RESUMEN

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.

Asunto(s)

Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Humanos , Animales , Transducción de Señal , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo

RESUMEN

IGFBP6, a member of the IGF binding protein (IGFBP) family, is a specific inhibitor of insulin-like growth factor II (IGF-II) and can inhibit the growth of malignant tumors overexpressing IGF-II. Type 2 diabetes (T2D) is a basic disorder of glucose metabolism that can be regulated by IGF-related pathways. We performed bioinformatics analysis of the TCGA database to explore the possible mechanism of IGFBP6 in breast cancer (BC) metabolism and prognosis and collected clinical samples from BC patients with and without T2D to compare and verify the prognostic effect of IGFBP6. In our study, the levels of IGFBP1-6 were positively correlated with overall survival (OS) in patients with breast cancer. IGFBP6 was upregulated in estrogen receptor (ER)-positive BC, and ER-positive and progesterone receptor (PR) positive patients had a higher expression level of IGFBP6 than ER-negative and PR-negative patients. IGFBP6 could be used as an independent prognostic factor in BC. The expression of IGFBP6 was decreased in BC tissue, and BC tissue from patients with T2D had lower IGFBP6 expression levels than BC tissue from patients without T2D. IGFBP6 is mainly involved in the PI3K-Akt and TGF-ß signaling pathways and tumor microenvironment regulation. In terms of metabolism, the expression of IGFBP6 was negatively correlated with that of most glucose metabolism-related genes. IGFBP6 expression was mainly correlated with mutations in TP53, PIK3CA, CDH1, and MAP3K1. In addition, the upregulation of IGFBP6 in BC increased the drug sensitivity to docetaxel, paclitaxel and gemcitabine. Overall, these results indicated that high expression of IGFBP6 is associated with a good prognosis in BC patients, especially in those without T2D. It is not only involved in the maintenance of the tumor microenvironment in BC but also inhibits the energy metabolism of cancer cells through glucose metabolism-related pathways. These findings may provide a new perspective on IGFBP6 as a potential prognostic marker for BC.

Asunto(s)

Biomarcadores de Tumor , Neoplasias de la Mama , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina , Humanos , Femenino , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Pronóstico , Biomarcadores de Tumor/metabolismo , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Regulación Neoplásica de la Expresión Génica , Biología Computacional/métodos , Transducción de Señal , Glucosa/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Persona de Mediana Edad , Estimación de Kaplan-Meier , Bases de Datos Genéticas

RESUMEN

Pancreatic ß­cells are the only cells that synthesize insulin to regulate blood glucose levels. Various conditions can affect the mass of pancreatic ß­cells and decrease insulin levels. Diabetes mellitus is a disease characterized by insulin resistance and chronic hyperglycemia, mainly due to the loss of pancreatic ß­cells caused by an increase in the rate of apoptosis. Additionally, hyperglycemia has a toxic effect on ß­cells. Although the precise mechanism of glucotoxicity is not fully understood, several mechanisms have been proposed. The most prominent changes are increases in reactive oxygen species, the loss of mitochondrial membrane potential and the activation of the intrinsic pathway of apoptosis due to p53. The present review analyzed the location of p53 in the cytoplasm, mitochondria and nucleus in terms of post­translational modifications, including phosphorylation, O­GlcNAcylation and poly­ADP­ribosylation, under hyperglycemic conditions. These modifications protect p53 from degradation by the proteasome and, in turn, enable it to regulate the intrinsic pathway of apoptosis through the regulation of anti­apoptotic and pro­apoptotic elements. Degradation of p53 occurs in the proteasome and depends on its ubiquitination by Mdm2. Understanding the mechanisms that activate the death of pancreatic ß­cells will allow the proposal of treatment alternatives to prevent the decrease in pancreatic ß­cells.

Asunto(s)

Apoptosis , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Procesamiento Proteico-Postraduccional , Proteína p53 Supresora de Tumor , Proteína p53 Supresora de Tumor/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Animales

