D-chiro-Inositol is a rare inositol isomer present in inositol phosphoglycans which are proposed mediators of insulin action. To study D-chiro-inositol metabolism in diabetes mellitus, a sensitive and specific assay was developed using negative-ion chemical ionization gas chromatography/mass spectrometry. Median urinary D-chiro-inositol excretion, which was 2.1 ,umol/day in nondiabetics, was substantially increased to 12 ,umol/day in non-insulin-dependent diabetes (P < 0.0001) and to 74 j,mol/day in insulin-dependent diabetes (P < 0.0001). Urinary D-chiro-inositol was strongly correlated with fasting plasma glucose (r = 0.568, P < 0.0001), glycated hemoglobin (r = 0.529, P < 0.0001), and urinary glucose (r = 0.368, P = 0.01). The renal clearance of D-chiro-inositol was selectively elevated in both non-insulin-dependent and insulindependent diabetes when compared with the clearances of L-chiro-inositol or myo-inositol and exceeded the glomerular filtration rate in 71% of the diabetics but in none of the nondiabetics. In poorly controlled diabetic patients insulin treatment reduced urinary D-chiro-inositol losses by 63% and increased plasma levels by 8.8-fold. The metabolism of D-chiroinositol is abnormal in diabetes and appears to be influenced by short-and long-term metabolic control.One of the most important problems in endocrinology is the rigorous description of the mechanism of insulin action. Previous work suggests that some (but not all) of the actions of insulin may be mediated through inositol phosphoglycan molecules released from cell membranes (1-4). When such putative mediators were hydrolyzed and analyzed chemically it was found unexpectedly that in some preparations much or all of the inositol present was not myo-inositol (which is, by far, the most common mammalian inositol) but rather the rare epimer D-chiro-inositol (5, 6). Kennington et al. (7) reported abnormally low or unmeasurable levels of D-chiro-inositol in urine and muscle from patients with non-insulin-dependent diabetes mellitus (NIDDM) and suggested that D-chiroinositol deficiency might be related to the insulin resistance observed in NIDDM.However (9) and urinary albumin (Diagnostic Products, Los Angeles) were determined by radioimmunoassay, and glycated hemoglobin was determined by affinity chromatography (Pierce; normal range 4.4-6.3%).Inositol Analysis. Twenty-four-hour urine specimens were collected with cooling but without preservatives and aliquots were stored frozen at -20°C. D-chiro-Inositol levels changed <3% after incubation of nonsterile urine from two poorly controlled diabetics and two normal subjects for 24 hr at 25°C, indicating that urinary D-chiro-inositol levels are stable during collection. To 0.25 ml of urine were added 10 nmol of deuterated DL-chiro-inositol and 20 nmol of deuterated myoinositol as internal standards. The samples were then purified by a modification of a procedure (7) in which the sample was first passed over a 0.6-ml column of water-washed Amberlite IR-120(+) (Aldrich) and then over a 0....

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