RESUMEN
Type 2 diabetes (T2D) is associated with insulin resistance and progressive dysfunction of ß-pancreatic cells, leading to persistent hyperglycemia. Macrophages play a crucial role in this context, influencing both the development and progression of insulin resistance. These innate immune cells respond to inflammatory stimuli and reprogram their metabolism, directly impacting the pathophysiology of T2D. Macrophages are highly plastic and can adopt either pro-inflammatory or pro-resolutive phenotypic profiles. In T2D, pro-inflammatory macrophages, which rely on glycolysis, exacerbate insulin resistance through increased production of pro-inflammatory cytokines and nitric oxide. In contrast, pro-resolutive macrophages, which prioritize fatty acid metabolism, have different effects on glucose homeostasis. Metaflammation, a chronic low-grade inflammation, is induced by pro-inflammatory macrophages and significantly contributes to the progression of T2D, creating an environment conducive to metabolic dysfunction. This review aims to clarify the contribution of macrophages to the progression of T2D by detailing how their inflammatory responses and metabolic reprogramming influence insulin resistance and the disease's pathophysiology. The review seeks to deepen the understanding of the biochemical and metabolic mechanisms involved, offering broader insights into the impact on the quality of life for millions of patients worldwide.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Macrófagos , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Inflamación/metabolismo , Animales , Reprogramación Celular , Reprogramación MetabólicaRESUMEN
Obesity causes insulin resistance (IR) through systemic low-grade inflammation and can lead to type 2 diabetes mellitus (T2DM). However, the mechanisms that cause IR and T2DM in non-obese individuals are unclear. The Goto-Kakizaki (GK) rat develops IR spontaneously and is a model of non-obese T2DM. These rats exhibit hyperglycemia beginning at weaning and exhibit lower body mass than control Wistar rats. Herein, we tested the hypothesis that macrophages of GK rats are permanently in a pro-inflammatory state, which may be associated with a systemic inflammation condition that mimics the pathogenesis of obesity-induced T2DM. Using eighteen-week-old GK and control Wistar rats, we investigated the proportions of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages isolated from the peritoneal cavity. Additionally, the production of inflammatory cytokines and reactive oxygen species (ROS) in cultured macrophages under basal and stimulated conditions was assessed. It was found that phorbol myristate acetate (PMA) stimulation increased GK rat macrophage ROS production 90-fold compared to basal levels. This response was also three times more pronounced than in control cells (36-fold). The production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), tended to be upregulated in cultured macrophages from GK rats under basal conditions. Macrophages from GK rats produced 1.6 times more granulocyte-macrophage colony-stimulating factor (GM-CSF), 1.5 times more monocyte chemoattractant protein-1 (MCP-1) and 3.3 times more TNF-α than control cells when stimulated with lipopolysaccharide (LPS) (p = 0.0033; p = 0.049; p = 0.002, respectively). Moreover, compared to control cells, GK rats had 60% more M1 (p = 0.0008) and 23% less M2 (p = 0.038) macrophages. This study is the first to report macrophage inflammatory reprogramming towards a pro-inflammatory state in GK rats.
Asunto(s)
Diabetes Mellitus Tipo 2 , Inflamación , Macrófagos , Ratas Wistar , Especies Reactivas de Oxígeno , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/inmunología , Ratas , Macrófagos/metabolismo , Macrófagos/inmunología , Especies Reactivas de Oxígeno/metabolismo , Inflamación/patología , Inflamación/metabolismo , Masculino , Citocinas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Modelos Animales de Enfermedad , Resistencia a la InsulinaRESUMEN
BACKGRUOUND: This study investigated the prognostic importance of the hemoglobin glycation index (HGI) for macrovascular and microvascular outcomes, mortality, and hypoglycemia occurrence in a type 2 diabetes cohort and compared it to glycated hemoglobin (HbA1c). METHODS: Baseline and mean first-year HGI and HbA1c, and the variability thereof, were assessed in 687 individuals with type 2 diabetes (median follow-up, 10.6 years). Multivariable Cox regression was conducted to evaluate the associations of HGI and HbA1c parameters with macrovascular (total and major cardiovascular events) and microvascular outcomes (microalbuminuria, advanced renal failure, retinopathy, and peripheral neuropathy), mortality (all-cause and cardiovascular), and moderate/severe hypoglycemia occurrence. RESULTS: During follow-up, there were 215 total cardiovascular events (176 major) and 269 all-cause deaths (131 cardiovascular). Microalbuminuria developed in 126 patients, renal failure in 104, retinopathy in 161, and neuropathy in 177. There were 90 hypoglycemia episodes. Both HGI and HbA1c predicted all adverse outcomes, except microalbuminuria and hypoglycemia. Their adjusted risks were roughly equivalent for all outcomes. For example, the adjusted hazard ratios (HRs) with 95% confidence intervals (CIs), estimated for 1 standard deviation increments, of mean first-year HGI were 1.23 (1.05 to 1.44), 1.20 (1.03 to 1.38), 1.36 (1.11 to 1.67), 1.28 (1.09 to 1.67), and 1.29 (1.09 to 1.54), respectively, for cardiovascular events, all-cause mortality, renal failure, retinopathy, and neuropathy; whereas the respective HRs (95% CIs) of mean HbA1c were 1.31 (1.12 to 1.53), 1.28 (1.11 to 1.48), 1.36 (1.11 to 1.67), 1.33 (1.14 to 1.55), and 1.29 (1.09 to 1.53). CONCLUSION: HGI was no better than HbA1c as a predictor of adverse outcomes in individuals with type 2 diabetes, and its clinical use cannot be currently advised.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hemoglobina Glucada , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Femenino , Hemoglobina Glucada/análisis , Persona de Mediana Edad , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/etiología , Anciano , Pronóstico , Angiopatías Diabéticas/mortalidad , Angiopatías Diabéticas/etiología , Factores de Riesgo , Estudios de Seguimiento , Hipoglucemia/mortalidadRESUMEN
