D-chiro-inositol metabolism in diabetes mellitus.

Abstract

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....

Insulin mediators in man: effects of glucose ingestion and insulin resistance

“…Moreover, bioactivity of the pH 2.0 IPG isolated from haemodialysate, urine and muscle from NIDDM patients was attenuated vs control [9]. On the other hand, Ostlund et al [23] showed that patients with NIDDM, as well as insulin-dependent diabetes IDDM, excreted substantially more d -chiro-inositol in urine than obese nondiabetic patients (control group), while plasma d -chiro-inositol levels were similar among the three groups. The possibility exists, however, that the obese non-diabetic patients were insulin resistant [24], and therefore were not appropriate control subjects.…”

Identification of a Novel Na+/myo-Inositol Cotransporter

“…Furthermore, the K m for glucose is well above normal serum glucose levels. It seems clear that MI is the physiological substrate for the protein; although D-chiro-inositol is transported as readily as MI, the average serum level of D-chiroinositol is less than 100 nM (38), and thus D-chiro-inositol transport represents a minor physiological role for SMIT2. It should be noted that there has been one previous publication suggesting the names SMIT1, SMIT2, and SMIT3 for three alternate transcripts from the SLC5A3 gene (39); we suggest that these be named SMIT1a, SMIT1b, and SMIT1c, in which we have the consent of the authors of that work.…”

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

“…[106] The urinary excretion of D-chiro-inositol has been measured at 2.1 μmol/day in nondiabetics, but increases six-fold in non-insulin-dependent diabetics and another six-fold in insulindependent diabetics. [107] In a rat model of type 1 diabetes and a mouse model of type 2 diabetes the urinary excretion of D-chiro-inositol was much greater than in healthy rats and mice. [108] These studies contradict earlier work showing a lower urinary excretion (and lower muscle content) of D-chiro-inositol in non-insulin-dependent diabetics than in nondiabetics.…”

“…[48] Between nondiabetics and noninsulin-dependent diabetics there was little difference in the urinary excretion of L-chiroinositol, but excretion increased just over three-fold, to 0.51 μmol/day, in insulin-dependent diabetics. [107] The non-mammalian biology of L-chiro-inositol is discussed in the Supporting Information (SI_2).…”