John R. Turtle

Changes in Hepatic Glutathione Metabolism in Diabetes

Glutathione is important in the regulation of the redox state, and a decline in its tissue level has often been considered to be indicative of increased oxidative stress in diabetes. In this study of diabetic rats, the level of hepatic glutathione was normal unless food intake was restricted. Thus, the previous report of a reduction in hepatic glutathione in diabetes is likely to be the result of food deprivation rather than diabetes alone. In contrast to changes characteristic of oxidative stress, the efflux of glutathione in bile from diabetic animals was significantly decreased, whereas hepatic mixed disulfides were unchanged, and the hepatic γ-glutamyltransferase activity was considerably increased. These changes were not reproduced by food deprivation. The decrease in biliary excretion of glutathione in diabetes may reflect an attempt to conserve glutathione by activation of the hepatic γ-glutamyl cycle. We conclude that the disturbances of glutathione metabolism in diabetes are not typical of those seen in oxidative stress or food restriction.

The Effect of Aldose Reductase Inhibition on Motor Nerve Conduction Velocity in Diabetic Rats

This study examined the effects of an aldose reductase inhibitor (CP 45634, Sorbinil, Pfizer, New York, New York) on the neuropathy of streptozotocin-induced diabetic rats. Sorbinil treatment for 4 wk reduced sciatic nerve sorbitol concentration and improved motor nerve conduction velocity in diabetes of 2–9 mo duration. It remains to be determined whether Sorbinil can prevent chronic diabetic neuropathy.

Young's syndrome. Obstructive azoospermia and chronic sinopulmonary infections.

We studied 29 men with Youngs syndrome, a combination of obstructive azoospermia and chronic sinopulmonary infections. Men with this syndrome have only mildly impaired respiratory function and normal spermatogenesis; the azoospermia is due to obstruction of the epididymis by inspissated secretions. The diagnosis is based on the occurrence of chronic sinopulmonary infections, persistent azoospermia, normal spermatogenesis, and characteristic epididymal findings, as well as exclusion of cystic fibrosis and the immotile-cilia syndrome. The sperm themselves appear to be normal in Youngs syndrome. Pregnancies had occurred in five couples; in three paternity was documented by genotyping. Thus, improved microsurgical and medical therapy might restore fertility. We suggest that Youngs syndrome has a prevalence comparable to that of Klinefelters syndrome and is a common cause of both chronic sinopulmonary infection and azoospermia.

Development of the Diabetes Knowledge (DKN) Scales: Forms DKNA, DKNB, and DKNC

The Diabetes Knowledge Assessment (DKN) scales were developed to meet a specific need for rapid and reliable knowledge assessment in diabetic patients. Item format and item selection from an initial pool of 89 items were determined by pilot-testing over 300 diabetic subjects. Reliability analysis of the resulting 40 multiple-choice items, with a further sample of 56 subjects, gave a Cronbachs alpha coefficient of 0.92. Parallel forms DKNA, DKNB, and DKNC, each of 15 items selected from the parent set, had alpha coefficients above 0.82 and correlated 0.90 with each other. A full clinical trial, using DKNA, DKNB, and DKNC in randomized order of presentation, was conducted with 219 subjects attending a 2-day diabetes education program. Overall DKN scores improved from 7.6 (51%) to 11.3 (75%). Analysis of variance confirmed that DKNA, DKNB, and DKNC were equivalent forms at pretest. Mean posttest scores on DKNB were lower than the other scales (P < 0.001), but variances were equivalent for all three. A specific local change in the education program format was found to account for this discrepancy in the DKNB posttest mean. In situations where comprehensive assessment of diabetes knowledge would be time-consuming and unnecessary, these results indicate that rapid and reliable assessment is possible with a scale of only 15 validated items. The development of parallel forms of the scale extends the range of retesting possibilities for diagnosis and research.

Measurement of Emotional Adjustment in Diabetic Patients: Validity and Reliability of ATT39

The ATT39 scale was developed as a norm-referenced measure of emotional adjustment in diabetic patients. Scores on three parallel forms of the parent scale changed in response to educational intervention, and the change in scores was predictive of subsequent improvement in metabolic control. We describe further reliability and validity studies with six factorially derived subscales of the ATT39, which measured perceived levels of stress, adaptation, guilt, alienation, illness conviction, and tolerance for ambiguity. Internal consistency (Cronbach α) of the unweighted total score was 0.78, and the Guttman lower bound estimate of reliability was 0.86. The test-retest reliability of the total score varied from 0.70 to 0.87, over intervals of 2 wk, 3 mo, and 6 mo, and reliability coefficients for the six factor scores averaged 0.56. ATT39 factor scores, in 134 insulin-dependent diabetes mellitus (IDDM) and 166 noninsulin- dependent diabetes mellitus (NIDDM) patients, were correlated with scores on the Cattell 16 personality factor questionnaire and the locus of control of behavior scale (LCB). In IDDM, age was related to better adaptation, increased feelings of guilt, and a more cooperative attitude to staff and treatment. In NIDDM, age was associated with increasing resignation to a conviction of chronic illness and less tolerance for the ambiguities involved in diabetes. Intelligence was correlated with less guilt and more tolerance. Anxiety was associated with significant diabetes-related stress, regardless of treatment, and with poorer adaptation and guilt in NIDDM. An external LCB was related to increased stress and guilt. The results confirm that emotional adjustment in diabetes involves dynamic interactions among feelings that are relatively stable over periods up to 6 mo and that relate meaningfully to other aspects of personality functioning.

Effects of Experimental Diabetes, Uremia, and Malnutrition on Wound Healing

The strength of linear wounds was studied in normal and diabetic rats in the first 8 wk after wounding. The strength of wounds from diabetic animals was found to be reduced compared with normal controls but could be improved by insulin treatment, especially when excellent metabolic control was achieved. There appeared to be both quantitative and qualitative defects in the formation of wound tissues in diabetic animals, because wound strength was not normalized when the thinner skin of diabetic animals was takeninto consideration. This was different from the findings in rats with renal failure or malnutrition: in these two conditions, wound strength appeared reduced but was normalized when adjusted for skin thickness. Increased activity of aldose reductase did not appear to be an important factor in the impairment of wound healing in diabetes, because wound strength was not corrected by treatment with sorbinil, an aldose reductase inhibitor. The precise mechanism of abnormal wound strength in diabetes remains to be studied further, but careful control of diabetes, maintenance of nutrition, and treatment of systemic illness are important factors in the promotion of wound healing.

Glycosylation of Plasma Protein and its Relation to Glycosylated Hemoglobin in Diabetes

Glycosylation of plasma proteins was studied in diabetic and normal subjects by an adaptation of a thiobarbituric acid method previously used for glycosylated hemoglobin. There was a highly significant correlation between the degree of glycosylation in vivo of plasma protein and hemoglobin. The process of glycosylation depended on time and temperature and was not mediated enzymatically. Plasma protein of all molecular sizes could be glycosylated. At 37°C, 4.6% of 14C-glucose became attached to plasma protein after 24 h of incubation in vitro; no difference between normal and diabetic plasma protein could be demonstrated. After glycosylation, glucose dissociated from protein slowly; 72% remained attached after dialysis for 24 h. As an estimate of diabetic control, measurement of glycosylation of plasma protein is a suitable alternative to determination of glycosylated hemoglobin. Results of each method correlated equally well with the degree of diabetic control when this was assessed by calculation of the M-factor, mean plasma glucose concentrations, or variance of the plasma glucose determinations. In hemolytic anemia, hemoglobinopathy, and recent transfusion, measurement of glycosylation of plasma protein may be more accurate than that of glycosylated hemoglobin. It may also provide an estimate of diabetic control between that provided by short-term blood glucose determination and long-term glycosylated hemoglobin.

The Myth of the Diabetic Personality

Since Daniels comprehensive literature review in 1935, there have been 7 major review articles and 28 empirical studies of the personality characteristics of the diabetic patient. The results have been contradictory and inconclusive. A critical review of the methodologic problems in the literature leads to the conclusion that sampling bias invalidates the generalization of specific findings from these studies to the diabetic population as a whole. The clinical heterogeneity of diabetes is matched by the psychological heterogeneity of its sufferers.

Regulation of hepatic growth hormone receptors by insulin

Abstract Induction of diabetes in the rat with streptozotocin caused a decrease in the specific binding of human growth hormone to liver receptors. The decrease was due to a loss of binding sites, with no change in the affinity constant for growth hormone (5.6 × 10 9 M −1 ). A highly significant correlation was seen between serum insulin levels and hepatic growth hormone binding. Specific insulin binding to hepatic receptors was increased in diabetes, with a highly significant negative correlation between serum insulin levels and insulin binding. The loss of growth hormone receptors was reversed by treating diabetic rats with insulin. Since hormones which bind to “lactogenic” binding sites in the liver are reported to regulate somatomedin levels, the insulin dependence of human growth hormone receptors might account for the decrease in serum somatomedin in diabetes.

High Glucose Concentration Causes a Decrease in Mesangium Degradation: A Factor in the Pathogenesis of Diabetic Nephropathy

Mesangium enlargement is a constant feature of diabetic nephropathy and is likely to be important in the pathogenesis of this diabetic complication. Whether decreased degradation of mesangium plays any role in causing the enlargement is uncertain. We developed a system of preparing radioactively labeled mesangium matrix from mesangial cell cultures to be used as substrates for studies of mesangium degradation. Degradation is commenced by growing mesangial cells on the labeled matrix and monitored by the release of radioactivity into the culture medium. High glucose concentration (30 mM), whether present 1) when the matrix is being made or 2) when the degradation is taking place, reduces the rate of mesangium degradation. The second but not the first of these two phenomena was abolished by aminoguanidine. Phorbol 12-myristate 13-acetate, added in a manner to antagonize the action of protein kinase C, inhibited mesangium degradation and was not able to nullify the effect of high glucose. Thus it appears unlikely that a high glucose concentration inhibits mesangium degradation by increasing mesangial cell protein kinase C activity. We conclude that decreased degradation of mesangium as a result of hyperglycemia may play a role in causing the mesangium enlargement that occurs in diabetic nephropathy.