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1.
Nat Commun ; 12(1): 5242, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475398

RESUMO

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 ß cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving ß cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in ß cell transcriptional stress response and T2D genetics.


Assuntos
Diabetes Mellitus Tipo 2/genética , Estresse do Retículo Endoplasmático/genética , Células Secretoras de Insulina/patologia , Polimorfismo de Nucleotídeo Único , Ativação Transcricional/genética , Alelos , Animais , Linhagem Celular , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Locos de Características Quantitativas , Elementos Nucleotídeos Curtos e Dispersos/genética
2.
Medicine (Baltimore) ; 100(35): e27141, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477167

RESUMO

ABSTRACT: The aim of this study is to compare the endothelial cell density (ECD) and morphology between diabetic mellitus (DM) and nondiabetic patients at 1 year after phacoemulsification in operated eyes and nonoperated eyes.Evaluation was performed in 28 patients (56 eyes) with type 2 diabetes and 37 patients (74 eyes) without diabetes who underwent 1-year interval cataract surgery. Using a noncontact specular microscope and Scheimpflug rotating camera, corneal parameters were analyzed before and 1 year after surgery. Subgroups analysis was performed based on a disease duration 10 years and HbA1c concentration 7% and Pearson correlation analysis was performed.The mean change in ECD at 1 year after surgery was 13.28% in the DM group and 11.40% in the control group. In the fellow nonoperated eyes, the mean change was 4.47% and 3.63% in the DM and control groups, respectively. There was no significant difference in postoperative ECD, coefficient of variance, hexagonality, and central corneal thickness between 2 groups. In the subgroup analysis, the long disease duration DM group (≥10 years) had a significantly greater ECD loss than the control and short disease duration DM groups (<10 years). Blood urea nitrogen (BUN) showed a significant correlation with postoperative ECD change (r = -0.474, P = .011).The diabetic group with a longer disease duration showed significantly greater ECD decrease compared to the nondiabetic group and BUN correlated with ECD changes after phacoemulsification. Postoperative ECD loss may be high if the disease duration is long or if the BUN level is high.


Assuntos
Córnea/patologia , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais , Facoemulsificação/efeitos adversos , Idoso , Catarata/complicações , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
3.
Aliment Pharmacol Ther ; 54(7): 952-966, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34398492

RESUMO

BACKGROUND: One of the unmet needs in patients with type 2 diabetes mellitus (T2DM) is the prediction of non-alcoholic liver disease by non-invasive blood tests, for each of the three main histological features, fibrosis, non-alcoholic steatohepatitis (NASH) and steatosis. AIMS: To validate externally the performances of a recent panel, Nash-FibroTest, for the assessment of the severity of fibrosis stages, NASH grades and steatosis grades. METHODS: We prospectively analysed 272 patients with T2DM. Standard definitions of stages and grades were used, and analyses were centralised and blinded. The performances of the FibroTest, NashTest-2 and SteatoTest-2 were assessed using the Obuchowski measure (OM), the main outcome recommended as a summary measure of accuracy includeing all pairwise stages and grades comparisons, which is not provided par the extensively used binary area under the ROC curve. RESULTS: The diagnostic performance of each component of the panel was significant. OM (SE; significance) of the FibroTest, the NashTest-2 and the SteatoTest-2 was 0.862 (0.012; P < 0.001), 0.827 (0.015; P < 0.001) and 0.794 (0.020; P < 0.01), respectively. For ballooning and lobular inflammation, OM was 0.794 (0.021; P < 0.001) and 0.821 (0.017; P < 0.001), respectively. In a post hoc analysis the FibroTest outperformed VCTE by 4.1% (2.5-6.5; P < 0.001) for reliability, with a non-significant difference for OM for fibrosis staging, 0.859 (0.012) for FibroTest vs 0.870 (0.009) for VCTE. CONCLUSIONS: From a single blood sample, the panel provides non-invasive diagnosis of the stages of fibrosis, and the grades of NASH and steatosis in patients with T2DM. TRIAL REGISTRATION NUMBER: NCT03634098.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Biópsia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Humanos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Estudos Prospectivos , Reprodutibilidade dos Testes
4.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445300

