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1.
Front Immunol ; 11: 591815, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33362773

RESUMEN

Background: NOD-like receptors (NLR) are intracellular sensors of the innate immune system, with the NLRP3 being a pro-inflammatory member that modulates cardiac ischemia-reperfusion injury (IRI) and metabolism. No information is available on a possible role of anti-inflammatory NLRs on IRI and metabolism in the intact heart. Here we hypothesize that the constitutively expressed, anti-inflammatory mitochondrial NLRX1, affects IRI and metabolism of the isolated mouse heart. Methods: Isolated C57Bl/6J and NLRX1 knock-out (KO) mouse hearts were perfused with a physiological mixture of the essential substrates (lactate, glucose, pyruvate, fatty acid, glutamine) and insulin. For the IRI studies, hearts were subjected to either mild (20 min) or severe (35 min) ischemia and IRI was determined at 60 min reperfusion. Inflammatory mediators (IL-6, TNFα) and survival pathways (mito-HKII, p-Akt, p-AMPK, p-STAT3) were analyzed at 5 min of reperfusion. For the metabolism studies, hearts were perfused for 35 min with either 5.5 mM 13C-glucose or 0.4 mM 13C-palmitate under normoxic conditions, followed by LC-MS analysis and integrated, stepwise, mass-isotopomeric flux analysis (MIMOSA). Results: NLRX1 KO significantly increased IRI (infarct size from 63% to 73%, end-diastolic pressure from 59 mmHg to 75 mmHg, and rate-pressure-product recovery from 15% to 6%), following severe, but not mild, ischemia. The increased IRI in NLRX1 KO hearts was associated with depressed Akt signaling at early reperfusion; other survival pathways or inflammatory parameters were not affected. Metabolically, NLRX1 KO hearts displayed increased lactate production and glucose oxidation relative to fatty acid oxidation, associated with increased pyruvate dehydrogenase flux and 10% higher cardiac oxygen consumption. Conclusion: Deletion of the mitochondrially-located NOD-like sensor NLRX1 exacerbates severe cardiac IR injury, possibly through impaired Akt signaling, and increases cardiac glucose metabolism.


Asunto(s)
Metabolismo de los Hidratos de Carbono , Eliminación de Gen , Glucosa/metabolismo , Proteínas Mitocondriales/genética , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/metabolismo , Animales , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Daño por Reperfusión Miocárdica/patología , Oxidación-Reducción , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt/metabolismo
2.
Cell Metab ; 32(5): 736-750.e5, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33147484

RESUMEN

Pancreatic ß cells couple nutrient metabolism with appropriate insulin secretion. Here, we show that pyruvate kinase (PK), which converts ADP and phosphoenolpyruvate (PEP) into ATP and pyruvate, underlies ß cell sensing of both glycolytic and mitochondrial fuels. Plasma membrane-localized PK is sufficient to close KATP channels and initiate calcium influx. Small-molecule PK activators increase the frequency of ATP/ADP and calcium oscillations and potently amplify insulin secretion. PK restricts respiration by cyclically depriving mitochondria of ADP, which accelerates PEP cycling until membrane depolarization restores ADP and oxidative phosphorylation. Our findings support a compartmentalized model of ß cell metabolism in which PK locally generates the ATP/ADP required for insulin secretion. Oscillatory PK activity allows mitochondria to perform synthetic and oxidative functions without any net impact on glucose oxidation. These findings suggest a potential therapeutic route for diabetes based on PK activation that would not be predicted by the current consensus single-state model of ß cell function.

3.
Cell Metab ; 32(5): 751-766.e11, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33147485

RESUMEN

The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2-/- mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity.

4.
Cell Rep ; 31(6): 107623, 2020 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-32402282

RESUMEN

Stem cell-derived ß (SC-ß) cells could provide unlimited human ß cells toward a curative diabetes treatment. Differentiation of SC-ß cells yields transplantable islets that secrete insulin in response to glucose challenges. Following transplantation into mice, SC-ß cell function is comparable to human islets, but the magnitude and consistency of response in vitro are less robust than observed in cadaveric islets. Here, we profile metabolism of SC-ß cells and islets to quantify their capacity to sense glucose and identify reduced anaplerotic cycling in the mitochondria as the cause of reduced glucose-stimulated insulin secretion in SC-ß cells. This activity can be rescued by challenging SC-ß cells with intermediate metabolites from the TCA cycle and late but not early glycolysis, downstream of the enzymes glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate kinase. Bypassing this metabolic bottleneck results in a robust, bi-phasic insulin release in vitro that is identical in magnitude to functionally mature human islets.


Asunto(s)
Linfocitos B/metabolismo , Glucosa/metabolismo , Glucólisis/genética , Células Madre/metabolismo , Animales , Diferenciación Celular , Humanos , Ratones
5.
Cell ; 181(4): 832-847.e18, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32304665

RESUMEN

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.


Asunto(s)
Carcinoma Ductal Pancreático/etiología , Carcinoma Ductal Pancreático/metabolismo , Obesidad/metabolismo , Animales , Carcinogénesis/genética , Carcinoma Ductal Pancreático/patología , Línea Celular , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Endocrinas/metabolismo , Glándulas Exocrinas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Obesidad/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transducción de Señal/genética , Microambiente Tumoral/fisiología
6.
Diabetes Care ; 43(1): 145-151, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31694859

RESUMEN

OBJECTIVE: The relationship between acute pancreatitis and incident diabetes is unclear. We assessed whether a resolved single event of acute pancreatitis in childhood was associated with incident diabetes in adulthood. RESEARCH DESIGN AND METHODS: A nationwide, population-based study of 1,802,110 Israeli adolescents (mean age 17.4 years [range 16-20]) who were examined before compulsory military service between 1979 and 2008 and whose data were linked to the Israeli National Diabetes Registry (INDR). Resolved pancreatitis was defined as a history of a single event of acute pancreatitis with normal pancreatic function at enrollment. Logistic regression analysis was applied. RESULTS: Incident diabetes developed in 4.6% of subjects with resolved pancreatitis (13 of 281; none of these cases were identified as type 1 diabetes) and 2.5% among the unexposed group (44,463 of 1,801,716). Resolved acute pancreatitis was associated with incident diabetes with an odds ratio (OR) of 2.23 (95% CI 1.25-3.98) with adjustment for age, sex, and birth year. Findings persisted after further adjustments for baseline BMI and sociodemographic confounders (OR 2.10 [95% CI 1.15-3.84]). Childhood pancreatitis was associated with a diagnosis of diabetes at a younger age, with 92% of diabetes case subjects diagnosed before 40 years of age compared with 47% in the unexposed group (P = 0.002). The association accentuated when the study sample was limited to individuals of unimpaired health or normal BMI at baseline. CONCLUSIONS: A history of acute pancreatitis in childhood with normal pancreatic function in late adolescence is a risk factor for incident type 2 diabetes, especially at young adulthood.


Asunto(s)
Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etiología , Pancreatitis/epidemiología , Enfermedad Aguda , Adolescente , Adulto , Edad de Inicio , Niño , Femenino , Humanos , Incidencia , Israel/epidemiología , Masculino , Pancreatitis/complicaciones , Sistema de Registros , Factores de Riesgo , Adulto Joven
7.
Diabetes ; 69(2): 131-145, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31740442

RESUMEN

Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non-glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by ß-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak-mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the KATP channel. In summary, we have described a novel nonesterified free fatty acid-stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.


Asunto(s)
Ciclofilina D/metabolismo , Ciclofilinas/metabolismo , Secreción de Insulina/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Mitocondrias/metabolismo , Animales , Glucemia , Ciclofilinas/genética , Dieta Alta en Grasa , Ácidos Grasos no Esterificados/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Humanos , Insulina , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ácido Oléico/química , Ácido Oléico/farmacología , Consumo de Oxígeno , Ácido Palmítico/química , Ácido Palmítico/farmacología , Protones
8.
Cell Rep ; 29(11): 3394-3404.e9, 2019 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-31825824

