Beta cell function, incretin hormones, and incretin effect in obese children and adolescents with prediabetes.

BACKGROUND: Defects of incretin hormones and incretin effect may be underlying mechanisms of abnormal glucose metabolism in youth. OBJECTIVE: To assess incretin hormone dynamics during an oral glucose tolerance test (OGTT) and incretin effect in obese children with prediabetes in comparison with those with normal glucose tolerance (NGT). METHODS: Overweight and obese children were enrolled and classified according to OGTT results as NGT and prediabetes. Insulin sensitivity, insulin secretion, incretin hormone concentrations during OGTT; and incretin effect derived from OGTT and intravenous glucose tolerance test were determined and compared between NGT and prediabetes groups. RESULTS: Sixty-three patients (43 NGT and 20 prediabetes) were enrolled. Their median (interquartile range) age was 12.5 (11.1, 13.8) years. Peak glucagon-like peptide-1 (GLP-1) was demonstrated at 30 min during OGTT and was higher in the prediabetes group (49.2 [35.6, 63.6] versus 36.5 [27.6, 44.2] pmol/L, p = 0.009). However, incremental areas under the curves (iAUCs) of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were not different between the two groups. There was no difference in incretin effect between NGT and prediabetes (NGT: 66.5% [60.2%, 77.5%] vs. prediabetes: 70.0% [61.5%, 75.0%], p = 0.645). Incretin effect had positive correlations with iAUCs of both GLP-1 and GIP (GLP-1: r = 0.40, p = 0.004 and GIP: r = 0.37, p = 0.009). CONCLUSIONS: Comparing between obese children with prediabetes and NGT, there were no differences in overall incretin hormone changes during OGTT and incretin effect. Incretin effect was positively correlated with iAUCs of GLP-1 and GIP.

Effect of Laparoscopic Sleeve Gastrectomy on Static and Dynamic Measures of Glucose Homeostasis and Incretin Hormone Response 4-Years Post-Operatively.

INTRODUCTION: There is limited literature available on the long-term effect of bariatric surgery especially laparoscopic sleeve gastrectomy (LSG) on the incretin hormone response. AIM: Our primary aim was to investigate changes in glucose metabolism and incretin hormone responses in participants with impaired glucose regulation approximately 4 years after LSG. The secondary aim was to examine the long-term incretin hormone changes of biliopancreatic diversion (BPD). METHOD: A non-randomised prospective study comprising of 10 participants undergoing LSG and 6 participants undergoing BPD. Serial measurements of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were performed during an oral glucose tolerance test pre-operatively and 1 month, 6 months and at approximately 4-7 years post-operatively. Area under the curve (AUC) was examined at 60 and 120 min. RESULTS: In the LSG group, a significant reduction in 2-h plasma glucose (2 h PG), HbA1c and HOMA-IR was observed at 4 years. Compared with pre-operative levels, significant increases in post-glucose GLP-1 secretion were observed at 1 and 6 months, but not maintained at 4 years. A linear increase was seen in post-glucose GIP response at 1 month and 6 months and 4 years. Within the BPD group, a reduction in HbA1c along with an increase GLP-1 response was observed at 7 years. CONCLUSION: An increase in GLP-1 response was not preserved at 4 years, but a significant increase in GIP response was observed along with improved glycaemic control following LSG.

[Incretins-adipocytokines interactions in type 2 diabetic subjects with or without non-alcoholic fatty liver disease: interest of GLP-1 (glucagon-like peptide-1) as a modulating biomarker]. / Interactions incrétines-adipocytokines chez le sujet diabétique de type 2 avec ou sans stéatose hépatique non alcoolique : intérêt du GLP-1 (glucagon-like peptide-1) comme biomarqueur modulateur.