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 , AnimalesRESUMEN
Goto-Kakizaki (GK) rats develop a well-defined insulin resistance (IR) and type 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyte profile in nonobese diabetic conditions is not yet characterized. Therefore, GK rats were chosen to explore T lymphocyte (TL) dynamics at various stages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at 21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucose transporter 1 (GLUT1) expression was consistently elevated in GK rats, suggesting heightened TL activation. T-regulatory lymphocyte markers diminished at 21 days. However, GK rats showed increased Th1 markers and reduced Gata-3 expression (crucial for Th2 cell differentiation) at 120 days. These findings underscore an early breakdown of anti-inflammatory mechanisms in GK rats, indicating a proinflammatory TL profile that may worsen chronic inflammation in T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Ratas Wistar , Animales , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Ratas , Masculino , Inflamación/metabolismo , Inflamación/patología , Inflamación/inmunología , Factor de Transcripción GATA3/metabolismo , Factor de Transcripción GATA3/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 1/genética , Células TH1/inmunología , Células TH1/metabolismoRESUMEN
Exercise increases peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) expression, which in turn causes the fibronectin type III domain containing 5 (FNDC5) protein to be produced. This protein is then cleaved, primarily in skeletal muscle fibers, to produce irisin. When the mature FNDC5 is cleaved by proteases, Irisin - which is the fibronectin III domain without the signal sequence - is released. Resistance, aerobic, and high-intensity interval training (HIIT) are recognized as forms of physical exercise that raise irisin levels, and insulin receptor phosphorylation in tyrosine residues, favoring an increase in the activity of the insulin-dependent pathway (PI3K pathway) and assisting in the fight against insulin resistance, inflammation, and cognitive decline. Irisin may represent a promising option for the therapeutic targeting in several brain-related pathological conditions, like Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, type 2 diabetes, and obesity. Exercise protocols are healthy and inexpensive interventions that can help find cellular and molecular changes in several brain-related pathological conditions. Here, it was reviewed what is known about exercise-produced irisin studies involving AD, PD, epilepsy, type 2 diabetes, and obesity.
Asunto(s)
Ejercicio Físico , Fibronectinas , Humanos , Fibronectinas/metabolismo , Ejercicio Físico/fisiología , Animales , Enfermedad de Alzheimer/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/terapia , Obesidad/metabolismo , Epilepsia/metabolismo , Encéfalo/metabolismoRESUMEN
Type 2 diabetes mellitus is a metabolic disorder that causes chronic high blood sugar levels, and diabetic patients are more susceptible to infections. American cutaneous leishmaniasis is an infectious disease caused by a parasite that affects the skin and mucous membranes, leading to one or multiple ulcerative lesions. Chronic inflammation and functional changes in various organs and systems, including the immune system, are the primary causes of both diseases. Melatonin, an essential immunomodulatory, antioxidant, and neuroprotective agent, can benefit many immunological processes and infectious diseases, including leishmaniasis. Although, limited reports are available on diabetic patients with leishmaniasis. The literature suggests that melatonin may play a promising role in inflammatory disorders. This study was designed to assess melatonin levels and inflammatory mediators in diabetic patients affected by leishmaniasis. Blood samples from 25 individuals were analyzed and divided into four groups: a control group (without any diseases), a Leishmania-positive group, patients with type 2 diabetes mellitus, and patients with a combination of both diseases. This study measured the serum levels of melatonin through ELISA, while IL-4 and TNF-α were measured using flow cytometry, and C-reactive protein was measured through turbidimetry. This study found that patients with leishmaniasis significantly increased TNF-α and decreased melatonin levels. However, the group of diabetic patients with leishmaniasis showed higher melatonin levels than the control group. These observations suggest that TNF-α may influence melatonin production in patients with American cutaneous leishmaniasis, potentially contributing to the inflammatory characteristics of both diseases.
