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1.
Lipids Health Dis ; 22(1): 11, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36694216

RESUMO

OBJECTIVE: This study investigated the correlation of liver fat content (LFC) with metabolic characteristics and its association with chronic complications in type 2 diabetes mellitus (T2DM) patients. METHODS: Eighty-one prospectively enrolled T2DM patients were divided into non-alcoholic fatty liver disease (NAFLD) group and the non-NAFLD group according to the presence of NAFL complications. LFC was determined by MRI IDEAL-IQ Sequence, and patients were divided into 4 groups according to LFC by quartile method. Basic information, metabolic indexes, and occurrence of chronic complications in different groups were analyzed and compared. RESULTS: BMI, SBP, DBP, TG, ALT, AST, GGT, UA, HbA1c, FCP, 2 h CP, HOMA-IR, and HOMA-IS in the NAFLD group were significantly higher than the non-NAFLD group (P < 0.05). The incidences of chronic complications in the NAFLD group were higher than in the non-NAFLD group but not statistically significant (P > 0.05). BMI, SBP, DBP, TC, TG, ALT, AST, FCP, 2 h CP, HOMA-IR, and HOMA-IS showed significant differences between the patients with different LFC, and these indexes were significantly higher in patients with higher LFC than those with lower LFC (P < 0.05). Moreover, diabetes duration, TC, HOMA-IR, and LFC were the risk factors for ASCVD complications, while diabetes duration, TG, and LDL-C were risk factors for DN complications. Also, diabetes duration and SBP were risk factors for both DR and DPN complications in T2DM patients (P < 0.05). CONCLUSION: LFC is positively correlated with the severity of the systemic metabolic disorder and chronic complications in T2DM patients.


Assuntos
Tecido Adiposo , Diabetes Mellitus Tipo 2 , Fígado , Hepatopatia Gordurosa não Alcoólica , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Fatores de Risco , Fígado/metabolismo , Fígado/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Gorduras/análise
2.
Int J Mol Sci ; 24(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36674688

RESUMO

Intrahepatic oxidative stress is a key driver of inflammation and fibrogenesis in non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the role of extracellular Nicotinamide phosphoribosyltransferase (eNAMPT) and extracellular nicotinic acid phosphoribosyltransferase (eNAPRT) for the detection of advanced fibrosis. eNAMPT and eNAPRT were tested in 180 consecutive biopsy-proven NAFLD patients and compared with liver stiffness (LS) and the FIB-4 score. eNAMPT was similarly distributed across fibrosis stages, whereas eNAPRT was increased in patients with advanced fibrosis (p = 0.036) and was associated with advanced fibrosis (OR 1.08, p = 0.016). A multiple stepwise logistic regression model containing significant variables for advanced fibrosis (eNAPRT, type 2 diabetes, age, male sex, ALT) had an area under the curve (AUC) of 0.82 (Se 89.6%, Sp 67.3%, PPV 46.7%, NPV 93.8%) when compared to that of LS (0.79; Se 63.5%, Sp 86.2%, PPV 66.0%, NPV 84.8%) and to that of the FIB-4 score (0.73; Se 80.0%, Sp 56.8%, PPV 44.9%, NPV 86.6%). The use of eNAPRT in clinical practice might allow for the better characterization of NAFLD patients at higher risk of disease progression.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/patologia , Cirrose Hepática/patologia , Diabetes Mellitus Tipo 2/patologia , Alanina Transaminase , Fibrose , Biópsia , Fígado/patologia
3.
Int J Mol Sci ; 24(2)2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36675217

RESUMO

To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.


Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hepatopatia Gordurosa não Alcoólica , Humanos , Diabetes Mellitus Tipo 2/patologia , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
4.
BMJ Open ; 13(1): e063959, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639212

