RESUMEN
Type 1 Diabetes (T1D) is a chronic metabolic disease resulting from insulin deficiency due to autoimmune loss of pancreatic ß cells. In addition to ß cell destruction, it is now accepted that ß cell stress and dysfunction, such as senescence, plays a crucial role in the development of the disease. Accumulation of senescent ß cells occurs during development of T1D in humans and contributes to the progression of T1D in the nonobese diabetic (NOD) mouse model. Senescent ß cells are thought to exacerbate the inflammatory response within the islets by production and secretion of senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) from ß cells have been shown to carry protein and microRNAs (miRNAs), influencing cellular signaling and may contribute to the development of T1D but it remains to be addressed how senescence impacts ß cell EV cargo. In this minireview, we discuss emerging evidence that EV cargo proteins and miRNAs associated with senescence could contribute to the development of T1D and could suggest potential biomarkers and therapeutic targets for the regulation of SASP and elimination of senescent ß cells in T1D. Future investigation exploring the intricate relationship between ß cell senescence, EVs and miRNAs could pave the way for the development of novel diagnostic techniques and therapeutic interventions.
Asunto(s)
Senescencia Celular , Diabetes Mellitus Tipo 1 , Vesículas Extracelulares , Células Secretoras de Insulina , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Humanos , Vesículas Extracelulares/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Animales , MicroARNs/metabolismo , MicroARNs/genética , Fenotipo Secretor Asociado a la SenescenciaRESUMEN
Apart from insulin, physical exercise is a crucial component of therapy in patients with type 1 diabetes mellitus (T1DM). The benefits of physical activity in such patients include improved insulin sensitivity, lowered blood glucose, reduced body fat and improved cardiovascular function and physical performance. Hypoglycemia is a crucial issue in the peri-training period in insulin-treated patients. Proper preparation for exercise is the key to reducing the risk of hypoglycemia. The selection of the training type and the patient's knowledge of the effect of such training on glycemia are also significant. Physical exercise under normobaric hypoxia in the training rooms is also available commercially and is becoming increasingly popular. Under such conditions, the air consists of 15.4% oxygen and 84.5% nitrogen, which corresponds to the conditions at an altitude of approximately 2,500 meters above sea level. Hypoxia induces the production of the hypoxia-inducible factor (HIF-1), which regulates the expression of over 100 genes. It modulates key metabolic pathways to optimize glucose utilization by increasing cell sensitivity to insulin, more efficient glucose uptake from the blood and activating effect on glycolytic enzymes. Additionally, HIF-1 shows beneficial effects on the lipid profile, vascular endothelium and performance as measured by the maximal oxygen uptake (VO2max). The aim of this paper was to review and summarize the most recent studies on the effects of exercise on glycemic control and physical performance under normoxia and normobaric hypoxia in patients with T1DM.
Asunto(s)
Diabetes Mellitus Tipo 1 , Hipoxia , Humanos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/complicaciones , Ejercicio Físico/fisiología , Glucemia/metabolismo , Terapia por Ejercicio/métodos , HipoglucemiaRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 1 , Edición Génica , Hiperglucemia , Células Secretoras de Insulina , Insulina , Humanos , Animales , Hiperglucemia/terapia , Hiperglucemia/metabolismo , Ratones , 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 , Edición Génica/métodos , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Sitios Internos de Entrada al Ribosoma/genética , Regiones Promotoras Genéticas , Sistemas CRISPR-CasRESUMEN
GLP-1 receptor agonists, which were initially intended to treat type 2 diabetes patients, have demonstrated promise as an adjuvant therapy for type 1 diabetes (T1D). These medications can manage T1D by improving ß-cell function, reducing glucose fluctuation, and providing cardioprotective effects. Recent research suggests that boosting cell proliferation and lowering apoptosis can help maintain the bulk of ß-cells. Furthermore, GLP-1 receptor agonists have potent anti-inflammatory characteristics, improving immunological control and lowering systemic inflammation, both of which are critical for reducing autoimmune damage in T1D. Beyond glucose control, these agonists have neuroprotective qualities and aid in weight management. Combining these medications with insulin could significantly change how T1D is managed. The clinical data and biological mechanisms discussed in this review support the potential use of GLP-1 receptor agonists in T1D.