RESUMEN

BACKGROUND: Random-pattern skin flaps are commonly used to repair skin tissue defects in surgical tissue reconstruction. However, flap necrosis in the distal area due to ischemia injury is still challenging for its applications in plastic surgery. The complications of diabetes will further increase the risk of infection and necrosis. METHODS: This study induced type 2 diabetes mellitus (T2DM) rats with a high-fat diet and STZ. The survival rate of the skin flap was observed by adding inorganic sodium nitrate to drinking water. Histology and immunohistochemistry were used to detect the damage to the skin flap. The nitrate content was measured by total nitric oxide and nitrate/nitrite parameter assay. Dihydroethidium and malondialdehyde (MDA) assays were used to value oxidative stress. Rat colon feces were collected for 16s rRNA gene sequence. RESULTS: Our studies showed that nitrate administration leads to anti-obesity and anti-diabetic effects. Nitrate directly increased the survival area of skin flaps in diabetic rats and mean blood vessel density by enhancing angiogenesis, inhibiting apoptosis, and reducing oxidative stress. The 16s rRNA sequence revealed that nitrate may regulate the homeostasis of the gut microbiota and re-store energy metabolism. CONCLUSION: Dietary nitrate has been shown to maintain the homeostasis of oxidative stress and gut microbiota to promote flap survival in rats with T2DM.

Asunto(s)

Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Homeostasis , Nitratos , Estrés Oxidativo , Colgajos Quirúrgicos , Animales , Estrés Oxidativo/efectos de los fármacos , Ratas , Nitratos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Microbioma Gastrointestinal/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Masculino , Ratas Sprague-Dawley , Supervivencia de Injerto/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos

RESUMEN

Background: Heterogenous deposition and homeostasis roles of physiologic and ectopic adipose tissues underscore the impact of fat compartmentalization on cardiometabolic risk. We aimed to characterize the distribution of abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), epicardial adipose tissue (EAT), and liver fat on magnetic resonance imaging (MRI), and evaluate their associations with anthropometric indices and adverse cardiac remodeling. Methods: In this cross-sectional observational study, 149 Asian adults (57.0 ± 12.8 years; 65% males) with at least one cardiometabolic risk factor underwent multiparametric fat and cardiovascular MRI. Anthropometric indices included body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and bioimpedance body fat mass (BFM). Associations between fat depots and anthropometric measures as well as cardiac remodeling features were examined as a single cohort and stratified by type 2 diabetes mellitus (T2DM) status. Results: VAT and SAT had opposing associations with liver fat and EAT. Therefore the VAT/SAT ratio was explored as an integrated marker of visceral adiposity. VAT/SAT was positively associated with EAT (ß=0.35, P<0.001) and liver fat (ß=0.32, P=0.003) independent of confounders. Of the anthropometric measurements assessed, only WHR was independently associated with VAT/SAT (ß=0.17, P=0.021). Individuals with T2DM had higher VAT and lower SAT compared to those without T2DM, translating to a significantly higher VAT/SAT ratio. EAT volume was independently associated with adverse features of cardiac remodeling: increased left ventricular (LV) mass (ß=0.24, P=0.005), larger myocyte volume (ß=0.26, P=0.001), increased myocardial fibrosis (ß=0.19, P=0.023), higher concentricity (ß=0.18, P=0.035), and elevated wall stress (ß=-0.18, P=0.023). Conclusion: Multiparametric MRI revealed abdominal VAT and SAT have differential associations with anthropometric indices and ectopic fats in a single cohort of Asians at risk of cardiometabolic disease. People with T2DM have expanded VAT and diminished SAT, endorsing the VAT/SAT ratio beyond usual anthropometric measurements as a marker for multiorgan visceral fat composition. Among the fat depots examined, EAT is uniquely associated with adverse cardiac remodeling, suggesting its distinctive cardiometabolic properties and implications.

Asunto(s)

Adiposidad , Grasa Intraabdominal , Pericardio , Remodelación Ventricular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Adiposidad/fisiología , Pericardio/diagnóstico por imagen , Pericardio/patología , Grasa Intraabdominal/diagnóstico por imagen , Grasa Intraabdominal/patología , Anciano , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Pueblo Asiatico , Hígado/diagnóstico por imagen , Hígado/patología , Antropometría , Imagen por Resonancia Magnética , Adulto , Grasa Abdominal/diagnóstico por imagen , Grasa Abdominal/patología

RESUMEN

Investigate the impact of remnant cholesterol (RC) levels on carotid artery intima thickness (CIT) in type 2 diabetes mellitus (T2DM) patients. From September 2021 to September 2023, a prospective multicenter study involved 158 T2DM patients. They were divided into a higher RC group (n = 80) and a lower RC group (n = 78) based on median RC levels. Additionally, 92 healthy volunteers served as the control group. CIT, carotid media thickness (CMT), and carotid intima-media thickness (CIMT) were measured. General clinical data, lab results, CIMT, CIT, and CMT differences among the three groups were compared. Multiple regression analysis explored CIT factors in T2DM patients. 1. No significant sex, age, BMI, high-density lipoprotein cholesterol (HDL-C), T2DM duration, fasting blood glucose, or glycated hemoglobin differences were found among the groups (p > 0.05). 2. CIMT and CIT were significantly higher in T2DM than the control group (p < 0.05). 3. The higher RC group had thicker CIT than the lower RC group (p < 0.05), while CIMT differences were not significant (p > 0.05). Multiple linear regression analysis showed RC as an influencing CIT factor in T2DM patients (ß = 0.473, p = 0.005). CIT is significantly thicker in T2DM patients with higher RC than in those with lower RC, and RC is the influence factor of CIT, which suggests that more attention should be paid to the detection of RC in T2DM patients.