Type 2 diabetes (T2DM) associated with non-alcoholic fatty liver disease (NAFLD) increases cardiovascular risk. Complex and subtle connections are established between hepatic dysfunction and adipose tissue hyperactivity. This relationship is mediated by insulin resistance, dyslipidemia and inflammation. Recently incretins have been involved in this connection including GLP-1 (glucagon-like peptide-1). The aim of this study is to establish interactions between the GLP-1 plasma levels and metabolic syndrome clusters and adipocytokines profile (leptin, adiponectin, resistin, TNFα and IL-6) in diabetic subjects with or without NAFLD. The study was undertaken on 320 adult subjects divided into four groups: NAFLD, DT2, NAFLD+DT2 and control. In all subjects, the metabolic syndrome clusters was investigated according to the NCEP/ATPIII criteria. Insulin resistance was evaluated by the Homa-IR model. The metabolic parameters were determined on Cobas® automated biochemical analysis. The adipocytokines are determined by immunoassay method on Elisa human reader - Biotek ELX 800. The NAFLD has been confirmed by abdominal ultrasound and by histology. Feeding and fasting plasma GLP-1 was assessed by Elisa method. The data revealed that insulin resistance (Homa-IR) is present in all groups. Homa-IR is negatively associated with plasma GLP-1 depletion in the NAFLD, DT2 and NAFLD+DT2 groups. Adiponectin levels are decreased in all groups as for GLP-1. At the opposite, leptin, resistin, TNFα and IL-6 levels show an inverse correlation with GLP-1. This study suggests that plasma GLP-1 can be considered as a transition and evolution biomarker between NAFLD and T2D. GLP-1 accurately reflects metabolic and inflammatory status, both in subjects with NAFLD only or with T2D only, before the diabetes - steatosis stage.

[Incretin secretion and glucose metabolism in morbidly obese patients in the early and late periods after biliopancreatic diversion]. / Produktsiya inkretinov i obmen glyukozy u bol'nykh patologicheskim ozhireniem v rannem i otdalennom periode posle biliopankreaticheskogo shuntirovaniya.

AIM: To estimate the parameters of glucose metabolism and to assess the secretion of incretins in patients after biliopancreatic diversion (BPD) for morbid obesity (MO) in the early and late postoperative periods. SUBJECTS AND METHODS: The prospective part of the investigation included 22 patients with a body mass index of 35.8 to 68.4 kg/m2 and type 2 diabetes mellitus (T2DM). All the patients were examined before, 3 weeks and 3 months after BPD. The retrospective part covered 23 patients who were examined after BPD for MO; the postoperative period was 4.7 [2.3; 7.2] years. A control group consisted of 22 healthy, normal weight volunteers. A 75-g oral glucose tolerance test was carried out in all the groups to study the levels of glucose, immunoreactive insulin (IRI), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon at 0, 30, 60, and 120 min. RESULTS: T2DM patients showed improvement in glucose metabolism just 3 weeks after BPD; following 3 months, they had normalized fasting blood glucose levels (5.6 [5.0; 6.0] mmol/l). During 3 months, glycated hemoglobin decreased from 7.5 [6.6; 8.5] to 5.7 [5.3; 5.9]%. In the early period following BPD, there was an increase in basal and postprandial GLP-1 levels associated with the peak IRI concentration. In the late period after BPD, the enhanced secretion of IRI and GLP-1 persisted, which was followed by a reduction in postprandial glucose levels in 4 of the 23 patients. CONCLUSION: T2DM remission does not depend on weight loss in the early period after BPD. In this period, the significant improvement of glucose metabolic parameters in patients with obesity and T2DM is associated with elevated GLP-1 levels. The altered incretin response is a stable effect of BPD and remains in its late period.

