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AIMS: To assess the impact of bariatric surgery on remission and relapse of type 2 diabetes mellitus (T2DM) at 10 years of follow-up and analyze predictive factors. MATERIALS AND METHODS: Eighty-eight obese subjects undergoing Roux-en-Y gastric bypass (RYGB) and 25 subjects assigned to medical therapy (MT) were evaluated every year for 10 years. T2DM remission was defined by the American Diabetes Association criteria. RESULTS: Body mass index (BMI), fasting glucose, and haemoglobin A1c (HbA1c) improved more markedly in RYGB than MT patients throughout the 10-year period. Post-surgery remission rates were 74% and 53% at 1 and 10 years, respectively, while remission did not occur in MT patients. One-year post-surgery, BMI decreased more in subjects with remission than in those without, but no further decrease was observed thereafter. By partial-least-squares analysis, T2DM duration, baseline HbA1c, and ensuing insulin therapy were the strongest predictors of remission. Remission was achieved at one year in 91% of patients with T2DM duration < 4 years, and 79% of them remained in remission at 10 years. On the contrary only 42% of patients with T2DM duration ≥ 4 years achieved remission, which was maintained only in 6% at the end of 10 years. By survival analysis, patients with T2DM duration < 4 years had higher remission rates than those with duration ≥ 4 years (hazards ratio (HR) 3.1 [95%CI 1.8-5.7]). Relapse did not occur before two years post-surgery and was much less frequent in patients with < 4- vs ≥ 4-year duration (HR 11.8 [4.9-29.4]). CONCLUSIONS: Short T2DM duration and good glycemic control before RYGB surgery were the best requisites for a long-lasting T2DM remission, whereas weight loss had no impact on the long-term relapse of T2DM.
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Diabetes Mellitus Tipo 2 , Derivación Gástrica , Obesidad Mórbida , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/cirugía , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Obesidad Mórbida/complicaciones , Obesidad Mórbida/epidemiología , Obesidad Mórbida/cirugía , Recurrencia , Inducción de Remisión , Resultado del TratamientoRESUMEN
Mannose is a glucose-associated serum metabolite mainly released by the liver. Recent studies have shown several unexpected pleiotropic effects of mannose including increased regulatory T cells (Tregs), prevention of auto-immune disease and ability to reduce growth of human cancer cells. We have previously shown in large cohorts that elevated serum mannose levels are associated with future development of type 2 diabetes (T2D) and cardiovascular disease. However, potential direct effects of mannose on insulin sensitivity in vivo or in vitro are unknown. We here show that administration of mannose (0.1â¯g/kg BW twice daily) for one week in man did not elicit negative effects on meal-modified glucose tolerance, markers of inflammation or insulin levels. Tregs number and insulin signaling in human liver cells were unchanged. These data suggest that mannose is a marker, and not a mediator, of insulin resistance. To verify this, we examined serum mannose levels during long-term euglycemic hyperinsulinemic clamps in non-diabetic and T2D individuals. Mannose was reduced by insulin infusion in proportion to whole-body insulin sensitivity. Thus, mannose is a biomarker of insulin resistance which may be useful for the early identification of diabetic individuals with insulin resistance and increased risk of its complications.
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Biomarcadores/sangre , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Manosa/sangre , Anciano , Biomarcadores/metabolismo , Estudios de Casos y Controles , Femenino , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Masculino , Manosa/metabolismo , Persona de Mediana Edad , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND AND AIMS: The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. METHODS AND RESULTS: Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p < 0.01). In the whole group, mean PIC, GIP and GLP-1 concentrations during the OGTT were inversely correlated with SINCR, but T2D had lower PIC, GIP and GLP-1 levels at the same SINCR (p < 0.05). CONCLUSION: Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Polipéptido Inhibidor Gástrico/sangre , Péptido 1 Similar al Glucagón/sangre , Incretinas/sangre , Células Secretoras de Insulina/metabolismo , Insulina/sangre , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Estudios de Casos y Controles , Dinamarca , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/metabolismo , Secreción de Insulina , Masculino , Persona de Mediana Edad , Modelos Biológicos , Factores de TiempoRESUMEN
BACKGROUND/OBJECTIVE: The present study tested the hypothesis that obesity-related changes in carotid intima-media thickness (IMT) might represent not only preclinical atherosclerosis but an adaptive remodeling meant to preserve circumferential wall stress (CWS) in altered hemodynamic conditions characterized by body size-dependent increase in stroke volume (SV) and blood pressure (BP). SUBJECTS/METHODS: Common carotid artery (CCA) luminal diameter (LD), IMT and CWS were measured in three different populations in order to study: (A) cross-sectional associations between SV, BP, anthropometric parameters and CCA LD (266 healthy subjects with wide range of body weight (24-159 kg)); (B) longitudinal associations between CCA LD and 3-year IMT progression rate (ΔIMT; 571 healthy non-obese subjects without increased cardiovascular (CV) risk); (C) the impact of obesity on CCA geometry and CWS (88 obese subjects without CV complications and 88 non-obese subjects matched for gender and age). RESULTS: CCA LD was independently associated with SV that was determined by body size. In the longitudinal study, baseline LD was an independent determinant of ΔIMT, and ΔIMT of subjects in the highest LD quartile was significantly higher (28±3 µm) as compared with those in the lower quartiles (8±3, 16±4 and 16±3 µm, P=0.001, P<0.05 and P=0.01, respectively). In addition, CCA CWS decreased during the observational period in the highest LD quartile (from 54.2±8.6 to 51.6±7.4 kPa, P<0.0001). As compared with gender- and age-matched lean individuals, obese subjects had highly increased CCA LD and BP (P<0.0001 for both), but only slightly higher CWS (P=0.05) due to a significant increase in IMT (P=0.005 after adjustment for confounders). CONCLUSIONS: Our findings suggest that in obese subjects, the CCA wall thickens to compensate the luminal enlargement caused by body size-induced increase in SV, and therefore, to normalize the wall stress. CCA diameter in obesity could represent an additional biomarker, depicting the impact of altered hemodynamics on arterial wall.
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AIMS: Amino acid (AA) metabolism is altered in type 2 diabetes (T2D), and fasting levels of α-hydroxybutyrate (α-HB), a biomarker for insulin resistance, have been suggested to track AA metabolism. We investigated the changes in AA and α-HB induced by a mixed-meal tolerance test (MTT) and the effects of sitagliptin treatment. METHODS: Forty-seven T2D patients [56 ± 7 years, body mass index (BMI) 29.9 ± 4.2 kg/m(2) ] were randomized to sitagliptin (100 mg/day, 6 weeks) or placebo. Seven age- and BMI-matched non-diabetic subjects served as control (CT). RESULTS: During a 5-h MTT, branched-chain AA (BCAA) peaked earlier in T2D than CT [75(25) vs. 62(3) mmol/l · h over 2 h, median(interquartile range), p = 0.05], and rose higher [5-h increment: 31(23) vs. 19(24) mmol/l · h, p = 0.05]. Fasting α-HB was higher [7.5(2.7) vs. 5.9(1.3) µg/ml, p = 0.04 T2D vs. CT], and its meal-induced increments were larger [24(99) vs. -41(86) µg/ml · h, p = 0.006]. Plasma non-esterified fatty acids (NEFA) declined during MTT, but their increments were greater in patients (53 ± 16 vs. 35 ± 10 mEq/l · h, p = 0.005). Compared to placebo, both BCAA [-6.4(21.1) vs. 0.0(48.0) mmol/l · h, p = 0.01] and α-HB increments [-114(250) vs. 114(428) µg/ml · h, p = 0.002] decreased with sitagliptin, and meal-induced NEFA suppression was improved. Changes in BCAA and α-HB were reciprocally related to changes in insulin sensitivity (ρ = -0.37 and -0.43, p ≤ 0.01). CONCLUSIONS: T2D is associated with a hyperaminoacidaemic response to MTT, which circulating α-HB levels track. Sitagliptin-induced glycaemic improvement was associated with reductions in BCAA and α-HB excursions and better NEFA suppression, in parallel with improved insulin sensitivity, confirming that α-HB is a readout of metabolic overload.
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Aminoácidos/efectos de los fármacos , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Hidroxibutiratos/metabolismo , Pirazinas/administración & dosificación , Triazoles/administración & dosificación , Adulto , Anciano , Aminoácidos/metabolismo , Biomarcadores/metabolismo , Glucemia/metabolismo , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/sangre , Ayuno , Femenino , Humanos , Insulina/sangre , Resistencia a la Insulina , Masculino , Comidas , Persona de Mediana Edad , Fosfato de SitagliptinaRESUMEN
The upregulation of (C-X-C motif) receptor 3 (CXCR3) and its ligand (C-X-C motif) ligand (CXCL)10 (CXCL10) has been documented in many autoimmune disorders. Many studies have suggested that the CXCL10/CXCR3 axis plays a critical role in the autoimmune process and in ß-cell destruction in Type 1 Diabetes (T1D). Serum CXCL10 level "Th1 chemokine" is high in T1D patients, and this suggests that CXCL10 may be a candidate for a predictive marker of T1D. Furthermore, serum CXCL10 levels measurement may be useful to assess the pathophysiology of the disease course in T1D. Blocking of the CXCL10 chemokine expression in newly onset of diabetes seems to be a possible approach for the therapy of T1D. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis of T1D.
