The synthesis of steroids by Taenia crassiceps WFU cysticerci and tapeworms is related to the developmental stages of the parasites.

Taeniids tapeworms are hermaphroditic helminths that gradually develop testis and ovaries in their reproductive units. The larval stage of the tapeworms named cysticercus is a vesicle that contains the scolex and proliferates asexually in the abdominal cavity of mice. Once in the host, they evaginate, attach to the gut and develop into an adult organism, the tapeworm. We have previously reported reported that T. crassiceps ORF and solium cysticerci transform steroid precursors to androgens and estrogens. Taenia crassiceps WFU cysticerci can also synthesize corticosteroids. The aim of the present work is to investigate the relationship between steroid synthesis ability and the developmental stage of the parasite T. crassiceps WFU. To this purpose, cysticerci were obtained from the abdominal cavity of female mice, manually separated in invaginated (IC) and evaginated parasites (EC) and preincubated for 24 h in DMEM plus antibiotics/antimycotics. Next step consisted in incubation for different periods in the fresh media added with tritiated androstenedione (3H-A4) or progesterone (3H-P4) and incubated for different periods. Taenia crassiceps WFU tapeworms were recovered from the intestine of golden hamsters that had been orally infected with cysticerci. The worms were pre-cultured in DMEM plus FBS and antibiotics, and then incubated without FBS for different time periods, in the presence of 3H-A4 or 3H-P4. At the end of the experiments the media from cysticerci and tapeworms were analyzed by thin layer chromatography. Results showed that testosterone synthesis was significantly higher in the evaginated cysticerci and increased with time in culture. The invaginated and evaginated cysticerci also synthesized small quantities of 17ß-estradiol (E2) and estrone. The evaginated cysticerci synthesized twice more 3H-deoxycorticosterone (3H-DOC) than the invaginated parasites, the production increased significantly with time in culture. Taenia crassiceps WFU tapeworms synthesized significant quantities of 3H-testosterone and small amounts of estrone after only 3 h of culture in the presence of 3H-A4. The tapeworms also transformed 3H-P4 to 3H-DOC and increased its synthesis after 24 h in culture. In summary, our data show the pathways that T. crassiceps WFU cysticerci use to synthesize sexual steroids in both larval developmental stages and reveals the steroidogenic capacity of the tapeworms.

Taenia solium tapeworms synthesize corticosteroids and sex steroids in vitro.

Cysticercosis is a disease caused by the larval stage of Taenia solium cestodes that belongs to the family Taeniidae that affects a number of hosts including humans. Taeniids tapeworms are hermaphroditic organisms that have reproductive units called proglottids that gradually mature to develop testis and ovaries. Cysticerci, the larval stage of these parasites synthesize steroids. To our knowledge there is no information about the capacity of T. solium tapeworms to metabolize progesterone or other precursors to steroid hormones. Therefore, the aim of this paper was to investigate if T. solium tapeworms were able to transform steroid precursors to corticosteroids and sex steroids. T. solium tapeworms were recovered from the intestine of golden hamsters that had been orally infected with cysticerci. The worms were cultured in the presence of tritiated progesterone or androstenedione. At the end of the experiments the culture media were analyzed by thin layer chromatography. The experiments described here showed that small amounts of testosterone were synthesized from (3)H-progesterone by complete or segmented tapeworms whereas the incubation of segmented tapeworms with (3)H-androstenedione, instead of (3)H-progesterone, improved their capacity to synthesize testosterone. In addition, the incubation of the parasites with (3)H-progesterone yielded corticosteroids, mainly deoxicorticosterone (DOC) and 11-deoxicortisol. In summary, the results described here, demonstrate that T. solium tapeworms synthesize corticosteroid and sex steroid like metabolites. The capacity of T. solium tapeworms to synthesize steroid hormones may contribute to the physiological functions of the parasite and also to their interaction with the host.

Steroid synthesis by Taenia crassiceps WFU cysticerci is regulated by enzyme inhibitors.

Cysticerci and tapeworms from Taenia crassiceps WFU, ORF and Taenia solium synthesize sex-steroid hormones in vitro. Corticosteroids increase the 17ß-estradiol synthesis by T. crassiceps cysticerci. T. crassiceps WFU cysticerci synthesize corticosteroids, mainly 11-deoxycorticosterone (DOC). The aim of this work was to investigate whether classical steroidogenic inhibitors modify the capacity of T. crassiceps WFU cysticerci to synthesize corticosteroids and sex steroid hormones. For this purpose, T. crassiceps WFU cysticerci were obtained from the abdominal cavity of mice, pre-cultured for 24h in DMEM+antibiotics/antimycotics and cultured in the presence of tritiated progesterone ((3)H-P4), androstendione ((3)H-A4), or dehydroepiandrosterone ((3)H-DHEA) plus different doses of the corresponding inhibitors, for different periods. Blanks with the culture media adding the tritiated precursors were simultaneously incubated. At the end of the incubation period, parasites were separated and media extracted with ether. The resulting steroids were separated by thin layer chromatography (TLC). Data were expressed as percent transformation of the tritiated precursors. Results showed that after 2h of exposure of the cysticerci to 100 µM formestane, the (3)H-17ß-estradiol synthesis from tritiated androstenedione was significantly inhibited. The incubation of cysticerci in the presence of (3)H-DHEA and danazol (100 nM) resulted in (3)H-androstenediol accumulation and a significant reduction of the 17ß-estradiol synthesis. The cysticerci (3)H-DOC synthesis was significantly inhibited when the parasites were cultured in the presence of different ketoconazole dosis. The drug treatments did not affect parasite's viability. The results of this study showed that corticosteroid and sex steroid synthesis in T. crassiceps WFU cysticerci can be modified by steroidogenic enzyme inhibitors. As was shown previously by our laboratory and others, parasite survival and development depends on sex steroids, therefore the inhibition of their synthesis is a good starting point exploited in situations where the inhibition of steroidogenesis could help to control the infection for the development of new treatments, or replacement of the usual therapy in resistant parasite infections. We raise the possibility that these drug actions may be beneficially.

Taenia crassiceps WFU cysticerci synthesize corticosteroids in vitro: metyrapone regulates the production.

Taenia solium and Taenia crassiceps WFU cysticerci and tapeworms have the ability to synthesize sex steroid hormones and have a functional 3ß-hydroxisteroid dehydrogenase. Corticosteroids (CS) like corticosterone and dexamethasone have been shown to stimulate in vitro estrogen production by Taenia crassiceps WFU cysticerci. The aim of this work was to study the ability of T. crassiceps WFU cysticerci to synthesize corticosteroids, and the effect of the inhibitor metyrapone on the CS synthesis. For this purpose T. crassiceps WFU cysticerci were obtained from the abdominal cavity of mice, thoroughly washed and pre-incubated in multiwells for 24 h in DMEM plus antibiotics/antimycotics. The tritiated CS precursor progesterone ((3)H-P4) was added to the culture media and parasites cultured for different periods. Blanks containing the culture media plus the (3)H-P4 were simultaneously incubated. Blanks and parasite culture media were ether extracted and analyzed by thin layer chromatography (TLC) in two different solvent systems. Corticosterone production was measured in the culture media by RIA. In some experiments metyrapone (0.1-0.5 mM) was added for 24, 48 or 72 h. Results showed that cysticerci mainly synthesized tritiated 11-deoxy corticosterone (DOC) and small amounts of corticosterone that was also detected by RIA. Small amounts of (3)H-11-deoxy cortisol were also found. Corticosteroid synthesis was time dependent. The addition of metyrapone significantly inhibited tritiated DOC, deoxycortisol and corticosterone synthesis. These results show for the first time that parasites have the capacity to synthesize CS that is modulated by metyrapone. Data suggest that DOC is the main corticosteroid in the parasites.

The effect of glucocorticoids on sex steroid synthesis in cultured Taenia crassiceps Wake Forest University (WFU) cysticerci.

