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1.
Front Endocrinol (Lausanne) ; 15: 1359147, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38586449

RESUMO

Introduction: Proinflammatory cytokines are implicated in pancreatic ß cell failure in type 1 and type 2 diabetes and are known to stimulate alternative RNA splicing and the expression of nonsense-mediated RNA decay (NMD) components. Here, we investigate whether cytokines regulate NMD activity and identify transcript isoforms targeted in ß cells. Methods: A luciferase-based NMD reporter transiently expressed in rat INS1(832/13), human-derived EndoC-ßH3, or dispersed human islet cells is used to examine the effect of proinflammatory cytokines (Cyt) on NMD activity. The gain- or loss-of-function of two key NMD components, UPF3B and UPF2, is used to reveal the effect of cytokines on cell viability and function. RNA-sequencing and siRNA-mediated silencing are deployed using standard techniques. Results: Cyt attenuate NMD activity in insulin-producing cell lines and primary human ß cells. These effects are found to involve ER stress and are associated with the downregulation of UPF3B. Increases or decreases in NMD activity achieved by UPF3B overexpression (OE) or UPF2 silencing raise or lower Cyt-induced cell death, respectively, in EndoC-ßH3 cells and are associated with decreased or increased insulin content, respectively. No effects of these manipulations are observed on glucose-stimulated insulin secretion. Transcriptomic analysis reveals that Cyt increases alternative splicing (AS)-induced exon skipping in the transcript isoforms, and this is potentiated by UPF2 silencing. Gene enrichment analysis identifies transcripts regulated by UPF2 silencing whose proteins are localized and/or functional in the extracellular matrix (ECM), including the serine protease inhibitor SERPINA1/α-1-antitrypsin, whose silencing sensitizes ß-cells to Cyt cytotoxicity. Cytokines suppress NMD activity via UPR signaling, potentially serving as a protective response against Cyt-induced NMD component expression. Conclusion: Our findings highlight the central importance of RNA turnover in ß cell responses to inflammatory stress.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Insulinas , Humanos , Ratos , Animais , RNA/metabolismo , Células Secretoras de Insulina/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Insulinas/metabolismo , Proteínas de Ligação a RNA/genética
2.
Sci Rep ; 14(1): 8043, 2024 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580733

RESUMO

Bisphenol-A (BPA) is widely used in food packaging and household products, leading to daily human exposure and potential health risks including metabolic diseases like type 2 diabetes mellitus (T2DM). Understanding BPA's mechanisms and developing intervention strategies is urgent. Centella asiatica, a traditional herbal medicine containing pentacyclic triterpenoids, shows promise due to its antioxidant and anti-inflammatory properties, utilized for centuries in Ayurvedic therapy. We investigated the effect of Centella asiatica (CA) ethanol extract on BPA-induced pancreatic islet toxicity in male Swiss albino mice. BPA administration (10 and 100 µg/kg body weight, twice daily) for 21 days caused glucose homeostasis disturbances, insulin resistance, and islet dysfunction, which were partially mitigated by CA supplementation (200 and 400 mg/kg body weight). Additionally, heightened oxidative stress, elevated levels of proinflammatory cytokines, loss of mitochondrial membrane potential (MMP), abnormal cell cycle, and increased apoptosis were implicated in the detrimental impact of BPA on the endocrine pancreas which were effectively counteracted by CA supplementation. In summary, CA demonstrated a significant ability to mitigate BPA-induced apoptosis, modulate redox homeostasis, alleviate inflammation, preserve MMP, and regulate the cell cycle. As a result, CA emerged as a potent agent in neutralizing the diabetogenic effects of BPA to a considerable extent.


Assuntos
Centella , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Fenóis , Camundongos , Animais , Masculino , Humanos , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ilhotas Pancreáticas/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Compostos Benzidrílicos/farmacologia , Peso Corporal
3.
Sci Rep ; 14(1): 7670, 2024 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561446

RESUMO

Dietary factors such as food texture affect feeding behavior and energy metabolism, potentially causing obesity and type 2 diabetes. We previously found that rats fed soft pellets (SPs) were neither hyperphagic nor overweight but demonstrated glucose intolerance, insulin resistance, and hyperplasia of pancreatic ß-cells. In the present study, we investigated the mechanism of muscle atrophy in rats that had been fed SPs on a 3-h time-restricted feeding schedule for 24 weeks. As expected, the SP rats were normal weight; however, they developed insulin resistance, glucose intolerance, and fat accumulation. In addition, skeletal muscles of SP rats were histologically atrophic and demonstrated disrupted insulin signaling. Furthermore, we learned that the muscle atrophy of the SP rats developed via the IL-6-STAT3-SOCS3 and ubiquitin-proteasome pathways. Our data show that the dietary habit of consuming soft foods can lead to not only glucose intolerance or insulin resistance but also muscle atrophy.


Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Resistência à Insulina , Ratos , Animais , Resistência à Insulina/fisiologia , Intolerância à Glucose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Músculo Esquelético/metabolismo , Dieta , Dieta Hiperlipídica
4.
BMJ Open Diabetes Res Care ; 12(2)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38575156

RESUMO

INTRODUCTION: Diabetic kidney disease (DKD) is a major complication in patients with diabetes and the main contributor to the chronic kidney disease (CKD) global burden. Oxidative stress is a crucial factor in DKD pathogenesis but the role of the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) and its molecular regulators has been poorly investigated in man. RESEARCH DESIGN AND METHODS: In this case-control study, we analyzed the roles of Nrf2, a transcription factor shielding cells from oxidative stress, its repressor Kelch-like ECH-associated protein 1 (Keap1) and six microRNAs (miRNAs) that potentially suppress Nrf2. We categorized 99 participants into 3 groups: 33 non-dialysis patients with type 2 diabetes with DKD, 33 patients with type 2 diabetes without DKD and 33 control subjects and quantified the gene expression (messenger RNA (mRNA)) levels of Nrf2, Keap1 and 6 miRNAs. Moreover, we studied the correlation between gene expression levels and clinical indicators of kidney health. RESULTS: In patients with diabetes with DKD, Nrf2 mRNA levels were significantly lower than in patients without DKD (p=0.01) and controls (p=0.02), whereas no difference in Nrf2 expression levels existed between patients without DKD and controls. Conversely, in patients with and without DKD, Keap1 expression levels were significantly higher than in controls. Of the six miRNAs studied, miRNA 30e-5p showed differential expression, being markedly reduced in patients with DKD (p=0.007). Nrf2 mRNA levels directly correlated with estimated glomerular filtration rate (eGFR) in patients with DKD (r=0.34, p=0.05) and in a formal mediation analysis the eGFR emerged as the first factor in rank for explaining the difference in Nrf2 mRNA levels between patients with and without DKD. CONCLUSIONS: The observed dysregulation in the Nrf2-Keap1 axis and the unique expression pattern of miRNA30e-5p in DKD underscore the need for more focused research in this domain that can help identify novel intervention strategies for DKD in patients with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , MicroRNAs , Humanos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/patologia , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/genética
5.
Biol Pharm Bull ; 47(4): 791-795, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38583950

RESUMO

The number of patients with type 2 diabetes is increasing worldwide. The mechanisms leading to type 2 diabetes and its complications is being researched; however, the pathological mechanisms of diabetes in the small intestine remain unclear. Therefore, we examined these pathological mechanisms in the small intestine using a mouse model of type 2 diabetes (KK-Ay/TaJcl) aged 10 and 50 weeks. The results showed that diabetes worsened with age in the mice with type 2 diabetes. In these mice, advanced glycation end products (AGEs) in the small intestine and mast cell expression increased, whereas diamine oxidase (DAO) decreased; increased tumor necrosis factor (TNF)-α and histamine levels in the plasma and small intestine were also detected. Additionally, the expression of zonula occludens (ZO)-1 and Claudin1 and cell adhesion molecules in the small intestine reduced. These results exacerbated with age. These findings indicate that type 2 diabetes causes AGE/mast cell/histamine and TNF-α signal transmission in the small intestine and decreases small intestinal wall cell adhesion molecules cause TNF-α and histamine to flow into the body, worsening the diabetic condition. In addition, this sequence of events is suggested to be strengthened in aged mice with type 2 diabetes, thus exacerbating the disease. These findings of this study may facilitate the elucidation of the pathological mechanisms of type 2 diabetes and its associated complications.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Histamina/metabolismo , Intestino Delgado/metabolismo , Moléculas de Adesão Celular , Produtos Finais de Glicação Avançada/metabolismo
6.
Int J Mol Sci ; 25(5)2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38473908