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Quimiocina CXCL10/fisiología , Diabetes Mellitus Tipo 1/etiología , Enfermedades Autoinmunes/etiología , Enfermedades del Sistema Endocrino/etiología , HumanosRESUMEN
BACKGROUND AND AIMS: We have previously shown that the anti-inflammatory and anti-oxidant functions of HDL are impaired in T2D patients. In this study, we examined whether HDL from T2D patients contains elevated levels of oxidized fatty acids and whether those levels correlate with cardiovascular disease (CVD). METHODS AND RESULTS: HETEs and HODEs on HDL were determined by LC-MS/MS in 40 non-diabetic controls (ND), 40 T2D without CVD (DâºCVDâ») and 38 T2D with known history of CVD (DâºCVDâº). HDL oxidant index was evaluated by a cell-free assay using dichlorofluorescein. Twenty-six randomly selected subjects from the three groups underwent coronary calcium score evaluation (CAC). Major cardiovascular risk factors were similar among the groups. HETEs and HODEs content were significantly increased in HDL from DâºCVD⺠when compared to DâºCVDâ» and ND patients. HDL oxidant index was not different among the three groups; however, it was significantly higher in patients with CAC score >100 when compared to patients with CAC score <100. CONCLUSION: Patients with DâºCVDâ» and DâºCVD⺠are characterized by a severe, graded enrichment of oxidized fatty acids on HDL. In the present study, a loss of HDL function (as estimated by the HDL oxidant index) is observed only in patients with more advanced atherosclerosis.
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Aterosclerosis/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/sangre , Peroxidación de Lípido , Lipoproteínas HDL/química , Regulación hacia Arriba , Calcificación Vascular/etiología , Adulto , Anciano , Anciano de 80 o más Años , Antioxidantes/análisis , Aterosclerosis/sangre , Aterosclerosis/epidemiología , Aterosclerosis/fisiopatología , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/fisiopatología , Femenino , Hospitales Universitarios , Humanos , Ácidos Hidroxieicosatetraenoicos/sangre , Ácidos Hidroxieicosatetraenoicos/química , Italia/epidemiología , Ácidos Linoleicos/sangre , Ácidos Linoleicos/química , Lipoproteínas HDL/sangre , Masculino , Persona de Mediana Edad , Servicio Ambulatorio en Hospital , Factores de Riesgo , Índice de Severidad de la Enfermedad , Calcificación Vascular/complicacionesRESUMEN
BACKGROUND & AIMS: The bases of the link between reduced glomerular filtration rate (GFR) and coronary artery disease (CAD) are complex and to some extent still unclear. We performed this observational, single referral center, cohort study to evaluate whether mild to moderate GFR reduction is associated with more severe CAD and/or with a worse cardiac prognosis independently of proteinuria, diabetes and traditional risk factors. METHODS AND RESULTS: In 1752 consecutive non-diabetic patients without proteinuria or moderate/severe kidney disease undergoing a clinically driven coronary angiography, coronary arteries lesions, myocardial function and hypertrophy and 10-yrs incidence of cardiac events and death were evaluated in relation to classes of estimated GFR defined according the lowest eGFR value (105+, 90+, 75+, 60+, 45+). A reduced eGFR was independently associated with hypertension, myocardial hypertrophy and stress induced ischemia, while the excess coronary lesions and the worse myocardial systolic function were both largely explained by age and cardiovascular risk factors. When compared to subjects 75+, both the risk of cardiac death (1.67[1.10-2.57] and 3.06[1.85-5.10]) and non-fatal myocardial infarction (2.58[1.12-6.49] and 2.73[1.31-6.41]) adjusted for age and comorbidities were higher in eGFR 60+ and 45+ patients. CONCLUSIONS: A mild-moderate reduction of eGFR is closely associated to higher rates of stress-induced ischemia, myocardial hypertrophy and higher risk of fatal and non-fatal cardiac events. The associations of reduced eGFR with coronary atherosclerosis and myocardial systolic dysfunction are both largely explained by age and traditional risk factors.
