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1.
Diabetes Technol Ther ; 18(1): 39-46, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26756104

RESUMEN

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a powerful insulin secretagogue that is secreted in response to meal ingestion. The ability to quantify the effect of GLP-1 on insulin secretion could provide insights into the pathogenesis and treatment of diabetes. We used a modification of a model of GLP-1 action on insulin secretion using data from a hyperglycemic clamp with concomitant GLP-1 infusion. We tested this model using data from a mixed meal test (MMT), thereby measuring GLP-1-induced potentiation of insulin secretion in response to a meal. MATERIALS AND METHODS: The GLP-1 model is based on the oral C-peptide minimal model and assumes that over-basal insulin secretion depends linearly on GLP-1 concentration through the parameter Π, representing the ß-cell sensitivity to GLP-1. The model was tested on 62 subjects across the spectrum of glucose tolerance (age, 53 ± 1 years; body mass index, 29.7 ± 0.6 kg/m(2)) studied with an MMT and provided a precise estimate of both ß-cell responsivity and Π indices. By combining Π with a measure of L-cell responsivity to glucose, one obtains a potentiation index (PI) (i.e., a measure of the L-cell's function in relation to prevailing ß-cell sensitivity to GLP-1). RESULTS: Model-based measurement of GLP-1-induced insulin secretion demonstrates that the PI is significantly reduced in people with impaired glucose tolerance, compared with those with normal glucose tolerance. CONCLUSIONS: We describe a model that can quantitate the GLP-1-based contribution to insulin secretion in response to meal ingestion. This methodology will allow a better understanding of ß-cell function at various stages of glucose tolerance.


Asunto(s)
Péptido 1 Similar al Glucagón/metabolismo , Insulina/metabolismo , Comidas/fisiología , Glucemia/metabolismo , Péptido C , Ingestión de Alimentos/fisiología , Técnica de Clampeo de la Glucosa , Intolerancia a la Glucosa/sangre , Voluntarios Sanos , Humanos , Insulina/sangre , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Modelos Lineales , Persona de Mediana Edad
2.
J Nutr ; 145(9): 2046-51, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26246321

RESUMEN

BACKGROUND: Caloric restriction alone has been shown to improve insulin action and fasting glucose metabolism; however, the mechanism by which this occurs remains uncertain. OBJECTIVE: We sought to quantify the effect of caloric restriction on ß cell function and glucose metabolism in people with type 2 diabetes. METHODS: Nine subjects (2 men, 7 women) with type 2 diabetes [BMI (in kg/m(2)): 40.6 ± 1.4; age: 58 ± 3 y; glycated hemoglobin: 6.9% ± 0.2%] were studied using a triple-tracer mixed meal after withdrawal of oral diabetes therapy. The oral minimal model was used to measure ß cell function. Caloric restriction limited subjects to a pureed diet (<900 kcal/d) for the 12 wk of study. The studies were repeated after 6 and 12 wk of caloric restriction. RESULTS: Fasting glucose concentrations decreased significantly from baseline after 6 wk of caloric restriction with no further reduction after a further 6 wk of caloric restriction (9.8 ± 1.3, 5.9 ± 0.2, and 6.2 ± 0.3 mmol/L at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01) because of decreased fasting endogenous glucose production (EGP: 20.4 ± 1.1, 16.2 ± 0.8, and 17.4 ± 1.1 µmol · kg(-1) · min(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.03). These changes were accompanied by an improvement in ß cell function measured by the disposition index (189 ± 51, 436 ± 68, and 449 ± 67 10(-14) dL · kg(-1) · min(-2) · pmol(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01). CONCLUSIONS: Six weeks of caloric restriction lowers fasting glucose and EGP with accompanying improvements in ß cell function in people with type 2 diabetes. An additional 6 wk of caloric restriction maintained the improvement in glucose metabolism. This trial was registered at clinicaltrials.gov as NCT01094054.


