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1.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360550

RESUMO

A growing body of evidence points to the role of glucose variability (GV) in the development of the microvascular and macrovascular complications of diabetes. In this review, we summarize data on GV-induced biochemical, cellular and molecular events involved in the pathogenesis of diabetic complications. Current data indicate that the deteriorating effect of GV on target organs can be realized through oxidative stress, glycation, chronic low-grade inflammation, endothelial dysfunction, platelet activation, impaired angiogenesis and renal fibrosis. The effects of GV on oxidative stress, inflammation, endothelial dysfunction and hypercoagulability could be aggravated by hypoglycemia, associated with high GV. Oscillating hyperglycemia contributes to beta cell dysfunction, which leads to a further increase in GV and completes the vicious circle. In cells, the GV-induced cytotoxic effect includes mitochondrial dysfunction, endoplasmic reticulum stress and disturbances in autophagic flux, which are accompanied by reduced viability, activation of apoptosis and abnormalities in cell proliferation. These effects are realized through the up- and down-regulation of a large number of genes and the activity of signaling pathways such as PI3K/Akt, NF-κB, MAPK (ERK), JNK and TGF-ß/Smad. Epigenetic modifications mediate the postponed effects of glucose fluctuations. The multiple deteriorative effects of GV provide further support for considering it as a therapeutic target in diabetes.


Assuntos
Glicemia/análise , Complicações do Diabetes/etiologia , Diabetes Mellitus/fisiopatologia , Hiperglicemia/complicações , Hipoglicemia/complicações , Animais , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Humanos
2.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361774

RESUMO

Polyphenols play a therapeutic role in vascular diseases, acting in inherent illness-associate conditions such as inflammation, diabetes, dyslipidemia, hypertension, and oxidative stress, as demonstrated by clinical trials and epidemiological surveys. The main polyphenol cardioprotective mechanisms rely on increased nitric oxide, decreased asymmetric dimethylarginine levels, upregulation of genes encoding antioxidant enzymes via the Nrf2-ARE pathway and anti-inflammatory action through the redox-sensitive transcription factor NF-κB and PPAR-γ receptor. However, poor polyphenol bioavailability and extensive metabolization restrict their applicability. Polyphenols carried by nanoparticles circumvent these limitations providing controlled release and better solubility, chemical protection, and target achievement. Nano-encapsulate polyphenols loaded in food grade polymers and lipids appear to be safe, gaining resistance in the enteric route for intestinal absorption, in which the mucoadhesiveness ensures their increased uptake, achieving high systemic levels in non-metabolized forms. Nano-capsules confer a gradual release to these compounds, as well as longer half-lives and cell and whole organism permanence, reinforcing their effectiveness, as demonstrated in pre-clinical trials, enabling their application as an adjuvant therapy against cardiovascular diseases. Polyphenol entrapment in nanoparticles should be encouraged in nutraceutical manufacturing for the fortification of foods and beverages. This study discusses pre-clinical trials evaluating how nano-encapsulate polyphenols following oral administration can aid in cardiovascular performance.


Assuntos
Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Composição de Medicamentos/métodos , Hipertensão/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Polifenóis/farmacologia , Elementos de Resposta Antioxidante , Antioxidantes/química , Antioxidantes/farmacocinética , Arginina/análogos & derivados , Arginina/antagonistas & inibidores , Arginina/metabolismo , Cardiotônicos/química , Cardiotônicos/farmacocinética , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Portadores de Fármacos , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Nanocápsulas/administração & dosagem , Nanocápsulas/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/química , Polifenóis/farmacocinética , Transdução de Sinais
3.
Pan Afr Med J ; 38: 394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34381538

RESUMO

Acromegaly is, in most cases, caused by growth hormone secreting pituitary adenomas. Those patients often develop different pathologies of the thyroid gland, however, the occurrence of Grave´s disease is quite a rare situation. We report a case of a 64-year-old female patient who presented with signs of hyperthyroidism and imbalance of her diabetes mellitus. On physical examination, she had facial features of acromegaly. Biochemical testing confirmed the suspicion of acromegaly and Grave´s disease, with an elevated insulin-like growth factor-1 and a suppressed thyroid stimulation hormone (TSH) with positive TSH-receptor antibodies. A pituitary Magnetic Resonance Imaging (MRI) was performed, revealing a macro-adenoma and an empty sella. The patient successfully underwent a transsphenoidal surgery and obtained a remission of her hyperthyroidism under anti-thyroid drugs.