RESUMO

Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic ß-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in insulin resistance. Insulin resistance is a consequence of a complex combination of metabolic disorders, lipotoxicity, glucotoxicity, and inflammation. There is ample evidence linking different mechanistic approaches as the cause of insulin resistance, but no central mechanism is yet described as an underlying reason behind this condition. This review combines and interlinks the defects in the insulin signal transduction pathway of the insulin resistance state with special emphasis on the AGE-RAGE-NF-κB axis. Here, we describe important factors that play a crucial role in the pathogenesis of insulin resistance to provide directionality for the events. The interplay of inflammation and oxidative stress that leads to ß-cell decline through the IAPP-RAGE induced ß-cell toxicity is also addressed. Overall, by generating a comprehensive overview of the plethora of mechanisms involved in insulin resistance, we focus on the establishment of unifying mechanisms to provide new insights for the future interventions of type 2 diabetes mellitus.


Assuntos
Resistência à Insulina/fisiologia , Insulina/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia
5.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445304

RESUMO

Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.


Assuntos
Processamento Alternativo/fisiologia , Diabetes Mellitus Tipo 2/genética , Ilhotas Pancreáticas/metabolismo , Processamento Alternativo/genética , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Suscetibilidade a Doenças , Secreção de Insulina/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Regulação para Cima/genética
6.
Life Sci ; 283: 119870, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352258

RESUMO

OBJECTIVE: Increased renal and hepatic gluconeogenesis are important sources of fasting hyperglycemia in type 2 diabetes (T2D). The inhibitory effect of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on hepatic but not renal gluconeogenesis has been reported in rats with T2D. The present study aimed to determine the effects of co-administration of sodium nitrite and NaSH on the expression of genes involved in renal gluconeogenesis in rats with T2D. METHODS: T2D was induced by a combination of a high-fat diet and low-dose streptozotocin (30 mg/kg). Male Wistar rats were divided into 5 groups (n = 6/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite and NaSH were administered for nine weeks at a dose of 50 mg/L (in drinking water) and 0.28 mg/kg (daily intraperitoneal injection), respectively. Serum levels of urea and creatinine, and mRNA expressions of PEPCK, G6Pase, FBPase, PC, PI3K, AKT, PGC-1α, and FoxO1 in the renal tissue, were measured at the end of the study. RESULTS: Nitrite decreased mRNA expression of PEPCK by 39%, G6Pase by 43%, FBPase by 41%, PC by 63%, PGC-1α by 45%, and FoxO1 by 27% in the renal tissue of rats with T2D; co-administration of nitrite and NaSH further decreases FoxO1, while had no additive effects on the tissue expression of the other genes. In addition, nitrite+NaSH decreased elevated serum urea levels by 58% and creatinine by 37% in rats with T2D. CONCLUSION: The inhibitory effect of nitrite on gluconeogenesis in T2D rats is at least in part due to decreased mRNA expressions of renal gluconeogenic genes. Unlike effects on hepatic gluconeogenesis, co-administration of nitrite and NaSH has no additive effects on genes involved in renal gluconeogenesis in rats with T2D.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/efeitos dos fármacos , Rim/metabolismo , Nitrito de Sódio/farmacologia , Sulfetos/farmacologia , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Rim/patologia , Masculino , Ratos , Ratos Wistar
7.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360563

RESUMO

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the "modern" Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin-GH-IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin-GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.


Assuntos
Envelhecimento/patologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/patologia , Hiperinsulinismo/complicações , Resistência à Insulina , Neoplasias/patologia , Obesidade/patologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Humanos , Neoplasias/etiologia
8.
Med Sci Monit ; 27: e934134, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34456329

RESUMO

Non-alcoholic fatty liver disease (NAFLD) affects almost a quarter of the world's population and is the most common cause of chronic liver disease in children and adolescents. The recent proposal to replace the terminology of NAFLD with metabolic-associated fatty liver disease (MAFLD) aims to reflect the pathophysiology and risk factors for this disease. Importantly, the risk factors for MAFLD may be prenatal, such as genetic factors, or postnatal, such as obesity and insulin resistance. MAFLD is increasingly recognized in children and adolescents. Early diagnosis and identification of high-risk individuals with type 2 diabetes mellitus and metabolic syndrome is important. The diagnosis and management of MAFLD in children and adolescents should follow international clinical guidelines, such as those from the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD). Current guidelines recommend lifestyle and dietary modifications, exercise, screening, individualized patient assessment, and multidisciplinary patient management. This review assesses the revised terminology and discusses the epidemiology, risk factors, pathophysiology, diagnosis, and prevention of MAFLD in children and adolescents worldwide and in Mexico, and also considers the implications for public health.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Síndrome Metabólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/fisiopatologia , Adolescente , Criança , Diabetes Mellitus Tipo 2/patologia , Saúde Global , Humanos , México/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Prevalência , Prognóstico , Saúde Pública
9.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360753

