RESUMEN
Diabetes, a complex multisystem metabolic disorder characterized by hyperglycemia, leads to complications that reduce quality of life and increase mortality. Diabetes pathophysiology includes dysfunction of beta cells, adipose tissue, skeletal muscle, and liver. Type 1 diabetes (T1D) results from immune-mediated beta cell destruction. The more prevalent type 2 diabetes (T2D) is a heterogeneous disorder characterized by varying degrees of beta cell dysfunction in concert with insulin resistance. The strong association between obesity and T2D involves pathways regulated by the central nervous system governing food intake and energy expenditure, integrating inputs from peripheral organs and the environment. The risk of developing diabetes or its complications represents interactions between genetic susceptibility and environmental factors, including the availability of nutritious food and other social determinants of health. This perspective reviews recent advances in understanding the pathophysiology and treatment of diabetes and its complications, which could alter the course of this prevalent disorder.
Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Obesidad/complicaciones , Obesidad/epidemiología , Animales , Resistencia a la Insulina , Epidemias , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/metabolismoRESUMEN
Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.
Asunto(s)
Consanguinidad , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Homocigoto , Fenotipo , Polimorfismo de Nucleótido Simple , Bancos de Muestras Biológicas , Genoma Humano , Predisposición Genética a la Enfermedad , Reino UnidoRESUMEN
The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.
Asunto(s)
COVID-19/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/terapia , Obesidad/epidemiología , Obesidad/terapia , Pandemias , Medicina de Precisión/métodos , SARS-CoV-2 , COVID-19/virología , Ritmo Circadiano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigénesis Genética , Predisposición Genética a la Enfermedad , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Obesidad/genética , Obesidad/metabolismo , Prevalencia , Factores de Riesgo , TermotoleranciaRESUMEN
The 2021 Gairdner Prize is awarded to Daniel Drucker, Joel Habener, and Jens Juul Holst for the discovery of novel peptides encoded in the proglucagon sequence and the establishment of their physiological roles. These discoveries underpinned the development of therapeutics that are now benefiting patients with type 2 diabetes and other disorders worldwide.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/uso terapéutico , Péptido 2 Similar al Glucagón/uso terapéutico , Proglucagón/química , Diabetes Mellitus Tipo 2/metabolismo , Péptido 1 Similar al Glucagón/química , Péptido 1 Similar al Glucagón/metabolismo , Péptido 2 Similar al Glucagón/química , Péptido 2 Similar al Glucagón/metabolismo , Humanos , Islotes Pancreáticos/metabolismo , Proglucagón/metabolismo , Receptores de Glucagón/metabolismo , Síndrome del Intestino Corto/tratamiento farmacológico , Síndrome del Intestino Corto/metabolismoRESUMEN
Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.
Asunto(s)
Enfermedad/genética , Herencia Multifactorial/genética , Población/genética , ARN Largo no Codificante/genética , Transcriptoma , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Perfilación de la Expresión Génica , Variación Genética , Humanos , Enfermedades Inflamatorias del Intestino/genética , Especificidad de Órganos/genética , Sitios de Carácter CuantitativoRESUMEN
The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient-mTORC1 signalling in multiple diseases.
Asunto(s)
Diabetes Mellitus Tipo 2 , Complejos Multiproteicos , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Complejos Multiproteicos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , NutrientesRESUMEN
The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of ß-arrestin recruitment to MC4R, rather than canonical Gαs-mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. While most MC4R variants caused loss of function, a subset caused gain of function; these variants were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. Protective associations were driven by MC4R variants exhibiting signaling bias toward ß-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing ß-arrestin-biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases.
Asunto(s)
Mutación con Ganancia de Función/genética , Obesidad/patología , Receptor de Melanocortina Tipo 4/genética , Transducción de Señal , Adulto , Anciano , Índice de Masa Corporal , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , AMP Cíclico/metabolismo , Bases de Datos Factuales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/metabolismo , Polimorfismo de Nucleótido Simple , Receptor de Melanocortina Tipo 4/química , Receptor de Melanocortina Tipo 4/metabolismo , beta-Arrestinas/metabolismoRESUMEN
Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Interacciones Microbiota-Huesped/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Agmatina/metabolismo , Animales , Caenorhabditis elegans/microbiología , Proteína Receptora de AMP Cíclico , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Humanos , Hipoglucemiantes/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Longevidad/efectos de los fármacos , Metformina/farmacología , Nutrientes/metabolismoRESUMEN
Metabolic inflammation is closely linked to obesity, and is implicated in the pathogenesis of metabolic diseases. FTO harbors the strongest genetic association with polygenic obesity, and IRX3 mediates the effects of FTO on body weight. However, in what cells and how IRX3 carries out this control are poorly understood. Here we report that macrophage IRX3 promotes metabolic inflammation to accelerate the development of obesity and type 2 diabetes. Mice with myeloid-specific deletion of Irx3 were protected against diet-induced obesity and metabolic diseases via increasing adaptive thermogenesis. Mechanistically, macrophage IRX3 promoted proinflammatory cytokine transcription and thus repressed adipocyte adrenergic signaling, thereby inhibiting lipolysis and thermogenesis. JNK1/2 phosphorylated IRX3, leading to its dimerization and nuclear translocation for transcription. Further, lipopolysaccharide stimulation stabilized IRX3 by inhibiting its ubiquitination, which amplified the transcriptional capacity of IRX3. Together, our findings identify a new player, macrophage IRX3, in the control of body weight and metabolic inflammation, implicating IRX3 as a therapeutic target.
Asunto(s)
Proteínas de Homeodominio/metabolismo , Inflamación/metabolismo , Macrófagos/metabolismo , Obesidad/metabolismo , Factores de Transcripción/metabolismo , Adipocitos/metabolismo , Adulto , Animales , Peso Corporal/fisiología , Línea Celular , Diabetes Mellitus Tipo 2/metabolismo , Dieta/métodos , Células HEK293 , Humanos , Masculino , Enfermedades Metabólicas/metabolismo , Ratones , Células RAW 264.7 , Células THP-1 , Termogénesis/fisiología , Transcripción Genética/fisiología , Adulto JovenRESUMEN
Metabolic homeostasis in mammals is tightly regulated by the complementary actions of insulin and glucagon. The secretion of these hormones from pancreatic ß-cells and α-cells, respectively, is controlled by metabolic, endocrine, and paracrine regulatory mechanisms and is essential for the control of blood levels of glucose. The deregulation of these mechanisms leads to various pathologies, most notably type 2 diabetes, which is driven by the combined lesions of impaired insulin action and a loss of the normal insulin secretion response to glucose. Glucose stimulates insulin secretion from ß-cells in a bi-modal fashion, and new insights about the underlying mechanisms, particularly relating to the second or amplifying phase of this secretory response, have been recently gained. Other recent work highlights the importance of α-cell-produced proglucagon-derived peptides, incretin hormones from the gastrointestinal tract and other dietary components, including certain amino acids and fatty acids, in priming and potentiation of the ß-cell glucose response. These advances provide a new perspective for the understanding of the ß-cell failure that triggers type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Glucosa/metabolismo , Homeostasis , Secreción de Insulina , Células Secretoras de Insulina/fisiología , Animales , Humanos , Células Secretoras de Insulina/citologíaRESUMEN
Insulin resistance, defined as a defect in insulin-mediated control of glucose metabolism in tissues - prominently in muscle, fat and liver - is one of the earliest manifestations of a constellation of human diseases that includes type 2 diabetes and cardiovascular disease. These diseases are typically associated with intertwined metabolic abnormalities, including obesity, hyperinsulinaemia, hyperglycaemia and hyperlipidaemia. Insulin resistance is caused by a combination of genetic and environmental factors. Recent genetic and biochemical studies suggest a key role for adipose tissue in the development of insulin resistance, potentially by releasing lipids and other circulating factors that promote insulin resistance in other organs. These extracellular factors perturb the intracellular concentration of a range of intermediates, including ceramide and other lipids, leading to defects in responsiveness of cells to insulin. Such intermediates may cause insulin resistance by inhibiting one or more of the proximal components in the signalling cascade downstream of insulin (insulin receptor, insulin receptor substrate (IRS) proteins or AKT). However, there is now evidence to support the view that insulin resistance is a heterogeneous disorder that may variably arise in a range of metabolic tissues and that the mechanism for this effect likely involves a unified insulin resistance pathway that affects a distal step in the insulin action pathway that is more closely linked to the terminal biological response. Identifying these targets is of major importance, as it will reveal potential new targets for treatments of diseases associated with insulin resistance.
Asunto(s)
Antígenos CD/genética , Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina/genética , Insulina/genética , Receptor de Insulina/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Glucosa/genética , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Hígado/metabolismo , Hígado/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/genéticaRESUMEN
We report here a simple and global strategy to map out gene functions and target pathways of drugs, toxins, or other small molecules based on "homomer dynamics" protein-fragment complementation assays (hdPCA). hdPCA measures changes in self-association (homomerization) of over 3,500 yeast proteins in yeast grown under different conditions. hdPCA complements genetic interaction measurements while eliminating the confounding effects of gene ablation. We demonstrate that hdPCA accurately predicts the effects of two longevity and health span-affecting drugs, the immunosuppressant rapamycin and the type 2 diabetes drug metformin, on cellular pathways. We also discovered an unsuspected global cellular response to metformin that resembles iron deficiency and includes a change in protein-bound iron levels. This discovery opens a new avenue to investigate molecular mechanisms for the prevention or treatment of diabetes, cancers, and other chronic diseases of aging.
Asunto(s)
Hierro/metabolismo , Metaloproteínas/metabolismo , Metformina/farmacología , Saccharomyces cerevisiae/metabolismo , Sirolimus/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Prueba de Complementación Genética , Humanos , Metaloproteínas/genética , Saccharomyces cerevisiae/genéticaRESUMEN
Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Microbioma Gastrointestinal , Imidazoles/metabolismo , Insulina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Transducción de Señal , Animales , Células Cultivadas , Diabetes Mellitus Tipo 2/microbiología , Células HEK293 , Histidina/metabolismo , Humanos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Sequestosoma-1/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to ß cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to degrade peptides stuck within the translocon between the cytoplasm and the endoplasmic reticulum, was the strongest suppressor of IAPP toxicity. By testing variants of the human homolog, ZMPSTE24, with varying activity levels, the rescue of IAPP toxicity proved to be directly proportional to the declogging efficiency. Clinically relevant ZMPSTE24 variants identified in the largest database of exomes sequences derived from T2D patients were characterized using the yeast model, revealing 14 partial loss-of-function variants, which were enriched among diabetes patients over 2-fold. Thus, clogging of the translocon by IAPP oligomers may contribute to ß cell failure.
Asunto(s)
Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Proteínas de la Membrana/metabolismo , Metaloendopeptidasas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/química , Polipéptido Amiloide de los Islotes Pancreáticos/toxicidad , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Metaloendopeptidasas/química , Metaloendopeptidasas/genética , Modelos Biológicos , Mutagénesis , Agregado de Proteínas/fisiología , Estructura Terciaria de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.
Asunto(s)
Enfermedad de Alzheimer/historia , Amiloide/química , Amiloidosis/historia , Diabetes Mellitus Tipo 2/historia , Enfermedad de Parkinson/historia , Deficiencias en la Proteostasis/historia , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/genética , Amiloide/metabolismo , Amiloidosis/tratamiento farmacológico , Amiloidosis/metabolismo , Amiloidosis/patología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Drogas en Investigación , Regulación de la Expresión Génica , Historia del Siglo XXI , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Terapia Molecular Dirigida , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Agregación Patológica de Proteínas/historia , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Agregación Patológica de Proteínas/prevención & control , Conformación Proteica , Pliegue de Proteína , Deficiencias en la Proteostasis/tratamiento farmacológico , Deficiencias en la Proteostasis/metabolismo , Deficiencias en la Proteostasis/patología , Deficiencias en la Proteostasis/prevención & controlRESUMEN
Genetic studies can identify novel therapeutic targets for common complex diseases. In this issue of Cell, Rusu et al. demonstrate that a cluster of genetic variants associated with an increased risk of type 2 diabetes affect the function of a monocarboxylate transporter involved in nutrient flux and hepatic lipid metabolism.
Asunto(s)
Diabetes Mellitus Tipo 2 , Hígado , Humanos , Metabolismo de los Lípidos , LípidosRESUMEN
Innate lymphoid cells (ILCs) are tuned to quickly respond to and amplify tissue-specific signals. Work of three independent groups in Nature uncovers a novel mode of inflammatory communication between ILC2s and neurons at mucosal surfaces.
Asunto(s)
Diabetes Mellitus Tipo 2 , Linfocitos , Humanos , Inmunidad Innata , Neuronas , NeuropéptidosRESUMEN
Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains â¼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Basigina/metabolismo , Membrana Celular/metabolismo , Cromosomas Humanos Par 17/metabolismo , Técnicas de Silenciamiento del Gen , Haplotipos , Hepatocitos/metabolismo , Heterocigoto , Código de Histonas , Humanos , Hígado/metabolismo , Modelos Moleculares , Transportadores de Ácidos Monocarboxílicos/químicaRESUMEN
Stem-cell-based therapies can potentially reverse organ dysfunction and diseases, but the removal of impaired tissue and activation of a program leading to organ regeneration pose major challenges. In mice, a 4-day fasting mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing ß cells, resembling that observed during pancreatic development. FMD cycles restore insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production. The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition. These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models. PAPERCLIP.
Asunto(s)
Diabetes Mellitus Tipo 1/dietoterapia , Diabetes Mellitus Tipo 2/dietoterapia , Ayuno , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Dieta , Prueba de Tolerancia a la Glucosa , Humanos , Técnicas In Vitro , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos , Ratones , Proteínas del Tejido Nervioso/genética , Páncreas/citología , Páncreas/metabolismo , Transducción de Señal , TranscriptomaRESUMEN
Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.