RESUMEN

Pyruvate kinase is an important enzyme in glycolysis and a key metabolic control point. We recently observed a pyruvate kinase liver isoform (PKL) phosphorylation site at S113 that correlates with insulin resistance in rats on a 3 day high-fat diet (HFD) and suggests additional control points for PKL activity. However, in contrast to the classical model of PKL regulation, neither authentically phosphorylated PKL at S12 nor S113 alone is sufficient to alter enzyme kinetics or structure. Instead, we show that cyclin-dependent kinases (CDKs) are activated by the HFD and responsible for PKL phosphorylation at position S113 in addition to other targets. These CDKs control PKL nuclear retention, alter cytosolic PKL activity, and ultimately influence glucose production. These results change our view of PKL regulation and highlight a previously unrecognized pathway of hepatic CDK activity and metabolic control points that may be important in insulin resistance and type 2 diabetes.


Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Gluconeogénesis , Hepatocitos/metabolismo , Piruvato Quinasa/metabolismo , Transducción de Señal , Animales , Línea Celular Tumoral , Células Cultivadas , Dieta Alta en Grasa , Glucosa/metabolismo , Resistencia a la Insulina , Masculino , Fosforilación , Piruvato Quinasa/química , Ratas , Ratas Sprague-Dawley
9.
Proc Natl Acad Sci U S A ; 116(49): 24770-24778, 2019 12 03.
Artículo en Inglés | MEDLINE | ID: mdl-31740614

RESUMEN

Fatty acid amide hydrolase (FAAH) degrades 2 major classes of bioactive fatty acid amides, the N-acylethanolamines (NAEs) and N-acyl taurines (NATs), in central and peripheral tissues. A functional polymorphism in the human FAAH gene is linked to obesity and mice lacking FAAH show altered metabolic states, but whether these phenotypes are caused by elevations in NAEs or NATs is unknown. To overcome the problem of concurrent elevation of NAEs and NATs caused by genetic or pharmacological disruption of FAAH in vivo, we developed an engineered mouse model harboring a single-amino acid substitution in FAAH (S268D) that selectively disrupts NAT, but not NAE, hydrolytic activity. The FAAH-S268D mice accordingly show substantial elevations in NATs without alterations in NAE content, a unique metabolic profile that correlates with heightened insulin sensitivity and GLP-1 secretion. We also show that N-oleoyl taurine (C18:1 NAT), the most abundant NAT in human plasma, decreases food intake, improves glucose tolerance, and stimulates GPR119-dependent GLP-1 and glucagon secretion in mice. Together, these data suggest that NATs act as a class of lipid messengers that improve postprandial glucose regulation and may have potential as investigational metabolites to modify metabolic disease.


Asunto(s)
Amidohidrolasas/genética , Glucemia/metabolismo , Síndrome Metabólico/metabolismo , Ácidos Oléicos/metabolismo , Taurina/análogos & derivados , Amidohidrolasas/metabolismo , Sustitución de Aminoácidos , Animales , Glucemia/análisis , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Etanolaminas/sangre , Etanolaminas/metabolismo , Femenino , Glucagón/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Inyecciones Intravenosas , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/genética , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Ácidos Oléicos/administración & dosificación , Ácidos Oléicos/sangre , Periodo Posprandial/efectos de los fármacos , Periodo Posprandial/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Taurina/administración & dosificación , Taurina/sangre , Taurina/metabolismo
10.
Cell Rep ; 28(3): 759-772.e10, 2019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31315053

RESUMEN

Mechanisms coordinating pancreatic ß cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of ß cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and ß cell health.


Asunto(s)
Adenosina Trifosfato/metabolismo , Glucosa/metabolismo , Guanosina Trifosfato/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Mitocondrias/metabolismo , Succinato-CoA Ligasas/metabolismo , Animales , Diferenciación Celular/genética , Línea Celular , Proliferación Celular/genética , Ciclo del Ácido Cítrico/genética , Homeostasis , Humanos , Secreción de Insulina/genética , Secreción de Insulina/fisiología , Células Secretoras de Insulina/enzimología , Células Secretoras de Insulina/ultraestructura , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Mitocondrias/enzimología , Mitocondrias/ultraestructura , Membranas Mitocondriales/metabolismo , Fosforilación Oxidativa , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Regulación hacia Arriba
11.
Nat Genet ; 51(8): 1233-1243, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31358993

RESUMEN

Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.


Asunto(s)
Aterosclerosis/patología , Insulina/sangre , Islotes Pancreáticos/patología , Síndrome Metabólico/patología , Mutación , Elastasa Pancreática/sangre , Elastasa Pancreática/genética , Serina Endopeptidasas/genética , Adulto , Edad de Inicio , Aterosclerosis/sangre , Aterosclerosis/etiología , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Resistencia a la Insulina , Islotes Pancreáticos/metabolismo , Desequilibrio de Ligamiento , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/etiología , Persona de Mediana Edad , Linaje , Activación Plaquetaria
12.
Nat Commun ; 10(1): 548, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30710078

RESUMEN

Sodium-glucose transport protein 2 (SGLT2) inhibitors are a class of anti-diabetic agents; however, concerns have been raised about their potential to induce euglycemic ketoacidosis and to increase both glucose production and glucagon secretion. The mechanisms behind these alterations are unknown. Here we show that the SGLT2 inhibitor (SGLT2i) dapagliflozin promotes ketoacidosis in both healthy and type 2 diabetic rats in the setting of insulinopenia through increased plasma catecholamine and corticosterone concentrations secondary to volume depletion. These derangements increase white adipose tissue (WAT) lipolysis and hepatic acetyl-CoA content, rates of hepatic glucose production, and hepatic ketogenesis. Treatment with a loop diuretic, furosemide, under insulinopenic conditions replicates the effect of dapagliflozin and causes ketoacidosis. Furthermore, the effects of SGLT2 inhibition to promote ketoacidosis are independent from hyperglucagonemia. Taken together these data in rats identify the combination of insulinopenia and dehydration as a potential target to prevent euglycemic ketoacidosis associated with SGLT2i.


Asunto(s)
Deshidratación/complicaciones , Insulina/metabolismo , Cetosis/inducido químicamente , Cetosis/etiología , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Animales , Compuestos de Bencidrilo/efectos adversos , Deshidratación/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Glucocorticoides/metabolismo , Glucosa/metabolismo , Glucósidos/efectos adversos , Humanos , Cetosis/patología , Lipólisis/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas Sprague-Dawley , Receptores Adrenérgicos beta 1/metabolismo
13.
Methods Mol Biol ; 1846: 325-334, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30242770

RESUMEN

Metabolism is pivotal for formation of the lymphatic vasculature. Understanding metabolism in lymphatic endothelial cells (LECs) requires quantitative characterization of specific metabolic pathways. Here we describe methods for using radioactive tracers to assess flux rates of glycolysis, fatty acid ß-oxidation, glucose oxidation, and glutamine oxidation. We also provide a detailed method for utilizing mass spectrometry (MS) to measure glycolytic intermediates and ATP.


Asunto(s)
Células Endoteliales/metabolismo , Metaboloma , Metabolómica , Adenosina Trifosfato/metabolismo , Cromatografía Liquida , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Glutamina/metabolismo , Glucólisis , Humanos , Metabolómica/métodos , Oxidación-Reducción , Espectrometría de Masas en Tándem
14.
Islets ; 10(5): 181-189, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30118626

RESUMEN

Inhibition of the sodium-glucose co-transporter type 2 (SGLT2) has received growing acceptance as a novel, safe and effective means to improve glycemic control in patients with type 2 diabetes. Inhibition of SGLT2 lowers the renal glucose threshold and reduces plasma glucose by promoting glucose excretion in urine. Both animal studies and clinical trials in man suggest that SGLT2 inhibition has the potential to improve pancreatic ß-cell function by reducing glucose toxicity. However, there is limited data exploring how reducing glucotoxicity via SGLT2 inhibition affects rates of ß-cell proliferation and death throughout life in the context of insulin resistance and type 2 diabetes. SGLT2-/- mice were backcrossed to the db/db strain to produce littermate control db/db-SGLT2+/+ and experimental db/db-SGLT2-/- mice. Mice were euthanized at 5, 12 and 20 weeks of age to collect plasma for glucose, insulin, lipid and cytokine measures, and pancreata for histological analysis including determination of ß-cell mass and rates of proliferation and death. SGLT2 deletion in db/db mice reduced plasma glucose as early as 5 weeks of age and continued throughout life without changes in plasma lipids or cytokines. Reduced plasma glucose levels occurred in parallel with an increase in the relative ß-cell volume and reduced frequency of ß-cell death, and no apparent change in rates of ß-cell proliferation. These data add to a growing body of evidence demonstrating that improved glycemic control achieved through SGLT2 inhibition can preserve ß-cell function and endogenous insulin secretion by reducing glucose toxicity and rates of ß-cell death.


Asunto(s)
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Animales , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Monitoreo de Drogas/métodos , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Ratones , Ratones Noqueados , Resultado del Tratamiento
15.
J Clin Endocrinol Metab ; 103(8): 2843-2850, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29726999

RESUMEN

Context: Glycogen synthesis is a critical metabolic function of the endometrium to prepare for successful implantation and sustain embryo development. Yet, regulation of endometrial carbohydrate metabolism is poorly characterized. Whereas glycogen synthesis is attributed to progesterone, we previously found that the metabolic B isoform of the insulin receptor is maximally expressed in secretory-phase endometrium, indicating a potential role of insulin in glucose metabolism. Objective: We sought to determine whether insulin or progesterone regulates glycogen synthesis in human endometrium. Design, Participants, Outcome Measurements: Endometrial epithelial cells were isolated from 28 healthy women and treated with insulin, medroxyprogesterone (MPA), or vehicle. Intracellular glycogen and the activation of key enzymes were quantified. Results: In epithelia, insulin induced a 4.4-fold increase in glycogen, whereas MPA did not alter glycogen content. Insulin inactivated glycogen synthase (GS) kinase 3α/ß (GSK3α/ß), relieving inhibition of GS. In a regulatory mechanism, distinct from liver and muscle, insulin also increased GS by 3.7-fold through increased GS 2 (GYS2) gene expression. Conclusions: We demonstrate that insulin, not progesterone, directly regulates glycogen synthesis through canonical acute inactivation of GSK3α/ß and noncanonical stimulation of GYS2 transcription. Persistently elevated GS enables endometrium to synthesize glycogen constitutively, independent of short-term nutrient flux, during implantation and early pregnancy. This suggests that insulin plays a key, physiological role in endometrial glucose metabolism and underlines the need to delineate the effect of maternal obesity and hyperinsulinemia on fertility and fetal development.


Asunto(s)
Endometrio/efectos de los fármacos , Endometrio/metabolismo , Glucógeno Sintasa/genética , Glucógeno/biosíntesis , Insulina/farmacología , Adulto , Células Cultivadas , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Glucógeno Sintasa/metabolismo , Glucogenólisis/efectos de los fármacos , Humanos , Hiperinsulinismo/metabolismo , Medroxiprogesterona/farmacología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo
16.
Proc Natl Acad Sci U S A ; 114(43): E9172-E9180, 2017 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-29073114

RESUMEN

Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization. NAFLD was induced by impaired suppression of adipose tissue lipolysis due to decreased insulin secretion and to a reduced response of adipose tissue itself to insulin. This condition leads to increased shuttling of fatty acids (FAs) to the liver, where they are esterified and accumulated as triglycerides. Lipid accumulation in the liver induces hepatic insulin resistance, which leads to impaired suppression of endogenous glucose production after feeding. Hepatic insulin resistance, synergistically with lowered insulin secretion, increases serum glucose levels, which stimulates de novo lipogenesis (DNL) in the liver. Up-regulation of DNL also contributes to NAFLD. In contrast, severely hypothyroid mice show down-regulation of TH signaling in their livers and profound suppression of adipose tissue lipolysis, which decreases delivery of FAs to the liver. The resulting lack of substrates for triglyceride esterification protects severely hypothyroid mice against NAFLD. Our findings demonstrate that NAFLD occurs when TH levels are mildly reduced, but, paradoxically, not when they are severely reduced. Our results show that the pathogenesis of hypothyroidism-induced NAFLD is both intra- and extrahepatic; they also reveal key metabolic differences between mild and severe hypothyroidism.


Asunto(s)
Hipotiroidismo/complicaciones , Resistencia a la Insulina , Células Secretoras de Insulina/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiopatología , Animales , Modelos Animales de Enfermedad , Hipotiroidismo/etiología , Insulina/metabolismo , Secreción de Insulina , Metabolismo de los Lípidos , Lipólisis/fisiología , Hígado/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/complicaciones , Simportadores/genética
17.
Nature ; 545(7653): 224-228, 2017 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-28467822

RESUMEN

Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism, little is understood about the role of fibroblast growth factors (FGFs) in this context. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/Fgfr3 double mutant mice, while HK2 overexpression partly rescues the defects caused by suppression of FGF signalling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development.


Asunto(s)
Células Endoteliales/citología , Células Endoteliales/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Glucólisis , Neovascularización Fisiológica , Transducción de Señal , Animales , Movimiento Celular , Proliferación Celular , Femenino , Hexoquinasa/metabolismo , Linfangiogénesis , Vasos Linfáticos/citología , Vasos Linfáticos/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/deficiencia , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/deficiencia , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo
18.
Am J Physiol Endocrinol Metab ; 311(2): E461-70, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27406738

RESUMEN

Imeglimin is a promising new oral antihyperglycemic agent that has been studied in clinical trials as a possible monotherapy or add-on therapy to lower fasting plasma glucose and improve hemoglobin A1c (1-3, 9). Imeglimin was shown to improve both fasting and postprandial glycemia and to increase insulin secretion in response to glucose during a hyperglycemic clamp after 1-wk of treatment in type 2 diabetic patients. However, whether the ß-cell stimulatory effect of imeglimin is solely or partially responsible for its effects on glycemia remains to be fully confirmed. Here, we show that imeglimin directly activates ß-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than trigger the ß-cell mechanism that explains the acute, antidiabetic activity of imeglimin.


Asunto(s)
Glucemia/efectos de los fármacos , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Insulina/metabolismo , Triazinas/farmacología , Animales , Glucemia/metabolismo , Dieta Alta en Grasa , Ayuno , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Resistencia a la Insulina , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Periodo Posprandial , Ratas , Ratas Sprague-Dawley
19.
Nature ; 534(7606): 213-7, 2016 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-27279214

RESUMEN

Obesity, insulin resistance and the metabolic syndrome are associated with changes to the gut microbiota; however, the mechanism by which modifications to the gut microbiota might lead to these conditions is unknown. Here we show that increased production of acetate by an altered gut microbiota in rodents leads to activation of the parasympathetic nervous system, which, in turn, promotes increased glucose-stimulated insulin secretion, increased ghrelin secretion, hyperphagia, obesity and related sequelae. Together, these findings identify increased acetate production resulting from a nutrient-gut microbiota interaction and subsequent parasympathetic activation as possible therapeutic targets for obesity.


Asunto(s)
Acetatos/metabolismo , Encéfalo/fisiología , Microbioma Gastrointestinal/fisiología , Células Secretoras de Insulina/metabolismo , Síndrome Metabólico/metabolismo , Animales , Dieta Alta en Grasa , Ghrelina/metabolismo , Glucosa/metabolismo , Hiperfagia/metabolismo , Insulina/metabolismo , Secreción de Insulina , Obesidad/metabolismo , Sistema Nervioso Parasimpático/fisiología , Ratas
20.
Proc Natl Acad Sci U S A ; 113(24): E3423-30, 2016 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-27247419

RESUMEN

A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma ß-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Argininosuccinato Sintasa/biosíntesis , Regulación Enzimológica de la Expresión Génica/fisiología , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Urea/metabolismo , Animales , Activación Enzimática , Ratas , Ratas Sprague-Dawley
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