RESUMO

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1ß from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proteína HMGB1/farmacologia , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Interleucina-2/farmacologia , Leptina/metabolismo , Leucócitos Mononucleares/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Hiperglicemia/patologia , Hiperinsulinismo/patologia , Leucócitos Mononucleares/patologia
10.
Eur J Endocrinol ; 185(4): 565-576, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34374650

RESUMO

Objective: Progressive beta-cell dysfunction is a hallmark of type 2 diabetes (T2D). Increasing evidence indicates that over-stimulating proinsulin synthesis causes proinsulin misfolding and impairs insulin maturation and storage in db/db mice. However, defective insulin maturation in patients with T2D remains unknown. Methods: We examined intra-islet and intra-cellular distributions of proinsulin and insulin and proinsulin to insulin ratio in the islets of patients with T2D. The expression of transcription factor NKX6.1 and dedifferentiation marker ALDH1A3, as well as glucagon, were detected by immunofluorescence. Results: We identified a novel subgroup of beta cells expressing only proinsulin but not insulin. Importantly, significantly increased proinsulin positive and insulin negative (PI+/INS-) cells were evident in T2D, and this increase was strongly correlated with levels of hemoglobin A1C (HbA1c) in T2D and prediabetes. The percentages of beta cells expressing prohormone convertase 1/3 and carboxypeptidase E were not reduced. Indeed, while proinsulin displayed a higher degree of co-localization with the golgi markers GM130/TGN46 in control beta cells, it appeared to be more diffused within the cytoplasm and less co-localized with GM130/TGN46 in PI+/INS- cells. Furthermore, the key functional transcription factor NKX6.1 markedly decreased in the islets of T2D, especially in the cells with PI+/INS-. The decreased NKX6.1+/PI+/INS+ was strongly correlated with levels of HbA1c in T2D. Almost all PI+/INS- cells showed absence of NKX6.1. Moreover, the percentages of PI+/INS- cells expressing ALDH1A3 were elevated along with an increased acquisition of glucagon immunostaining. Conclusion: Our data demonstrate defective insulin maturation in patients with T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proinsulina/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Adulto , Aldeído Oxirredutases/metabolismo , Estudos de Casos e Controles , Desdiferenciação Celular/fisiologia , China , Diabetes Mellitus Tipo 2/patologia , Feminino , Glucagon/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia
11.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361079

RESUMO

The liver has a most indispensable role in glucose and lipid metabolism where we see some of the most serious worldwide health problems. The serine protease prostasin (PRSS8) cleaves toll-like receptor 4 (TLR4) and regulates hepatic insulin sensitivity under PRSS8 knockout condition. However, liver substrate proteins of PRSS8 other than TLR4 and the effect to glucose and lipid metabolism remain unclarified with hepatic elevation of PRSS8 expression. Here we show that high-fat-diet-fed liver-specific PRSS8 transgenic mice improved glucose tolerance and hepatic steatosis independent of body weight. PRSS8 amplified extracellular signal-regulated kinase phosphorylation associated with matrix metalloproteinase 14 activation in vivo and in vitro. Moreover, in humans, serum PRSS8 levels reduced more in type 2 diabetes mellitus (T2DM) patients than healthy controls and were lower in T2DM patients with increased maximum carotid artery intima media thickness (>1.1 mm). These results identify the regulatory mechanisms of PRSS8 overexpression over glucose and lipid metabolism, as well as excessive hepatic fat storage.


Assuntos
Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/patologia , Serina Endopeptidases/metabolismo , Animais , Peso Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Feminino , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Serina Endopeptidases/genética
12.
Molecules ; 26(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299638

RESUMO

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Estresse do Retículo Endoplasmático , Estresse Oxidativo , Transdução de Sinais , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia
13.
Am J Hum Genet ; 108(9): 1578-1589, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34265237

RESUMO

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.