RESUMO

INTRODUCTION: Identification of advanced hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) is important as this may progress to cirrhosis and hepatocellular carcinoma. The risk of hepatic fibrosis is especially high among patients with diabetes with NAFLD. Annual screening of patients with diabetes for fatty liver and calculation of Fibrosis-4 (FIB-4) score and exclusion of significant fibrosis with vibration-controlled transient elastography (VCTE) have been recommended. However, VCTE is expensive and may not be freely available in resource-limited settings. We aim to identify predictors of significant liver fibrosis who are at increased risk of progression to advanced liver fibrosis and to develop a prediction model to prioritise referral of patients with diabetes and NAFLD for VCTE. METHODS AND ANALYSIS: This cross-sectional study is conducted among all consenting adults with type 2 diabetes mellitus with NAFLD at the Colombo North Teaching Hospital, Ragama, Sri Lanka. All patients get the FIB-4 score calculated. Those with FIB-4 ≥1.3 undergo VCTE (with FibroScan by Echosens). Risk associations for progression to advanced liver fibrosis/cirrhosis will be identified by comparing patients with significant fibrosis (liver stiffness measure (LSM) ≥8 kPa) and without significant fibrosis (LSM <8 kPa). A model to predict significant liver fibrosis will be developed using logistic regression. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (P/66/07/2021). Results of the study will be disseminated as scientific publications in reputable journals.


Assuntos
Diabetes Mellitus Tipo 2 , Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Adulto , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Fibrose , Cirrose Hepática/diagnóstico por imagem , Técnicas de Imagem por Elasticidade/métodos , Fígado/diagnóstico por imagem , Fígado/patologia
5.
ACS Appl Mater Interfaces ; 15(2): 2617-2629, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36596222

RESUMO

The fibrillization and deposition of the human islet amyloid polypeptide (hIAPP) are the pathological hallmark of type 2 diabetes mellitus (T2DM), and these insoluble fibrotic depositions of hIAPP are considered to strongly affect insulin secretion by inducing toxicity toward pancreatic islet ß-cells. The current strategy of preventing amyloid aggregation by nanoparticle-assisted inhibitors can only disassemble fibrotic amyloids into more toxic oligomers and/or protofibrils. Herein, for the first time, we propose a type of cysteine-derived chiral carbon quantum dot (CQD) that targets plasmin, a core natural fibrinolytic protease in humans. These CQDs can serve as fibrinolytic activity regulators for plasmin to cleave hIAPP into nontoxic polypeptides or into even smaller amino acid fragments, thus alleviating hIAPP's fibrotic amyloid-induced cytotoxicity. Our experiments indicate that chiral CQDs have opposing effects on plasmin activity. The l-CQDs promote the cleavage of hIAPP by enhancing plasmin activity at a promotion ratio of 23.2%, thus protecting ß-cells from amyloid-induced toxicity. In contrast, the resultant d-CQDs significantly inhibit proteolysis, decreasing plasmin activity by 31.5% under the same reaction conditions. Second harmonic generation (SHG) microscopic imaging is initially used to dynamically characterize hIAPP before and after proteolysis. The l-CQD promotion of plasmin activity thus provides a promising avenue for the hIAPP-targeted treatment of T2DM to treat low fibrinolytic activity, while the d-CQDs, as inhibitors of plasmin activity, may improve patient survival for hyperfibrinolytic conditions, such as those existing during surgeries and traumas.


Assuntos
Diabetes Mellitus Tipo 2 , Pontos Quânticos , Humanos , Diabetes Mellitus Tipo 2/patologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Cisteína , Fibrinolisina , Carbono , Amiloide/química
6.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166283, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34601015

RESUMO

Advanced glycation end products (AGEs) play a critical pathogenic role in the development of diabetic complications. Recent studies have shown that diabetes is associated with not only abnormal glucose metabolism but also abnormal ribose and fructose metabolism, although glucose is present at the highest concentration in humans. The glycation ability and contribution of ribose and fructose to diabetic complications remain unclear. Here, the glycation ability of ribose, fructose and glucose under a mimic physiological condition, in which the concentration of ribose or fructose was one-fiftieth that of glucose, was compared. Bovine serum albumin (BSA) was used as the working protein in our experiments. Ribose generated more AGEs and was markedly more cytotoxic to SH-SY5Y cells than fructose. The first-order rate constant of ribose glycation was found to be significantly greater than that of fructose glycation. LC-MS/MS analysis revealed 41 ribose-glycated Lys residues and 12 fructose-glycated residues. Except for the shared Lys residues, ribose reacted selectively with 17 Lys, while no selective Lys was found in fructose-glycated BSA. Protein conformational changes suggested that ribose glycation may induce BSA into amyloid-like monomers compared with fructose glycation. The levels of serum ribose were correlated positively with glycated serum protein (GSP) and diabetic duration in type 2 diabetes mellitus (T2DM), respectively. These results indicate that ribose has a greater glycation ability than fructose, while ribose largely contributes to the production of AGEs and provides a new insight to understand in the occurrence and development of diabetes complications.


Assuntos
Complicações do Diabetes/sangue , Diabetes Mellitus Tipo 2/sangue , Produtos Finais de Glicação Avançada/genética , Soroalbumina Bovina/metabolismo , Animais , Bovinos , Cromatografia Líquida , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Frutose/sangue , Glucose/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Glicosilação , Humanos , Ribose/sangue , Espectrometria de Massas em Tandem
7.
Hum Exp Toxicol ; 41: 9603271221143713, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36510688

RESUMO

BACKGROUND: Diabetes nephropathy (DN) is a serious diabetic problem that may progress to renal failure. The root of Curcuma longa L., often known as turmeric, provides various health benefits. Bisacurone is a bioactive terpenoid found in small amounts in turmeric that possesses anti-inflammatory and antioxidant properties. The present study focuses on the potential protective effects of bisacurone against DN via reducing renal inflammation, oxidative stress, and apoptosis. METHODS: Type 2 diabetes was created in rats by feeding them a high-fat/high-sugar diet for 8 weeks, followed by a low dose of streptozotocin and Bisacurone (50 and 100 µg/kg bisacurone) given for 4 weeks. RESULTS: In diabetic rats, bisacurone reduced hyperglycemia, protected against body weight (BW) loss, lowered renal markers, reduced lipid profile alterations and avoided histological abnormalities. Bisacurone treatment reduced oxidative stress by decreasing malondialdehyde (MDA) levels while enhancing antioxidant defenses through superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) levels. Furthermore, bisacurone treatment activated the renal Nrf2/Keap1 signaling pathway but attenuated the high levels of NFκB p65, TNF-α, IL-1ß, IL-6, Cox2, and iNOS. Bisacurone also reduced Bax, caspase-3, caspase-9 and cytochrome c but increased Bcl-2 in the kidneys of diabetic rats. CONCLUSION: In the present study, bisacurone reduces DN by reducing hyperglycemia, oxidative stress, inflammation, and apoptosis, while also increasing Nrf2/HO-1 signaling.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Ratos , Animais , Nefropatias Diabéticas/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estresse Oxidativo , Apoptose , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Inflamação/metabolismo , Rim
8.
Sci Rep ; 12(1): 21527, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36513692

RESUMO

This cross-sectional, age- and gender-matched study included 20 eyes of non-diabetic subjects (non-DM group) and 60 eyes of type 2 diabetes mellitus (DM group). Subgroups of DM were classified by diabetic retinopathy (DR) staging into no DR (DM-no DR), non-proliferative DR (DM-NPDR), proliferative DR (DM-PDR), and by glycemic control (well-controlled DM; HbA1c < 7%, poorly controlled DM; HbA1c ≥ 7%). Conjunctival swabs were performed for ocular surface microbiome analysis using conventional culture and next-generation sequencing analysis (NGS). A higher culture-positive rate was found in DM (15%) than in non-DM group (5%) (p value = 0.437). Pathogenic organisms and antibiotic-resistant strains were detected in the DR groups (DM-NPDR and DM-PDR). The NGS analysis showed that potentially pathogenic bacteria such as Enterobacteriaceae, Neisseriaceae, Escherichia-Shigella, and Pseudomonas predominated in DM, especially in DR. There was dissimilarity in the ocular surface microbiome between DM and non-DM groups. The subgroup analysis showed that the DR group had significantly different microbial community from DM-no DR and non-DM groups (p value < 0.05). The microbial community in the poorly controlled DM was also significantly different from well-controlled DM and non-DM groups (p < 0.001). Using the NGS method, our study is the first to signify the importance of DR and glycemic control status, which affect the changes in the ocular surface microbiome.


Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Microbiota , Humanos , Diabetes Mellitus Tipo 2/patologia , Estudos Transversais , Retinopatia Diabética/patologia , Corioide/patologia , Microbiota/genética
9.
Technol Cancer Res Treat ; 21: 15330338221146870, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36575633

RESUMO

The major predisposing factors of developing oral cancer include smoking, alcohol drinking, and betel quid chewing. Betel quid chewing could cause the abrasion and damage of oral mucosa by crude fibers, chemical insults by additive slaked lime, and arecoline from areca nut. These would lead to the local consequence of oral submucosal fibrosis, which is regarded clinically as a precancer lesion and a major cause of trismus. In addition, the components and additives in betel quid contain chemical toxins and carcinogens, which would further affect the oral mucosa and gradually develop a malignancy. Following literature review, aside from having a greater total tumor burden and more local diseases in the oral cavity and digestive tract, patients with betel quid-related oral cancer also have more systemic diseases from metabolic syndrome, hypertension, cardiovascular disease, type II diabetes mellitus, and obesity than those without this habit. In conclusion, those patients who have the history of smoking, alcohol drinking, and betel quid chewing would present much more unique clinical characteristics than those who only have a history of smoking and alcohol drinking. More attention should therefore be paid to pretreatment evaluation, treatment strategy, and posttreatment follow-up among betel quid chewers.


Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias Bucais , Humanos , Areca/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Neoplasias Bucais/etiologia , Neoplasias Bucais/patologia , Mucosa Bucal , Consumo de Bebidas Alcoólicas/efeitos adversos
10.
BMC Med ; 20(1): 440, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369023

RESUMO

BACKGROUND: Untreated celiac disease (CD) patients have increased levels of blood glutamine and a lower duodenal expression of glutaminase (GLS). Intestinal gluconeogenesis (IGN) is a process through which glutamine is turned into glucose in the small intestine, for which GLS is crucial. Animal studies suggest impaired IGN may have long-term effects on metabolic control and be associated with the development of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The aim of this study was to thoroughly investigate IGN at the gene expression level in children with untreated celiac disease. METHODS: Quantitative polymerase chain reaction (qPCR) was used to quantify the expression of 11 target genes related to IGN using the delta-delta Ct method with three reference genes (GUSB, IPO8, and YWHAZ) in duodenal biopsies collected from 84 children with untreated celiac disease and 58 disease controls. RESULTS: Significantly lower expression of nine target genes involved in IGN was seen in duodenal biopsies from CD patients compared with controls: FBP1, G6PC, GLS, GPT1, PCK1, PPARGC1A, SLC2A2, SLC5A1, and SLC6A19. No significant difference in the expression was observed for G6PC3 or GOT1. CONCLUSIONS: Children with untreated celiac disease have lower expression of genes important for IGN. Further studies are warranted to disentangle whether this is a consequence of intestinal inflammation or due to an impaired metabolic pathway shared with other chronic metabolic diseases. Impaired IGN could be a mechanism behind the increased risk of NAFLD seen in CD patients.


Assuntos
Doença Celíaca , Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Animais , Doença Celíaca/genética , Gluconeogênese/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Glutamina/metabolismo , Diabetes Mellitus Tipo 2/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia
11.
Sci Rep ; 12(1): 19323, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369319

RESUMO

Renal ischemia/reperfusion (I/R) can induce acute kidney injury. Empagliflozin is a newly developed inhibitor of sodium-glucose cotransporter-2 (SGLT2) approved as an antidiabetic medication for patients with type 2 diabetes mellitus. Despite the established cardioprotective functions of empagliflozin, its protective role in renal I/R is unclear. Here, the present study evaluated the renoprotective effects of empagliflozin in a mouse model of renal I/R injury. Male C57/BL6 mice were allocated to sham-operated, I/R, and empagliflozin groups. Kidney pedicles on both sides were clamped for 45 min and were reperfused for 24 h. Empagliflozin (1 mg/kg) was administered to the mice for 2 days preischemia. The GSK-3ß inhibitor SB216763 was administered intravenously at the beginning of reperfusion (0.1 mg/kg). Renal function and histological scores were evaluated. The kidneys were taken for immunohistochemical analysis, western blotting and apoptosis measurements. We found that empagliflozin decreased serum levels of creatinine and urea, reduced the average kidney weight-to-tibia length ratio, attenuated tubular damage, reduced renal proinflammatory cytokine expression and inhibited apoptosis in injured kidneys. Furthermore, empagliflozin increased renal glycogen synthase kinase 3ß (GSK-3ß) phosphorylation post I/R. Pharmacological inhibition of GSK-3ß activity mimicked the renal protective effects offered by empagliflozin. In summary, these results support a protective role of empagliflozin against renal I/R injury.


