RESUMEN
Viral infection makes us feel sick as the immune system alters systemic metabolism to better fight the pathogen. The extent of these changes is relative to the severity of disease. Whether blood glucose is subject to infection-induced modulation is mostly unknown. Here we show that strong, nonlethal infection restricts systemic glucose availability, which promotes the antiviral type I interferon (IFN-I) response. Following viral infection, we find that IFNγ produced by γδ T cells stimulates pancreatic ß cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens hepatic glucose output. Glucose restriction enhances IFN-I production by curtailing lactate-mediated inhibition of IRF3 and NF-κB signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune-endocrine circuit is disrupted in hyperglycemia, possibly explaining why patients with diabetes are more susceptible to viral infection.
Asunto(s)
Glucemia , Inmunidad Innata , Interferón gamma , Animales , Interferón gamma/metabolismo , Interferón gamma/inmunología , Ratones , Glucemia/metabolismo , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal/inmunología , Insulina/metabolismo , Insulina/inmunología , Ratones Noqueados , Hiperglucemia/inmunología , Factor 3 Regulador del Interferón/metabolismo , FN-kappa B/metabolismo , Humanos , Hígado/inmunología , Hígado/virología , Hígado/metabolismo , MasculinoRESUMEN
The transition from the fed to the fasted state necessitates a shift from carbohydrate to fat metabolism that is thought to be mostly orchestrated by reductions in plasma insulin concentrations. Here, we show in awake rats that insulinopenia per se does not cause this transition but that both hypoleptinemia and insulinopenia are necessary. Furthermore, we show that hypoleptinemia mediates a glucose-fatty acid cycle through activation of the hypothalamic-pituitary-adrenal axis, resulting in increased white adipose tissue (WAT) lipolysis rates and increased hepatic acetyl-coenzyme A (CoA) content, which are essential to maintain gluconeogenesis during starvation. We also show that in prolonged starvation, substrate limitation due to reduced rates of glucose-alanine cycling lowers rates of hepatic mitochondrial anaplerosis, oxidation, and gluconeogenesis. Taken together, these data identify a leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, WAT, and liver to promote a shift from carbohydrate to fat oxidation and maintain glucose homeostasis during starvation.
Asunto(s)
Glucemia/metabolismo , Ácidos Grasos/metabolismo , Gluconeogénesis , Homeostasis , Leptina/metabolismo , Inanición/metabolismo , Tejido Adiposo Blanco/metabolismo , Alanina/metabolismo , Animales , Insulina/sangre , Leptina/sangre , Lipólisis , Hígado/metabolismo , Masculino , Mitocondrias/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gluconeogénesis/efectos de los fármacos , Hipoglucemiantes/administración & dosificación , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/antagonistas & inhibidores , Acetilación , Animales , Glucemia/metabolismo , Células Cultivadas , Glucosa/metabolismo , Factor Nuclear 4 del Hepatocito/metabolismo , Hepatocitos/metabolismo , Ensayos Analíticos de Alto Rendimiento , Resistencia a la Insulina , Ratones , Factores de Transcripción p300-CBP/metabolismoRESUMEN
Control of plasma glucose level is essential to organismal survival. Sustained inflammation has been implicated in control of glucose homeostasis in cases of infection, obesity, and type 2 diabetes; however, the precise role of inflammation in these complex disease states remains poorly understood. Here, we find that sustained inflammation results in elevated plasma glucose due to increased hepatic glucose production. We find that sustained inflammation suppresses CYP7A1, leading to accumulation of intermediate metabolites at the branch point of the mevalonate pathway. This results in prenylation of RHOC, which is concomitantly induced by inflammatory cytokines. Subsequent activation of RHO-associated protein kinase results in elevated plasma glucose. These findings uncover an unexpected mechanism by which sustained inflammation alters glucose homeostasis.
Asunto(s)
Vías Biosintéticas , Hepatitis/metabolismo , Hiperglucemia/metabolismo , Ácido Mevalónico/metabolismo , Animales , Glucemia/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Colesterol 7-alfa-Hidroxilasa/metabolismo , Ayuno/sangre , Lipopolisacáridos , Ratones , Ratones Obesos , Prenilación de Proteína , Transcripción Genética , Triglicéridos/sangre , Proteínas ras/metabolismo , Quinasas Asociadas a rho/metabolismo , Proteína rhoC de Unión a GTPRESUMEN
The cephalic phase insulin response (CPIR) is classically defined as a head receptor-induced early release of insulin during eating that precedes a postabsorptive rise in blood glucose. Here we discuss, first, the various stimuli that elicit the CPIR and the sensory signaling pathways (sensory limb) involved; second, the efferent pathways that control the various endocrine events associated with eating (motor limb); and third, what is known about the central integrative processes linking the sensory and motor limbs. Fourth, in doing so, we identify open questions and problems with respect to the CPIR in general. Specifically, we consider test conditions that allow, or may not allow, the stimulus to reach the potentially relevant taste receptors and to trigger a CPIR. The possible significance of sweetness and palatability as crucial stimulus features and whether conditioning plays a role in the CPIR are also discussed. Moreover, we ponder the utility of the strict classical CPIR definition based on what is known about the effects of vagal motor neuron activation and thereby acetylcholine on the ß-cells, together with the difficulties of the accurate assessment of insulin release. Finally, we weigh the evidence of the physiological and clinical relevance of the cephalic contribution to the release of insulin that occurs during and after a meal. These points are critical for the interpretation of the existing data, and they support a sharper focus on the role of head receptors in the overall insulin response to eating rather than relying solely on the classical CPIR definition.
Asunto(s)
Insulina , Papilas Gustativas , Humanos , Insulina/metabolismo , Gusto/fisiología , Glucemia/metabolismo , Transducción de SeñalRESUMEN
In this paper, we provide an overview of the evolution of the definition of hyperglycemia during the past century and the alterations in glucose dynamics that cause fasting and postprandial hyperglycemia. We discuss how extensive mechanistic, physiological research into the factors and pathways that regulate the appearance of glucose in the circulation and its uptake and metabolism by tissues and organs has contributed knowledge that has advanced our understanding of different types of hyperglycemia, namely prediabetes and diabetes and their subtypes (impaired fasting plasma glucose, impaired glucose tolerance, combined impaired fasting plasma glucose, impaired glucose tolerance, type 1 diabetes, type 2 diabetes, gestational diabetes mellitus), their relationships with medical complications, and how to prevent and treat hyperglycemia.
Asunto(s)
Diabetes Mellitus Tipo 2 , Intolerancia a la Glucosa , Hiperglucemia , Estado Prediabético , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Glucosa , Intolerancia a la Glucosa/metabolismo , Humanos , Hiperglucemia/metabolismo , Estado Prediabético/diagnóstico , Embarazo , AzúcaresRESUMEN
Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.
Asunto(s)
Bancos de Muestras Biológicas , Genética Médica , Genoma Humano , Genómica , Hispánicos o Latinos , Humanos , Glucemia/genética , Glucemia/metabolismo , Estatura/genética , Índice de Masa Corporal , Interacción Gen-Ambiente , Marcadores Genéticos/genética , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos/clasificación , Hispánicos o Latinos/genética , Homocigoto , México , Fenotipo , Triglicéridos/sangre , Triglicéridos/genética , Reino Unido , Genoma Humano/genéticaRESUMEN
As a master regulator of metabolism, AMP-activated protein kinase (AMPK) is activated upon energy and glucose shortage but suppressed upon overnutrition. Exaggerated negative regulation of AMPK signaling by nutrient overload plays a crucial role in metabolic diseases. However, the mechanism underlying the negative regulation is poorly understood. Here, we demonstrate that high glucose represses AMPK signaling via MG53 (also called TRIM72) E3-ubiquitin-ligase-mediated AMPKα degradation and deactivation. Specifically, high-glucose-stimulated reactive oxygen species (ROS) signals AKT to phosphorylate AMPKα at S485/491, which facilitates the recruitment of MG53 and the subsequent ubiquitination and degradation of AMPKα. In addition, high glucose deactivates AMPK by ROS-dependent suppression of phosphorylation of AMPKα at T172. These findings not only delineate the mechanism underlying the impairment of AMPK signaling in overnutrition-related diseases but also highlight the significance of keeping the yin-yang balance of AMPK signaling in the maintenance of metabolic homeostasis.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus/enzimología , Glucosa/farmacología , Proteínas de la Membrana/metabolismo , Músculo Esquelético/efectos de los fármacos , Obesidad/enzimología , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Quinasas Activadas por AMP/genética , Animales , Glucemia/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus/genética , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Macaca mulatta , Masculino , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Músculo Esquelético/enzimología , Obesidad/sangre , Obesidad/genética , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteolisis , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , UbiquitinaciónRESUMEN
Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1-6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.
Asunto(s)
Tejido Adiposo Pardo , Frío , Metabolismo Energético , Neoplasias , Adipocitos/metabolismo , Tejido Adiposo Pardo/metabolismo , Animales , Glucemia/metabolismo , Terapia Combinada , Glucólisis , Humanos , Ratones , Neoplasias/metabolismo , Neoplasias/prevención & control , Neoplasias/terapia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/prevención & control , Neoplasias Pancreáticas/terapia , Termogénesis/genética , Proteína Desacopladora 1/metabolismoRESUMEN
Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth1-5. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels6-8, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth.
Asunto(s)
Glucemia/metabolismo , Dieta Baja en Carbohidratos , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos , Neoplasias/metabolismo , Neoplasias/patología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Aloinjertos , Animales , Restricción Calórica , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular , Dieta Cetogénica , Líquido Extracelular/química , Ácidos Grasos Insaturados/metabolismo , Femenino , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Nutrientes/análisis , Nutrientes/sangre , Estearoil-CoA Desaturasa/metabolismo , Microambiente Tumoral/efectos de los fármacosRESUMEN
Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic ß-cells causes overt diabetes in mice; thus, therapies that sensitize ß-cells to insulin may protect patients with diabetes against ß-cell failure1-3. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse ß-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene Iir). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R4, and a mannose 6-phosphate receptor domain that is also found in the IGF2 receptor (IGF2R)5. Knockout mice that lack inceptor (Iir-/-) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from Iir-/- mice showed an increase in the activation of INSR-IGF1R in Iir-/- pancreatic tissue, resulting in an increase in the proliferation and mass of ß-cells. Similarly, inducible ß-cell-specific Iir-/- knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR-IGF1R and increased proliferation of ß-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR-IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR-IGF1R in ß-cells. Together, our findings show that inceptor shields insulin-producing ß-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR-IGF1R sensitization and diabetes therapy.
Asunto(s)
Glucemia/metabolismo , Antagonistas de Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Animales , Glucemia/análisis , Línea Celular , Proliferación Celular/efectos de los fármacos , Tamaño de la Célula , Clatrina/metabolismo , Células Endocrinas/metabolismo , Endocitosis , Retículo Endoplásmico/metabolismo , Prueba de Tolerancia a la Glucosa , Aparato de Golgi/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/efectos de los fármacos , Lisosomas/metabolismo , Masculino , Proteínas de la Membrana , Ratones , Proteínas de Neoplasias/química , Receptor de Insulina/metabolismo , Transducción de Señal/efectos de los fármacos , Tamoxifeno/farmacologíaRESUMEN
The glucocorticoid receptor (GR) is a potent metabolic regulator and a major drug target. While GR is known to play integral roles in circadian biology, its rhythmic genomic actions have never been characterized. Here we mapped GR's chromatin occupancy in mouse livers throughout the day and night cycle. We show how GR partitions metabolic processes by time-dependent target gene regulation and controls circulating glucose and triglycerides differentially during feeding and fasting. Highlighting the dominant role GR plays in synchronizing circadian amplitudes, we find that the majority of oscillating genes are bound by and depend on GR. This rhythmic pattern is altered by high-fat diet in a ligand-independent manner. We find that the remodeling of oscillatory gene expression and postprandial GR binding results from a concomitant increase of STAT5 co-occupancy in obese mice. Altogether, our findings highlight GR's fundamental role in the rhythmic orchestration of hepatic metabolism.