Assuntos
Aneurisma da Aorta Torácica/genética , Diabetes Mellitus Tipo 2/genética , Células Endoteliais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Locos de Características Quantitativas , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Estudos de Casos e Controles , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/patologia , Regulação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Michigan , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
14.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299173

RESUMO

Diabetic nephropathy (DN) is one of the most significant microvascular complications in diabetic patients. DN is the leading cause of end-stage renal disease, accounting for approximately 50% of incident cases. The current treatment options, such as optimal control of hyperglycemia and elevated blood pressure, are insufficient to prevent its progression. DN has been considered as a nonimmune, metabolic, or hemodynamic glomerular disease initiated by hyperglycemia. However, recent studies suggest that DN is an inflammatory disease, and immune cells related with innate and adaptive immunity, such as macrophage and T cells, might be involved in its development and progression. Although it has been revealed that kidney dendritic cells (DCs) accumulation in the renal tissue of human and animal models of DN require activated T cells in the kidney disease, little is known about the function of DCs in DN. In this review, we describe kidney DCs and their subsets, and the role in the pathogenesis of DN. We also suggest how to improve the kidney outcomes by modulating kidney DCs optimally in the patients with DN.


Assuntos
Células Dendríticas/imunologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/patologia , Ativação Linfocitária/imunologia , Animais , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/etiologia , Humanos
15.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299172

RESUMO

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


Assuntos
Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/patologia , Edição de Genes , Modelos Biológicos , Animais , Complicações do Diabetes/etiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Humanos
16.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209800

RESUMO

Diabetes mellitus (DM) is a chronic metabolic disease characterised by insulin deficiency, resulting in hyperglycaemia, a characteristic symptom of type 2 diabetes mellitus (DM2). DM substantially affects numerous metabolic pathways, resulting in ß-cell dysfunction, insulin resistance, abnormal blood glucose levels, impaired lipid metabolism, inflammatory processes, and excessive oxidative stress. Oxidative stress can affect the body's normal physiological function and cause numerous cellular and molecular changes, such as mitochondrial dysfunction. Animal models are useful for exploring the cellular and molecular mechanisms of DM and improving novel therapeutics for their safe use in human beings. Due to their health benefits, there is significant interest in a wide range of natural compounds that can act as naturally occurring anti-diabetic compounds. Due to rodent models' relatively similar physiology to humans and ease of handling and housing, they are widely used as pre-clinical models for studying several metabolic disorders. In this review, we analyse the currently available rodent animal models of DM and their advantages and disadvantages and highlight the potential anti-oxidative effects of natural compounds and their mechanisms of action.


Assuntos
Produtos Biológicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Produtos Biológicos/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Estresse Oxidativo/fisiologia , Roedores
17.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200240

RESUMO

The term neuroinflammation refers to inflammation of the nervous tissue, in general, and in the central nervous system (CNS), in particular. It is a driver of neurotoxicity, it is detrimental, and implies that glial cell activation happens prior to neuronal degeneration and, possibly, even causes it. The inflammation-like glial responses may be initiated in response to a variety of cues such as infection, traumatic brain injury, toxic metabolites, or autoimmunity. The inflammatory response of activated microglia engages the immune system and initiates tissue repair. Through translational research the role played by neuroinflammation has been acknowledged in different disease entities. Intriguingly, these entities include both those directly related to the CNS (commonly designated neuropsychiatric disorders) and those not directly related to the CNS (e.g., cancer and diabetes type 2). Interestingly, all the above-mentioned entities belong to the same group of "complex disorders". This review aims to summarize cumulated data supporting the hypothesis that neuroinflammation is a common denominator of a wide variety of complex diseases. We will concentrate on cancer, type 2 diabetes (T2DM), and neuropsychiatric disorders (focusing on mood disorders).


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Inflamação/complicações , Transtornos Mentais/etiologia , Neoplasias/etiologia , Neurônios/patologia , Animais , Diabetes Mellitus Tipo 2/patologia , Humanos , Transtornos Mentais/patologia , Neoplasias/patologia
18.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209306