Assuntos
Acromegalia/diagnóstico , Síndrome da Sela Vazia/diagnóstico por imagem , Doença de Graves/diagnóstico por imagem , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico por imagem , Antitireóideos/administração & dosagem , Diabetes Mellitus/fisiopatologia , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Humanos , Hipertireoidismo/diagnóstico , Hipertireoidismo/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Tireotropina/metabolismo
4.
J Clin Endocrinol Metab ; 106(9): e3364-e3368, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34406396

RESUMO

CONTEXT: Diabetes is reported as a risk factor for severe coronavirus disease 2019 (COVID-19), but whether this risk is similar in all categories of age remains unclear. OBJECTIVE: To investigate the risk of severe COVID-19 outcomes in hospitalized patients with and without diabetes according to age categories. DESIGN SETTING AND PARTICIPANTS: We conducted a retrospective observational cohort study of 6314 consecutive patients hospitalized for COVID-19 between February and 30 June 2020 in the Paris metropolitan area, France; follow-up was recorded until 30 September 2020. MAIN OUTCOME MEASURE(S): The main outcome was a composite outcome of mortality and orotracheal intubation in subjects with diabetes compared with subjects without diabetes, after adjustment for confounding variables and according to age categories. RESULTS: Diabetes was recorded in 39% of subjects. Main outcome was higher in patients with diabetes, independently of confounding variables (hazard ratio [HR] 1.13 [1.03-1.24]) and increased with age in individuals without diabetes, from 23% for those <50 to 35% for those >80 years but reached a plateau after 70 years in those with diabetes. In direct comparison between patients with and without diabetes, diabetes-associated risk was inversely proportional to age, highest in <50 years and similar after 70 years. Similarly, mortality was higher in patients with diabetes (26%) than in those without diabetes (22%, P < 0.001), but adjusted HR for diabetes was significant only in patients younger than age 50 years (HR 1.81 [1.14-2.87]). CONCLUSIONS: Diabetes should be considered as an independent risk factor for the severity of COVID-19 in young adults more so than in older adults, especially for individuals younger than 70 years.


Assuntos
COVID-19/epidemiologia , Diabetes Mellitus/fisiopatologia , Mortalidade Hospitalar/tendências , Hospitalização/estatística & dados numéricos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Idoso , Idoso de 80 Anos ou mais , COVID-19/virologia , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco
5.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201756

RESUMO

Diabetes mellitus and related disorders significantly contribute to morbidity and mortality worldwide. Despite the advances in the current therapeutic methods, further development of anti-diabetic therapies is necessary. Mitochondrial dysfunction is known to be implicated in diabetes development. Moreover, specific types of mitochondrial diabetes have been discovered, such as MIDD (maternally inherited diabetes and deafness) and DAD (diabetes and Deafness). Hereditary mitochondrial disorders are caused by certain mutations in the mitochondrial DNA (mtDNA), which encodes for a substantial part of mitochondrial proteins and mitochondrial tRNA necessary for mitochondrial protein synthesis. Study of mtDNA mutations is challenging because the pathogenic phenotype associated with such mutations depends on the level of its heteroplasmy (proportion of mtDNA copies carrying the mutation) and can be tissue-specific. Nevertheless, modern sequencing methods have allowed describing and characterizing a number of mtDNA mutations associated with human disorders, and the list is constantly growing. In this review, we provide a list of mtDNA mutations associated with diabetes and related disorders and discuss the mechanisms of their involvement in the pathology development.


Assuntos
Diabetes Mellitus/genética , Genoma Mitocondrial/genética , Inflamação/genética , Mutação , Animais , Doença Crônica , DNA Mitocondrial/genética , Surdez/genética , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Camundongos , Doenças Mitocondriais/genética
6.
Neurology ; 97(8): e836-e848, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34210821

RESUMO

OBJECTIVE: To assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition. METHODS: The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aß42/Aß40 ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders. RESULTS: There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: -0.061, 95% confidence interval: -0.089, -0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning. CONCLUSION: In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers.


