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1.
Front Immunol ; 12: 722979, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489972

RESUMO

The immunopathology of type I diabetes (T1D) presents a complicated case in part because of the multifactorial origin of this disease. Typically, T1D is thought to occur as a result of autoimmunity toward islets of Langerhans, resulting in the destruction of insulin-producing cells (ß cells) and thus lifelong reliance on exogenous insulin. However, that explanation obscures much of the underlying mechanism, and the actual precipitating events along with the associated actors (latent viral infection, diverse immune cell types and their roles) are not completely understood. Notably, there is a malfunctioning in the regulation of cytotoxic CD8+ T cells that target endocrine cells through antigen-mediated attack. Further examination has revealed the likelihood of an imbalance in distinct subpopulations of tolerogenic and cytotoxic natural killer (NK) cells that may be the catalyst of adaptive immune system malfunction. The contributions of components outside the immune system, including environmental factors such as chronic viral infection also need more consideration, and much of the recent literature investigating the origins of this disease have focused on these factors. In this review, the details of the immunopathology of T1D regarding NK cell disfunction is discussed, along with how those mechanisms stand within the context of general autoimmune disorders. Finally, the rarer cases of latent autoimmune, COVID-19 (viral), and immune checkpoint inhibitor (ICI) induced diabetes are discussed as their exceptional pathology offers insight into the evolution of the disease as a whole.


Assuntos
Doenças Autoimunes/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Autoanticorpos/imunologia , Doenças Autoimunes/patologia , COVID-19/complicações , Diabetes Mellitus Tipo 1/etiologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Viroses/complicações
2.
Pediatr Endocrinol Diabetes Metab ; 27(2): 123-133, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34514768

RESUMO

C-peptide, the molecule produced in an equimolar concentration to insulin, has become an established insulin secretion biomarker in diabetic patients. Measurement of C-peptide level can be helpful in clinical practice for assessing insulin-producing b-cells residual function, especially in the patients who have already started exogenous insulin therapy. Advances in assays have made measurement of C-peptide more reliable and inexpensive. Traditionally, C-peptide is widely used to differentiate between type 1, type 2 and monogenic types in diabetic patients of all ages, both when the diabetes occurs and even months and years after the initial diagnosis. Moreover, in the patients with type 1 diabetes, the C-peptide secretion can become a reliable predictor of the clinical partial remission in the first months after diagnosis, although noteworthy, its' any specified level is not included in the definition of this phase of the disease. Many other clinical factors such as age, use of innovative technologies, the intensity of physical activity or body mass influence the concentration of C-peptide as well as diabetes remission occurrence and duration. They may interfere the interpretation of C-peptide level in the diabetes course. There is a great need to assess the new, adjusted C-peptide levels in these situations. A multitude novel therapies including immunomodulative factors and stem cell transplants can also use C-peptide in the patient selection and post-therapeutic monitoring of the outcome in researches aimed in extension of remission period. Recent research proves C-peptide presence and preserved function and being the possible important player in better metabolic control in long-lasting diabetes type 1. These findings may open the area for trials to regenerate b-cells and save endogenous insulin secretion for many years after diagnosis. Last but not the least, C-peptide presents its own physiological effect on other tissues, among others on the endothelial function, thus participates in inhibiting micro- and macrovascular diabetes complications. The idea of C-peptide as a new, additional to insulin cure remains as much attractive as elusive.


Assuntos
Diabetes Mellitus Tipo 1 , Insulina , Biomarcadores , Peptídeo C , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Insulina/metabolismo , Insulina/uso terapêutico , Secreção de Insulina
3.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445075

RESUMO

Pre-weaned porcine islets (PPIs) represent an unlimited source for islet transplantation but are functionally immature. We previously showed that necrostatin-1 (Nec-1) immediately after islet isolation enhanced the in vitro development of PPIs. Here, we examined the impact of Nec-1 on the in vivo function of PPIs after transplantation in diabetic mice. PPIs were isolated from pancreata of 8-15-day-old, pre-weaned pigs and cultured in media alone, or supplemented with Nec-1 (100 µM) on day 0 or on day 3 of culture (n = 5 for each group). On day 7, islet recovery, viability, oxygen consumption rate, insulin content, cellular composition, insulin secretion capacity, and transplant outcomes were evaluated. While islet viability and oxygen consumption rate remained high throughout 7-day tissue culture, Nec-1 supplementation on day 3 significantly improved islet recovery, insulin content, endocrine composition, GLUT2 expression, differentiation potential, proliferation capacity of endocrine cells, and insulin secretion. Adding Nec-1 on day 3 of tissue culture enhanced the islet recovery, proportion of delta cells, beta-cell differentiation and proliferation, and stimulation index. In vivo, this leads to shorter times to normoglycemia, better glycemic control, and higher circulating insulin. Our findings identify the novel time-dependent effects of Nec-1 supplementation on porcine islet quantity and quality prior to transplantation.


Assuntos
Diabetes Mellitus Experimental/terapia , Imidazóis/farmacologia , Indóis/farmacologia , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/efeitos dos fármacos , Técnicas de Cultura de Tecidos/métodos , Animais , Diabetes Mellitus Experimental/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/fisiologia , Camundongos Nus , Suínos , Transplante Heterólogo/métodos , Transplantes/efeitos dos fármacos , Transplantes/fisiologia
4.
Am J Physiol Endocrinol Metab ; 321(3): E376-E391, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34338042

RESUMO

Tissue iron overload is associated with insulin resistance and mitochondrial dysfunction in rodents and humans; however, the mechanisms or cell types that mediate this phenotype are not completely understood. Macrophages (Mɸs) are known to contribute to iron handling; thus, we hypothesized that perturbed iron handling by Mɸs impairs mitochondrial energetics and evokes systemic insulin resistance in mice. Male and female mice with myeloid-targeted (LysMCre) deletion of the canonical iron exporter, ferroportin (Fpn, encoded by Slc40a1), floxed littermates, and C57BL/6J wild-type mice were used to test our hypotheses. Myeloid-targeted deletion of Fpn evoked multitissue iron accumulation and reduced mitochondrial respiration in bone marrow-derived Mɸs, liver leukocytes, and Mɸ-enriched populations from adipose tissue (AT). In addition, a single bolus of exogenous iron administered to C57BL/6J mice phenocopied the loss of Fpn, resulting in a reduction in maximal and mitochondrial reserve capacity in Mɸ-enriched cellular fractions from liver and AT. In vivo exogenous iron chelation restored mitochondrial reserve capacity in liver leukocytes from Fpn LysMCre mice, but had no effect in AT myeloid populations. However, despite the impairments in mitochondrial respiration, neither loss of myeloid-specific Fpn nor exogenous iron overload perturbed glucose homeostasis or systemic insulin action in lean or obese mice, whereas aging coupled with lifelong loss of Fpn unmasked glucose intolerance. Together these data demonstrate that iron handling is critical for the maintenance of macrophage mitochondrial function, but perturbing myeloid iron flux via the loss of Fpn action is not sufficient to evoke systemic insulin resistance in young adult mice. These findings also suggest that if Mɸs are capable of storing iron properly, they have a pronounced ability to withstand iron excess without evoking overt collateral damage and associated insulin resistance that may be age dependent.NEW & NOTEWORTHY We used myeloid-specific knockout of ferroportin to determine whether macrophage iron enrichment alters systemic metabolism. We found that macrophages in several tissues showed mitochondrial defects such as a reduction in mitochondrial reserve capacity. However, insulin action in the mice was preserved. These findings also suggest that Mɸs have a pronounced ability to withstand iron excess without evoking overt collateral damage and associated insulin resistance, which appears to be age dependent.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Insulina/metabolismo , Macrófagos/metabolismo , Células Mieloides/metabolismo , Animais , Metabolismo Energético , Feminino , Glucose/metabolismo , Glicoproteínas de Membrana , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Receptores de Interleucina-1
5.
Nat Immunol ; 22(9): 1175-1185, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34429546

RESUMO

Systematic characterizations of adipose regulatory T (Treg) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose Treg cells, we identified CD73hiST2lo and CD73loST2hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73hiST2lo and CD73loST2hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α-Med23-PPAR-γ axis to drive the transition of CD73hiST2lo into a CD73loST2hi adipose Treg cell subset. Treg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73hiST2lo adipose Treg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose Treg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose Treg cell subsets in aged and obese contexts.


