RESUMO
Rationale: MG53's known function in facilitating tissue repair and anti-inflammation has broad applications to regenerative medicine. There is controversy regarding MG53's role in the development of type 2 diabetes mellitus. Objective: This study aims to address this controversy - whether MG53's myokine function contributes to inhibition of insulin signaling in muscle, heart, and liver tissues. Study design: We determined the binding affinity of the recombinant human MG53 (rhMG53) to the insulin receptor extracellular domain (IR-ECD) and found low affinity of interaction with Kd (>480 nM). Using cultured C2C12 myotubes and HepG2 cells, we found no effect of rhMG53 on insulin-stimulated Akt phosphorylation (p-Akt). We performed in vivo assay with C57BL/6J mice subjected to insulin stimulation (1 U/kg, intraperitoneal injection) and observed no effect of rhMG53 on insulin-stimulated p-Akt in muscle, heart and liver tissues. Conclusion: Overall, our data suggest that rhMG53 can bind to the IR-ECD, however has a low likelihood of a physiologic role, as the Kd for binding is ~10,000 higher than the physiologic level of MG53 present in the serum of rodents and humans (~10 pM). Our findings question the notion proposed by Xiao and colleagues - whether targeting circulating MG53 opens a new therapeutic avenue for type 2 diabetes mellitus and its complications.
Assuntos
Insulina , Fígado , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt , Receptor de Insulina , Animais , Humanos , Camundongos , Fosforilação/efeitos dos fármacos , Receptor de Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Insulina/metabolismo , Insulina/farmacologia , Miocárdio/metabolismo , Células Hep G2 , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Masculino , Transdução de Sinais/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Citocinas/metabolismo , Proteínas de MembranaRESUMO
Diabetes mellitus (DM) and Alzheimer's disease (AD) rates are rising, mirroring the global trend of an aging population. Numerous epidemiological studies have shown that those with Type 2 diabetes (T2DM) have an increased risk of developing dementia. These degenerative and progressive diseases share some risk factors. To a large extent, the amyloid cascade is responsible for AD development. Neurofibrillary tangles induce neurodegeneration and brain atrophy; this chain reaction begins with hyperphosphorylation of tau proteins caused by progressive amyloid beta (Aß) accumulation. In addition to these processes, it seems that alterations in brain glucose metabolism and insulin signalling lead to cell death and reduced synaptic plasticity in AD, before the onset of symptoms, which may be years away. Due to the substantial evidence linking insulin resistance in the brain with AD, researchers have coined the name "Type 3 diabetes" to characterize the condition. We still know little about the processes involved, even though current animal models have helped illuminate the links between T2DM and AD. This brief overview discusses insulin and IGF-1 signalling disorders and the primary molecular pathways that may connect them. The presence of GSK-3ß in AD is intriguing. These proteins' association with T2DM and pancreatic ß-cell failure suggests they might be therapeutic targets for both disorders.
Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Animais , Transdução de Sinais , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismoRESUMO
AIM: In previous studies, the researchers observed an increase in insulin secretion in STZ-treated diabetic rats following treatment with the hydroalcoholic extract of Securigera securidaca (HESS) seeds. This study focuses on the relationship between the antioxidant properties of HESS with changes in diabetic pancreatic tissue and the gene expression of factors that impact insulin secretion. METHODS: In this controlled experimental study, three varying doses of HESS were administered to three groups of diabetic rats induced by STZ. Oxidative stress indicators like total antioxidant capacity (TAC), total oxidant status (TOS) and malondialdehyde were assessed in both pancreatic and liver tissues. Pancreatic histology was studied post-haematoxylin staining. Insulin and FGF21 levels in the blood were measured using the ELISA method. The expression of Nrf2 and FGF21 genes in the pancreas and liver, along with MafA and PDX-1 genes in the pancreas, was quantified using real-time PCR. RESULTS: The administration of HESS in varying doses led to a dose-dependent rise in blood insulin levels and a decrease in blood glucose levels and oxidative stress. By reducing oxidative stress, HESS treatment lowered the heightened levels of NRF2 and FGF21 in the liver and pancreas of diabetic rats, improving pancreatic tissue health. As oxidative stress decreased, the expression of MafA and PDX1 genes in the pancreas approached levels seen in healthy rats. CONCLUSION: HESS elicits an increase in insulin secretion through the mitigation of oxidative stress and tissue damage, as well as the modulation of gene expression related to the insulin transcription factors PDX-1 and MafA.