Comportamiento del eje entero-insular en una poblacion deportista; influencia de la dieta y el ejercicio / Performance of entero-insular axis in an athletic population: diet and exercise influence

Introducción: La relación existente entre el ejercicio físico y la regulación del apetito puede conducir a una mejora del rendimiento competitivo de los deportistas. Los mediadores del eje entero-insular generan señales neurohumorales que influyen en la regulación del apetito y la homeostasis energética. Objetivo: Determinar la influencia de la dieta y el ejercicio prolongado sobre los péptidos intestinales, grelina, resistina, leptina, e incretinas (GLP-1 y GIP) en una población deportista. MÉTODOS: Este es un estudio prospectivo, de intervención desarrollado desde Octubre 2012 a Marzo 2013. Se incluyeron 32 jugadores de rugby sanos. Se tomaron medidas antropométricas y muestras de sangre en el momento 0 y a los seis meses del estudio. Se distribuyeron aleatoriamente a una dieta bien proteica (DP) o mediterránea (DM) y estudiamos los niveles plasmáticos de adipoquinas e incretinas. Resultados: Las concentraciones plasmáticas de GLP- 1 y GIP presentaron un descenso (p < 0.03; p< 0.01 respectivamente) en los seguidores de la DP. Los niveles de GLP-1 y de grelina mostraron un descenso significativo (p< 0.03 respectivamente) en el grupo con ganancia de masa muscular (MM). Finalmente, las concentraciones de GLP-1 disminuyeron significativamente en el grupo vinculado a la DP que incrementó su MM (p<0.002) y peso total (p<0.03). Conclusión: Los niveles de GLP-1 muestran un descenso con la DP en aquellos deportistas que aumentan su MM y peso total. Ello sugiere que este tipo de dieta puede mejorar el rendimiento en determinadas modalidades deportivas y disminuir el riesgo de hipoglucemias (AU)

Introduction: The relationship between physical exercise and appetite regulation can lead to improved competitive performance of athletes. Mediators of the entero-insular axis generate neurohumoral signals that influence on the appetite regulation and energy homeostasis. AIM: Determine the influence of diet and prolonged exercise on intestinal peptide, ghrelin, resistin, leptin, and incretins (GLP-1 and GIP) in an athlete population. Methods: It is a prospective intervention study, conducted from October 2012 to March 2013. 32 healthy semiprofessional rugby players, aged 13-39 years were included. Anthropometric measurements and blood samples were taken at time 0 and after six months of study. Athletes were randomized to a protein diet (PD) or Mediterranean diet (MD) and plasma levels of intestinal peptide, ghrelin, resistin, leptin, and incretins were calculated. Results: In the PD group, GLP-1 and GIP plasmatic levels showed a significant decrease (p<0.03; p<0.01 respectively). GLP-1 and ghrelin plasmatic concentration demonstrated a significant decrease (p<0.03 and p<0.002, respectively). Conclusion: GLP-1 plasmatic concentration was decreased, with the PD suggesting to be more beneficial for the athletes in order to avoid hypoglycemia. Furthermore, muscle mass and total weight gain, linked to the PD, could enhance athletic performance in certain sport modalities (AU)

Measurement of the incretin hormones: glucagon-like peptide-1 and glucose-dependent insulinotropic peptide.

The two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are secreted from the gastrointestinal tract in response to meals and contribute to the regulation of glucose homeostasis by increasing insulin secretion. Assessment of plasma concentrations of GLP-1 and GIP is often an important endpoint in both clinical and preclinical studies and, therefore, accurate measurement of these hormones is important. Here, we provide an overview of current approaches for the measurement of the incretin hormones, with particular focus on immunological methods.