Assuntos
Tecido Adiposo/imunologia , Resistência à Insulina/imunologia , Insulina/metabolismo , Receptor de Insulina/metabolismo , Linfócitos T Reguladores/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Tecido Adiposo/citologia , Envelhecimento/imunologia , Animais , Células Cultivadas , Sequenciamento de Nucleotídeos em Larga Escala , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Masculino , Complexo Mediador/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/imunologia , PPAR gama/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologia
6.
J Agric Food Chem ; 69(34): 9813-9821, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415766

RESUMO

ι-Carrageenan tetrasaccharide (ιCTs), a novel oligosaccharide, was hydrolyzed from ι-carrageenan with targeting marine tool-enzyme Cgi82A. Previously, we have found ιCTs exhibited a hypoglycemic effect, whether it could regulate lipid metabolism remains unknown. In this study, the insulin-resistant mice induced by high-fat-high-sucrose diet were orally administrated with ιCTs (30 mg/kg·bw) for 20 weeks. The results showed that the contents of triglyceride and cholesterol in both serum and liver were reduced by ιCTs, and their excretion in feces were promoted, suggesting lipid accumulation was inhibited. Intriguingly, the overall levels of bile acid in serum, liver, and feces were all raised by ιCTs. Given that bile acids are the essential signal factors for regulating lipid metabolism via the farnesoid-X-receptor (FXR), we conducted serum bile acid profile analysis and found that the levels of high-affinity agonists deoxycholic acid and lithocholic acid were decreased in the ιCTs group, showing that ιCTs failed to activate FXR. Western blot analysis showed that ιCTs downregulated hepatic FXR and small heterodimer partner (SHP) expression and increased downstream CYP7A1 expression via regulating the FXR-SHP signal to accelerate liver cholesterol conversion. Meanwhile, ιCTs decreased the expression of PXR and SREBP1c and elevated the expression of PPARα and CPT1α via regulating the FXR-PXR-SREBP1c/PPARα signal to inhibit fatty acid synthesis and promote fatty acid ß-oxidation. To the best of our knowledge, this study for the first time reported that ιCTs alleviated liver lipid accumulation via the bile acid-FXR-SHP/PXR signal to regulate cholesterol conversion and fatty acid metabolism, which highlighted a new idea for ameliorating insulin resistance.


Assuntos
Ácidos e Sais Biliares , Insulina , Animais , Ácidos e Sais Biliares/metabolismo , Carragenina , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismo , Ácidos Graxos/metabolismo , Insulina/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Oligossacarídeos/metabolismo
7.
Free Radic Biol Med ; 174: 135-143, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34363947

RESUMO

Aquaporin-8 (AQP8) is a peroxiporin, a transmembrane water and hydrogen peroxide (H2O2) transport protein expressed in the mitochondrial and plasma membranes of pancreatic ß-cells. AQP8 protein expression is low under physiological conditions, but it increases after cytokine exposure both, in vitro and in vivo, possibly related to a NF-κB consensus sequence in the promoter. AQP8 knockdown (KD) insulin-producing RINm5F cells are particularly susceptible to cytokine-mediated oxidative stress. Cytokine (a mixture of IL-1ß, TNF-α, and IFN-γ) treated AQP8 KD cells exhibited pronounced sensitivity to reactive oxygen and nitrogen species (ROS and RNS), resulting in a significant loss of ß-cell viability due to enhanced toxicity of the increased concentrations of H2O2 and hydroxyl radicals (●OH) in mitochondria of AQP8 KD cells. This viability loss went along with increased caspase activities, reduced nitrite concentration (representative of nitric oxide (NO●) accumulation) and increased lipid peroxidation. The explanation for the increased toxicity of the proinflammatory cytokines in AQP8 KD cells resides in the fact that efflux of the H2O2 generated during oxidative stress in the ß-cell mitochondria is hampered through the loss of the peroxiporin channels in the mitochondrial membranes of the AQP8 KD cells. The increased proinflammatory cytokine toxicity due to loss of AQP8 expression in the KD ß-cell mitochondria is thus the result of increased rates of apoptosis. This decreased cell viability is caused by increased levels of oxidative stress along with a ferroptosis-mediated cell death component due to decreased NO● generation.


