Relationship between glycemic control and coronary artery disease severity, prevalence and plaque characteristics by computed tomography coronary angiography in asymptomatic type 2 diabetic patients.

Evaluate whether glycemic control in type 2 diabetes (DM2) asymptomatic for coronary artery disease (CAD) affects not only the presence and magnitude of CAD but also the characteristics of plaque vulnerability using multidetector row computed coronary tomography (MDCT). Acute coronary syndrome (ACS) is frequently observed in asymptomatic DM2 patients. Positive vessel remodeling (PR) and low-attenuation plaques (LAP) identified by MDCT have been demonstrated to be characteristics of subsequent culprit lesions of ACS. However, little is known regarding plaque characteristics in asymptomatic diabetic patients and their relationship with glycemic control. Ninety asymptomatic DM2 patients, aged 40-65 years old, underwent MDCT. The presence of atherosclerotic obstruction, defined as coronary stenosis ≥50 %, and plaque characteristics were compared between two groups of patients with A1c < 7 and A1c ≥ 7 %. Of the 90 patients, 38 (42.2 %) presented with coronary atherosclerotic plaques, 11 had A1c < 7 % and 27 had A1c ≥ 7 % (p = 0.0006). Fourteen patients had significant lumen obstruction higher than 50 %: 3 in the A1c < 7 % group and 11 in the A1c ≥ 7 % group (p = 0.02). Non-calcified plaque was more prevalent in the A1c ≥ 7 % group (p = 0.005). In eleven patients, the simultaneous presence of two vulnerability plaque characteristics (PR and LAP) were observed more frequently in the A1c ≥ 7 group (n = 8) than in the A1c < 7 group (n = 3) (p = 0.04). Asymptomatic DM2 patients with A1c ≥ 7 % have a higher frequency of CAD and a higher proportion of vulnerable atherosclerotic coronary plaque by MDCT compared to patients with DM2 with A1c < 7 in our study.

Effect of thalidomide and rosiglitazone on the prevention of diabetic retinopathy in streptozotocin-induced diabetic rats.

AIMS/HYPOTHESIS: Our aim was to compare the therapeutic effect of thalidomide and rosiglitazone on the prevention of diabetic retinopathy in streptozotocin-induced diabetic rats. METHODS: Male Holtzman rats of 6 to 8 weeks of age and weighing 170+/-30 g were randomly divided into four groups: control ( n=13), untreated diabetic ( n=17) and diabetic rats treated with thalidomide (200 mg kg(-1) day(-1)) ( n=8) or rosiglitazone (1 mg kg(-1) day(-1)) ( n=22) for 3 months. Diabetes was induced by streptozotocin with the rats having a body weight of 70 mg/kg. After treatment, vascular endothelial growth factor (VEGF) concentrations in ocular fluid were compared between the different groups, and retinal capillary basement membrane thickness was measured by electron microscopy. RESULTS: Higher VEGF concentrations in ocular fluid and thicker basement membranes were observed in untreated diabetic rats compared to the control rats. Similar VEGF concentrations and basement membrane thickness were observed for the thalidomide-treated group compared with the control group, whereas no difference in these parameters was observed between the rosiglitazone-treated rats and the control or untreated diabetic rats. CONCLUSIONS/INTERPRETATION: Our findings confirm the association between VEGF concentrations and diabetic retinopathy as suggested by other investigators. Thalidomide, but not rosiglitazone, was associated with the inhibition of basement membrane thickening and the blockade of the increase of VEGF in ocular fluid, thus representing a potential therapeutic drug for the prevention of diabetic retinopathy.

Effect of fat distribution on the pharmacokinetics of cortisol in obesity.

OBJECTIVE: Patients with predominantly upper body obesity are at greater risk for developing diabetes mellitus, hyperlipidemia, hypertension, and cardiovascular disease. Little is known about the mechanisms involved in the regulation of regional body distribution. It has been accepted that the accumulation of fat into adipose tissue depends on regional metabolic regulation of adipocytes and that glucocorticoids play a role in this mechanism. The aim of the present study is to investigate how the pharmacokinetics of cortisol correlate to intraabdominal and subcutaneous fat distribution in obese patients. METHODS: A group of 24 obese patients (13 males and 11 females) were submitted to a CT scan for intraabdominal and subcutaneous fat area evaluation. A 30-min cortisol infusion (0.25 mg/kg) was administered and plasma cortisol was measured over 6 hours. RESULTS: Patients with larger intraabdominal fat areas were found to have a higher cortisol clearance than those with lower intraabdominal fat areas. Cortisol clearance (both, absolute and body-weight corrected) showed a statistically significant correlation with intraabdominal fat area, either expressed by waist-hip ratio or obtained by computerized tomography. CONCLUSIONS: These findings indicate a more effective clearance capability for cortisol in patients with central obesity resulting in lowered cortisol plasma levels despite an increased cortisol secretion observed in this patient group.