Asunto(s)
Diabetes Mellitus Tipo 1 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Animales , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Insulina/uso terapéutico , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
Nutritional status assessment, including amino acids, carnitine, and acylcarnitine profile, is an important component of diabetes care management, influencing growth and metabolic regulation. A designed case-control research included 100 Egyptian participants (50 T1DM and 50 healthy controls) aged 6 to 18 years old. The participants' nutritional status was assessed using the Body Mass Index (BMI) Z-score. Extended metabolic screening (EMS) was performed using a high-performance liquid chromatography-electrospray ionization-mass spectroscopy system to evaluate the levels of 14 amino acids, free carnitine, and 27 carnitine esters. T1DM children had considerably lower anthropometric Z-scores than the control group, with 16% undernutrition and 32% short stature. Total aromatic amino acids, phenylalanine, phenylalanine/tyrosine ratio, proline, arginine, leucine, isoleucine, free carnitine, and carnitine esters levels were considerably lower in the diabetic group, suggesting an altered amino acid and carnitine metabolism in type 1 diabetes. BMI Z-score showed a significant positive correlation with Leucine, Isoleucine, Phenylalanine, Citrulline, Tyrosine, Arginine, Proline, free carnitine, and some carnitine esters (Acetylcarnitine, Hydroxy-Isovalerylcarnitine, Hexanoylcarnitine, Methylglutarylcarnitine, Dodecanoylcarnitine, Tetradecanoylcarnitine, and Hexadecanoylcarnitine). HbA1c% had a significant negative correlation with Total aromatic amino acids, Branched-chain amino acid/Total aromatic amino acids ratio, Glutamic Acid, Citrulline, Tyrosine, Arginine, Proline, and certain carnitine esters (Propionylcarnitine, Methylglutarylcarnitine, Decanoylcarnitine, Octadecanoylcarnitine and Octadecenoylcarnitine), suggest that dysregulated amino acid and carnitine metabolism may be negatively affect the glycaemic control in children with TIDM. In conclusion, regular nutritional assessments including EMS of T1DM patients are critical in terms of diet quality and protein content for improved growth and glycemic management.
Asunto(s)
Aminoácidos , Carnitina , Diabetes Mellitus Tipo 1 , Estado Nutricional , Humanos , Niño , Masculino , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Adolescente , Egipto , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina/sangre , Estudios de Casos y Controles , Aminoácidos/metabolismo , Índice de Masa CorporalRESUMEN
Metabolomics and lipidomics have emerged as tools in understanding the connections of metabolic syndrome (MetS) with cardiovascular diseases (CVD), type 1 and type 2 diabetes (T1D, T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD). This review highlights the applications of these omics approaches in large-scale cohort studies, emphasizing their role in biomarker discovery and disease prediction. Integrating metabolomics and lipidomics has significantly advanced our understanding of MetS pathology by identifying unique metabolic signatures associated with disease progression. However, challenges such as standardizing analytical workflows, data interpretation, and biomarker validation remain critical for translating research findings into clinical practice. Future research should focus on optimizing these methodologies to enhance their clinical utility and address the global burden of MetS-related diseases.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Lipidómica , Síndrome Metabólico , Metabolómica , Humanos , Síndrome Metabólico/metabolismo , Metabolómica/métodos , Lipidómica/métodos , Diabetes Mellitus Tipo 2/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Animales , Biomarcadores/metabolismo , Hígado Graso/metabolismoRESUMEN
BACKGROUND: Diabetic cardiomyopathy (DCM) is one of leading causes of diabetes-associated mortality. The gut microbiota-derived branched-chain amino acids (BCAA) have been reported to play a central role in the onset and progression of DCM, but the potential mechanisms remain elusive. RESULTS: We found the type 1 diabetes (T1D) mice had higher circulating BCAA levels due to a reduced BCAA degradation ability of the gut microbiota. Excess BCAA decreased hepatic FGF21 production by inhibiting PPARα signaling pathway and thereby resulted in a higher expression level of cardiac LAT1 via transcription factor Zbtb7c. High cardiac LAT1 increased the levels of BCAA in the heart and then caused mitochondrial damage and myocardial apoptosis through mTOR signaling pathway, leading to cardiac fibrosis and dysfunction in T1D mice. Additionally, transplant of faecal microbiota from healthy mice alleviated cardiac dysfunction in T1D mice, but this effect was abolished by FGF21 knockdown. CONCLUSIONS: Our study sheds light on BCAA-mediated crosstalk among the gut microbiota, liver and heart to promote DCM and FGF21 serves as a key mediator. Video Abstract.