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Enfermedad de la Arteria Coronaria/etiología , Vasos Coronarios/diagnóstico por imagen , Riñón/fisiopatología , Insuficiencia Renal/fisiopatología , Adulto , Cardiomiopatía Hipertrófica/epidemiología , Cardiomiopatía Hipertrófica/etiología , Cardiomiopatía Hipertrófica/mortalidad , Cardiomiopatía Hipertrófica/fisiopatología , Estudios de Cohortes , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/mortalidad , Estudios Transversales , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Incidencia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Mortalidad , Isquemia Miocárdica/epidemiología , Isquemia Miocárdica/etiología , Isquemia Miocárdica/mortalidad , Isquemia Miocárdica/fisiopatología , Prevalencia , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
Hepatitis C virus (HCV) infection and Type 2 diabetes mellitus (T2DM) are two worldwide, major public health problems with increasing complication and mortality rates. Many epidemiological studies have demonstrated the significant association between T2DM and chronic HCV infection. In this paper we have reviewed the increasing evidence linking HCV infection and DM in more than one field (epidemiology, pathogenesis, clinical aspects, prevention and treatment). We have considered T2DM, acute and chronic HCV infection, and cirrhotic patients. Moreover, we have considered some particular populations, solid organ transplant recipients or HCV/human immunodeficiency virus (HIV) coinfected patients. In the final part we have analyzed the potential effect of the association between HCV infection and the development of DM in term of outcome and possibilities for prevention and treatment.
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Diabetes Mellitus Tipo 2/virología , Hepatitis C Crónica/complicaciones , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/inmunología , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 2/prevención & control , Susceptibilidad a Enfermedades , Genotipo , Glucosa/metabolismo , Infecciones por VIH/epidemiología , Hepacivirus/genética , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/metabolismo , Hepatitis C Crónica/prevención & control , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Hígado/metabolismo , Cirrosis Hepática/complicaciones , Cirrosis Hepática/metabolismo , Cirrosis Hepática/virología , Trasplante de Órganos , Complicaciones Posoperatorias/etiología , Prevalencia , Pronóstico , Enfermedades de la Tiroides/etiologíaRESUMEN
CONTEXT: In obese patients with type 2 diabetes (T2DM), Roux-en-Y-gastric-bypass (RYGB) and sleeve gastrectomy (SLG) improve glycemic control. OBJECTIVE: The objective of this study was to investigate the mechanisms of surgery-induced T2DM improvement and role of gastrointestinal hormones. PATIENTS, SETTING, AND INTERVENTION: In 35 patients with T2DM, we performed a mixed-meal test before and 15 days and 1 year after surgery (23 RYGB and 12 SLG). MAIN OUTCOME MEASURES: Insulin sensitivity, ß-cell function, and amylin, ghrelin, PYY, pancreatic polypeptide (PP), glucagon, and glucagon-like peptide-1 (GLP-1) responses to the meal were measured. RESULTS: T2DM remission occurred in 13 patients undergoing RYGB and in 7 patients undergoing SLG. Similarly in the RYGB and SLG groups, ß-cell glucose sensitivity improved both early and long term (P < .005), whereas insulin sensitivity improved long term only (P < .006), in proportion to body mass index changes (P < .001). Early after RYGB, glucagon and GLP-1 responses to the meal increased, whereas the PP response decreased. At 1 year, PYY was increased, and PP, amylin, ghrelin, and GLP-1 were reduced. After SLG, hormonal responses were similar to those with RYGB except that PP was increased, whereas amylin was unchanged. In remitters, fasting GLP-1 was higher (P = .04), but its meal response was flat compared with that of nonremitters; postsurgery, however, the GLP-1 response was higher. Other hormone responses were similar between the 2 groups. In logistic regression, presurgery ß-cell glucose sensitivity (positive, P < .0001) and meal-stimulated GLP-1 response (negative, P = .004) were the only predictors of remission. CONCLUSIONS: RYGB and SLG have a similar impact on diabetes remission, of which baseline ß-cell glucose sensitivity and a restored GLP-1 response are the chief determinants. Other hormonal responses are the consequences of the altered gastrointestinal anatomy.
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Diabetes Mellitus Tipo 2/metabolismo , Gastrectomía/métodos , Derivación Gástrica , Hormonas Gastrointestinales/metabolismo , Células Secretoras de Insulina/metabolismo , Obesidad Mórbida/cirugía , Adulto , Femenino , Glucagón/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Índice Glucémico/fisiología , Humanos , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Masculino , Persona de Mediana Edad , Obesidad Mórbida/metabolismo , Polipéptido Pancreático/metabolismo , Péptido YY/metabolismo , Inducción de RemisiónRESUMEN
AIM: This Phase IIb, randomized, double-blind, placebo-controlled trial evaluated the efficacy, safety, tolerability and pharmacokinetics of empagliflozin in patients with type 2 diabetes. METHODS: Four hundred and eight patients (treatment-naïve or after a 4-week wash-out period) were randomized to receive empagliflozin 5, 10 or 25 mg once daily, placebo or open-label metformin for 12 weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) after 12 weeks. RESULTS: After 12 weeks' treatment, empagliflozin showed dose-dependent reductions in HbA1c from baseline [5 mg: -0.4%, 10 mg: -0.5%, 25 mg: -0.6%; all doses p < 0.0001 vs. placebo (+0.09%)]. Fasting plasma glucose (FPG) decreased with empagliflozin [5 mg: -1.29 mmol/l, 10 mg: -1.61 mmol/l, 25 mg: -1.72 mmol/l; all doses p < 0.0001 vs. placebo (+0.04 mmol/l)]. Body weight decreased in all empagliflozin groups (all doses p < 0.001 vs. placebo). The incidence of adverse events (AEs) was similar in the placebo (32.9%) and empagliflozin (29.1%) groups. The most frequently reported AEs on empagliflozin were pollakiuria (3.3% vs. 0% for placebo), thirst (3.3% vs. 0% for placebo) and nasopharyngitis (2.0% vs. 1.2% for placebo). AEs consistent with urinary tract infections (UTIs) were reported in four (1.6%) patients on empagliflozin vs. one (1.2%) on placebo. Genital infections were reported in five (2%) patients on empagliflozin vs. 0% on placebo. No UTIs or genital infections led to premature discontinuation. CONCLUSIONS: In patients with type 2 diabetes, empagliflozin resulted in dose-dependent, clinically meaningful reductions in HbA1c and FPG, and reductions in body weight compared with placebo. Empagliflozin was well-tolerated with a favourable safety profile.
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Compuestos de Bencidrilo/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/administración & dosificación , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Nasofaringitis/inducido químicamente , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Trastornos Urinarios/inducido químicamente , Adulto , Anciano , Anciano de 80 o más Años , Argentina/epidemiología , Compuestos de Bencidrilo/efectos adversos , Glucemia , Peso Corporal , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Europa (Continente)/epidemiología , Femenino , Glucósidos/efectos adversos , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Persona de Mediana Edad , Nasofaringitis/epidemiología , República de Corea/epidemiología , Federación de Rusia/epidemiología , Taiwán/epidemiología , Sed , Resultado del Tratamiento , Ucrania/epidemiología , Trastornos Urinarios/epidemiología , Pérdida de PesoRESUMEN
AIMS/HYPOTHESIS: Endogenous NO inhibits insulin release in isolated beta cells and insulin-degrading enzyme activity in hepatocytes, while NO release from endothelial cells has been suggested to enhance insulin action. We assessed the overall effect of systemic inhibition of endogenous NO synthesis on glucose homeostasis in humans. METHODS: Twenty-four non-diabetic volunteers underwent two hyperglycaemic (+7 mmol/l) clamps with either saline or L-NG-nitroarginine methyl ester (L-NAME, at rates of 2.5, 5, 10 and 20 µg min⻹ kg⻹) infusion. Another five volunteers underwent an OGTT with either saline or L-NAME (20 µg min⻹ kg⻹) infusion. Blood pressure and heart rate were measured to monitor NO blockade; during the OGTT, endothelial function was assessed by peripheral arterial tonometry and insulin secretion by C-peptide deconvolution and insulin secretion modelling. RESULTS: Compared with saline, L-NAME at the highest dose raised mean blood pressure (+20 ± 2 mmHg), depressed heart rate (-12 ± 2 bpm) and increased insulin clearance (+50%). First-phase insulin secretion was impaired, but insulin sensitivity (M/I index) was unchanged. During the OGTT, L-NAME raised 2 h plasma glucose by 1.8 mmol/l (p < 0.01), doubled insulin clearance and impaired beta cell glucose sensitivity while depressing endothelial function. CONCLUSIONS/INTERPRETATION: In humans, systemic NO blockade titrated to increase blood pressure and induce endothelial dysfunction does not affect insulin action but significantly impairs glucose tolerance by increasing plasma insulin clearance and depressing insulin secretion, namely first-phase and beta cell glucose sensitivity.
