Urinary Excretion Of Myo-inositol Research Articles

Urinary Excretion of Myo-Inositol and D-Chiro-Inositol in Early Pregnancy Is Enhanced in Gravidas With Gestational Diabetes Mellitus.

The effects of gestational diabetes mellitus (GDM) were determined on urinary excretion of putative components of insulin signaling. Random urine samples were collected from 375 gravidas at 6 to 14 weeks' gestation, 22 to 32 weeks' gestation, and ∼6 weeks' postpartum. Gestational diabetes mellitus developed in 35 women who were matched with 59 normal gravidas. Urinary concentrations of myo-inositol (MI) and D-chiro-inositol (DCI) were measured by gas chromatography/mass spectrometry and normalized to creatinine levels. Compared to postpartum values, urinary excretion of MI and DCI was increased 2.9-fold and 2-fold, respectively, in early pregnancy, and 5.5-fold and 4.5-fold, respectively, in later gestation. Gravidas with GDM had significantly greater MI and DCI excretion than controls in the first trimester but not subsequently. The results suggest that gravidas destined to develop GDM have altered synthesis, metabolism, and/or renal excretion of MI and DCI in early pregnancy.

Serum ethanolamine plasmalogens improve detection of cognitive impairment among elderly with high excretion levels of urinary myo-inositol: A cross-sectional study

BackgroundSeveral reports have implicated myo-inositol (MI) in myelin formation. We hypothesized that MI is involved in this process through facilitating the biosynthesis of ethanolamine plasmalogens (PlsEtns), which are the major component of myelin membranes, and essential for myelin formation and function. Excessive MI urinary excretion possibly causes PlsEtn deficiency, leading to demyelinating diseases including dementia. MethodsWe examined the association between cognitive impairment, serum levels of PlsEtn, and baseline levels of urinary MI excretion, in the enrollment of 55 memory clinic outpatients and 107 cognitively normal elderly. ResultsSerum PlsEtns were independently associated with cognitive impairment, and significantly reduced in memory clinic outpatients, especially in those with high urinary MI, as compared to normal elderly. On the other hand, there was no direct association between urinary MI and cognitive impairment, but urinary MI was significantly associated with serum hemoglobin A1c and amyloid β 1–40. The interaction between PlsEtn and urinary MI for cognitive impairment was statistically confirmed, and their combined usage improved diagnosis of cognitive impairment. ConclusionsWe proposed the involvement of MI and PlsEtn in cognitive impairment pathology. In conclusion, serum PlsEtn may be useful in detecting cognitive decline among elderly with hyperglycemia.

The diabetic rat kidney mediates inosituria and selective urinary partitioning of D-chiro-inositol.

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.

Inositol, Glycogen, Insulin, and Six Nobelists

My reflections cover my scientific work over a sixty-year period. At the University of Michigan, I was initially interested in embryology. In medical school in the army, I became entranced with biochemistry and DeWitt Stetten, who introduced me to Carl Cori. Carl along with Gerty Cori and Earl Sutherland became my scientific mentors. After medical school and a nine-month medical internship, I re-entered the army and was assigned to Edgewood Arsenal in Maryland, where I established the NAD requirement for brain pyruvate dehydrogenase to oxidize pyruvate and published my first Journal of Biological Chemistry (JBC) paper. At the University of Illinois, I obtained an M.S. degree in chemistry and was influenced by Will Rose and Herb Carter. At Washington University in St. Louis, I worked with Gerty and Carl Cori on glycogen metabolism and obtained my Ph.D. degree. I also worked with Bill Daughaday on the increased urinary excretion of myo-inositol in diabetic subjects and in rats preloaded with glucose. I was offered an instructor's appointment in biochemistry at Washington University, but I decided to accept an assistant professor's appointment in the Division of Biochemistry of the Chemistry Department at the University of Illinois. I spent four years at Illinois working on intestinal starch digestion with particular reference to glycosidases hydrolyzing the α1,6-branch point linkages. I was recruited by Earl Sutherland to join his Department of Pharmacology as an associate professor at Western Reserve University in Cleveland. Here, Carlos Villar-Palasi, my first postdoctoral fellow, and I began our insulin studies, which led to the discovery of two covalent forms of glycogen synthase controlled by insulin and epinephrine. These continued at the University of Minnesota, where I held an endowed chair in biochemistry. Here, with students and postdoctoral fellows, we further defined the two forms of glycogen synthase and worked on the possible role of cAMP in insulin action. Moving to the University of Virginia as Chair of Pharmacology, I recruited two future Nobelists, Al Gilman and Ferid (Fred) Murad, with Ted Rall, their past mentor for their Ph.D. degrees, as well as other faculty who would become departmental chairs. Our early studies on glycogen and inositol became united with studies on insulin action. We isolated a novel inositol glycan pseudo-disaccharide insulin second messenger containing a rare inositol, d-chiro-inositol (DCI). Its structure was determined as galactosamine β1,4-pinitol, where pinitol is the 3-O-methyl ether of DCI. It was chemically synthesized. We and others found that insulin resistance in several human diseases is related to an inositol imbalance consisting of a deficit of chiro-inositol and an excess of myo-inositol, an unfolding story now under way involving the myo-inositol to chiro-inositol epimerase. I am blessed to have had such superlative scientific mentors, a productive group of students and postdoctoral fellows, a loving wife of sixty-five years, three remarkable sons, and eight wonderful grandchildren. I am working full time on insulin, which has entranced me for a long time.