RESUMO

As the burden of type 2 diabetes (T2D) continues to escalate globally, there is a growing need for novel, less-invasive biomarkers capable of early diabetes detection and monitoring of disease progression. Liquid biopsy, recognized for its minimally invasive nature, is increasingly being applied beyond oncology, and nevertheless shows its potential when the collection of the tissue biopsy is not possible. This diagnostic approach involves utilizing liquid biopsy markers such as cell-free nucleic acids, extracellular vesicles, and diverse metabolites for the molecular diagnosis of T2D and its related complications. In this context, we thoroughly examine recent developments in T2D liquid biopsy research. Additionally, we discuss the primary challenges and future prospects of employing liquid biopsy in the management of T2D. Prognosis, diagnosis and monitoring of T2D through liquid biopsy could be a game-changing technique for personalized diabetes management.


Assuntos
Ácidos Nucleicos Livres , Diabetes Mellitus Tipo 2 , Vesículas Extracelulares , Células Neoplásicas Circulantes , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Biomarcadores Tumorais/metabolismo , Biópsia Líquida/métodos , Vesículas Extracelulares/metabolismo , Ácidos Nucleicos Livres/metabolismo , Células Neoplásicas Circulantes/patologia
7.
Int J Mol Sci ; 25(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38474098

RESUMO

Type 2 diabetes mellitus (T2DM) represents a significant health problem globally and is linked to a number of complications such as cardiovascular disease, bone fragility and periodontitis. Autologous bone marrow mesenchymal stem cells (BM-MSCs) are a promising therapeutic approach for bone and periodontal regeneration; however, the effect of T2DM on the expression of osteogenic and periodontal markers in BM-MSCs is not fully established. Furthermore, the effect of the presence of comorbidities such as diabetes and osteoarthritis on BM-MSCs is also yet to be investigated. In the present study, BM-MSCs were isolated from osteoarthritic knee joints of diabetic and nondiabetic donors. Both cell groups were compared for their clonogenicity, proliferation rates, MSC enumeration and expression of surface markers. Formation of calcified deposits and expression of osteogenic and periodontal markers were assessed after 1, 2 and 3 weeks of basal and osteogenic culture. Diabetic and nondiabetic BM-MSCs showed similar clonogenic and growth potentials along with comparable numbers of MSCs. However, diabetic BM-MSCs displayed lower expression of periostin (POSTN) and cementum protein 1 (CEMP-1) at Wk3 osteogenic and Wk1 basal cultures, respectively. BM-MSCs from T2DM patients might be suitable candidates for stem cell-based therapeutics. However, further investigations into these cells' behaviours in vitro and in vivo under inflammatory environments and hyperglycaemic conditions are still required.


Assuntos
Diabetes Mellitus Tipo 2 , Células-Tronco Mesenquimais , Humanos , Diferenciação Celular , Diabetes Mellitus Tipo 2/metabolismo , Osteogênese , Células-Tronco Mesenquimais/metabolismo , Articulação do Joelho , Células da Medula Óssea
8.
Int J Mol Sci ; 25(5)2024 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-38474201

RESUMO

In recent years, the potent influence of tocotrienol (T3) on diminishing blood glucose and lipid concentrations in both Mus musculus (rats) and Homo sapiens (humans) has been established. However, the comprehensive exploration of tocotrienol's hypolipidemic impact and the corresponding mechanisms in aquatic species remains inadequate. In this study, we established a zebrafish model of a type 2 diabetes mellitus (T2DM) model through high-fat diet administration to zebrafish. In the T2DM zebrafish, the thickness of ocular vascular walls significantly increased compared to the control group, which was mitigated after treatment with T3. Additionally, our findings demonstrate the regulatory effect of T3 on lipid metabolism, leading to the reduced synthesis and storage of adipose tissue in zebrafish. We validated the expression patterns of genes relevant to these processes using RT-qPCR. In the T2DM model, there was an almost two-fold upregulation in pparγ and cyp7a1 mRNA levels, coupled with a significant downregulation in cpt1a mRNA (p < 0.01) compared to the control group. The ELISA revealed that the protein expression levels of Pparγ and Rxrα exhibited a two-fold elevation in the T2DM group relative to the control. In the T3-treated group, Pparγ and Rxrα protein expression levels consistently exhibited a two-fold decrease compared to the model group. Lipid metabolomics showed that T3 could affect the metabolic pathways of zebrafish lipid regulation, including lipid synthesis and decomposition. We provided experimental evidence that T3 could mitigate lipid accumulation in our zebrafish T2DM model. Elucidating the lipid-lowering effects of T3 could help to minimize the detrimental impacts of overfeeding in aquaculture.


