title: Enhanced glucose-induced intracellular signaling promotes insulin hypersecretion: pancreatic beta-cell functional adaptations in a model of genetic obesity and prediabetes.
abstract: Obesity is associated with insulin resistance and is known to be a risk factor for type-2 diabetes. In obese individuals, pancreatic beta-cells try to compensate for the increased insulin demand in order to maintain euglycemia. Most studies have reported that this adaptation is due to morphological changes. However, the involvement of beta-cell functional adaptations in this process needs to be clarified. For this purpose, we evaluated different key steps in the glucose-stimulated insulin secretion (GSIS) in intact islets from female ob/ob obese mice and lean controls. Obese mice showed increased body weight, insulin resistance, hyperinsulinemia, glucose intolerance and fed hyperglycemia. Islets from ob/ob mice exhibited increased glucose-induced mitochondrial activity, reflected by enhanced NAD(P)H production and mitochondrial membrane potential hyperpolarization. Perforated patch-clamp examination of beta-cells within intact islets revealed several alterations in the electrical activity such as increased firing frequency and higher sensitivity to low glucose concentrations. A higher intracellular Ca(2+) mobilization in response to glucose was also found in ob/ob islets. Additionally, they displayed a change in the oscillatory pattern and Ca(2+) signals at low glucose levels. Capacitance experiments in intact islets revealed increased exocytosis in individual ob/ob beta-cells. All these up-regulated processes led to increased GSIS. In contrast, we found a lack of beta-cell Ca(2+) signal coupling, which could be a manifestation of early defects that lead to beta-cell malfunction in the progression to diabetes. These findings indicate that beta-cell functional adaptations are an important process in the compensatory response to obesity.
authors: Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors: Esperanza
authors: E
authors: Irles
authors: Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors: Patricia
authors: P
authors: Ñeco
authors: Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors: Mónica
authors: M
authors: Lluesma
authors: Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors: Sabrina
authors: S
authors: Villar-Pazos
authors: Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, Brazil.
authors: Junia Carolina
authors: JC
authors: Santos-Silva
authors: Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, Brazil.
authors: Jean F
authors: JF
authors: Vettorazzi
authors: Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors: Paloma
authors: P
authors: Alonso-Magdalena
authors: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, Brazil.
authors: Everardo M
authors: EM
authors: Carneiro
authors: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, Brazil.
authors: Antonio C
authors: AC
authors: Boschero
authors: Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors: Ángel
authors: Á
authors: Nadal
authors: Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain. Electronic address: ivanq@umh.es.
authors: Ivan
authors: I
authors: Quesada
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D011236:Prediabetic State / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D002118:Calcium
keywords: Calcium signals; Diabetes; Electrical activity; Insulin secretion; Obesity; Pancreatic beta-cell