Asunto(s)

Grosor Intima-Media Carotídeo , Colesterol , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Masculino , Femenino , Persona de Mediana Edad , Colesterol/sangre , Estudios Prospectivos , Anciano , Estudios de Casos y Controles , Adulto , Factores de Riesgo

RESUMEN

Autophagy is the primary intracellular degradation system, and it plays an important role in many biological and pathological processes. Studies of autophagy involvement in developmental processes are important for understanding various processes. Among them are fibrosis, degenerative diseases, cancer development, and metastasis formation. Diabetic kidney disease is one of the main causes of chronic kidney disease and end-stage renal failure. The aim of this study was to investigate the immunohistochemical expression patterns of LC3B, LAMP2A, and GRP78 during different developmental stages of early-developing human kidneys and in samples from patients with type II diabetes mellitus. During the 7/8th DW, moderate expression of LC3B and LAMP2A and strong expression of GRP78 were found in the mesonephric glomeruli and tubules. In the 9/10th DW, the expression of LC3B and LAMP2A was even more pronounced in the mesonephric tubules. LC3B, LAMP2A, and GRP78 immunoreactivity was also found in the paramesonephric and mesonephric ducts and was stronger in the 9/10th DW compared with the 7/8th DW. In addition, the expression of LC3B, LAMP2A, and GRP78 also appeared in the mesenchyme surrounding the paramesonephric duct in the 9/10th DW. In the 15/16th DW, the expression of LC3B in the glomeruli was weak, that of LAMP2A was moderate, and that of GRP78 was strong. In the tubuli, the expression of LC3B was moderate, while the expression of LAMP2A and GRP78 was strong. The strongest expression of LC3B, LAMP2A, and GRP78 was observed in the renal medullary structures, including developing blood vessels. In postnatal human kidneys, the most extensive LC3B, LAMP2A, and GRP78 expression in the cortex was found in the epithelium of the proximal convoluted tubules, with weak to moderate expression in the glomeruli. The medullary expression of LC3B was weak, but the expression of LAMP2A and GRP78 was the strongest in the medullary tubular structures. Significantly lower expression of LC3B was found in the glomeruli of the diabetic patients in comparison with the nondiabetic patients, but there was no difference in the expression of LC3B in the tubule-interstitial compartment. The expression of LAMP2A was significantly higher in the tubule-interstitial compartments of the diabetic patients in comparison with the nondiabetic patients, while its expression did not differ in the glomeruli. Extensive expression of GRP78 was found in the glomeruli and the tubule-interstitial compartments, but there was no difference in the expression between the two groups of patients. These data give us new information about the expression of LC3B, LAMP2A, and GRP78 during embryonic, fetal, and early postnatal development. The spatiotemporal expression of LC3B, LAMP2A, and GRP78 indicates the important role of autophagy during the early stages of renal development. In addition, our data suggest a disturbance in autophagy processes in the glomeruli and tubuli of diabetic kidneys as an important factor in the pathogenesis of diabetic kidney disease.

Asunto(s)

Autofagia , Nefropatías Diabéticas , Chaperón BiP del Retículo Endoplásmico , Riñón , Proteína 2 de la Membrana Asociada a los Lisosomas , Proteínas Asociadas a Microtúbulos , Humanos , Chaperón BiP del Retículo Endoplásmico/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Riñón/metabolismo , Riñón/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Biomarcadores/metabolismo , Femenino , Masculino , Proteínas de Choque Térmico/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología

RESUMEN

INTRODUCTION: We undertook phenotypic characterization of early-onset and late-onset type 2 diabetes (T2D) in adult black African and white European populations with recently diagnosed T2D to explore ethnic differences in the manifestation of early-onset T2D. RESEARCH DESIGN AND METHODS: Using the Uganda Diabetes Phenotype study cohort of 500 adult Ugandans and the UK StartRight study cohort of 714 white Europeans with recently diagnosed islet autoantibody-negative T2D, we compared the phenotypic characteristics of participants with early-onset T2D (diagnosed at <40 years) and late-onset T2D (diagnosed at ≥40 years). RESULTS: One hundred and thirty-four adult Ugandans and 113 white Europeans had early-onset T2D. Compared with late-onset T2D, early-onset T2D in white Europeans was significantly associated with a female predominance (52.2% vs 39.1%, p=0.01), increased body mass index (mean (95% CI) 36.7 (35.2-38.1) kg/m2 vs 33.0 (32.4-33.6) kg/m2, p<0.001), waist circumference (112.4 (109.1-115.6) cm vs 108.8 (107.6-110.1) cm, p=0.06), and a higher frequency of obesity (82.3% vs 63.4%, p<0.001). No difference was seen with the post-meal C-peptide levels as a marker of beta-cell function (mean (95% CI) 2130.94 (1905.12-2356.76) pmol/L vs 2039.72 (1956.52-2122.92), p=0.62).In contrast, early-onset T2D in Ugandans was associated with less adiposity (mean (95% CI) waist circumference 93.1 (89.9-96.3) cm vs 97.4 (95.9-98.8) cm, p=0.006) and a greater degree of beta-cell dysfunction (120 min post-glucose load C-peptide mean (95% CI) level 896.08 (780.91-1011.24) pmol/L vs 1310.10 (1179.24-1440.95) pmol/L, p<0.001), without female predominance (53.0% vs 57.9%, p=0.32) and differences in the body mass index (mean (95% CI) 27.3 (26.2-28.4) kg/m2 vs 27.9 (27.3-28.5) kg/m2, p=0.29). CONCLUSIONS: These differences in the manifestation of early-onset T2D underscore the need for ethnic-specific and population-specific therapeutic and preventive approaches for the condition.

Asunto(s)

Edad de Inicio , Diabetes Mellitus Tipo 2 , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores/análisis , Población Negra/estadística & datos numéricos , Índice de Masa Corporal , Estudios de Cohortes , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/patología , Etnicidad/estadística & datos numéricos , Estudios de Seguimiento , Pronóstico , Factores de Riesgo , Uganda/epidemiología , Circunferencia de la Cintura , Población Blanca/estadística & datos numéricos

RESUMEN

Type 2 diabetes (T2D) and Parkinson's disease (PD) are the two most frequent age-related chronic diseases. There are many similarities between the two diseases: both are chronic diseases; both are the result of a decrease in a specific substance-insulin in T2D and dopamine in PD; and both are caused by the destruction of specific cells-beta pancreatic cells in T2D and dopaminergic neurons in PD. Recent epidemiological and experimental studies have found that there are common underlying mechanisms in the pathophysiology of T2D and PD: chronic inflammation, mitochondrial dysfunction, impaired protein handling and ferroptosis. Epidemiological research has indicated that there is a higher risk of PD in individuals with T2D. Moreover, clinical studies have observed that the symptoms of Parkinson's disease worsen significantly after the onset of T2D. This article provides an up-to-date review on the intricate interplay between oxidative stress, reactive oxygen species (ROS) and ferroptosis in PD and T2D. By understanding the shared molecular pathways and how they can be modulated, we can develop more effective therapies, or we can repurpose existing drugs to improve patient outcomes in both disorders.

Asunto(s)

Diabetes Mellitus Tipo 2 , Ferroptosis , Estrés Oxidativo , Enfermedad de Parkinson , Especies Reactivas de Oxígeno , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Especies Reactivas de Oxígeno/metabolismo , Animales

RESUMEN

Diabetic cardiomyopathy (DbCM) is a common complication in individuals with type 2 diabetes mellitus (T2DM), and its exact pathogenesis is still debated. It was hypothesized that chronic hyperglycemia and insulin resistance activate critical cellular pathways that are responsible for numerous functional and anatomical perturbations in the heart. Interstitial inflammation, oxidative stress, myocardial apoptosis, mitochondria dysfunction, defective cardiac metabolism, cardiac remodeling, hypertrophy and fibrosis with consequent impaired contractility are the most common mechanisms implicated. Epigenetic changes also have an emerging role in the regulation of these crucial pathways. The aim of this review was to highlight the increasing knowledge on the molecular mechanisms of DbCM and the new therapies targeting specific pathways.

Asunto(s)

Diabetes Mellitus Tipo 2 , Cardiomiopatías Diabéticas , Estrés Oxidativo , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/complicaciones , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/etiología , Animales , Resistencia a la Insulina , Epigénesis Genética , Miocardio/metabolismo , Miocardio/patología , Apoptosis/genética

RESUMEN

Lipid metabolism is a critical component in preserving homeostasis and health, and lipids are significant chemicals involved in energy metabolism in living things. With the growing interest in lipid metabolism in recent years, an increasing number of studies have demonstrated the close relationship between abnormalities in lipid metabolism and the development of numerous human diseases, including cancer, cardiovascular, neurological, and endocrine system diseases. Thus, understanding how aberrant lipid metabolism contributes to the development of related diseases and how it works offers a theoretical foundation for treating and preventing related human diseases as well as new avenues for the targeted treatment of related diseases. Therefore, we discuss the processes of aberrant lipid metabolism in various human diseases in this review, including diseases of the cardiovascular system, neurodegenerative diseases, endocrine system diseases (such as obesity and type 2 diabetes mellitus), and other diseases including cancer.

Asunto(s)

Metabolismo de los Lípidos , Neoplasias , Enfermedades Neurodegenerativas , Humanos , Neoplasias/metabolismo , Neoplasias/etiología , Neoplasias/patología , Animales , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/etiología , Obesidad/metabolismo , Enfermedades del Sistema Endocrino/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/patología , Trastornos del Metabolismo de los Lípidos/metabolismo

RESUMEN

Neuroinflammation, aging, and neurodegenerative disorders are associated with excessive accumulation of neutral lipids in lipid droplets (LDs) in microglia. Type 2 diabetes mellitus (T2DM) may cause neuroinflammation and is a risk factor for neurodegenerative disorders. Here, we show that hippocampal pyramidal neurons contain smaller, more abundant LDs than their neighboring microglia. The density of LDs varied between pyramidal cells in adjacent subregions, with CA3 neurons containing more LDs than CA1 neurons. Within the CA3 region, a gradual increase in the LD content along the pyramidal layer from the hilus toward CA2 was observed. Interestingly, the high neuronal LD content correlated with less ramified microglial morphotypes. Using the db/db model of T2DM, we demonstrated that diabetes increased the number of LDs per microglial cell without affecting the neuronal LD density. High-intensity interval exercise induced smaller changes in the number of LDs in microglia but was not sufficient to counteract the diabetes-induced changes in LD accumulation. The changes observed in response to T2DM may contribute to the cerebral effects of T2DM and provide a mechanistic link between T2DM and neurodegenerative disorders.

Asunto(s)

Diabetes Mellitus Tipo 2 , Hipocampo , Gotas Lipídicas , Microglía , Neuronas , Microglía/metabolismo , Animales , Gotas Lipídicas/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Neuronas/metabolismo , Neuronas/patología , Masculino , Ratones , Condicionamiento Físico Animal , Células Piramidales/metabolismo , Células Piramidales/patología , Ratones Endogámicos C57BL , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Metabolismo de los Lípidos , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología

RESUMEN

Inbred mouse strains KK.Cg-a/a and KK.Cg-Ay/a known as genetic models of type 2 diabetes mellitus significantly surpassed the control strain C57BL/6J in the body weight, relative weight of extractable fat, and basal blood glucose levels. Real-timePCR of fecal samples from KK.Cg-a/a and KK.Cg-Ay/a mice revealed dysbiosis typical of type 2 diabetes mellitus in humans and animals. Long-term intragastric administration of a suspension of Hafnia alvei bacteria had no effect on the above morphometric and biochemical parameters. At the same time, recovery of the Bacteroides spp. population in KK.Cg-Ay/a mice and a decrease in the number of Bifidobacterium spp. in KK.Cg-a/a mice were observed. The possibility of therapeutic use of the probiotic based on H. alvei is discussed.

Asunto(s)

Diabetes Mellitus Tipo 2 , Heces , Microbioma Gastrointestinal , Hafnia alvei , Ratones Endogámicos C57BL , Probióticos , Animales , Diabetes Mellitus Tipo 2/microbiología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Microbioma Gastrointestinal/genética , Ratones , Probióticos/administración & dosificación , Hafnia alvei/genética , Heces/microbiología , Masculino , Bacteroides/genética , Bifidobacterium/genética , Glucemia/metabolismo , Peso Corporal , Disbiosis/microbiología , Modelos Animales de Enfermedad

