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1.
Artigo em Inglês | PAHO-IRIS | ID: phr-61439

RESUMO

[ABSTRACT]. Objective. To evaluate whether use of a culturally adapted mobile application (app) for adolescents with type 1 diabetes is associated with improved metabolic control. Methods. The Dominican Republic’s National Institute of Diabetes, Endocrinology, and Nutrition and the Learning to Live clinic recruited 23 pediatric participants for the study. Blood tests were performed before and after use of the app for a period of 3 months. Based on the user profile, participants were encouraged to use the app’s bolus insulin calculator after each meal. The app included a list of regionally and culturally specific foods, color-coded to indicate a high glycemic index (GI) as red; medium GI as yellow; and low GI as green. The color-coding was designed to assist participants in making healthier eating choices. Results. There were statistically significant improvements in lipid profile. Mean high-density lipoprotein values rose to acceptable levels, while low-density lipoproteins and triglyceride levels fell to the recommended values. The overall quality of life increased, although glycated hemoglobin levels showed no statistically significant changes. Conclusion. The findings of this study suggest that using this culturally tailored app can help young patients with type 1 diabetes to improve metabolic health.


[RESUMEN]. Objetivo. Evaluar si el uso de una aplicación móvil (app) para adolescentes con diabetes tipo 1, adaptada desde el punto de vista cultural, se asocia a una mejora del control metabólico. Métodos. El Instituto Nacional de Diabetes, Endocrinología y Nutrición de República Dominicana y Learning to Live Clinic reclutaron a 23 participantes pediátricos para el estudio. Se realizaron análisis de sangre antes y después de utilizar la aplicación durante un período de 3 meses. En función del perfil de usuario, se alentó a los participantes a utilizar la calculadora del bolo de insulina de la aplicación después de cada comida. La aplicación incluía una lista de alimentos propios de la región y la cultura, codificados por colores para indicar un índice glucémico (IG) alto (rojo), medio (amarillo) o bajo (verde). El código de colores se diseñó para ayudar a los participantes a adoptar opciones de alimentación más saludables. Resultados. Se observaron mejoras estadísticamente significativas en el perfil lipídico. Los valores medios de las lipoproteínas de alta densidad aumentaron hasta niveles aceptables, mientras que los niveles de las lipoproteínas de baja densidad y los triglicéridos descendieron hasta los valores recomendados. Se observó una mejora en la calidad de vida general, si bien no se observaron cambios estadísticamente significativos en los niveles de hemoglobina glucosilada. Conclusiones. Los resultados de este estudio sugieren que el uso de esta aplicación adaptada desde el punto de vista cultural puede ayudar a los pacientes jóvenes con diabetes mellitus tipo 1 a mejorar su salud metabólica.


[RESUMO]. Objetivo. Avaliar se o uso de um aplicativo móvel culturalmente adaptado para adolescentes com diabetes tipo 1 está associado a um melhor controle metabólico. Métodos. O Instituto Nacional de Diabetes, Endocrinologia e Nutrição da República Dominicana e a clínica Learning to Live recrutaram 23 participantes pediátricos para o estudo. Foram realizados exames de sangue antes e depois do uso do aplicativo por um período de 3 meses. Com base no perfil de usuário, os participantes foram incentivados a usar a calculadora de bolus de insulina do aplicativo após cada refeição. O aplicativo incluía uma lista de alimentos específicos da região e da cultura, codificados por cores para indicar índices glicêmicos (IG) altos em vermelho; IG médios em amarelo; e IG baixos em verde. O código de cores foi criado para ajudar os participantes a fazer escolhas alimentares mais saudáveis. Resultados. Houve melhoras estatisticamente significantes no perfil lipídico. Os valores médios de lipoproteínas de alta densidade subiram para níveis aceitáveis, e os níveis de lipoproteínas de baixa densidade e de triglicerídeos caíram para os valores recomendados. A qualidade de vida geral aumentou, embora os níveis de hemoglobina glicada não tenham apresentado alterações estatisticamente significantes. Conclusão. Os resultados deste estudo sugerem que o uso desse aplicativo culturalmente adaptado pode ajudar pacientes jovens com diabetes tipo 1 a melhorar sua saúde metabólica.