We have shown previously that cultured Taenia crassiceps Wake Forest University (WFU) and Taenia solium cysticerci, as well as the adult worms, synthesize sex steroid hormones from [3H]steroid precursors and that androgens and oestrogens influence the in vitro development of the parasites. Glucocorticoids (GCs) are used to control the inflammation caused by T. solium cysticerci in the brain. These steroids stimulate oestrogen synthesis in several tissues. Since there is no information on the effect of GC on the endocrine function of cysticerci, we investigated the effect of natural and synthetic GCs on the synthesis of oestrogens in cultured T. crassiceps WFU cysticerci. The cysticerci were obtained from the peritoneal cavity of infected female BALB/c mice; the cysts were washed extensively and pre-cultured in Dulbecco's Modified Eagle's Medium (DMEM) plus antibiotics for 5 days. The parasites were further cultured with different doses of corticosterone, dexamethasone or the vehicle for 5 days. [3H]Dehydroepiandrosterone (3H-DHEA) was added to the media and the cysticerci were further incubated for 6 or 24 h. Media were then removed and the steroids ether-extracted. Aliquots of the media were seeded on silica gel plates and developed in solvent systems. Parasites incubated in the presence of 3H-DHEA synthesized [3H]androstenediol, [3H]testosterone and [3H]17ß-oestradiol ([3H]17ß-E2). The addition of 100 nm or higher corticosterone doses to the media increased [3H]17ß-E2 synthesis fourfold after 24 h. Dexamethasone also increased [3H]17ß-E2 synthesis. The experiments presented here show for the first time that corticosterone and the synthetic GC dexamethasone modulate the synthesis of oestrogens by cysticerci.

Dutasteride combined with androgen receptor antagonists inhibit glioblastoma U87 cell metabolism, proliferation, and invasion capacity: Androgen regulation.

Glioblastoma (GB) is the most common and aggressive primary brain tumor in adult humans. Therapeutic resistance and tumor recurrence after surgical resection contributes to a poor prognosis for glioblastoma patients. Men are known to be more likely than women to develop an aggressive form of GB. Although the reasons for this disparity remain poorly understood, differences in sex steroids have emerged as a leading explanation. Studies indicate that GB-derived cells express androgen receptors (ARs) and synthesize androgens, suggesting that androgens may have a role in the tumor pathogenesis. Thus, our objective was to investigate the effects of the 5α-reductase enzyme inhibitor dutasteride, the AR antagonists cyproterone and flutamide, and combinations of these drugs on the metabolism, proliferation, and invasion capacity of GB-derived U87 cells. We also examined the effects of three natural androgens testosterone, androstenedione and dihydrotestosterone (T, A4, and DHT) on these cells. Cell metabolism was investigated by MTT assay, proliferation was assessed by the bromodeoxyuridine (BrdU) incorporation assay, and invasion was assessed by Boyden chamber assay. The results revealed that T and especially DHT, but not A4, increased U87 cell metabolism and proliferation. Following these findings, we examined the effect of adding dutasteride, cyproterone, or flutamide to the culture media and found that they all significantly decreased cell metabolism and proliferation. Dutasteride also significantly reduced cell invasion. Moreover, any combination of these drugs enhanced their inhibitory effects; the combination of dutasteride to flutamide was most effective at decreasing GB cell proliferation. Our results suggest that administering a combination of AR antagonists and enzyme blockers may be a more effective alternative treatment for GB.

Steroidogenic capacity of Trypanosoma cruzi trypomastigotes.

American Trypanosomiasis is caused by the hemoflagellate Trypanosoma cruzi (T. cruzi) and affects millions of persons causing variable degrees of digestive and heart disturbances. As far as we concerned, T. cruzi capacity to synthesize steroid hormones has not been investigated. Therefore, the aim of this work was to investigate the capacity of T. cruzi trypomastigotes to transform tritiated steroid precursors into androgens and estrogens. The T. cruzi Tulahuén strain was obtained from mice blood. The trypomastigotes were cultured for 6 and 24h in Dulbbeco's modified Eagle's medium plus FCS and antibiotics. Tritiated dehydroepiandrosterone or androstendione were added to the culture media and parasites were incubated for 6 or 24h. The cultures were centrifuged and ether extracted. The steroids were analyzed by thin layer chromatography (TLC) in two solvent systems. After incubation with 3H-androstenedione, T. cruzi trypomastigotes synthesized 3H-testosterone (T), 3H-17beta-estradiol (E2) and 3H-estrone (E1). Metabolism of 3H-DHEA by the parasites yielded 3H-androstendione and 3H-androstendiol at 6h of incubation. The recrystallization procedure further demonstrated the 3H-androstendiol and 3H-17beta-estradiol syntheses. Results indicate for the first time that T. cruzi trypomastigotes produce androgens and estrogens when incubated in the presence of steroid precursors and suggest the presence of active parasite steroidogenic enzymes.