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Inhibidores Enzimáticos/efectos adversos , Intolerancia a la Glucosa/etiología , Hiperglucemia/fisiopatología , Células Secretoras de Insulina/efectos de los fármacos , Insulina/metabolismo , Modelos Biológicos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Adulto , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Inhibidores Enzimáticos/administración & dosificación , Femenino , Técnica de Clampeo de la Glucosa , Intolerancia a la Glucosa/inducido químicamente , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/fisiopatología , Prueba de Tolerancia a la Glucosa , Humanos , Hiperglucemia/etiología , Hipertensión/etiología , Infusiones Intravenosas , Insulina/sangre , Antagonistas de Insulina/administración & dosificación , Antagonistas de Insulina/efectos adversos , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Masculino , NG-Nitroarginina Metil Éster/administración & dosificación , NG-Nitroarginina Metil Éster/efectos adversos , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Método Simple Ciego , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) lowers glucose levels by potentiating glucose-induced insulin secretion and inhibiting glucagon release. The question of whether GLP-1 exerts direct effects on the liver, independently of the hormonal changes, is controversial. We tested whether an exogenous GLP-1 infusion, designed to achieve physiological postprandial levels, directly affects endogenous glucose production (EGP) under conditions mimicking the fasting state in diabetes. METHODS: In 14 healthy volunteers, we applied the pancreatic clamp technique, whereby plasma insulin and glucagon levels are clamped using somatostatin and hormone replacement. The clamp was applied in paired, 4 h experiments, during which saline (control) or GLP-1(7-37)amide (0.4 pmol min⻹ kg⻹) was infused. RESULTS: During the control study, plasma insulin and glucagon were maintained at basal levels and plasma C-peptide was suppressed, such that plasma glucose rose to a plateau of ~10.5 mmol/l and tracer-determined EGP increased by ~60%. During GLP-1 infusion at matched plasma glucose levels, the rise of EGP from baseline was fully prevented. Lipolysis (as indexed by NEFA concentrations and tracer-determined glycerol rate of appearance) and substrate utilisation (by indirect calorimetry) were similar between control and GLP-1 infusion. CONCLUSIONS/INTERPRETATION: GLP-1 inhibits EGP under conditions where plasma insulin and glucagon are not allowed to change and glucose concentrations are matched, indicating either a direct effect on hepatocytes or neurally mediated inhibition.
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Péptido 1 Similar al Glucagón/farmacología , Gluconeogénesis/efectos de los fármacos , Hipoglucemiantes/farmacología , Hígado/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Regulación hacia Arriba/efectos de los fármacos , Adulto , Glucemia/análisis , Calorimetría Indirecta , Estudios Cruzados , Ácidos Grasos no Esterificados/sangre , Femenino , Péptido 1 Similar al Glucagón/administración & dosificación , Glucosa/biosíntesis , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Glicerol/sangre , Humanos , Hipoglucemiantes/administración & dosificación , Infusiones Intravenosas , Lipólisis/efectos de los fármacos , Hígado/metabolismo , Masculino , Fragmentos de Péptidos/administración & dosificación , Simpatomiméticos/administración & dosificación , Simpatomiméticos/farmacología , Adulto JovenRESUMEN
AIMS: Ipragliflozin is a novel, selective inhibitor of sodium glucose co-transporter 2 (SGLT2 inhibitor) in clinical development for type 2 diabetes mellitus (T2DM) treatment. This study assessed the efficacy and safety of different doses of ipragliflozin. METHODS: In a 12-week, multicentre, double-blind, randomized, placebo-controlled, dose-finding study patients with inadequate glycaemic control on metformin monotherapy (≥1500 mg/day) were randomized to one of four ipragliflozin treatment groups (12.5, 50, 150 or 300 mg once daily) or placebo. Primary efficacy outcome was mean change from baseline in haemoglobin A1c (HbA1c) compared to placebo at week 12. Adverse events (AEs), vital signs and laboratory safety measurements were assessed. RESULTS: Ipragliflozin dose dependently decreased HbA1c from baseline to week 12 compared to placebo (-0.22, -0.34, -0.40 and -0.48% for ipragliflozin 12.5, 50, 150 and 300 mg, respectively). Decreases in body weight and blood pressure were observed for all ipragliflozin groups. AEs occurred in 39.7-51.4% of the ipragliflozin groups and 39.4% of placebo patients. Urinary tract infections (1.4-6.9 vs. 6.1%), genital infections (0-4.3 vs. 1.5%) and hypoglycaemia (0-5.9 vs. 3.0%) were similar in the ipragliflozin and placebo groups, respectively, without dose dependency. There were no clinically relevant effects on other safety measurements. CONCLUSIONS: Ipragliflozin treatment improved glycaemic control when added to metformin therapy and may be associated with weight loss and reductions in blood pressure compared to placebo. No safety or tolerability concerns were identified at any of the tested doses supporting the further development of ipragliflozin at ≥50 mg doses in T2DM patients.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/administración & dosificación , Hemoglobina Glucada/metabolismo , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Tiofenos/administración & dosificación , Biomarcadores/sangre , Diabetes Mellitus Tipo 2/epidemiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
AIMS/HYPOTHESIS: Type 2 diabetes and insulin resistance are often associated with the co-occurrence of coronary atherosclerosis and cardiac dysfunction. The aim of this study was to define the independent relationships between left ventricular dysfunction or ischaemia and patterns of myocardial perfusion and metabolism in type 2 diabetes. METHODS: Twenty-four type 2 diabetic patients--12 with coronary artery disease (CAD) and preserved left ventricular function and 12 with non-ischaemic heart failure (HF)--were enrolled in a cross-sectional study. Positron emission tomography (PET) was used to assess myocardial blood flow (MBF) at rest, after pharmacological stress and under euglycaemic hyperinsulinaemia. Insulin-mediated myocardial glucose disposal was determined with 2-deoxy-2-[(18)F]fluoroglucose PET. RESULTS: There was no difference in myocardial glucose uptake (MGU) between the healthy myocardium of CAD patients and the dysfunctional myocardium of HF patients. MGU was strongly influenced by levels of systemic insulin resistance in both groups (CAD, r = 0.85, p = 0.005; HF, r = 0.77, p = 0.01). In HF patients, there was an inverse association between MGU and the coronary flow reserve (r = -0.434, p = 0.0115). A similar relationship was observed in non-ischaemic segments of CAD patients. Hyperinsulinaemia increased MBF to a similar extent in the non-ischaemic myocardial of CAD and HF patients. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, similar metabolic and perfusion patterns can be detected in the non-ischaemic regions of CAD patients with normal cardiac function and in the dysfunctional non-ischaemic myocardium of HF patients. This suggests that insulin resistance, rather than diagnosis of ischaemia or left ventricular dysfunction, affects the metabolism and perfusion features of patients with type 2 diabetes.
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Enfermedad de la Arteria Coronaria/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/fisiopatología , Fluorodesoxiglucosa F18/metabolismo , Isquemia Miocárdica/fisiopatología , Radiofármacos/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Anciano , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/metabolismo , Circulación Coronaria , Estudios Transversales , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Diabetes Mellitus Tipo 2/metabolismo , Angiopatías Diabéticas/diagnóstico por imagen , Angiopatías Diabéticas/metabolismo , Femenino , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Humanos , Resistencia a la Insulina , Masculino , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/metabolismo , Tomografía de Emisión de Positrones/métodos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/metabolismoRESUMEN
Hypertension has been suggested to exert pro-inflammatory actions through increased expression of several mediators, including chemokines. Chemokines are involved in inflammatory and autoimmune disorders, and in the formation of atherosclerotic lesions through promotion of inflammatory cell migration. The aim of this study is to evaluate the influence of high blood pressure on circulating levels of the prototype chemokines C-X-C motif ligand (CXCL)10 and C-C motif ligand (CCL)2 in 140 patients with essential hypertension not affected by thyroid disorders or overt autoimmune or inflammatory diseases, and 140 gender- and age-matched healthy controls. Mean CXCL10 and CCL2 levels were significantly higher in hypertensive patients than in controls. Among hypertensive patients, chemokines levels were higher in those with systo-diastolic hypertension compared to those with isolated systolic hypertension. In a multiple linear regression model using CXCL10 or CCL2 as dependent variables and age, body mass index, glycemia, serum creatinine, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, triglycerides, and systolic or diastolic blood pressure values as covariates, only systolic or diastolic blood pressure values were significantly related to CXCL10 or CCL2 levels. In conclusion, this study demonstrates increased circulating levels of the prototype chemokines CXCL10 and CCL2 in patients with hypertension.
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Quimiocina CCL2/sangre , Quimiocina CXCL10/sangre , Hipertensión/inmunología , Mediadores de Inflamación/sangre , Anciano , Análisis de Varianza , Presión Sanguínea , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Estudios Transversales , Diástole , Femenino , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Italia , Modelos Lineales , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Sístole , Regulación hacia ArribaRESUMEN
CONTEXT: Impaired adipose tissue (AT) blood flow has been implicated in the pathogenesis of insulin resistance in obesity. Insulin and bradykinin are meal-stimulated promoters of AT blood flow and glucose metabolism. OBJECTIVE: We tested whether blood flow regulates glucose metabolism in AT, insulin and bradykinin exert additive effects on AT blood flow and metabolism, and any of these actions explains the insulin resistance observed in obese individuals. DESIGN: Perfusion and glucose metabolism in the AT of the thighs were studied by positron emission tomography and H(2)(15)O (flow tracer) and (18)F-2-fluoro-2-deoxyglucose. Study I included five subjects in whom positron emission tomography imaging was performed in the fasting state during intraarterial infusion of bradykinin in the left leg; the right leg served as a control. Study II included seven lean and eight obese subjects in whom the imaging protocol was performed during euglycemic hyperinsulinemia. RESULTS: Bradykinin alone doubled fasting AT blood flow without modifying glucose uptake. Hyperinsulinemia increased AT blood flow (P ≤ 0.05) similarly in lean and obese individuals. In the lean group, bradykinin increased insulin-mediated AT glucose uptake from 8.6 ± 1.6 to 12.3 ± 2.4 µmol/min · kg (P = 0.038). In the obese group, AT glucose uptake was impaired (5.0 ± 1.0 µmol/min · kg, P = 0.05 vs. the lean group), and bradykinin did not exert any metabolic action (6.0 ± 0.8 µmol/min · kg, P = 0.01 vs. the lean group). CONCLUSION: AT blood flow is not an independent regulator of AT glucose metabolism. Insulin is a potent stimulator of AT blood flow, and bradykinin potentiates the hemodynamic and metabolic actions of insulin in lean but not in obese individuals.
