Improvement of oral glucose tolerance in gestational diabetes by pyridoxine.
Bennink HJ, Schreurs WH
Br Med J 1975 Jul 5;3(5974):13-5
Fourteen pregnant women were shown by the oral glucose tolerance test to have gestational diabetes. In 13 an increased urinary xanthurenic-acid excretion after an oral load of L-tryptophan indicated a relative pyridoxine deficiency. All patients were treated with vitamin B6 (pyridoxine) 100 mg/day for 14 days by mouth, after which the pyridoxine deficiency disappeared and the oral glucose tolerance improved considerably. Only two patients then had sufficiently impaired glucose tolerance to justify the diagnosis of gestational diabetes; Our results substantiated our hypothesis that increased xanthurenic-acid synthesis during pregnancy may cause gestational diabetes. Treatment with vitamin B6 makes the production of xanthurenic-acid normal by restoring tryptophan metabolism and improves the oral glucose tolerance in patients with gestational diabetes.
Vitamin B6 status in pregnancy.
Heller S, Salkeld RM, Korner WF
Am J Clin Nutr 1973 Dec;26(12):1339-48
[Study of vitamin B6 metabolism during various stages of experimental diabetes]
Shuvalova TI, Smurnov MI
Probl Endokrinol (Mosk) 1970 Jan-Feb;16(1):79-81
[Studies on vitamin B6 deficiency during pregnacy and in various pathological states using pyridoxine saturation test]
Karlin R, Croizat P, Revol L, Pommatau E, Viala JJ, Dumont M
Pathol Biol 1968 Nov;16(21):917-24
[Studies on carbohydrate metabolism in vitamin B6-deficient albino rat]
Nippon Naibunpi Gakkai Zasshi 1968 May 20;44(2):154-67
[Contribution to the study of latent B6 avitaminoses in pregnant women]
Karlin R, Dumont M
Gynecol Obstet (Paris) 1967 Jun-Aug;66(3):339-46
[Effect of vitamin B6 on the lecithin-cholesterin ratio and protein fraction of the blood serum of patients with diabetes mellitus]
Ter Arkh 1966 Jan;38(1):96-9
[Clinical studies on the relation between endocrine function and vitamin B6 metabolism. II. Vitamin B6 metabolism in patients with pituitary, adrenal diseases and diabetes mellitus]
Naika Hokan 1966 Apr;13(4):205-16
Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and noninsulin-dependent diabetes in postmenopausal women: the Rancho Bernardo Study.
Barrett-Connor E, Ferrara A
Department of Family and Preventive Medicine, University of California, San Diego, La Jolla 92093, USA.
J Clin Endocrinol Metab 1996 Jan;81(1):59-64
Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) levels were determined in morning specimens from 659 fasting postmenopausal women who were not using estrogen therapy or antidiabetic medication. All women had concurrent oral glucose tolerance tests and measurements of body mass index (BMI) and waist-hip ratio (WHR). DHEA levels were weakly and inversely associated with BMI but not with WHR or glucose tolerance status. DHEAS levels were not associated with BMI but were positively associated with WHR, diabetes, and impaired glucose tolerance. In analyses adjusted for or stratified by WHR, the DHEAS association with abnormal carbohydrate tolerance was reduced but still independent of fat distribution. Because this was a cross-sectional study, it was not possible to determine whether DHEAS levels were raised by central obesity or vice versa. At a minimum, these data strongly suggest that the positive association of DHEAS with both central obesity and abnormal glucose tolerance does not support the thesis that DHEAS protect against diabetes or obesity in older women as had been suggested by animal studies.
Differences in substrate metabolism between selperceived 'large-eating' and 'small-eating' women.
Clark DG, Tomas FM, Withers RT, Brinkman M, Berry MN, Oliver JR, Owens PC, Butler RN, Ballard FJ, Nestel PJ
CSIRO, Division of Human Nutrition, Adelaide, Australia.
Int J Obes Relat Metab Disord 1995 Apr;19(4):245-52
OBJECTIVE: To compare different aspects of intermediary metabolism in self perceived 'small-eating' females and selperceived near normal weight 'large-eating' females and relate the data to those reported for Pima Indians who have the world's highest prevalence of non-insulin dependent diabetes mellitus and obesity.
DESIGN: Make repeat measurements of rates of oxygen consumption, carbon dioxide production and blood metabolites in 'large-' and 'small-eating' females at rest, during different activities and after ingestion of a standardised liquid meal.
SUBJECTS: Nine self perceived, 'large-eating' females and nine self perceived 'small-eating' females.
MEASUREMENTS: Resting metabolic rates (RMR), respiratory quotient (RQ) values and plasma insulin, glucagon insulin-like growth factor (IGF-1), dehydroepiandrosterone sulphate (DHEA-SO4) and glucose.
RESULTS: RMR (adjusted for FFM) averaged 3891 +/- 93 J/min in the 'small-eaters' and 3375 +/- 107 J/min in the 'large-eaters' for ten consecutive measurements conducted at 30 min intervals during the control period for the measurement of the thermic effect of food. Over this period the average RQ for the 'small-eating' women (0.81) was significantly greater than that of the 'large-eating' women (0.78). The two groups responded similarly to an oral glucose tolerance test but the concentration of DHEA-SO4 in plasma was 35% higher in the 'small-eaters'.
CONCLUSION: The 'small-eating' women may have a greater risk of weight gain but they counteract this tendency by maintaining high activity levels.
[43 cases of primary empty sella syndrome: a case series]
Bragagni G, Bianconcini G, Mazzali F, Baldini A, Brogna R, Iori I, Sarti G
Divisione di Medicina Generale, USL 30 di Cento.
Ann Ital Med Int 1995 Apr-Jun;10(2):138-42
Primary empty sella syndrome (ESS) is an anatomo-radiological picture characterized by the presence of an arachnoid herniation filled with liquor that compresses the pituitary against the sellar wall. ESS occurs particularly in obese, hypertensive, cephalalgic women. It is often asymptomatic but may be associated with ophthalmologic, neurologic and non-characterizing endocrine disorders. We report here 43 cases of primary ESS observed and assessed in our Departments of Internal Medicine from June 1983 to May 1993. The following endocrinological diagnostic procedures were carried out: hormonal (RIA) basal profile: FT3, FT4, TSH, PRL, ACTH, FSH, LH, 8.00 a.m. and p.m., blood cortisol, aldo, PRA, DHEA-S, FTe, E2, P, PTH, CT, and calcemia and phosphoremia; provocative tests: TRH, GnRH, etc.; inhibition tests: high dose dexamethasone. Clinical, neurologic (skull radiographs, sellar stratigraphy, computed tomography scan and magnetic resonance), and ophthalmologic (fundus, visual fields) assessments were also made. Our findings fit with the data in the literature concerning common symptoms of ESS, associated endocrinopathies and other illness. We found obesity (62.7%), oligo-amenorrhea (16.6%), galactorrhea (14.6%), hyperPRL (11.6%), hypopituitarism (9.3%), hypogonadism (4.6%), diabetes insipidus (2.3%), (micro-)polycystic ovary syndrome (19%), hyperACTH (2.3%). In 9.3% of the cases, endocrinopathy referred to pituitary adenomas. Moreover, we noted a high frequency of psychological disorders, to our knowledge not previously reported in the literature, including anxiety or dysthymic disorders with altered behavior (chiefly oral compulsion). We also make the hypothesis that obesity (occurring in 62.7% of our patients) and hypertension (62.7%) may be related to hypothalamic alterations.
Differential expression of hepatic oestrogen, phenol and dehydroepiandrosterone sulphotransferases in genetically obese diabetic (ob/ob) male and female mice.
Borthwick EB, Burchell A, Coughtrie MW
Department of Biochemical Medicine, University of Dundee, Ninewells Hospital and Medical School, UK.
J Endocrinol 1995 Jan;144(1):31-7
Sulphotransferases (STs) are a family of closely related enzymes playing a key role in regulation of the bioavailability and activity of important endogenous molecules such as steroid hormones. A relationship between the expression of steroid STs and the diabetic state has been demonstrated in various laboratory animal models, and steroid sulphates such as dehydroepiandrosterone sulphate are known to have anti-diabetic properties. In order to further our understanding of the molecular basis for the association of steroid hormone sulphation and diabetes, we have examined the expression of oestrogen, phenol and dehydroepiandrosterone (DHEA) STs in mice carrying the obesity mutation (ob), which in the homozygous state (ob/ob) produces mice which are obese and diabetic. Our data show that, in male mice, ST activities towards oestrone (E1), oestriol (E3), DHEA and the xenobiotic 1-naphthol are elevated in ob/ob mice, whereas in female mice, only the oestrogen ST activities were elevated, with the DHEA and 1-naphthol ST activities reduced. Using antibodies directed against oestrogen ST, it was demonstrated that the induction of E1 and E3 ST activity in ob/ob mice correlated with the expression of an ST isoenzyme not constitutively expressed in control mouse liver.
[Isolated gonadotropin deficiency and secretory discrepancy of cortisol and adrenal androgen by hemochromatosis secondary to congenital dyserythropoietic anemia]
Okano J, Yanase T, Takayanagi R, Mimura K, Nawata H
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka
Nippon Naibunpi Gakkai Zasshi 1994 Jan 20;70(1):57-64
A 37-yr-old woman was admitted to our hospital for evaluation of diabetes mellitus, liver cirrhosis and primary amenorrhea. Serological and hematological examinations revealed that she suffered from hemochromatosis secondary to congenital dyserythropoietic anemia (CDA), characterized by ineffective hematopoiesis and erythropoietic dysplasia. Iron deposition was suggested by MRI on the pancreas, liver and pituitary gland. Endocrinological examinations demonstrated that she had isolated gonadotropin deficiency and ovarian failure, resulting in hypogonadotropic hypogonadism. In addition, despite normal responses of serum cortisol and plasma aldosterone to ACTH and furosemide-standing tests, respectively, serum dehydroepiandrosterone (DHEA) responded poorly to ACTH test, suggesting selective damage of zona reticularis in adrenocortical steroidogenesis in association with hemochromatosis.
Decreased testosterone and dehydroepiandrosterone sulfate concentrations are associated with increased insulin and glucose concentrations in nondiabetic men.
Haffner SM, Valdez RA, Mykkanen L, Stern MP, Katz MS
Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78284
Metabolism 1994 May;43(5):599-603
Although many studies indicate that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both premenopausal and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol to glucose and insulin concentrations before and during an oral glucose tolerance test in 178 men from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Total and free testosterone and DHEA-SO4 were significantly inversely associated with insulin concentrations. Free testosterone and DHEA-SO4 were also significantly inversely correlated with glucose concentrations. SHBG was weakly positively associated with glucose concentrations. Estradiol was not related to glucose or insulin concentrations. After adjustment for age, obesity, and body fat distribution, insulin concentrations remained significantly inversely correlated with free testosterone (r = -.23), total testosterone (r = -.21), and DHEA-SO4 (r = -.21; all P < .01). In conclusion, we observed that increased testosterone and DHEA-SO4 are associated with lower insulin concentrations in men. This is in striking contrast to women, where increased androgenicity is associated with insulin resistance and hyperinsulinemia.
Enhanced adrenocortical activity as a contributing factor to diabetes in hyperandrogenic women.
Buffington CK, Givens JR, Kitabchi AE
Department of Medicine, University of Tennessee, Memphis.
Metabolism 1994 May;43(5):584-90
The high incidence of non-insulin-dependent diabetes mellitus (NIDDM) in women with polycystic ovarian syndrome (PCO) is believed to occur secondary to the insulin resistance associated with their androgenicity. In the present study, we have examined the interrelationships between glucose tolerance, androgenicity, and various in vivo and in vitro parameters of insulin sensitivity in 11 obese PCO patients with NIDDM, 14 PCO patients without diabetes, and 14 weight-matched controls. Both groups of PCO patients were hypertestosteronemic, hyperinsulinemic, and insulin-resistant when compared with a group of weight-matched controls. However, PCO patients with NIDDM differed from those without diabetes in that they had elevated basal and corticotropin-stimulated adrenal steroids (cortisol, dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate [DHEAS]). The hyperglycemia of our diabetic patients was not related to their elevated testosterone levels or to their degree of insulin resistance, but was significantly and positively correlated with adrenal hypersecretion, which in turn was associated with postreceptor defects in insulin action. These findings would suggest that enhanced adrenocortical activity may be an important factor underlying the development of NIDDM in women with PCO.
Obesity, body fat distribution and sex hormones in men.
Haffner SM, Valdez RA, Stern MP, Katz MS
Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7873.
