title: The diabetic rat kidney mediates inosituria and selective urinary partitioning of D-chiro-inositol.
abstract: Diabetic nephropathy is a serious complication of diabetes mellitus with a pressing need for effective metabolic markers to detect renal impairment. Of potential significance are the inositol compounds, myo-inositol (MI), and the less abundant stereoisomer, D-chiro-inositol (DCI), which are excreted at increased levels in the urine in diabetes mellitus, a phenomenon known as inosituria. There is also a selective urinary excretion of DCI compared to MI. As the biological origins of altered inositol metabolism in diabetes mellitus are unknown, the aim of this study was to determine whether the diabetic kidney was directly responsible. Kidneys isolated from four-week streptozotocin-induced diabetic rats were characterized by a 3-fold reduction in glomerular filtration rate (GFR) compared to matched non-diabetic kidneys. When perfused with fixed quantities of MI (50 µM) and DCI (5 µM) under normoglycemic conditions (5 mM glucose), GFR-normalized urinary excretion of MI was increased by 1.7-fold in diabetic vs. non-diabetic kidneys. By comparison, GFR-normalized urinary excretion of DCI was increased by 4-fold. Perfusion conditions replicating hyperglycemia (20 mM glucose) potentiated DCI but not MI urinary excretion in both non-diabetic and diabetic kidneys. Overall, there was a 2.4-fold increase in DCI urinary excretion compared to MI in diabetic kidneys that was independent of glucose ambience. This increased urinary excretion of DCI and MI in diabetic kidneys occurred despite increased renal expression of the inositol transporters, sodium myo-inositol transporter subtype 1 and 2 (SMIT1 and SMIT2). These findings show that the diabetic kidney primarily mediates inosituria and altered urinary partitioning of MI and DCI. Urinary inositol levels might therefore serve as an indicator of impaired renal function in diabetes mellitus with wider implications for monitoring chronic kidney disease.
authors: School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand.
authors: Hao-Han
authors: HH
authors: Chang
authors: School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand.
authors: Bernard
authors: B
authors: Choong
authors: School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand Department of Surgery, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand.
authors: Anthony R J
authors: AR
authors: Phillips
authors: School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand k.loomes@auckland.ac.nz.
authors: Kerry M
authors: KM
authors: Loomes
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D005919:Glomerular Filtration Rate; D007294:Inositol / Q000378:metabolism / Q000652:urine*; D008297:Male; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D007294:Inositol
keywords:   Myo-inositol; D-chiro-inositol; diabetes mellitus; diabetic nephropathy; inosituria; polycystic ovary syndrome