Quantification of myo‐inositol cotransporter expression in control and streptozotocin‐treated rats.

Myo‐inositol (MI) uptakes in cells is essentially performed by two Na+‐coupled transport systems; SMIT1, a basolateral system inducible through hypertonicity and SMIT2, an apical system responsible for MI uptake in the kidney and intestine, amongst other tissues. In diabetes, urinary MI excretion is increased by 1 order of magnitude through a non‐established mechanism. The purpose of this study is thus to investigate the influence of an acute diabetic condition (5‐day streptozotocintreatment) on the expression of both SMIT mRNA's in rat brain, liver, muscle, kidney and intestine through quantitative‐RT‐PCR (qRT‐PCR). Also, SMIT2 activity was determined by measuring MI transport in purified brush border membranes (BBMv) from kidney and intestine. SMIT1 transcripts are mainly found in the kidney where it doubles in diabetic rats. Other tissues show more modest mRNA levels and were not altered in diabetes. SMIT2 transcripts were found in all tested tissues in varying levels but were not modified in diabetes. MI uptakes performed on kidney and intestine BBMv confirmed the qRT‐PCR results showing no variations of transport in STZ rats due to SMIT2. We thus conclude that the increase in MI urinary excretion is not due to a reduction in the apical expression of MI cotransporter SMIT2.

Clinical usefulness of measuring urinary polyol excretion by gas-chromatography/mass-spectrometry in type 2 diabetes to assess polyol pathway activity

Introduction: Decreased myo-inositol levels and increased activity of the polyol pathway have been proposed to play a role in causing diabetic microvascular complications. There are few clinical methods for examining the activity of the polyol pathway in diabetic patients. We assessed the effect of changes in glycemic control on polyol pathway activity by measuring urinary polyol excretion. Materials and methods: Gas-chromatography/mass-spectrometry (GC/MS) was used to assess the urinary excretion of glucose and polyols (myo-inositol, sorbitol, and fructose) in 50 patients who had type 2 diabetes without nephropathy and 20 healthy subjects. Results: In the diabetic patients with poor glycemic control, urinary sorbitol levels were significantly increased and urinary myo-inositol excretion was approximately 6.5-fold higher than in healthy controls (33.0 ± 6.5 vs 221.7 ± 45.9 mg/day, mean ± SE, P < 0.01). During strict glycemic control, some patients (Group A) showed simultaneous disappearance of glucosuria and normalization of the urinary excretion of myo-inositol (<50 mg/day) and, while others (Group B) showed delayed normalization of urinary myo-inositol excretion. Group B showed significantly higher urinary myo-inositol, sorbitol, and fructose excretion than Group A at the time of disappearance of glucosuria. These findings suggest that patients in Group B may have increased polyol pathway activity. Conclusion: Even though short-term strict glycemic regulations were established in long-standing hyperglycemic diabetic patients, to normalize the once-exaggerated polyol pathway activities, it was essential to maintain glucosuria-free conditions for some period. Quantitation of urinary polyols using GC/MS appears to be a clinically useful method for assessing polyol pathway activity.

Relationships of plasma C-peptide and gender to the urinary excretion of inositols in older people.