Diabetes mellitus tipo 2: nuevos tratamientos / Type 2 diabetes mellitus: New treatmen

Se revisan los efectos beneficiosos y los problemas relacionados con los fármacos hipoglucemiantes tradicionales y se analizan los nuevos medicamentos de esta clase relacionados con el efecto incretina: análogos del péptido similar al glucagón tipo 1 e inhibidores de las dipeptidil peptidasas tipo 4. Ambos producen, de forma dependiente de la glucosa, una reducción de la glucemia, no se relacionan con la hipoglucemia y no aumentan el peso. Otro nuevo grupo son los inhibidores del cotransportador sodio-glucosa tipo 2, que disminuyen la glucemia con bajo riesgo de hipoglucemia y con discreta pérdida de peso. Los efectos beneficiosos a largo plazo y la prevención cardiovascular no están demostrados. Disponemos cada vez de más y mejores fármacos. Por otra parte, el tratamiento farmacológico hipoglucemiante debe ser personalizado, considerando los valores de hemoglobina glucosilada, el riesgo-beneficio, el riesgo de hipoglucemia, los cambios en el peso y el estado cardiovascular, entre otros factores. No tenemos el hipoglucemiante ideal y no debemos olvidar que, junto al control de la hiperglucemia, el tratamiento precoz e intensivo de la dislipidemia y de la hipertensión es fundamental en la prevención cardiovascular del paciente con diabetes tipo 2 (AU)

The benefits and problems associated with traditional hypoglycemic drugs, such as failure of beta cells, hypoglycemia and weight gain, that lead to a worsening of diabetes, are reviewed. New hypoglycemic drugs with incretin effect (glucagon-like peptide-1 agonists and dipeptidyl peptidase 4 inhibitors), achieve, in a glucose dependent manner, an glycosylated hemoglobin reduction without hypoglycemia or increase in body weight. Recently, another group of oral hypoglycemic drugs, sodium-glucosecotransporter type 2 inhibitors, have demonstrated efficacy in diabetes control by inhibiting renal glucose reabsorption. However, long-term effects and cardiovascular prevention remain to be demonstrated. We have more and better drugs nowadays. Hypoglycemic treatment should be customized (glycosylated hemoglobin levels, risk-benefit, risk of hypoglycemia, weight changes, cardiovascular risk), with a combination of drugs being necessary in most cases. However, we do not have yet an ideal hypoglycemic drug. Moreover we must remember that an early and intensive treatment of dyslipidemia and hypertension is essential for the prevention of cardiovascular disease in patients with type 2 diabetes (AU)

Control metabólico y pérdida de peso en pacientes con obesidad y diabetes mellitus tipo 2 tratados con exenatida / Metabolic control and weight loss in patients with obesity and type 2 diabetes mellitus, treated with exenatide

Fundamento y objetivo. Exenatida es un análogo de GLP1 diseñado para mejorar el control glucémico en pacientes con obesidad y diabetes mellitus tipo 2 (DM2). Además, presenta otras acciones de control metabólico. El objetivo de este estudio fue valorar si exenatida ayuda a conseguir objetivos de control metabólico en pacientes con obesidad y DM2 tras 24 semanas de tratamiento. Pacientes y método. Ensayo clínico abierto en 102 pacientes, 69 mujeres y 33 varones, con edades comprendidas entre 19-77 años (media [DE] de 53,2 [1,1] años, con DM2 de evolución media de 4,88 [0,5] años (extremos entre 1 y 20 años) en tratamiento con antidiabéticos orales (ADO) y obesidad. Resultados. Se observó una diferencia significativa de la glucosa basal, con reducción promedio de 19,7 (7,1) mg/dl, y de hemoglobina glucosilada (HbA1c) de 0,33 (0,17)%, siendo esta última mayor en pacientes con mal control previo al tratamiento (HbA1c>8,5%), en los que la disminución fue de una media del 2,12 (0,53)%. Se tomó como objetivo establecido respecto a HbA1c < 7%, alcanzado en un 14% más de los pacientes tratados que de los controles (43,6 frente a 57,9; p < 0,05). El peso disminuyó en 4,4 (0,8) kg y el índice de masa corporal en 1,7 (0,3) kg/m2. Se redujeron de forma no significativa el colesterol total (una media de 4,9 [1,5] mg/dl), el colesterol unido a lipoproteínas de baja densidad (colesterol LDL) (una media de 3,2 [3,4] mg/dl, el colesterol unido a lipoproteínas de no alta densidad (de 8,6 [5,6] mg/dl) y el colesterol unido a lipoproteínas de alta densidad (de 2,5 [1,4] mg/dl). En pacientes fuera de objetivo (colesterol LDL>100mg/dl y/o triglicéridos>150mg/dl) sí se observaron diferencias significativas en el colesterol LDL y los triglicéridos. En cuanto a la presión arterial (PA), solo se obtuvieron diferencias significativas en las cifras de PA diastólica (descenso medio de 18,9 [5,7] mmHg), mientras que la PA sistólica se redujo de forma no significativa. Se tomó como objetivo establecido respecto a HbA1c<7%, alcanzado en un 14% más de los pacientes tratados que de los controles (43,6 frente a 57,9; p<0,05). Conclusiones. Exenatida es un fármaco efectivo no solo para el control de la glucemia (HbA1c), sino también para otros parámetros como perfil lipídico, PA y peso corporal(AU)