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Tejido Adiposo/metabolismo , Bradiquinina/farmacología , Glucosa/farmacocinética , Insulina/farmacología , Extremidad Inferior/irrigación sanguínea , Obesidad , Flujo Sanguíneo Regional/fisiología , Delgadez , Tejido Adiposo/efectos de los fármacos , Adulto , Bradiquinina/administración & dosificación , Interacciones Farmacológicas , Femenino , Glucosa/metabolismo , Humanos , Insulina/administración & dosificación , Insulina/sangre , Pierna/irrigación sanguínea , Pierna/fisiopatología , Extremidad Inferior/fisiopatología , Masculino , Obesidad/sangre , Obesidad/metabolismo , Obesidad/fisiopatología , Muslo/irrigación sanguínea , Muslo/fisiopatología , Delgadez/sangre , Delgadez/metabolismo , Delgadez/fisiopatologíaAsunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Manejo de la Enfermedad , Europa (Continente) , Humanos , Hiperglucemia/etiología , Hiperglucemia/patología , Hipoglucemiantes/uso terapéutico , Sociedades Médicas , Estados UnidosRESUMEN
OBJECTIVE: We aimed at evaluating the impact of short and prolonged mild manipulations of intracellular nitric oxide (NO) bioavailability on the main features of insulin secretion and whether NO promotes mitochondrial biogenesis in isolated ß-cells. MATERIALS/METHODS: INS-1E ß-cells were exposed to either the intracellular NO donor, hydroxylamine (HA), or the NO synthase inhibitor, L-nitro-arginine-methyl-ester (L-NAME), at concentrations lower than 2.0 mM. Glucose and arginine-induced insulin secretion (GIIS and AIIS) were measured after short (1 h) or prolonged (48 h) exposure to L-NAME 1.0 and 2.0 mM or HA 0.4 and 0.8 mM, lower concentrations were also evaluated for the 1 h effects. Basal insulin secretion (BIS), with either HA or L-NAME added to culture media, and peroxisome proliferators-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor-1 (NRF-1), and mitochondrial DNA transcription factor-A (Tfam) gene expression during chronic HA supplementation were also measured. RESULTS: Neither L-NAME nor HA affected insulin release at glucose 3.3 mM or in cell culture (BIS). Both short and prolonged cell exposure to L-NAME potentiated GIIS though with a flat dose-response curve while HA inhibited GIIS only at the highest concentration. AIIS was prevented by short exposure to L-NAME and potentiated by HA, while it did not respond to prolonged incubations. Prolonged cell exposure to HA had no effect on PGC-1α, NRF-1 or Tfam gene expression. CONCLUSION: In INS1E cells an intact NO synthesis is necessary to limit insulin release in response to acute glucose gradients and to fully respond to arginine while intracellular NO enrichment above the physiologic levels further inhibits GIIS and potentiate AIIS only when excessive. Prolonged NO manipulations do not affect AIIS, BIS or mitochondrial biogenesis.
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Hidroxilamina/farmacología , Células Secretoras de Insulina/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , Animales , Arginina/farmacología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Glucosa/farmacología , Insulina/metabolismo , Insulina/farmacología , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Líquido Intracelular/efectos de los fármacos , Líquido Intracelular/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/fisiología , Ratas , Factores de TiempoRESUMEN
The mechanisms responsible for the accelerated atherosclerosis observed in type 2 diabetes are not fully understood. One of the earliest events in the development of atherosclerosis is endothelial dysfunction, namely, a reduction in nitric oxide (NO) synthesis or its bioavailability within the peri-endothelial environment, where it is responsible for maintenance of vascular tissue integrity. The clinical evaluation of this pathway is hampered by the fact that in vivo NO cannot be directly measured; however, exploiting a novel, complex and elegant experimental setup, McVeigh and co-workers (Diabetologia 1992;35:771-776) were the first to document that NO bioavailability in type 2 diabetic patients is indeed reduced. In this edition of 'Then and now' that paper is reappraised not only for its originality, but also for the broad and extensive evaluation of the vascular functions explored, the complete clinical characterisation of patients enrolled and for the fact that all the major findings were subsequently replicated.