Assuntos
Aquaporinas , Células Secretoras de Insulina , Animais , Citocinas/genética , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/toxicidade , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ratos
8.
Eur J Endocrinol ; 185(4): 565-576, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34374650

RESUMO

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


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proinsulina/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Adulto , Aldeído Oxirredutases/metabolismo , Estudos de Casos e Controles , Desdiferenciação Celular/fisiologia , China , Diabetes Mellitus Tipo 2/patologia , Feminino , Glucagon/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia
9.
In Vivo ; 35(5): 2551-2558, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410942

RESUMO

BACKGROUND/AIM: We developed an experimental method to reproduce insulin secretion from isolated rat pancreas preparations using an organ bath system. However, secretion of trypsin, another pancreatic enzyme, interferes with insulin production in such systems. We aimed to ascertain the minimum trypsin inhibitor (TI), dose for obtaining a sustained, stable rate of insulin secretion. MATERIALS AND METHODS: The action of TI (1-10 µg/ml) on pancreatic preparations of male Wistar-Imamichi rats in organ bath experiments was assessed by measuring insulin, amylase, and trypsin activity. RESULTS: The level of insulin outflow remained steady in the TI-treated samples, in contrast to that in the untreated control, where insulin secretion decreased over time. The level of amylase outflow did not change significantly. Trypsin activity was significantly lower in the TI-treated samples than in the control. CONCLUSION: Even low concentrations of TI can maintain insulin secretion by inhibiting trypsin activity in organ bath experiments.


Assuntos
Amilases , Inibidores da Tripsina , Animais , Insulina/metabolismo , Secreção de Insulina , Masculino , Pâncreas/metabolismo , Ratos , Ratos Wistar , Inibidores da Tripsina/metabolismo , Inibidores da Tripsina/farmacologia
10.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445300

RESUMO

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


Assuntos
Resistência à Insulina/fisiologia , Insulina/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia
11.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360906

RESUMO

The most common cause of dementia, especially in elderly people, is Alzheimer's disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer's disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glucose/metabolismo , Terapia de Alvo Molecular/métodos , Idoso , Envelhecimento/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Insulina/metabolismo , Insulina/uso terapêutico , Neuroglia/metabolismo , Neurônios/metabolismo , Fatores de Risco
12.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361788

RESUMO

This research investigated a UPLC-QTOF/ESI-MS-based phytochemical profiling of Combretum indicum leaf extract (CILEx), and explored its in vitro antioxidant and in vivo antidiabetic effects in a Long-Evans rat model. After a one-week intervention, the animals' blood glucose, lipid profile, and pancreatic architectures were evaluated. UPLC-QTOF/ESI-MS fragmentation of CILEx and its eight docking-guided compounds were further dissected to evaluate their roles using bioinformatics-based network pharmacological tools. Results showed a very promising antioxidative effect of CILEx. Both doses of CILEx were found to significantly (p < 0.05) reduce blood glucose, low-density lipoprotein (LDL), and total cholesterol (TC), and increase high-density lipoprotein (HDL). Pancreatic tissue architectures were much improved compared to the diabetic control group. A computational approach revealed that schizonepetoside E, melianol, leucodelphinidin, and arbutin were highly suitable for further therapeutic assessment. Arbutin, in a Gene Ontology and PPI network study, evolved as the most prospective constituent for 203 target proteins of 48 KEGG pathways regulating immune modulation and insulin secretion to control diabetes. The fragmentation mechanisms of the compounds are consistent with the obtained effects for CILEx. Results show that the natural compounds from CILEx could exert potential antidiabetic effects through in vivo and computational study.


Assuntos
Antioxidantes/farmacologia , Combretum/química , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Arbutina/química , Arbutina/isolamento & purificação , Sítios de Ligação , Glicemia/efeitos dos fármacos , HDL-Colesterol/agonistas , HDL-Colesterol/sangue , LDL-Colesterol/antagonistas & inibidores , LDL-Colesterol/sangue , Biologia Computacional/métodos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Flavonoides/química , Flavonoides/isolamento & purificação , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Insulina/agonistas , Insulina/metabolismo , Masculino , Modelos Moleculares , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Extratos Vegetais/química , Folhas de Planta/química , Ligação Proteica , Conformação Proteica , Ratos , Ratos Long-Evans , Triterpenos/química , Triterpenos/isolamento & purificação
13.
FASEB J ; 35(9): e21847, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34405464