Background and objective. Exenatide is an analogue of GLP1 designed to improve the glycemic control in patients with obesity and type 2 diabetes. It may control other metabolic processes as well. We aimed to evaluate whether exenatide helps to achieve metabolic control goals in patients with obesity and type 2 diabetes (T2DM) after 24 weeks of treatment. Patients and method. Open clinical trial in 102 obese patients, with age between 19-77 years (mean [ED] 53,2 [1,1] years), T2DM with mean evolution of 4,88 [0,5] years (range 1 to 20 years) with oral antidiabetic treatment. Results. There was a reduction of 19.7±7.1mg/dl in the fasting glucose average and of 0.33±0.17% in glycated hemoglobin (HbA1c). These last values were higher (2.12±0.53%) in patients with bad control prior to treatment (HbA1c>8.5%). The desirable threshold of HbA1c<7% was fulfilled by 14% more treated than control patients (43.6 vs. 57.9, P<.05). Reductions of 4.4±0.8kg average weight and of 1.7±0.3kg/m2 body mass index were recorded. Although there was not a significant reduction in the overall lipid profile, a decrease of 4.9±5.1mg/dl total cholesterol, 3.2±4.3mg/dl LDL-C, 8.6±5.6mg/dl noHDL-C and 2.5±1, 4mg/dl HDL-C was observed. Patients outside target (LDL>100 and/or triglycerides>150mg/dl) showed significant differences in their concentrations of LDL-C and triglycerides. With respect to blood pressure (BP), significant differences were observed in diastolic BP (-18.9±5.7mmHg) but not in systolic BP (P<.05). Conclusions. Exenatide is an effective drug not only for glycemic control but also for the overall metabolic control of HbA1c, lipid profile, BP and body weight(AU)

Stress hyperglycaemia in critically ill patients; Potential role of incretinhormones; a preliminary study / Hiperglucemia de estrés en el paciente crítico; papel potencial de las incretinas; estudio preliminar

Background: Stress hyperglycaemia is common in the intensive care unit (ICU) setting and has been related to a worst outcome. Objective: The objective was to characterize the association of glucoregulatory hormones, mainly incretins, with the levels of glycaemia, and its relationship with outcome in ICU patients. Methods: We prospectively studied 60 patients. Stress hyperglycaemia was diagnosed when glycaemia was > 115 mg/dL. At ICU admission we determined glycaemia, insulin, glucagon, cortisol, glucose-dependent insulino -tropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1) plasma levels. Groups were compared using Kruskal-Wallis test. The association between glycaemia levels and glucoregulatory hormones was evaluated using linear regression. Results: Forty-five patients (75%) had hyperglycaemia.We observed no differences in glucoregulatory hormones levels between normo- and hyper- glycaemia groups. Glycaemia levels were not significantly correlated with insulin, glucagon, cortisol or GIP levels, but were correlated withGLP-1 (p = 0.04). GLP-1 was also correlated with cortisol (p = 0.01), but failed to show a significant correlation withinsulin, glucagon or GIP levels. Lower levels of plasmaGLP-1 were found in patients with stress hyperglycaemia requiring vasoactive support (p = 0.02).Conclusions: Glycaemia levels were correlated withGLP-1 levels in ICU patients. GLP-1 levels were also associated with cortisol. Patients with stress hyperglycaemia who required vasoactive support had lower incretin levels compared with those patients with stress hyperglycaemia who were hemodynamically stables.(ClinicalTrials.gov Identifier: NCT01087372) (AU)