Assuntos
Diabetes Mellitus Tipo 1 , Controle Glicêmico , Insulisina , Aplicativos Móveis , Diabetes Mellitus Tipo 1 , Controle Glicêmico , Insulina , Aplicativos Móveis , Controle Glicêmico , Aplicativos Móveis
2.
Protein Expr Purif ; 222: 106539, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38960013

RESUMO

PF11_0189 is a putative insulin degrading enzyme present in Plasmodium falciparum genome. The catalytic domain of PF11_0189 is about 27 kDa. Substrate specificity study shows PF11_0189 acts upon different types of proteins. The substrate specificity is found to be highest when insulin is used as a substrate. Metal dependency study shows highest dependency of PF11_0189 towards zinc metal for its proteolytic activity. Chelation of zinc metal with EDTA shows complete absence of PF11_0189 activity. Peptide inhibitors, P-70 and P-121 from combinatorial peptide library prepared against PF11_0189 show inhibition with an IC50 value of 4.8 µM and 7.5 µM respectively. A proven natural anti-malarial peptide cyclosporin A shows complete inhibition against PF11_0189 with an IC50 value of 0.75 µM suggesting PF11_0189 as a potential target for peptide inhibitors. The study implicates that PF11_0189 is a zinc metalloprotease involved in catalysis of insulin. The study gives a preliminary insight into the mechanism of complications arising from glucose abnormalities during severe malaria.


Assuntos
Insulisina , Plasmodium falciparum , Proteínas de Protozoários , Plasmodium falciparum/enzimologia , Plasmodium falciparum/genética , Insulisina/genética , Insulisina/química , Insulisina/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Especificidade por Substrato , Insulina/química , Insulina/metabolismo , Insulina/genética , Zinco/química , Zinco/metabolismo , Genoma de Protozoário , Proteínas Recombinantes/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/isolamento & purificação , Expressão Gênica , Clonagem Molecular , Antimaláricos/química , Antimaláricos/farmacologia , Ciclosporina/química , Ciclosporina/farmacologia
3.
J Alzheimers Dis ; 99(3): 1033-1046, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38728183

RESUMO

Background: Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-ß peptides (Aß) play a key role in AD pathophysiology. Therefore, human studies on Aß metabolism and T2D are warranted. Objective: The objective of this study was to examine whether acute hyperglycemia affects plasma Aß1-40 and Aß1-42 concentrations in individuals with T2D and matched controls. Methods: Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aß1-40, Aß1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aß1-40 and Aß1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. Results: At baseline, Aß1-40 and Aß1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aß decreased in the control group, compared to the placebo clamp (Aß1-40: p = 0.034, Aß1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aß or IDE was noted in the T2D group. Conclusions: Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aß40 and Aß42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.


Assuntos
Peptídeos beta-Amiloides , Diabetes Mellitus Tipo 2 , Técnica Clamp de Glucose , Hiperglicemia , Fragmentos de Peptídeos , Humanos , Peptídeos beta-Amiloides/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/sangue , Idoso , Masculino , Hiperglicemia/sangue , Feminino , Fragmentos de Peptídeos/sangue , Glicemia/metabolismo , Insulisina/metabolismo
4.
Geroscience ; 46(5): 4461-4478, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38767782

RESUMO

Maintaining insulin homeostasis is critical for cellular and organismal metabolism. In the liver, insulin is degraded by the activity of the insulin-degrading enzyme (IDE). Here, we establish a hepatic regulatory axis for IDE through WDR23-proteostasis. Wdr23KO mice have increased IDE expression, reduced circulating insulin, and defective insulin responses. Genetically engineered human cell models lacking WDR23 also increase IDE expression and display dysregulated phosphorylation of insulin signaling cascade proteins, IRS-1, AKT2, MAPK, FoxO, and mTOR, similar to cells treated with insulin, which can be mitigated by chemical inhibition of IDE. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults, supporting the use of WDR23 as a new molecular determinant of metabolic health in humans.


