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1.
Diabetes Res Clin Pract ; 153: 14-22, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31078666

RESUMEN

AIMS: To compare the effects of long-term treatment with the GLP-1RA exenatide twice-daily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. METHODS: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean  ±â€¯SD age 60 ±â€¯8 years, HbA1c 7.5 ±â€¯0.9%, eGFR 86 ±â€¯16 mL/min/1.73 m2, median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 µg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albumin-excretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. RESULTS: HbA1c-reductions were similar with exenatide (mean ±â€¯SEM -0.80 ±â€¯0.10%) and iGlar (-0.79 ±â€¯0.14%; treatment-difference 0.02%; 95% CI -0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P < 0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 ±â€¯2.1 mL/min/1.73 m2; P = 0.069) and iGlar (-2.7 ±â€¯1.2 mL/min/1.73 m2; P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P < 0.001), but did not affect blood pressure, lipids or plasma uric acid. CONCLUSIONS: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT00097500.


Asunto(s)
Albuminuria/orina , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Exenatida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina Glargina/uso terapéutico , Pruebas de Función Renal/métodos , Nefropatías Diabéticas/patología , Exenatida/farmacología , Femenino , Humanos , Hipoglucemiantes/farmacología , Insulina Glargina/farmacología , Masculino , Persona de Mediana Edad
2.
Artículo en Inglés | MEDLINE | ID: mdl-29735021

RESUMEN

Glucocorticoid treatment decreases liver insulin sensitivity and may modify fatty acid metabolism. We investigated the influence of oral prednisolone on indices for de novo lipogenesis (DNLi), stearoyl-CoA desaturase (SCDi) and Δ6-desaturase (D6Di) activity in healthy males. In addition, we explored whether the changes may be associated with prednisolone-induced changes in glucose and lipid metabolism and insulin sensitivity. Thirty-two healthy young males (mean ±â€¯SD age 22 ±â€¯3 years, BMI 22.4 ±â€¯1.7 kg/m2) were allocated to receive prednisolone 7.5 mg/day (PRED7.5; n = 12), prednisolone 30 mg/day (PRED30; n = 12), or placebo (n = 8) in a randomized double-blind fashion for 2 weeks. Fatty acid compositions of plasma cholesteryl esters (CE), phospholipids (PL) and triglycerides (TG) were measured at baseline and on day 14. DNLi, SCDi and D6Di were estimated from product/precursor ratios in CE, with DNLi primary deriving from 16:1ω7/18:2ω6, SCDi from 16:1ω7/16:0 and D6Di from 22:6ω3/20:5ω3. Ratios were also assessed in PL and TG. In CE, PRED30 increased DNLi by 51.2 [95%CI 14.8; 87.6]%, increased SCDi by 48.6 [18.7; 78.5]%, and decreased D6Di by 57.7 [-91.8; -23.5]% (p ≤ 0.01 for all, compared to placebo). The prednisolone-induced increases in DNLi and SCDi were positively correlated with insulin sensitivity (r = 0.35 and 0.50, respectively). Similar results were found in PL and TG. Prednisolone dose-dependently increases DNLi and SCDi and decreases D6Di in plasma CE, PL and TG in healthy males after 2 weeks. The observed unfavorable effects on fatty acid metabolism were related to the induction of glucocorticoid-induced insulin resistance.


Asunto(s)
Antiinflamatorios/farmacología , Linoleoil-CoA Desaturasa/genética , Metabolismo de los Lípidos/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Prednisolona/farmacología , Estearoil-CoA Desaturasa/genética , Administración Oral , Adulto , Glucemia/efectos de los fármacos , Ésteres del Colesterol/sangre , Método Doble Ciego , Esquema de Medicación , Expresión Génica , Voluntarios Sanos , Humanos , Resistencia a la Insulina , Linoleoil-CoA Desaturasa/sangre , Metabolismo de los Lípidos/genética , Lipogénesis/genética , Masculino , Fosfolípidos/sangre , Estearoil-CoA Desaturasa/sangre , Triglicéridos/sangre
4.
Diabetes Obes Metab ; 18(3): 224-35, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26500045

RESUMEN

The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose-lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP-1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorized as short- or long-acting, with each having unique islet-cell and gastrointestinal effects that lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long-acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual ß-cell function.


Asunto(s)
Fármacos Gastrointestinales/farmacología , Péptido 1 Similar al Glucagón/farmacología , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ayuno/metabolismo , Vaciamiento Gástrico/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Glucagón/metabolismo , Humanos , Insulina/metabolismo , Secreción de Insulina , Intestino Delgado/metabolismo , Hígado/metabolismo , Periodo Posprandial/efectos de los fármacos
5.
Diabetes Obes Metab ; 18(2): 178-85, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26636423

RESUMEN

AIMS: To determine the acute effect of glucagon-like peptide-1 (GLP-1) receptor agonist exenatide and the involvement of nitric oxide (NO) on renal haemodynamics and tubular function, in healthy overweight men. METHODS: Renal haemodynamics and tubular electrolyte handling were measured in 10 healthy overweight men (aged 20-27 years; BMI 26-31 kg/m(2)) during intravenous administration of placebo (saline 0.9%), exenatide, and exenatide combined with the NO-synthase inhibitor L-N(G)-monomethyl arginine (L-NMMA). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance techniques, respectively, based on timed urine sampling. Glomerular hydrostatic pressure and vascular resistance of afferent and efferent renal arterioles were calculated using the Gomez formulae. Urinary electrolytes, osmolality and pH were also measured. RESULTS: GFR increased by a mean of 18 ± 20 (+20%; p = 0.021) and ERPF increased by a median (interquartile range) of 68 (26; 197) ml/min/1.73 m(2) (+14%; p = 0.015) during exenatide infusion versus placebo. During L-NMMA infusion, exenatide increased GFR by mean 8 ± 12 ml/min/1.73 m(2) (+9%; p = 0.049). Exenatide increased estimated glomerular pressure by +6% (p = 0.015) and reduced afferent renal vascular resistance by -33% (p = 0.038), whereas these effects were blunted during L-NMMA infusion. Exenatide increased absolute and fractional sodium excretion, urinary osmolality and urinary pH. The tubular effects of exenatide were not altered by concomitant L-NMMA infusion. CONCLUSIONS: Exenatide infusion in healthy overweight men acutely increases GFR, ERPF and glomerular pressure, probably by reducing afferent renal vascular resistance, and at least partially in an NO-dependent manner. As baseline renal haemodynamics in patients with type 2 diabetes differ from those in healthy individuals, clinical studies on the renal effects of GLP-1 receptor agonists are warranted.


Asunto(s)
Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/farmacología , Riñón/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Sobrepeso/fisiopatología , Péptidos/farmacología , Resistencia Vascular/efectos de los fármacos , Ponzoñas/farmacología , Adulto , Índice de Masa Corporal , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Exenatida , Tasa de Filtración Glomerular/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/antagonistas & inhibidores , Infusiones Intravenosas , Riñón/irrigación sanguínea , Riñón/metabolismo , Riñón/fisiopatología , Túbulos Renales/irrigación sanguínea , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/fisiopatología , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Sobrepeso/metabolismo , Sobrepeso/orina , Péptidos/administración & dosificación , Péptidos/antagonistas & inhibidores , Circulación Renal/efectos de los fármacos , Ponzoñas/administración & dosificación , Adulto Joven , omega-N-Metilarginina/administración & dosificación , omega-N-Metilarginina/farmacología
6.
Diabetes Obes Metab ; 18(3): 281-8, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26640129

RESUMEN

AIMS: To investigate the effect of infusion of the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide on exocrine pancreatic function. METHODS: This was a randomized, placebo-controlled, double-blind, crossover study in 12 male patients with type 2 diabetes, treated with oral glucose-lowering agents. On two separate occasions, exenatide or placebo (saline 0.9%) were administered intravenously, in randomized order. Exocrine pancreatic function was measured using secretin-enhanced magnetic resonance cholangiopancreatography. The primary outcome measure was defined as secretin-stimulated pancreatic excretion volume. Secondary outcome measures were maximum secretion speed and the time to reach this maximum. In addition, changes in pancreatic duct (PD) diameter were measured. RESULTS: Exenatide did not change secretin-stimulated pancreatic excretion volume, as compared with placebo (mean ± standard error of the mean 142.2 ± 15.6 ml vs 142.6 ± 8.5 ml, respectively; p = 0.590). Also, exenatide did not change the maximum secretion speed (33.1 ± 1.4 vs 36.9 ± 2.2; p = 0.221), nor the time to reach this maximum (both 4 min 30 s). No differences in PD diameter were observed between the two groups. CONCLUSIONS: Infusion of exenatide did not directly influence MRI-measured exocrine pancreatic excretion in patients with type 2 diabetes. Although long-term studies are warranted, these findings suggest that potential adverse pancreatic effects of GLP-1 receptor agonists are not mediated by changes in exocrine pancreatic secretion.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/farmacología , Páncreas Exocrino/efectos de los fármacos , Péptidos/farmacología , Ponzoñas/farmacología , Adulto , Anciano , Pancreatocolangiografía por Resonancia Magnética/métodos , Estudios Cruzados , Diabetes Mellitus Tipo 2/fisiopatología , Método Doble Ciego , Exenatida , Humanos , Masculino , Persona de Mediana Edad , Conductos Pancreáticos/patología , Secretina/metabolismo
7.
Neth J Med ; 69(9): 372-8, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21978979