Metabolism of steroid hormones by Taenia solium and Taenia crassiceps cysticerci.

Previous in vitro experiments showed that both, Taenia crassiceps and Taenia solium cysticerci have the ability to metabolize exogenous androstenedione to testosterone. Here we evaluate on the capacity of both cysticerci to synthesize several sex steroid hormones, using different hormonal precursors. Experiments using thin layer chromatography (TLC) showed that both cysticerci were able to produce (3)H-hydroxyprogesterone, (3)H-androstenedione and (3)H-testosterone when (3)H-progesterone was used as the precursor. They also synthesized (3)H-androstenediol and (3)H-testosterone when (3)H-dehydroepiandrosterone was the precursor. In addition, both cysticerci interconverted (3)H-estradiol and (3)H-estrone. These results, strongly suggest the presence and activity of the Delta4 and Delta5 steroid pathway enzymes, 3beta-hydroxysteroid dehydrogenase/Delta(5-4) isomerase-like enzyme (3beta-HSD), that converts androstenediol into testosterone; and the 17beta-hydroxysteroid dehydrogenase that interconverts estradiol and estrone, in both types of cysticerci.

Relationship of proinsulin and insulin to cardiovascular risk factors in nondiabetic subjects.

Recent data suggest that proinsulin is strongly associated with cardiovascular risk factors in diabetic subjects. However, this relationship has not been examined in nondiabetic subjects. Therefore, we examined the relation of proinsulin to lipids, obesity (body mass index), and waist-to-hip ratio in 260 nondiabetic individuals from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Proinsulin was measured by radioimmunoassay, and insulin was measured by a Linco radioimmunoassay that does not cross-react with proinsulin. Fasting insulin was significantly associated with body mass index (0.42), waist-to-hip ratio (r = 0.30), triglyceride (r = 0.29), high-density lipoprotein cholesterol (r = -0.20), and systolic blood pressure (r = 0.16) but not significantly related to diastolic blood pressure (r = 0.11). Fasting proinsulin was significantly associated with body mass index (r = 0.19), waist-to-hip ratio (r = 0.25), triglyceride (r = 0.41), systolic blood pressure (r = 0.19), and diastolic blood pressure (r = 0.15). Proinsulin was more strongly related to increased triglyceride than insulin despite its weaker relationship to obesity. In multivariate analyses, proinsulin continued to be significantly related to triglyceride concentrations (explaining 23.1% of the variance) and to systolic blood pressure (explaining 4.0% of the variance), even after adjusting for insulin. These observations suggest that proinsulin should be measured in addition to insulin in epidemiological studies. Proinsulin may be a marker for metabolic decompensation in prediabetic subjects.

Incidence of NIDDM and impaired glucose tolerance in hypertensive subjects. The San Antonio Heart Study.

Hypertension often occurs in association with NIDDM and IGT. We examined the association of hypertension at baseline to the 8-yr incidence of NIDDM and IGT in 1471 subjects who participated in the San Antonio Heart Study. Subjects who were hypertensive at baseline had a higher incidence of NIDDM (8.9 vs. 4.9%, P = 0.041) and IGT (25.2 vs. 10.0%, P < 0.001) than subjects who were normotensive at baseline. After adjusting for age, sex, ethnicity, obesity, body fat distribution, fasting glucose, and insulin, this excess was eliminated for NIDDM, but not for IGT. Specifically, the adjusted OR for NIDDM in hypertensive versus normotensive patients was 0.73 (95% Cl 0.34-1.58), whereas the adjusted OR for IGT was 1.87 (95% Cl 1.08-3.22). The excess risk of NIDDM in hypertensive patients can be explained by their greater age, obesity, more unfavorable body fat distribution, and hyperinsulinemia, whereas the excess risk of IGT is independent of these factors.