RESUMO

Mounting evidence demonstrates that paternal diet programs offspring metabolism. However, the contribution of a pre-conception paternal high protein (HP) diet to offspring metabolism, gut microbiota, and epigenetic changes remains unclear. Here we show that paternal HP intake in Sprague Dawley rats programs protective metabolic outcomes in offspring. Compared to paternal high fat/sucrose (HF/S), HP diet improved body composition and insulin sensitivity and improved circulating satiety hormones and cecal short-chain fatty acids compared to HF/S and control diet (P < .05). Further, using 16S rRNA gene sequencing to assess gut microbial composition, we observed increased alpha diversity, distinct bacterial clustering, and increased abundance of Bifidobacterium, Akkermansia, Bacteroides, and Marvinbryantia in HP fathers and/or male and female adult offspring. At the epigenetic level, DNMT1and 3b expression was altered intergenerationally. Our study identifies paternal HP diet as a modulator of gut microbial composition, epigenetic markers, and metabolic function intergenerationally.


Assuntos
Composição Corporal , Dieta Rica em Proteínas , Epigênese Genética , Pai , Microbioma Gastrointestinal , Insulina/metabolismo , Exposição Paterna , Tecido Adiposo/metabolismo , Adiposidade , Envelhecimento , Animais , Peso Corporal , DNA (Citosina-5-)-Metiltransferases/metabolismo , Dieta Hiperlipídica , Sacarose na Dieta , Ingestão de Energia , Metabolismo Energético , Ácidos Graxos/metabolismo , Feminino , Fertilidade , Teste de Tolerância a Glucose , Hormônios/metabolismo , Resistência à Insulina , Fígado/metabolismo , Masculino , Tamanho do Órgão , Gravidez , Pequeno RNA não Traduzido/metabolismo , Ratos , Ratos Sprague-Dawley , Resposta de Saciedade , Desmame
14.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3643-3649, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402288

RESUMO

Type 2 diabetes mellitus( T2 DM) is a common chronic metabolic disease characterized by persistent hyperglycemia and insulin resistance. In pancreatic ß-cells,glucose-stimulated insulin secretion( GSIS) plays a pivotal role in maintaining the balance of blood glucose level. Previous studies have shown that geniposide,one of the active components of Gardenia jasminoides,could quickly regulate the absorption and metabolism of glucose,and affect glucose-stimulated insulin secretion in pancreatic ß cells,but the specific mechanism needs to be further explored. Emerging evidence indicated that glycosylation of glucose transporter( GLUT) has played a key role in sensing cell microenvironmental changes and regulating glucose homeostasis in eucaryotic cells. In this study,we studied the effects of geniposide on the key molecules of GLUT2 glycosylation in pancreatic ß cells. The results showed that geniposide could significantly up-regulate the mRNA and protein levels of Glc NAc T-Ⅳa glycosyltransferase( Gn T-Ⅳa) and galectin-9 but had no signi-ficant effect on the expression of clathrin,and geniposide could distinctively regulate the protein level of Gn T-Ⅳa in a short time( 1 h) under the conditions of low and medium glucose concentrations,but had no significant effect on the protein level of galectin-9. In addition,geniposide could also remarkably affect the protein level of glycosylated GLUT2 in a short-time treatment. The above results suggested that geniposide could quickly regulate the protein level of Gn T-Ⅳa,a key molecule of protein glycosylation in INS-1 rat pancreatic ßcells and affect the glycosylation of GLUT2. These findings suggested that the regulation of geniposide on glucose absorption,metabolism and glucose-stimulated insulin secretion might be associated with its efficacy in regulating GLUT2 glycosylation and affecting its distribution on the cell membrane and cytoplasm in pancreatic ß cells.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Glicosilação , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Iridoides , Ratos
15.
Theranostics ; 11(16): 7829-7843, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335967