RESUMEN

The dietary intake of saturated fatty acids (SAFA) is associated with a modest increase in serum total cholesterol, but not with cardiovascular disease (CVD). Replacing dietary SAFA with carbohydrates (CHO), notably those with a high glycaemic index, is associated with an increase in CVD risk in observational cohorts, while replacing SAFA with polyunsaturated fatty acids (PUFA) is associated with reduced CVD risk. However, replacing a combination of SAFA and trans-fatty acids with n-6 PUFA (notably linoleic acid) in controlled trials showed no indication of benefit and a signal toward increased coronary heart disease risk, suggesting that n-3 PUFA may be responsible for the protective association between total PUFA and CVD. High CHO intakes stimulate hepatic SAFA synthesis and conservation of dietary SAFA . Hepatic de novo lipogenesis from CHO is also stimulated during eucaloric dietary substitution of SAFA by CHO with high glycaemic index in normo-insulinaemic subjects and during hypocaloric high-CHO/low-fat diets in subjects with the metabolic syndrome. The accumulation of SAFA stimulates chronic systemic low-grade inflammation through its mimicking of bacterial lipopolysaccharides and÷or the induction of other pro-inflammatory stimuli. The resulting systemic low-grade inflammation promotes insulin resistance, reallocation of energy-rich substrates and atherogenic dyslipidaemia that concertedly give rise to increased CVD risk. We conclude that avoidance of SAFA accumulation by reducing the intake of CHO with high glycaemic index is more effective in the prevention of CVD than reducing SAFA intake per se.


Asunto(s)
Enfermedades Cardiovasculares/etiología , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/administración & dosificación , Aterosclerosis/prevención & control , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/prevención & control , Colesterol/sangre , Carbohidratos de la Dieta/efectos adversos , Grasas de la Dieta/efectos adversos , Grasas Insaturadas en la Dieta/administración & dosificación , Grasas Insaturadas en la Dieta/efectos adversos , Grasas Insaturadas/administración & dosificación , Grasas Insaturadas/efectos adversos , Grasas Insaturadas/química , Humanos , Inflamación/etiología , Inflamación/prevención & control , Lipoproteínas LDL/sangre
8.
J Clin Endocrinol Metab ; 96(2): 459-67, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21084401

RESUMEN

CONTEXT: Pancreatic fat content (PFC) may have deleterious effects on ß-cell function. OBJECTIVE: We hypothesized that ectopic fat deposition, in particular pancreatic fat accumulation, is related to ß-cell dysfunction in individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). DESIGN, SETTING AND PARTICIPANTS: This was a cross-sectional study in 64 age- and body mass index-matched individuals, with normal glucose tolerance (NGT; n = 16, 60% males), IFG (n = 29, 52% males), or IFG/IGT (n = 19, 63% males) was conducted. INTERVENTION AND MAIN OUTCOME MEASURES: Participants underwent the following: 1) a combined hyperinsulinemic-euglycemic and hyperglycemic clamp, with subsequent arginine stimulation to quantify insulin sensitivity and ß-cell function; 2) proton-magnetic resonance spectroscopy to assess PFC and liver fat content (LFC); and 3) magnetic resonance imaging to quantify visceral (VAT) and sc (SAT) adipose tissue. The disposition index (DI; insulin sensitivity adjusted ß-cell function) was assessed. RESULTS: IFG and IFG/IGT were more insulin resistant (P < 0.001) compared with NGT. Individuals with IFG/IGT had the lowest values of glucose- and arginine-stimulated C-peptide secretion (both P < 0.03) and DI (P < 0.001), relative to IFG and NGT. PFC and LFC gradually increased between NGT, IFG, and IFG/IGT (P = 0.02 and P = 0.01, respectively), whereas VAT and SAT were similar between groups. No direct associations were found between PFC, LFC, VAT, and SAT and C-peptide secretion. The DI was inversely correlated with PFC, LFC, and VAT (all P < 0.05). CONCLUSIONS: PFC was increased in individuals with IFG and/or IGT, without a direct relation with ß-cell function.


Asunto(s)
Grasa Abdominal/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Grasas/metabolismo , Intolerancia a la Glucosa/metabolismo , Células Secretoras de Insulina/fisiología , Hígado/metabolismo , Páncreas/metabolismo , Grasa Abdominal/patología , Anciano , Glucemia/metabolismo , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/patología , Ayuno/metabolismo , Femenino , Técnica de Clampeo de la Glucosa , Intolerancia a la Glucosa/patología , Humanos , Resistencia a la Insulina/fisiología , Hígado/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Sobrepeso/metabolismo , Páncreas/patología , Pruebas de Función Pancreática , Estado Prediabético/metabolismo , Grasa Subcutánea/metabolismo
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