Asunto(s)
Aminoácidos de Cadena Ramificada , Cardiomiopatías Diabéticas , Factores de Crecimiento de Fibroblastos , Microbioma Gastrointestinal , Hígado , Animales , Factores de Crecimiento de Fibroblastos/metabolismo , Ratones , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/microbiología , Hígado/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Transducción de Señal , Diabetes Mellitus Tipo 1/microbiología , Diabetes Mellitus Tipo 1/metabolismo , Masculino , Miocardio/metabolismo , Miocardio/patología , PPAR alfa/metabolismo , Ratones Endogámicos C57BL , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/microbiologíaRESUMEN
Objective: Beta cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In recent years, the role played by beta cells in the development of T1D has evolved from passive victims of the immune system to active contributors in their own destruction. We and others have demonstrated that perturbations in the islet microenvironment promote endoplasmic reticulum (ER) stress in beta cells, leading to enhanced immunogenicity. Among the underlying mechanisms, secretion of extracellular vesicles (EVs) by beta cells has been suggested to mediate the crosstalk with the immune cell compartment. Methods: To study the role of cellular stress in the early events of T1D development, we generated a novel cellular model for constitutive ER stress by modulating the expression of HSPA5, which encodes BiP/GRP78, in EndoC-ßH1 cells. To investigate the role of EVs in the interaction between beta cells and the immune system, we characterized the EV miRNA cargo and evaluated their effect on innate immune cells. Results: Analysis of the transcriptome showed that HSPA5 knockdown resulted in the upregulation of signaling pathways involved in the unfolded protein response (UPR) and changes the miRNA content of EVs, including reduced levels of miRNAs involved in IL-1ß signaling. Treatment of primary human monocytes with EVs from stressed beta cells resulted in increased surface expression of CD11b, HLA-DR, CD40 and CD86 and upregulation of IL-1ß and IL-6. Conclusion: These findings indicate that the content of EVs derived from stressed beta cells can be a mediator of islet inflammation.
Asunto(s)
Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Vesículas Extracelulares , Células Secretoras de Insulina , MicroARNs , Monocitos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/inmunología , Monocitos/inmunología , Monocitos/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/inmunología , Humanos , Estrés del Retículo Endoplásmico/inmunología , MicroARNs/genética , Inflamación/inmunología , Inflamación/metabolismo , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Animales , Línea Celular , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/metabolismo , Transducción de Señal , Respuesta de Proteína Desplegada/inmunologíaRESUMEN
Well-controlled type 1 diabetes (T1DM) is characterized by inflammation and endothelial dysfunction, thus constituting a suitable model of subclinical cardiovascular disease (CVD). miR-199b-5p overexpression in murine CVD has shown proatherosclerotic effects. We hypothesized that miR-199b-5p would be overexpressed in subclinical CVD yet downregulated following metformin therapy. Inflammatory and vascular markers were measured in 29 individuals with T1DM and 20 matched healthy controls (HCs). miR-199b-5p expression in CFU-Hill's colonies was analyzed from each study group, and correlations with inflammatory/vascular health indices were evaluated. Significant upregulation of miR-199b-5p was observed in T1DM, which was significantly downregulated by metformin. miR-199b-5p correlated positively with vascular endothelial growth factor-D and c-reactive protein (CRP: nonsignificant). ROC analysis determined miR-199b-5p to define subclinical CVD by discriminating between HCs and T1DM individuals. ROC analyses of HbA1c and CRP showed that the upregulation of miR-199b-5p in T1DM individuals defined subclinical CVD at HbA1c > 44.25 mmol and CRP > 4.35 × 106 pg/mL. Ingenuity pathway analysis predicted miR-199b-5p to inhibit the target genes SIRT1, ETS1, and JAG1. Metformin was predicted to downregulate miR-199b-5p via NFATC2 and STAT3 and reverse its downstream effects. This study validated the antiangiogenic properties of miR-199b-5p and substantiated miR-199b-5p overexpression as a biomarker of subclinical CVD. The downregulation of miR-199b-5p by metformin confirmed its cardio-protective effect.