Assuntos
Homeostase , Insulina , Insulisina , Fígado , Camundongos Knockout , Proteostase , Humanos , Homeostase/fisiologia , Animais , Insulina/metabolismo , Camundongos , Insulisina/metabolismo , Insulisina/genética , Fígado/metabolismo , Masculino , Feminino , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais , Hemoglobinas Glicadas/metabolismo , Idoso , Pessoa de Meia-Idade
5.
Br J Pharmacol ; 181(19): 3610-3626, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38812293

RESUMO

BACKGROUND AND PURPOSE: Nonalcoholic fatty liver disease refers to liver pathologies, ranging from steatosis to steatohepatitis, with fibrosis ultimately leading to cirrhosis and hepatocellular carcinoma. Although several mechanisms have been suggested, including insulin resistance, oxidative stress, and inflammation, its pathophysiology remains imperfectly understood. Over the last decade, a dysfunctional unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress emerged as one of the multiple driving factors. In parallel, growing evidence suggests that insulin-degrading enzyme (IDE), a highly conserved and ubiquitously expressed metallo-endopeptidase originally discovered for its role in insulin decay, may regulate ER stress and UPR. EXPERIMENTAL APPROACH: We investigated, by genetic and pharmacological approaches, in vitro and in vivo, whether IDE modulates ER stress-induced UPR and lipid accumulation in the liver. KEY RESULTS: We found that IDE-deficient mice display higher hepatic triglyceride content along with higher inositol-requiring enzyme 1 (IRE1) pathway activation. Upon induction of ER stress by tunicamycin or palmitate in vitro or in vivo, pharmacological inhibition of IDE, using its inhibitor BDM44768, mainly exacerbated ER stress-induced IRE1 activation and promoted lipid accumulation in hepatocytes, effects that were abolished by the IRE1 inhibitors 4µ8c and KIRA6. Finally, we identified that IDE knockout promotes lipolysis in adipose tissue and increases hepatic CD36 expression, which may contribute to steatosis. CONCLUSION AND IMPLICATIONS: These results unravel a novel role for IDE in the regulation of ER stress and development of hepatic steatosis. These findings pave the way to innovative strategies modulating IDE to treat metabolic diseases.


Assuntos
Estresse do Retículo Endoplasmático , Insulisina , Metabolismo dos Lipídeos , Fígado , Resposta a Proteínas não Dobradas , Animais , Humanos , Masculino , Camundongos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/metabolismo , Endorribonucleases/antagonistas & inibidores , Insulisina/metabolismo , Insulisina/antagonistas & inibidores , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Resposta a Proteínas não Dobradas/efeitos dos fármacos
6.
J Huntingtons Dis ; 13(2): 201-214, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38640164

RESUMO

Background: Huntington's disease is an inheritable autosomal dominant disorder caused by an expanded CAG trinucleotide repeat within the Huntingtin gene, leading to a polyglutamine (polyQ) expansion in the mutant protein. Objective: A potential therapeutic approach for delaying or preventing the onset of the disease involves enhancing the degradation of the aggregation-prone polyQ-expanded N-terminal mutant huntingtin (mHTT) exon1 fragment. A few proteases and peptidases have been identified that are able to cleave polyQ fragments with low efficiency. This study aims to identify a potent polyQ-degrading endopeptidase. Methods: Here we used quenched polyQ peptides to identify a polyQ-degrading endopeptidase. Next we investigated its role on HTT turnover, using purified polyQ-expanded HTT fragments and striatal cells expressing mHTT exon1 peptides. Results: We identified insulin-degrading enzyme (IDE) as a novel endopeptidase for degrading polyQ peptides. IDE was, however, ineffective in reducing purified polyQ-expanded HTT fragments. Similarly, in striatal cells expressing mHTT exon1 peptides, IDE did not enhance mHTT turnover. Conclusions: This study shows that despite IDE's efficiency in degrading polyQ peptides, it does not contribute to the direct degradation of polyQ-expanded mHTT fragments.