Assuntos
Diabetes Mellitus Tipo 2 , Hiperlipidemias , Tocotrienóis , Humanos , Camundongos , Ratos , Animais , Tocotrienóis/metabolismo , Peixe-Zebra/metabolismo , Dieta Hiperlipídica , Hiperlipidemias/metabolismo , Óleo de Farelo de Arroz , Diabetes Mellitus Tipo 2/metabolismo , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo
9.
Int J Mol Sci ; 25(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474208

RESUMO

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with MASLD treated with semaglutide, a glucagon-like peptide-1 receptor agonist, demonstrate improvement in terms of liver damage. However, the mechanisms underlaying this beneficial effect are not yet fully elucidated. We investigated the efficacy of semaglutide in halting MASLD progression using a genetic mouse model of diabesity. Leptin-receptor-deficient mice with obesity and diabetes (BKS db/db) were either untreated or administered with semaglutide for 11 weeks. Changes in food and water intake, body weight and glycemia were monitored throughout the study. Body fat composition was assessed by dual-energy X-ray absorptiometry. Upon sacrifice, serum biochemical parameters, liver morphology, lipidomic profile and liver-lipid-related pathways were evaluated. The semaglutide-treated mice exhibited lower levels of glycemia, body weight, serum markers of liver dysfunction and total and percentage of fat mass compared to untreated db/db mice without a significant reduction in food intake. Histologically, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. Furthermore, the treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition by increasing the amount of polyunsaturated fatty acids. The administration of semaglutide to leptin-receptor-deficient, hyperphagic and diabetic mice resulted in the amelioration of MASLD, likely independently of daily caloric intake, suggesting a direct effect of semaglutide on the liver through modulation of the lipid profile.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Peptídeos Semelhantes ao Glucagon , Hepatopatia Gordurosa não Alcoólica , Humanos , Animais , Camundongos , Lipogênese , Leptina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fígado Gorduroso/metabolismo , Obesidade/metabolismo , Fígado/metabolismo , Peso Corporal , Triglicerídeos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Camundongos Obesos
10.
J Diabetes Res ; 2024: 3759339, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38455849

RESUMO

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood glucose levels resulting from insulin resistance and impaired insulin secretion. Immune dysregulation-mediated chronic low-grade inflammation is a critical factor that poses a significant risk to the metabolic disorders of T2DM and its related complications. Exosomes, as small extracellular vesicles secreted by various cells, have emerged as essential regulators of intercellular communication and immune regulation. In this review, we summarize the current understanding of the role of exosomes derived from immune and nonimmune cells in modulating immune responses in T2DM by regulating immune cell functions and cytokine production. More importantly, we suggest potential strategies for the clinical applications of exosomes in T2DM management, including biomarkers for disease diagnosis and monitoring, exosome-based therapies for drug delivery vehicles, and targeted therapy for exosomes.


Assuntos
Diabetes Mellitus Tipo 2 , Exossomos , Hiperglicemia , Resistência à Insulina , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Exossomos/metabolismo , Hiperglicemia/metabolismo , Imunidade
11.
Diabetes Metab Res Rev ; 40(3): e3787, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38461408