RESUMO

Aims/hypothesis: MicroRNAs (miRNAs) are known to contribute to many metabolic diseases, including type 2 diabetes. This study aimed to investigate the roles and molecular mechanisms of miR-185-5p in the regulation of hepatic gluconeogenesis. Methods: MicroRNA high-throughput sequencing was performed to identify differentially expressed miRNAs. High-fat diet-induced obese C57BL/6 mice and db/db mice, a genetic mouse model for diabetes, were used for examining the regulation of hepatic gluconeogenesis. Quantitative reverse transcriptase PCR and Western blotting were performed to measure the expression levels of various genes and proteins. Luciferase reporter assays were used to determine the regulatory roles of miR-185-5p on G6Pase expression. Results: Hepatic miR-185-5p expression was significantly decreased during fasting or insulin resistance. Locked nucleic acid (LNA)-mediated suppression of miR-185-5p increased blood glucose and hepatic gluconeogenesis in healthy mice. In contrast, overexpression of miR-185-5p in db/db mice alleviated blood hyperglycemia and decreased gluconeogenesis. At the molecular level, miR-185-5p directly inhibited G6Pase expression by targeting its 3'-untranslated regions. Furthermore, metformin, an anti-diabetic drug, could upregulate miR-185-5p expression to suppress G6Pase, leading to hepatic gluconeogenesis inhibition. Conclusions/interpretation: Our findings provided a novel insight into the role of miR-185-5p that suppressed hepatic gluconeogenesis and alleviated hyperglycemia by targeting G6Pase. We further identified that the /G6Pase axis mediated the inhibitory effect of metformin on hepatic gluconeogenesis. Thus, miR-185-5p might be a therapeutic target for hepatic glucose overproduction and fasting hyperglycemia.


Assuntos
Gluconeogênese/genética , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Gluconeogênese/fisiologia , Glucose/metabolismo , Glucose-6-Fosfatase/metabolismo , Hiperglicemia/metabolismo , Insulina/metabolismo , Resistência à Insulina/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/metabolismo , Obesidade/genética
16.
Nat Commun ; 12(1): 4818, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376687

RESUMO

The enteroendocrine cell (EEC)-derived incretins play a pivotal role in regulating the secretion of glucagon and insulins in mammals. Although glucagon-like and insulin-like hormones have been found across animal phyla, incretin-like EEC-derived hormones have not yet been characterised in invertebrates. Here, we show that the midgut-derived hormone, neuropeptide F (NPF), acts as the sugar-responsive, incretin-like hormone in the fruit fly, Drosophila melanogaster. Secreted NPF is received by NPF receptor in the corpora cardiaca and in insulin-producing cells. NPF-NPFR signalling resulted in the suppression of the glucagon-like hormone production and the enhancement of the insulin-like peptide secretion, eventually promoting lipid anabolism. Similar to the loss of incretin function in mammals, loss of midgut NPF led to significant metabolic dysfunction, accompanied by lipodystrophy, hyperphagia, and hypoglycaemia. These results suggest that enteroendocrine hormones regulate sugar-dependent metabolism through glucagon-like and insulin-like hormones not only in mammals but also in insects.


Assuntos
Drosophila melanogaster/metabolismo , Células Enteroendócrinas/metabolismo , Glucagon/metabolismo , Hormônios/metabolismo , Insulina/metabolismo , Neuropeptídeos/metabolismo , Animais , Animais Geneticamente Modificados , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemia/genética , Hipoglicemia/metabolismo , Incretinas/metabolismo , Secreção de Insulina , Metabolismo dos Lipídeos/genética , Mutação , Neuropeptídeos/genética , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Açúcares/metabolismo
17.
Insect Biochem Mol Biol ; 136: 103623, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34246764

RESUMO

Aphids were the first animals described as photoperiodic due to their seasonal switch from viviparous parthenogenesis to sexual reproduction (cyclical parthenogenesis) caused by the shortening of the photoperiod in autumn. This switch produces a single sexual generation of oviparous females and males that mate and lay diapausing cold-resistant eggs that can overcome the unfavourable environmental conditions typical of winter in temperate regions. Previous studies have hinted at a possible implication of two insulin-like peptides (ILP1 and ILP4) in the aphid seasonal response, changing their expression levels between different photoperiodic conditions. Moreover, in situ localization of their transcripts in particular neurosecretory cells (NSCs) in the aphid brain supported the idea that these neuropeptides could correspond to the formerly called virginoparin, an uncharacterized factor originally proposed to be transported directly to the aphid embryos to promote their development as parthenogenetic individuals. To further investigate the fate of these ILPs, we raised a specific antiserum against one of them (ILP4) and mapped this neuropeptide by immunohistochemistry (IHC) in Acyrthosiphon pisum and Megoura viciae aphids. Coincident with in situ localization, our results show that ILP4 is synthesized in two groups (one in each brain hemisphere) of four neurosecretory cells in the pars intercerebralis (NSC group I) and then it is transported outside the brain to the corpora cardiaca. From there, three nerves (two laterals and one medial) transport it to the abdomen. Although no precise site of release has been found, the terminations of these nerves near the germaria would be compatible with the proposal of a direct connection between group I of NSCs and the reproductive system by localized release. In addition, we detected some collateral arborizations originating from the eight NSCs going to the pars lateralis, where clock neurons and some photoreceptors have been previously localized, suggesting a possible communication between the circadian and photoperiodic systems.