Assuntos
Doença de Alzheimer/diagnóstico , Doenças de Pequenos Vasos Cerebrais/diagnóstico , Disfunção Cognitiva/diagnóstico , Diabetes Mellitus/diagnóstico , Degeneração Neural/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores , Doenças de Pequenos Vasos Cerebrais/epidemiologia , Doenças de Pequenos Vasos Cerebrais/metabolismo , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Comorbidade , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Feminino , França/epidemiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Degeneração Neural/epidemiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons
7.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201520

RESUMO

Autophagy is a vital cell mechanism which plays an important role in many physiological processes including clearing long-lived, accumulated and misfolded proteins, removing damaged organelles and regulating growth and aging. Autophagy also participates in a variety of biological functions, such as development, cell differentiation, resistance to pathogens and nutritional hunger. Recently, autophagy has been reported to be involved in diabetes, but the mechanism is not fully understood. Hydrogen sulfide (H2S) is a colorless, water-soluble, flammable gas with the typical odor of rotten eggs, which has been known as a highly toxic gas for many years. However, it has been reported recently that H2S, together with nitric oxide and carbon monoxide, is an important gas signal transduction molecule. H2S has been reported to play a protective role in many diabetes-related diseases, but the mechanism is not fully clear. Recent studies indicate that H2S plays an important role by regulating autophagy in many diseases including cancer, tissue fibrosis diseases and glycometabolic diseases; however, the related mechanism has not been fully studied. In this review, we summarize recent research on the role of H2S in regulating autophagy in diabetic-related diseases to provide references for future related research.


Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus/fisiopatologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Animais , Autofagia/fisiologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Transtorno Depressivo/patologia , Diabetes Mellitus/psicologia , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Humanos , Sulfeto de Hidrogênio/farmacocinética , Transdução de Sinais
8.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205870

RESUMO

Diabetic patients are predisposed to diabetic cardiomyopathy, a specific form of cardiomyopathy which is characterized by the development of myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis that develops independently of concomitant macrovascular and microvascular diabetic complications. Its pathophysiology is multifactorial and poorly understood and no specific therapeutic guideline has yet been established. Diabetic cardiomyopathy is a challenging diagnosis, made after excluding other potential entities, treated with different pharmacotherapeutic agents targeting various pathophysiological pathways that need yet to be unraveled. It has great clinical importance as diabetes is a disease with pandemic proportions. This review focuses on the potential mechanisms contributing to this entity, diagnostic options, as well as on potential therapeutic interventions taking in consideration their clinical feasibility and limitations in everyday practice. Besides conventional therapies, we discuss novel therapeutic possibilities that have not yet been translated into clinical practice.


Assuntos
Diabetes Mellitus/fisiopatologia , Cardiomiopatias Diabéticas/fisiopatologia , Fibrose/fisiopatologia , Miocárdio/patologia , Apoptose/genética , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/terapia , Cardiomiopatias Diabéticas/diagnóstico , Cardiomiopatias Diabéticas/terapia , Fibrose/diagnóstico , Fibrose/terapia , Humanos
9.
Vasc Health Risk Manag ; 17: 389-394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262283

RESUMO

Background: The World Health Organization (WHO) proposed the integrated care for older people (ICOPE) screening tool to identify functional impairment. We explore the association of geriatric functional impairment and hypertension, diabetes, dyslipidemia in the community-dwelling elderly. Methods: We enrolled individuals aged at least 65 with hypertension, diabetes, or dyslipidemia; or those aged at least 75 from May to July 2019. We applied ICOPE tools to evaluate six function assessments: cognitive decline, limited mobility, malnutrition, visual impairment, hearing loss, and depressive symptoms. Factors were analyzed using stepwise multivariable linear regression for ICOPE scores and logistic regression for geriatric functional impairment. All analyses were adjusted for age and glomerular filtration rate. Results: We enrolled 457 participants including 303 (66.3%) participants with hypertension, 296 (64.8%) diabetes, and 221 (48.4%) dyslipidemia. Seventy-eight (17.1%) participants have at least one geriatric functional impairment, including 41 (25.9%) participants aged ≥ 75 and 37 (12.4%) aged 65-74. The ICOPE score (0.4 ± 0.6) of participants aged at least 75 was higher than that (0.1 ± 0.4) of the participants aged 65-74 (p < 0.001). Dyslipidemia (p = 0.002) was positively associated with ICOPE score. Dyslipidemia (odds ratio: 2.15, 95% confidence interval: 1.27-3.70, p = 0.005), not hypertension (p = 0.3) and diabetes (p = 0.9), was associated with geriatric functional impairment. Visual impairment was the most common function impairment. Female was linked to limited mobility, renal function was associated with mobility (p < 0.001) and nutrition (p = 0.02). Conclusion: Dyslipidemia but not hypertension, diabetes is linked to geriatric functional impairment in community-dwelling elderly. Lower renal function is associated with decreased mobility and nutrition. More studies are needed to determine if treatment of dyslipidemia reduces geriatric functional impairment.


Assuntos
Dislipidemias/diagnóstico , Idoso Fragilizado , Fragilidade/diagnóstico , Avaliação Geriátrica , Vida Independente , Afeto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Cognição , Estudos Transversais , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/psicologia , Dislipidemias/fisiopatologia , Dislipidemias/psicologia , Dislipidemias/terapia , Feminino , Fragilidade/fisiopatologia , Fragilidade/psicologia , Fragilidade/terapia , Estado Funcional , Taxa de Filtração Glomerular , Audição , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Hipertensão/psicologia , Rim/fisiopatologia , Masculino , Saúde Mental , Limitação da Mobilidade , Estado Nutricional , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Visão Ocular
10.
Diabetes Metab Syndr ; 15(4): 102196, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34246939

RESUMO

AIMS: Diabetes Mellitus predisposes patients to invasive fungal infections. There has been a recent surge of Mucormycosis with COVID 19 infection particularly in patients with diabetes. This study aims to study the clinical spectrum of CAM (COVID -associated Mucormycosis) with diabetes and subsequent outcomes. MATERIAL AND METHODS: This was a descriptive study conducted at a single COVID Care Centre in India in patients with COVID Associated Mucormycosis from April 12, 2021 to May 31, 2021. RESULTS: Among 953 hospitalized patients with COVID 19 infection, 32 patients had CAM with an incidence of 3.36%. In patients with CAM, 87.5% had Diabetes Mellitus as the most common co-morbidity. The majority of the patients had poor glycemic control with a mean HbA1c of 9.06%. Out of the total study population, 93% had prior exposure to high dose corticosteroids. During the study period, 12.5% patients of CAM did not survive. CONCLUSION: Mucormycosis is an angioinvasive fungal infection with high mortality. The disease has surged in COVID 19 pandemic due to uncontrolled diabetes and improper corticosteroid use.


Assuntos
COVID-19/complicações , Diabetes Mellitus/fisiopatologia , Hospitalização/estatística & dados numéricos , Mucormicose/mortalidade , SARS-CoV-2/isolamento & purificação , COVID-19/transmissão , COVID-19/virologia , Diabetes Mellitus/virologia , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Mucormicose/epidemiologia , Mucormicose/patologia , Mucormicose/virologia , Prognóstico , Fatores de Risco , Taxa de Sobrevida
11.
Aging (Albany NY) ; 13(11): 14785-14805, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34088887

RESUMO

OBJECTIVE: To demonstrate differences in cardiovascular structure and function between diabetic and non-diabetic older adults. To investigate associations between acyl-carnitines and cardiovascular function as indexed by imaging measurements. METHODS: A community-based cohort of older adults without cardiovascular disease underwent current cardiovascular imaging and metabolomics acyl-carnitines profiling based on current and archived sera obtained fifteen years prior to examination. RESULTS: A total of 933 participants (women 56%, n=521) with a mean age 63±13 years were studied. Old diabetics compared to old non-diabetics had lower myocardial relaxation (0.8±0.2 vs 0.9±0.3, p=0.0039); lower left atrial conduit strain (12±4.3 vs 14±4.1, p=0.045), lower left atrial conduit strain rate (-1.2±0.4 vs -1.3±0.5, p=0.042) and lower ratio of left atrial conduit strain to left atrial booster strain (0.5±0.2 vs 0.7±0.3, p=0.0029). Higher levels of archived short chain acyl-carnitine were associated with present-day impairments in myocardial relaxation (C5:1; OR 1.03, p=0.011), worse left atrial conduit strain function (C5:1; OR 1.03, p=0.037). Increases in hydroxylated acyl-carnitines were associated with worse left atrial conduit strain [(C4-OH; OR 1.05, p=0.0017), (C16:2-OH; OR 1.18, p=0.037)]. Current, archived and changes in long chain acyl-carnitines were associated with cardiovascular functions [(C16; OR 1.02, p=0.002), (C20:3; OR 1.01, p=0.014), (C14:3; OR 1.12, p=0.033), (C18:1; OR 1.01, p=0.018), (C18:2; OR 1.01, p=0.028), (C20:4; OR 1.10, p=0.038)] (all p<0.05). CONCLUSION: Older diabetic adults had significant impairments in left ventricular myocardial relaxation and left atrial strain, compared to older non-diabetic adults. Short chain and long chain, di-carboxyl and hydroxylated acyl-carnitines were associated with these cardiovascular functional differences.