RESUMEN

INTRODUCTION: Diabetes mellitus leads to maldevelopment of the villous morphology in the human placenta, disrupting the exchange of materials between the maternal and fetal compartments, consequently compromising fetal development. This study aims to explore how different types of diabetes mellitus affect human placental villous geometric morphology including branching numbers and sizes (length, diameter). METHODS: Here an optical coherence tomography (OCT)-based 3D imaging platform was utilized to capture 3D images of placental villi from different types of diabetes, including type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM). RESULTS: Different types of diabetes mellitus exhibit different effects on human placental villous geometric morphological parameters: GDM had greater placenta villous parameters at intermediate villous diameter (IVD), terminal villous diameter (TVD), terminal villous length (TVL) compared to the healthy, T1DM, and T2DM, and these differences were statistically significant. The TVD of T1DM and T2DM had significantly greater sizes than the healthy. There was no statistically significant difference in the number of villous branches among the three types of diabetes, but T1DM and GDM had more villous branches than healthy individuals. DISCUSSION: Diabetes mellitus affects the geometric morphology of human placental villi, with varying effects observed in pregnancies of different diabetes types. These findings offer a novel avenue for exploring underlying pathophysiological mechanisms and enhancing the management of women with diabetes from preconception through pregnancy.

Asunto(s)

Vellosidades Coriónicas , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Imagenología Tridimensional , Embarazo en Diabéticas , Tomografía de Coherencia Óptica , Humanos , Femenino , Embarazo , Diabetes Gestacional/patología , Diabetes Gestacional/diagnóstico por imagen , Vellosidades Coriónicas/patología , Vellosidades Coriónicas/diagnóstico por imagen , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/diagnóstico por imagen , Adulto , Embarazo en Diabéticas/patología , Embarazo en Diabéticas/diagnóstico por imagen , Tomografía de Coherencia Óptica/métodos , Placenta/diagnóstico por imagen , Placenta/patología

RESUMEN

Functional enhancer annotation is critical for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants. However, unbiased enhancer discovery in disease-relevant contexts remains challenging. To identify enhancers pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers identified, we focused on an enhancer we named ONECUT1e-664kb, ∼664 kb from the ONECUT1 promoter. Previous studies have linked ONECUT1 coding mutations to pancreatic hypoplasia and neonatal diabetes. We found that homozygous deletion of ONECUT1e-664kb in hPSCs leads to a near-complete loss of ONECUT1 expression and impaired pancreatic differentiation. ONECUT1e-664kb contains a type 2 diabetes-associated variant (rs528350911) disrupting a GATA motif. Introducing the risk variant into hPSCs reduced binding of key pancreatic transcription factors (GATA4, GATA6, and FOXA2), supporting its causal role in diabetes. This work highlights the utility of unbiased enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.

Asunto(s)

Diferenciación Celular , Elementos de Facilitación Genéticos , Páncreas , Humanos , Elementos de Facilitación Genéticos/genética , Diferenciación Celular/genética , Páncreas/metabolismo , Páncreas/patología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Células Madre Pluripotentes/metabolismo , Sistemas CRISPR-Cas/genética , Factor de Transcripción GATA6/metabolismo , Factor de Transcripción GATA6/genética

RESUMEN

AIM: Asprosin, a protein hormone, is released by unilocular adipocytes in reaction to low blood sugar. We aimed to examine how exercise affects asprosin hormone levels and associated organs, including the liver and pancreas, in diabetes. METHODS: Twenty-one male Wistar albino rats were firstly allocated into two main groups: control (n = 7) and diabetes (n = 14). Then, the diabetes group was further separated into two subgroups: sedentary (n = 7) and exercise (n = 7). The exercise group participated in a swimming training regimen (30 min/daily, six weeks). Serum levels of asprosin and various other biochemical parameters were evaluated through commercial ELISA kits. The liver was analyzed histopathologically, and pancreatic islet cells were examined for Cas-3 immune expression. RESULTS: Asprosin and total oxidant status decreased significantly in the exercise diabetic subgroup (p < 0.05). Glucose, insulin, creatinine, IL-6, and HomaIR concentrations decreased slightly with exercise (p > 0.05). Liver tissue injury scores and Cas-3 immune expression in pancreas islet cells decreased in exercise diabetic rats. CONCLUSIONS: Reducing asprosin may lower glucose, insulin, and HOMA-IR. Physical activity decreases asprosin and total oxidative status, fostering anti-apoptosis and tissue healing in diabetes, potentially enhancing health. Monitoring asprosin levels offers insights into diabetes progression. Our findings imply that asprosin can be a therapeutic target for diabetes.