Assuntos
Proteína Huntingtina , Insulisina , Peptídeos , Insulisina/metabolismo , Insulisina/genética , Proteína Huntingtina/metabolismo , Proteína Huntingtina/genética , Peptídeos/metabolismo , Humanos , Animais , Doença de Huntington/metabolismo , Doença de Huntington/genética , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Corpo Estriado/metabolismo
7.
J Neuroinflammation ; 20(1): 233, 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37817156

RESUMO

The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzheimer's disease (AD) and type 2 diabetes (T2D). These antecedents led us to address the impact of IDE absence in hippocampus and olfactory bulb. A specific induction of microgliosis was found in the hippocampus of IDE knockout (IDE-KO) mice, without any effects in neither hippocampal volume nor astrogliosis. Performance on hippocampal-dependent memory tests is influenced by IDE gene dose in 12-month-old mice. Furthermore, a comprehensive characterization of the impact of IDE haploinsufficiency and total deletion in metabolic, behavioral, and molecular parameters in the olfactory bulb, a site of high insulin receptor levels, reveals an unambiguous barcode for IDE-KO mice at that age. Using wildtype and IDE-KO primary microglial cultures, we performed a functional analysis at the cellular level. IDE absence alters microglial responses to environmental signals, resulting in impaired modulation of phenotypic states, with only transitory effects on amyloid-ß management. Collectively, our results reveal previously unknown physiological functions for IDE in microglia that, due to cell-compartment topological reasons, cannot be explained by its enzymatic activity, but instead modulate their multidimensional response to various damaging conditions relevant to aging and AD conditions.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Insulisina , Camundongos , Animais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Insulisina/genética , Insulisina/metabolismo , Insulisina/farmacologia , Microglia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Encéfalo/metabolismo , Fenótipo
8.
Biomolecules ; 13(10)2023 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-37892174

RESUMO

The insulin-degrading enzyme (IDE) is a Zn2+ peptidase originally discovered as the main enzyme involved in the degradation of insulin and other amyloidogenic peptides, such as the ß-amyloid (Aß) peptide. Therefore, a role for the IDE in the cure of diabetes and Alzheimer's disease (AD) has been long envisaged. Anyway, its role in degrading amyloidogenic proteins remains not clearly defined and, more recently, novel non-proteolytic functions of the IDE have been proposed. From a structural point of view, the IDE presents an atypical clamshell structure, underscoring unique enigmatic enzymological properties. A better understanding of the structure-function relationship may contribute to solving some existing paradoxes of IDE biology and, in light of its multifunctional activity, might lead to novel therapeutic approaches.


Assuntos
Doença de Alzheimer , Insulisina , Humanos , Insulisina/química , Insulisina/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Proteínas Amiloidogênicas , Desenho de Fármacos
9.
J Math Biol ; 87(5): 73, 2023 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-37856001

RESUMO

This paper investigates the dynamics of a glucose-insulin regulatory system model that incorporates: (1) insulin-degrading enzyme in the insulin equation; and (2) discrete time delays respectively in the insulin production term, hepatic glucose production term, and the insulin-degrading enzyme. We provide rigorous results of our model including the asymptotic stability of the equilibrium solution and the existence of Hopf bifurcation. We show that analytically and numerically at a certain value the time delays driven stability or instability occurs when the corresponding model has an interior equilibrium. Moreover, we illustrate the oscillatory regulation and insulin secretion via numerical simulations, which show that the model dynamics exhibit physiological observations and more information by allowing parameters to vary. Our results may provide useful biological insights into diabetes for the glucose-insulin regulatory system model.


