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1.
Cell Rep ; 31(6): 107623, 2020 May 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.

2.
Cell Rep ; 29(11): 3394-3404.e9, 2019 Dec 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.

3.
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
4.
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.

5.
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
6.
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
7.
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
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