Asunto(s)
Cromatina/metabolismo , Relojes Circadianos , Ritmo Circadiano , Dieta Alta en Grasa , Grasas de la Dieta/metabolismo , Metabolismo Energético , Hígado/metabolismo , Obesidad/metabolismo , Receptores de Glucocorticoides/metabolismo , Animales , Glucemia/metabolismo , Relojes Circadianos/genética , Ritmo Circadiano/genética , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/sangre , Modelos Animales de Enfermedad , Metabolismo Energético/genética , Ayuno/metabolismo , Regulación de la Expresión Génica , Glucocorticoides/metabolismo , Gluconeogénesis , Ligandos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/sangre , Obesidad/genética , PPAR alfa/genética , PPAR alfa/metabolismo , Periodo Posprandial , Receptores de Glucocorticoides/deficiencia , Receptores de Glucocorticoides/genética , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Vías Secretoras , Transducción de Señal , Factores de Tiempo , Transcripción Genética , Triglicéridos/sangreRESUMEN
Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation.
Asunto(s)
Aminoácidos/metabolismo , Proteína 7 Relacionada con la Autofagia/metabolismo , Metabolismo Energético , Lisosomas/enzimología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de la Membrana/metabolismo , Células 3T3-L1 , Adipocitos/enzimología , Adipogénesis , Sistema de Transporte de Aminoácidos ASC/genética , Sistema de Transporte de Aminoácidos ASC/metabolismo , Sistema de Transporte de Aminoácidos y+L/genética , Sistema de Transporte de Aminoácidos y+L/metabolismo , Animales , Proteína 7 Relacionada con la Autofagia/genética , Glucemia/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Activación Enzimática , Células HEK293 , Células HeLa , Humanos , Insulina/sangre , Transportador de Aminoácidos Neutros Grandes 1/genética , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismo , Transporte de ProteínasRESUMEN
Type 2 diabetes (T2D) mellitus has emerged as a major global health concern that has accelerated in recent years due to poor diet and lifestyle. Afflicted individuals have high blood glucose levels that stem from the inability of the pancreas to make enough insulin to meet demand. Although medication can help to maintain normal blood glucose levels in individuals with chronic disease, many of these medicines are outdated, have severe side effects, and often become less efficacious over time, necessitating the need for insulin therapy. G protein-coupled receptors (GPCRs) regulate many physiologic processes, including blood glucose levels. In pancreatic ß cells, GPCRs regulate ß-cell growth, apoptosis, and insulin secretion, which are all critical in maintaining sufficient ß-cell mass and insulin output to ensure euglycemia. In recent years, new insights into the signaling of incretin receptors and other GPCRs have underscored the potential of these receptors as desirable targets in the treatment of diabetes. The signaling of these receptors is modulated by GPCR kinases (GRKs) that phosphorylate agonist-activated GPCRs, marking the receptor for arrestin binding and internalization. Interestingly, genome-wide association studies using diabetic patient cohorts link the GRKs and arrestins with T2D. Moreover, recent reports show that GRKs and arrestins expressed in the ß cell serve a critical role in the regulation of ß-cell function, including ß-cell growth and insulin secretion in both GPCR-dependent and -independent pathways. In this review, we describe recent insights into GPCR signaling and the importance of GRK function in modulating ß-cell physiology. SIGNIFICANCE STATEMENT: Pancreatic ß cells contain a diverse array of G protein-coupled receptors (GPCRs) that have been shown to improve ß-cell function and survival, yet only a handful have been successfully targeted in the treatment of diabetes. This review discusses recent advances in our understanding of ß-cell GPCR pharmacology and regulation by GPCR kinases while also highlighting the necessity of investigating islet-enriched GPCRs that have largely been unexplored to unveil novel treatment strategies.