Asunto(s)
Glucemia/metabolismo , Restricción Calórica , Diabetes Mellitus Tipo 2/dietoterapia , Células Secretoras de Insulina/metabolismo , Periodo Posprandial , Índice de Masa Corporal , Péptido C/sangre , Ingestión de Energía , Ayuno , Femenino , Glucagón/sangre , Hemoglobina Glucada/metabolismo , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Factores de Tiempo
3.
J Diabetes Sci Technol ; 8(1): 26-34, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24876534

RESUMEN

Recent studies have provided new insights into nonlinearities of insulin action in the hypoglycemic range and into glucagon kinetics as it relates to response to hypoglycemia. Based on these data, we developed a new version of the UVA/PADOVA Type 1 Diabetes Simulator, which was submitted to FDA in 2013 (S2013). The model of glucose kinetics in hypoglycemia has been improved, implementing the notion that insulin-dependent utilization increases nonlinearly when glucose decreases below a certain threshold. In addition, glucagon kinetics and secretion and action models have been incorporated into the simulator: glucagon kinetics is a single compartment; glucagon secretion is controlled by plasma insulin, plasma glucose below a certain threshold, and glucose rate of change; and plasma glucagon stimulates with some delay endogenous glucose production. A refined statistical strategy for virtual patient generation has been adopted as well. Finally, new rules for determining insulin to carbs ratio (CR) and correction factor (CF) of the virtual patients have been implemented to better comply with clinical definitions. S2013 shows a better performance in describing hypoglycemic events. In addition, the new virtual subjects span well the real type 1 diabetes mellitus population as demonstrated by good agreement between real and simulated distribution of patient-specific parameters, such as CR and CF. S2013 provides a more reliable framework for in silico trials, for testing glucose sensors and insulin augmented pump prediction methods, and for closed-loop single/dual hormone controller design, testing, and validation.

4.
Diabetes ; 63(2): 483-93, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24089513

RESUMEN

The contribution of elevated glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y gastric bypass (RYGB) has been the subject of uncertainty. We used exendin-9,39, a competitive antagonist of GLP-1, to examine glucose metabolism, islet hormone secretion, and gastrointestinal transit in subjects after RYGB and in matched control subjects. Subjects were studied in the presence or absence of exendin-9,39 infused at 300 pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6 ± 0.5 vs. 2.0 ± 0.4 mol/6 h, P = 0.001). Exendin-9,39 decreased insulin concentrations (12.3 ± 2.2 vs. 18.1 ± 3.1 nmol/6 h, P = 0.002) and the ß-cell response to glucose (Total, 13 ± 1 vs. 11 ± 1 × 10(-9) min(-1), P = 0.01) but did not alter the disposition index (DI). In control subjects, exendin-9,39 also increased glucose (2.2 ± 0.4 vs. 1.7 ± 0.3 mol/6 h, P = 0.03) without accompanying changes in insulin concentrations, resulting in an impaired DI. Post-RYGB, acceleration of stomach emptying during the first 30 min by exendin-9,39 did not alter meal appearance, and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain whether this explains all of the changes after RYGB.


Asunto(s)
Derivación Gástrica , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Estudios de Casos y Controles , Femenino , Regulación de la Expresión Génica , Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Péptido 1 Similar al Glucagón/genética , Humanos , Masculino , Fragmentos de Péptidos/farmacología
5.
Diabetes Technol Ther ; 15(10): 802-9, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23865841

RESUMEN

BACKGROUND: The ability to simulate in silico experiments is crucial for fast and cost-effective preliminary studies prior to clinical trials. We present an in silico approach to the design of optimal pramlintide-to-insulin (P/I) ratios, using our computer simulator of the human metabolic system, with a population of virtual adult type 1 diabetes mellitus patients and with individual parameters modified to account for the dynamic effects of pramlintide. MATERIALS AND METHODS: A model of pramlintide action on gastric emptying was built using data of 15 type 1 diabetes mellitus subjects studied twice with a standardized dual-tracer meal on placebo and pramlintide, which was incorporated in our type 1 diabetes simulator. Extensive in silico experiments on 100 virtual subjects were performed to optimize the co-administration of pramlintide and insulin prior to its submission to clinical trials; several P/I ratios were tested in terms of efficacy, in attenuating postprandial hyperglycemia, and in hypoglycemia safety. RESULTS: In silico experiments estimated the optimal P/I ratio to be 9 µg of pramlintide per unit (U) of insulin. Additional simulations narrowing the investigated range indicated that P/I ratios of 8 and 10 µg/U would achieve similar performance. Moreover, simulation results suggested that in clinical trials, insulin boluses should be reduced by approximately 21% at a P/I ratio of 9 µg/U to account for the effects of pramlintide and avoid postprandial hypoglycemia. CONCLUSIONS: We can assert that a valid simulation model of pramlintide action was developed, leading to in silico estimation of optimal pramlintide:insulin co-administration ratio. Clinical trials will confirm (or adjust) this initial estimation.


Asunto(s)
Glucemia/efectos de los fármacos , Simulación por Computador , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Polipéptido Amiloide de los Islotes Pancreáticos/administración & dosificación , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Quimioterapia Combinada , Femenino , Vaciamiento Gástrico , Humanos , Hipoglucemia/sangre , Hipoglucemia/prevención & control , Hipoglucemiantes/farmacología , Insulina/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Masculino , Periodo Posprandial , Factores de Tiempo , Resultado del Tratamiento
6.
Diabetes ; 61(5): 1082-9, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22461567

RESUMEN

The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1-induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp and GLP-1 infusion. In addition, we measured active and total GLP-1 in response to an oral challenge in nondiabetic subjects. After genotyping the relevant single nucleotide polymorphisms, generalized linear regression models and repeated-measures ANCOVA models incorporating potential confounders, such as age and BMI, were used to assess the associations, if any, of response with genotype. These variants did not alter GLP-1 concentrations in response to oral intake. No effects on ß-cell responsiveness to hyperglycemia and GLP-1 infusion were apparent. Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02). In nondiabetic subjects, diabetes-associated genetic variation does not alter GLP-1 concentrations after an oral challenge or its effect on insulin secretion.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Variación Genética , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Péptido C/genética , Péptido C/metabolismo , Predisposición Genética a la Enfermedad , Genotipo , Glucagón/metabolismo , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/genética , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Humanos , Hiperglucemia , Insulina/genética , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ1/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/genética , Proteína 2 Similar al Factor de Transcripción 7/metabolismo
7.
Diabetes Care ; 33(9): 2074-6, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20805279

RESUMEN

OBJECTIVE: Glucagon-like peptide (GLP)-1 receptor is encoded by GLP1R. The effect of genetic variation at this locus on the response to GLP-1 is unknown. This study assessed the effect of GLP1R polymorphisms on insulin secretion in response to hyperglycemia and to infused GLP-1 in nondiabetic subjects. RESEARCH DESIGN AND METHODS: Eighty-eight healthy individuals (aged 26.3 +/- 0.6 years, fasting glucose 4.83 +/- 0.04 mmol/l) were studied using a hyperglycemic clamp. GLP-1 was infused for the last 2 h of the study (0.75 pmol/kg/min over 121-180 min, 1.5 pmol/kg/min over 181-240 min). beta-Cell responsivity (Phi(Total)) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on Phi(Total) was examined. RESULTS: Two SNPs (rs6923761 and rs3765467) were nominally associated with altered beta-cell responsivity in response to GLP-1 infusion. CONCLUSIONS: Variation in GLP1R may alter insulin secretion in response to exogenous GLP-1. Future studies will determine whether such variation accounts for interindividual differences in response to GLP-1-based therapy.


Asunto(s)
Péptido 1 Similar al Glucagón/farmacología , Insulina/metabolismo , Receptores de Glucagón/genética , Péptido C/metabolismo , Genotipo , Receptor del Péptido 1 Similar al Glucagón , Heterocigoto , Humanos , Secreción de Insulina , Polimorfismo de Nucleótido Simple/genética
8.
Am J Physiol Endocrinol Metab ; 298(6): E1115-21, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20179243