RESUMO

AIMS: Given the increasing number of individuals developing metabolic dysfunction-associated steatotic liver disease (MASLD) and the low rate of those with progressive liver disease, there is a pressing need to conceive affordable biomarkers to assess MASLD in general population settings. Herein, we aimed to investigate the performance of the ultrasound-derived fat fraction (UDFF) for hepatic steatosis in high-risk individuals. METHODS: A total of 302 Europeans with obesity, type 2 diabetes, or a clinical history of hepatic steatosis were included in the analyses. Clinical, laboratory, and imaging data were collected using standardized procedures during a single screening visit in Rome, Italy. Hepatic steatosis was defined by controlled attenuation parameter (CAP) or ultrasound-based Hamaguchi's score. UDFF performance for hepatic steatosis was estimated by the area under the receiver operating characteristic curve (AUC). RESULTS: Overall, median (IQR) UDFF was 12% (7-20). UDFF was positively correlated with CAP (ρ = 0.73, p < 0.0001) and Hamaguchi's score (ρ = 0.79, p < 0.0001). Independent predictors of UDFF were circulating triglycerides, alanine aminotransferase (ALT), and ultrasound-measured visceral adipose tissue (VAT). UDFF AUC was 0.89 (0.85-0.93) and 0.92 (0.88-0.95) for CAP- and ultrasound-diagnosed hepatic steatosis, respectively. UDFF AUC for hepatic steatosis was higher than those of fatty liver index (FLI), hepatic steatosis index (HSI), CAP-score (CAPS), and ALT (p < 0.0001). Lower age, ALT, and VAT were associated with discordance between UDFF and ultrasound. CONCLUSIONS: UDFF may be a simple and accurate imaging biomarker to assess hepatic steatosis and monitor changes in hepatic fat content over time or in response to therapeutic interventions beyond clinical trials.


Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Doenças Metabólicas , Hepatopatia Gordurosa não Alcoólica , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/diagnóstico por imagem , Fígado , Ultrassonografia/métodos , Curva ROC , Biomarcadores/metabolismo , Doenças Metabólicas/metabolismo , Hepatopatia Gordurosa não Alcoólica/diagnóstico
12.
Front Immunol ; 15: 1201439, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38482013

RESUMO

Introduction: Obesity is associated with chronic low-grade inflammation of adipose tissue (AT) and an increase of AT macrophages (ATMs) that is linked to the onset of type 2 diabetes. We have recently shown that neutralization of interleukin (IL)-6 in obese AT organ cultures inhibits proliferation of ATMs, which occurs preferentially in alternatively activated macrophage phenotype. Methods: In this study, we investigated AT biology and the metabolic phenotype of mice with myeloid cell-specific IL-6Rα deficiency (Il6ra Δmyel) after normal chow and 20 weeks of high-fat diet focusing on AT inflammation, ATM polarization and proliferation. Using organotypical AT culture and bone marrow derived macrophages (BMDMs) of IL-4Rα knockout mice (Il4ra -/-) we studied IL-6 signaling. Results: Obese Il6ra Δmyel mice exhibited no differences in insulin sensitivity or histological markers of AT inflammation. Notably, we found a reduction of ATMs expressing the mannose receptor 1 (CD206), as well as a decrease of the proliferation marker Ki67 in ATMs of Il6ra Δmyel mice. Importantly, organotypical AT culture and BMDM data of Il4ra -/- mice revealed that IL-6 mediates a shift towards the M2 phenotype independent from the IL-6/IL-4Rα axis. Discussion: Our results demonstrate IL-4Rα-independent anti-inflammatory effects of IL-6 on macrophages and the ability of IL-6 to maintain proliferation rates in obese AT.


Assuntos
Diabetes Mellitus Tipo 2 , Interleucina-6 , Camundongos , Animais , Interleucina-6/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Tecido Adiposo/metabolismo , Macrófagos/metabolismo , Inflamação/metabolismo , Camundongos Knockout , Obesidade/metabolismo
13.
BMC Pharmacol Toxicol ; 25(1): 26, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38504370

RESUMO

Browning of white adipose tissue (WAT) is become an appealing target for therapeutics in the treatment of obesity and related metabolic diseases. Dapagliflozin is widely used in the treatment of type 2 diabetes, and it is also found that the drug exhibits regulate systemic metabolism such as obesity, insulin resistance and hepatic steatosis. However, the precise role of dapagliflozin on WAT remodeling remains to be elucidated. The current study aimed to explore the role of dapagliflozin on WAT browning in high-fat diet (HFD)-induced obese mice. Male C57BL/6J mice (n = 6 per group) were used to establish obesity model by following feeding with HFD for 6 weeks. The mice were randomly treated with or without dapagliflozin for the experimental observation. The volume and fat fraction of WAT were quantified, H&E, UCP-1 staining and immunohistochemistry were conducted to investigate the white-to-brown fat conversion and angiogenesis in WAT respectively. Quantitative real-time polymerase chain reaction (qPCR) was employed to explore the mRNA expression levels of genes related to fat browning and angiogenesis in WAT. Subsequently, 3T3-L1 cells were used to explore the effect of dapagliflozin on preadipocytes differentiation in vitro. Our results demonstrated that dapagliflozin could reduce body weight gain and promote WAT browning in HFD induced obese mice via regulating lipogenesis and angiogenesis in WAT. Furthermore, dapagliflozin reduce cells differentiation, up-regulate the expression of WAT browning and angiogenesis genes in 3T3-L1 adipocytes in vitro. In conclusion, dapagliflozin can potentially promote WAT browning in HFD induced obese mice via improving lipogenesis and angiogenesis in WAT.


Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Masculino , Camundongos , Animais , Camundongos Obesos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Tecido Adiposo Branco/metabolismo , Dieta Hiperlipídica/efeitos adversos
14.
BMC Oral Health ; 24(1): 356, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509482

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) causes severe bone loss after tooth extraction as a hyperglycemic environment causes aberrant bone homeostasis. Artesunate (ART) is known to possess anti-inflammation and osteogenic properties. However, its osteogenesis property in alveolar bone remains unclear. This study aimed to explore the osteogenic and immunoregulatory effects of artesunate-loaded thermosensitive chitosan hydrogel (ART-loaded TCH) on maxilla tooth extraction in T2DM rats. METHODS: T2DM rats were induced by a high-fat diet and streptozotocin. Different concentrations of ART-loaded TCH were applied in tooth extraction sockets. Bone loss and the expression of osteogenic regulatory factors (OPG, ALP, RANK) were evaluated. The immunoregulatory effects of ART-loaded TCH were observed through detecting the infiltration of T lymphocytes and their cytokines. The underlying mechanisms were explored. RESULTS: Results showed that the 150 mg/ml ART-loaded TCH group significantly ameliorated maxilla bone height and bone mineral density when compared with the T2DM group (p < 0.05). It also improved the expression of OPG, ALP, and RANK. Although the alteration of CD4+ T, CD8+ T, and CD4+:CD8+ T ratio has no significant difference among groups, the release of Th1 and Th2 in the 150 mg/ml ART-loaded TCH group has been significantly regulated than in the T2DM group (p < 0.05). Besides, ART-loaded TCH treatment inhibited the expression of p38 MAPK and ERK1 in T2DM maxilla. CONCLUSIONS: Therefore, the results indicated that 150 mg/ml ART-loaded TCH could be an effective method to prevent bone loss in T2DM tooth extraction rats by modulating the immunoregulation of Th1 and Th2 and the MAPK signaling pathway.


Assuntos
Quitosana , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ratos , Animais , Osteogênese , Hidrogéis/farmacologia , Quitosana/uso terapêutico , Quitosana/farmacologia , Artesunato/uso terapêutico , Artesunato/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Maxila , Linfócitos T/metabolismo , Extração Dentária/métodos
15.
Cell Mol Life Sci ; 81(1): 146, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38502310

RESUMO

Complications associated with Type 1 and Type 2 diabetes, such as diabetic peripheral neuropathy and diabetic foot ulcers, are a growing health-care concern. In addition, this concern increases as diabetic patients age due to their increased susceptibility to complications. To address this growing problem, it is important to understand fluctuations in physiology which lead to pathological changes associated with the metabolic disturbances of diabetes. Our study explores dysregulation of immune cell populations in the hindpaws of healthy and diabetic mice at 12 and 21 weeks of age using single-cell RNA sequencing to provide insight into immune disruptions occurring in the distal limb during chronic diabetes. In 21-week-old Leprdb/db mice, increases were seen in mast cells/basophils, dermal γδ T cells, heterogeneous T cells, and Type 2 innate lymphoid cells. In addition, macrophages represented the largest cluster of immune cells and showed the greatest increase in genes associated with immune-specific pathways. Sub-clustering of macrophages revealed a bias toward angiogenic Lyve1+MHCIIlo macrophages in the hindpaws of 21-week-old diabetic mice, which corresponded to an increase in Lyve1+ macrophages in the hindpaws of 21-week-old diabetic mice on histology. Our results show that in Type 2 diabetes, the immunological function and phenotype of multiple immune cell types shift not only with metabolic disturbance, but also with duration of disease, which may explain the increased susceptibility to pathologies of the distal limb in patients with more chronic diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Humanos , Camundongos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Imunidade Inata , Linfócitos/metabolismo , Leucócitos/metabolismo , Análise de Célula Única
16.
Theranostics ; 14(5): 2058-2074, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505613

RESUMO

Rationale: NPC1 is a protein localized on the lysosome membrane regulating intracellular cholesterol transportation and maintaining normal lysosome function. GWAS studies have found that NPC1 variants in T2D was a pancreatic islet expression quantitative trait locus, suggesting a potential role of NPC1 in T2D islet pathophysiology. Methods: Two-week-old Npc1-/- mice and wild type littermates were employed to examine pancreatic ß cell morphology and functional changes induced by loss of Npc1. Single cell RNA sequencing was conducted on primary islets. Npc1-/- Min6 cell line was generated using CRISPR/Cas9 gene editing. Seahorse XF24 was used to analyze primary islet and Min6 cell mitochondria respiration. Ultra-high-resolution cell imaging with Lattice SIM2 and electron microscope imaging were used to observe mitochondria and lysosome in primary islet ß and Min6 cells. Mitophagy Dye and mt-Keima were used to measure ß cell mitophagy. Results: In Npc1-/- mice, we found that ß cell survival and pancreatic ß cell mass expansion as well as islet glucose induced insulin secretion in 2-week-old mice were reduced. Npc1 loss retarded postnatal ß cell differentiation and growth as well as impaired mitochondria oxidative phosphorylation (OXPHOS) function to increase mitochondrial superoxide production, which might be attributed to impaired autophagy flux particularly mitochondria autophagy (mitophagy) induced by dysfunctional lysosome in Npc1 null ß cells. Conclusion: Our study revealed that NPC1 played an important role in maintaining normal lysosome function and mitochondria turnover, which ensured establishment of sufficient mitochondria OXPHOS for islet ß cells differentiation and maturation.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Ilhotas Pancreáticas , Animais , Camundongos , Diferenciação Celular , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Mitocôndrias/metabolismo , Proteína C1 de Niemann-Pick/metabolismo
17.
Front Endocrinol (Lausanne) ; 15: 1350796, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38510703

RESUMO

Introduction: Type 2 diabetes (T2D) onset, progression and outcomes differ substantially between individuals. Multi-omics analyses may allow a deeper understanding of these differences and ultimately facilitate personalised treatments. Here, in an unsupervised "bottom-up" approach, we attempt to group T2D patients based solely on -omics data generated from plasma. Methods: Circulating plasma lipidomic and proteomic data from two independent clinical cohorts, Hoorn Diabetes Care System (DCS) and Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS), were analysed using Similarity Network Fusion. The resulting patient network was analysed with Logistic and Cox regression modelling to explore relationships between plasma -omic profiles and clinical characteristics. Results: From a total of 1,134 subjects in the two cohorts, levels of 180 circulating plasma lipids and 1195 proteins were used to separate patients into two subgroups. These differed in terms of glycaemic deterioration (Hazard Ratio=0.56;0.73), insulin sensitivity and secretion (C-peptide, p=3.7e-11;2.5e-06, DCS and GoDARTS, respectively; Homeostatic model assessment 2 (HOMA2)-B; -IR; -S, p=0.0008;4.2e-11;1.1e-09, only in DCS). The main molecular signatures separating the two groups included triacylglycerols, sphingomyelin, testican-1 and interleukin 18 receptor. Conclusions: Using an unsupervised network-based fusion method on plasma lipidomics and proteomics data from two independent cohorts, we were able to identify two subgroups of T2D patients differing in terms of disease severity. The molecular signatures identified within these subgroups provide insights into disease mechanisms and possibly new prognostic markers for T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Proteômica , Multiômica
18.
Front Biosci (Schol Ed) ; 16(1): 5, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38538341

RESUMO

The pathogenesis of type 2 diabetes mellitus (T2DM) is based on the development of insulin resistance, which is a disruption to the ability of the tissues to bind to insulin, leading to a general metabolic disorder. Mitochondria are the main participants in cellular energy metabolism, meaning their dysfunction is associated with the development of insulin resistance in T2DM. Mitochondrial function is affected by insulin resistance in various tissues, including skeletal muscle and the liver, which greatly influence glucose homeostasis throughout the body. This review studies mitochondrial dysfunction in T2DM and its impact on disease progression. In addition, it considers the causes underlying the development of mitochondrial dysfunction in T2DM, including mutations in the mitochondrial genome, mitochondrial DNA methylation, and other epigenetic influences, as well as the impact of impaired mitochondrial membrane potential. New therapeutic strategies for diabetes that have been developed to target the mitochondria will also be presented.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Doenças Metabólicas , Doenças Mitocondriais , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Metabolismo Energético , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia
19.
Biomed Pharmacother ; 173: 116395, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38460364

RESUMO

Dendrobium officinale (DEN) is recognized as a kind of functional food that can effectively ameliorate endocrine and metabolic disruptions. This study delved into the pharmacological mechanism of DEN on hepatic lipotoxicity associated with Type II diabetes mellitus (T2DM). In vivo study experiments on db/db mice indicated that DEN treatment notably enhanced liver function, decreased blood lipid levels, and improved insulin sensitivity. Non-targeted metabolomics analysis revealed that DEN significantly ameliorated metabolism pathways, including lipoic acid, linoleic acid, bile secretion, and the alanine/aspartate/glutamate metabolism, as well as taurine and hypotaurine metabolism. Transcriptomics analysis demonstrated DEN treatment could modulate the expression of genes such as Cpt1b, Scd1, G6pc2, Fos, Adrb2, Atp2a1, Ppp1r1b, and Cyp7a1. Furthermore, Proteomics analysis indicated that the beneficial effect of DEN on lipid metabolism was linked to pathways like AMPK and PPAR signaling. The integrative analysis of multi-omics revealed that the PPAR-RXR signaling was critical to the therapeutic effect of DEN on T2DM-induced fatty liver. Additionally, in vitro study on AML-12 cells confirmed that DEN counteract PA-induced lipid accumulation by activating the PPAR-RXR pathway. Overall, these findings suggested that DEN exhibited the potential to mitigate T2DM-induced hepatic lipo-toxicity and manage lipid imbalances in T2DM.


Assuntos
Dendrobium , Diabetes Mellitus Tipo 2 , Camundongos , Animais , Metabolismo dos Lipídeos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Multiômica , Fígado , Transdução de Sinais , Lipídeos/farmacologia , Camundongos Endogâmicos C57BL
20.
Biomolecules ; 14(3)2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38540669

RESUMO

Browning of white adipose tissue (WAT) is a focus of research in type 2 diabetes mellitus (T2DM) and metabolism, which may be a potential molecular mechanism for high-intensity interval training (HIIT) to improve T2DM. In this study, male C57BL/6J wild-type mice were subjected to an 8-week HIIT regimen following T2DM induction through a high-fat diet (HFD) combined with streptozotocin (STZ) injection. We found that HIIT improved glucose metabolism, body weight, and fat mass in T2DM mice. HIIT also decreased adipocyte size and induced browning of WAT. Our data revealed a decrease in TNFα and an increase in IL-10 with HIIT, although the expression of chemokines MCP-1 and CXCL14 was increased. We observed increased pan-macrophage infiltration induced by HIIT, along with a simultaneous decrease in the expression of M1 macrophage markers (iNOS and CD11c) and an increase in M2 macrophage markers (Arg1 and CD206), suggesting that HIIT promotes M2 macrophage polarization. Additionally, HIIT upregulated the expression of Slit3 and neurotrophic factors (BDNF and NGF). The expression of the sympathetic marker tyrosine hydroxylase (TH) and the nerve growth marker GAP43 was also increased, demonstrating the promotion of sympathetic nerve growth and density by HIIT. Notably, we observed macrophages co-localizing with TH, and HIIT induced the accumulation of M2 macrophages around sympathetic nerves, suggesting a potential association between M2 macrophages and increased density of sympathetic nerves. In conclusion, HIIT induces adipose tissue browning and improves glucose metabolism in T2DM mice by enhancing M2 macrophage polarization and promoting sympathetic nerve growth and density.


Assuntos
Diabetes Mellitus Tipo 2 , Treinamento Intervalado de Alta Intensidade , Masculino , Animais , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Camundongos Endogâmicos C57BL , Tecido Adiposo/metabolismo , Macrófagos/metabolismo , Tecido Adiposo Branco/metabolismo , Glucose/metabolismo , Proteínas de Membrana/metabolismo
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