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1.
Basic Res Cardiol ; 113(6): 43, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30310998

RESUMO

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury.


Assuntos
Cardiologia , Oncologia , Infarto do Miocárdio , Acidente Vascular Cerebral , Animais , Antineoplásicos/efeitos adversos , Cardiologia/métodos , Cardiologia/tendências , Citoproteção , Humanos , Precondicionamento Isquêmico Miocárdico/métodos , Oncologia/métodos , Oncologia/tendências , Traumatismo por Reperfusão Miocárdica/prevenção & controle
2.
Diabetes Obes Metab ; 20(4): 1080-1085, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29227575

RESUMO

To explore the effects of a single dose of the DPP-4 inhibitor sitagliptin on glucose-standardized insulin secretion and ß-cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug-naïve, well-controlled type 2 diabetes (T2D) subjects (mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100 mg) or placebo before a meal (525 kcal). ß-cell function was measured as the insulin secretory rate at a standardized glucose concentration and the ß-cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing ß-cell glucose sensitivity. Sitagliptin also increased active glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and reduced total (reflecting the secretion) GIP, but not total GLP-1 levels. We conclude that a single dose of DPP-4 inhibition induces dissociated effects on different aspects of ß-cell function and incretin hormones after meal ingestion in both healthy and well-controlled T2D subjects.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Incretinas/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Adulto , Idoso , Glicemia/efeitos dos fármacos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/metabolismo , Secreção de Insulina , Masculino , Refeições/fisiologia , Pessoa de Meia-Idade , Período Pós-Prandial , Fosfato de Sitagliptina/administração & dosagem , Adulto Jovem
3.
Am J Physiol Endocrinol Metab ; 305(1): E59-66, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23651846

RESUMO

The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI × 104 min⁻¹·pM⁻¹: 1.11 ± 0.44 vs. 0.62 ± 0.22, P < 0.015, in controls and 0.79 ± 0.34 vs. 0.40 ± 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 ± 1.36 vs. 1.13 ± 0.78 × 106, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 ± 1.05 vs. 1.09 ± 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Duodeno/metabolismo , Nutrição Enteral/métodos , Resistência à Insulina/fisiologia , Jejuno/metabolismo , Obesidade/fisiopatologia , Adulto , Cirurgia Bariátrica , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/cirurgia , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Feminino , Alimentos , Intolerância à Glucose/dietoterapia , Intolerância à Glucose/fisiopatologia , Intolerância à Glucose/cirurgia , Humanos , Incretinas/metabolismo , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Intubação Gastrointestinal , Masculino , Pessoa de Meia-Idade , Obesidade/dietoterapia , Obesidade/cirurgia
4.
J Clin Endocrinol Metab ; 96(8): 2519-24, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21593115

RESUMO

CONTEXT: The incretin effect is responsible for the higher insulin response to oral glucose than to iv glucose at matching glucose levels. It is not known whether this effect is restricted to glucose only. OBJECTIVE: The aim of the study was to examine whether insulin and incretin hormone responses are higher after oral vs. iv challenge of a lipid emulsion with matching triglyceride levels in humans. DESIGN, SETTINGS, AND PARTICIPANTS: A lipid emulsion (Intralipid) was administered orally (3 ml/kg) or iv (variable infusion rates to match triglyceride levels after oral ingestion) in healthy lean males (n = 12) at a University Clinical Research Unit. Samples were collected during 300 min. MAIN OUTCOME MEASURES: We measured the suprabasal area under the curve for insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and the insulin secretory rate based on C-peptide levels by deconvolution. RESULTS: Triglyceride levels increased similarly after oral and iv lipid; also, glucose and free fatty acid levels were similar in the two tests. Oral lipid elicited a clear insulin and C-peptide response, whereas no insulin or C-peptide responses were observed during iv lipid. Total and intact GIP and GLP-1 levels both increased after oral lipid administration but were not significantly altered after iv lipid. CONCLUSIONS: At matching triglyceride levels and with no difference in glucose and free fatty acid levels, oral lipid ingestion but not iv lipid infusion elicits a clear insulin response in association with increased GIP and GLP-1 concentrations. This may suggest that the incretin hormones also contribute to the islet response to noncarbohydrate nutrients.