Risk factors in obese women, with particular reference to visceral fat component.

Possible associations between increased visceral fat component and serum lipid concentrations, glucose tolerance and insulinaemia (specific radioimmunoassay) were studied as risk factors for cardiovascular disease in 50 adult obese women without known diabetes and 11 lean normal women. Visceral abdominal fat areas were evaluated by computed tomography and "true" insulin concentrations. Diabetes was observed in 6 obese women (12%) and impaired glucose tolerance in 13 (26%). In obese women, visceral fat area correlated significantly with VLDL-cholesterol, triglycerides, and systolic and diastolic blood pressure, whereas subcutaneous area correlated negatively with cholesterol and LDL-cholesterol. Insulinaemia was not increased in visceral obesity nor correlated with other risk factors. An association between increased visceral fat accumulation, dyslipidaemia and increased diastolic blood pressure was observed, but no significant correlations were noted between fasting "true" insulin or insulin response on an oral glucose tolerance test and intra-abdominal fat areas or dyslipidemia. The gender of the patients could have been an important factor in these last observations.

Effect of glycemic control on growth hormone and IGFBP-1 secretion in patients with type I diabetes mellitus.

Growth hormone (GH) secretion disorders have been reported in poorly controlled type I diabetes mellitus patients. Our work was aimed to evaluate GH secretion in 9 type I young diabetes mellitus patients as well as the low molecular weight IGF-binding protein secretion (IGFBP-1) in 5 of them. The patients did not show any signs of malnutrition or neurovascular complications, neither were they on any medication except for insulin. The study protocol included blood samples collection during a 24-h period for measurement of glucose, glycated hemoglobin, GH IGF-I and IGFBP-1 levels under two situations: on poor glycemic control and after 2-3 months on better control through systematic diet, low in carbohydrates and increase in insulin dosage. GH secretion data were analyzed by Cluster algorithm for pulsatility parameters; for rhythm assessment Cosinor method was used. The first study (poor control) reported significant increase of GH maximal and incremental amplitude and duration pulse values, when compared to the second study (better control). Mean 24-h secretion values as well mean GH for interpulse intervals (valleys) decreased, although not statistically significant. The fraction of pulsatile GH/24 h GH did not change significantly with better glycemic control. No changes in pulse frequency were observed. Mean IGF-I concentrations were significantly higher when patients were on better glycemic control. An ultradian variation for GH secretion was noticed in the first study (poor control) and a circadian variation in the second one (better control). IGFBP-1 analysis showed significant decrease of the mean 24-h values under better glycemic control. Linear regression analysis demonstrated a correlation between IGFBP-1 levels and fasting glucose levels. A circadian variation was present in IGFBP-1 secretion, irrespective of glycemic control. Therefore, we concluded that for type I diabetic patients: 1. GH secretion is increased on poor control, through maximal, incremental amplitude and pulse duration values; 2. IGFBP-1 values were significantly reduced and IGF-1 levels significantly higher after better glycemic control; 4. GH ultradian secretion is reported on poor control, and circadian on the better one, 5. IGFBP-1 circadian secretion occurred irrespective of glycemic control.

Estimation of body fat and lean tissue distribution by dual energy X-ray absorptiometry and abdominal body fat evaluation by computed tomography in Cushing's disease.

Body composition determined by dual energy x-ray absorptiometry and the abdominal visceral fat component determined by computed tomographic scanning were examined in women with Cushing's disease and compared with those in obese women with the same anthropometric parameters and those in nonobese women. Patients with Cushing's had no increase in total body fat or the trunk region (android) component, but had a higher intraabdominal fat area compared to the obese subjects. The total lean tissue mass was slightly reduced in Cushing's compared to that in the obese subjects due to a significant decrease in the muscle of the legs and arms; the reduced amounts of fat and lean tissue masses in the arms were the most significant findings in hypercortisolism. The body mineral and bone calcium contents were slightly reduced in Cushing's compared to those in the obese controls. Thus, although obese subjects had more fat and lean tissue and mineral masses than their normal weight counterparts, the Cushing's patients, with the same total fat mass and its components (except in the arms) as obese individuals, present total lean tissue and fractions, including body mineral and bone calcium contents, similar to those in nonobese subjects due to the depletion of the protein depots, as seen in hypercortisolism.

