RESUMEN
The contribution of chronic kidney disease (CKD) towards the risk of developing cardiovascular disease (CVD) is magnified with co-existing type 1 or type 2 diabetes. Lipids are a modifiable risk factor and good lipid management offers improved outcomes for people with diabetic kidney disease (DKD).The primary purpose of this guideline, written by the Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) working group, is to provide practical recommendations on lipid management for members of the multidisciplinary team involved in the care of adults with DKD.
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Nefropatías Diabéticas , Humanos , Nefropatías Diabéticas/terapia , Adulto , Reino Unido/epidemiología , Enfermedades Cardiovasculares/terapia , Lípidos/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéuticoRESUMEN
Managing type 1 diabetes in frail elderly people can be logistically challenging, particularly for those living alone. District nurse visits are unpredictable and coincide poorly with meal time insulin regimes. Elderly people, particularly those with dementia, have variable oral intake and activity. For some, poor glycaemic control leads to frequent and prolonged inpatient admissions. The use of technology, such as flash glucose monitoring, and the use of analogue insulins can be helpful in this setting. Increased monitoring enables more accurate titration of insulin doses and the information can be accessed by healthcare professionals and carers remotely. Longer lasting analogue insulins allow for a greater margin of error in the timing of insulin administration.
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Diabetes Mellitus Tipo 1 , Fragilidad , Humanos , Anciano , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Automonitorización de la Glucosa Sanguínea , Glucemia , Insulina/uso terapéuticoRESUMEN
Diabetic kidney disease (DKD) accounts for >40% cases of chronic kidney disease (CKD) globally. Hypertension is a major risk factor for progression of DKD and the high incidence of cardiovascular disease and mortality in these people. Meticulous management of hypertension is therefore crucial to slow down the progression of DKD and reduce cardiovascular risk. Randomized controlled trial evidence differs in type 1 and type 2 diabetes and in different stages of DKD in terms of target blood pressure (BP). Renin-angiotensin blocking agents reduce progression of DKD and cardiovascular events in both type 1 and type 2 diabetes, albeit differently according to the stage of CKD. There is emerging evidence for the benefit of sodium glucose cotransporter 2, nonsteroidal selective mineralocorticoid antagonists, and endothelin-A receptor antagonists in slowing progression and reducing cardiovascular events in DKD. This UK guideline, developed jointly by diabetologists and nephrologists, has reviewed all available current evidence regarding the management of hypertension in DKD to produce a set of comprehensive individualized recommendations for BP control and the use of antihypertensive agents according to age, type of diabetes, and stage of CKD (https://ukkidney.org/sites/renal.org/files/Management-of-hypertension-and-RAAS-blockade-in-adults-with-DKD.pdf). A succinct summary of the guideline, including an infographic, is presented here.
RESUMEN
A significant percentage of people with diabetes develop chronic kidney disease and diabetes is also a leading cause of end-stage kidney disease (ESKD). The term diabetic kidney disease (DKD) includes both diabetic nephropathy (DN) and diabetes mellitus and chronic kidney disease (DM CKD). DKD is associated with high morbidity and mortality, which are predominantly related to cardiovascular disease. Hyperglycaemia is a modifiable risk factor for cardiovascular complications and progression of DKD. Recent clinical trials of people with DKD have demonstrated improvement in clinical outcomes with sodium glucose co-transporter-2 (SGLT-2) inhibitors. SGLT-2 inhibitors have significantly reduced progression of DKD and onset of ESKD and these reno-protective effects are independent of glucose lowering. At the time of this update Canagliflozin and Dapagliflozin have been approved for delaying the progression of DKD. The Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) Diabetic Kidney Disease Clinical Speciality Group have undertaken a literature review and critical appraisal of the available evidence to inform clinical practice guidelines for management of hyperglycaemia in adults with DKD. This 2021 guidance is for the variety of clinicians who treat people with DKD, including GPs and specialists in diabetes, cardiology and nephrology.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Hiperglucemia , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Adulto , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/terapia , Nefropatías Diabéticas/complicaciones , Femenino , Glucosa , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/prevención & control , Masculino , Insuficiencia Renal Crónica/complicaciones , Sociedades Médicas , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
People with type 1 and type 2 diabetes are at risk of developing progressive chronic kidney disease (CKD) and end-stage kidney failure. Hypertension is a major, reversible risk factor in people with diabetes for development of albuminuria, impaired kidney function, end-stage kidney disease and cardiovascular disease. Blood pressure control has been shown to be beneficial in people with diabetes in slowing progression of kidney disease and reducing cardiovascular events. However, randomised controlled trial evidence differs in type 1 and type 2 diabetes and different stages of CKD in terms of target blood pressure. Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mechanism for the development and progression of CKD and cardiovascular disease. Randomised trials demonstrate that RAAS blockade is effective in preventing/ slowing progression of CKD and reducing cardiovascular events in people with type 1 and type 2 diabetes, albeit differently according to the stage of CKD. Emerging therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid antagonists and endothelin-A receptor antagonists have been shown in randomised trials to lower blood pressure and further reduce the risk of progression of CKD and cardiovascular disease in people with type 2 diabetes. This guideline reviews the current evidence and makes recommendations about blood pressure control and the use of RAAS-blocking agents in different stages of CKD in people with both type 1 and type 2 diabetes.
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Antihipertensivos/uso terapéutico , Angiopatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Adulto , Albuminuria , Monitoreo Ambulatorio de la Presión Arterial , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/fisiopatología , Angiopatías Diabéticas/orina , Nefropatías Diabéticas/fisiopatología , Nefropatías Diabéticas/orina , Humanos , Hipertensión/fisiopatología , Hipertensión/orina , Cooperación del Paciente , Conducta de Reducción del Riesgo , Reino UnidoRESUMEN
Post-transplant diabetes mellitus (PTDM) is common after solid organ transplantation (SOT) and associated with increased morbidity and mortality for allograft recipients. Despite the significant burden of disease, there is a paucity of literature with regards to detection, prevention and management. Evidence from the general population with diabetes may not be translatable to the unique context of SOT. In light of emerging clinical evidence and novel anti-diabetic agents, there is an urgent need for updated guidance and recommendations in this high-risk cohort. The Association of British Clinical Diabetologists (ABCD) and Renal Association (RA) Diabetic Kidney Disease Clinical Speciality Group has undertaken a systematic review and critical appraisal of the available evidence. Areas of focus are; (1) epidemiology, (2) pathogenesis, (3) detection, (4) management, (5) modification of immunosuppression, (6) prevention, and (7) PTDM in the non-renal setting. Evidence-graded recommendations are provided for the detection, management and prevention of PTDM, with suggested areas for future research and potential audit standards. The guidelines are endorsed by Diabetes UK, the British Transplantation Society and the Royal College of Physicians of London. The full guidelines are available freely online for the diabetes, renal and transplantation community using the link below. The aim of this review article is to introduce an abridged version of this new clinical guideline ( https://abcd.care/sites/abcd.care/files/site_uploads/Resources/Position-Papers/ABCD-RA%20PTDM%20v14.pdf).
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Diabetes Mellitus/etiología , Medicina Interna , Nefrología , Trasplante de Órganos/efectos adversos , Complicaciones Posoperatorias/terapia , Guías de Práctica Clínica como Asunto , Sociedades Médicas , Diabetes Mellitus/epidemiología , Diabetes Mellitus/terapia , Humanos , Terapia de Inmunosupresión/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
Introduction: Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). This review covers the pillars of care essential for the management of diabetic kidney disease (DKD) including (1) early diagnosis, (2) improved glycaemic control, (3) treatment of hypertension, (4) identification and treatment of associated metabolic bone disease and (5) identification and effective management of dyslipidaemia and additional cardiovascular risk factors. Sources of data: We searched PubMed for articles using search terms: diabetic nephropathy, diabetic kidney disease, diabetes and chronic kidney disease. We used clinical guidelines from NICE, the Association of British Clinical Diabetologists (ABCD), the Joint British Societies (JBS) and the Kidney Disease: Improving Global Outcomes (KDIGO) working group. Areas of agreement: Multiple risk factor reduction targeting glycaemic control, blood pressure control, dyslipidaemia, smoking and management of obesity is important in preventing and in managing DKD. Areas of controversy: Guidelines disagree on the individualized glycaemic targets for patients with diabetic kidney disease. Growing points: The growing number of patients with DKD is causing increased pressure on limited primary care and specialized services. New ways of managing patients using novel technology solutions are required. Areas timely for development: The use of novel anti-hyperglycaemic agents, particularly sodium glucose co-transporter 2 inhibitors and GLP-1 receptor agonists, has been associated with a reduction in cardiovascular disease and DKD.
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Nefropatías Diabéticas/terapia , Manejo de Atención al Paciente/métodos , Humanos , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND: Short-chain fatty acids (SCFA) produced through fermentation of nondigestible carbohydrates by the gut microbiota are associated with positive metabolic effects. However, well-controlled trials are limited in humans. AIMS: To develop a methodology to deliver SCFA directly to the colon, and to optimise colonic propionate delivery in humans, to determine its role in appetite regulation and food intake. METHODS: Inulin SCFA esters were developed and tested as site-specific delivery vehicles for SCFA to the proximal colon. Inulin propionate esters containing 0-61 wt% (IPE-0-IPE-61) propionate were assessed in vitro using batch faecal fermentations. In a randomised, controlled, crossover study, with inulin as control, ad libitum food intake (kcal) was compared after 7 days on IPE-27 or IPE-54 (10 g/day all treatments). Propionate release was determined using (13) C-labelled IPE variants. RESULTS: In vitro, IPE-27-IPE-54 wt% propionate resulted in a sevenfold increase in propionate production compared with inulin (P < 0.05). In vivo, IPE-27 led to greater (13) C recovery in breath CO2 than IPE-54 (64.9 vs. 24.9%, P = 0.001). IPE-27 also led to a reduction in energy intake during the ad libitum test meal compared with both inulin (439.5 vs. 703.9 kcal, P = 0.025) and IPE-54 (439.5 vs. 659.3 kcal, P = 0.025), whereas IPE-54 was not significantly different from inulin control. CONCLUSIONS: IPE-27 significantly reduced food intake suggesting colonic propionate plays a role in appetite regulation. Inulin short-chain fatty acid esters provide a novel tool for probing the diet-gut microbiome-host metabolism axis in humans.
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Colon/metabolismo , Ácidos Grasos Volátiles/administración & dosificación , Inulina/administración & dosificación , Adulto , Estudios Cruzados , Ingestión de Alimentos , Ingestión de Energía , Ésteres/química , Ácidos Grasos Volátiles/metabolismo , Heces , Fermentación , Humanos , Masculino , Persona de Mediana Edad , PropionatosRESUMEN
BACKGROUND: Enteroendocrine L-cells synthesise and release the gut hormone glucagon-like peptide-1 (GLP-1) in response to food transit. Deletion of the tumour suppressor kinase LKB1 from proglucagon-expressing cells leads to the generation of intestinal polyps but no change in circulating GLP-1 levels. Here, we explore the role of the downstream kinase AMP-activated protein kinase (AMPK) in these cells. METHOD: Loss of AMPK from proglucagon-expressing cells was achieved using a preproglucagon promoter-driven Cre (iGluCre) to catalyse recombination of floxed alleles of AMPKα1 and α2. Oral and intraperitoneal glucose tolerance were measured using standard protocols. L-cell mass was measured by immunocytochemistry. Hormone and peptide levels were measured by electrochemical-based luminescence detection or radioimmunoassay. RESULTS: Recombination with iGluCre led to efficient deletion of AMPK from intestinal L- and pancreatic alpha-cells. In contrast to mice rendered null for LKB1 using the same strategy, mice deleted for AMPK displayed an increase (WT: 0.05 ± 0.01, KO: 0.09±0.02%, p<0.01) in L-cell mass and elevated plasma fasting (WT: 5.62 ± 0.800 pg/ml, KO: 14.5 ± 1.870, p<0.01) and fed (WT: 15.7 ± 1.48pg/ml, KO: 22.0 ± 6.62, p<0.01) GLP-1 levels. Oral, but not intraperitoneal, glucose tolerance was significantly improved by AMPK deletion, whilst insulin and glucagon levels were unchanged despite an increase in alpha to beta cell ratio (WT: 0.23 ± 0.02, KO: 0.33 ± 0.03, p<0.01). CONCLUSION: AMPK restricts L-cell growth and GLP-1 secretion to suppress glucose tolerance. Targeted inhibition of AMPK in L-cells may thus provide a new therapeutic strategy in some forms of type 2 diabetes.
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Proteínas Quinasas Activadas por AMP/genética , Eliminación de Gen , Péptido 1 Similar al Glucagón/sangre , Prueba de Tolerancia a la Glucosa , Proglucagón/genética , Animales , Femenino , Células Secretoras de Glucagón/citología , Células Secretoras de Glucagón/metabolismo , Glucosa/metabolismo , Insulina/sangre , Mucosa Intestinal/metabolismo , Intestinos/citología , Masculino , Ratones , Regiones Promotoras GenéticasRESUMEN
OBJECTIVE: The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. DESIGN: To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. RESULTS: Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10â g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24â weeks, 10â g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. CONCLUSIONS: These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans. TRIAL REGISTRATION NUMBER: NCT00750438.
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Adiposidad/efectos de los fármacos , Regulación del Apetito/efectos de los fármacos , Mantenimiento del Peso Corporal/efectos de los fármacos , Colon/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Sobrepeso/tratamiento farmacológico , Péptido YY/metabolismo , Propionatos/administración & dosificación , Células Cultivadas , Colon/citología , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Propionatos/farmacologíaRESUMEN
Liver kinase B1 (LKB1; also known as STK11) is a serine/threonine kinase and tumour suppressor that is mutated in Peutz-Jeghers syndrome (PJS), a premalignant syndrome associated with the development of gastrointestinal polyps. Proglucagon-expressing enteroendocrine cells are involved in the control of glucose homeostasis and the regulation of appetite through the secretion of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY). To determine the role of LKB1 in these cells, we bred mice bearing floxed alleles of Lkb1 against animals carrying Cre recombinase under proglucagon promoter control. These mice (GluLKB1KO) were viable and displayed near-normal growth rates and glucose homeostasis. However, they developed large polyps at the gastro-duodenal junction, and displayed premature mortality (death from 120 days of age). Histological analysis of the polyps demonstrated that they had a PJS-like appearance with an arborising smooth-muscle core. Circulating GLP-1 levels were normal in GluLKB1KO mice and the polyps expressed low levels of the peptide, similar to levels in the neighbouring duodenum. Lineage tracing using a Rosa26tdRFP transgene revealed, unexpectedly, that enterocytes within the polyps were derived from non-proglucagon-expressing precursors, whereas connective tissue was largely derived from proglucagon-expressing precursors. Developmental studies in wild-type mice suggested that a subpopulation of proglucagon-expressing cells undergo epithelial-mesenchymal transition (EMT) to become smooth-muscle-like cells. Thus, it is likely that polyps in the GluLKB1KO mice developed from a unique population of smooth-muscle-like cells derived from a proglucagon-expressing precursor. The loss of LKB1 within this subpopulation seems to be sufficient to drive tumorigenesis.
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Pólipos Intestinales/patología , Proglucagón/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Animales , Transición Epitelial-Mesenquimal , Ratones , Ratones NoqueadosAsunto(s)
Absceso/diagnóstico , Infecciones de los Tejidos Blandos/diagnóstico , Infecciones Estreptocócicas/diagnóstico , Streptococcus pyogenes/aislamiento & purificación , Enfermedades de la Tiroides/diagnóstico , Glándula Tiroides/anomalías , Absceso/tratamiento farmacológico , Adulto , Amoxicilina/uso terapéutico , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Antibacterianos/uso terapéutico , Ceftriaxona/uso terapéutico , Clindamicina/uso terapéutico , Diagnóstico Diferencial , Humanos , Masculino , Dolor de Cuello/diagnóstico , Dolor de Cuello/etiología , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Infecciones Estreptocócicas/tratamiento farmacológico , Enfermedades de la Tiroides/tratamiento farmacológico , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
CONTEXT: Adrenal vein sampling (AVS) is recommended in all patients with hyperaldosteronism to whom surgery would be offered if the results indicated unilateral hypersecretion. OBJECTIVE: To assess the performance of AVS against radiological findings and to evaluate the Endocrine Society's Practice Guidelines for diagnostic cut-offs. PATIENTS: Retrospective study of 41 patients with hyperaldosteronism who underwent both AVS and computed tomography (CT) imaging. RESULTS: CT and AVS results were concordant in 73.7%. Unilateral lesions on CT had a greater positive predictive value (85%) than non-unilateral lesions (50%). In patients with subsequently confirmed adrenal adenomas, a lateralisation ratio >2 when comparing cortisol-corrected aldosterone ratios from the affected versus unaffected side was 100% sensitive. Patients who were managed surgically experienced significant reductions in blood pressure and medication burden and 46% were cured. CONCLUSIONS: AVS is important in establishing unilateral or bilateral adrenal secretion of aldosterone in patients with primary hyperaldosteronism. However, it may not be essential for the work-up in patients below the age of 40, in whom adrenal incidentalomas adrenal incidentalomas are known to be rarer, and a unilateral lesion on CT therefore has a greater positive predictive value.
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Glándulas Suprarrenales/cirugía , Hiperaldosteronismo/diagnóstico , Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/patología , Adrenalectomía , Adulto , Femenino , Humanos , Hiperaldosteronismo/diagnóstico por imagen , Hiperaldosteronismo/cirugía , Masculino , Persona de Mediana Edad , Derivación y Consulta , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
AIMS: The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug's pharmacokinetics and dose proportionality. METHODS: This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by C(max) and AUC(0,∞). RESULTS: PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C(max) was reached at a median t(max) of approximately 1 h post dose (range 0.32-2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t(1/2) ranging from 2.42-2.61 h (range 1.64-3.95 h) across all dose levels. CONCLUSIONS: Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2-8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.
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Depresores del Apetito/farmacocinética , Apetito/efectos de los fármacos , Obesidad/prevención & control , Polipéptido Pancreático/análogos & derivados , Receptores de Neuropéptido Y/agonistas , Adolescente , Adulto , Depresores del Apetito/efectos adversos , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Polipéptido Pancreático/efectos adversos , Polipéptido Pancreático/farmacocinética , Reino Unido , Adulto JovenRESUMEN
The obesity epidemic has a direct impact on every aspect of health. Current strategies to treat obesity are limited and there is a need to pioneer novel solutions. Anorectic gut hormones, physiologically secreted post-prandially to mediate satiety, have recently emerged as potential therapeutic targets in obesity. Peptide tyrosine tyrosine (PYY) is one such anorectic gut hormone, secreted from entero-endocrine L cells, which acts on neuropeptide Y (NPY) receptors within the central appetite circuit. Since the first intravenous administration of PYY to man nearly a decade ago, a number of translational studies and clinical trials have ensued with a view to developing this peptide as a treatment for obesity. This review reports on the current state of play of this on-going research.
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Fármacos Antiobesidad/uso terapéutico , Terapia Molecular Dirigida , Obesidad/tratamiento farmacológico , Péptido YY/uso terapéutico , Investigación Biomédica Traslacional , Animales , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/farmacología , Depresores del Apetito/farmacología , Depresores del Apetito/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/farmacología , Fármacos Gastrointestinales/uso terapéutico , Humanos , Obesidad/metabolismo , Péptido YY/administración & dosificación , Péptido YY/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
No truly effective drugs exist to treat obesity, which is reaching pandemic proportions. The search for new treatments has led to an interest into the homeostatic system of central appetite regulation. Key components of this system include the hypothalamus and brainstem, the gut, and adipose tissue. It is now recognized that food intake leads to the release of various gut hormones. There are several anorectic (appetite suppressing) gut hormones released, including cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine, and pancreatic polypeptide. To date, only one example is known of an orexigenic (appetite stimulating) hormone, ghrelin. These hormones circulate in the blood and signal via vagal nerve afferents to communicate with the hypothalamus and brainstem. This information is integrated and processed in key hypothalamic nuclei. The arcuate nucleus appears to be a central controller of the appetite circuit, integrating both peripheral and central signals. This information is translated into downstream signals affecting body metabolism and food intake. Increased understanding and successful manipulation of this system should enable the design of a successful and much needed anti-obesity treatment.
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Regulación del Apetito/fisiología , Encéfalo/metabolismo , Hormonas Gastrointestinales/metabolismo , Animales , HumanosRESUMEN
AIMS: To investigate (i) if kisspeptin administration alters heart rate (HR) or blood pressure (BP) in healthy male and female volunteers, (ii) whether circulating plasma kisspeptin concentrations in healthy pregnant women and women with hypertensive diseases of pregnancy correlate with BP and (iii) whether women with hypertensive diseases of pregnancy have altered plasma kisspeptin concentrations. METHODS: We have previously reported the effects of administration of kisspeptin-54 on gonadotrophin secretion in healthy male and female volunteers. In these studies, cardiovascular parameters were not a primary endpoint. However, data were also collected on BP and HR for 4h post administration of kisspeptin-54. Blood samples were taken from 105 women in the third trimester of pregnancy (27 women with hypertensive diseases of pregnancy and 78 controls). Samples were assayed for plasma kisspeptin immunoreactivity (IR). RESULTS: Administration of kisspeptin was not associated with significant changes in HR or BP in healthy men or women. There was no significant correlation between plasma kisspeptin concentration and BP in healthy pregnant women or in those with hypertensive diseases of pregnancy. No significant differences in plasma kisspeptin-IR concentrations were observed between women with hypertensive diseases of pregnancy and normotensive pregnant controls, plasma kisspeptin concentrations ±SE: controls 2878 ± 157pmol l(-1) ; pregnancy-induced hypertension 2696 ± 299pmoll(-1) (95% CI vs. controls -514, 878pmoll(-1) ); pre-eclampsia 3519 ± 357 (95% CI vs. controls -1644, 362pmoll(-1) ). CONCLUSIONS: Elevation of plasma kisspeptin-IR is not associated with an alteration in BP in humans.
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Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Hipertensión Inducida en el Embarazo/fisiopatología , Preeclampsia/fisiopatología , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Proteínas Supresoras de Tumor/sangre , Proteínas Supresoras de Tumor/farmacología , Adulto , Estudios de Casos y Controles , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión Inducida en el Embarazo/sangre , Kisspeptinas , Masculino , Preeclampsia/sangre , Embarazo , Complicaciones Cardiovasculares del Embarazo/sangre , Tercer Trimestre del EmbarazoRESUMEN
The way in which the composition of the diet may affect appetite, food intake and body weight is now receiving considerable attention in a bid to halt the global year-on-year rise in obesity prevalence. Epidemiological evidence suggests that populations who follow a fibre-rich, traditional diet are likely to have a lower body weight and improved metabolic parameters than their Western-diet counterparts. The colonic effects of fibre, and more specifically the SCFA that the fermentation process produces, may play a role in maintaining energy homeostasis via their action on the G-coupled protein receptor free fatty acid receptor 2 (FFA2; formerly GPR43). In the present review, we summarise the evidence for and against the role of FFA2 in energy homeostasis circuits and the possible ways that these could be exploited therapeutically. We also propose that the decline in fibre content of the diet since the Industrial Revolution, particularly fermentable fractions, may have resulted in the FFA2-mediated circuits being under-utilised and hence play a role in the current obesity epidemic.