Asunto(s)
Diabetes Mellitus Tipo 2 , Hiperglucemia , Inflamación , Melatonina , Factor de Necrosis Tumoral alfa , Melatonina/sangre , Melatonina/metabolismo , Humanos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/inmunología , Masculino , Femenino , Persona de Mediana Edad , Hiperglucemia/metabolismo , Hiperglucemia/sangre , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismo , Inflamación/metabolismo , Inflamación/sangre , Adulto , Interleucina-4/sangre , Leishmaniasis Cutánea/sangre , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/metabolismo , Proteína C-Reactiva/metabolismo , Leishmaniasis/sangre , Leishmaniasis/inmunología , Leishmaniasis/metabolismo , Leishmaniasis/parasitología , AncianoRESUMEN
The accumulation of advanced glycation end-products (AGEs) elicits morphofunctional kidney impairment. AGEs levels can be noninvasively estimated by skin autofluorescence (SAF). We explored whether high SAF predicts kidney outcomes in type 2 diabetes (T2D) individuals. The study was conducted as a predefined analysis of the Brazilian Diabetes Study, a prospective single-center cohort of T2D adults. Data from 155 individuals followed for up to 1716 days were considered. The incidence of major adverse kidney events (MAKE) was 9.6%. Individuals with above-median SAF had a higher incidence of MAKEs (4.6% vs. 21%; p = 0.002), with an HR of 3.39 [95% CI: 1.06-10.85; p = 0.040] after adjustment by age and gender. The mean adjusted eGFR change was 1.08 units (SE: 1.15; 95%CI: -1.20, 3.37) in the low SAF and -5.19 units [SE: 1.93; 95%CI: -9.10, -1.29] in the high SAF groups (between-subject difference: F: 5.62, p = 0.019). The high-SAF group had a greater prevalence of rapid decliners than the low-SAF group (36.7% vs. 15.8%; p = 0.028). In conclusion, high SAF was related to increased incidence of MAKEs and faster decline in eGFR among T2D subjects. This should be considered by healthcare providers when identifying individuals more prone to diabetes-related kidney complications.
Asunto(s)
Diabetes Mellitus Tipo 2 , Productos Finales de Glicación Avanzada , Piel , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Femenino , Productos Finales de Glicación Avanzada/metabolismo , Productos Finales de Glicación Avanzada/análisis , Brasil/epidemiología , Persona de Mediana Edad , Estudios Prospectivos , Piel/metabolismo , Piel/química , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/etiología , Anciano , PronósticoRESUMEN
Renal iron overload is a common complication of diabetes that leads to oxidative stress and mitochondrial dysfunction in the kidneys. This study investigated the effects of iron chelation using deferiprone on mitochondrial dysfunction and oxidative stress in the renal cortex of a murine model of type 2 diabetes. Diabetic rats were treated with deferiprone (50 mg/kg BW) for 16 weeks. Our results show that iron chelation with deferiprone significantly increased the nuclear accumulation of Nrf2, a transcription factor that regulates the expression of antioxidant enzymes. This led to enhanced antioxidant capacity, reduced production of reactive oxygen species, and improved mitochondrial bioenergetic function in diabetic rats. However, chronic iron chelation led to altered mitochondrial respiration and increased oxidative stress in non-diabetic rats. In conclusion, our findings suggest that iron chelation with deferiprone protects mitochondrial bioenergetics and mitigates oxidative stress in the renal cortex, involving the NRF2 pathway in type 2 diabetes.