Asunto(s)

Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Condicionamiento Físico Animal , Ratas Wistar , Animales , Masculino , Ratas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Hígado/metabolismo , Hígado/patología , Glucemia/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/sangre , Fibrilina-1/metabolismo

RESUMEN

Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, increases worldwide and associates with type 2 diabetes and other cardiometabolic diseases. Here we demonstrate that Sema3a is elevated in liver sinusoidal endothelial cells of animal models for obesity, type 2 diabetes and MASLD. In primary human liver sinusoidal endothelial cells, saturated fatty acids induce expression of SEMA3A, and loss of a single allele is sufficient to reduce hepatic fat content in diet-induced obese mice. We show that semaphorin-3A regulates the number of fenestrae through a signaling cascade that involves neuropilin-1 and phosphorylation of cofilin-1 by LIM domain kinase 1. Finally, inducible vascular deletion of Sema3a in adult diet-induced obese mice reduces hepatic fat content and elevates very low-density lipoprotein secretion. Thus, we identified a molecular pathway linking hyperlipidemia to microvascular defenestration and early development of MASLD.

Asunto(s)

Células Endoteliales , Hígado , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Semaforina-3A , Transducción de Señal , Animales , Humanos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Hígado/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Semaforina-3A/metabolismo , Semaforina-3A/genética , Neuropilina-1/metabolismo , Neuropilina-1/genética , Obesidad/metabolismo , Obesidad/patología , Obesidad/genética , Cofilina 1/metabolismo , Cofilina 1/genética , Modelos Animales de Enfermedad , Masculino , Fosforilación , Células Cultivadas , Ratones , Ratones Noqueados , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/genética , Dieta Alta en Grasa/efectos adversos

RESUMEN

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.

Asunto(s)

Tejido Adiposo , Diabetes Mellitus Tipo 2 , Hígado Graso , Factor 15 de Diferenciación de Crecimiento , Hepatocitos , Macrófagos , Obesidad , Factor 15 de Diferenciación de Crecimiento/metabolismo , Factor 15 de Diferenciación de Crecimiento/genética , Animales , Obesidad/metabolismo , Obesidad/patología , Hepatocitos/metabolismo , Masculino , Macrófagos/metabolismo , Ratones , Humanos , Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Hígado Graso/metabolismo , Hígado Graso/patología , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/patología , Modelos Animales de Enfermedad , Transducción de Señal

RESUMEN

Bombesin receptor-activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin-induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004-/-). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high-fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004+/+ mice. Compared to control mice, BC004004-/- mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004+/+ mice after UUO surgery showed a more significant decrease in E-cadherin expression and a more significant increase in both α smooth muscle actin (α-SMA) and vimentin expression compared to BC004004-/- mice. Additionally, stimulation with transforming growth factor-ß1 (TGF-ß1) led to a more significant decrease in E-cadherin expression and a more significant increase in α-SMA and vimentin expression in isolated TECs from BC004004+/+ than in those from BC004004-/- mice. These results suggest that an enhanced epithelial-mesenchymal transition (EMT) process occurred in TECs in BC004004+/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004-/- mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury.

Asunto(s)

Fibrosis , Animales , Ratones , Masculino , Humanos , Transición Epitelial-Mesenquimal , Ratones Noqueados , Obstrucción Ureteral/patología , Obstrucción Ureteral/complicaciones , Riñón/patología , Riñón/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Actinas/metabolismo , Ratones Endogámicos C57BL , Cadherinas/metabolismo , Cadherinas/genética , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/genética

RESUMEN

Introdução:O diabetes mellitus é uma doença metabólica caracterizada pelo controle inadequado dos níveis de glicose no sangue, principalmente um estado crônico de hiperglicemia, causado por diferentes processos patogênicos, levando a complicaçõesdosistema nervoso do diabético queincluem axonopatias, doenças neurodegenerativas, doenças neurovasculares e comprometimento cognitivo geral.Objetivo:Avaliar as complicações clínicas da diabetes tipo 2 em mulheres. Metodologia:Tratou-se de um transversal, do tipo prevalência. Foram usados dois grupos de mulheres, onde todas as mulheres estavam com diagnóstico de diabetes Tipo 2 e idade de 40 e 60 anos, comotratamentooral -G1e com tratamentocominsulinoterapia ­G2,ambosfornecidospelarede pública Para comparação das variáveis estudadas foi utilizado o método de Mann-Whitney, adotando-se o nível de significância menor que 5% (p, valor ,0,05). Resultados:Aproporçãode pessoas com diabetes no Piauí, com consulta e hemoglobina glicada solicitada no primeiro quadrimestre de 2021, 2022, 2023, foi de18, 16 e 34 percentuais,respectivamenteeem Boa Hora nos mesmos quadrimestres foi 36, 39, 56 percentuais, respectivamente.Osprocedimentoshospitalares-por local de residência -Piauí foi de um total de 1.193e em Boa Hora 24. O grupo de mulheres estudadas mostrou uma diferença significativa para a glicemia em jejum e a Hemoglobina glicada quando comparados os grupos G1 e G2. Quase 100% da amostra estava obesa (IMC > 25), não fumava e não praticava atividade física.Conclusões:Concluiu-se que a as pacientes tiveram um agravamento do adoecimento ao longo dos anos com aumento de medicação. A ausência das boas práticas de promoção de saúde, atividade física e alimentação, podem ter contribuídocom o agravamento. Outrossim há necessidade urgente de uma intervenção para mudança de hábitos na população para que a medicalização seja diminuída para a promoção da saúde (AU).