Asunto(s)
Enfermedades Cardiovasculares , Metformina , MicroARNs , MicroARNs/genética , MicroARNs/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Humanos , Masculino , Femenino , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Adulto , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Inflamación/genética , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Sirtuina 1/metabolismo , Sirtuina 1/genética , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/genética , Persona de Mediana Edad , Regulación de la Expresión Génica/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Proteína Jagged-1/metabolismo , Proteína Jagged-1/genética , Biomarcadores , Estudios de Casos y ControlesRESUMEN
Multicenter international clinical trials demonstrated the clinical safety and efficacy by using stem cell educator therapy to treat type 1 diabetes (T1D) and other autoimmune diseases. Previous studies characterized the peripheral blood insulin-producing cells (PB-IPC) from healthy donors with high potential to give rise to insulin-producing cells. PB-IPC displayed the molecular marker glucose transporter 2 (GLUT2), contributing to the glucose transport and sensing. To improve the clinical efficacy of stem cell educator therapy in the restoration of islet ß-cell function, we explored the GLUT2 expression on PB-IPC in recent onset and longstanding T1D patients. In the Food and Drug Administration (FDA)-approved phase 2 clinical studies, patients received one treatment with the stem cell educator therapy. Peripheral blood mononuclear cells (PBMC) were isolated for flow cytometry analysis of PB-IPC and other immune markers before and after the treatment with stem cell educator therapy. Flow cytometry revealed that both recent onset and longstanding T1D patients displayed very low levels of GLUT2 on PB-IPC. After the treatment with stem cell educator therapy, the percentages of GLUT2+CD45RO+ PB-IPC were markedly increased in these T1D subjects. Notably, we found that T1D patients shared common clinical features with patients with other autoimmune and inflammation-associated diseases, such as displaying low or no expression of GLUT2 on PB-IPC at baseline and exhibiting a high profile of the inflammatory cytokine interleukin (IL)-1ß. Flow cytometry demonstrated that their GLUT2 expressions on PB-IPC were also markedly upregulated, and the levels of IL-1ß-positive cells were significantly downregulated after the treatment with stem cell educator therapy. Stem cell educator therapy could upregulate the GLUT2 expression on PB-IPC and restore their function in T1D patients, leading to the improvement of clinical outcomes. The clinical data advances current understanding about the molecular mechanisms underlying the stem cell educator therapy, which can be expanded to treat patients with other autoimmune and inflammation-associated diseases.
Asunto(s)
Diabetes Mellitus Tipo 1 , Transportador de Glucosa de Tipo 2 , Células Secretoras de Insulina , Insulina , Humanos , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/sangre , Transportador de Glucosa de Tipo 2/metabolismo , Transportador de Glucosa de Tipo 2/genética , Células Secretoras de Insulina/metabolismo , Masculino , Femenino , Insulina/metabolismo , Adulto , Leucocitos Mononucleares/metabolismo , Persona de Mediana Edad , Trasplante de Células MadreRESUMEN
Diabetic retinopathy (DR) is one of the most prevalent secondary complications associated with diabetes. Specifically, Type 1 Diabetes Mellitus (T1D) has an immune component that may determine the evolution of DR by compromising the immune response of the retina, which is mediated by microglia. In the early stages of DR, the permeabilization of the blood-retinal barrier allows immune cells from the peripheral system to interact with the retinal immune system. The use of new bioactive molecules, such as 3-(2,4-dihydroxyphenyl)phthalide (M9), with powerful anti-inflammatory activity, might represent an advance in the treatment of diseases like DR by targeting the immune systems responsible for its onset and progression. Our research aimed to investigate the molecular mechanisms involved in the interaction of specific cells of the innate immune system during the progression of DR and the reduction in inflammatory processes contributing to the pathology. In vitro studies were conducted exposing Bv.2 microglial and Raw264.7 macrophage cells to proinflammatory stimuli for 24 h, in the presence or absence of M9. Ex vivo and in vivo approaches were performed in BB rats, an animal model for T1D. Retinal explants from BB rats were cultured with M9. Retinas from BB rats treated for 15 days with M9 via intraperitoneal injection were analyzed to determine survival, cellular signaling, and inflammatory markers using qPCR, Western blot, or immunofluorescence approaches. Retinal structure images were acquired via Spectral-Domain-Optical Coherence Tomography (SD-OCT). Our results