Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
1.
PLoS Biol ; 17(12): e3000482, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31805040

RESUMEN

Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that captures the complexity of feeding behaviour. We construct an accurate stochastic model of rodent feeding at the bout level in order to perform quantitative behavioural analysis. Analysing the different effects on feeding behaviour of peptide YY3-36 (PYY3-36), lithium chloride, glucagon-like peptide 1 (GLP-1), and leptin shows the precise behavioural changes caused by each anorectic agent. Our analysis demonstrates that the changes in feeding behaviour evoked by the anorectic agents investigated do not mimic the behaviour of well-fed animals and that the intermeal interval is influenced by fullness. We show how robust homeostatic control of feeding thwarts attempts to reduce food intake and how this might be overcome. In silico experiments suggest that introducing a minimum intermeal interval or modulating upper gut emptying can be as effective as anorectic drug administration.


Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Animales , Depresores del Apetito/farmacología , Ingestión de Alimentos/fisiología , Péptido 1 Similar al Glucagón/farmacología , Homeostasis/efectos de los fármacos , Leptina/farmacología , Masculino , Ratones , Obesidad , Fragmentos de Péptidos/farmacología , Péptido YY/farmacología , Ratas
2.
Diabetes Obes Metab ; 24(11): 2090-2101, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35676825

RESUMEN

AIMS: To describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034. MATERIALS AND METHODS: Glucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice. RESULTS: Compared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and ß-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg). CONCLUSIONS: GL0034 is a G protein-biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with type 2 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2 , Insulinas , Adenosina Monofosfato , Animales , Glucemia , AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Células HEK293 , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Ligandos , Ratones , Pérdida de Peso , beta-Arrestinas/metabolismo
3.
Diabetologia ; 59(4): 659-67, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26791990

RESUMEN

The physiologically predominant signal for pancreatic beta cells to secrete insulin is glucose. While circulating glucose levels and beta cell glucose metabolism regulate the amount of released insulin, additional signals emanating from other tissues and from neighbouring islet endocrine cells modulate beta cell function. To this end, each individual beta cell can be viewed as a sensor of a multitude of stimuli that are integrated to determine the extent of glucose-dependent insulin release. This review discusses recent advances in our understanding of inter-organ communications that regulate beta cell insulin release in response to elevated glucose levels.


Asunto(s)
Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Galanina/metabolismo , Ghrelina/metabolismo , Glucosa/metabolismo , Humanos , Incretinas/metabolismo
4.
bioRxiv ; 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38712064

RESUMEN

Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing Type 2 Diabetes (T2D). Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high fat diet-fed control, chronically dapagliflozin-treated mice and total-body SGLT2/Slc5a2 knockout mice. SGLT2 null mice exhibited superior glucose tolerance and insulin sensitivity compared to control or dapagliflozin-treated mice, independent of glycosuria and body weight. Moreover, SGLT2 null mice demonstrated physiological regulation of corticosterone secretion, with lowered morning levels compared to control mice. Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly interleukin 6 (IL-6). Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 increased SGLT2 expression in kidney HK2 cells suggesting a role for cytokines in the effects of hyperglycemia. Collectively, our study elucidates a potential interplay between SGLT2 activity, immune modulation, and metabolic homeostasis.

5.
Nat Commun ; 14(1): 2533, 2023 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-37137910

RESUMEN

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.


Asunto(s)
Diabetes Mellitus Tipo 2 , Islotes Pancreáticos , Ratones , Animales , Masculino , Diabetes Mellitus Tipo 2/metabolismo , Glucemia/metabolismo , Islotes Pancreáticos/metabolismo , Insulina/metabolismo , Lípidos , Biomarcadores/metabolismo , Moléculas de Adhesión Celular/metabolismo , Proteínas de la Matriz Extracelular/metabolismo
6.
Endocr Rev ; 43(1): 19-34, 2022 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-34363458

RESUMEN

Obesity surgery remains the most effective treatment for obesity and its complications. Weight loss was initially attributed to decreased energy absorption from the gut but has since been linked to reduced appetitive behavior and potentially increased energy expenditure. Implicated mechanisms associating rearrangement of the gastrointestinal tract with these metabolic outcomes include central appetite control, release of gut peptides, change in microbiota, and bile acids. However, the exact combination and timing of signals remain largely unknown. In this review, we survey recent research investigating these mechanisms, and seek to provide insights on unanswered questions over how weight loss is achieved following bariatric surgery which may eventually lead to safer, nonsurgical weight-loss interventions or combinations of medications with surgery.