Assuntos
Diabetes Mellitus Tipo 2 , Traumatismo por Reperfusão , Camundongos , Masculino , Animais , Glicogênio Sintase Quinase 3 beta , Diabetes Mellitus Tipo 2/patologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Rim/metabolismo , Camundongos Endogâmicos C57BL
12.
Artigo em Inglês | MEDLINE | ID: mdl-36418057

RESUMO

INTRODUCTION: Microvascular changes in eye and kidney shares some common factors in diabetes mellitus (DM). The purpose was to evaluate choroidal thickness (CT) and choriocapillaris (CC) density in patients with type 2 diabetes (T2D) and their association with diabetic kidney disease (DKD) using swept-source optical coherence tomography (SS-OCT). RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted with patients with T2D with mild or no diabetic retinopathy (DR) and non-diabetic controls. CT was measured with SS-OCT, and CC vascular density was measured with OCT angiography. These parameters were compared with inner retinal layers thickness in patients with and without DKD and non-diabetic controls. RESULTS: Ninety-three eyes from patients with T2D and 34 eyes from controls volunteers were included. Within the T2D group, 56 eyes with DKD and 37 eyes from patients with no diabetic kidney disease were examined. A statistically significant reduction of CT was observed in patients with DKD compared with controls, with no difference in CC density. There was an association between ganglion cell layer and central choroidal thickness reduction in the DKD group. CONCLUSIONS: Patients with T2D with DKD showed a decrease in CT with no difference in CC density compared with non-diabetic controls. This thinning might be related to vascular changes of choroidal layers such as Haller's and Sattler's with preservation of CC density, which is crucial for outer retina and retinal pigment epithelium health. Longitudinal studies are warranted to determine the association of choroidal changes with the pathogenesis of diabetes, and its association with early DKD and progression to more severe DR.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Retinopatia Diabética , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/patologia , Estudos Transversais , Corioide/diagnóstico por imagem , Corioide/irrigação sanguínea , Corioide/patologia , Tomografia de Coerência Óptica/efeitos adversos , Tomografia de Coerência Óptica/métodos , Retinopatia Diabética/etiologia , Retinopatia Diabética/complicações , Nefropatias Diabéticas/patologia
13.
Biomed Pharmacother ; 156: 113947, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411661

RESUMO

BACKGROUND: Sodium glucose cotransporter 2 (SGLT2) inhibitors originally developed for the treatment of type 2 diabetes are clinically very effective drugs halting chronic kidney disease progression. The underlying mechanisms are, however, not fully understood. METHODS: We generated single-cell transcriptomes of kidneys from rats with 5/6 nephrectomy before and after SGLT2 inhibitors treatment by single-cell RNA sequencing. FINDINGS: Empagliflozin treatment decreased BUN, creatinine and urinary albumin excretion compared to placebo by 39.8%, 34.1%, and 55%, respectively (p < 0.01 in all cases). Renal interstitial fibrosis and glomerulosclerosis was likewise decreased by 51% and 66.8%; respectively (p < 0.05 in all cases). 14 distinct kidney cell clusters could be identified by scRNA-seq. The polarization of M2 macrophages from state 1 (CD206-CD68- M2 macrophages) to state 5 (CD206+CD68+ M2 macrophages) was the main pro-fibrotic process, as CD206+CD68+ M2 macrophages highly expressed fibrosis-promoting genes and can convert into fibrocytes. Empagliflozin remarkably inhibited the expression of fibrosis-promoting (IFG1 and TREM2) and polarization-associated genes (GPNMB, LGALS3, PRDX5, and CTSB) in CD206+CD68+ M2 macrophages and attenuated inflammatory signals from CD8+ effector T cells. The inhibitory effect of empagliflozin on CD206+CD68+ M2 macrophages polarization was mainly achieved by affecting mitophagy and mTOR pathways. INTERPRETATION: We propose that the beneficial effects of empagliflozin on kidney function and morphology in 5/6 nephrectomyiced rats with established CKD are at least partially due to an inhibition of CD206+CD68+ M2 macrophage polarization by targeting mTOR and mitophagy pathways and attenuating inflammatory signals from CD8+ effector T cells. FUNDINGS: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Ratos , Animais , Ativação de Macrófagos , Diabetes Mellitus Tipo 2/patologia , Fibrose , Rim/patologia , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Nefrectomia , Serina-Treonina Quinases TOR , Glicoproteínas de Membrana
14.
Fluids Barriers CNS ; 19(1): 88, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36345028

RESUMO

BACKGROUND: While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-ß (Aß) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85-95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aß. METHODS: To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aß deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ™ Gelatin, and vascular functionality. RESULTS: We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aß. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. CONCLUSIONS: Our data support the cross-talk between metabolic disease and Aß deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.


Assuntos
Doença de Alzheimer , Angiopatia Amiloide Cerebral , Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Animais , Camundongos , Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estado Pré-Diabético/complicações , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , Angiopatia Amiloide Cerebral/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/complicações , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Encéfalo/metabolismo , Metaloproteinases da Matriz
15.
PLoS One ; 17(11): e0276976, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36322557

RESUMO

OBJECTIVE: We previously showed that low serum bilirubin levels are associated with disability in quality of daily living in older patients with diabetes. However, the underlying mechanism is not fully understood. The aim of this study is to assess the relationship between serum bilirubin levels and skeletal muscle mass in older patients with type2 diabetes. METHODS: A total of 272 older patients with type2 diabetes (152 male and 120 female) aged 60 years and over were continuously recruited from April 2020 to July 2020. Body composition was evaluated by bioelectrical impedance analysis. The skeletal muscle mass index (SMI) was calculated as appendicular muscle mass divided by height squared (m2). RESULTS: The SMI was markedly lower in old-old patients (aged 75 years and over) than in young-old patients (aged 60-74 years) in both male and female (7.1 ± 0.8 kg/m2 vs 7.6 ± 0.9 kg/m2, P<0.001; 5.5 ± 0.9 kg/m2 vs 6.3 ± 0.8 kg/m2, P<0.001, respectively). Multivariate regression analysis showed that the SMI was associated with body mass index (BMI) (p<0.001) and age (p = 0.048) in male young-old patients, while it was associated with BMI (p<0.001), age (p = 0.008), and serum indirect bilirubin levels (p = 0.038) in male old-old patients. In female, the SMI was associated with BMI (p<0.001) and age (p = 0.042) in young-old patients and associated with BMI alone (p<0.001) in old-old patients. CONCLUSION: Serum indirect bilirubin levels may be associated with the decreased skeletal muscle mass in male older patients (aged 75 years and over) with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Sarcopenia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Diabetes Mellitus Tipo 2/patologia , Músculo Esquelético/fisiologia , Índice de Massa Corporal , Composição Corporal , Bilirrubina , Sarcopenia/patologia
16.
Theranostics ; 12(17): 7250-7266, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36438502

RESUMO

Rationale: Extracellular matrix (ECM) remodeling, a key pathological feature in diabetic cardiomyopathy (DCM), is triggered by oxidative stress, inflammation, and various metabolic disorders in the heart. Cardiac fibroblasts (CFs) are the primary source of ECM proteins and the ultimate effector cells in ECM remodeling. CFs are turned on and differentiated into myofibroblasts in response to profibrotic signaling. Rnd3 is a small Rho-GTPase involved in the regulation of cell-cycle distribution, cell migration, and cell morphogenesis. Emerging evidence suggests a link between Rnd3 expression and onset of cardiovascular diseases. However, the role of Rnd3 in DCM remains unknown. Methods: Flow cytometry was employed to separate different types of cardiac cells. Type 2 diabetes mellitus was established in Rnd3 fibroblast-specific knockout and transgenic mice. RNA sequencing and chromatin immunoprecipitation assay were used to discern signaling pathways involved. Results: Rnd3 expression was reduced in cardiac tissues of diabetic mice, with CFs being the primary cell type. Fibroblast-specific upregulation of Rnd3 in vivo was protective against DCM, whereas Rnd3 downregulation in fibroblasts accentuated cardiac oxidative stress, fibrosis, ventricular remodeling, and dysfunction. Moreover, in vitro Rnd3 overexpression significantly attenuated reactive oxygen species production, CF migration and proliferation under high levels of glucose (35 mmol/L) and palmitic acid (500 µmol/L) challenge. Furthermore, RNA sequencing indicated that Notch and TGF-ß signaling were significantly suppressed upon Rnd3 overexpression. Mechanistically, Rnd3 regulated Notch and TGF-ß signaling by interacting with NICD and ROCK1, respectively. Specifically, glucotoxicity and lipotoxicity control Rnd3 expression by regulating the binding of Nr1H2 and Rnd3 promoter. Conclusions: Our findings provide compelling evidence in that fibroblast-specific activation of Rnd3 protects against cardiac remodeling in DCM, indicating promises of targeting Rnd3 in the treatment of DCM.