RESUMEN

Glucagon-like peptide-1 (GLP-1)-based therapies for diabetes have aroused interest because of their effects on insulin secretion and glycemic control. However, a mechanistic model enabling quantitation of pancreatic response to GLP-1 has never been developed. To develop such a model we studied 88 healthy individuals (age 26.3 +/- 0.6 yr, BMI 24.9 +/- 0.4 kg/m(2)) by use of a hyperglycemic clamp. A variable infusion maintained glucose concentrations at 150 mg/dl for 240 min. At 120 min, an intravenous infusion of GLP-1 was started (0.75 pmol kg(-1) min(-1) from 120-180 min, 1.5 pmol kg(-1) min(-1) from 181-240 min). Consequently, plasma C-peptide concentration rose from 1,852.0 +/- 62.8 pmol/l at 120 min to 4,272.2 +/- 176.4 pmol/l at 180 min and to 6,995.8 +/- 323.5 pmol/l at 240 min. Four models of GLP-1 action on insulin secretion were considered. All models share the common assumption that insulin secretion is made up of two components, one proportional to glucose rate of change through dynamic responsivity, Phi(d), and one proportional to glucose through static responsivity, Phi(s), but differing by modality of GLP-1 control. The model that best fit C-peptide data assumes that above-basal insulin secretion depends linearly on GLP-1 concentration and its rate of change. An index (Pi) measuring the percentage increase of secretion due to GLP-1 is derived. Before GLP-1 infusion, Phi(d) = 245.7 +/- 15.6 10(-9) and Phi(s) = 25.2 +/- 1.4 10(-9) min(-1). Under GLP-1 stimulus, Pi = 12.6 +/- 0.71% per pmol/l, meaning that an increase of 5 pmol/l in peripheral GLP-1 concentrations induces an approximately 60% increase in over-basal insulin secretion.


Asunto(s)
Péptido 1 Similar al Glucagón/administración & dosificación , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Modelos Biológicos , Adulto , Glucemia/metabolismo , Péptido C/sangre , Femenino , Glucagón/sangre , Técnica de Clampeo de la Glucosa/métodos , Humanos , Infusiones Intravenosas , Secreción de Insulina , Masculino
9.
Clin Endocrinol (Oxf) ; 73(2): 189-96, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20039889

RESUMEN

OBJECTIVE: Low glucagon-like peptide-1 (GLP-1) concentrations have been observed in impaired fasting glucose (IFG). It is uncertain whether these abnormalities contribute directly to the pathogenesis of IFG and impaired glucose tolerance. Dipeptidyl peptidase-4 (DPP-4) inhibitors raise incretin hormone concentrations enabling an examination of their effects on glucose turnover in IFG. RESEARCH DESIGN AND METHODS: We studied 22 subjects with IFG using a double-blinded, placebo-controlled, parallel-group design. At the time of enrollment, subjects ate a standardized meal labelled with [1-(13)C]-glucose. Infused [6-(3)H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6-(2)H(2)] glucose enabled measurement of endogenous glucose production (EGP) and glucose disappearance (Rd). Subsequently, subjects were randomized to 100 mg of sitagliptin daily or placebo. After an 8-week treatment period, the mixed meal was repeated. RESULTS: As expected, subjects with IFG who received placebo did not experience any change in glucose concentrations. Despite raising intact GLP-1 concentrations, treatment with sitagliptin did not alter either fasting or postprandial glucose, insulin or C-peptide concentrations. Postprandial EGP (18.1 +/- 0.7 vs 17.6 +/- 0.8 micromol/kg per min, P = 0.53), Rd (55.6 +/- 4.3 vs 58.9 +/- 3.3 micromol/kg per min, P = 0.47) and MRa (6639 +/- 377 vs 6581 +/- 316 micromol/kg per 6 h, P = 0.85) were unchanged. Sitagliptin was associated with decreased total GLP-1 implying decreased incretin secretion. CONCLUSIONS: DPP-4 inhibition did not alter fasting or postprandial glucose turnover in people with IFG. Low incretin concentrations are unlikely to be involved in the pathogenesis of IFG.


Asunto(s)
Glucemia/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Intolerancia a la Glucosa/metabolismo , Incretinas/metabolismo , Pirazinas/farmacología , Triazoles/farmacología , Glucemia/efectos de los fármacos , Método Doble Ciego , Ayuno/sangre , Ayuno/metabolismo , Femenino , Intolerancia a la Glucosa/sangre , Humanos , Incretinas/sangre , Masculino , Persona de Mediana Edad , Placebos , Periodo Posprandial/fisiología , Fosfato de Sitagliptina
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