show that the treatment with M9 significantly reduces inflammatory processes in in vitro, ex vivo, and in vivo models of DR. M9 works by inhibiting the proinflammatory responses during DR progression mainly affecting immune cell responses. It also induces an anti-inflammatory response, primarily mediated by microglial cells, leading to the synthesis of Arginase-1 and Hemeoxygenase-1(HO-1). Ultimately, in vivo administration of M9 preserves the retinal integrity from the degeneration associated with DR progression. Our findings demonstrate a specific interaction between both retinal and systemic immune cells in the progression of DR, with a differential response to treatment, mainly driven by microglia in the anti-inflammatory action. In vivo treatment with M9 induces a switch in immune cell phenotypes and functions that contributes to delaying the DR progression, positioning microglial cells as a new and specific therapeutic target in DR.
Asunto(s)
Diabetes Mellitus Tipo 1 , Retinopatía Diabética , Modelos Animales de Enfermedad , Microglía , Animales , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/patología , Retinopatía Diabética/inmunología , Ratas , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Retina/efectos de los fármacos , Retina/patología , Retina/metabolismo , Células RAW 264.7 , Masculino , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Inmunomodulación/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/patología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Ratas Endogámicas BBRESUMEN
The development of advanced diabetes technology has permitted persons with type 1 diabetes mellitus to improve metabolic control significantly, particularly with the development of advanced hybrid closed-loop systems which have improved the quality of life by reducing hypoglycemia, decreasing macroangiopathy and microangiopathy-related complications, ameliorating HbA1c and improving glycemic variability. Despite the progression made over the past few decades, there is still significant margin for improvement to be made in terms of attaining appropriate metabolic control. Various factors are responsible for poor glycemic control including inappropriate carbohydrate counting, repeated bouts of hypoglycemia, hypoglycemia unawareness, cutaneous manifestations due to localized insulin use and prolonged use of diabetes technology, psychosocial comorbidities such as eating disorders or 'diabulimia', the coexistence of insulin resistance among people with type 1 diabetes and the inability to mirror physiological endogenous pancreatic insulin secretion appropriately. Hence, the aim of this review is to highlight and overcome the barriers in attaining appropriate metabolic control among people with type 1 diabetes by driving research into adjunctive treatment for coexistent insulin resistance and developing new advanced diabetic technologies to preserve ß cell function and mirror as much as possible endogenous pancreatic functions.
Asunto(s)
Diabetes Mellitus Tipo 1 , Control Glucémico , Resistencia a la Insulina , Insulina , Humanos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Resistencia a la Insulina/fisiología , Insulina/uso terapéutico , Control Glucémico/métodos , Hipoglucemiantes/uso terapéutico , Hipoglucemia/prevención & control , Glucemia/metabolismo , Sistemas de Infusión de Insulina , Calidad de Vida , Hemoglobina Glucada/metabolismo , Hemoglobina Glucada/análisisRESUMEN
New therapeutic approaches to treat type 1 diabetes mellitus relies on pancreatic islet transplantation. Here, developing immuno-isolation strategies is essential to eliminate the need for systemic immunosuppression after pancreatic islet grafts. A solution is the macro-encapsulation of grafts in semipermeable matrixes with a double function: separating islets from host immune cells and facilitating the diffusion of insulin, glucose, and other metabolites. This study aims to synthesize and characterize different types of gelatin-collagen matrixes to prepare a macro-encapsulation device for pancreatic islets that fulfill these functions. While natural polymers exhibit superior biocompatibility compared to synthetic ones, their mechanical properties are challenging to reproduce. To address this issue, we conducted a comparative analysis between photo-crosslinked gelatin matrixes and chemically crosslinked collagen matrixes. We show that the different crosslinkers and polymerization methods influence the survival and glucose-stimulated insulin production of pancreatic ß cells (INS1) in vitro, as well as the in vitro and in vivo stability of the matrix and the immuno-isolation in vivo. Among the matrixes, the stiff multilayer GelMA matrixes (8.5 kPa), fabricated by digital light processing, were the best suited for pancreatic ß cells macro-encapsulation regarding these parameters. Within the alveoli of this matrix, pancreatic ß cells spontaneously formed aggregates.