Asunto(s)
Cirugía Bariátrica , Cirugía Bariátrica/efectos adversos , Metabolismo Energético , Humanos , Obesidad/metabolismo , Obesidad/cirugía , Pérdida de Peso
7.
Diabetes ; 71(8): 1623-1635, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35594379

RESUMEN

Bariatric surgery improves glucose homeostasis, but the underlying mechanisms are not fully elucidated. Here, we show that the expression of sodium-glucose cotransporter 2 (SGLT2/Slc5a2) is reduced in the kidney of lean and obese mice following vertical sleeve gastrectomy (VSG). Indicating an important contribution of altered cotransporter expression to the impact of surgery, inactivation of the SGLT2/Slc5a2 gene by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 attenuated the effects of VSG, with glucose excursions following intraperitoneal injection lowered by ∼30% in wild-type mice but by ∼20% in SGLT2-null animals. The effects of the SGLT2 inhibitor dapaglifozin were similarly blunted by surgery. Unexpectedly, effects of dapaglifozin were still observed in SGLT2-null mice, consistent with the existence of metabolically beneficial off-target effects of SGLT2 inhibitors. Thus, we describe a new mechanism involved in mediating the glucose-lowering effects of bariatric surgery.


Asunto(s)
Glucemia , Células Secretoras de Insulina , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Transportador 2 de Sodio-Glucosa/metabolismo , Animales , Glucemia/metabolismo , Gastrectomía , Glucosa/metabolismo , Células Secretoras de Insulina/metabolismo , Riñón/metabolismo , Ratones , Ratones Noqueados , Transportador 2 de Sodio-Glucosa/genética , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
8.
Front Endocrinol (Lausanne) ; 13: 1020576, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36246869

RESUMEN

Objectives: Glucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. Glucocorticoid activation is catalysed by 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1). Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have demonstrated effects on glucocorticoid metabolism of bariatric surgery, a group of gastrointestinal procedures known to improve insulin sensitivity and secretion, which were assumed to result from weight loss. In this study, we hypothesize that a reduction in glucocorticoid action following bariatric surgery contributes to the widely observed euglycemic effects of the treatment. Methods: Glucose and insulin tolerance tests were performed at ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvested from fed mice and 11ß-HSD1 levels were measured by quantitative RT-PCR or Western (immuno-) blotting, respectively. 11ß-HSD1 null mice (Hsd11b1 -/-) were generated using CRISPR/Cas9 genome editing. Wild type and littermate Hsd11b1 -/- mice underwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Results: Under the conditions used, no differences in weight loss were observed between VSG treated and sham operated mice. However, both lean and obese WT VSG mice displayed significantly improved glucose clearance and insulin sensitivity. Remarkably, VSG restored physiological corticosterone production in HFD mice and reduced 11ß-HSD1 expression in liver and adipose tissue post-surgery. Elimination of the 11ß-HSD1/Hsd11b1 gene by CRISPR/Cas9 mimicked the effects of VSG on body weight and tolerance to 1g/kg glucose challenge. However, at higher glucose loads, the euglycemic effect of VSG was superior to Hsd11b1 elimination. Conclusions: Bariatric surgery improves insulin sensitivity and reduces glucocorticoid activation at the tissular level, under physiological and pathophysiological (obesity) conditions, irrespective of weight loss. These findings point towards a physiologically relevant gut-glucocorticoid axis, and suggest that lowered glucocorticoid exposure may represent an additional contribution to the health benefits of bariatric surgery.