Asunto(s)
Deferiprona , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Corteza Renal , Factor 2 Relacionado con NF-E2 , Animales , Masculino , Ratones , Ratas , Antioxidantes/farmacología , Antioxidantes/metabolismo , Deferiprona/farmacología , Deferiprona/uso terapéutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Quelantes del Hierro/farmacología , Corteza Renal/metabolismo , Corteza Renal/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Alzheimer's disease (AD) constitutes a major public-health issue of our time. Regrettably, despite our considerable understanding of the pathophysiological aspects of this disease, current interventions lead to poor outcomes. Furthermore, experimentally promising compounds have continuously failed when translated to clinical trials. Along with increased population ageing, Type 2 Diabetes Mellitus (T2DM) has become an extremely common condition, mainly due to unbalanced dietary habits. Substantial epidemiological evidence correlates T2DM with cognitive impairment as well. Considering that brain insulin resistance, mitochondrial dysfunction, oxidative stress, and amyloidogenesis are common phenomena, further approaching the common features among these pathological conditions. Metformin constitutes the first-choice drug to preclude insulin resistance in T2DM clinical management. Experimental evidence suggests that its functions might include neuroprotective effects, in addition to its hypoglycemic activity. This review aims to summarize and discuss current knowledge of experimental data on metformin on this path towards translational medicine. Finally, we discuss the controversial data of responses to metformin in vitro, and in vivo, animal models and human studies.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Metformina/uso terapéutico , Metformina/farmacología , Humanos , Animales , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Investigación Biomédica Traslacional/métodos , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Resistencia a la Insulina/fisiologíaRESUMEN
BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.
Asunto(s)
Cirugía Bariátrica , Obesidad , Inhibidor 1 de Activador Plasminogénico , Proproteína Convertasa 9 , Humanos , Inhibidor 1 de Activador Plasminogénico/sangre , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proproteína Convertasa 9/sangre , Proproteína Convertasa 9/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Obesidad/cirugía , Obesidad/metabolismo , Obesidad/sangre , Estudios Longitudinales , Resistencia a la Insulina , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1ß and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.
Asunto(s)
Ansiedad , Eje Cerebro-Intestino , Disfunción Cognitiva , Depresión , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Péptidos Similares al Glucagón , Ratones Endogámicos C57BL , Animales , Péptidos Similares al Glucagón/farmacología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/psicología , Diabetes Mellitus Tipo 2/metabolismo , Ratones , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Depresión/tratamiento farmacológico , Depresión/psicología , Depresión/metabolismo , Masculino , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Ansiedad/etiología , Microbioma Gastrointestinal/efectos de los fármacos , Eje Cerebro-Intestino/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/psicología , Diabetes Mellitus Experimental/metabolismo , Modelos Animales de Enfermedad , Antidepresivos/farmacología , Antidepresivos/uso terapéuticoRESUMEN
Fibroblast growth factor 19 (FGF19) is a hormone synthesized in enterocytes in response to bile acids. This review explores the pivotal role of FGF19 in metabolism, addressing the urgent global health concern of obesity and its associated pathologies, notably type 2 diabetes. The intriguing inverse correlation between FGF19 and body mass or visceral adiposity, as well as its rapid increase following bariatric surgery, emphasizes its potential as a therapeutic target. This article meticulously examines the impact of FGF19 on metabolism by gathering evidence primarily derived from studies conducted in animal models or cell lines, using both FGF19 treatment and genetic modifications. Overall, these studies demonstrate that FGF19 has antidiabetic and antiobesogenic effects. A thorough examination across metabolic tissues, including the liver, adipose tissue, skeletal muscle, and the central nervous system, is conducted, unraveling the intricate interplay of FGF19 across diverse organs. Moreover, we provide a comprehensive overview of clinical trials involving an FGF19 analog called aldafermin, emphasizing promising results in diseases such as nonalcoholic steatohepatitis and diabetes. Therefore, we aim to foster a deeper understanding of FGF19 role and encourage further exploration of its clinical applications, thereby advancing the field and offering innovative approaches to address the escalating global health challenge of obesity and related metabolic conditions.