Assuntos
Diabetes Mellitus Tipo 2 , Cardiomiopatias Diabéticas , Miofibroblastos , Remodelação Ventricular , Animais , Camundongos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Camundongos Transgênicos , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia
17.
Front Endocrinol (Lausanne) ; 13: 995028, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36246918

RESUMO

Backgrounds: Ectopic fat deposition is closely related to chronic kidney disease (CKD). Currently, there are few population studies that have been conducted to determine the relationship between renal parenchyma fat deposition and the risk of CKD among patients with type 2 diabetes mellitus (T2DM). Therefore, we employed magnetic resonance imaging (MRI) to detect renal parenchyma fat content in individuals with T2DM, expressed as renal fat fraction (FF), to explore whether renal FF is an important risk factor for CKD in patients with T2DM. Methods: In this cross-sectional study, 189 subjects with T2DM were enrolled. CKD was defined as the estimated glomerular filtration rate (eGFR)<60 mL/min/1.73m2. Measurement of the renal FF was performed on a 3.0-T MRI (MAGNETOM Skyra, Siemens, Erlangen, Germany). Binary logistic regression was used to determine the association between tertiles of renal FF and risk of CKD. Receiver-operator characteristic (ROC) curves were constructed to evaluate the sensitivity and specificity of renal FF in detecting CKD in T2DM patients. Results: The patients were divided into three groups according to tertiles of the renal FF level (2.498 - 7.434). As renal FF increases, patients tend to be older, and more abdominally obese, with a decreased eGFR (p<0.05). After adjustment for potential confounders, patients in the highest tertile of renal FF had a significantly increased risk of CKD than those in the lowest tertile (odds ratio (OR) = 3.98, 95% confidence interval (CI) = 1.12 - 14.09, p = 0.032), and the area under the ROC curve for this model was 0.836 (0.765-0.907). Conclusions: The renal FF is significantly independently associated with CKD in patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Estudos Transversais , Diabetes Mellitus Tipo 2/patologia , Taxa de Filtração Glomerular , Humanos , Rim/diagnóstico por imagem , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico
18.
Diabetes Care ; 45(12): 3032-3039, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36215704

RESUMO

OBJECTIVE: Myocardial interstitial fibrosis expands the extracellular volume (ECV) and in patients with type 2 diabetes is implicated in development of heart failure. ECV can be determined with gadolinium contrast MRI. We investigated which known risk factors for cardiovascular disease were associated with increased ECV in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 296 patients with type 2 diabetes and 25 sex and age-matched control subjects were included in a cross-sectional MRI study. The influence of risk factors on ECV was investigated with multiple regression analysis. RESULTS: Control subjects and patients with type 2 diabetes without complications had similar ECV (mean ± SD 27.4 ± 2.1% vs. 27.9 ± 2.6%, P = 0.4). Compared with patients without, ECV was significantly increased in patients with one or more complications (29.0 ± 3.3%, P = 0.02). Both in univariable analysis and after multivariable adjustment, ischemic heart disease, autonomic neuropathy, and active smoking were associated with increased levels of ECV. Active smoking exhibited the largest effect size (ß = 2.0 percentage points, 95% CI 0.7-3.3). Former smokers ECV similar to that of never smokers. Albuminuria and systolic blood pressure were inversely associated with ECV in multivariable analysis, but after adjustment for medication suspected to affect ECV, the association with albuminuria was no longer significant (P = 0.1). Sodium-glucose cotransporter 2 inhibitor treatment was not significantly associated with reduced ECV (-0.8%, 95% CI -1.7 to 0.06, P = 0.067). CONCLUSIONS: Patients with complications of diabetes have increased ECV, not seen in patients without complications. Ischemic heart disease, autonomic neuropathy, and active but not former smoking were highly associated with increased ECV.