RESUMO

Diabetic foot ulcer (DFU) is a diabetes complication which greatly impacts the patient's quality of life, often leading to amputation of the affected limb unless there is a timely and adequate management of the patient. DFUs have a high economic impact for the national health system. Data have indeed shown that DFUs are a major cause of hospitalization for patients with diabetes. Based on that, DFUs represent a very important challenge for the national health system. Especially in developed countries diabetic patients are increasing at a very high rate and as expected, also the incidence of DFUs is increasing due to longevity of diabetic patients in the western population. Herein, the surgical approach focused on the targeted use of the acellular dermal matrix has been integrated with biochemical and morphological/histological analyses to obtain evidence-based information on the mechanisms underlying tissue regeneration. In this research report, the clinical results indicated decreased postoperative wound infection levels and a short healing time, with a sound regeneration of tissues. Here we demonstrate that the key biomarkers of wound healing process are activated at gene expression level and also synthesis of collagen I, collagen III and elastin is prompted and modulated within the 28-day period of observation. These analyses were run on five patients treated with Integra® sheet and five treated with the injectable matrix Integra® Flowable, for cavitary lesions. In fact, clinical evaluation of improved healing was, for the first time, supported by biochemical and histological analyses. For these reasons, the present work opens a new scenario in DFUs treatment and follow-up, laying the foundation for a tailored protocol towards complete healing in severe pathological conditions.


Assuntos
Derme Acelular , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Pé Diabético , Cicatrização , Idoso , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Pé Diabético/metabolismo , Pé Diabético/patologia , Pé Diabético/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Am J Physiol Cell Physiol ; 321(1): C187-C198, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34106786

RESUMO

Ca2+ signaling plays a critical role in the regulation of hepatic metabolism by hormones including insulin. Changes in cytoplasmic Ca2+ regulate synthesis and posttranslational modification of key signaling proteins in the insulin pathways. Emerging evidence suggests that hepatocyte intracellular Ca2+ signaling is altered in lipid-loaded liver cells isolated from obese rodent models. The mechanisms of altered Ca2+-insulin and insulin-Ca2+ signaling pathways in obesity remain poorly understood. Here, we show that the kinetics of insulin-initiated intracellular (initial) Ca2+ release from endoplasmic reticulum is significantly impaired in steatotic hepatocytes from obese Alström syndrome mice. Furthermore, exenatide, a glucagon-like peptide-1 (GLP-1) analog, reversed lipid-induced inhibition of intracellular Ca2+ release kinetics in steatotic hepatocytes, without affecting the total content of intracellular Ca2+ released. Exenatide reversed the lipid-induced inhibition of intracellular Ca2+ release, at least partially, via lipid reduction in hepatocytes, which then restored hormone-regulated cytoplasmic Ca2+ signaling and insulin sensitivity. This data provides additional evidence for the important role of Ca2+ signaling pathways in obesity-associated impaired hepatic lipid homeostasis and insulin signaling. It also highlights a potential advantage of GLP-1 analogs when used to treat type 2 diabetes associated with hepatic steatosis.


Assuntos
Síndrome de Alstrom/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/farmacologia , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Síndrome de Alstrom/metabolismo , Síndrome de Alstrom/patologia , Animais , Glicemia/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Corantes Fluorescentes/metabolismo , Fura-2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Insulina/metabolismo , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/metabolismo , Obesidade/patologia , Ácido Palmítico/farmacologia
20.
Nat Med ; 27(6): 1079-1087, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34127852

RESUMO

Agonism of the glucagon-like peptide-1 receptor (GLP-1R) results in glycemic lowering and body weight loss and is a therapeutic strategy to treat type 2 diabetes (T2D) and obesity. We developed danuglipron (PF-06882961), an oral small-molecule GLP-1R agonist and found it had comparable efficacy to injectable peptidic GLP-1R agonists in a humanized mouse model. We then completed a placebo-controlled, randomized, double-blind, multiple ascending-dose phase 1 study ( NCT03538743 ), in which we enrolled 98 patients with T2D on background metformin and randomized them to receive multiple ascending doses of danuglipron or placebo for 28 d, across eight cohorts. The primary outcomes were assessment of adverse events (AEs), safety laboratory tests, vital signs and 12-lead electrocardiograms. Most AEs were mild, with nausea, dyspepsia and vomiting most commonly reported. There were no clinically meaningful AEs in laboratory values across groups. Heart rate generally increased with danuglipron treatment at day 28, but no heart-rate AEs were reported. Systolic blood pressure was slightly decreased and changes in diastolic blood pressure were similar with danuglipron treatment at day 28, compared with placebo. There were no clinically meaningful electrocardiogram findings. In this study in T2D, danuglipron was generally well tolerated, with a safety profile consistent with the mechanism of action of GLP-1R agonism.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Hipoglicemiantes/administração & dosagem , Obesidade/tratamento farmacológico , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/administração & dosagem , Camundongos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/genética , Obesidade/patologia
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