Assuntos
Insulinas , Insulisina , Simulação por Computador , Fatores de Tempo , Modelos Biológicos
10.
Biochemistry (Mosc) ; 88(6): 731-740, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37748870

RESUMO

Endopeptidases IdeS and IdeZ (streptococcal virulence factors that specifically cleave IgG heavy chains) are of particular interest because of their potential use in biotechnology, medicine, and veterinary. Genes encoding these enzymes were cloned and expressed in Escherichia coli heterologous expression system (ideS was cloned from a Streptococcus pyogenes collection strain; ideZ from Streptococcus zooepidemicus was synthesized). The 6His-tag was introduced into the amino acid sequence of each endopeptidase, and IdeS and IdeZ were purified by metal affinity chromatography to an apparent homogeneity (according to polyacrylamide gel electrophoresis). Purified enzymes were active against human and animal IgGs; their specificity toward human IgGs was confirmed by polyacrylamide gel electrophoresis. Recombinant IdeZ was used for immunological analysis of equine strangles infection (diagnostics and determination of the titer of specific antibodies in blood). Hence, IdeZ can be used in veterinary and sanitary microbiology to diagnose infections caused by Streptococcus equi and S. zooepidemicus in addition to its application in medicine and biotechnology.


Assuntos
Endopeptidases , Insulisina , Humanos , Animais , Cavalos , Endopeptidases/genética , Sequência de Aminoácidos , Biotecnologia , Cromatografia de Afinidade , Eletroforese em Gel de Poliacrilamida , Escherichia coli/genética , Imunossupressores
11.
Neuro Endocrinol Lett ; 44(4): 199-205, 2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37466059

RESUMO

OBJECTIVE: It has been increasingly recognized that the pathological progress of Alzheimer´s disease (AD) is connected to metabolic function and inflammation. Insulin-degrading enzyme (IDE) is essential for glucose metabolism and the degradation of amyloid-ß. We aimed to explore the associations between IDE, total tau, and cytokines levels in plasma from subjects with AD and non-demented controls. METHODS AND MATERIAL: Plasma samples (18 patients diagnosed with AD and 6 non-demented controls) from the Netherlands Brain Bank were used to analyze IDE levels and total tau with an enzyme-linked immunosorbent assay. Cytokines were analyzed with Luminex custom plex assays for interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α). Results were analyzed using the Mann-Whitney U and Spearman´s rank correlation tests. RESULTS: Total tau in plasma was significantly increased in AD subjects compared to non-demented control subjects (p = 0.044). Total tau was positively correlated with IDE levels in plasma in all subjects (r = 0.494, p = 0.017). Significant correlations could be demonstrated between plasma levels of IDE and IL-6 (r = 0.546, p = 0.019), IL-8 (r = 0.664, p = 0.003), IL-10 (r = 0.833, p < 0.001), and TNF-α (r = 0.633, p = 0.005) in subjects with AD, but not in non-demented controls. CONCLUSION: Results from this study suggest that plasma IDE levels may be associated with inflammation and neurodegeneration and could potentially be a target for future diagnostic and treatment strategies.


Assuntos
Doença de Alzheimer , Insulisina , Humanos , Peptídeos beta-Amiloides , Citocinas , Inflamação , Insulisina/metabolismo , Interleucina-10 , Interleucina-6 , Interleucina-8 , Proteínas tau , Fator de Necrose Tumoral alfa
12.
ACS Chem Neurosci ; 14(16): 2935-2943, 2023 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-37498802

RESUMO

The insulin-degrading enzyme (IDE) is an evolutionarily conserved protease implicated in the degradation of insulin and amyloidogenic peptides. Most of the biochemical and biophysical characterization of IDE's catalytic activity has been conducted using solutions containing a single substrate, i.e., insulin or Aß(1-40). IDE's activity toward a particular substrate, however, is likely to be influenced by the presence of other substrates. Here, we show by a kinetic assay based on insulin's helical circular dichroic signal and MALDI TOF mass spectrometry that Aß peptides modulate IDE's activity toward insulin in opposing ways. Aß(1-40) enhances IDE-dependent degradation of insulin, whereas Aß(pyroE3-42), the most pathogenic pyroglutamate-modified Aß peptide in AD, inhibits IDE's activity. Intriguingly, Aß(pyroE3-42) also inhibits IDE's ability to degrade Aß(1-40). Together, our results implicate Aß peptides in the abnormal catabolism of IDE's key substrates.


Assuntos
Insulisina , Insulisina/metabolismo , Peptídeos beta-Amiloides/metabolismo , Insulina/metabolismo
13.
Diabetes Obes Metab ; 25(11): 3268-3278, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37493025

RESUMO

AIM: To investigate the use of synthetic preimplantation factor (sPIF) as a potential therapeutic tool for improving glucose-stimulated insulin secretion (GSIS), glucose tolerance and insulin sensitivity in the setting of diabetes. MATERIALS AND METHODS: We used a preclinical murine model of type 2 diabetes (T2D) induced by high-fat diet (HFD) feeding for 12 weeks. Saline or sPIF (1 mg/kg/day) was administered to mice by subcutaneously implanted osmotic mini-pumps for 25 days. Glucose tolerance, circulating insulin and C-peptide levels, and GSIS were assessed. In addition, ß-cells (Min-6) were used to test the effects of sPIF on GSIS and insulin-degrading enzyme (IDE) activity in vitro. The effect of sPIF on GSIS was also tested in human islets. RESULTS: GSIS was enhanced 2-fold by sPIF in human islets ex vivo. Furthermore, continuous administration of sPIF to HFD mice increased circulating levels of insulin and improved glucose tolerance, independently of hepatic insulin clearance. Of note, islets isolated from mice treated with sPIF exhibited restored ß-cell function. Finally, genetic (shRNA-IDE) or pharmacological (6bK) inactivation of IDE in Min-6 abolished sPIF-mediated effects on GSIS, showing that both the protein and its protease activity are required for its action. CONCLUSIONS: We conclude that sPIF is a promising secretagogue for the treatment of T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Insulisina , Ilhotas Pancreáticas , Camundongos , Humanos , Animais , Secreção de Insulina , Insulisina/metabolismo , Insulisina/farmacologia , Camundongos Obesos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ilhotas Pancreáticas/metabolismo
14.
Int J Mol Sci ; 24(13)2023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-37446366

RESUMO

Metal-organic frameworks (MOFs) are a class of porous two- or three-dimensional infinite structure materials consisting of metal ions or clusters and organic linkers, which are connected via coordination bonds [...].


Assuntos
Cyprinidae , Insulisina , Estruturas Metalorgânicas , Animais , Imunossupressores , Metais
15.
Ageing Res Rev ; 90: 101999, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37414154

RESUMO

Accumulation of amyloid-ß in the central nervous system is a common feature of Alzheimer's disease (AD) and diabetes-related cognitive impairment. Since the insulin-degrading enzyme (IDE) can break down amyloid-ß plaques, there is considerable interest in using this enzyme to treat both neurological disorders. In this review, we have summarized the pre-clinical and clinical research on the potential application of IDE for the improvement of cognitive impairment. Furthermore, we have presented an overview of the main pathways that can be targeted to mitigate the progression of AD and the cognitive impairment caused by diabetes.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Insulisina , Humanos , Doença de Alzheimer/metabolismo , Insulisina/metabolismo , Peptídeos beta-Amiloides/metabolismo , Diabetes Mellitus Tipo 2/metabolismo
16.
J Clin Lab Anal ; 37(13-14): e24949, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37515308

RESUMO

BACKGROUND: Insulin-degrading enzyme (IDE) is an important gene in studies of the pathophysiology of type 2 diabetes mellitus (T2DM). Recent studies have suggested a possible link between type 2 diabetes mellitus (T2DM) and the pathophysiology of schizophrenia (SZ). At the same time, significant changes in insulin-degrading enzyme (IDE) gene expression have been found in the brains of people with schizophrenia. These findings highlight the need to further investigate the role of IDE in schizophrenia pathogenesis. METHODS: We enrolled 733 participants from the Czech Republic, including 383 patients with schizophrenia and 350 healthy controls. Our study focused on the single nucleotide polymorphism (SNP) rs2421943 in the IDE gene, which has previously been associated with the pathogenesis of Alzheimer's disease. The SNP was analyzed using the PCR-RFLP method. RESULTS: The G allele of the rs2421943 polymorphism was found to significantly increase the risk of developing SZ (p < 0.01) when a gender-based analysis showed that both AG and GG genotypes were associated with a more than 1.55 times increased risk of SZ in females (p < 0.03) but not in males. Besides, we identified a potential binding site at the G allele locus for has-miR-7110-5p, providing a potential mechanism for the observed association. CONCLUSION: Our results confirm the role of the IDE gene in schizophrenia pathogenesis and suggest that future research should investigate the relationship between miRNA and estrogen influence on IDE expression in schizophrenia pathogenesis.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Insulisina , Esquizofrenia , Masculino , Feminino , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Esquizofrenia/genética , Insulisina/genética , Insulisina/metabolismo , Genótipo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Polimorfismo de Nucleotídeo Único/genética
17.
Biomolecules ; 13(6)2023 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-37371470

RESUMO

Insulin-degrading enzyme (IDE) is a highly conserved metalloprotease that is mainly localized in the cytosol. Although IDE can degrade insulin and some other low molecular weight substrates efficiently, its ubiquitous expression suggests additional functions supported by experimental findings, such as a role in stress responses and cellular protein homeostasis. The translation of a long full-length IDE transcript has been reported to result in targeting to mitochondria, but the role of IDE in this compartment is unknown. To obtain initial leads on the function of IDE in mitochondria, we used a proximity biotinylation approach to identify proteins interacting with wild-type and protease-dead IDE targeted to the mitochondrial matrix. We find that IDE interacts with multiple mitochondrial ribosomal proteins as well as with proteins involved in the synthesis and assembly of mitochondrial complex I and IV. The mitochondrial interactomes of wild type and mutant IDE are highly similar and do not reveal any likely proteolytic IDE substrates. We speculate that IDE could adopt similar additional non-proteolytic functions in mitochondria as in the cytosol, acting as a chaperone and contributing to protein homeostasis and stress responses.


Assuntos
Transporte de Elétrons , Insulisina , Ribossomos Mitocondriais , Transporte de Elétrons/fisiologia , Insulina/metabolismo , Insulisina/metabolismo , Mitocôndrias/metabolismo , Ribossomos Mitocondriais/metabolismo , Peptídeo Hidrolases/metabolismo , Humanos
18.
Int J Parasitol ; 53(10): 545-554, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37150475

RESUMO

The horse genotype is one of three common Cryptosporidium spp. in equine animals and has been identified in some human cases. The species status of Cryptosporidium horse genotype remains unclear due to the lack of extensive morphological, biological, and genetic data. In the present study, we have conducted biological and whole genome sequence analyses of an isolate of the genotype from hedgehogs and proposed to name it Cryptosporidium equi n. sp. to reflect its common occurrence in equine animals. Oocysts of C. equi measured 5.12 ± 0.36 µm × 4.46 ± 0.21 µm with a shape index of 1.15 ± 0.08 (n = 50). Cryptosporidium equi was infectious to 3-week-old four-toed hedgehogs (Atelerix albiventris) and mice, with a prepatent period of 2-9 days and a patent period of 30-40 days in hedgehogs. It was not infectious to rats and rabbits. Phylogenetic analyses of small subunit rRNA, 70 kDa heat shock protein, actin, 60 kDa glycoprotein and 100 other orthologous genes revealed that C. equi is genetically distinct from other known Cryptosporidium species and genotypes. The sequence identity between C. equi and Cryptosporidium parvum genomes is 97.9%. Compared with C. parvum, C. equi has lost two MEDLE genes and one insulinase-like protease gene and gained one SKSR gene. In addition, 60 genes have highly divergent sequences (sequence differences ≥ 5.0%), including those encoding mucin-like glycoproteins, insulinase-like peptidases, and MEDLE and SKSR proteins. The genetic uniqueness of C. equi supports its increasing host range and the naming of it as a valid Cryptosporidium species. This is the first known use of whole genome sequence data in delineating new Cryptosporidium species.


