 308 variants with blood pressure traits, and 64 variants with coronary and cerebrovascular accidents. RESULTS: Patients with MetS had higher rates of type 2 diabetes mellitus (T2DM), hypertension and dyslipidemia (p < 0.0001). Waist circumference and T2DM were identified as the key risk factors for MetS development. Individuals with MetS were also found to have a higher rate of clinical complications than those without MetS (76% vs. 52%). Several gene variants including those of the FTO gene were found to be associated with a predisposition to developing MetS or some of its components (PFTO ~0.005-0.009). CONCLUSIONS: This study showed associations between MetS as well as clinical factors contributing to MetS and specific genetic and metabolic risk factors, providing an insight into the metabolic and genetic links to disease development. Knowledge with respect to population specific risk markers including at risk genotypes will help in early identification of individuals with increased susceptibility to MetS in the UAE and provide the opportunity for timely intervention to prevent or delay the onset of MetS.


Assuntos
Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Adulto , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos Transversais , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Prevalência , Fatores de Risco , Emirados Árabes Unidos/epidemiologia , Circunferência da Cintura , Relação Cintura-Quadril
19.
Diabetes ; 69(4): 647-660, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32005707

RESUMO

Aging-dependent changes in tissue function are associated with the development of metabolic diseases. However, the molecular connections linking aging, obesity, and diabetes remain unclear. Lamin A, lamin C, and progerin, products of the Lmna gene, have antagonistic functions on energy metabolism and life span. Lamin C, albeit promoting obesity, increases life span, suggesting that this isoform is crucial for maintaining healthy conditions under metabolic stresses. Because ß-cell loss during obesity or aging leads to diabetes, we investigated the contribution of lamin C to ß-cell function in physiopathological conditions. We demonstrate that aged lamin C only-expressing mice (Lmna LCS/LCS ) become obese but remain glucose tolerant due to adaptive mechanisms including increased ß-cell mass and insulin secretion. Triggering diabetes in young mice revealed that Lmna LCS/LCS animals normalize their fasting glycemia by both increasing insulin secretion and regenerating ß-cells. Genome-wide analyses combined to functional analyses revealed an increase of mitochondrial biogenesis and global translational rate in Lmna LCS/LCS islets, two major processes involved in insulin secretion. Altogether, our results demonstrate for the first time that the sole expression of lamin C protects from glucose intolerance through a ß-cell-adaptive transcriptional program during metabolic stresses, highlighting Lmna gene processing as a new therapeutic target for diabetes treatment.


Assuntos
Envelhecimento/metabolismo , Diabetes Mellitus/metabolismo , Intolerância à Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Lamina Tipo A/metabolismo , Obesidade/metabolismo , Envelhecimento/genética , Animais , Glicemia/metabolismo , Diabetes Mellitus/genética , Metabolismo Energético/fisiologia , Glucagon/metabolismo , Intolerância à Glucose/genética , Insulina/metabolismo , Lamina Tipo A/genética , Camundongos , Camundongos Transgênicos , Obesidade/genética , Pâncreas/metabolismo
20.
Oxid Med Cell Longev ; 2020: 4105382, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064023

RESUMO

Harmful, stressful conditions or events in the cardiovascular system result in cellular damage, inflammation, and fibrosis. Currently, there is no targeted therapy for myocardial fibrosis, which is highly associated with a large number of cardiovascular diseases and can lead to fatal heart failure. Hydrogen sulfide (H2S) is an endogenous gasotransmitter similar to nitric oxide and carbon monoxide. H2S is involved in the suppression of oxidative stress, inflammation, and cellular death in the cardiovascular system. The level of H2S in the body can be boosted by stimulating its synthesis or supplying it exogenously with a simple H2S donor with a rapid- or slow-releasing mode, an organosulfur compound, or a hybrid with known drugs (e.g., aspirin). Hypertension, myocardial infarction, and inflammation are exaggerated when H2S is reduced. In addition, the exogenous delivery of H2S mitigates myocardial fibrosis caused by various pathological conditions, such as a myocardial infarct, hypertension, diabetes, or excessive ß-adrenergic stimulation, via its involvement in a variety of signaling pathways. Numerous experimental findings suggest that H2S may work as a potential alternative for the management of myocardial fibrosis. In this review, the antifibrosis role of H2S is briefly addressed in order to gain insight into the development of novel strategies for the treatment of myocardial fibrosis.


Assuntos
Cardiomiopatias/metabolismo , Diabetes Mellitus/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hipertensão/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Animais , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/genética , Diabetes Mellitus/enzimologia , Diabetes Mellitus/genética , Fibrose , Humanos , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/genética , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Espécies Reativas de Oxigênio/metabolismo
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