The urinary excretions of myo-inositol and D-chiro-inositol are elevated in diabetes, and have been suggested as possible markers or effectors of insulin action. The aim of the present study was to measure the urinary excretion of these compounds, and to assess possible relationships with the metabolic control of glucose, in older, non-diabetic men and women. 32 older (age range 54-71 yrs), moderately overweight (body mass index 29.1 +/- 0.4 kg/m2, mean +/- SEM), non-diabetic men (n = 17) and women (n = 15). 75 g oral glucose tolerance testing was done the day after all subjects had consumed nutrient-defined menus for five days. Plasma samples were analyzed for the concentrations of glucose, insulin, and C-peptide, and the 180-minute area under the curve (AUC) for each of these compounds was calculated. Samples from 24-hour urine collections were analyzed for the concentrations of myo-inositol, D-chiro-inositol, L-chiro-inositol, and pinitol. The fasting glucose, insulin, and C-peptide, and the AUC for glucose and insulin, were not different between men and women. C-peptide AUC was greater in the men versus the women (p < 0.001). The median urinary excretions (micromol/g creatinine) of myo-inositol (p < 0.001), D-chiro-inositol (p < 0.001), L-chiro-inositol (p < 0.05), and pinitol (p < 0.001) were higher, and the myo-inositol:D-chiro-inositol ratio was lower (p < 0.001), in the men versus women. For all subjects combined, C-peptide AUC was positively correlated with the urinary excretion of each of the measured inositols, as well as the myo-inositol:D-chiro-inositol ratio. The correlations between C-peptide AUC and these inositols were strongly influenced by the co-linear relationship between C-peptide AUC and gender. Collectively, these data show that older, moderately overweight, non-diabetic men and women with gender-related differences in glucose-stimulated C-peptide AUC, an indirect indicator of insulin secretion, also display differences in the urinary excretion of myo-inositol, D-chiro-inositol, L-chiro-inositol, and pinitol. The gender-related difference in the myo-inositol:D-chiro-inositol ratio suggests that, while the urinary excretion of all of the inositols measured were higher in the men than the women, the difference was more pronounced for D-chiro-inositol.

Low Urinarychiro-Inositol Excretion in Non-Insulin-Dependent Diabetes Mellitus

Inositol is a major component of the intracellular mediators of insulin action. To investigate the possible role of altered inositol metabolism in non-insulin-dependent diabetes mellitus (NIDDM), we used gas chromatography and mass spectrometry to measure the myo-inositol and chiro-inositol content of urine specimens from normal subjects and patients with NIDDM: The study subjects were whites, blacks, and Pima Indians. The type of inositol and its concentration in insulin-mediator preparations from muscle-biopsy specimens from normal subjects and diabetic patients were also determined. The urinary excretion of chiro-inositol was much lower in the patients with NIDDM (mean [+/- SE], 1.8 +/- 0.8 mumol per day) than in the normal subjects (mean, 84.9 +/- 26.9 mumol per day; P less than 0.01). In contrast, the mean urinary myo-inositol excretion was higher in the diabetic patients than in the normal subjects (444 +/- 135 vs. 176 +/- 46 mumol per day; P less than 0.05). There was no correlation between chiro-inositol excretion and the age, sex, or weight of the diabetic patients, nor was there any correlation between urinary chiro-inositol and myo-inositol excretion in either group. The results were similar in a primate model of NIDDM, and chiro-inositol excretion was decreased to a lesser extent in animals with prediabetic insulin resistance. chiro-Inositol was undetectable in insulin-mediator preparations from muscle-biopsy samples obtained from patients with NIDDM: Similar preparations from normal subjects contained substantial amounts of chiro-inositol. Furthermore, the chiro-inositol content of such preparations increased after the administration of insulin during euglycemic-hyperinsulinemic-clamp studies in normal subjects but not in patients with NIDDM: NIDDM is associated with decreased chiro-inositol excretion and decreased chiro-inositol content in muscle. These abnormalities seem to reflect the presence of insulin resistance in NIDDM:

Gas chromatographic—mass spectrometric analysis of polyols in urine and serum of uremic patients : Identification of new deoxyalditols and inositol isomers

A gas chromatographic—mom spectrometric method was applied to a study of polyols in urine and serum of normal subjects and uremic patients. 4-Deoxythreitol, 4-deoxyerythritol, 5-deoxyxylitol, 5-deoxyarabitol, 2-deoxyribitol, 6-deoxymannitol, 6-deoxygalactitol, neoinositol and chiroinositol were identified in normal urine as well as in uremic urine for the first time. In uremia the urinary excretion of myoinositol and chiroinositol was significantly increased. The serum levels of myoinositol, chiroinositol and scylloinositol were increased in the uremic patients, whereas the serum level of 1-deoxyglucose (1,5-anhydroglucitol) was significantly decreased in the uremic patients as compared with the normal subjects. These findings suggest the altered metabolism of chiroinositol and 1-deoxyglucose in the uremic state.