Assuntos
Envelhecimento/patologia , Sistema Cardiovascular/patologia , Carnitina/análogos & derivados , Diabetes Mellitus/patologia , Idoso , Sistema Cardiovascular/fisiopatologia , Carnitina/metabolismo , Diabetes Mellitus/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Nutrients ; 13(5)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066662

RESUMO

The prevalence of diabetes is on the increase worldwide, being one of the fastest growing international health emergencies in the 21st century [...].


Assuntos
Diabetes Mellitus/dietoterapia , Dieta para Diabéticos/tendências , Microbioma Gastrointestinal/fisiologia , Controle Glicêmico/tendências , Estado Nutricional , Diabetes Mellitus/microbiologia , Diabetes Mellitus/fisiopatologia , Disbiose/etiologia , Humanos , Inflamação
13.
Diabetes ; 70(6): 1229-1241, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34016598

RESUMO

Insulin-producing pancreatic ß-cells are central to glucose homeostasis, and their failure is a principal driver of diabetes development. To preserve optimal health ß-cells must withstand both intrinsic and extrinsic stressors, ranging from inflammation to increased peripheral insulin demand, in addition to maintaining insulin biosynthesis and secretory machinery. Autophagy is increasingly being appreciated as a critical ß-cell quality control system vital for glycemic control. Here we focus on the underappreciated, yet crucial, roles for selective and organelle-specific forms of autophagy as mediators of ß-cell health. We examine the unique molecular players underlying each distinct form of autophagy in ß-cells, including selective autophagy of mitochondria, insulin granules, lipid, intracellular amyloid aggregates, endoplasmic reticulum, and peroxisomes. We also describe how defects in selective autophagy pathways contribute to the development of diabetes. As all forms of autophagy are not the same, a refined view of ß-cell selective autophagy may inform new approaches to defend against the various insults leading to ß-cell failure in diabetes.


Assuntos
Autofagia/fisiologia , Células Secretoras de Insulina/fisiologia , Animais , Diabetes Mellitus/etiologia , Diabetes Mellitus/patologia , Diabetes Mellitus/fisiopatologia , Humanos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/fisiopatologia , Mitofagia/fisiologia , Agregados Proteicos/fisiologia , Fatores de Transcrição/fisiologia , Ubiquitina-Proteína Ligases/fisiologia
15.
Vascul Pharmacol ; 139: 106879, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051372

RESUMO

Toll-like receptor 4 (TLR4) contributes to the pathophysiology of diabetes. This happens, at least in part, because TLR4 modulates the enzyme NADPH oxidase, a primary source of ROS in vascular structures. Increased oxidative stress disrupts key vascular signaling mechanisms and drives the progression of diabetes, elevating the likelihood of cardiovascular diseases. Recently, it has been shown that patients with diabetes are also at a higher risk of developing severe coronavirus disease 2019 (COVID-19). Given the importance of the interaction between TLR4 and NADPH oxidase to the disrupted diabetic vascular system, we put forward the hypothesis that TLR4-mediated NADPH oxidase-derived ROS might be a critical mechanism to help explain why this disparity appears in diabetic patients, but unfortunately, conclusive experimental evidence still lacks in the literature. Herein, we focus on discussing the pathological implications of this signaling communication in the diabetic vasculature and exploring this crosstalk in the context of diabetes-associated severe COVID-19.


Assuntos
Vasos Sanguíneos/enzimologia , COVID-19/virologia , Diabetes Mellitus/enzimologia , Angiopatias Diabéticas/enzimologia , NADPH Oxidases/metabolismo , SARS-CoV-2/patogenicidade , Receptor 4 Toll-Like/metabolismo , Animais , Vasos Sanguíneos/fisiopatologia , Vasos Sanguíneos/virologia , COVID-19/enzimologia , COVID-19/fisiopatologia , Diabetes Mellitus/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Ativação Enzimática , Interações Hospedeiro-Patógeno , Humanos , Estresse Oxidativo , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
16.
Br J Anaesth ; 127(2): 224-235, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34023055

RESUMO

BACKGROUND: Gastric emptying may be delayed in patients with diabetes mellitus (DM). However, the incidence of full stomach in fasting patients with DM and their risk of pulmonary aspiration under anaesthesia is not well understood. METHODS: A scoping review was undertaken to map the literature on aspiration risk in DM. A search was conducted in seven bibliographic databases, including MEDLINE and Embase, for original articles that studied aspiration risk, gastric emptying, or gastric content and volume. Selection and characterisation were performed by two independent reviewers using a predefined protocol registered externally. RESULTS: The search identified 5063 unique records, and 16 studies (totalling 775 patients with DM) were selected: nine studied gastric emptying and seven studied gastric content or volume. There were no studies reporting the incidence of aspiration in subjects with DM. All nine studies reported delayed emptying in patients with DM compared with healthy controls. Amongst the seven studies that compared gastric residual content/volume (GRV) in the perioperative period, five reported clinically negligible GRV in both patients with DM and controls, whereas two observed a higher incidence of 'full' stomach in patients with DM. CONCLUSIONS: The evidence concerning the aspiration risk for surgical patients with DM is based on a limited number of studies, mostly unblinded, reporting physiological data on gastric emptying and gastric volume as surrogate markers of aspiration risk. Data on fasting gastric content and volume in patients with DM are limited and contradictory; hence, the true risk of aspiration in fasting patients with DM is unknown.


Assuntos
Anestesia , Diabetes Mellitus/epidemiologia , Esvaziamento Gástrico/fisiologia , Conteúdo Gastrointestinal/diagnóstico por imagem , Complicações Intraoperatórias/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Aspiração Respiratória/epidemiologia , Comorbidade , Diabetes Mellitus/fisiopatologia , Jejum , Humanos , Complicações Intraoperatórias/fisiopatologia , Complicações Pós-Operatórias/fisiopatologia , Aspiração Respiratória/fisiopatologia , Ultrassonografia/métodos
17.
J Biol Chem ; 296: 100761, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33971198

RESUMO

Diabetes mellitus (DM) causes injury to tissues and organs, including to the heart and kidney, resulting in increased morbidity and mortality. Thus, novel potential therapeutics are continuously required to minimize DM-related organ damage. We have previously shown that dipeptidyl peptidase III (DPPIII) has beneficial roles in a hypertensive mouse model, but it is unknown whether DPPIII has any effects on DM. In this study, we found that intravenous administration of recombinant DPPIII in diabetic db/db mice for 8 weeks suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. This treatment inhibited inflammatory cell infiltration and fibrosis in the heart and blocked the increase in albuminuria by attenuating the disruption of the glomerular microvasculature and inhibiting the effacement of podocyte foot processes in the kidney. The beneficial role of DPPIII was, at least in part, mediated by the cleavage of a cytotoxic peptide, named Peptide 2, which was increased in db/db mice compared with normal mice. This peptide consisted of nine amino acids, was a digested fragment of complement component 3 (C3), and had an anaphylatoxin-like effect determined by the Miles assay and chemoattractant analysis. The effect was dependent on its interaction with the C3a receptor and protein kinase C-mediated RhoA activation downstream of the receptor in endothelial cells. In conclusion, DPPIII plays a protective role in the heart and kidney in a DM animal model through cleavage of a peptide that is a part of C3.


Assuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Terapia Enzimática , Coração/fisiopatologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico
18.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801956

RESUMO

Diabetes mellitus is a major healthcare problem. It is not only characterized by hyperglycemia and chronic complications, but in longer lasting diabetes and a longer living population, it is also associated with accelerated arterial ageing, which importantly contributes to cardiovascular complications. The accelerated arterial ageing in patients with diabetes should be considered separately from arterial ageing in patients without diabetes. Basic and clinical research have allowed better insight into the mechanisms of arterial ageing. In a simplified mechanistic way, it could be considered that the three tightly connected cornerstone characteristics of arterial ageing in patients with diabetes are: phenotypic presentation as endothelial dysfunction and arterial stiffness, and the underlying basic ageing-facilitating mechanism represented as the impaired expression of genetic longevity pathways. Currently, specific drugs for preventing/treating arterial ageing are not available. Therefore, we aimed to review the capacity of available drugs, particularly antidiabetic drugs, to interfere with the arterial ageing process. In the near future, these characteristics could help to guide therapy in patients with diabetes. Overall, it appears that arterial ageing could become a new target in diabetes. The expanding knowledge regarding the capability of antidiabetic drugs and other available drugs to inhibit/delay arterial aging is therefore essential.


