title: Short and prolonged exposure to hyperglycaemia in human fibroblasts and endothelial cells: metabolic and osmotic effects.
abstract: High blood glucose levels are the main feature of diabetes. However, the underlying mechanism linking high glucose concentration to diabetic complications is still not fully elucidated, particularly with regard to human physiology. Excess of glucose is likely to trigger a metabolic response depending on the cell features, activating deleterious pathways involved in the complications of diabetes. In this study, we aim to elucidate how acute and prolonged hyperglycaemia alters the biology and metabolism in human fibroblasts and endothelial cells. We found that hyperglycaemia triggers a metabolic switch from oxidative phosphorylation to glycolysis that is maintained over prolonged time. Moreover, osmotic pressure is a major factor in the early metabolic response, decreasing both mitochondrial transmembrane potential and cellular proliferation. After prolonged exposure to hyperglycaemia we observed decreased mitochondrial steady-state and uncoupled respiration, together with a reduced ATP/ADP ratio. At the same time, we could not detect major changes in mitochondrial transmembrane potential and reactive oxygen species. We suggest that the physiological and metabolic alterations observed in healthy human primary fibroblasts and endothelial cells are an adaptive response to hyperglycaemia. The severity of metabolic and bioenergetics impairment associated with diabetic complications may occur after longer glucose exposure or due to interactions with cell types more sensitive to hyperglycaemia.
authors.affiliation: The Rolf Luft Research Center, Department of Endocrinology, Metabolism and Diabetes, Karolinska University/Hospital, 17176 Stockholm, Sweden. Electronic address: noah.moruzzi@helmholtz-muenchen.de.
authors.forename: Noah
authors.initials: N
authors.lastname: Moruzzi
authors.affiliation: The Rolf Luft Research Center, Department of Endocrinology, Metabolism and Diabetes, Karolinska University/Hospital, 17176 Stockholm, Sweden.
authors.forename: Marianna
authors.initials: M
authors.lastname: Del Sole
authors.affiliation: Department of Pharmacology and Biotechnology (FaBiT), University of Bologna, 40126 Bologna, Italy.
authors.forename: Romana
authors.initials: R
authors.lastname: Fato
authors.affiliation: The Rolf Luft Research Center, Department of Endocrinology, Metabolism and Diabetes, Karolinska University/Hospital, 17176 Stockholm, Sweden; Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München, Parkring 11, 85748 Garching, Germany.
authors.forename: Jantje M
authors.initials: JM
authors.lastname: Gerdes
authors.affiliation: The Rolf Luft Research Center, Department of Endocrinology, Metabolism and Diabetes, Karolinska University/Hospital, 17176 Stockholm, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: Department of Pharmacology and Biotechnology (FaBiT), University of Bologna, 40126 Bologna, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Bergamini
authors.affiliation: The Rolf Luft Research Center, Department of Endocrinology, Metabolism and Diabetes, Karolinska University/Hospital, 17176 Stockholm, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
mesh_terms: D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004734:Energy Metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009995:Osmosis; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D005947:Glucose
keywords: Human endothelial cells; Human fibroblasts; Hyperglycaemia; Hyperosmosis; Mitochondria