Asunto(s)
Diabetes Mellitus Tipo 2 , Factores de Crecimiento de Fibroblastos , Obesidad , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Animales , Obesidad/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ensayos Clínicos como Asunto , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéuticoRESUMEN
INTRODUCTION: Type 2 Diabetes (T2D) is associated with fractures, despite preserved Bone Mineral Density (BMD). This study aimed to evaluate the relationship between BMD and trabecular bone score (TBS) with the reallocation of fat within muscle in individuals with eutrophy, obesity, and T2D. METHODS: The subjects were divided into three groups: eutrophic controls paired by age and sex with the T2D group (n = 23), controls diagnosed with obesity paired by age, sex, and body mass index with the T2D group (n = 27), and the T2D group (n = 29). BMD and body fat percentage were determined using dual-energy X-Ray absorptiometry. TBS was determined using TBS iNsight software. Intra and extramyocellular lipids in the soleus were measured using proton magnetic resonance spectroscopy. RESULTS: TBS was lower in the T2D group than in the other two groups. Glycated hemoglobin (A1c) was negatively associated with TBS. Body fat percentage was negatively associated with TBS and Total Hip (TH) BMD. TH BMD was positively associated with intramuscular lipids. A trend of negative association was observed between intramuscular lipids and TBS. CONCLUSION: This study showed for the first time that the reallocation of lipids within muscle has a negative association with TBS. Moreover, these results are consistent with previous studies showing a negative association between a parameter related to insulin resistance (intramuscular lipids) and TBS.
Asunto(s)
Absorciometría de Fotón , Tejido Adiposo , Densidad Ósea , Hueso Esponjoso , Diabetes Mellitus Tipo 2 , Músculo Esquelético , Humanos , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Densidad Ósea/fisiología , Hueso Esponjoso/diagnóstico por imagen , Estudios de Casos y Controles , Tejido Adiposo/diagnóstico por imagen , Adulto , Obesidad/fisiopatología , Obesidad/metabolismo , Hemoglobina Glucada/análisis , Índice de Masa Corporal , Anciano , Control Glucémico , Valores de ReferenciaRESUMEN
INTRODUCTION: Type 2 diabetes mellitus (T2DM) is associated with dysbiosis in the gut microbiota (MB). Individually, each medication appears to partially correct this. However, there are no studies on the response of the MB to changes in A1c. Therefore, we investigated the MB's response to intensive glycemic control. RESEARCH DESIGN AND METHODS: We studied two groups of patients with uncontrolled T2DM, one group with an A1c <9% (18 patients-G1) and another group with an A1c >9% (13 patients-G2), aiming for at least a 1% reduction in A1c. We collected A1c and fecal samples at baseline, 6, and 12 months. G1 achieved an average A1c reduction of 1.1%, while G2 a reduction of 3.13%. RESULTS: G1's microbiota saw a decrease in Erysipelotrichaceae_UCG_003 and in Mollicutes order (both linked to metabolic syndrome and associated comorbidities). G2, despite having a more significant reduction in A1c, experienced an increase in the proinflammatory bacteria Megasphaera and Acidaminococcus, and only one beneficial genus, Phascolarctobacterium, increased, producer of butyrate. CONCLUSION: Despite a notable A1c outcome, G2 could not restore its MB. This seeming resistance to change, leading to a persistent inflammation component found in G2, might be part of the "metabolic memory" in T2DM.
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Diabetes Mellitus Tipo 2 , Disbiosis , Microbioma Gastrointestinal , Hemoglobina Glucada , Humanos , Diabetes Mellitus Tipo 2/microbiología , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Hemoglobina Glucada/análisis , Anciano , Heces/microbiología , Glucemia/análisis , Estudios de Seguimiento , Hipoglucemiantes/uso terapéutico , Control Glucémico/métodos , Biomarcadores/análisis , PronósticoRESUMEN
AIMS/HYPOTHESIS: Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites. METHODS: We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA1c) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors. RESULTS: Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures. CONCLUSIONS/INTERPRETATION: The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.