Assuntos
Cardiomiopatias , Diabetes Mellitus Tipo 2 , Isquemia Miocárdica , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Albuminúria/patologia , Estudos Transversais , Miocárdio/patologia , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/patologia , Fibrose , Fumar/efeitos adversos , Valor Preditivo dos Testes
19.
Sci Rep ; 12(1): 17166, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229584

RESUMO

Decreased pancreatic volume, increased pancreatic fat mass, and serrated pancreatic margins are characteristic morphological changes of the pancreas in subjects with type 2 diabetes mellitus. This retrospective study aimed to clarify the clinical significance of pancreatic morphological changes in subjects with type 2 diabetes mellitus who underwent abdominal magnetic resonance imaging. The mean age and HbA1c value were 59.1 ± 16.3 years old and 8.9 ± 2.3%, respectively. Pancreatic body mass corrected for body surface area (BSA) in subjects with diabetes mellitus was lower compared to those in normal glucose tolerance (49.4 ± 15.3 cm3 vs. 60.9 ± 7.8 cm3), although it did not reach a statistic significance. There was a negative correlation between BSA-corrected pancreatic volume and age, duration of diabetes, glycoalbumin, mean and max IMT, and there was a positive correlation between BSA-corrected pancreatic volume and HOMA2-ß. Serration of the pancreatic limbus was more often observed in subjects with diabetes mellitus compared to those in normal glucose tolerance (74.1% vs. 14.3%). Subjects with serrated changes were older and had higher HbA1c, and visceral fat area was significantly larger in subjects with serrated changes. BSA-corrected pancreatic volume in subjects with serrated changes was significantly smaller, and mean IMT was significantly thicker in subjects with serrulation. Furthermore, advanced diabetic retinopathy and diabetic nephropathy were more often observed in subjects with serrated changes. Taken together, decreased BSA-corrected pancreatic volume and serrated changes were associated with the progression of vascular complications in subjects with type 2 diabetes mellitus.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Adulto , Idoso , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Glucose , Humanos , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Estudos Retrospectivos
20.
Kidney Int ; 102(6): 1345-1358, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36055599

RESUMO

Hyperfiltration is a state of high glomerular filtration rate (GFR) observed in early diabetes that damages glomeruli, resulting in an iterative process of increasing filtration load on fewer and fewer remaining functional glomeruli. To delineate underlying cellular mechanisms of damage associated with hyperfiltration, transcriptional profiles of kidney biopsies from Pima Indians with type 2 diabetes with or without early-stage diabetic kidney disease were grouped into two hyperfiltration categories based on annual iothalamate GFR measurements. Twenty-six participants with a peak GFR measurement within two years of biopsy were categorized as the hyperfiltration group, and 26 in whom biopsy preceded peak GFR by over two years were considered pre-hyperfiltration. The hyperfiltration group had higher hemoglobin A1c, higher urine albumin-to-creatinine ratio, increased glomerular basement membrane width and lower podocyte density compared to the pre-hyperfiltration group. A glomerular 1240-gene transcriptional signature identified in the hyperfiltration group was enriched for endothelial stress response signaling genes, including endothelin-1, tec-kinase and transforming growth factor-ß1 pathways, with the majority of the transcripts mapped to endothelial and inflammatory cell clusters in kidney single cell transcriptional data. Thus, our analysis reveals molecular pathomechanisms associated with hyperfiltration in early diabetic kidney disease involving putative ligand-receptor pairs with downstream intracellular targets linked to cellular crosstalk between endothelial and mesangial cells.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Glomérulos Renais/patologia , Taxa de Filtração Glomerular , /metabolismo
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