title: Insulin hypersecretion in islets from diet-induced hyperinsulinemic obese female mice is associated with several functional adaptations in individual β-cells.
abstract: Insulin resistance and hyperinsulinemia are generally associated with obesity. Obese nondiabetic individuals develop a compensatory β-cell response to adjust insulin levels to the increased demand, maintaining euglycemia. Although several studies indicate that this compensation relies on structural changes, the existence of β-cell functional adaptations is incompletely understood. Here, we fed female mice with a high-fat diet (HFD) for 12 weeks. These animals became obese, hyperinsulinemic, insulin-resistant, and mildly glucose-intolerant while fed, and fasting glycemia was comparable in HFD and control mice. Islets from HFD animals exhibited increased β-cell mass and hypertrophy. Additionally, they had enhanced insulin gene expression and content and augmented glucose-induced insulin secretion. Electrophysiological examination of β-cells from both groups showed no differences in KATP channel open probability and conductance. However, action potentials elicited by glucose had larger amplitude in obese mice. Glucose-induced Ca²⁺ signals in intact islets, in isolated β-cells, and individual β-cells within islets were also increased in HFD mice. Additionally, a higher proportion of glucose-responsive cells was present in obese mice. In contrast, whole-cell Ca²⁺ current densities were similar in both groups. Capacitance measurements showed that depolarization-evoked exocytosis was enhanced in HFD β-cells compared with controls. Although this augment was not significant when capacitance increases of the whole β-cell population were normalized to cell size, the exocytotic output varied significantly when β-cells were distributed by size ranges. All these findings indicate that β-cell functional adaptations are present in the islet compensatory response to obesity.
authors.affiliation: Universidad Miguel Hernández, Avenida de la Universidad s/n, 03202 Elche, Spain. ivanq@umh.es.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Beatriz
authors.initials: B
authors.lastname: Merino
authors.forename: Laura
authors.initials: L
authors.lastname: Marroquí
authors.forename: Patricia
authors.initials: P
authors.lastname: Ñeco
authors.forename: Paloma
authors.initials: P
authors.lastname: Alonso-Magdalena
authors.forename: Ernesto
authors.initials: E
authors.lastname: Caballero-Garrido
authors.forename: Elaine
authors.initials: E
authors.lastname: Vieira
authors.forename: Sergi
authors.initials: S
authors.lastname: Soriano
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.forename: Angel
authors.initials: A
authors.lastname: Nadal
authors.forename: Ivan
authors.initials: I
authors.lastname: Quesada
mesh_terms: D000200:Action Potentials; D052636:Allostasis; D000818:Animals; D020013:Calcium Signaling; D048429:Cell Size; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004553:Electric Conductivity; D005089:Exocytosis; D005260:Female; D018149:Glucose Intolerance / Q000209:etiology; D006946:Hyperinsulinism / Q000097:blood / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006984:Hypertrophy; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D054086:KATP Channels / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000503:physiopathology*; D015854:Up-Regulation
chemical_list: D007328:Insulin; D054086:KATP Channels