Assuntos
Diabetes Mellitus Experimental , Secreção de Insulina , Insulina , Extratos Vegetais , Sementes , Regulação para Cima , Animais , Extratos Vegetais/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Ratos , Sementes/química , Secreção de Insulina/efeitos dos fármacos , Insulina/metabolismo , Masculino , Securidaca , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Fator 2 Relacionado a NF-E2/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Antioxidantes/farmacologia , Fígado/metabolismo , Transativadores , Proteínas de HomeodomínioRESUMO
Insulin resistance is the primary contributor to the disruption in glucose homeostasis in the body, playing a significant causative role in many metabolic diseases. Insulin resistance is characterized by compensatory insulin secretion and reduced insulin responsiveness in target organs. Dysregulation of the interaction between insulin-secreting cells and insulin-responsive target organs is an important factor driving the progression of insulin resistance. Circulating endocrine hormones are important mediators mediating the interaction between insulin-secreting cells and insulin-responsive target organs. In addition to the classical hormones secreted by endocrine glands and organ-specific hormones secreted by metabolism-related organs (adipose tissue, muscle, liver, etc.), extracellular vesicles have been recognized as a novel class of endocrine hormones with a complex composition. Extracellular vesicles can transport signaling molecules, such as miRNAs and LncRNAs, to vital organs related to insulin resistance, in a manner akin to conventional hormones. The significant role in regulating the development of insulin resistance underscores the increasing interest in extracellular vesicles as essential contributors to this process. In this review, we summarize the three types of hormones (classical hormones, organokines and extracellular vesicles) that play a regulatory role in insulin resistance, and focus on the novel endocrine hormones, extracellular vesicles, to elaborate the mechanism of extracellular vesicles' regulation of insulin resistance progress from two aspects: the impact on insulin-secreting cells and the influence on insulin-responsive target organs. In addition, this paper outlines the clinical applications of extracellular vesicles in insulin resistance. A comprehensive understanding of the regulatory mechanisms and diagnostic status of the inter-organ network in insulin resistance has great potential to advance targeted therapeutic interventions and diagnostic markers, thereby benefiting both the prevention and treatment of insulin resistance.
Assuntos
Vesículas Extracelulares , Resistência à Insulina , Humanos , Vesículas Extracelulares/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Hormônios/metabolismo , Animais , Tecido Adiposo/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genéticaRESUMO
CD8+ T cells destroy insulin-producing pancreatic ß cells in type 1 diabetes through HLA class I-restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02-peptide-TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A*24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A*24+ healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease.
Assuntos
Diabetes Mellitus Tipo 1 , Antígeno HLA-A24 , Insulina , Precursores de Proteínas , Receptores de Antígenos de Linfócitos T , Humanos , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/genética , Precursores de Proteínas/imunologia , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Insulina/imunologia , Insulina/metabolismo , Antígeno HLA-A24/imunologia , Antígeno HLA-A24/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Linfócitos T CD8-Positivos/imunologia , Feminino , MasculinoRESUMO
This study aims to explore the improvement effect of Sijunzi Decoction on intestinal barrier in diabetic mice. A type 2 diabetes mellitus(T2DM) model was established in C57BL/6J mice by feeding them with high-sugar and high-fat diet combined with streptozotocin(STZ). The T2DM mice were randomly divided into a control group, a T2DM group, a donepezil(DON) group, a rosiglitazone(RGZ) group, and Sijunzi Decoction groups(7. 5, 15, and 30 g·kg~(-1)), and orally administered for six weeks. The body weight and fasting plasma glucose(FBG) of mice were recorded. Fasting plasma insulin(FINS) and insulin resistance index(HOMA-IR) were observed to assess insulin resistance(IR). Intestinal flora and levels of serotonin(5-HT), lipopolysaccharide(LPS), and short-chain fatty acids(SCFAs) in serum were analyzed. Changes in colonic structure and tight junction proteins occludin, claudin-1,and ZO-1 were observed through HE staining and immunohistochemistry. Spontaneous alternation test was conducted to observe the effect on spatial memory ability. Compared with the results in the control group, FBG and HOMA-IR in the T2DM group were significantly increased(P< 0. 01); species richness index(Sobs index), Shannon diversity index(Shannon index), and species abundance estimate index(Chao index) were decreased; LPS was significantly increased(P< 0. 001), while the levels of 5-HT,SCFAs, occludin, claudin-1, and ZO-1 were significantly decreased(P< 0. 01), indicating impaired colonic barrier function;spontaneous alternation accuracy was significantly decreased(P<0. 05). After 6 weeks of Sijunzi Decoction treatment, compared with the results in the T2DM group, FBG and HOMA-IR in the Sijunzi Decoction 15 g·kg~(-1) group were significantly decreased(P<0. 01);Sobs index, Shannon index, and Chao index were increased; LPS was significantly decreased(P<0. 01), while the levels of 5-HT,SCFAs, occludin, claudin-1, and ZO-1 were significantly increased(P< 0. 05), indicating improved colonic barrier function;spontaneous alternation accuracy was increased(P<0. 001). In conclusion, Sijunzi Decoction has the effect of improving intestinal barrier in diabetic mice.
Assuntos
Diabetes Mellitus Tipo 2 , Medicamentos de Ervas Chinesas , Camundongos Endogâmicos C57BL , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Camundongos , Masculino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Resistência à Insulina , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Insulina/sangue , Insulina/metabolismo , Humanos , Proteína da Zônula de Oclusão-1/metabolismo , Proteína da Zônula de Oclusão-1/genética , Ocludina/metabolismo , Ocludina/genética , Claudina-1/metabolismo , Claudina-1/genéticaRESUMO
Decisions made over long time scales, such as life cycle decisions, require coordinated interplay between sensory perception and sustained gene expression. The Caenorhabditis elegans dauer (or diapause) exit developmental decision requires sensory integration of population density and food availability to induce an all-or-nothing organismal-wide response, but the mechanism by which this occurs remains unknown. Here, we demonstrate how the Amphid Single Cilium J (ASJ) chemosensory neurons, known to be critical for dauer exit, perform sensory integration at both the levels of gene expression and calcium activity. In response to favorable conditions, dauers rapidly produce and secrete the dauer exit-promoting insulin-like peptide INS-6. Expression of ins-6 in the ASJ neurons integrates population density and food level and can reflect decision commitment since dauers committed to exiting have higher ins-6 expression levels than those of noncommitted dauers. Calcium imaging in dauers reveals that the ASJ neurons are activated by food, and this activity is suppressed by pheromone, indicating that sensory integration also occurs at the level of calcium transients. We find that ins-6 expression in the ASJ neurons depends on neuronal activity in the ASJs, cGMP signaling, and the pheromone components ascr#8 and ascr#2. We propose a model in which decision commitment to exit the dauer state involves an autoregulatory feedback loop in the ASJ neurons that promotes high INS-6 production and secretion. These results collectively demonstrate how insulin-like peptide signaling helps animals compute long-term decisions by bridging sensory perception to decision execution.
Assuntos
Caenorhabditis elegans , Insulina , Transdução de Sinais , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Insulina/metabolismo , Diapausa/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Cálcio/metabolismo , Densidade Demográfica , Células Quimiorreceptoras/metabolismoRESUMO
Accurate prediction of blood glucose level (BGL) has proven to be an effective way to help in type 1 diabetes management. The choice of input, along with the fundamental choice of model structure, is an existing challenge in BGL prediction. Investigating the performance of different data-driven time series forecasting approaches with different inputs for BGL prediction is beneficial in advancing BGL prediction performance. Limited work has been made in this regard, which has resulted in different conclusions. This paper performs a comprehensive investigation of different data-driven time series forecasting approaches using different inputs. To do so, BGL prediction is comparatively investigated from two perspectives; the model's approach and the model's input. First, we compare the performance of BGL prediction using different data-driven time series forecasting approaches, including classical time series forecasting, traditional machine learning, and deep neural networks. Secondly, for each prediction approach, univariate input, using BGL data only, is compared to a multivariate input, using data on carbohydrate intake, injected bolus insulin, and physical activity in addition to BGL data. The investigation is performed on two publicly available Ohio datasets. Regression-based and clinical-based metrics along with statistical analyses are performed for evaluation and comparison purposes. The outcomes show that the traditional machine learning model is the fastest model to train and has the best BGL prediction performance especially when using multivariate input. Also, results show that simply adding extra variables does not necessarily improve BGL prediction performance significantly, and data fusion approaches may be required to effectively leverage other variables' information.
Assuntos
Glicemia , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 1/sangue , Humanos , Glicemia/análise , Glicemia/metabolismo , Aprendizado de Máquina , Redes Neurais de Computação , Masculino , Feminino , Previsões/métodos , Insulina/metabolismo , Insulina/sangue , AdultoRESUMO
Celastrol, the primary constituent of Tripterygium wilfordii, has demonstrated neuroprotective properties in rats with dementia by reducing inflammation. A high-fat diet and streptozotocin injection were utilized to establish a diabetic rat model, which was then employed to investigate the possible protective effect of celastrol against the development of diabetes-induced learning and memory deficits. Afterwards, the experimental animals received a dose of celastrol by gavage (4â¯mg/kg/d). An animal study showed that celastrol enhanced insulin sensitivity and glucose tolerance in diabetic rats. In the Morris water maze test, rats with diabetes performed poorly in terms of spatial learning and memory; treatment with celastrol improved these outcomes. Additionally, administration of celastrol downregulated the expression of inflammatory-related proteins (NF-κB, IKKα, TNF-α, IL-1ß, and IL-6) and greatly reduced the generation of Aß in the diabetic hippocampus tissue. Moreover, the insulin signaling pathway-related proteins PI3K, AKT, and GSK-3ß were significantly upregulated in diabetic rats after celastrol was administered. Also, celastrol prevented damage to the brain structures and increased the synthesis of synaptic proteins like PSD-95 and SYT1. In conclusion, celastrol exerts a neuroprotective effect by modulating the insulin signaling system and reducing inflammatory responses, which helps to ameliorate the cognitive impairment associated with diabetes.
Assuntos
Peptídeos beta-Amiloides , Diabetes Mellitus Experimental , Hipocampo , Inflamação , Insulina , Plasticidade Neuronal , Fármacos Neuroprotetores , Triterpenos Pentacíclicos , Transdução de Sinais , Triterpenos , Animais , Triterpenos Pentacíclicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Insulina/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ratos , Plasticidade Neuronal/efeitos dos fármacos , Triterpenos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Ratos Sprague-Dawley , Resistência à InsulinaRESUMO
Background: Endogenous insulin supplementation is essential for individuals with type 1 diabetes (T1D). However, current treatments, including pancreas transplantation, insulin injections, and oral medications, have significant limitations. The development of engineered cells that can secrete endogenous insulin offers a promising new therapeutic strategy for type 1 diabetes (T1D). This approach could potentially circumvent autoimmune responses associated with the transplantation of differentiated ß-cells or systemic delivery of viral vectors. Methods: We utilized CRISPR/Cas9 gene editing coupled with homology-directed repair (HDR) to precisely integrate a promoter-free EMCVIRES-insulin cassette into the 3' untranslated region (UTR) of the GAPDH gene in human HEK-293T cells. Subsequently quantified insulin expression levels in these engineered cells, the viability and functionality of the engineered cells when seeded on different cell vectors (GelMA and Cytopore I) were also assessed. Finally, we investigated the therapeutic potential of EMCVIRES-based