Asunto(s)
Diabetes Mellitus Tipo 2 , Progresión de la Enfermedad , Resistencia a la Insulina , Metabolómica , Estado Prediabético , Saliva , Humanos , Saliva/metabolismo , Saliva/química , Resistencia a la Insulina/fisiología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Estado Prediabético/metabolismo , Estado Prediabético/sangre , Adulto , Estudios Longitudinales , Anciano , Hispánicos o Latinos , Puerto Rico/epidemiologíaRESUMEN
Genetic factors, diet, lifestyle, and other factors lead to various complications in the body, such as obesity and other chronic diseases. The inflammatory state caused by excessive accumulation of body fat affects the pathways related to the control of glycemic homeostasis, leading to a high demand for insulin, to subsequent failure of stressed ß cells, and development of type 2 diabetes mellitus (T2DM). The study of new endocrine signalers, such as bile acids (BAs), becomes necessary as it allows the development of alternatives for T2DM treatment. In this work, a methodology was developed to quantify tauroursodeoxycholic BA (TUDCA) in liver cells of the HepG2 strain treated in hyperlipidic medium. This BA helps to improve insulin clearance by increasing the expression of the insulin-degrading enzyme, restoring sensitivity to this hormone, and making it viable for treating T2DM. Herein, a targeted metabolomic method for TUDCA determination in extracellular medium of hepatocyte matrices by micellar electrokinetic chromatography-UV was optimized, validated, and applied. The optimized background electrolyte was composed of 40 mmol/L sodium cholate and 30 mmol/L sodium tetraborate at pH 9.0. The following figures of merit were evaluated: linearity, limit of quantification, limit of detection, accuracy, and precision. Data obtained with the validated electrophoretic method showed a self-stimulation of TUDCA production in media supplemented only with BA. On the other hand, TUDCA concentration was reduced in the hyperlipidic medium. This suggests that, in these media, the effect of TUDCA is reduced, such as self-stimulated production and consequent regulation of glycemic homeostasis. Therefore, the results reinforce the need for investigating TUDCA as a potential T2DM biomarker as well as its use to treat several comorbidities, such as obesity and diabetes mellitus.
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Cromatografía Capilar Electrocinética Micelar , Diabetes Mellitus Tipo 2 , Obesidad , Ácido Tauroquenodesoxicólico , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/análisis , Ácido Tauroquenodesoxicólico/metabolismo , Humanos , Obesidad/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Hep G2 , Cromatografía Capilar Electrocinética Micelar/métodos , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Reproducibilidad de los Resultados , Metabolómica/métodos , Modelos Lineales , Límite de DetecciónAsunto(s)
Glucemia , Control Glucémico , Hipoglucemiantes , Humanos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismoRESUMEN
The gut microbiome, a complex assembly of microorganisms, significantly impacts human health by influencing nutrient absorption, the immune system, and disease response. These microorganisms form a dynamic ecosystem that is critical to maintaining overall well-being. Prebiotics and probiotics are pivotal in regulating gut microbiota composition. Prebiotics nourish beneficial bacteria and promote their growth, whereas probiotics help maintain balance within the microbiome. This intricate balance extends to several aspects of health, including maintaining the integrity of the gut barrier, regulating immune responses, and producing metabolites crucial for metabolic health. Dysbiosis, or an imbalance in the gut microbiota, has been linked to metabolic disorders such as type 2 diabetes, obesity, and cardiovascular disease. Impaired gut barrier function, endotoxemia, and low-grade inflammation are associated with toll-like receptors influencing proinflammatory pathways. Short-chain fatty acids derived from microbial fermentation modulate anti-inflammatory and immune system pathways. Prebiotics positively influence gut microbiota, whereas probiotics, especially Lactobacillus and Bifidobacterium strains, may improve metabolic outcomes, such as glycemic control in diabetes. It is important to consider strain-specific effects and study variability when interpreting these findings, highlighting the need for further research to optimize their therapeutic potential. The aim of this report is therefore to review the role of the gut microbiota in metabolic health and disease and the effects of prebiotics and probiotics on the gut microbiome and their therapeutic role, integrating a broad understanding of physiological mechanisms with a clinical perspective.
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Microbioma Gastrointestinal , Prebióticos , Probióticos , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Prebióticos/administración & dosificación , Animales , Disbiosis/microbiología , Enfermedades Metabólicas/microbiología , Diabetes Mellitus Tipo 2/microbiología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/inmunologíaRESUMEN
Tyrosine protein phosphatase non-receptor type 1 (PTP1B; also known as protein tyrosine phosphatase 1B) is a member of the protein tyrosine phosphatase (PTP) family and is a soluble enzyme that plays an essential role in different physiological processes, including the regulation of metabolism, specifically in insulin and leptin sensitivity. PTP1B is crucial in the pathogenesis of type 2 diabetes mellitus and obesity. These biological functions have made PTP1B validated as an antidiabetic and anti-obesity, and potentially anticancer, molecular target. Four main approaches aim to inhibit PTP1B: orthosteric, allosteric, bidentate inhibition, and PTPN1 gene silencing. Developing a potent and selective PTP1B inhibitor is still challenging due to the enzyme's ubiquitous expression, subcellular location, and structural properties. This article reviews the main advances in the study of PTP1B since it was first isolated in 1988, as well as recent contextual information related to the PTP family to which this protein belongs. Furthermore, we offer an overview of the role of PTP1B in diabetes and obesity, and the challenges to developing selective, effective, potent, bioavailable, and cell-permeable compounds that can inhibit the enzyme.