Proinsulin and specific insulin concentration in high- and low-risk populations for NIDDM.

Hyperinsulinemia and insulin resistance have been implicated as risk factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). Recent data suggest that proinsulin may comprise a large proportion of immunoreactive insulin in subjects with NIDDM and possibly in those with impaired glucose tolerance (IGT) as well. Increased proinsulin concentrations are thought to be an early indicator of a failing pancreas. We examined proinsulin, insulin (using an assay that does not display appreciable cross-reactivity with proinsulin), and the fasting proinsulin:insulin ratio in 206 nondiabetic Mexican-American (a high-risk population for NIDDM) and 123 nondiabetic non-Hispanic white (a low-risk population for NIDDM) participants in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Mexican-Americans had significantly higher fasting and 2-h proinsulin and insulin levels but similar fasting proinsulin:insulin ratios compared with non-Hispanic whites. After statistical adjustment for age, body mass index, waist-to-hip ratio, and glucose tolerance status, Mexican-Americans continued to have higher fasting and 2-h insulin and fasting and 2-h proinsulin concentrations but similar proinsulin:insulin ratios compared with non-Hispanic whites. The fasting proinsulin:insulin ratio was higher in 85 subjects with NIDDM compared with subjects with IGT or normal glucose tolerance (0.31, 0.09, and 0.07, respectively). Thus, nondiabetic subjects from a high-risk population for NIDDM are hyperinsulinemic (using an assay that does not cross-react with proinsulin) and, further, do not secrete more proinsulin relative to insulin itself than do nondiabetic subjects from a low-risk population.

Prospective analysis of the insulin-resistance syndrome (syndrome X).

Many studies have shown that hyperinsulinemia and/or insulin resistance are related to various metabolic and physiological disorders including hypertension, dyslipidemia, and non-insulin-dependent diabetes mellitus. This syndrome has been termed Syndrome X. An important limitation of previous studies has been that they all have been cross sectional, and thus the presence of insulin resistance could be a consequence of the underlying metabolic disorders rather than its cause. We examined the relationship of fasting insulin concentration (as an indicator of insulin resistance) to the incidence of multiple metabolic abnormalities in the 8-yr follow-up of the cohort enrolled in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease in Mexican Americans and non-Hispanic whites. In univariate analyses, fasting insulin was related to the incidence of the following conditions: hypertension, decreased high-density lipoprotein cholesterol concentration, increased triglyceride concentration, and non-insulin-dependent diabetes mellitus. Hyperinsulinemia was not related to increased low-density lipoprotein or total cholesterol concentration. In multivariate analyses, after adjustment for obesity and body fat distribution, fasting insulin continued to be significantly related to the incidence of decreased high-density lipoprotein cholesterol and increased triglyceride concentrations and to the incidence of non-insulin-dependent diabetes mellitus. Baseline insulin concentrations were higher in subjects who subsequently developed multiple metabolic disorders. These results were not attributable to differences in baseline obesity and were similar in Mexican Americans and non-Hispanic whites. These results support the existence of a metabolic syndrome and the relationship of that syndrome to multiple metabolic disorders by showing that elevations of insulin concentration precede the development of numerous metabolic disorders.

Predicting diabetes. Moving beyond impaired glucose tolerance.