insulin secretion circuits in reversing Hyperglycaemia in T1D mice. Result: Our results demonstrate that HDR-mediated gene editing successfully integrated the IRES-insulin loop into the genome of HEK-293T cells, a non-endocrine cell line, enabling the expression of human-derived insulin. Furthermore, Cytopore I microcarriers facilitated cell attachment and proliferation during in vitro culture and enhanced cell survival post-transplantation. Transplantation of these cell-laden microcarriers into mice led to the development of a stable, fat-encapsulated structure. This structure exhibited the expression of the platelet-endothelial cell adhesion molecule CD31, and no significant immune rejection was observed throughout the experiment. Diabetic mice that received the cell carriers reversed hyperglycemia, and blood glucose fluctuations under simulated feeding stimuli were very similar to those of healthy mice. Conclusion: In summary, our study demonstrates that Cytopore I microcarriers are biocompatible and promote long-term cell survival in vivo. The promoter-free EMCVIRES-insulin loop enables non-endocrine cells to secrete mature insulin, leading to a rapid reduction in glucose levels. We have presented a novel promoter-free genetic engineering strategy for insulin secretion and proposed an efficient cell transplantation method. Our findings suggest the potential to expand the range of cell sources available for the treatment of diabetes, offering new avenues for therapeutic interventions.
Assuntos
Diabetes Mellitus Tipo 1 , Edição de Genes , Hiperglicemia , Células Secretoras de Insulina , Insulina , Humanos , Animais , Hiperglicemia/terapia , Hiperglicemia/metabolismo , Camundongos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Insulina/genética , Células HEK293 , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/genética , Edição de Genes/métodos , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Sítios Internos de Entrada Ribossomal/genética , Regiões Promotoras Genéticas , Sistemas CRISPR-CasRESUMO
The insulin-heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) and other CVDs. This review was conducted by systematically searching PubMed, Scopus, and Web of Science databases for peer-reviewed studies published in the past decade, focusing on therapeutic interventions targeting the insulin-heart axis. Studies were selected based on their relevance to insulin resistance, cardiovascular outcomes, and the efficacy of pharmacologic treatments. Key findings from the review highlight the efficacy of lifestyle modifications, such as dietary changes and physical activity, which remain the cornerstone of managing insulin resistance and improving cardiovascular outcomes. Moreover, pharmacologic interventions, such as metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors, have shown efficacy in reducing cardiovascular risk by addressing metabolic dysfunction, reducing inflammation, and improving endothelial function. Furthermore, emerging treatments, such as angiotensin receptor-neprilysin inhibitors, and mechanical interventions like ventricular assist devices offer new avenues for managing HF in insulin-resistant patients. The potential of these therapies to improve left ventricular ejection fraction and reverse pathological cardiac remodeling highlights the importance of early intervention. However, challenges remain in optimizing treatment regimens and understanding the long-term cardiovascular effects of these agents. Future research should focus on personalized approaches that integrate lifestyle and pharmacologic therapies to effectively target the insulin-heart axis and mitigate the burden of cardiovascular complications in insulin-resistant populations.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Insulina , Humanos , Insulina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/terapia , Hipoglicemiantes/uso terapêuticoRESUMO
Ketogenic diet (KD) may benefit patients with liver cancer, but the underlying mechanism of its anti-cancer effect remains an open issue. This work aimed to explore the influence of simulated KD on the proliferation and migration of cultured hepatoma cells. The low-glucose medium supplemented with ß-hydroxybutyrate (BHB-Glow) was utilized to simulate clinical KD treatment. Western blot was utilized for detecting the expression of glycolysis-related proteins, Seahorse XF96 for oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), and ELISA for insulin content. Expression of FOXC2 in liver cancer cells was analyzed by bioinformatics and qPCR. Cell Count Kit-8 (CCK-8) testing kit was utilized for testing cell viability. KD treatment significantly reduced the expression of glycolysis-related proteins in Huh-7 cells, inhibited insulin production in ß islet cells, reduced ECAR, and increased OCR. FOXC2 was significantly up-regulated in Huh-7 cell line, and sh-FOXC2 hindered the proliferation and migration of Huh-7 cells. The exogenous addition of insulin promoted the malignant progression of Huh-7 cells. Together, the medium simulating KD environment strengthened the protection of liver cancer cells by reducing insulin production and down-regulating FOXC2 expression. This study confirmed through in vitro cell experiments that KD could inhibit the proliferation and migration of liver cancer cells by targeting down regulation of insulin and FOXC2 expression, providing new theoretical basis for the treatment of liver cancer patients.
Assuntos
Movimento Celular , Proliferação de Células , Dieta Cetogênica , Regulação para Baixo , Fatores de Transcrição Forkhead , Insulina , Neoplasias Hepáticas , Humanos , Proliferação de Células/efeitos dos fármacos , Dieta Cetogênica/métodos , Insulina/metabolismo , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Linhagem Celular Tumoral , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/dietoterapiaRESUMO
The existence of functionally diverse and plastic ß cells in islets of Langerhans has been reported since the 1980s. Recently, high-resolution technologies have advanced our understanding of ß-cell heterogeneity and plasticity. Here, we define plasticity broadly as dynamic changes in cellular phenotypes and heterogeneity as differences in cellular behaviors. Individual ß cells react differently to environmental challenges and act together to maintain ß-cell mass and glucose homeostasis within a narrow range of 70-140 mg/dL. During the progress of diabetes, this elaborate balance is disrupted, and a lack of ß-cell compensation leads to dysregulated blood glucose. In this chapter, we assess ß-cell stress that instigates increased ß-cell heterogeneity and adaptive ß-cell responses such as proliferation, dedifferentiation, maturity, and insulin secretion. We also discuss the maturity, electrical activity, and insulin secretion of well-characterized ß-cell subgroups. Finally, we touch upon the plasticity of other non-ß pancreatic cells and their cooperation with ß cells to maintain homeostasis.
Assuntos
Plasticidade Celular , Células Secretoras de Insulina , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Humanos , Animais , Secreção de Insulina , Insulina/metabolismo , HomeostaseRESUMO
The pancreatic ß cells are at the hub of myriad signals to regulate the secretion of an adequate amount of insulin needed to re-establish postprandial euglycemia. The ß cell possesses sophisticated metabolic enzymes and a variety of extracellular receptors and channels that amplify insulin secretion in response to autocrine, paracrine, and neurohormonal signals. Considerable research has been undertaken to decipher the mechanisms regulating insulin secretion. While the triggering pathway induced by glucose is needed to initiate the exocytosis process, multiple other stimuli modulate the insulin secretion response. This chapter will discuss the recent advances in understanding the role of the diverse glucose- and fatty acid-metabolic coupling factors in amplifying insulin secretion. It will also highlight the intracellular events linking the extracellular receptors and channels to insulin secretion amplification. Understanding these mechanisms provides new insights into learning more about the etiology of ß-cell failure and paves the way for developing new therapeutic strategies for type 2 diabetes.
Assuntos
Secreção de Insulina , Células Secretoras de Insulina , Insulina , Humanos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Animais , Glucose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Transdução de Sinais , Ácidos Graxos/metabolismoRESUMO
Pancreatic δ cells act locally to repress both insulin and glucagon secretion. Because they are a rare cell type, experimentation examining δ-cell function and control has lagged that of the more abundant α and ß cells. Emerging evidence, enabled partly by developing single-cell technology, demonstrates that δ-cell function is, in part, directed by δ cells but that δ cells also have intrinsic control. The contribution of these cells to overall glucose homeostasis and diabetes onset and progression is still unclear. However, they regulate both α and ß cells, both of which are dysfunctional in diabetes, and their numbers are disrupted in humans with diabetes and in multiple animal models of diabetes, suggesting δ cells are a pivotal character in both health and disease.
Assuntos
Células Secretoras de Insulina , Humanos , Animais , Células Secretoras de Insulina/fisiologia , Diabetes Mellitus , Células Secretoras de Somatostatina/metabolismo , Insulina/metabolismo , Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismoRESUMO
Dysfunction or loss of pancreatic ß cells can cause insulin deficiency and impaired glucose regulation, resulting in conditions like type 2 diabetes. The ATP-binding cassette transporter A1 (ABCA1) plays a key role in the reverse cholesterol transport system, and its decreased expression is associated with pancreatic ß cell lipotoxicity, resulting in abnormal insulin synthesis and secretion. Increased glutamate release can cause glucotoxicity in ß cells, though the detailed mechanisms remain unclear. This study investigated the effect of N-methyl-D-aspartic acid (NMDA) on ABCA1 expression in INS-1 cells and primary pancreatic islets to elucidate the signaling mechanisms that suppress insulin secretion. Using Western blotting, microscopy, and biochemical analyses, we found that NMDA activated the mitogen-activated protein kinase (MEK)-dependent pathway, suppressing ABCA1 protein and mRNA expression. The MEK-specific inhibitor PD98059 restored ABCA1 promoter activity, indicating the involvement of the extracellular signal-regulated kinase (MEK/ERK) pathway. Furthermore, we identified the liver X receptor (LXR) as an effector transcription factor in NMDA regulation of ABCA1 transcription. NMDA treatment increased cholesterol and triglyceride levels while decreasing insulin secretion, even under high-glucose conditions. These effects were abrogated by treatment with PD98059. This study reveals that NMDA suppresses ABCA1 expression via the MEK/ERK/LXR pathway, providing new insights into the pathological suppression of insulin secretion in pancreatic ß cells and emphasizing the importance of investigating the role of NMDA in ß cell dysfunction.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Células Secretoras de Insulina , Receptores X do Fígado , Sistema de Sinalização das MAP Quinases , N-Metilaspartato , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , N-Metilaspartato/farmacologia , Ratos , Receptores X do Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Colesterol/metabolismo , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Masculino , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Linhagem CelularRESUMO
In the study of obesity and diabetes, mice are widely used for experimental research, and fasting is a common procedure used to reset metabolism in mouse models. The fasting duration for experimental mice varies greatly in nutritional and metabolic studies, ranging from 2 to 48 h. This study aims to assess the optimal fasting duration for mice fed low- and high-fat diets over a short period of time. C57BL/6J mice were fed a low-fat diet (LFD) or high-fat diet (HFD) and fasted for 4, 6, 8, 10, 12, or 24 h. The effects of different conditions after fasting on the metabolic level of mice were explored, and the data were collected for analysis. Our data indicate that fasting has inconsistent effects on mice fed a low-fat or high-fat diet. To compare the metabolic differences between mice in different dietary levels and thereby secure better scientific data, mice should fast for 6 h in animal experiments. Fasting for 6 h is also recommended when comparing glucose tolerance with insulin tolerance.
Assuntos
Dieta Hiperlipídica , Jejum , Camundongos Endogâmicos C57BL , Animais , Dieta Hiperlipídica/efeitos adversos , Camundongos , Masculino , Glicemia/metabolismo , Dieta com Restrição de Gorduras , Resistência à Insulina , Fatores de Tempo , Insulina/metabolismo , Insulina/sangue , Teste de Tolerância a Glucose , Obesidade/metabolismoRESUMO
Gestational diabetes mellitus (GDM) adversely affects offspring glucose homeostasis and risk of developing obesity. Here, we examined the association between glycemia in pregnant women with overweight or obesity without GDM and offspring metabolic health. Maternal fasting glucose concentrations and glucose 2-h after an oral glucose tolerance test (OGTT) were measured in 208 women with a pre-pregnancy body mass index (BMI) of 28-45 kg/m2 without GDM. Offspring outcomes were collected at birth, 3, and 5 years of age. Linear mixed models with time as fixed factor and subject ID as random effects were used for analysis. No associations were found between maternal fasting or 2-h glucose concentrations with offspring glucose and insulin concentrations from birth to 5 years of age. However, maternal fasting glucose in GW 28 and 36, and 2-h OGTT glucose in GW 28 were positively associated with C-peptide concentration at birth. Maternal fasting glucose concentrations in GW 28 and 36 were positively associated with weight-for-length, and maternal fasting glucose in GW 36 was associated with BMI z-score at birth. In summary, blood glucose in pregnant women with overweight or obesity is positively associated with offspring C-peptide concentration, weight-for-length, and BMI z-score at birth, even in the absence of GDM.
