title: Lipotoxicity in human pancreatic islets and the protective effect of metformin.
abstract: Human pancreatic islets from eight donors were incubated for 48 h in the presence of 2.0 mmol/l free fatty acid (FFA) (oleate to palmitate, 2 to 1). Insulin secretion was then assessed in response to glucose (16.7 mmol/l), arginine (20 mmol/l), and glyburide (200 micromol/l) during static incubation or by perifusion. Glucose oxidation and utilization and intra-islet triglyceride content were measured. The effect of metformin (2.4 microg/ml) was studied because it protects rat islets from lipotoxicity. Glucose-stimulated but not arginine- or glyburide-stimulated insulin release was significantly lower from FFA-exposed islets. Impairment of insulin secretion after exposure to FFAs was mainly accounted for by defective early-phase release. In control islets, increasing glucose concentration was associated with an increase in glucose utilization and oxidation. FFA incubation reduced both glucose utilization and oxidation at maximal glucose concentration. Islet triglyceride content increased significantly after FFA exposure. Addition of metformin to high-FFA media prevented impairment in glucose-mediated insulin release, decline of first-phase insulin secretion, and reduction of glucose utilization and oxidation without significantly affecting islet triglyceride accumulation. These results show that lipotoxicity in human islets is characterized by selective loss of glucose responsiveness and impaired glucose metabolism, with a clear defect in early-phase insulin release. Metformin prevents these deleterious effects, supporting a direct protective action on human beta-cells.
authors.affiliation: Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Lupi
authors.forename: Silvia
authors.initials: S
authors.lastname: Del Guerra
authors.forename: Vanna
authors.initials: V
authors.lastname: Fierabracci
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.forename: Michela
authors.initials: M
authors.lastname: Novelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Patanè
authors.forename: Ugo
authors.initials: U
authors.lastname: Boggi
authors.forename: Franco
authors.initials: F
authors.lastname: Mosca
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piro
authors.forename: Stefano
authors.initials: S
authors.lastname: Del Prato
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D001120:Arginine / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000633:toxicity*; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D019301:Oleic Acid / Q000633:toxicity; D010168:Palmitates / Q000633:toxicity
chemical_list: D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D010168:Palmitates; D019301:Oleic Acid; D008687:Metformin; D001120:Arginine; D005947:Glucose; D005905:Glyburide