Asunto(s)
Gelatina , Células Secretoras de Insulina , Trasplante de Islotes Pancreáticos , Células Secretoras de Insulina/metabolismo , Animales , Trasplante de Islotes Pancreáticos/métodos , Gelatina/química , Ratas , Colágeno/metabolismo , Insulina/metabolismo , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/metabolismo , Supervivencia Celular , Humanos , Materiales Biocompatibles , Glucosa/metabolismoRESUMEN
Background: The functional changes in alpha cells in patients with type 1 diabetes (T1D) with different residual beta cell functions remain poorly elucidated. The study aimed to investigate the relationship between glucagon secretion and C-peptide levels and to explore the relationship between glucagon response and glucose increment in respond to a secretagogue in a steamed bread meal tolerance test (BMTT) in T1D. Methods: The study enrolled 43 adult patients with T1D and 24 healthy control subjects. Patients with T1D who underwent BMTT were divided into two groups based on peak C-peptide levels: C peptide low (CPL; C-peptide < 200 pmol/L; n=14) and high (CPH; C peptide ≥ 200 pmol/L; n=29). Plasma glucose, C-peptide, glucagon levels at 0, 30, 60, 120, and 180 min were measured. The glucagon response to the BMTT was defined by areas under the curve (AUC) as early (AUC0-30), late (AUC30-180), or total (AUC0-180) glucagon. Results: Compared to healthy individuals, fasting plasma glucagon was lower and postprandial plasma glucagon level was increased in patients with T1D. Glucagon levels after BMTT between the CPL and CPH group showed significant group by time interaction. Peak glucagon and glucagon at 60-180 min, total and late glucagon response were higher in CPL than CPH group, while fasting glucagon and early glucagon response adjusted for glucose were comparable between CPL and CPH group. The higher late glucagon response and late glucagon response adjusted for glucose were associated with lower peak C-peptide in T1D. The higher late glucagon response and lower peak C-peptide were associated with the higher value of âµglucose at 180 min. Conclusion: Stimulated C-peptide levels affect the paradoxical increase in postprandial glucagon secretion in patients with T1D, especially late glucagon response. The exaggerated postprandial glucagon secretion further stimulates the elevation of postprandial glucose in patients with T1D.
Asunto(s)
Glucemia , Péptido C , Diabetes Mellitus Tipo 1 , Glucagón , Periodo Posprandial , Humanos , Glucagón/sangre , Péptido C/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Masculino , Femenino , Periodo Posprandial/fisiología , Adulto , Glucemia/metabolismo , Persona de Mediana Edad , Estudios de Casos y Controles , Adulto JovenRESUMEN
Type 1 diabetes (T1D) is a common autoimmune disease in which dysregulated glucose metabolism is a key feature. T1D is both poorly understood and in need of improved therapeutics. Hypoxia is frequently encountered in multiple tissues in T1D patients including the pancreas and sites of diabetic complications. Hypoxia-inducible factor (HIF)-1, a ubiquitous master regulator of the adaptive response to hypoxia, promotes glucose metabolism through transcriptional and non-transcriptional mechanisms and alters disease progression in multiple preclinical T1D models. However, how HIF-1 activation in ß-cells of the pancreas and immune cells (two key cell types in T1D) ultimately affects disease progression remains controversial. We discuss recent advances in our understanding of the role of hypoxia/HIF-1-induced glycolysis in T1D and explore the possible use of drugs targeting this pathway as potential new therapeutics.