Assuntos
Glicemia , Índice de Massa Corporal , Teste de Tolerância a Glucose , Homeostase , Obesidade , Sobrepeso , Humanos , Feminino , Gravidez , Adulto , Glicemia/metabolismo , Obesidade/metabolismo , Obesidade/sangue , Sobrepeso/metabolismo , Sobrepeso/sangue , Diabetes Gestacional/metabolismo , Diabetes Gestacional/sangue , Recém-Nascido , Pré-Escolar , Insulina/sangue , Insulina/metabolismo , Peptídeo C/sangue , Jejum/sangue , Complicações na Gravidez/metabolismo , Complicações na Gravidez/sangueRESUMO
Hippocampal neurons can be the first to be impaired with neurodegenerative disorders, including Alzheimer's disease (AD). Most drug candidates for causal therapy of AD cannot either enter the brain or accumulate around hippocampal neurons. Here, we genetically engineered insulin-fusion proteins, called hippocampal neuron-targeting (Ht) proteins, for targeting protein drugs to hippocampal neurons because insulin tends to accumulate in the neuronal cell layers of the hippocampus. In vitro examinations clarified that insulin and Ht proteins were internalized into the cultured hippocampal neurons through insulin receptor-mediated macropinocytosis. Cysteines were key determinants of the delivery of Ht proteins to hippocampal neurons, and insulin B chain mutant was most potent in delivering cargo proteins. In vivo accumulation of Ht proteins to hippocampal neuronal layers occurred after intracerebroventricular administration. Thus, hippocampal neuron-targeting technology can provide great help for developing protein drugs against neurodegenerative disorders.
Assuntos
Sistemas de Liberação de Medicamentos , Hipocampo , Insulina , Neurônios , Animais , Hipocampo/metabolismo , Neurônios/metabolismo , Insulina/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Ratos , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Humanos , Camundongos , Pinocitose , Receptor de Insulina/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Células CultivadasRESUMO
Type 2 diabetes mellitus (T2DM) as a chronic metabolic disease has become a global public health problem. Insulin resistance (IR) is the main pathogenesis of T2DM. Oxidative stress refers to an imbalance between free radical production and the antioxidant system, causing insulin resistance and contributing to the development of T2DM via several molecular mechanisms. Besides, the reduction in hepatic glycogen synthesis also leads to a decrease in peripheral insulin sensitivity. Thus, reducing oxidative stress and promoting glycogen synthesis are both targets for improving insulin resistance and treating T2DM. The current study aims to investigate the pharmacological effects of single-atom Ce-N-C nanozyme (SACe-N-C) on the improvement of insulin resistance and to elucidate its underlying mechanisms using HFD/STZ-induced C57BL/6J mice and insulin-resistant HepG2 cells. The results indicate that SACe-N-C significantly improves hepatic glycogen synthesis and reduces oxidative stress, as well as pancreatic and liver injury. Specifically, compared to the T2DM model group, fasting blood glucose decreased by 29%, hepatic glycogen synthesis increased by 17.13%, and insulin secretion increased by 18.87%. The sod and GPx in the liver increased by 17.80% and 25.28%, respectively. In terms of mechanism, SACe-N-C modulated glycogen synthesis through the PI3K/AKT/GSK3ß signaling pathway and activated the Keap1/Nrf2 pathway to alleviate oxidative stress. Collectively, this study suggests that SACe-N-C has the potential to treat T2DM.