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 mM) and DCI (5 mM) 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.

Abnormalities inmyo-inositol metabolism associated with type 2 diabetes in mice fed a high-fat diet: benefits of a dietarymyo-inositol supplementation

“…Indeed, a study of Chang et al ( 26 ) on isolated kidneys has shown that perfusion conditions replicating hyperglycaemia (20 m m -glucose) significantly potentiated D -chiro-inositol (DCI) but not MI urinary excretion in both non-diabetic and diabetic kidneys. The diabetic kidneys, however, presented 2-fold increased urinary excretion of myo -inositol compared with the non-diabetic kidneys.…”

ChemInform Abstract: The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo‐Inositol Chemistry)

“…[113] Compared with the kidneys from nondiabetic rats,those from diabetic rats had af ourfold greater excretion of d-chiroinositol under normoglycemic conditions,w ith higher excretion under hyperglycemic conditions. [114] Increases in myoinositol excretion also occurred but were not as great, despite increased renal expression of both SMIT1 and SMIT2.…”

Nutritional and Acquired Deficiencies in Inositol Bioavailability. Correlations with Metabolic Disorders

“…It is noticeable that, despite increased expression of the inositol transporter systems (SMT1/2), inositol reabsorption is significantly inhibited at the tubular level [ 136 ]. Other pathophysiological processes should therefore explain increased urinary loss of inositol isomers in diabetic kidneys [ 137 ].…”