Assuntos
Afídeos , Hormônios de Inseto/metabolismo , Insulina/metabolismo , Oligopeptídeos/metabolismo , Fotoperíodo , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Afídeos/metabolismo , Afídeos/fisiologia , Encéfalo/metabolismo , Relógios Circadianos/fisiologia , Diapausa/fisiologia , Imuno-Histoquímica , Proteínas de Insetos/metabolismo , Neuropeptídeos/metabolismo , Partenogênese/fisiologia , Peptídeos/metabolismo , Ácido Pirrolidonocarboxílico/metabolismo , Reprodução/fisiologia
18.
Nat Commun ; 12(1): 4178, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234147

RESUMO

Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10-10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10-12), 4 kg higher fat mass (p = 1.3 × 10-4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10-4) and 4.5 kg lower handgrip strength (p = 4.7 × 10-7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Y/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Mosaicismo , Adulto , Idoso , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Insulina/metabolismo , Leucócitos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/genética , Sequenciamento Completo do Exoma
19.
Sci Transl Med ; 13(600)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193609

RESUMO

The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-ßH1, the db/db mouse model, and primary human pancreatic islets. Through loss- and gain-of-function approaches, we uncovered a mechanism by which PAX6 modulates glucose-stimulated insulin secretion (GSIS) through a cAMP response element-binding protein (CREB)/Munc18-1/2 pathway. Moreover, under diabetic conditions, beta cells and pancreatic islets displayed dampened PAX6/CREB/Munc18-1/2 pathway activity and impaired GSIS, which were reversed by PAX6 replenishment. Adeno-associated virus-mediated PAX6 overexpression in db/db mouse pancreatic beta cells led to a sustained amelioration of glycemic perturbation in vivo but did not affect insulin resistance. Our study highlights the pathophysiological role of PAX6 in T2D-associated beta cell dysfunction in humans and suggests the potential of PAX6 gene transfer in preserving and restoring beta cell function.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Ilhotas Pancreáticas , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Homeostase , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo
20.
Nutrients ; 13(6)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203642

RESUMO

Based on the Digestible Indispensable Amino Acid Score (DIAAS), egg white protein (EGG) has an excellent score, comparable to that of whey protein but with a lower amount of leucine. We examined the effect of EGG feeding on rat skeletal muscle gain in comparison to that of two common animal-derived protein sources: casein (CAS) and whey (WHE). To explore the full potential of EGG, this was examined in clenbuterol-treated young rats. Furthermore, we focused on leucine-associated anabolic signaling in response to EGG after single-dose ingestion and chronic ingestion, as well as clenbuterol treatment. Because EGG is an arginine-rich protein source, a portion of the experiment was repeated with diets containing equal amounts of arginine. We demonstrated that EGG feeding accelerates skeletal muscle gain under anabolism-dominant conditions more efficiently than CAS and WHE and this stronger effect with EGG is not dependent on the arginine-rich composition of the protein source. We also demonstrated that the plausible mechanism of the stronger muscle-gain effect with EGG is not detectable in the mechanistic target of rapamycin (mTOR) or insulin signaling under our experimental conditions. We conclude that EGG may have a superior efficiency in muscle gain compared to other common animal-based proteins.


Assuntos
Clembuterol/metabolismo , Clembuterol/farmacologia , Dieta , Proteínas do Ovo/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Animais , Arginina , Caseínas/metabolismo , Ingestão de Alimentos , Insulina/metabolismo , Leucina , Masculino , Músculo Esquelético/crescimento & desenvolvimento , Ratos , Ratos Wistar , Transdução de Sinais , Serina-Treonina Quinases TOR , Proteínas do Soro do Leite
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