Int J Obes Relat Metab Disord 1993 Nov;17(11):643-9
An unfavourable body fat distribution may cause metabolic abnormalities including diabetes and dyslipidemia. These effects may be mediated by alterations in sex hormones. In women the available data suggest that upper body adiposity is related to increased androgenicity (especially as indicated by low concentrations of sex hormone binding globulin). Few data, however, are available on these relationships in men. We therefore examined the association of total testosterone, free testosterone, oestradiol, dehydroepiandrosterone sulphate (DHEA-SO4) and sex hormone binding globulin (SHBG) to waist-to-hip ratio (WHR) and conicity index in 178 men from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. The conicity index is equal to the abdominal circumference divided by 0.109 x the square root of (weight/height). The conicity index and WHR were significantly inversely related to DHEA-SO4 and free testosterone. SHBG was only weakly associated with body mass index (r = -0.18, P < 0.05). After adjustment for age and body mass index, DHEA-SO4 remained inversely correlated with WHR (r = -0.22, P < 0.01) and conicity index (r = -0.31, P < 0.001) and free testosterone remained inversely associated with conicity index (r = -0.21, P < 0.01). Thus, in men, the association between unfavourable body fat distribution and increased androgenicity is inverse in contrast to the situation in women.
Relationship of sex hormones to lipids and lipoproteins in nondiabetic men.
Haffner SM, Mykkanen L, Valdez RA, Katz MS
Department of Medicine, University of Texas Health Science Center, San Antonio.
J Clin Endocrinol Metab 1993 Dec;77(6):1610-5
Although many studies show that increased androgenicity is associated with increased triglyceride (TG) and decreased high density lipoprotein cholesterol in both pre- and postmenopausal women, relatively few data are available on the association of sex hormones to lipids and lipoproteins in men. We examined the association of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol with lipids and lipoproteins in 178 nondiabetic men from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. The TG concentration was significantly inversely related to SHBG (r = -0.22), free testosterone (r = -0.15), total testosterone (r = -0.22), and DHEA-SO4 (r = -0.16). High density lipoprotein (HDL) cholesterol was significantly positively correlated to SHBG (r = 0.21), free testosterone (r = 0.15), total testosterone (r = 0.17), and DHEA-SO4 (r = 0.16). Total testosterone was significantly related to total cholesterol (r = -0.17) and low density lipoprotein cholesterol (r = -0.15). After adjustment for age, body mass index, waist to hip ratio, and glucose and insulin concentrations, TG concentrations remained significantly related to SHBG (r = -0.20), free testosterone (r = -0.15), and DHEA-SO4 (r = -0.18), and HDL cholesterol remained significantly associated with SHBG (r = 0.17), free testosterone (r = 0.15), total testosterone (r = 0.14), and DHEA-SO4 (r = 0.16). In conclusion, we observed a less atherogenic lipid and lipoprotein profile with increased testosterone concentrations. This was not explained by differences in glucose or insulin concentrations. However, sex hormones explained only a small percentage of the variation in total TG and HDL cholesterol concentrations. These findings are in striking contrast to data from women, in whom increased androgenicity is strongly associated with increased TG and decreased HDL cholesterol levels.
Adrenal steroid and adrenocorticotropin responses to human corticotropin-releasing hormone stimulation test in adolescents with type I diabetes mellitus.
Ghizzoni L, Vanelli M, Virdis R, Alberini A, Volta C, Bernasconi S
Department of Pediatrics, University of Parma, Italy.
Metabolism 1993 Sep;42(9):1141-5
To determine whether abnormalities of hypothalamic-pituitary-adrenal axis function occur in type I diabetes mellitus, corticotropin, cortisol, 17-hydroxyprogesterone (17-OHP), androstenedione (D4-A), dehydroepiandroste rone (DHEA), and DHEA sulfate (DS) levels were measured after an intravenous (IV) injection of 1 microgram/kg human corticotropin-releasing hormone (CRH) in diabetic adolescents and normal age-matched subjects. CRH produced a consistent increase in corticotropin blood levels that was comparable in the two groups. In contrast, both baseline and stimulated cortisol concentrations were greater in diabetic patients. Levels of 17-OHP increased after CRH administration, and the magnitude of increase was similar in all subjects. Stimulation with CRH determined an attenuated integrated DS response in diabetics compared with normal subjects with a different pattern of the hormone secretion, whereas no differences in D4-A concentrations were detected between the two groups. DHEA serum levels of subjects from both groups underwent similar changes following administration of CRH. In conclusion, patients with type I diabetes have a discrete response of adrenal steroids to CRH stimulation that appears to be independent of corticotropin secretion. This phenomenon might be related to a direct effect of insulin on enzyme systems involved in the biosynthetic pathway of adrenal steroids or, alternatively, to an intra-adrenal CRH/corticotropin mechanism acting on the adrenal cortex in a paracrine manner.
Excess androgenicity only partially explains the relationship between obesity and bone density in premenopausal women.
Haffner SM, Bauer RL
Department of Medicine, University of Texas Health Science Center, San Antonio.
Int J Obes Relat Metab Disord 1992 Nov;16(11):869-74
Obese subjects have increased bone density relative to non-obese subjects yet this relationship is not fully understood. We examined whether alterations in sex hormones or binding proteins might explain the effect of obesity on osteoporosis in 83 premenopausal women from the San Antonio Heart Study, a population-based study of diabetes. We measured total testosterone, oestradiol, oestrone, sex hormone binding globulin (SHBG), and serum dehydroepiandrosterone sulphate (DHEA-SO4). Bone density was assessed by a Hologic dual photon absorptometer. Lumbar spine and femoral neck density were positively correlated with body mass index (BMI). In addition, femoral neck density was positively correlated with DHEA-SO4. BMI was negatively correlated with SHBG. After adjustment for sex hormones by multiple linear regression a positive association between bone density and obesity still exists suggesting that the association between obesity and bone density is at least partially independent of sex steroids in premenopausal women.
Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus
Department of Community and Family Medicine, University of California, San Diego, La Jolla 92093-0607.
Ann Intern Med 1992 Nov 15;117(10):807-11
OBJECTIVE: To compare plasma androgen levels in diabetic and nondiabetic men and to determine their relation to diabetic dyslipidemia.
DESIGN: A population-based, case-control study.
PARTICIPANTS: Men 53 to 88 years of age from the Rancho Bernardo, California, cohort who were screened for diabetes using an oral glucose tolerance test.
MEASUREMENTS: Plasma androgen levels were compared in 44 men with untreated non-insulin-dependent diabetes mellitus and 88 age-matched men who had a normal glucose tolerance test. The relation of lipid and lipoprotein levels to androgen level and diabetic status was assessed before and after adjusting for covariates.
RESULTS: Men with diabetes had significantly lower plasma levels of free (4.96 nmol/L compared with 5.58 nmol/L) and total testosterone (14.7 nmol/L compared with 17.4 nmol/L), dihydrotestosterone (428 pg/mL compared with 533 pg/mL), and dehydroepiandrosterone sulfate (DHEA-S) (1.92 mumol/L compared with 2.42 mumol/L) than nondiabetic men. They also had significantly lower high-density lipoprotein (HDL) cholesterol and significantly higher triglyceride levels. Differences were not explained by obesity, alcohol use, or cigarette habit. Overall, the total testosterone level, but not the free testosterone level, was positively correlated with the HDL cholesterol level (P = 0.009) and negatively correlated with the triglyceride level (P = 0.0001). Similar associations were seen in analyses restricted to the men without diabetes.
CONCLUSIONS: Lower levels of endogenous androgens are seen in older diabetic men, and low androgen levels are associated with diabetic dyslipidemia.
Increased testosterone in type I diabetic subjects with severe retinopathy.
Haffner SM, Klein R, Dunn JF, Moss SE, Klein BE
Department of Medicine, University of Texas Health Science Center, San Antonio.
Ophthalmology 1990 Oct;97(10):1270-4
Diabetic retinopathy rarely occurs before puberty, suggesting that changes in sex hormones may influence the development of this condition. The authors measured serum testosterone, estradiol, DHEA-S, and sex hormone binding globulin levels in 26 men and 22 women with type I diabetes from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), a population-based study of diabetic complications. The mean age was 23 years and the mean duration of diabetes was 14 years. Subjects with proliferative or preproliferative retinopathy (greater than or equal to retinopathy level 51-80) were matched by duration of diabetes (+/- 2 years) and sex to subjects with minimal or no retinopathy (less than or equal to retinopathy level 21). Seven stereoscopic retinal photographs of each eye were obtained and photographs were read by the University of Wisconsin Reading Center. Serum testosterone concentrations were significantly higher in male diabetic subjects with proliferative retinopathy (648 +/- 36 ng/dl) than in male diabetic subjects with minimal or no retinopathy (512 +/- 43 ng/dl) (P = 0.017). No other statistically significant differences in sex hormones between subjects with and without proliferative retinopathy were observed. Although these results should be regarded as preliminary because of the small number of subjects, they support the hypothesis that testosterone concentrations may be associated with the development of retinopathy in type I diabetic patients.
Increase in plasma 5 alpha-androstane-3 alpha,17 beta-diol glucuronide as a marker of peripheral androgen action in hirsutism: a side-effect induced by cyclosporine A.
Vexiau P, Fiet J, Boudou P, Villette JM, Feutren G, Hardy N, Julien R, Dreux C, Bach JF, Cathelineau G
Diabetology and Endocrinology Department, Hopital Saint-Louis, Paris, France.
J Steroid Biochem 1990 Jan;35(1):133-7
Dose-dependent hypertrichosis is a common dermatological side-effect affecting the majority of patients treated with cyclosporine A (CSA). Previous studies have not demonstrated the influence of CSA on specific sex hormone levels. The aim of this study is to investigate whether CSA increases the activity of 5 alpha-reductase, an enzyme which transforms androgens into dihydrotestosterone in peripheral tissues. The metabolite which best reflects this activity is 5 alpha-androstane-3 alpha,17 beta-diol glucuronide (Adiol G). The study was carried out on 49 insulin-dependent diabetes patients participating in the double-blind "Cyclosporine-Diabete-France" clinical trial, of which 28 were treated with CSA (16 males and 12 females), and 21 received only placebo (10 males and 11 females). All patients underwent extensive clinical and laboratory evaluations prior to and during the present study. In addition to Adiol G, testosterone (T), dehydroepiandrosterone sulfate (DHEA S) and sex hormone-binding globulin (SHBG) were assayed. Levels of Adiol G increased significantly in CSA-treated groups: males, 11.86 +/- 2.58 vs 7.83 +/- 2.30 nmol/l; females, 4.48 +/- 2.70 vs 2.10 +/- 1.22 nmol/l; P less than 0.02 (comparison of means). There were no significant differences in this parameter before and during treatment in either the male or female placebo groups (paired t-test). During the treatment period, T, DHEA S, SHBG and the T/SHBG ratio did not significantly change with respect to their baseline values in any of the groups studied (comparison of means). Comparison (using paired t-test) showed a significant increase of DHEA S in CSA-treated groups: males, delta = 3.08 +/- 3.33 nmol/l, P less than 0.01; females, delta = 0.98 +/- 1.13 nmol/l, P less than 0.05. In conclusion, it is possible that CSA induces hypertrichosis or hirsutism by increasing 5 alpha-reductase activity in peripheral tissues. Nevertheless the role of increased DHEA S as a possible Adiol G precursor cannot be excluded.
[Dehydroepiandrosterone. Renaissance after 13 years]
Cas Lek Cesk 1989 Sep 8;128(37):1157-60
DHEA, a steroid precursor of androgens and estrogens has also an inhibitory effect on several enzymes, namely on 11 beta-hydroxylase, NADH oxidase and glucose 6-phosphate dehydrogenase. The latter is the rate limiting enzyme of the pentose phosphate cycle. This metabolic pathway provides the cells with extramitochondrial NADPH and pentose phosphates. NADPH is used for the synthesis of fatty acids and steroids. Together with ribose 5-phosphate, NADPH (as coenzyme of folate reductases) is required for the synthesis of nucleic acids. A deficient production of DHEA has been found to be responsible for several diseases obesity, diabetes type 2, hypertension, arteriosclerosis and hyperuricemia as well as malignant growth (low DHEA syndrome). DHEA administration favourably modified several of these metabolic disorders. These studies were started in our laboratory in 1962 and stopped in 1976 because we were short of DHEA. At that time the response to our results was rather theoretical, but the last years a new wave of interest in DHEA called for two consecutive symposia, where important findings were presented (Paris in January and Jena in April 1989). It is a damage that this new trend, started in our laboratory, could not be pursued up to now without interruption.
[Effect of androgen on the onset of diabetes in the KK mice treated with monosodium aspartate]
Higuchi N, Sasaki M, Arai T, Oki Y
Department of Veterinary Biochemistry, Nippon Veterinary and Zootechnical College, Tokyo, Japan.
Jikken Dobutsu 1989 Jan;38(1):25-9
Obese diabetes was induced by monosodium aspartate (MSA) administration in KK male mice and the diabetic KK mice were divided into two groups, younger (12-week-old) and older (35-week-old). The diabetic KK mice were castrated and administered with androgen and effect of androgen on glycosuria appearance was investigated. Androgen dependent tear proteins (Mtp-M) were detected by the method of polyacrylamide gel electrophoresis. Blood androgen level was estimated by observation of change of the pattern of Mtp-M. In the younger mice group, glycosuria disappeared temporarily after castration and then appeared naturally again. The Mtp-M declined with castration, but did not disappear in this experimental period. In the older mice group, glycosuria and Mtp-M disappeared completely and blood glucose level decreased considerably after castration. However, in the castrated older mice, the glycosuria and the Mtp-M appeared again after the administration of dehydroepiandrosterone (DHEA), and the increasing of blood glucose level was observed. These results strongly suggested that androgen had an important role in the onset of diabetes in the KK mice treated with MSA.
The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. V. Interaction between the db gene and hepatic sex steroid sulfotransferases correlates with gender-dependent susceptibility to hyperglycemia.
Leiter EH, Chapman HD, Coleman DL
Jackson Laboratory, Bar Harbor, Maine 04609.
Endocrinology 1989 Feb;124(2):912-22
Steroid sulfurylation represents a potential mechanism for controlling the level of active steroids within a tissue. We have elucidated an inbred strain background-dependent interaction between the diabetes (db) mutation and steroid sulfotransferase (ST) enzymes, potentially modulating the level of active steroid hormones or their precursors in the liver. Gonadectomized mutants were analyzed to correlate how strain- and gender-dependent variation in ST activities interacted with db to achieve diabetogenesis. Both sexes on the C57BL/KsChp (BKs) background developed severe early-onset hyperglycemia, and gonadectomy failed to prevent diabetes. In contrast, C3HeB/FeChp (C3HeB)-db/db males, but not females, were diabetes susceptible, and the male susceptibility was completely dependent upon endogenous testes-derived testosterone. The female resistance, in turn, was dependent upon ovarian sex steroids. The differential requirements of BKs- and C3HeB-db/db males and females for gonadal sex steroids could be explained on the basis of the differential strength of the interaction between the db mutation and hepatic ST activities. Hepatic ST from normal adult females sulfurylated dehydroepiandrosterone (DHEA), whereas this activity disappeared in cytosols of normal adult males by 8 weeks of age. This sexually dimorphic inability to sulfurylate (pre)androgens was controlled by testosterone. Diabetogenic susceptibility in BKs mutant mice of both sexes was associated with marked depression of preandrogen/androgen sulfurylation [female mutants exhibiting at least a 5-fold reduced DHEA sulfurylation at a near-physiological concentration (0.2 microM)]. This reduced preandrogen/androgen sulfurylation occurred concomitant with a 10-fold acceleration of estrone (E1) sulfurylation at a limiting (0.2 microM) concentration, essentially producing a hyperandrogenized hepatic tissue state. These extreme shifts in ST substrate preferences were not observed in the diabetes-resistant C3HeB-db/db females. Kinetic analysis of semipurified hepatic ST from BKs-db/db females showed a 10-fold decrease in Km for E1 (apparent Km = 0.9 microM in mutants vs. 9.0 microM in normals). Whereas the Km for DHEA did not differ from the control value, hepatic ST from BKs-db/db females showed a 10-fold decreased maximal velocity for DHEA sulfurylation (1230 vs. 12750 pmol/mg.h in control preparations). The antihyperglycemic effects of dietary E1 therapy were associated with enhanced androgen sulfurylation in BKs-db/db females and restoration of androgen sulfurylation in BKs-db/db males.
Therapeutic effects of dehydroepiandrosterone (DHEA) and its metabolites in obese-hyperglycemic mutant mice.
Jackson Laboratory, Bar Harbor, ME 04609.
Prog Clin Biol Res 1988;265:161-75
Dehydroepiandrosterone (DHEA) fed at 0.4%, and its metabolites, 3 alpha-hydroxyetiocholanolone (alpha-ET) and 3 beta-hydroxyetiocholanolone (beta-ET), fed at 0.1%, had marked anti-hyperglycemic and anti-obesity properties in mutant mice with single gene obesity mutations (diabetes, db; obese, ob; viable yellow, Avy). The therapeutic effects differed depending on the mutation as well as the inbred background on which the mutation was maintained. These steroids prevented onset of hyperglycemia and reduced the rate of weight gain in C57BL/6J-db/db and ob/ob mice, whereas in C57BL/KsJ-db/db mice, only hyperglycemia was prevented. The viable yellow (Avy) mutant, exhibiting a more slowly developing obesity condition, responded to all steroids with a marked decrease in rate of weight gain associated with decreased plasma insulin concentrations. Steroid treatment of most mouse mutants was associated with normal or increased food intake, a feature that suggests a decrease in metabolic efficiency. In order to assess any potential energy wastage by steroid stimulation of futile cycles we looked at the rates of lipogenesis, gluconeogenesis and oxygen consumption in steroid-treated normal and mutant mice. With the possible exception of the rate of gluconeogenesis that in obesity mutants was consistently reduced to normal by treatment, no metabolic changes were of sufficient magnitude to account for the marked decrease in metabolic efficiency. All treatments potentiated the action of insulin. This potentiation may change the hormonal balance such that minor changes in the rates of many metabolic pathways may interact to produce a large decrease in metabolic efficiency.
Hormonal intervention: "buffer hormones" or "state dependency". The role of dehydroepiandrosterone (DHEA), thyroid hormone, estrogen and hypophysectomy in aging.
Regelson W, Loria R, Kalimi M
Department of Medicine, Medical College of Virginia, Richmond 23298.
Ann N Y Acad Sci 1988;521:260-73
Modulation of growth, differentiation and carcinogenesis by dehydroepiandrosterone.
Gordon GB, Shantz LM, Talalay P
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Adv Enzyme Regul 1987;26:355-82
Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one; DHEA) and its conjugates are abundant circulating steroids that originate largely from the adrenal cortex. Their levels decline profoundly with age in human beings of both sexes, as the incidence of most cancers rises. Low levels of these steroids have been associated with the presence and risk ofdevelopment of cancer. Administration of DHEA to rodents produces protection against spontaneous tumors and chemical carcinogenesis, suppresses weight gain without significantly affecting food intake, ameliorates the severity of diabetes in genetically diabetic mice, and restrains autoimmune processes. DHEA and related steroids also depress the mitogenic effects of carcinogens, tumor promoters and plant lectins, and block viral and carcinogen-induced cell transformations. DHEA and certain congeners are also potent and quite specific inhibitors of mammalianglucose-6-phosphate dehydrogenases. We have observed that the conversion of 3T3-L1 and 3T3-F442A preadipocyte clones to the adipocyte phenotype, in response to appropriate differentiation stimuli (fetal calf serum, insulin, dexamethasone, and 1-methyl-3-isobutylxanthine), is blocked by DHEA and other steroidal inhibitors of glucose-6-phosphate dehydrogenase. The structural requirements for blocking adipocyte differentiation and for inhibiting glucose-6-phosphate dehydrogenase are closely correlated. Evidence is reviewed suggesting that the inhibition of glucose-6-phosphatedehydrogenase is central to the anticarcinogenic and differentiation-blocking actions of DHEA and related steroids. The 3T3 preadipocyte clones provide a valuable system for the analysis of the mechanisms of the effects of DHEA on growth, differentiation and carcinogenesis. (94 Refs.)
Androgenic and estrogenic metabolites in serum of mice fed dehydroepiandrosterone: relationship to antihyperglycemic effects.
Leiter EH, Beamer WG, Coleman DL, Longcope C
Metabolism 1987 Sep;36(9):863-9
The steroid prehormone, dehydroepiandrosterone (DHEA) has potentanti hyperglycemic effects when fed in the diet of genetically diabetic C57BL/KsJ-db/db mice. The purpose of this investigation was to analyze changes in sex steroid levels in serum of mice fed DHEA, and to compare the antihyperglycemic potencies of the various metabolites in order to clarify the mechanism of DHEA action. Steroid radioimmunoassays showed that dietary DHEA entered the blood in high concentrations and was actively metabolized to both androgens (testosterone, T; dihydrotestosterone, DHT) and estrogens (estrone, E1; 17 beta-estradiol, E2). This metabolism did not require intact adrenal glands or gonads. In C57BL/KsJ normal (+/+) males, conversion of DHEA to androgens was the prominent feature; in db/db males, DHEA feeding not only increased serum T and DHT, but also serum E1 and E2 levels. The db/db mice had increased amounts of adipose tissue that sequestered more intravenously injected 3H-E2; this additional body fat could account for increased aromatization of DHEA-derived estrogen precursors. Comparisons of the relative antihyperglycemic potencies of androgenic and estrogenic steroid metabolites of DHEA in db/db mice showed that the estrogens and metabolites with estrogenic properties (androstenediol) or those convertible to estrogens (DHEA sulfate) were the most potent. Although 17 beta-E2 was effective by injection or per os, DHEA was effective only when administered per os, implicating alimentary tract conversion of DHEA to more biologically active reactants. Based on the pivotal position of DHEA as a prehormone for androgens, estrogens, andetiocholanolones, an explanation of the seemingly paradoxical effects exerted by this compound in blocking autoimmune disease, hyperglycemia, obesity, and neoplasia was proposed.