Assuntos
Cryptosporidiidae , Criptosporidiose , Cryptosporidium , Insulisina , Animais , Cavalos , Camundongos , Ratos , Humanos , Coelhos , Cryptosporidium/genética , Filogenia , Ouriços , Insulisina/genética , Genótipo , Fezes
19.
Cell Mol Biol (Noisy-le-grand) ; 69(1): 13-18, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-37213163

RESUMO

Sertoli cells, the only somatic cells in testis seminiferous tubules, provide a supporting microenvironment for male germ cells and play essential roles in spermatogenesis. The insulin-degrading enzyme (IDE), a ubiquitous zinc peptidase of the inverzincin family, plays crucial role in sperm production, as IDE-knockout mice presented decreased testis weight and impaired sperm viability and morphology. However, whether and how IDE affects swine Sertoli cell proliferation remains unclear. Thus, in the present study, we aimed to evaluate the effects of IDE on the proliferation of swine Sertoli cells, as well as its underlying molecular mechanism. After knocking down IDE expression with small interfering RNA transfection, we analyzed the proliferation of swine Sertoli cells as well as the expression of related regulatory factors (WT1, ERK, and AKT). The results showed that IDE knockdown promoted swine Sertoli cell proliferation and increased WT1 expression, possibly through activating ERK and AKT. Overall, our findings suggest that IDE may be involved in male reproduction by regulating Sertoli cell proliferation, which provides new information to better understand the regulatory mechanisms of swine Sertoli cells and improve the reproductive traits of male pigs.


Assuntos
Insulisina , Células de Sertoli , Animais , Masculino , Proliferação de Células , Insulisina/genética , Insulisina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sêmen , Células de Sertoli/metabolismo , Suínos , Testículo/metabolismo
20.
Diabetologia ; 66(5): 884-896, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36884057

RESUMO

AIMS/HYPOTHESIS: Transcriptome analyses revealed insulin-gene-derived transcripts in non-beta endocrine islet cells. We studied alternative splicing of human INS mRNA in pancreatic islets. METHODS: Alternative splicing of insulin pre-mRNA was determined by PCR analysis performed on human islet RNA and single-cell RNA-seq analysis. Antisera were generated to detect insulin variants in human pancreatic tissue using immunohistochemistry, electron microscopy and single-cell western blot to confirm the expression of insulin variants. Cytotoxic T lymphocyte (CTL) activation was determined by MIP-1ß release. RESULTS: We identified an alternatively spliced INS product. This variant encodes the complete insulin signal peptide and B chain and an alternative C-terminus that largely overlaps with a previously identified defective ribosomal product of INS. Immunohistochemical analysis revealed that the translation product of this INS-derived splice transcript was detectable in somatostatin-producing delta cells but not in beta cells; this was confirmed by light and electron microscopy. Expression of this alternatively spliced INS product activated preproinsulin-specific CTLs in vitro. The exclusive presence of this alternatively spliced INS product in delta cells may be explained by its clearance from beta cells by insulin-degrading enzyme capturing its insulin B chain fragment and a lack of insulin-degrading enzyme expression in delta cells. CONCLUSIONS/INTERPRETATION: Our data demonstrate that delta cells can express an INS product derived from alternative splicing, containing both the diabetogenic insulin signal peptide and B chain, in their secretory granules. We propose that this alternative INS product may play a role in islet autoimmunity and pathology, as well as endocrine or paracrine function or islet development and endocrine destiny, and transdifferentiation between endocrine cells. INS promoter activity is not confined to beta cells and should be used with care when assigning beta cell identity and selectivity. DATA AVAILABILITY: The full EM dataset is available via www.nanotomy.org (for review: http://www.nanotomy.org/OA/Tienhoven2021SUB/6126-368/ ). Single-cell RNA-seq data was made available by Segerstolpe et al [13] and can be found at https://sandberglab.se/pancreas . The RNA and protein sequence of INS-splice was uploaded to GenBank (BankIt2546444 INS-splice OM489474).


Assuntos
Insulisina , Ilhotas Pancreáticas , Humanos , Células Secretoras de Somatostatina/metabolismo , Insulisina/metabolismo , Insulina/genética , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , RNA , Sinais Direcionadores de Proteínas
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