Assuntos
Envelhecimento , Artérias/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus/fisiopatologia , Calcificação Vascular/fisiopatologia , Rigidez Vascular/fisiologia , Artérias/efeitos dos fármacos , Artérias/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/metabolismo , Rigidez Vascular/efeitos dos fármacos
19.
Nutrients ; 13(3)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799575

RESUMO

The regulation of energy balance requires the complex integration of homeostatic and hedonic pathways, but sensory inputs from the gastrointestinal (GI) tract are increasingly recognized as playing critical roles. The stomach and small intestine relay sensory information to the central nervous system (CNS) via the sensory afferent vagus nerve. This vast volume of complex sensory information is received by neurons of the nucleus of the tractus solitarius (NTS) and is integrated with responses to circulating factors as well as descending inputs from the brainstem, midbrain, and forebrain nuclei involved in autonomic regulation. The integrated signal is relayed to the adjacent dorsal motor nucleus of the vagus (DMV), which supplies the motor output response via the efferent vagus nerve to regulate and modulate gastric motility, tone, secretion, and emptying, as well as intestinal motility and transit; the precise coordination of these responses is essential for the control of meal size, meal termination, and nutrient absorption. The interconnectivity of the NTS implies that many other CNS areas are capable of modulating vagal efferent output, emphasized by the many CNS disorders associated with dysregulated GI functions including feeding. This review will summarize the role of major CNS centers to gut-related inputs in the regulation of gastric function with specific reference to the regulation of food intake.


Assuntos
Vias Aferentes , Encéfalo/fisiologia , Ingestão de Alimentos , Vias Eferentes , Trato Gastrointestinal/inervação , Trato Gastrointestinal/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Diabetes Mellitus/fisiopatologia , Hipocampo/fisiologia , Humanos , Hipotálamo/fisiologia , Inflamação/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Obesidade/fisiopatologia , Rombencéfalo/fisiologia , Nervo Vago/fisiologia
20.
Nutr Metab Cardiovasc Dis ; 31(5): 1516-1520, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33810956

RESUMO

BACKGROUND AND AIMS: Diabetes mellitus (DM) is a frequent comorbidity in ST-elevation-myocardial infarction (STEMI) patients and carries a higher risk of in-hospital mortality. We recently demonstrated that the higher in-hospital mortality of STEMI patients with DM, when compared to that of patients without DM, is mainly associated with their more frequent cardiac and renal dysfunction. These exploratory results prompted us to hypothesize that this higher risk in DM patients is mediated by their lower cardio-renal functional reserve. METHODS AND RESULTS: We included 5152 STEMI patients treated with primary angioplasty. By using an advanced statistical methodology (path analysis), able to clarify the putative causal paths between variables of interest, we reported that the higher in-hospital mortality of STEMI patients with DM is possibly caused by its adverse impact on cardio-renal function. CONCLUSION: This statistical approach allows to reinforce the well-known notion that DM is associated with an increased in-hospital mortality risk in STEMI and sheds lights on the causal relationship among DM, cardio-renal dysfunction, and higher in-hospital mortality. Whether the mortality gap between DM and non-DM patients with STEMI can be reduced by pharmacological strategies combining cardio-renal protective effects is an intriguing question that deserves an answer in the future.


Assuntos
Diabetes Mellitus/mortalidade , Coração/fisiopatologia , Mortalidade Hospitalar , Rim/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Comorbidade , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/fisiopatologia , Taxa de Filtração Glomerular , Coração/efeitos dos fármacos , Humanos , Hipoglicemiantes/uso terapêutico , Pacientes Internados , Rim/efeitos dos fármacos , Intervenção Coronária Percutânea/mortalidade , Prognóstico , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Volume Sistólico , Função Ventricular Esquerda
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