Dietary myo-inositol intake and peripheral nerve function in diabetic neuropathy

The effect of variations in dietary myo-inositol intake upon plasma myo-inositol concentrations, urinary myo-inositol excretion, motor nerve conduction velocities in the median and peroneal nerves, and sensory nerve conduction velocities in the median and sural nerves was studied in six nondiabetic subjects and in twenty patients with symptomatic distal symmetrical diabetic polyneuropathy. Diets were developed which provided either a low, a normal, or a high intake of myo-inositol. In control subjects, the low- myo-inositol diet was found to decrease, while the high- myo-inositol diet increased both the preprandial plasma myo-inositol concentrations and the daily urinary excretion of myo-inositol. These diets had little effect upon measured nerve function in the control subjects, although the high- myo-inositol diet appeared to slightly reduce the median sensory nerve conduction velocity in this group. In the neuropathic diabetics, the low- and high- myo-inositol diets were found to have similar effects upon the plasma myo-inositol concentrations and urinary myo-inositol excretion, but did not affect the plasma glucose concentrations. When analyzed by groups, no statistically significant changes were observed in any of the measured nerve conduction velocities in the diabetic patients. However, when the change in nerve conduction velocity was analyzed, it was found that the ingestion of the high- myo-inositol diet resulted in a statistically significant increase in the median sensory (+1.92 m/sec, p < 0.001) and the sural sensory nerve conduction velocity (+6.67 m/sec, p < 0.001). In contrast, ingestion of the low- myo-inositol diet produced a statistically significant decrease in the median motor (−2.35 m/sec, p < 0.001) and the peroneal motor nerve conduction velocity (−1.18 m/sec, p < 0.001). Thus, ingestion of a diet enriched in myo-inositol may have a salutory effect upon peripheral nerve function in the patient with symptomatic diabetic neuropathy and appears to be without significant side effects in this patient group.

Myoinositol metabolism in diabetes mellitus. Effect of insulin treatment.

The metabolism of myoinositol has been studied in 10 nondiabetic subjects and in six patients with diabetes mellitus before and after insulin therapy. While dietary myoinositol intake and fecal myoinositol excretion were similar in both groups, urinary myoinositol excretion was increased 10-fold in the untreated diabetic and accounted for a significant fraction of his dietary myoinositol intake. Insulin treatment restored the urinary myoinositol excretion toward normal. Despite increased myoinositol excretion, plasma myoinositol concentrations were significantly higher in the diabetics following the ingestion of a standard diet or of a 3.0-gm. myoinositol load. This abnormality in oral myoinositol tolerance was also corrected by insulin treatment. The size of the rapidly equilibrating myoinositol pool was significantly decreased in the untreated diabetic and returned to normal following a brief period of insulin treatment. The elevated plasma myoinositol concentrations observed following myoinositol ingestion in the uncontrolled diabetic presumably represents a combination of enhanced gastrointestinal absorption and impaired intracellular transport of myoinositol. The decreased space of distribution of myoinositol also suggests an impairment of intracellular myoinositol transport in the untreated diabetic. These observations are consistent with the speculation that hyperglycemia may condition a widespread relative intracellular myoinositol deficiency in man and suggest that restoration of normal intracellular myoinositol concentrations might prove to be of benefit in the prevention and treatment of certain of the complications associated with human diabetes mellitus.

Accumulation of myoinositol in plasma and red cells of diabetic patients.

The concentration of myoinositol in plasma, cerebrospinal fluid and red cells and its elimination by the kidneys have been studied in 51 diabetic patients with normal or impaired kidney function, 16 non-diabetic patients with renal failure and 37 healthy controls. All diabetic patients who had a glomerular filtration rate considerably below normal, was the plasma concentration of myoinositol higher than in controls. The findings show that the rise in plasma concentration of myoinositol most probably results from a decreased glomerular filtration rate. In diabetic patients, urinary excretion of myoinositol correlated with an exponential increase in glucose excretion. That myoinositol accumulates in red cells of diabetic patients may be the result of its retention within these cells caused primarily by a transient, abnormal increase in the plasma concentration of myoinositol after an average meal.