Asunto(s)
Gastrectomía , Glucocorticoides , Resistencia a la Insulina , Insulinas , Animales , Ratones , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Corticosterona , Glucocorticoides/sangre , Glucosa , Ratones Obesos , Pérdida de Peso
9.
Diabetes ; 71(7): 1472-1489, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35472764

RESUMEN

Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic ß-cells. Whether mitofusin gene expression, and hence, mitochondrial network integrity, is important for glucose or incretin signaling has not previously been explored. Here, we generated mice with ß-cell-selective, adult-restricted deletion knock-out (dKO) of the mitofusin genes Mfn1 and Mfn2 (ßMfn1/2 dKO). ßMfn1/2-dKO mice displayed elevated fed and fasted glycemia and a more than fivefold decrease in plasma insulin. Mitochondrial length, glucose-induced polarization, ATP synthesis, and cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in ßMfn1/2-dKO mice, and glucagon-like peptide 1 or glucose-dependent insulinotropic peptide receptor agonists largely corrected defective glucose-stimulated insulin secretion through enhanced EPAC-dependent signaling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps-based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the ß-cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in ß-cells, the potential contributions of altered mitochondrial dynamics to diabetes development, and the impact of incretins on this process.


Asunto(s)
GTP Fosfohidrolasas , Glucosa , Incretinas , Células Secretoras de Insulina , Animales , GTP Fosfohidrolasas/genética , Glucosa/metabolismo , Glucosa/farmacología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Incretinas/metabolismo , Incretinas/farmacología , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Ratones , Ratones Noqueados
10.
Nat Commun ; 12(1): 5165, 2021 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-34453049

RESUMEN

Bariatric surgery improves both insulin sensitivity and secretion and can induce diabetes remission. However, the mechanisms and time courses of these changes, particularly the impact on ß cell function, are difficult to monitor directly. In this study, we investigated the effect of Vertical Sleeve Gastrectomy (VSG) on ß cell function in vivo by imaging Ca2+ dynamics in islets engrafted into the anterior eye chamber. Mirroring its clinical utility, VSG in mice results in significantly improved glucose tolerance, and enhanced insulin secretion. We reveal that these benefits are underpinned by augmented ß cell function and coordinated activity across the islet. These effects involve changes in circulating GLP-1 levels which may act both directly and indirectly on the ß cell, in the latter case through changes in body weight. Thus, bariatric surgery leads to time-dependent increases in ß cell function and intra-islet connectivity which are likely to contribute to diabetes remission.


Asunto(s)
Calcio/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/cirugía , Células Secretoras de Insulina/metabolismo , Animales , Cirugía Bariátrica , Glucemia/metabolismo , Diabetes Mellitus/diagnóstico por imagen , Femenino , Gastrectomía , Péptido 1 Similar al Glucagón/metabolismo , Humanos , Insulina/metabolismo , Microscopía Intravital , Masculino , Ratones , Ratones Endogámicos C57BL , Estómago/cirugía
11.
Artículo en Inglés | MEDLINE | ID: mdl-32153504

RESUMEN

Glucocorticoids are steroid hormones produced by the adrenal cortex and are essential for the maintenance of various metabolic and homeostatic functions. Their function is regulated at the tissue level by 11ß-hydroxysteroid dehydrogenases and they signal through the glucocorticoid receptor, a ligand-dependent transcription factor. Clinical observations have linked excess glucocorticoid levels with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance and dyslipidaemia. In this review, we discuss the physiological mechanisms of glucocorticoid secretion, regulation and function, and survey the metabolic consequences of excess glucocorticoid action resulting from elevated release and activation or up-regulated signaling. Finally, we summarize the reported impact of weight loss by diet, exercise, or bariatric surgery on circulating and tissue-specific glucocorticoid levels and examine the therapeutic possibility of reversing glucocorticoid-associated metabolic disorders.


Asunto(s)
Glucocorticoides/metabolismo , Obesidad/fisiopatología , Pérdida de Peso , Humanos
12.
Front Endocrinol (Lausanne) ; 11: 582936, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33133024

RESUMEN

Covid-19 is a recently-emerged infectious disease caused by the novel severe acute respiratory syndrome coronavirus SARS-CoV2. SARS-CoV2 differs from previous coronavirus infections (SARS and MERS) due to its high infectivity (reproduction value, R0, typically 2-4) and pre- or asymptomatic transmission, properties that have contributed to the current global Covid-19 pandemic. Identified risk factors for disease severity and death from SARS-Cov2 infection include older age, male sex, diabetes, obesity and hypertension. The reasons for these associations are still largely obscure. Evidence is also emerging that SARS-CoV2 infection exacerbates the underlying pathophysiology of hyperglycemia in people with diabetes. Here, we discuss potential mechanisms through which diabetes may affect the risk of more severe outcomes in Covid-19 and, additionally, how diabetic emergencies and longer term pathology may be aggravated by infection with the virus. We consider roles for the immune system, the observed phenomenon of microangiopathy in severe Covid-19 infection and the potential for direct viral toxicity on metabolically-relevant tissues including pancreatic beta cells and targets of insulin action.


Asunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/complicaciones , Complicaciones de la Diabetes , Diabetes Mellitus/epidemiología , Diabetes Mellitus/virología , Neumonía Viral/complicaciones , COVID-19 , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/virología , Humanos , Pandemias , Neumonía Viral/transmisión , Neumonía Viral/virología , Factores de Riesgo , SARS-CoV-2
13.
Lab Anim ; 53(4): 362-371, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30227760

RESUMEN

Gastric bypass surgery, an operation that restricts the stomach and bypasses the duodenum and part of the jejunum, results in major improvement or remission of type 2 diabetes. Duodenual-jejunal bypass was developed by one of the authors (FR) as an experimental, stomach-sparing variant of gastric bypass surgery to investigate weight-independent mechanisms of surgical control of diabetes. Duodenual-jejunal bypass has been shown to improve various aspects of glucose homeostasis in rodents and in humans, thus providing an experimental model for investigating mechanisms of action of surgery and elusive aspects of gastrointestinal physiology. Performing duodenual-jejunal bypass in rodents, however, is associated with a steep learning curve. Here we report our experience with duodenual-jejunal bypass and provide practical tips for successful surgery in rats. Duodenual-jejunal bypass was performed on 50 lean rats as part of a study aimed at investigating the effect of the procedure on the physiologic mechanisms of glucose homeostasis. During the study, we have progressively refined details of anatomic exposure, technical aspects of duodeno-jejunostomy and peri-operative care. We analysed the role of such refinements in improving operative time and post-operative mortality. We found that refinement of exposure methods of the gastro-duodenal junction aimed at minimizing tension on small visceral vasculature, technical aspects of duodeno-jejunal anastomosis and peri-operative management played a major role in improving the survival rate and operative time. Overall, an experimental model of duodenual-jejunal bypass was successfully reproduced. Based on this experience, we describe here what we believe are the most important technical tips to reduce the learning curve for the procedure.


Asunto(s)
Anastomosis Quirúrgica/métodos , Duodeno/cirugía , Derivación Gástrica/métodos , Yeyuno/cirugía , Ratas/cirugía , Estómago/cirugía , Animales , Masculino , Ratas Sprague-Dawley/cirugía , Ratas Wistar/cirugía
14.
Pancreas ; 45(7): 967-73, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-26731187

RESUMEN

OBJECTIVES: Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogs and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential antiobesity therapy, but little is known about its pancreatic safety. The aim of the study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas. METHODS: Glucagon-like peptide 1, oxyntomodulin, glucagon, and exendin-4 were infused into anesthetized rats to measure plasma amylase concentration changes. In addition, the effect of each peptide on both amylase release and proliferation in rat pancreatic acinar (AR42J) and primary isolated ductal cells was determined. RESULTS: Plasma amylase did not increase postpeptide infusion, compared with vehicle and cholecystokinin; however, oxyntomodulin inhibited plasma amylase when coadministered with cholecystokinin. None of the peptides caused a significant increase in proliferation rate or amylase secretion from acinar and ductal cells. CONCLUSIONS: The investigated peptides do not have an acute effect on the exocrine pancreas with regard to proliferation and plasma amylase, when administered individually. Oxyntomodulin seems to be a potent inhibitor of amylase release, potentially making it a safer antiobesity agent regarding pancreatitis, compared with GLP-1 agonists.


Asunto(s)
Oxintomodulina/farmacología , Páncreas Exocrino/efectos de los fármacos , Péptidos/farmacología , Proglucagón/farmacología , Actinas/genética , Amilasas/sangre , Amilasas/metabolismo , Animales , Línea Celular Tumoral , Células Cultivadas , Exenatida , Expresión Génica , Glucagón/administración & dosificación , Glucagón/farmacología , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/farmacología , Inyecciones Intravenosas , Antígeno Ki-67/genética , Masculino , Oxintomodulina/administración & dosificación , Páncreas Exocrino/metabolismo , Péptidos/administración & dosificación , Proglucagón/administración & dosificación , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ponzoñas/administración & dosificación , Ponzoñas/farmacología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA