RESUMO
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.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 1/complicações , Obesidade/complicações , Obesidade/epidemiologia , Animais , Resistência à Insulina , Epidemias , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/metabolismoRESUMO
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.
Assuntos
Consanguinidade , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Homozigoto , Fenótipo , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Genoma Humano , Predisposição Genética para Doença , Reino UnidoRESUMO
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.
Assuntos
COVID-19/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Obesidade/epidemiologia , Obesidade/terapia , Pandemias , Medicina de Precisão/métodos , SARS-CoV-2 , COVID-19/virologia , Ritmo Circadiano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética , Predisposição Genética para Doença , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Obesidade/genética , Obesidade/metabolismo , Prevalência , Fatores de Risco , TermotolerânciaRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Peptídeo 2 Semelhante ao Glucagon/uso terapêutico , Proglucagon/química , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/química , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 2 Semelhante ao Glucagon/química , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Humanos , Ilhotas Pancreáticas/metabolismo , Proglucagon/metabolismo , Receptores de Glucagon/metabolismo , Síndrome do Intestino Curto/tratamento farmacológico , Síndrome do Intestino Curto/metabolismoRESUMO
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.
Assuntos
Doença/genética , Herança Multifatorial/genética , População/genética , RNA Longo não Codificante/genética , Transcriptoma , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Perfilação da Expressão Gênica , Variação Genética , Humanos , Doenças Inflamatórias Intestinais/genética , Especificidade de Órgãos/genética , Locos de Características QuantitativasRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Complexos Multiproteicos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , NutrientesRESUMO
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.
Assuntos
Mutação com Ganho de Função/genética , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Transdução de Sinais , Adulto , Idoso , Índice de Massa Corporal , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , AMP Cíclico/metabolismo , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único , Receptor Tipo 4 de Melanocortina/química , Receptor Tipo 4 de Melanocortina/metabolismo , beta-Arrestinas/metabolismoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Agmatina/metabolismo , Animais , Caenorhabditis elegans/microbiologia , Proteína Receptora de AMP Cíclico , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Humanos , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Metformina/farmacologia , Nutrientes/metabolismoRESUMO
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.
Assuntos
Proteínas de Homeodomínio/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Adipócitos/metabolismo , Adulto , Animais , Peso Corporal/fisiologia , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Dieta/métodos , Células HEK293 , Humanos , Masculino , Doenças Metabólicas/metabolismo , Camundongos , Células RAW 264.7 , Células THP-1 , Termogênese/fisiologia , Transcrição Gênica/fisiologia , Adulto JovemRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Glucose/metabolismo , Homeostase , Secreção de Insulina , Células Secretoras de Insulina/fisiologia , Animais , Humanos , Células Secretoras de Insulina/citologiaRESUMO
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.
Assuntos
Antígenos CD/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Insulina/genética , Receptor de Insulina/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Glucose/genética , Glucose/metabolismo , Humanos , Insulina/metabolismo , Fígado/metabolismo , Fígado/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genéticaRESUMO
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.
Assuntos
Ferro/metabolismo , Metaloproteínas/metabolismo , Metformina/farmacologia , Saccharomyces cerevisiae/metabolismo , Sirolimo/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Teste de Complementação Genética , Humanos , Metaloproteínas/genética , Saccharomyces cerevisiae/genéticaRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Microbioma Gastrointestinal , Imidazóis/metabolismo , Insulina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/microbiologia , Células HEK293 , Histidina/metabolismo , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Sequestossoma-1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
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.
Assuntos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Proteínas de Membrana/metabolismo , Metaloendopeptidases/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/toxicidade , Proteínas de Membrana/química , Proteínas de Membrana/genética , Metaloendopeptidases/química , Metaloendopeptidases/genética , Modelos Biológicos , Mutagênese , Agregados Proteicos/fisiologia , Estrutura Terciária de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
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.
Assuntos
Doença de Alzheimer/história , Amiloide/química , Amiloidose/história , Diabetes Mellitus Tipo 2/história , Doença de Parkinson/história , Deficiências na Proteostase/história , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/genética , Amiloide/metabolismo , Amiloidose/tratamento farmacológico , Amiloidose/metabolismo , Amiloidose/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Drogas em Investigação , Regulação da Expressão Gênica , História do Século XXI , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Terapia de Alvo Molecular , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/história , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Agregação Patológica de Proteínas/prevenção & controle , Conformação Proteica , Dobramento de Proteína , Deficiências na Proteostase/tratamento farmacológico , Deficiências na Proteostase/metabolismo , Deficiências na Proteostase/patologia , Deficiências na Proteostase/prevenção & controleRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Fígado , Humanos , Metabolismo dos Lipídeos , LipídeosRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Linfócitos , Humanos , Imunidade Inata , Neurônios , NeuropeptídeosRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Basigina/metabolismo , Membrana Celular/metabolismo , Cromossomos Humanos Par 17/metabolismo , Técnicas de Silenciamento de Genes , Haplótipos , Hepatócitos/metabolismo , Heterozigoto , Código das Histonas , Humanos , Fígado/metabolismo , Modelos Moleculares , Transportadores de Ácidos Monocarboxílicos/químicaRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 1/dietoterapia , Diabetes Mellitus Tipo 2/dietoterapia , Jejum , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Dieta , Teste de Tolerância a Glucose , Humanos , Técnicas In Vitro , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas , Camundongos , Proteínas do Tecido Nervoso/genética , Pâncreas/citologia , Pâncreas/metabolismo , Transdução de Sinais , TranscriptomaRESUMO
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.