RESUMEN

CONTEXT: Dipeptidyl peptidase-4 inhibitors act by increasing plasma levels of glucagon-like peptide-1 and suppressing excessive glucagon secretion in patients with type 2 diabetes. However, their effects on the glucagon response to hypoglycemia are not established. OBJECTIVE: The aim of the study was to assess effects of the dipeptidyl peptidase-4 inhibitor vildagliptin on alpha-cell response to hyper- and hypoglycemia. DESIGN: We conducted a single-center, randomized, double-blind, placebo-controlled, two-period crossover study of 28-d treatment, with a 4-wk between-period washout. PATIENTS: We studied drug-naive patients with type 2 diabetes and baseline glycosylated hemoglobin of 7.5% or less. INTERVENTION: Participants received vildagliptin (100 mg/d) or placebo as outpatients. PRIMARY OUTCOME MEASURE(S): We measured the following: 1) change in plasma glucagon levels during hypoglycemic (2.5 mm glucose) clamp; and 2) incremental (Delta) glucagon area under the concentration-time curve from time 0 to 60 min (AUC(0-60 min)) during standard meal test. Before the study, it was hypothesized that vildagliptin would suppress glucagon secretion during meal tests and enhance the glucagon response to hypoglycemia. RESULTS: The mean change in glucagon during hypoglycemic clamp was 46.7 +/- 6.9 ng/liter with vildagliptin treatment and 33.9 +/- 6.7 ng/liter with placebo; the between-treatment difference was 12.8 +/- 7.0 ng/liter (P = 0.039), representing a 38% increase with vildagliptin. In contrast, the mean glucagon DeltaAUC(0-60 min) during meal test with vildagliptin was 512 +/- 163 ng/liter x min vs. 861 +/- 130 ng/liter x min with placebo; the between-treatment difference was -349 +/- 158 ng/liter x min (P = 0.019), representing a 41% decrease with vildagliptin. CONCLUSIONS: Vildagliptin enhances alpha-cell responsiveness to both the suppressive effects of hyperglycemia and the stimulatory effects of hypoglycemia. These effects likely contribute to the efficacy of vildagliptin to improve glycemic control as well as to its low hypoglycemic potential.

Asunto(s)

Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Nitrilos/uso terapéutico , Pirrolidinas/uso terapéutico , Adamantano/uso terapéutico , Anciano , Glucemia/metabolismo , Índice de Masa Corporal , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Femenino , Glucagón/sangre , Péptido 1 Similar al Glucagón/sangre , Hemoglobina Glucada/metabolismo , Humanos , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Masculino , Persona de Mediana Edad , Vildagliptina

RESUMEN

CONTEXT: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state. OBJECTIVE: The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function. DESIGN: We conducted a randomized, double-blind, placebo-controlled trial. SETTING: The study was performed in General Clinical Research Centers at two University Hospitals. SUBJECTS: Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2-7.5%. INTERVENTION: Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout. Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout. RESULTS: There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P < 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023). CONCLUSION: Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.

Asunto(s)

Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Ayuno/fisiología , Islotes Pancreáticos/efectos de los fármacos , Nitrilos/uso terapéutico , Pirrolidinas/uso terapéutico , Adamantano/farmacología , Adamantano/uso terapéutico , Anciano , Diabetes Mellitus Tipo 2/fisiopatología , Método Doble Ciego , Péptido 1 Similar al Glucagón/sangre , Hemoglobina Glucada/análisis , Humanos , Islotes Pancreáticos/fisiopatología , Persona de Mediana Edad , Nitrilos/farmacología , Pirrolidinas/farmacología , Vildagliptina

RESUMEN

In healthy individuals, the ability of the pancreatic islets to sense and respond appropriately to changes in plasma glucose levels maintains plasma glucose levels within a narrow range despite broad fluctuations in nutrient intake and variable "demand" for insulin imposed by changes in insulin sensitivity. This ability of the pancreatic islets is lost in type 2 diabetes (T2DM). For studies on the pathophysiology of T2DM, methods for analyzing islet function are therefore required. Many methods of varying degrees of complexity have been developed and used to measure pancreatic beta-cell function in humans and to characterize the defects existing in patients with T2DM or precursors thereof (impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]). Significant, although perhaps less progress has been made toward development of methods to characterize alpha-cell function. This work presents an overview of clinical measures of islet function, from simple static measures such as HOMA-beta to the more complex dynamic measures such as those utilizing stepped hyperglycemic clamps and acute administration of arginine to obtain more detailed information regarding the interaction of glucose and non-glucose secretagogues. We emphazise the need for accurate measures of alpha-cell function, and we discuss the strengths and limitations of the various methods, highlighting the many aspects of both alpha- and beta-cell function that become impaired during development of T2DM.

Asunto(s)

Diabetes Mellitus/fisiopatología , Islotes Pancreáticos/fisiopatología , Arginina/farmacología , Glucemia/análisis , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus/patología , Glucagón/sangre , Glucagón/metabolismo , Glucagón/farmacología , Intolerancia a la Glucosa/sangre , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Cinética , Valores de Referencia

RESUMEN

OBJECTIVE: This study was conducted to characterize the effects of vildagliptin on beta-cell function in patients with type 2 diabetes and mild hyperglycemia. DESIGN: A 52-wk double-blind, randomized, parallel-group study comparing vildagliptin (50 mg every day) and placebo was conducted in 306 patients with mild hyperglycemia (glycosylated hemoglobin of 6.2-7.5%). Plasma glucose and C-peptide levels were measured during standard meal tests performed at baseline, wk 24 and 52, and after 4-wk washout. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution, and beta-cell function was quantified with a mathematical model that describes ISR as a function of absolute glucose levels (insulin secretory tone and glucose sensitivity), the glucose rate of change (rate sensitivity), and a potentiation factor. RESULTS: Vildagliptin significantly increased fasting insulin secretory tone [between-group difference in adjusted mean change from baseline to wk 52 (AM Delta) = +34.1 +/- 9.5 pmol.min(-1).m(-2), P < 0.001] glucose sensitivity (AM Delta = +20.7 +/- 5.2 pmol.min(-1).m(-2).mm(-1), P < 0.001), and rate sensitivity (AM Delta = +163.6 +/- 67.0 pmol.m(-2).mm(-1), P = 0.015), but total insulin secretion (ISR area under the curve at 0-2 h) and the potentiation factor excursion during meals were unchanged. These improvements in beta-cell function were accompanied by a decrease in the glucose area under the curve at 0-2 h (AM Delta = -1.7 +/- 0.5 mm/h, P = 0.002) and in glycosylated hemoglobin (AM Delta = -0.3 +/- 0.1%, P < 0.001). None of the effects of vildagliptin remained after 4-wk washout from study medication. CONCLUSIONS: Consistent with previous findings from shorter-term studies in patients with more severe hyperglycemia, in patients with mild hyperglycemia, improved beta-cell function is maintained throughout 52-wk treatment with vildagliptin and underlies a sustained improvement in glycemic control. However, no effects remain after washout.

Asunto(s)

Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Nitrilos/farmacología , Pirrolidinas/farmacología , Adamantano/farmacología , Adamantano/uso terapéutico , Glucemia/metabolismo , Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hiperglucemia/sangre , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Masculino , Persona de Mediana Edad , Modelos Biológicos , Nitrilos/uso terapéutico , Pirrolidinas/uso terapéutico , Vildagliptina

RESUMEN

This randomized, open-label, placebo-controlled, 7-period crossover study assessed dose-response relationships following single oral doses (10-400 mg) of vildagliptin in 16 patients with type 2 diabetes mellitus. Plasma levels of parent drug, dipeptidyl peptidase-4 activity, glucose, insulin, and glucagon were measured during 75-g oral glucose tolerance tests performed after an overnight fast, 30 minutes after drug administration. The t(max) for parent drug was observed between 0.5 and 1.5 hours postdose. Both C(max) and AUC(0-8 h) increased dose proportionately. Both onset and duration of dipeptidyl peptidase-4 inhibition were dose dependent, but >90% inhibition occurred within 45 minutes and was maintained for >/=4 hours after each dose. Glucose excursions and glucagon levels during oral glucose tolerance tests were significantly and similarly decreased after each dose of vildagliptin, and insulin levels were significantly and similarly increased after each dose level. Unlike findings during mixed-meal challenges, vildagliptin increases plasma insulin levels during oral glucose tolerance tests in patients with type 2 diabetes mellitus.

Asunto(s)

Adamantano/análogos & derivados , Inhibidores de la Adenosina Desaminasa , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV , Glicoproteínas/antagonistas & inhibidores , Hipoglucemiantes/farmacología , Nitrilos/farmacología , Pirrolidinas/farmacología , Adamantano/sangre , Adamantano/farmacocinética , Adamantano/farmacología , Adenosina Desaminasa/sangre , Glucemia/análisis , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Dipeptidil Peptidasa 4/sangre , Femenino , Polipéptido Inhibidor Gástrico/sangre , Glucagón/sangre , Péptido 1 Similar al Glucagón/sangre , Prueba de Tolerancia a la Glucosa , Glicoproteínas/sangre , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Insulina/sangre , Masculino , Persona de Mediana Edad , Nitrilos/sangre , Nitrilos/farmacocinética , Pirrolidinas/sangre , Pirrolidinas/farmacocinética , Vildagliptina

RESUMEN

OBJECTIVE: We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS: We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design. RESULTS: Fasting (7.3 +/- 0.5 vs. 7.9 +/- 0.5 mmol/l) and peak postprandial (14.1 +/- 0.6 vs. 15.9 +/- 0.9 mmol/l) glucose concentrations were lower (P < 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 +/- 1.6 vs. 23.7 +/- 1.3 mg/ml per 5 h, P < 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 +/- 270 vs. 1,277 +/- 312 pmol/l per 5 h, P = 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments. CONCLUSIONS: Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.

Asunto(s)

Inhibidores de la Adenosina Desaminasa , Apetito , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Inhibidores de la Dipeptidil-Peptidasa IV , Ingestión de Alimentos , Tracto Gastrointestinal/fisiopatología , Glicoproteínas/antagonistas & inhibidores , Estudios Cruzados , Dipeptidil Peptidasa 4 , Método Doble Ciego , Ayuno , Vaciamiento Gástrico , Péptido 1 Similar al Glucagón/sangre , Humanos , Periodo Posprandial

RESUMEN

AIMS/HYPOTHESIS: Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration. METHODS: Sixteen patients with type 2 diabetes (age, 48+/-3 yr; body mass index, 34.4+/-1.7 kg/m2; hemoglobin A1c, 9.0+/-0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-(3)H-glucose iv and 1-(14)C-glucose orally). RESULTS: After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02+/-0.06 vs. 0.74+/-0.06 mg.kg-1.min-1; P=0.004), and insulin secretion rate increased by 21% (P=0.003) despite significant reduction in mean plasma glucose (213+/-4 vs. 230+/-4 mg/dl; P=0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P=0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P<0.02). The decline in EGP was positively correlated (r=0.55; P<0.03) with the decrease in fasting plasma glucose (change=-14 mg/dl). CONCLUSIONS: During MTT, vildagliptin augments insulin secretion and inhibits glucagon release, leading to enhanced suppression of EGP. During the postprandial period, a single dose of vildagliptin reduced plasma glucose levels by enhancing suppression of EGP.

Asunto(s)

Adamantano/análogos & derivados , Inhibidores de la Adenosina Desaminasa , Adenosina Desaminasa/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/sangre , Inhibidores de la Dipeptidil-Peptidasa IV , Glucosa/metabolismo , Glicoproteínas/antagonistas & inhibidores , Glicoproteínas/sangre , Hipoglucemiantes/uso terapéutico , Islotes Pancreáticos/metabolismo , Nitrilos/uso terapéutico , Pirrolidinas/uso terapéutico , Adamantano/uso terapéutico , Índice de Masa Corporal , Estudios Cruzados , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Inhibidores Enzimáticos/farmacología , Femenino , Hemoglobina Glucada/análisis , Humanos , Cinética , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Vildagliptina

RESUMEN

Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.

Asunto(s)

Adamantano/síntesis química , Dipeptidil Peptidasa 4/metabolismo , Inhibidores Enzimáticos/síntesis química , Hipoglucemiantes/síntesis química , Pirrolidinas/síntesis química , Adamantano/análogos & derivados , Adamantano/química , Adamantano/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Glucemia/análisis , Células CACO-2 , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Macaca fascicularis , Masculino , Pirrolidinas/química , Pirrolidinas/farmacología , Ratas , Ratas Zucker , Relación Estructura-Actividad

RESUMEN

We sought to determine whether an incretin effect could be observed when glucose was infused via the hepatic portal (Po) vein versus a peripheral (Pe) vein. Identical hyperglycemia (155 +/- 7 and 154 +/- 8 mg/dL, respectively) was produced in 2 groups (n = 9 each) of conscious dogs by Po or Pe glucose infusion. During glucose infusion, arterial plasma insulin levels increased by 28 +/- 5 and 16 +/- 3 microU/mL in Po and Pe, respectively (P <.05 between groups). Pancreatic insulin output increased by 10.4 +/- 3.2 and 6.7 +/- 2.3 mU/min in Po and Pe, respectively (P =.12 between groups). Arterial plasma glucagon levels and pancreatic glucagon output were similarly suppressed by Po and Pe glucose infusion. Pancreatic polypeptide (PP) output and norepinephrine (NE) spillover were measured as indices of pancreatic parasympathetic and sympathetic neural activity, respectively. During Pe, pancreatic PP output decreased from basal (delta -4.8 +/- 2.5 ng/min, P <.05), with no significant change in NE spillover (delta +4.4 +/- 4.0 ng/min). The PP output:NE spillover ratio decreased by 65% (P <.05), suggesting a shift toward a dominance of sympathetic tone. During Po, there were no significant changes in PP output (delta -1.4 +/- 3.1 ng/min) or NE spillover (delta +1.6 +/- 1.2 ng/min), and consequently there was no significant change in the PP output:NE spillover ratio. Thus, activation of the Po glucose signal appears to inhibit the shift toward sympathetic dominance that would otherwise result, thereby causing an incretin effect.

Asunto(s)

Glucosa/farmacología , Páncreas/inervación , Algoritmos , Animales , Perros , Femenino , Glucagón/sangre , Glucosa/administración & dosificación , Glucosa/metabolismo , Hematócrito , Hormonas/sangre , Hidrocortisona/sangre , Infusiones Intravenosas , Insulina/sangre , Cinética , Masculino , Norepinefrina/metabolismo , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Polipéptido Pancreático/metabolismo , Sistema Nervioso Parasimpático/efectos de los fármacos , Vena Porta

RESUMEN

Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. We report the first use of solid-phase synthesis in the discovery of a new DPP-IV inhibitor class and a solution-phase synthesis that is practical up to the multikilogram scale. One compound, NVP-DPP728 (2), is profiled as a potent, selective, and short-acting DPP-IV inhibitor that has excellent oral bioavailability and potent antihyperglycemic activity.

Asunto(s)

Dipeptidil Peptidasa 4/metabolismo , Inhibidores Enzimáticos/síntesis química , Hipolipemiantes/síntesis química , Nitrilos/síntesis química , Inhibidores de Proteasas/síntesis química , Pirrolidinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Inhibidores Enzimáticos/farmacología , Prueba de Tolerancia a la Glucosa , Humanos , Hipolipemiantes/farmacología , Macaca fascicularis , Masculino , Nitrilos/farmacología , Inhibidores de Proteasas/farmacología , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad