title: Insufficient insulin administration to diabetic rats increases substrate utilization and maintains lactate production in the kidney.
abstract: Good glycemic control is crucial to prevent the onset and progression of late diabetic complications, but insulin treatment often fails to achieve normalization of glycemic control to the level seen in healthy controls. In fact, recent experimental studies indicate that insufficient treatment with insulin, resulting in poor glycemic control, has an additional effect on progression of late diabetic complications, than poor glycemic control on its own. We therefore compared renal metabolic alterations during conditions of poor glycemic control with and without suboptimal insulin administration, which did not restore glycemic control, to streptozotocin (STZ)-diabetic rats using noninvasive hyperpolarized (13)C-pyruvate magnetic resonance imaging (MRI) and blood oxygenation level-dependent (BOLD) (1)H-MRI to determine renal metabolic flux and oxygen availability, respectively. Suboptimal insulin administration increased pyruvate utilization and metabolic flux via both anaerobic and aerobic pathways in diabetic rats even though insulin did not affect kidney oxygen availability, HbA1c, or oxidative stress. These results imply direct effects of insulin in the regulation of cellular substrate utilization and metabolic fluxes during conditions of poor glycemic control. The study demonstrates that poor glycemic control in combination with suboptimal insulin administration accelerates metabolic alterations by increasing both anaerobic and aerobic metabolism resulting in increased utilization of energy substrates. The results demonstrate the importance of tight glycemic control in insulinopenic diabetes, and that insulin, when administered insufficiently, adds an additional burden on top of poor glycemic control.
authors.affiliation: Department of Clinical Medicine, MR Research Centre, Aarhus University, Aarhus, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Laustsen
authors.affiliation: Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Department of Electrical Engineering, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Lipsø
authors.affiliation: Department of Endocrinology and Internal Medicine and Danish Diabetes Academy, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
authors.forename: Jakob Appel
authors.initials: JA
authors.lastname: Ostergaard
authors.affiliation: Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Nørregaard
authors.affiliation: Department of Endocrinology and Internal Medicine and Danish Diabetes Academy, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Flyvbjerg
authors.affiliation: Department of Clinical Medicine, MR Research Centre, Aarhus University, Aarhus, Denmark Comparative Medicine Lab, Aarhus University, Aarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Palm
authors.affiliation: Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Department of Electrical Engineering, Technical University of Denmark, Kgs. Lyngby, Denmark GE Healthcare, Broendby, Denmark.
authors.forename: Jan Henrik
authors.initials: JH
authors.lastname: Ardenkjær-Larsen
keywords: Hyperpolarization; kidney; magnetic resonance imaging; renal metabolism; type 1 diabetes