Assuntos
Incretinas/sangue , Incretinas/metabolismo , Insulina/sangue , Insulina/metabolismo , Fosfolipídeos/administração & dosagem , Óleo de Soja/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Glicemia/metabolismo , Peptídeo C/sangue , Emulsões/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Polipeptídeo Inibidor Gástrico/sangue , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Infusões Intravenosas , Secreção de Insulina , Masculino , Triglicerídeos/sangue , Adulto Jovem
5.
Am J Physiol Heart Circ Physiol ; 300(4): H1361-72, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21278133

RESUMO

Activation of apoptosis contributes to cardiomyocyte dysfunction and death in diabetic cardiomyopathy. The peptide glucagon-like peptide-1 (GLP-1), a hormone that is the basis of emerging therapy for type 2 diabetic patients, has cytoprotective actions in different cellular models. We investigated whether GLP-1 inhibits apoptosis in HL-1 cardiomyocytes stimulated with staurosporine, palmitate, and ceramide. Studies were performed in HL-1 cardiomyocytes. Apoptosis was induced by incubating HL-1 cells with staurosporine (175 nM), palmitate (135 µM), or ceramide (15 µM) for 24 h. In staurosporine-stimulated HL-1 cardiomyocytes, phosphatidylserine exposure, Bax-to-Bcl-2 ratio, Bad phosphorylation (Ser(136)), BNIP3 expression, mitochondrial membrane depolarization, cytochrome c release, caspase-3 activation, DNA fragmentation, and mammalian target of rapamycin (mTOR)/p70S6K phosphorylation (Ser(2448) and Thr(389), respectively) were assessed. Apoptotic hallmarks were also measured in the absence or presence of low (5 mM) and high (10 mM) concentrations of glucose. In addition, phosphatidylserine exposure and DNA fragmentation were analyzed in palmitate- and ceramide-stimulated cells. Staurosporine increased apoptosis in HL-1 cardiomyocytes. GLP-1 (100 nM) partially inhibited staurosporine-induced mitochondrial membrane depolarization and completely blocked the rest of the staurosporine-induced apoptotic changes. This cytoprotective effect was mainly mediated by phosphatidylinositol 3-kinase (PI3K) and partially dependent on ERK1/2. Increasing concentrations of glucose did not influence GLP-1-induced protection against staurosporine. Furthermore, GLP-1 inhibited palmitate- and ceramide-induced phosphatidylserine exposure and DNA fragmentation. Incretin GLP-1 protects HL-1 cardiomyocytes against activation of apoptosis. This cytoprotective ability is mediated mainly by the PI3K pathway and partially by the ERK1/2 pathway and seems to be glucose independent. It is proposed that therapies based on GLP-1 may contribute to prevent cardiomyocyte apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Incretinas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Caspase 3/biossíntese , Linhagem Celular , Ceramidas/farmacologia , Citocromos c/metabolismo , Fragmentação do DNA , Inibidores Enzimáticos/farmacologia , Glucose/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Membrana/biossíntese , Camundongos , Proteínas Mitocondriais/biossíntese , Palmitatos/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilserinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Estaurosporina/farmacologia , Serina-Treonina Quinases TOR/metabolismo
6.
Vitam Horm ; 84: 203-20, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21094901

RESUMO

The two incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are key factors in the regulation of islet function and glucose metabolism, and incretin-based therapy for type 2 diabetes has gained considerable interest during recent years. Regulation of incretin hormone secretion is less well characterized. The main stimulus for incretin hormone secretion is presence of nutrients in the intestinal lumen, and carbohydrate, fat as well as protein all have the capacity to stimulate GIP and GLP-1 secretion. More recently, it has been established that a diurnal regulation exists with incretin hormone secretion to an identical meal being greater when the meal is served in the morning compared to in the afternoon. Finally, whether incretin hormone secretion is altered in disease states is an area with, so far, controversial results in different studies, although some studies have demonstrated reduced incretin hormone secretion in type 2 diabetes. This review summarizes our knowledge on regulation of incretin hormone secretion and its potential changes in disease states.


Assuntos
Ingestão de Alimentos/fisiologia , Polipeptídeo Inibidor Gástrico/fisiologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Animais , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos
7.
J Clin Endocrinol Metab ; 95(2): 872-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20008019

RESUMO

CONTEXT: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are cleaved by dipeptidyl peptidase-4 (DPP-4); plasma activity of DPP-4 may be increased in obesity. The impact of this increase on incretin hormone secretion and metabolism is not known. OBJECTIVE: The aim of the study was to assess incretin hormone secretion and degradation in lean and obese nondiabetic subjects. DESIGN, SETTINGS, AND PARTICIPANTS: We studied the ingestion of a mixed meal (560 kcal) or oral glucose (2 g/kg) in healthy lean (n = 12; body mass index, 20-25 kg/m(2)) or obese (n = 13; body mass index, 30-35 kg/m(2)) males at a University Clinical Research Unit. MAIN OUTCOME MEASURES: We measured the area under the curve of plasma intact (i) and total (t) GIP and GLP-1 after meal ingestion and oral glucose. RESULTS: Plasma DPP-4 activity was higher in the obese subjects (38.5 +/- 3.0 vs. 26.7 +/- 1.6 mmol/min . microl; P = 0.002). Although GIP secretion (AUC(tGIP)) was not reduced in obese subjects after meal ingestion or oral glucose, AUC(iGIP) was lower in obese subjects (8.5 +/- 0.6 vs. 12.7 +/- 0.9 nmol/liter x 300 min; P < 0.001) after meal ingestion. GLP-1 secretion (AUC(tGLP-1)) was reduced in obese subjects after both meal ingestion (7.3 +/- 0.9 vs. 10.0 +/- 0.6 nmol/liter x 300 min; P = 0.022) and oral glucose (6.6 +/- 0.8 vs. 9.6 +/- 1.1 nmol/liter x 180 min; P = 0.035). iGLP-1 was reduced in parallel to tGLP-1. CONCLUSIONS: 1) Release and degradation of the two incretin hormones show dissociated changes in obesity: GLP-1 but not GIP secretion is lower after meal ingestion and oral glucose, whereas GIP but not GLP-1 metabolism is increased after meal ingestion. 2) Increased plasma DPP-4 activity in obesity is not associated with a generalized augmented incretin hormone metabolism.


Assuntos
Dipeptidil Peptidase 4/fisiologia , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/administração & dosagem , Obesidade/metabolismo , Magreza/metabolismo , Acetaminofen/farmacologia , Adulto , Área Sob a Curva , Alimentos , Humanos , Resistência à Insulina , Masculino , Adulto Jovem
8.
J Clin Endocrinol Metab ; 94(8): 2887-92, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19435824

RESUMO

CONTEXT: The insulin response to meal ingestion is more rapid in the morning than in the afternoon. Whether this is explained by a corresponding variation in the incretin hormones is not known. OBJECTIVE: Our objective was to assess islet and incretin hormones after meal ingestion in the morning vs. afternoon. DESIGN, SETTINGS, AND PARTICIPANTS: Ingestion at 0800 and 1700 h of a standardized meal (524 kcal) in healthy lean males (n = 12) at a University Clinical Research Unit. MAIN OUTCOME MEASURES: We assessed early (30-min) area under the curve (AUC30) of plasma levels of insulin and intact (i) and total (t) glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) after meal ingestion and made an estimation of beta-cell function by model analysis of glucose and C-peptide. RESULTS: Peak glucose was lower in the morning than in the afternoon (6.1 +/- 0.2 vs. 7.4 +/- 0.3 mmol/liter, P = 0.001). AUC30(insulin) (4.9 +/- 0.6 vs. 2.8 +/- 0.4 nmol/liter . 30 min; P = 0.012), AUC30(tGLP-1) (300 +/- 40 vs. 160 +/- 30 pmol/liter . 30 min, P = 0.002), AUC30(iGIP) (0.7 +/- 0.1 vs. 0.3 +/- 0.1 nmol/liter . 30 min, P = 0.002), and AUC30(tGIP) (1.1 +/- 0.1 vs. 0.6 +/- 0.1 nmol/liter . min, P = 0.007) were all higher in the morning. AUC30(iGLP-1) (r = 0.68; P = 0.021) and AUC30(iGIP) (r = 0.78; P = 0.001) both correlated to AUC30(insulin). Model analysis of beta-cell function showed a higher first-hour potentiation factor in the morning (P = 0.009). This correlated negatively with the 60-min glucose level (r = -0.63; P < 0.001). CONCLUSIONS: The early release of GLP-1 and GIP are more pronounced in the morning than in the afternoon. This may contribute to the more rapid early insulin response, more pronounced potentiation of beta-cell function, and lower glucose after the morning meal.


Assuntos
Incretinas/sangue , Ilhotas Pancreáticas/fisiologia , Adulto , Glicemia/análise , Peptídeo C/análise , Ácidos Graxos não Esterificados/sangue , Polipeptídeo Inibidor Gástrico/sangue , Glucagon/sangue , Humanos , Insulina/sangue , Masculino , Período Pós-Prandial , Fatores de Tempo
9.
Am J Physiol Endocrinol Metab ; 295(4): E779-84, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18612044

RESUMO

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate islet function after carbohydrate ingestion. Whether incretin hormones are of importance for islet function after ingestion of noncarbohydrate macronutrients is not known. This study therefore examined integrated incretin and islet hormone responses to ingestion of pure fat (oleic acid; 0.88 g/kg) or protein (milk and egg protein; 2 g/kg) over 5 h in healthy men, aged 20-25 yr (n=12); plain water ingestion served as control. Both intact (active) and total GLP-1 and GIP levels were determined as was plasma activity of dipeptidyl peptidase-4 (DPP-4). Following water ingestion, glucose, insulin, glucagon, GLP-1, and GIP levels and DPP-4 activity were stable during the 5-h study period. Both fat and protein ingestion increased insulin, glucagon, GIP, and GLP-1 levels without affecting glucose levels or DPP-4 activity. The GLP-1 responses were similar after protein and fat, whereas the early (30 min) GIP response was higher after protein than after fat ingestion (P<0.001). This was associated with sevenfold higher insulin and glucagon responses compared with fat ingestion (both P<0.001). After protein, the early GIP, but not GLP-1, responses correlated to insulin (r(2)=0.86; P=0.0001) but not glucagon responses. In contrast, after fat ingestion, GLP-1 and GIP did not correlate to islet hormones. We conclude that, whereas protein and fat release both incretin and islet hormones, the early GIP secretion after protein ingestion may be of primary importance to islet hormone secretion.


Assuntos
Gorduras na Dieta/farmacologia , Proteínas Alimentares/farmacologia , Incretinas/biossíntese , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Hormônios Pancreáticos/metabolismo , Adulto , Glicemia/metabolismo , Água Corporal/metabolismo , Dieta , Dipeptidil Peptidase 4/sangue , Ácidos Graxos não Esterificados/sangue , Polipeptídeo Inibidor Gástrico/biossíntese , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/biossíntese , Humanos , Insulina/sangue , Masculino , Triglicerídeos/sangue
10.
Basic Res Cardiol ; 103(3): 274-84, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18080084

RESUMO

BACKGROUND: In the majority of studies, metformin has been demonstrated to cardioprotect diabetic patients, the mechanism of which is unclear. We hypothesized that metformin cardioprotects the ischemic heart through the Akt-mediated inhibition of mitochondrial permeability transition pore (mPTP) opening. MATERIALS AND METHODS: Isolated perfused hearts from normoglycemic Wistar or from diabetic Goto-Kakizaki (GK) rats (N > or = 6/group) were subjected to 35 min ischemia and 120 min of reperfusion. Metformin (50 micromol/l) was added for 15 min at reperfusion, alone or with LY294002 (15 micromol/l), a PI3K inhibitor. Infarct size and Akt phosphorylation were measured. Furthermore, the effect of metformin on mPTP opening in adult cardiomyocytes isolated from both strains was determined. RESULTS: Metformin reduced infarct size in both Wistar (35 +/- 2.7% metformin vs. 62 +/- 3.0% control: P < 0.05) and GK hearts (43 +/- 4.7% metformin vs. 60 +/- 3.8% control: P < 0.05). This protection was accompanied by a significant increase in Akt phosphorylation. LY294002 abolished the metformin-induced Akt phosphorylation and the infarct-limiting effect of metformin in Wistar (61 +/- 6.7% metformin + LY294002 vs. 35 +/- 2.7% metformin: P < 0.05) and GK rats (56 +/- 5.7% metformin + LY294002 vs. 43 +/- 4.7% metformin: P < 0.05). In addition, metformin significantly inhibited mPTP opening and subsequent rigor contracture in both Wistar and GK cardiomyocytes subjected to oxidative stress, in a LY-sensitive manner. CONCLUSIONS: We report that metformin given at the time of reperfusion reduces myocardial infarct size in both the non-diabetic and diabetic heart and this protective effect is mediated through PI3K and is associated with Akt phosphorylation. Furthermore, cardioprotection appears to be executed through a PI3K-mediated inhibition of mPTP opening. These findings may explain in part the cardioprotective properties of metformin observed in clinical studies of diabetic patients.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Cromonas/farmacologia , Diabetes Mellitus/enzimologia , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Hipoglicemiantes/administração & dosagem , Contratura Isquêmica/enzimologia , Contratura Isquêmica/prevenção & controle , Masculino , Metformina/administração & dosagem , Mitocôndrias Cardíacas/enzimologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Morfolinas/farmacologia , Isquemia Miocárdica/enzimologia , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar
11.
Front Biosci ; 13: 1780-94, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17981667

RESUMO

Many patients with type 2 diabetes fail to achieve adequate glycaemic control with available treatments, even when used in combination, and eventually develop microvascular and macrovascular diabetic complications. Even intensive interventions to control glycaemia reduce macrovascular complications only minimally. There is, therefore, a need for new agents that more effectively treat the disease, as well as target its prevention, its progression, and its associated complications. One emerging area of interest is centred upon the actions of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which enhance meal-induced insulin secretion and have trophic effects on the beta-cell. GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite. Two new classes of agents have recently gained regulatory approval for therapy of type 2 diabetes; long-acting stable analogues of GLP-1, the so-called incretin mimetics, and inhibitors of dipeptidyl peptidase 4 (DPP-4, the enzyme responsible for the rapid degradation of the incretin hormones), the so-called incretin enhancers. This article focuses on DPP-4 inhibitors.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Inibidores da Dipeptidil Peptidase IV , Inibidores Enzimáticos/farmacologia , Animais , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Polipeptídeo Inibidor Gástrico/química , Glucose/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Incretinas/metabolismo , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Camundongos , Ratos
12.
Eur J Endocrinol ; 155(3): 485-93, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16914604

RESUMO

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretin hormones, secreted in response to meal ingestion. The incretin hormones stimulate insulin secretion and are essential for the maintenance of normal plasma glucose concentrations. Both incretin hormones are metabolized quickly by the enzyme dipeptidyl peptidase-IV (DPP-IV). It is well known that type-2 diabetic patients have an impaired incretin effect. Therefore, the aim of the present study was to investigate plasma DPP-IV activity in the fasting and the postprandial state in type-2 diabetic patients and control subjects. DESIGN: The study included two protocols. Protocol one involved 40 fasting type-2 diabetic patients (28 men); age 61 +/- 1.4 (mean +/- s.e.m.) years; body mass index (BMI) 31 +/- 0.6 kg/m(2); HbAlc 7.2 +/- 0.2%; and 20 matched control subjects (14 men) were studied. Protocol two involved eight type-2 diabetic patients (six men); age 63 +/- 1.2 years; BMI 33 +/- 0.5 kg/m(2); HbAlc 7.5 +/- 0.4%; eight matched control subjects were included. METHODS: In protocol one, fasting values of DPP-IV activity were evaluated and in protocol two, postprandial DPP-IV activity during a standard meal test (566 kcal) was estimated. RESULTS: Mean fasting plasma DPP-IV activity (expressed as degradation of GLP-1) was significantly higher in this patient group compared with the control subjects (67.5 +/- 1.9 vs 56.8 +/- 2.2 fmol GLP-1/h (mean +/- s.e.m.); P=0.001). In the type-2 diabetic patients, DPP-IV activity was positively correlated to FPG and HbAlc and negatively to the duration of diabetes and age of the patients. No postprandial changes were seen in plasma DPP-IV activity in any of the groups. CONCLUSIONS: Plasma DPP-IVactivity increases in the fasting state and is positively correlated to FPG and HbAlc levels, but plasma DPP-IV activity is not altered following meal ingestion and acute changes in plasma glucose.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/sangue , Ingestão de Alimentos/fisiologia , Hemoglobinas Glicadas/metabolismo , Glicemia/metabolismo , Índice de Massa Corporal , Peptídeo C/sangue , Jejum/metabolismo , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Hipoglicemiantes/farmacologia , Insulina/sangue , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade
13.
Endocrinology ; 147(7): 3173-80, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16627575

RESUMO

Monounsaturated fatty acids, such as oleic acid (OA), and certain milk proteins, especially whey protein (WP), have insulinotropic effects and can reduce postprandial glycemia. This effect may involve the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). To explore this, we examined the release and inactivation of GIP and GLP-1 after administration of glucose with or without OA or WP through gastric gavage in anesthetized C57BL/6J mice. Insulin responses to glucose (75 mg) were 3-fold augmented by addition of WP (75 mg; P < 0.01), which was associated with enhanced oral glucose tolerance (P < 0.01). The insulin response to glucose was also augmented by addition of OA (34 mg; P < 0.05) although only 1.5-fold and with no associated increase in glucose elimination. The slope of the glucose-insulin curve was increased by OA (1.7-fold; P < 0.05) and by WP (4-fold; P < 0.01) compared with glucose alone, suggesting potentiation of glucose-stimulated insulin release. WP increased GLP-1 secretion (P < 0.01), whereas GIP secretion was unaffected. OA did not affect GIP or GLP-1 secretion. Nevertheless, WP increased the levels of both intact GIP and intact GLP-1 (both P < 0.01), and OA increased the levels of intact GLP-1 (P < 0.05). WP inhibited dipeptidyl peptidase IV activity in the proximal small intestine by 50% (P < 0.05), suggesting that luminal degradation of WP generates small fragments, which are substrates for dipeptidyl peptidase IV and act as competitive inhibitors. We therefore conclude that fat and protein may serve as exogenous regulators of secretion and inactivation of the incretin hormones with beneficial influences on glucose metabolism.


Assuntos
Hormônios Gastrointestinais/metabolismo , Glucose/metabolismo , Animais , Área Sob a Curva , Gorduras na Dieta/metabolismo , Dipeptidil Peptidase 4/metabolismo , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Teste de Tolerância a Glucose , Insulina/metabolismo , Cinética , Camundongos , Camundongos Endogâmicos C57BL
14.
Diabetes ; 54(8): 2360-4, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16046302

RESUMO

Conflicting evidence exists whether diabetic myocardium can be protected by ischemic preconditioning (IPC). The phosphatidylinositol 3-kinase (PI3K)-Akt pathway is important in IPC. However, components of this cascade have been found to be defective in diabetes. We hypothesize that IPC in diabetic hearts depends on intact signaling through the PI3K-Akt pathway to reduce myocardial injury. Isolated perfused Wistar (normal) and Goto-Kakizaki (diabetic) rat hearts were subjected to 1) 35 min of regional ischemia and 120 min of reperfusion with infarct size determined; 2) preconditioning (IPC) using 5 min of global ischemia followed by 10 min of reperfusion performed one, two, or three times before prolonged ischemia; or 3) determination of Akt phosphorylation after stabilization or after one and three cycles of IPC. In Wistar rats, one, two, and three cycles of IPC reduced infarct size 44.7 +/- 3.8% (P < 0.05), 31.4 +/- 4.9% (P < 0.01), and 34.3 +/- 6.1% (P < 0.01), respectively, compared with controls (60.7 +/- 4.5%). However, in diabetic rats only three cycles of IPC significantly reduced infarction to 20.8 +/- 2.6% from 46.6 +/- 5.2% in controls (P < 0.01), commensurate with significant Akt phosphorylation after three cycles of IPC. To protect the diabetic myocardium, it appears necessary to increase the IPC stimulus to achieve the threshold for cardioprotection and a critical level of Akt phosphorylation to mediate myocardial protection.


Assuntos
Precondicionamento Isquêmico Miocárdico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/fisiopatologia , Hemoglobinas Glicadas/análise , Masculino , Isquemia Miocárdica/prevenção & controle , Reperfusão Miocárdica , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Wistar
15.
Am J Physiol Regul Integr Comp Physiol ; 289(4): R1027-34, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15919730

RESUMO

We investigated the effect of subdiaphragmatic vagal deafferentation (SDA) on food intake, body weight gain, and metabolism in obese (fa/fa) and lean (Fa/?) Zucker rats. Before and after recovery from surgery, food intake and body weight gain were recorded, and plasma glucose and insulin were measured in tail-prick blood samples. After implantation of a jugular vein catheter, an intravenous glucose tolerance test (IVGTT) was performed, followed by minimal modeling to estimate the insulin sensitivity index. Food intake relative to metabolic body weight (g/kg(0.75)) and daily body weight gain after surgery were lower (P < 0.05) in SDA than in sham obese but not lean rats. Before surgery, plasma glucose and insulin concentrations were lower (P < 0.05) in lean than in obese rats but did not differ between surgical groups within both genotypes. Four weeks after surgery, plasma glucose and insulin were still similar in SDA and sham lean rats but lower (P < 0.05) in SDA than in sham obese rats. IVGTT revealed a downward shift of the plasma insulin profile by SDA in obese but not lean rats, whereas the plasma glucose profile was unaffected. SDA decreased (P < 0.05) area under the curve for insulin but not glucose in obese rats. The insulin sensitivity index was higher in lean than in obese rats but was not affected by SDA in both genotypes. These results suggest that elimination of vagal afferent signals from the upper gut reduces food intake and body weight gain without affecting the insulin sensitivity index measured by minimal modeling in obese Zucker rats.


Assuntos
Peso Corporal , Glucose/metabolismo , Intestinos/inervação , Obesidade/metabolismo , Nervo Vago/fisiopatologia , Nervo Vago/cirurgia , Aumento de Peso , Animais , Denervação/métodos , Diafragma/inervação , Diafragma/cirurgia , Mucosa Intestinal/metabolismo , Intestinos/cirurgia , Masculino , Ratos , Ratos Zucker
16.
Eur J Pharmacol ; 509(2-3): 211-7, 2005 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-15733558

RESUMO

Sensory nerve desensitization by capsaicin has been shown to improve the diabetic condition in Zucker Diabetic Fatty rats. However, administration of capsaicin to adult rats is associated with an increased mortality. Therefore, in this experiment, we examined the influence of resiniferatoxin, a tolerable analogue of capsaicin suitable for in vivo use, on the diabetic condition of Zucker Diabetic Fatty rats. A single subcutaneous injection of resiniferatoxin (0.01 mg/kg) to these rats was tolerable, with no mortality. When administered to early diabetic rats at 15 weeks of age, the further deterioration of glucose homeostasis was prevented by resiniferatoxin. Further, when administered to overtly diabetic rats at 19 weeks of age, resiniferatoxin markedly improved glucose tolerance at two weeks after administration and this was accompanied by an increased insulin response to oral glucose as well as a reduction in the plasma levels of dipeptidyl peptidase IV. Therefore, resiniferatoxin is a safe alternative to capsaicin for further investigations of the role of the sensory nerves in experimental diabetes.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Dipeptidil Peptidase 4/sangue , Diterpenos/farmacologia , Insulina/metabolismo , Neurônios Aferentes/efeitos dos fármacos , Obesidade/fisiopatologia , Animais , Área Sob a Curva , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/prevenção & controle , Glucose/administração & dosagem , Glucose/farmacocinética , Teste de Tolerância a Glucose , Insulina/sangue , Secreção de Insulina , Neurônios Aferentes/fisiologia , Obesidade/sangue , Obesidade/prevenção & controle , Ratos , Ratos Zucker , Fatores de Tempo
17.
Regul Pept ; 120(1-3): 261-7, 2004 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-15177945

RESUMO

Ghrelin is a peptide identified as an endogenous ligand for the growth hormone secretagogue receptor. Studies have shown that ghrelin stimulates growth hormone, promotes food intake and decreases energy expenditure. Furthermore, feeding status seems to influence plasma ghrelin levels, as these are increased during fasting, whereas feeding and oral glucose intake reduce plasma ghrelin. This study examined whether standardized obesity and fasting affect cellular expression of ghrelin. Specimens from the gastrointestinal tract of fed or 18-h fasted, low-fat or high-fat fed (10 weeks on diet) C57BL/6J mice were studied by immunocytochemistry (ICC) for ghrelin and in situ hybridization (ISH) for ghrelin mRNA. Ghrelin was expressed in especially the corpus but also the antrum of the stomach of all groups studied. Cells positive for ghrelin and ghrelin mRNA in the stomach were reduced in high-fat fed mice. In contrast, ghrelin expression was not affected by fasting. The reduction in ghrelin expression in the high-fat fed mice was associated with a reduction in plasma levels of ghrelin, whereas after fasting, when expression rate was not altered, there was an increase in plasma ghrelin. In conclusion, ghrelin is highly expressed in the corpus and antrum of the stomach of C57BL/6J mice. This expression is reduced in obesity, whereas fasting has no effect.


Assuntos
Gorduras na Dieta/administração & dosagem , Jejum , Hormônios Peptídicos/genética , Estômago/fisiologia , Animais , Feminino , Grelina , Hormônio do Crescimento/metabolismo , Técnicas Imunoenzimáticas , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Hormônios Peptídicos/metabolismo
18.
Eur J Pharmacol ; 494(2-3): 283-8, 2004 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-15212985

RESUMO

Glucagon-like peptide-1 (GLP-1), a future treatment for type 2 diabetes, is efficiently degraded by the enzyme dipeptidyl peptidase IV (DPP IV), yielding the major metabolite GLP-1-(9-36)-amide. In this study, we examined the potential glucose lowering effect of GLP-1-(9-36)-amide in mice and found that GLP-1-(9-36)-amide (3 and 10 nmol/kg) did not affect insulin secretion or glucose elimination when administered intravenously together with glucose (1 g/kg). This was observed both in normal mice and in transgenic mice having a complete disruption of the signalling from the GLP-1 receptor. Furthermore, after blocking insulin secretion, using diazoxide (25 mg/kg), no effect on insulin-independent glucose disposal of GLP-1-(9-36)-amide was observed. Therefore, GLP-1-(9-36)-amide does not affect glucose disposal in mice either in the presence or absence of intact GLP-1-receptors or in the presence or absence of stimulated insulin levels. This suggests that the GLP-1 metabolite is not involved in the regulation of glucose homeostasis.


Assuntos
Glicemia/metabolismo , Hipoglicemiantes/farmacologia , Insulina/sangue , Peptídeos/farmacologia , Animais , Diazóxido/farmacologia , Feminino , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes/administração & dosagem , Injeções Intravenosas , Insulina/fisiologia , Ilhotas Pancreáticas/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Peptídeos/administração & dosagem , Canais de Potássio/agonistas , Receptores de Glucagon/efeitos dos fármacos , Receptores de Glucagon/genética
19.
Am J Physiol Endocrinol Metab ; 287(3): E431-8, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15126240

RESUMO

Glucagon has a short plasma t(1/2) in vivo, with renal extraction playing a major role in its elimination. Glucagon is degraded by neutral endopeptidase (NEP) 24.11 in vitro, but the physiological relevance of NEP 24.11 in glucagon metabolism is unknown. Therefore, the influence of candoxatril, a selective NEP inhibitor, on plasma levels of endogenous and exogenous glucagon was examined in anesthetized pigs. Candoxatril increased endogenous glucagon concentrations, from 6.3 +/- 2.5 to 20.7 +/- 6.3 pmol/l [COOH-terminal (C)-RIA, P < 0.05]. During glucagon infusion, candoxatril increased the t(1/2) determined by C-RIA (from 3.0 +/- 0.5 to 17.0 +/- 2.5 min, P < 0.005) and midregion (M)-RIA (2.8 +/- 0.5 to 17.0 +/- 3.0 min, P < 0.01) and reduced metabolic clearance rates (MCR; 19.1 +/- 3.2 to 9.4 +/- 2.0 ml.kg(-1).min(-1), P < 0.02, C-RIA; 19.2 +/- 4.8 to 9.0 +/- 2.3 ml.kg(-1).min(-1), P < 0.05, M-RIA). However, neither t(1/2) nor MCR determined by NH2-terminal (N)-RIA were significantly affected (t(1/2), 2.7 +/- 0.4 to 4.5 +/- 1.6 min; MCR, 30.3 +/- 6.4 to 28.5 +/- 9.0 ml.kg(-1).min(-1)), suggesting that candoxatril had no effect on NH2-terminal degradation but leads to the accumulation of NH2-terminally truncated forms of glucagon. Determination of arteriovenous glucagon concentration differences revealed that renal glucagon extraction was reduced (but not eliminated) by candoxatril (from 40.4 +/- 3.8 to 18.6 +/- 4.1%, P < 0.02, C-RIA; 29.2 +/- 3.1 to 14.7 +/- 2.2%, P < 0.02, M-RIA; 26.5 +/- 4.0 to 19.7 +/- 3.5%, P < 0.06, N-RIA). Femoral extraction was reduced by candoxatril when determined by C-RIA (from 22.7 +/- 2.4 to 8.0 +/- 5.1%, P < 0.05) but was not changed significantly when determined using M- or N-RIAs (10.0 +/- 2.8 to 4.7 +/- 3.7%, M-RIA; 10.5 +/- 2.5 to 7.8 +/- 4.2%, N-RIA). This study provides evidence that NEP 24.11 is an important mediator of the degradation of both endogenous and exogenous glucagon in vivo.


Assuntos
Glucagon/metabolismo , Neprilisina/metabolismo , Animais , Sinergismo Farmacológico , Glucagon/administração & dosagem , Glucagon/sangue , Indanos/farmacologia , Infusões Intravenosas , Neprilisina/antagonistas & inibidores , Concentração Osmolar , Propionatos/farmacologia , Inibidores de Proteases/farmacologia , Radioimunoensaio/métodos , Suínos
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