We developed predictive models for type II diabetes using stepwise multiple logistic regression analyses of a cohort of 844 Mexican Americans and 641 non-Hispanic whites who were nondiabetic at baseline and who were then followed for 8 yr. Models were developed for the overall population and separately for each sex and ethnic group. For optimal models, the multiple logistic regression program selected potential risk factors from a panel of 5 categorical and 14 continuous demographic, anthropometric, metabolic, and hemodynamic variables. For reduced models, the list of candidate variables was restricted to those commonly used in ordinary clinical practice, i.e., skinfolds, and serum insulin and postural glucose load variables were excluded. For all models, the stepwise process selected a mixture of anthropometric, glucose, lipid, and hemodynamic variables. The top 15% of the risk continuum for each model was defined as high risk to compare the performance of the models with the performance of impaired glucose tolerance (15% prevalence) as a predictor of diabetes. The relative risk of being high risk ranged from 12.16 to 35.29, whereas the relative risk of having impaired glucose tolerance ranged from 7.11 to 10.0. The sensitivity of the multiple logistic regression models ranged from 67.7 to 83.3% compared with 56.5 to 62.1% for impaired glucose tolerance. The results indicate that multivariate predictive models perform at least as well, if not better than impaired glucose tolerance in predicting type II diabetes but need not require an oral glucose load. Moreover, the models highlight the complex metabolic and hemodynamic syndrome that precedes diabetes.

Stability over time of modern diagnostic criteria for type II diabetes.

OBJECTIVE: To examine the long-term stability of the World Health Organization criteria for diabetes in the 8-yr follow-up of the San Antonio Heart Study. A problem with older criteria for diagnosing diabetes was that many individuals classified as having borderline or chemical diabetes reverted to nondiabetic status on follow-up. Few studies have addressed this issue among diabetic patients who meet the more stringent, modern National Diabetes Data Group or World Health Organization criteria. RESEARCH DESIGN AND METHODS: We studied 98 Mexican-American and 44 non-Hispanic white type II diabetic patients 8 yr after they were diagnosed according to World Health Organization criteria in a population-based epidemiological survey. Patients were classified as follows: whether they were on pharmacological treatment for diabetes at baseline, or, if not, whether they had a prior diagnosis of diabetes at the time of their baseline survey visit or were newly diagnosed. RESULTS: Of the 142 patients who met the study criteria for type II diabetes at baseline and whose status at follow-up was known, 20 (14.1%; 95% confidence interval 9.0-20.5%) no longer met criteria at follow-up 8 yr later. All but 2 of those who reverted to nondiabetic status were from the newly diagnosed group. Two of 20 had lost more than 5.0 kg over the 8 yr and an additional 5 had lost 2.5-5.0 kg. The 20 patients who reverted to nondiabetic status lacked many of the associated anthropometric, physiological, and metabolic findings of diabetes such as obesity, unfavorable body fat distribution, and dyslipidemia. Moreover, only one had proteinuria, and none had any grade of diabetic retinopathy at baseline. CONCLUSIONS: Epidemiological surveys that rely on a single oral glucose tolerance test to determine the prevalence of type II diabetes may overestimate prevalence by as much as 16% (95% confidence interval 10.5-23.6%) (142/122 = 1.16). The actual overestimate could well be less because some patients who truly have diabetes at baseline may be in remission at follow-up as a result of significant weight loss. Despite these difficulties, the modern National Diabetes Data Group and World Health Organization criteria are more stable than earlier criteria.

Clinical characteristics of type II diabetic subjects consuming high versus low carbohydrate diets in Mexico City and San Antonio, Texas.

OBJECTIVE: To compare the clinical status of type II diabetic subjects identified in two population-based surveys, one performed in Mexico City, Mexico and the other in San Antonio, Texas. RESEARCH DESIGN AND METHODS: In a low income area of Mexico City, 3,517 age-eligible (35-64 years of age) individuals were randomly selected of whom 3,319 were interviewed at home and 2,198 were examined in a clinic (response rates 62.5%). In San Antonio, 2,357 similarly aged low-income Mexican Americans were randomly selected of whom 2,076 were interviewed at home and 1,511 were examined (response rate 64.1%). Oral glucose tolerance tests were performed at both sites and diabetes was diagnosed according to the World Health Organization (WHO) criteria. In Mexico City, 288 type II diabetic individuals were identified, and 255 were identified in San Antonio. The following variables were measured: height, weight, subscapular and triceps skinfolds, waist-to-hip circumference ratios (WHR), systolic and diastolic blood pressure (random 0 sphygmomanometer), fasting and 2-h postglucose load glucose and insulin concentrations, and fasting total-cholesterol, HDL-cholesterol, and triglyceride (TG) levels. A food frequency questionnaire was used to estimate total calories and the percentage of calories derived from protein, fat, and carbohydrate. Only type II diabetic patients were included in the analyses. Age-adjustment was performed by analysis of covariance for continuous variables and by the Mantel-Haenszel procedure for discrete variables. RESULTS: The mean age, the percentage newly diagnosed cases, and the percentage of males were similar in both sites. The percentage of diabetic patients treated with oral agents was significantly higher in Mexico City (56.9 vs. 72.7% in San Antonio and Mexico City, respectively, P < 0.001), whereas the percentage treated with insulin was significantly higher in San Antonio (18.8 vs. 2.1% for San Antonio and Mexico City, respectively, P < 0.001). A significant difference was observed in the percentage of calories derived from carbohydrate (61.7-63.2 vs. 47.1-47.5% for Mexico City and San Antonio, respectively, P < 0.001) and fat (18.4-20.0 and 30.1-33.0% for Mexico City and San Antonio, respectively, P < 0.001). Body mass index (BMI) was higher in San Antonio (27.6-30.4 vs. 30.2-32.9% for Mexico City and San Antonio, respectively, P < 0.05). Total serum cholesterol was similar at both sites. HDL cholesterol, however, was lower in Mexico City, both in newly and in previously diagnosed patients (30.5-35.8 vs. 39.6-43.3 mg/dl in Mexico City and San Antonio, respectively, P < 0.001). TG levels were higher in Mexico City patients (187-249 vs. 167-179 mg/dl in Mexico City and San Antonio, respectively, P < 0.001). The association between diabetes and the anthropometric and metabolic variables was similar in Mexico City and San Antonio with the following exceptions: Diabetes in Mexico City was associated with less of an elevation in BMI, WHR, and fasting insulin concentration and less of a reduction in the 2-h postoral glucose load insulin concentration compared with diabetes in San Antonio. In addition, although diabetes was associated with a lower HDL in San Antonio subjects, no association appeared between diabetes and HDL in Mexico City subjects. CONCLUSIONS: Diabetic subjects in Mexico City were more likely to be treated with oral agents and less likely to be treated with insulin compared with San Antonio patients. Previously diagnosed diabetic subjects in San Antonio had higher BMIs than diabetic subjects in Mexico City. Diabetic subjects in Mexico City ate less fat but more carbohydrate than those in San Antonio. TG levels were higher and HDL-cholesterol levels were lower in Mexico City diabetic subjects compared with those in San Antonio. San Antonio diabetic subjects had lower HDL levels than nondiabetic subjects but, in Mexico City, HDL levels were similar in diabetic subjects and nondiabetic subjects...

Relationship of sex hormones to lipids and lipoproteins in nondiabetic men.

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.

Decreased sex hormone-binding globulin predicts noninsulin-dependent diabetes mellitus in women but not in men.

Sex hormones may influence risk factors for noninsulin-dependent diabetes mellitus (NIDDM). Decreased sex hormone-binding globulin (SHBG; an indirect measure of androgenicity) is associated with hyperinsulinemia and insulin resistance. We measured SHBG concentrations in 58 subjects who later converted to diabetes and 107 subjects who remained normoglycemic throughout the 8 yr of follow-up of the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Among premenopausal women, SHBG concentrations (nanomoles per L) were significantly lower in converters than in nonconverters (41.6 +/- 12.4 vs. 74.4 +/- 10.0; P = 0.004), but corresponding differences were not observed in postmenopausal women or in men. Since, however, analysis of variance suggested no significant interaction between menopausal status and conversion to NIDDM, we pooled pre- and postmenopausal women. Subsequent analysis indicated that SHBG concentrations predicted the development of NIDDM in women independently of glucose and insulin concentrations. We conclude that increased androgenicity, as assessed by decreased SHBG concentrations, is an important independent risk factor for NIDDM in women.

Hyperdynamic circulation and the insulin resistance syndrome ("syndrome X").

The insulin resistance syndrome ("syndrome X") consists of hyperinsulinemia, glucose intolerance, dyslipidemia, and hypertension, although the inclusion of hypertension has been challenged. Insulin has biological effects that could produce a hyperdynamic circulation. We therefore postulated that an insulin-induced hyperdynamic circulation is an early feature of the insulin resistance syndrome and that this circulatory abnormality leads to later fixed hypertension. The San Antonio Heart Study cohort, a population-based cohort of 3,301 Mexican Americans and 1,857 non-Hispanic whites, was used to define individuals who were hyperdynamic (pulse pressure and heart rate in the upper quartile of their respective distributions), intermediate, and hypodynamic (pulse pressure and heart rate in the bottom quartile). The characteristics of the insulin resistance syndrome were then examined according to these three hemodynamic categories. We also examined the 8-year incidence of hypertension and of type II diabetes according to these hemodynamic categories. A hyperdynamic circulation was associated with statistically significant increases in body mass index (BMI) (p < 0.001), subscapular-to-triceps skinfold ratio (p = 0.042), triglyceride (p = 0.002), 2-hour glucose (p = 0.002), and fasting and 2-hour insulin (p = 0.019 and 0.006). When hemodynamic status was examined separately in lean (BMI < 27 kg/m2) and obese (BMI > or = 27 kg/m2) individuals, the above effects persisted, although they were somewhat attenuated. The odds ratio for the hyperdynamic state as a predictor of future hypertension was 1.66, although this was not statistically significant (p = 0.304). The odds ratio for predicting future type II diabetes was 3.97, which was statistically significant (p = 0.047).(ABSTRACT TRUNCATED AT 250 WORDS)

Disproportionately increased proinsulin levels are associated with the insulin resistance syndrome.

Recent data suggest that proinsulin may be associated with increased cardiovascular risk factors in both diabetic and nondiabetic subjects. We examined the relation of insulin, proinsulin, and the fasting proinsulin/insulin ratio to a number of metabolic disorders believed to be related to the insulin resistance syndrome (low high density lipoprotein cholesterol and high triglyceride levels, hypertension, and impaired glucose tolerance). Proinsulin was measured by a RIA, and insulin was measured by a Linco RIA that does not cross-react with proinsulin. The increased fasting proinsulin/insulin ratio was significantly associated with hypertension, low high density lipoprotein cholesterol and high triglyceride levels, and impaired glucose tolerance in 423 nondiabetic subjects. The fasting proinsulin/insulin ratio increased significantly with the number of metabolic disorders (zero, 0.060; one, 0.086; two, 0.098; three, 0.177; four, 0.182; P < 0.001). The increased proinsulin/insulin ratio was also associated with a greater number of metabolic disorders in diabetic subjects. Our results show that particularly nondiabetic individuals with the insulin resistance syndrome not only have hyperinsulinemia as a marker of insulin resistance, but also show an increase in proinsulin relative to insulin, which may reflect relative beta-cell failure or malfunction.

Endogenous sex hormones: impact on lipids, lipoproteins, and insulin.

Estrogen use has been reported to decrease triglyceride and low-density lipoprotein cholesterol (LDL-C) and increase high-density lipoprotein cholesterol (HDL-C). Estrogen use increases the secretion of large, very low-density lipoprotein cholesterol (VLDL-C) and also stimulates the uptake of VLDL-C by the liver and increases the catabolism of LDL-C in the liver. Sex hormones may affect several enzymes involved in the metabolism of HDL-C and triglyceride and may also affect lipolysis. In both pre- and postmenopausal women, several studies have shown that increased glucose and insulin concentrations are associated with increased free testosterone and decreased sex hormone binding globulin. The temporal direction of this relationship in premenopausal women is not clear, however. In contrast to women, increased androgen concentrations in men do not seem to be associated with increased cardiovascular risk factors, although testosterone concentrations are associated with increased HDL-C and decreased insulin concentrations. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) appear to be associated with improved cardiovascular risk factors in men, but this connection in women is less clear.