Erythrocyte insulin-like growth factor-I receptor evaluation in normal subjects, acromegalics, and growth hormone-deficient and insulin-dependent diabetic children.

Insulin-like growth factor-I (IGF-I) receptors are characterized in several animal and human tissues. IGF-I receptor studies performed in erythrocytes to assess IGF-I receptor status at target-cell tissues are potentially useful for clinical studies, since tissue biopsies or cultures are not required. However, validation of results is challenged by some investigators on the basis of discrepancies described in comparative studies with other cell types, probably related to populations of different cell ages affecting binding to red blood cells (RBCs). By correcting cell age for creatine, we studied IGF-I receptor status in 24 normal subjects (11 adults and 13 children, eight prepubertal and five pubertal) and 33 patients with pathologic conditions (five adult acromegalics, six children with pituitary dwarfism, and 22 type I diabetic children, 15 prepubertal and seven pubertal). Acromegalic patients with higher plasma IGF-I and insulin levels presented lower IGF-I specific binding ([Bo] mean +/- SEM, 6.1% +/- 0.8%) and affinity ([ED50] 28.5 +/- 2.2 ng/mL) than normal adults (Bo, 10.9% +/- 0.7%; ED50, 16.4 +/- 0.9 ng/mL; P < .001), and growth hormone (GH)-deficient children showed higher IGF-I binding 24.6% +/- 1.7%, P < .001) without significant affinity alterations than normal prepubertal children (Bo, 14.7% +/- 1.0%). Both prepubertal and pubertal type I diabetic children with higher GH levels presented decreased IGF-I binding (11.4% +/- 0.9% for prepubertal, P < .05; 10.0% +/- 1.1% for pubertal, P < .05) to RBC receptors in comparison to the respective control group (14.7% +/- 10% and 14.9% +/- 1.3%, prepubertal and pubertal, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of spironolactone on testosterone fractions and sex-hormone binding globulin binding capacity in hirsute women.

This study explored the effect of the anti-androgen spironolactone on sex-hormone binding globulin (SHBG) and the distribution of circulating testosterone (T) into various free and bound fractions in seven women with hirsutism assessed before and then monthly for three months on a regimen of spironolactone, 100 mg bid as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgen parameters and serum T fractions studies. None of the women were judged obese based upon body mass index values. After three months of spironolactone therapy, there was little change in the hirsutism index, and measurement of serum T, androstenedione, DHEA-S and 17 beta-estradiol showed no significant changes, the same occurring with SHBG-binding capacity. However, there was a shift in the distribution of circulating T, with a decrease in SHBG-bound T and an increase in albumin-bound and free T (non-SHBG-bound fractions). As previous reports suggest that non-SHBG-bound fractions represent bioavailable fractions, the current data suggests that T fraction studies may not be clinically useful parameters of hyperandrogenism in women receiving antiandrogen therapy.

Calcium and prolactin secretion in humans: effects of the channel blocker, verapamil, in the spontaneous and drug-induced hyperprolactinemia.

The effects of the intravenous administration of a calcium channel blocker, verapamil (0.0833 mg/min for 2-3 h after a 5 mg bolus) on prolactin (PRL) and thyrotropin (TSH) circulating levels were assessed in 7 normal subjects and in 17 patients with hyperprolactinemia (11 with prolactinoma and 6 sulpriride-induced). In the normal group a non-significant increase in PRL levels occurred (mean +/- SEM = 11.7 +/- 2.9 micrograms/l verapamil vs. 8.5 +/- 1.4 micrograms/l saline). In this control group the peak response of PRL and TSH to TRH (thyrotrophin releasing hormone) during verapamil or saline was also determined: PRL = 112.0 +/- 27.0 micrograms/l on verapamil vs. 53.6 micrograms/l on saline, p = 0.02; TSH 7.1 +/- 0.7 microU/l on verapamil vs. 9.0 +/- 0.6 mU/l on saline, p = 0.01. In the hyperprolactinemic subjects verapamil induced opposite effects on PRL levels, the prolactinoma group exhibiting an increase in the mean values (168.5 +/- 22.3 micrograms/l vs. 150.8 +/- 23.6 micrograms/l on saline, p = 0.04) whereas in the sulpiride-induced there was a reduction in the mean PRL levels (61.1 +/- 13.8 micrograms/l vs. 78.5 +/- 19.3 micrograms/l on saline, p = 0.002). In both groups of hyperprolactinemic patients no effects on TSH levels were observed. The authors discuss the possibility that the divergent effects of verapamil in hyperprolactinemia of different etiologies could be related to the balance between dopamine and calcium channel effects on hypothalamus and/or pituitary.

Tratamento de pacientes portadores de deficiência de hormônio de crescimento (DHC) com hormônio de crescimento recombinante autêntico / Treatment of patients carried of growth hormone deficiency with authentic recombinant growth hormone

Onze pacientes portadores de deficiência de hormônio de crescimento (DHC) foram tratados por três anos com hormônio de crescimento recombinante autêntico (HCr), em doses de 0,35 a 0,5U/Kg/semana. A velocidade de crescimento pré-tratamento de 2,91 ñ 1,58cm/a elevou-se a 11,07 ñ 2,52cm/a no primeiro ano, 8,62 ñ 2,81cm/a no segundo e 7,63 ñ 1,84 no terceiro ano de terapêutica. Embora tenha ocorrido importante ganho na idade estatural (deltaIE = 4,9 ñ 1 anos), houve também aceleraçäo significante da idade óssea (deltaIO = 4,3 ñ 1,4 anos), com relaçäo deltaIE/deltaIO de 1,1 ñ 0,2. Como o ganho em altura foi acompanhado de proporcional avanço de IO, a possibilidade de obter altura final normal näo seria alcançada a näo ser que a terapêutica com HCr seja instituída mais precocemente, antes do déficit estatural ser demasiadamente severo, como foi na maioria dos pacientes

[Treatment of growth hormone deficiency patients with authentic recombinant growth hormone]. / Tratamento de pacientes portadores de deficiência de hormônio de crescimento (DHC) com hormônio de crescimento recombinante autêntico.

Eleven growth hormone deficient (GHD) subjects were treated regularly for 3 years with an authentic recombinant growth hormone preparation (0.35 to 0.5U/kg/week). Growth velocity (GV) increased from a mean o 2.91 +/- 1.58cm/year during the 1st year to 8.62 +/- 2.81cm/y in the 2nd and 7.63 +/- 1.84cm/y in the 3th year of follow up. During that period height age (delta HA) increased by 4.9 +/- 1 years while bone age advanced 4.3 +/- 1.4 year (delta BA) resulting in a delta HA/delta BA of 1.1 +/- 0.2. Since the height increment was associated with BA advancement the final height within normal range could not be attained. Thus, GHr therapy should be instituted before the height deficit would became intense as it happened in the majority of our patients. Early diagnosis and therapy of GHD is important, when growth retardation is less severe, in order to allow a better final height.

Long-term treatment of central precocious puberty with a long-acting analogue of luteinizing hormone release hormone (D-Tryp6-GnRH) in monthly injections. Its possible use in normal puberty.

The gonadotropin-releasing-hormone-like agonist D-Tryp6-GnRH (GnRHa) has been shown to induce reversible suppression of gonadotropins and gonadal steroids in patients with central precocious puberty. We examined the effect of a long-acting preparation of GnRHa in biodegradable microcapsules. D-Tryptophane6-GnRH, administered intramuscularly at 1 month intervals, for 12 consecutive months, on growth and skeletal maturation in 3 girls and 4 boys with neurogenic or idiopathic precocious puberty. Suppression of gonadotropin release after GnRH stimulation and gonadal steroids was maintained in all subjects. Growth velocity fell from a mean rate (+/- SEM) or 8.60 +/- 0.75 cm/year before treatment to 5.81 +/- 0.60 cm/year (p < 0.005) after 1 year. Bone age advanced a mean of 8.0 +/- 0.45 months during treatment, suggesting an increase in predicted height from the ratio delta bone age/delta chronological age. Two subjects, one of them with compensated Bartter's syndrome with normal hypothalamic pituitary-gonadal-axis, received the analogue to delay pubertal growth with the hope to improve final height. In the first one, the growth velocity fell from 9.9 cm/year to 8 cm/year and delta bone age/delta chronological age decreased from 1.28 to 1.0 and in the other subject, the growth velocity fell from 12 cm/year to 6.0 cm/year in the last year of treatment and delta bone age/delta chronological age fell from 3.2 to 0.75, indicating an improvement in predicted height.

Insulin resistance in acromegaly: evaluation by studies of insulin binding to erythrocytes.

Insulin binding to erythrocytes (RBC) was evaluated in 10 acromegalic patients (6 females and 4 males) in comparison to 22 normal subjects (12 females and 10 males) in an attempt to study the insulin resistance of acromegaly. Basal glucose from all acromegalic patients were within the normal range but incremental glucose and insulin curves, respectively, on oGTT were significantly increased in the acromegalic patients suggesting an insulin resistant state. Basal growth hormone concentrations were elevated in all acromegalic patients, but no correlation was observed between insulin and GH levels. The insulin binding studies in the acromegalic patients showed a decreased binding due to a reduction in the receptor number per cell but with no alterations in the affinity state. Correction of data for creatine, as a procedure of normalization of binding data for a standardized RBC cell age, enhanced the reduction of insulin binding of the acromegalic patients in comparison to controls in consequence to the younger population of acromegalic RBC as indicated by their increased creatine concentrations. In conclusion, the insulin resistant state in acromegalics observed in our study is accompanied by a decrease in the insulin binding to the RBC receptor due to a reduction of the receptor concentration as mediated by the compensatory hyperinsulinemia.

Erythrocyte insulin receptor: normalization of binding data for the average cell age by the red cell creatine determination in obese, diabetic and acromegalic patients.

Insulin binding studies performed in erythrocytes (RBC) have been employed in clinical studies assessing the status of insulin receptors at target cell tissues. However, some authors challenged this assumption on the basis of some discrepancies described in comparative studies of other cell types, probably related to populations of different cell age affecting insulin binding to RBC. We evaluated insulin binding to RBC in normal males (n = 10), non-obese diabetic males (n = 13), normal females (n = 15), obese (n = 11) and acromegalic females (n = 5), before and after correction of insulin binding data for creatine concentration in the RBC as a procedure of correction for age, since a negative correlation was described between creatine content and RBC age which also correlates inversely with % insulin binding. Insulin binding in all three groups of patients was not statistically different from corresponding values for normal males and females respectively before correction of data for creatine, but significantly reduced values were found after adjustment for creatine in accordance with published data concerning monocytes. In conclusions, the procedure of correcting insulin binding in erythrocytes by the creatine content in RBC is potentially useful for clinical investigations, since the influence of RBC age is excluded.

Role of obesity and hyperinsulinemia in the insulin resistance of obese subjects with the clinical triad of polycystic ovaries, hirsutism and acanthosis nigricans.

The insulin resistance of 4 nonobese and 8 obese patients with polycystic ovaries, hirsutism and benign acanthosis nigricans, and of 6 'obese normal' apart from obesity and 10 normal female subjects was evaluated by means of an intravenous insulin tolerance test and by measuring basal and insulin responses to an oral glucose load. The patients with polycystic ovaries, hirsutism and acanthosis had a decreased hypoglycemic response to exogenous insulin. The subjects with polycystic ovaries presented a significantly greater mean glucose response area for the same or greater mean insulin response area than the obese or nonobese normal subjects. The insulin resistance in the patient with polycystic ovaries, hirsutism and acanthosis nigricans could not be exclusively ascribed to a reduced receptor number, but also appeared to be due to a simultaneous postbinding defect probably related to the high insulin levels in patients with polycystic ovaries be they obese or not. The elevated plasma androgens and the presence of acanthosis found in these patients are likely also related to the hyperinsulinemia. To evaluate the influence of obesity, obese and nonobese patients with acanthosis nigricans and polycystic ovaries were compared. Higher insulin levels were found in the thin subjects, which could explain their greater insulin resistance and more severe hyperandrogenism. The comparison between obese patients with and those without acanthosis nigricans and polycystic ovaries suggested that, despite similar insulin levels, the greater known duration of obesity (probably also of the hyperinsulinemia) of the former was a possible explanation for their more intense insulin resistance and higher testosterone levels.