Asunto(s)
Diabetes Mellitus Tipo 1 , Factor 1 Inducible por Hipoxia , Animales , Humanos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Glucólisis , Factor 1 Inducible por Hipoxia/metabolismo , Células Secretoras de Insulina/metabolismoRESUMEN
Diabetes mellitus (DM) is a chronic disorder of glucose metabolism that threatens several organs, including the submandibular (SMG) salivary glands. Antox (ANX) is a strong multivitamin with significant antioxidant benefits. The goal of this study was to demonstrate the beneficial roles of ANX supplementation in combination with insulin in alleviating diabetic SMG changes. For four weeks, 30 rats were divided into equal five groups (n = 6): (1) control group; (2) diabetic group (DM), with DM induced by streptozotocin (STZ) injection (50 mg/kg i.p.); (3) DM + ANX group: ANX was administrated (10 mg/kg/day/once daily/orally); (4) DM + insulin group: insulin was administrated 1U once/day/s.c.; and (5) DM + insulin + ANX group: co-administrated insulin. The addition of ANX to insulin in diabetic rats alleviated hyposalivation and histopathological alterations associated with diabetic rats. Remarkably, combined ANX and insulin exerted significant antioxidant effects, suppressing inflammatory and apoptotic pathways associated with increased salivary advanced glycation end-product (AGE) production and receptor for advanced glycation end-product expression (RAGE) activation in diabetic SMG tissues. Combined ANX and insulin administration in diabetic rats was more effective in alleviating SMG changes (functions and structures) than administration of insulin alone, exerting suppressive effects on AGE production and frustrating RAGE downstream pathways.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Productos Finales de Glicación Avanzada , Insulina , Receptor para Productos Finales de Glicación Avanzada , Glándula Submandibular , Animales , Glándula Submandibular/metabolismo , Glándula Submandibular/patología , Glándula Submandibular/efectos de los fármacos , Ratas , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/patología , Productos Finales de Glicación Avanzada/metabolismo , Insulina/metabolismo , Masculino , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Vitaminas/farmacologíaRESUMEN
A chronic autoimmune condition known as type 1 diabetes mellitus (T1DM) has characteristics marked by a gradual immune-mediated deterioration of the ß-cells that produce insulin and causes overt hyperglycemia. it affects more than 1.2 million kids and teenagers (0-19 years old). In both, the initiation and elimination phases of T1DM, cytokine-mediated immunity is crucial in controlling inflammation. T regulatory (Treg) cells, a crucial anti-inflammatory CD4+ T cell subset, secretes interleukin-35 (IL-35). The IL-35 has immunomodulatory properties by inhibiting pro-inflammatory cells and cytokines, increasing the secretion of interleukin-10 (IL-10) as well as transforming Growth Factor- ß (TGF-ß), along with stimulating the Treg and B regulatory (Breg) cells. IL-35, it is a possible target for cutting-edge therapies for cancers, inflammatory, infectious, and autoimmune diseases, including TIDM. Unanswered questions surround IL-35's function in T1DM. Increasing data suggests Treg cells play a crucial role in avoiding autoimmune T1DM. Throughout this review, we will explain the biological impacts of IL-35 and highlight the most recently progresses in the roles of IL-35 in treatment of T1DM; the knowledge gathered from these findings might lead to the development of new T1DM treatments. This review demonstrates the potential of IL-35 as an effective autoimmune diabetes inhibitor and points to its potential therapeutic value in T1DM clinical trials.
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Diabetes Mellitus Tipo 1 , Interleucinas , Linfocitos T Reguladores , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Humanos , Interleucinas/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Interleucina-10/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Niño , Adolescente , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Inflamación/metabolismo , Inflamación/inmunologíaRESUMEN
With the development of Type 1 diabetes mellitus (T1DM), various complications can be caused. Hyperglycemia affects the microenvironment of cardiomyocytes, changes endoplasmic reticulum homeostasis, triggers unfolding protein response and eventually promotes myocardial apoptosis. However, insulin therapy alone cannot effectively combat the complications caused by T1DM. Forty adult beagles were randomly divided into five groups: control group, diabetes mellitus group, insulin group, insulin combined with NAC group, and NAC group. 24-hour blood glucose, 120-day blood glucose, 120-day body weight, and serum FMN content were observed, furthermore, hematoxylin-eosin staining, Periodic acid Schiff reagent staining, and Sirius red staining of the myocardium were evaluated. The protein expressions of GRP78, ATF6, IRE1, PERK, JNK, CHOP, caspase 3, Bcl2, and Bax were detected. Results of the pathological section of myocardial tissue indicated that insulin combined with NAC therapy could improve myocardial pathological injury and glycogen deposition. Additionally, insulin combined with NAC therapy down-regulates the expression of GRP78, ATF6, IRE1, PERK, JNK, CHOP, caspase3, and Bax. These findings suggest that NAC has a phylactic effect on myocardial injury in beagles with T1DM, and the mechanism may be related to the improvement of endoplasmic reticulum stress-induced apoptosis.
