James W. Craig

Low Urinary chiro-Inositol Excretion in Non-Insulin-Dependent Diabetes Mellitus

BACKGROUND AND METHODS 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. RESULTS 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: CONCLUSIONS 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:

Urinary chiro-Inositol Excretion is an Index Marker of Insulin Sensitivity in Japanese Type II Diabetes

OBJECTIVE To determine the relationship between urinary chiro-inositol excretion and insulin sensitivity in Japanese type II diabetic patients. RESEARCH DESIGN AND METHODS Eighteen subjects were age-matched, nonobese, type II diabetic patients. Eight subjects had impaired glucose tolerance (IGT), and 10 had normal glucose tolerance (NGT). We quantified urinary chiro-inositol excretion using gas chromatography-mass spectrometry and the insulin sensitivity index (SI), and glucose effectiveness (SG) using Bergmans modified minimal model method. RESULTS The urinary excretion of chiro-inositol was much lower in the diabetic patients (32.3 ± 16.0 μmol/day, means ± SD) than in the NGT subjects (96.0 ± 17.6; P < 0.0001) and IGT subjects (58.9 ± 11.6; P < 0.0001). SI was much lower in the diabetic patients (3.81 ± 1.49) than in the NGT subjects 6.30 ± 1.59, P < 0.0005). SG was much lower in the diabetic patients (2.14 ± 0.56) than in the NGT subjects (3.07 ± 0.38, P < 0.0001). There was a significant correlation between urinary chiro-inositol excretion and SI (r = 0.766), as well as a significant correlation between urinary chiro-inositol excretion and SG (r = 0.747). CONCLUSIONS There is a direct relationship of urinary chiro-inositol excretion to insulin sensitivity and SG in humans. Urinary chiro-inositol excretion might be useful as a metabolic index of insulin sensitivity in type II diabetes.

Influence of Phenethylbiguanide on Lactic, Pyruvic and Citric Acids in Diabetic Patients

The biochemical effects of the oral hypoglycemic agent DBI (phenformin, phenethylbiguanide) in experimental animals have included alterations in the metabolism of lactic acid as well as of glucose, DBI not only increases the glucose uptake of the rat diaphragm in vitro but also decreases the oxygen uptake and increases the lactic acid production of that tissue. Lactic acid production by the guinea pig liver slice is also increased by the addition of DBI. In the same animal an elevation of the blood lactic acid concentration has been observed after administration of the drug. Accordingly, it appeared of interest to determine whether or not lactic acid metabolism was also altered in diabetic patients who were given DBI. The present studies on diabetic patients have included an investigation of the effects of DBI on ( i ) the concentration of lactic acid in the fasting blood, (2) the twenty-four-hour urinary excretion of lactic acid, (3) the changes in the blood lactic acid concentration after the administration of glucose or fructose, potential precursors of lactate, and (4) the changes in the blood lactic acid concentration after sodium lactate administration. Since lactate is in equilibrium with pyruvate, changes in lactic acid cannot be properly interpreted without a knowledge of the associated pyruvic acid changes. Therefore, both pyruvic and lactic acid concentrations were measured in the blood and urine specimens. In addition, changes in the blood concentrations and urinary excretions of glucose and citric acid were studied.

URINARY MYO-INOSITOL-TO-CHIRO-INOSITOL RATIOS AND INSULIN RESISTANCE

F ive papers have recently appeared dealing with urinary myoand chiroinositol excretion in diabetes in the Rhesus monkey and in humans, particularly as related to insulin resistance (1-5). Four papers (1,2,4,5) are in agreement, and a fifth (3) is in apparent disagreement. In the present report, we reevaluate the published data in the human studies and demonstrate overall agreement when 1) the ratio of increased urinary myoinositol to decreased chiro-inositol is examined rather than only the urinary chiroinositol excretion and 2) when the group of obese nondiabetic subjects studied by Ostlund et al. (3) is considered as potentially insulin resistant.

Effect of pH and 3-Hydroxybutyrate on Insulin Binding and Action in Cultured Human Fibroblasts

The influence of pH and 3-hydroxybutyrate on insulin binding and action has been studied in cultured human fibroblasts. When the pH of the incubation medium was decreased from 7.6 to 6.8, insulin stimulation of glycogen synthase and total glucose uptake was decreased. The decreased pH induced both an increase in the insulin concentration for half-maximal response, and a decrease in maximal responsiveness. When insulin binding was measured at lower pH, receptor affinity was decreased. The effect of 3-hydroxybutyrate on insulin binding and action was assessed at pH 7.4 and 6.9. In the presence of 3-hydroxybutyrate, insulin binding increased, but insulin action on glycogen synthase and total glucose uptake was unaffected. The data show that insulin action is impaired at lower pH. The decreased sensitivity is probably related to the decrease in insulin binding affinity at lower pH, but decreased maximal responsiveness implies that postreceptor components are also affected by lower pH. The results also suggest that 3-hydroxybutyrate induced a dissociation between binding and response, since an increase of insulin binding was not accompanied by changes in the regulation of glycogen synthase and total glucose uptake.

Studies of the effect of intravenous tolbutamide on pyruvic and lactic acid concentrations in peripheral venous blood in normal and diabetic subjects, and on splanchnic metabolism of fructose and glucose.

It has been known for some time that a blood sugar depression following the administration of insulin may be accompanied by concomitant elevations in blood pyruvate and blood lactate 1evels.l. 2 , Moorhouse and Kark4 have reported that the blood sugar depression following tolbutamide administration in a diabetic is not accompanied by these changes in pyruvate and lactate; and Hennes et aL6 have reported that in normal subjects the initial pyruvate change associated with hypoglycemia is an elevation following insulin, but a depression following tolbutamide. From this disparity the latter authors concluded that the hypoglycemic actions of the two agents are distinct and that a release of endogenous insulin is not the mechanism of action of tolbutamide. It was our objective to produce with insulin and tolbutamide (Orinase!) blood sugar depressions similar in magnitude and rate of fall and, under these conditions, to compare the pyruvate and lactate changes in both normal and diabetic subjects.

Metabolism of Fructose by the Liver of Diabetic and Non-Diabetic Subjects.∗

Summary and Conclusions The metabolism of fructose in the liver was investigated by hepatic vein catheterization studies in 3 diabetic patients deprived of insulin and in 3 non-diabetic subjects. (1) There was a large hepatic uptake of fructose during the period of intravenous administration in both diabetic and non-diabetic subjects. (2) In all but one case there was a large hepatic output of pyruvic and lactic acid during the fructose infusion. The liver of one diabetic patient in ketosis continued to remove pyruvic and lactic acid from the blood; hepatic glycogen depletion may have accounted for this divergent result. (3) In half the cases (2 diabetic patients and 1 non-diabetic subject) the output of glucose by the liver was increased during fructose administration. (4) In the absence of ketosis, the liver of the diabetic subject without insulin, therefore, metabolized fructose in a manner similar to that of the liver of the non-diabetic individual. The presence of ketosis, however, was accompanied by a decreased output of pyruvic and lactic acid, despite a normal uptake of fructose.

Lipoatrophic Diabetes and Mental Illness in Three Siblings

Three siblings with the syndrome of lipoatrophic diabetes who developed paranoid psychoses are described. Their parents and the other five siblings in the family were also studied. None of the other five siblings has been psychotic and none of them has diabetes mellitus or lipoatrophy. Although there is a family history of both diabetes mellitus and psychosis, a history of lipoatrophy was not obtained. There are several published descriptions of the occurrence of psychiatric disorders in patients with lipodystrophy. The findings in these siblings and in reports in the medical literature suggest that lipodystrophy may predispose, in some yet undefined manner, to the development of mental illness.