Antecedentes: La hiperglucemia de estrés es habitual en el contexto de la Unidad de cuidados intensivos (UCI) y se ha relacionado con un peor pronóstico. Objetivo: el objetivo fue caracterizar la asociación de hormonas glucorreguladoras, principalmente las incretinas, con las glucemias y su relación con el pronóstico de los pacientes de UCI. Métodos: Estudiamos de forma prospectiva a 60pacientes. La hiperglucemia de estrés se diagnosticaba cuando la glucemia era > 115 mg/dl. En el ingreso en la UCI, determinamos la glucemia y las concentraciones plasmáticas de insulina, glucagón, cortisol, polipéptidoinsulinotropo dependiente de glucosa (GIP) y péptido-1de tipo glucagón (GLP-1). Se compararon los grupos mediante la prueba de Kruskal-Wallis. La asociación entre las glucemias y las hormonas contrarreguladoras se evaluó mediante regresión linear. Resultados: 45 pacientes (75%) tenían hiperglucemia.No observamos diferencias en las concentraciones de hormonas glucorreguladoras entre los grupos de normo ehiperglucemia. Las glucemias no se correlacionaron de forma significativa con las concentraciones de insulina,glucagón, cortisol o GIP, pero sí con el GLP-1 (p = 0,04).El GLP-1 también se correlacionó con el cortisol (p =0,01), pero no consiguió mostrar una correlación significativa con las concentraciones de insulina, glucagón o GIP. Se encontraron menores concentraciones plasmáticas de GLP-1 en los pacientes con hiperglucemia de estrés que requerían soporte vasoactivo (p = 0,02). Conclusiones: las glucemias se correlacionaron con las concentraciones de GLP-1 en los pacientes en UCI . Las concentraciones de GLP-1 también se asociaron con el cortisol. Los pacientes con hiperglucemia de estrés que necesitaron soporte vasoactivo tenían menores concentraciones de incretina en comparación con aquellos con hiperglucemia de estrés con estabilidad hemodinámica(ClinicalTrials.gov Identifier: NCT01087372) (AU)

Combining enteral with parenteral nutrition to improve postoperative glucose control.

The provision of parenteral nutrition (PN) to 'stressed' patients often results in hyperglycaemia, which may be detrimental. In animal models limited amounts of enteral nutrition (EN) improve intestinal integrity and stimulate intestinal incretin production, which may lead to improved glucose control. We set out to assess if combining EN with PN results in improved glucose homeostasis rather than PN given alone. We conducted a randomised trial in a university teaching hospital of patients undergoing a 'curative' oesophagectomy for adenocarcinoma. Differences between the two intervention groups were assessed for continuous glucose measurement, insulin sensitivity using insulin tolerance tests (ITT) and homeostasis model analysis (HOMA), the incretin glucose-dependent insulinotropic polypeptide (GIP) and intestinal permeability. The combination of PN with EN resulted in lower interstitial glucose concentrations (P = 0.002), reduced insulin resistance, improved insulin sensitivity (HOMA-insulin resistance (IR) P = 0.045; HOMA beta P = 0.037; ITT P = 0.006), improved intestinal permeability (P < 0.001) and increased GIP (P = 0.01) when compared with PN alone. The combination of EN with PN, when compared with PN alone, results in reduced glucose concentrations, reduced insulin resistance, increased incretins and improvements in intestinal permeability.