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Introduction: Diabetes mellitus is a metabolic disease characterized by inadequate control of blood glucose levels, mainly a chronic state of hyperglycemia, caused by different pathogenic processes, leading to complications of the nervous system including axonopathies, neurodegenerative diseases,neurovascular diseases and general cognitive impairment.Objective: To evaluate the clinical complications of type 2 diabetes in women.Methodology: This was a cross-sectional, prevalence study.Two groupsof women were used, where all women were diagnosed with Type 2 diabetes and aged between 40 and 60 years, with oral treatment -G1 and treatment with insulin therapy -G2, both provided by the public network .To compare the variables studied, the Mann-Whitney method was used, adopting a significance level of less than 5% (p, value 0.05).Results:The proportion of people with diabetes in Piauí, with consultation and glycated hemoglobin requested in the first four months of 2021, 2022, 2023, was 18, 16 and34 percentages, respectively and in Boa Hora in the same four months it was 36, 39, 56percentages, respectively.SUS hospital procedures -by place of residence -Piauí was a total of 1,193 and in Boa Hora 24. The group of women studied showed a significant difference in fasting blood glucose and glycated hemoglobin when comparing groups G1 and G2.Almost 100% of the sample was obese (BMI > 25), did not smoke and did not practice physical activity.Conclusions: It was concluded that the patients' illness worsened over the years with increased medication.The absence of good health promotion practices, physical activity and nutrition may have contributed to the worsening.Furthermore, there is an urgent need for intervention to change habits in the population so that medicalization is reduced to promote health (AU).

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Introducción: La diabetes mellitus ecaracterizada por un control inadecuado de los niveles de glucosa en sangre, principalmente un estado crónico de hiperglucemia, causado por diferentes procesos patogénicos, derivando en complicaciones del sistema nervioso incluyendo axonopatías, enfermedades neurodegenerativas, enfermedades neurovasculares y deterioro cognitivo general.Objetivo: Evaluar las complicaciones clínicas de la diabetes tipo 2 en mujeres.Metodología: Se trata de un estudio transversal de prevalencia.Se utilizaron dos grupos de mujeres, donde todas fueron diagnosticadas con diabetes tipo 2 y con edades entre 40 y 60 años, con tratamiento oral -G1 y tratamiento con insulinoterapia -G2, ambos prestados por la red pública.Para comparar las variables estudiadas se utilizó el método de Mann-Whitney, adoptando un nivel de significancia inferior al 5% (p, valor 0,05).Resultados:La proporción de personas con diabetes en Piauí, con consulta y hemoglobina glucosilada solicitada en los primeros cuatro meses de 2021, 2022, 2023, fuede 18, 16 y 34 porcentajes, respectivamente y en Boa Hora en los mismos cuatro meses fue de 36 , 39, 56 porcentajes, respectivamente.Los procedimientos hospitalarios del SUS -por lugar de residencia -en Piauí fueron en total 1.193 y en Boa Hora 24. El grupo de mujeres estudiado presentó diferencia significativa en la glucemia en ayunas y en la hemoglobina glucosilada al comparar los grupos G1 y G2.Casi el 100% de la muestra era obesa (IMC > 25), no fumaba y no practicaba actividad física.Conclusiones:Se concluyó que la enfermedad de los pacientes empeoró con el paso de los años con el aumento de la medicación.La ausencia de buenas prácticas de promoción de la salud, actividad física y nutrición puede haber contribuido al empeoramiento.Además, es urgente intervenir para cambiar los hábitos de la población para promover la salud (AU).

Asunto(s)

Humanos , Femenino , Adulto , Persona de Mediana Edad , Enfermedades Neurodegenerativas/patología , Diabetes Mellitus Tipo 2/patología , Neuropatías Diabéticas/patología , Hiperglucemia , Hiperglucemia/inducido químicamente , Estudios Transversales/métodos , Estadísticas no Paramétricas , Diabetes Mellitus/patología