Asunto(s)
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Insulinas , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucemia/metabolismo , Estudio de Asociación del Genoma Completo , Células Secretoras de Insulina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Quinasas de Receptores Acoplados a Proteína-G/metabolismo , Arrestinas/metabolismo , Insulinas/metabolismo , FosforilaciónRESUMEN
Maintaining blood glucose at an appropriate physiological level requires precise coordination of multiple organs and tissues. The vagus nerve bidirectionally connects the central nervous system with peripheral organs crucial to glucose mobilization, nutrient storage, and food absorption, thereby presenting a key pathway for the central control of blood glucose levels. However, the precise mechanisms by which vagal populations that target discrete tissues participate in glucoregulation are much less clear. Here we review recent advances unraveling the cellular identity, neuroanatomical organization, and functional contributions of both vagal efferents and vagal afferents in the control of systemic glucose metabolism. We focus on their involvement in relaying glucoregulatory cues from the brain to peripheral tissues, particularly the pancreatic islet, and by sensing and transmitting incoming signals from ingested food to the brain. These recent findings - largely driven by advances in viral approaches, RNA sequencing, and cell-type selective manipulations and tracings - have begun to clarify the precise vagal neuron populations involved in the central coordination of glucose levels, and raise interesting new possibilities for the treatment of glucose metabolism disorders such as diabetes.
Asunto(s)
Glucemia , Nervio Vago , Glucemia/metabolismo , Nervio Vago/metabolismo , Glucosa/metabolismoRESUMEN
Many physiological osteocalcin-regulated functions are affected in adult offspring of mothers experiencing unhealthy pregnancy. Furthermore, osteocalcin signaling during gestation influences cognition and adrenal steroidogenesis in adult mice. Together these observations suggest that osteocalcin may broadly function during pregnancy to determine organismal homeostasis in adult mammals. To test this hypothesis, we analyzed in unchallenged wildtype and Osteocalcin-deficient, newborn and adult mice of various genotypes and origin maintained on different genetic backgrounds, the functions of osteocalcin in the pancreas, liver and testes and their molecular underpinnings. This analysis revealed that providing mothers are Osteocalcin-deficient, Osteocalcin haploinsufficiency in embryos hampers insulin secretion, liver gluconeogenesis, glucose homeostasis, testes steroidogenesis in adult offspring; inhibits cell proliferation in developing pancreatic islets and testes; and disrupts distinct programs of gene expression in these organs and in the brain. This study indicates that osteocalcin exerts dominant functions in most organs it influences. Furthermore, through their synergistic regulation of multiple physiological functions, osteocalcin of maternal and embryonic origins contributes to the establishment and maintenance of organismal homeostasis in newborn and adult offspring.
Asunto(s)
Glucemia , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Humanos , Ratones , Embarazo , Glucemia/análisis , Glucemia/metabolismo , Homeostasis , Insulina/metabolismo , Secreción de Insulina , Mamíferos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismoRESUMEN
Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.
Asunto(s)
Peso Corporal/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Factor 15 de Diferenciación de Crecimiento/metabolismo , Metformina/farmacología , Administración Oral , Adulto , Anciano , Animales , Glucemia/análisis , Glucemia/metabolismo , Dieta Alta en Grasa , Método Doble Ciego , Ingestión de Energía/efectos de los fármacos , Enterocitos/citología , Enterocitos/efectos de los fármacos , Femenino , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/antagonistas & inhibidores , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/deficiencia , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor 15 de Diferenciación de Crecimiento/sangre , Factor 15 de Diferenciación de Crecimiento/deficiencia , Factor 15 de Diferenciación de Crecimiento/genética , Homeostasis/efectos de los fármacos , Humanos , Intestinos/citología , Intestinos/efectos de los fármacos , Masculino , Metformina/administración & dosificación , Ratones , Ratones Obesos , Persona de Mediana Edad , Pérdida de Peso/efectos de los fármacosRESUMEN
The internal state of an animal, including homeostatic requirements, modulates its behavior. Negative energy balance stimulates hunger, thus promoting a range of actions aimed at obtaining food. While these survival actions are well established, the influence of the energy status on prosocial behavior remains unexplored. We developed a paradigm to assess helping behavior in which a free mouse was faced with a conspecific trapped in a restrainer. We measured the willingness of the free mouse to liberate the confined mouse under diverse metabolic conditions. Around 42% of ad libitum-fed mice exhibited a helping behavior, as evidenced by the reduction in the latencies to release the trapped cagemate. This behavior was independent of subsequent social contact reward and was associated with changes in corticosterone indicative of emotional contagion. This decision-making process was coupled with reduced blood glucose excursions and higher Adenosine triphosphate (ATP):Adenosine diphosphate (ADP) ratios in the forebrain of helper mice, suggesting that it was a highly energy-demanding process. Interestingly, chronic (food restriction and type 2 diabetes) and acute (chemogenetic activation of hunger-promoting AgRP neurons) situations mimicking organismal negative energy balance and enhanced appetite attenuated helping behavior toward a distressed conspecific. To investigate similar effects in humans, we estimated the influence of glycated hemoglobin (a surrogate of long-term glycemic control) on prosocial behavior (namely charity donation) using the Understanding Society dataset. Our results evidenced that organismal energy status markedly influences helping behavior and that hypothalamic AgRP neurons are at the interface of metabolism and prosocial behavior.
Asunto(s)
Metabolismo Energético , Conducta de Ayuda , Animales , Ratones , Glucemia/metabolismo , Adenosina Trifosfato/metabolismo , Adenosina Difosfato/metabolismo , Prosencéfalo/metabolismo , Hambre , Hemoglobina Glucada/análisis , Hipotálamo/metabolismo , Control Glucémico , Ratones Endogámicos C57BL , Masculino , Humanos , Organizaciones de Beneficencia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , EstreptozocinaRESUMEN
Recombinant insulin is a life-saving therapeutic for millions of patients affected by diabetes mellitus. Standard mutagenesis has led to insulin variants with improved control of blood glucose; for instance, the fast-acting insulin lispro contains two point mutations that suppress dimer formation and expedite absorption. However, insulins undergo irreversible denaturation, a process accelerated for the insulin monomer. Here we replace ProB29 of insulin lispro with 4R-fluoroproline, 4S-fluoroproline, and 4,4-difluoroproline. All three fluorinated lispro variants reduce blood glucose in diabetic mice, exhibit similar secondary structure as measured by CD, and rapidly dissociate from the zinc- and resorcinol-bound hexamer upon dilution. Notably, however, we find that 4S-fluorination of ProB29 delays the formation of undesired insulin fibrils that can accumulate at the injection site in vivo and can complicate insulin production and storage. These results demonstrate how subtle molecular changes achieved through non-canonical amino acid mutagenesis can improve the stability of protein therapeutics.
Asunto(s)
Halogenación , Insulina Lispro , Animales , Ratones , Humanos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Glucemia/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , MasculinoRESUMEN
Adenosine deaminase (ADA) catalyzes the irreversible deamination of adenosine (ADO) to inosine and regulates ADO concentration. ADA ubiquitously expresses in various tissues to mediate ADO-receptor signaling. A significant increase in plasma ADA activity has been shown to be associated with the pathogenesis of type 2 diabetes mellitus. Here, we show that elevated plasma ADA activity is a compensated response to high level of ADO in type 2 diabetes mellitus and plays an essential role in the regulation of glucose homeostasis. Supplementing with more ADA, instead of inhibiting ADA, can reduce ADO levels and decrease hepatic gluconeogenesis. ADA restores a euglycemic state and recovers functional islets in db/db and high-fat streptozotocin diabetic mice. Mechanistically, ADA catabolizes ADO and increases Akt and FoxO1 phosphorylation independent of insulin action. ADA lowers blood glucose at a slower rate and longer duration compared to insulin, delaying or blocking the incidence of insulinogenic hypoglycemia shock. Finally, ADA suppresses gluconeogenesis in fasted mice and insulin-deficient diabetic mice, indicating the ADA regulating gluconeogenesis is a universal biological mechanism. Overall, these results suggest that ADA is expected to be a new therapeutic target for diabetes.