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Acetilcisteína , Diabetes Mellitus Tipo 1 , Retículo Endoplásmico , Insulina , Miocardio , Animales , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/complicaciones , Insulina/farmacología , Insulina/metabolismo , Perros , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Acetilcisteína/farmacología , Miocardio/metabolismo , Miocardio/patología , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Apoptosis/efectos de los fármacos , Masculino , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: This study aims to investigate potential beneficial actions of icariin (ICA) on testicular spermatogenic function in male rats with streptozotocin (STZ)-induced diabetes and to explore the underlying mechanisms. Background: ICA was found to reduce blood glucose, regulate the endocrine function of the reproductive system, and improve testicular spermatogenic function. METHODS: Adult rats were intraperitoneally injected with STZ (65 mg/kg) to induce type 1 diabetes mellitus (T1DM). Diabetic rats were randomly classified intoT1DM (n = 6) and T1DM + ICA (n = 6) groups. Rats without STZ and ICA treatment were assigned as control group (n = 6). The morphology of testicular tissues was examined by histological staining. The mRNA and protein expression levels were determined by quantitative real-time PCR, Western blot and immunostaining, respectively. RESULTS: Rats from T1DM group showed a reduction in epididymis and testis weight, and a decrease in sperm count when compared to control group (p < 0.01), which was attenuated by ICA treatment (p < 0.05) Diabetic rats from T1DM group also exhibited reduced diameter and area of seminiferous tubules, along with decreased spermatogonia and primary spermatocytes number when compared to control group (p < 0.01), which was partially reversed by ICA treatment (p < 0.05) Rats from T1DM group exhibited down-regulation of PCNA mRNA and protein in the testis when compared to control group (p < 0.01); while ICA treatment up-regulated PCNA expression in the testis of diabetic rats compared to T1DM group (p < 0.05). Rats from T1DM group showed up-regulation of Bax and capase-3 and down-regulation of Bcl-2, PKM2, HK2 and lactate dehydrogenase A in the testes when compared to control group (p < 0.05), which was reversed by ICA treatment (p < 0.05). CONCLUSION: These findings suggest that ICA may exert its protective effects on testicular damage in diabetic rats through modulation of glycolysis pathway and suppression of apoptosis.
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Diabetes Mellitus Experimental , Flavonoides , Glucólisis , Testículo , Animales , Masculino , Flavonoides/farmacología , Flavonoides/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patología , Glucólisis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estreptozocina , Espermatogénesis/efectos de los fármacos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Apoptosis/efectos de los fármacos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Recuento de EspermatozoidesRESUMEN
Recent advances in mass spectrometry-based peptidomics have catalyzed the identification and quantification of thousands of endogenous peptides across diverse biological systems. However, the vast peptidomic landscape generated by proteolytic processing poses several challenges for downstream analyses and limits the comparability of clinical samples. Here, we present an algorithm that aggregates peptides into peptide clusters, reducing the dimensionality of peptidomics data, improving the definition of protease cut sites, enhancing inter-sample comparability, and enabling the implementation of large-scale data analysis methods akin to those employed in other omics fields. We showcase the algorithm by performing large-scale quantitative analysis of wound fluid peptidomes of highly defined porcine wound infections and human clinical non-healing wounds. This revealed signature phenotype-specific peptide regions and proteolytic activity at the earliest stages of bacterial colonization. We validated the method on the urinary peptidome of type 1 diabetics which revealed potential subgroups and improved classification accuracy.