Dimitrios Hadjidakis

Studies of insulin resistance in patients with clinical and subclinical hyperthyroidism

OBJECTIVE Although clinical hyperthyroidism (HR) is associated with insulin resistance, the information on insulin action in subclinical hyperthyroidism (SHR) is limited. DESIGN AND METHODS To investigate this, we assessed the sensitivity of glucose metabolism to insulin in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes) in 12 euthyroid subjects (EU), 16 patients with HR, and 10 patients with SHR. RESULTS HR and SHR patients displayed higher postprandial glucose levels (area under the curve, AUC(0)(-)(300) 32,190±1067 and 31,497±716,mg/dl min respectively) versus EU (27,119±1156 mg/dl min, P<0.05). HR but not SHR patients displayed higher postprandial insulin levels (AUC(0)(-)(300) 11,020±985 and 9565±904 mU/l min respectively) compared with EU subjects (AUC(0)(-)(300) 7588±743 mU/l min, P<0.05). Homeostasis model assessment index was increased in HR and SHR patients (2.81±0.3 and 2.43±0.38 respectively) compared with EU subjects (1.27±0.16, P<0.05), while Matsuda and Belfiore indices were decreased in HR (4.21±0.41 and 0.77±0.05 respectively, P<0.001) and SHR patients (4.47±0.33 and 0.85±0.05 respectively, P<0.05 versus EU (7.76±0.87 and 1 respectively). At 100 μU/ml insulin, i) GLUT3 levels on the monocyte plasma membrane were increased in HR (468.8±7 mean fluorescence intensity (MFI)) and SHR patients (522.2±25 MFI) compared with EU subjects (407±18 MFI, P<0.01 and P<0.05 respectively), ii) glucose transport rates in monocytes (increases from baseline) were decreased in HR patients (37.8±5%) versus EU subjects (61.26±10%, P<0.05). CONCLUSIONS Insulin-stimulated glucose transport in isolated monocytes of patients with HR was decreased compared with EU subjects. Insulin resistance was comparable in patients with both HR and SHR.

The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study.

OBJECTIVE The objective of the study was to evaluate the long-term effect of GnRH analog (GnRHa) treatment on final height (FH), body mass index (BMI), body composition, bone mineral density (BMD), and ovarian function. SUBJECTS/METHODS Ninety-two females, evaluated in adulthood, were categorized as follows: group A, 47 girls with idiopathic central precocious puberty (33 GnRHa treated and 14 nontreated); group B, 24 girls with isolated GH deficiency (15 GnRHa and GH treated and nine GH treated); group C, 21 girls with idiopathic short stature (seven GnRHa and GH treated, seven GnRHa treated, and seven nontreated). RESULTS FH, BMD, and percent fat mass of GnRHa-treated patients in all three groups were comparable with those of the respective nontreated subjects. BMI values of GnRHa-treated and nontreated subjects in groups A and C were comparable, whereas in group B, a higher BMI was found in subjects treated only with GH. Nontreated patients with ICPP had greater maximal ovarian volumes, higher LH and LH to FSH ratio, and more severe hirsutism than GnRHa-treated ones. Menstrual cycle characteristics were not different between treated and nontreated subjects. The prevalence of polycystic ovary syndrome in treated and untreated girls with ICPP was comparable, whereas in the entire cohort, it was 11.1% in GnRHa treated and 32.1% in the untreated (P = 0.02). CONCLUSIONS Girls treated in childhood with GnRHa have normal BMI, BMD, body composition, and ovarian function in early adulthood. FH is not increased in girls with ICPP in whom GnRHa was initiated at about 8 yr. There is no evidence that GnRHa treatment predisposes to polycystic ovary syndrome or menstrual irregularities.

Does subclinical hypercortisolism adversely affect the bone mineral density of patients with adrenal incidentalomas

objective Subclinical hypercortisolism (SH) is detected increasingly in a substantial proportion of patients with incidentally discovered adrenal adenomas. The clinical implications of SH are currently unclear. Osteoporosis is a well‐known complication of glucocorticoid excess. So far, the impact of SH on bone mineral density (BMD) has been studied in a limited number of reports with discordant results. In the present study we evaluated the BMD in a large cohort of post‐menopausal women with adrenal incidentalomas.

Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion.

CONTEXT Although adrenal incidentalomas (AIs) are associated with a high prevalence of cardiovascular risk (CVR) factors, it is not clear whether patients with nonfunctioning AI (NFAI) have increased CVR. OBJECTIVE Our objective was to investigate CVR in patients with NFAI. DESIGN AND SETTING This case-control study was performed in a tertiary general hospital. SUBJECTS SUBJECTS included 60 normotensive euglycemic patients with AI and 32 healthy controls (C) with normal adrenal imaging. MAIN OUTCOME MEASURES All participants underwent adrenal imaging, biochemical and hormonal evaluation, and the following investigations: 1) measurement of carotid intima-media thickness (IMT) and flow-mediated dilatation, 2) 2-hour 75-gram oral glucose tolerance test and calculation of insulin resistance indices (homeostasis model assessment, quantitative insulin sensitivity check, and Matsuda indices), 3) iv ACTH stimulation test, 4) low-dose dexamethasone suppression test, and 5) NaCl (0.9%) post-dexamethasone saline infusion test. RESULTS Based on cutoffs obtained from controls, autonomous cortisol secretion was documented in 26 patients (cortisol-secreting AI [CSAI] group), whereas 34 exhibited adequate cortisol and aldosterone suppression (NFAI group). IMT measurements were higher and flow-mediated vasodilatation was lower in the CSAI group compared with both NFAI and C and in the NFAI group compared with C. The homeostasis model assessment index was higher and quantitative insulin sensitivity check index and Matsuda indices were lower in the CSAI and NFAI groups compared with C as well as in CSAI compared with the NFAI group. The area under the curve for cortisol after ACTH stimulation was higher in the CSAI group compared with the NFAI group and C and in the NFAI group compared with C. In the CSAI group, IMT correlated with cortisol, urinary free cortisol, and cortisol after a low-dose dexamethasone suppression test, whereas in the NFAI group, IMT correlated with area under the curve for cortisol after ACTH stimulation and urinary free cortisol. CONCLUSIONS Patients with CSAI without hypertension, diabetes, and/or dyslipidemia exhibit adverse metabolic and CVR factors. In addition, NFAIs are apparently associated with increased insulin resistance and endothelial dysfunction that correlate with subtle but not autonomous cortisol excess.

Bone mineral density of vertebrae, proximal femur and os calcis in normal Greek subjects as assessed by dual‐energy X‐ray absorptiometry: comparison with other populations

Dual energy X‐ray absorptiometry (DXA) is an established method for the detection of even small changes in bone mineral density (BMD). It thus allows the earliest possible diagnosis of osteopenia, with consequent prompt estimation of fracture risk. However, for proper evaluation of densitometry results it is essential that a comparison with reference BMD values of normal age‐ and sex‐matched persons from the same population be performed. For this purpose we determined bone density of the L2–L4 vertebrae, the L3 vertebra in the lateral projection, the proximal femur and the os calcis in a cross‐sectional study of 168 men and 244 women from the Greek population. The age range of the subjects was 20–80 years. Peak bone mass for both sexes was attained in the 30–35 year age group for the vertebrae and in the 25–30 year age group for the proximal femur and os calcis. Mean annual vertebral bone loss calculated on cross‐sectional data ranged from 0.1% to 0.22% for women <50 years and from 1.3% to 1.6% for those >50 years, whereas in men the range was from 0.36% to 0.64% for the whole age spectrum. Regarding femoral neck, the values were 0.3% (women <50 years), 1.2–1.5% (>50 years) and 0.6–0.8% for men. Total bone loss between ages 20 and 70 was 29.5% for the vertebrae and 32% for the femoral neck in women, whereas the values for men were 19.5% and 29% respectively. A positive correlation was observed between bone density, body weight and body height in both sexes. Body mass index correlated significantly with density only in postmenopausal women. Compared with North American, Finnish and German populations, Greek men presented with lower BMD values in the decades above 40 years. Greek women exhibited lower vertebral BMD values than those from the USA, Germany and Japan (50–60 age group), whereas they did not differ from those of Finnish women. However, femoral neck BMD in Greek women was higher than in Japanese women in all age groups.

Insulin resistance and metabolic syndrome in patients with nonfunctioning adrenal incidentalomas: a cause-effect relationship?

The objective of the study was to assess insulin resistance (IR) and metabolic syndrome (MS) in patients with nonfunctioning adrenal incidentalomas (NFAIs). Among a total cohort of 46 patients with adrenal incidentalomas, we studied 29 patients with NFAIs (mean age, 54 ± 9 years; body mass index, 29 ± 3 kg/m(2)) and 37 age-, sex-, and body mass index-matched healthy controls. Besides the endocrine workup, IR was evaluated using fasting glucose and insulin concentrations, homeostasis model assessment of IR, and quantitative insulin sensitivity check index. In a subgroup of patients undergoing an oral glucose tolerance test, Matsuda index and total area under the curve for glucose and insulin were also evaluated. Total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and other biochemical parameters were measured with standard techniques. Body composition was determined with dual-energy x-ray absorptiometry. Patients with NFAIs exhibited higher fasting glucose, insulin, and homeostasis model assessment of IR values; decreased quantitative insulin sensitivity check index and Matsuda index; and an increased-although not statistically significant-area under the curve for glucose and insulin compared with controls (P < .05). In addition, they exhibited higher systolic and diastolic blood pressure, triglycerides, and γ-glutamyltransferase and lower high-density lipoprotein cholesterol levels compared with controls (P < .05). Patients with NFAIs were all obese with a central type of fat accumulation and increased appendicular lean mass. Indices of IR showed a positive correlation with indices of MS (P < .05), but no correlation with markers of hormonal activity. Nonfunctioning adrenal incidentalomas are characterized by IR, hypertension, dyslipidemia, and fatty liver disease, all of them being components of MS. Thus, patients with NFAIs should be screened for MS during their initial workup to identify those at cardiometabolic risk and implement the appropriate interventions.

Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene

INTRODUCTION Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant hereditary disorder, associated with a cluster of germline gain-of-function mutations of the RET proto-oncogene (RET), mainly in exons 10-15. The G533C mutation in exon 8 of the RET is rare and has been mainly related to the familial medullary thyroid carcinoma. PATIENTS-METHODS We describe the RET G533C mutation in exon 8 of the RET in two unrelated female index patients, with MEN2A phenotype, consisting of pheochromocytoma which was the presenting feature and medullary thyroid carcinoma. In addition, 12 family members were also studied. DNA extraction, PCR, and sequencing of RET was performed in exons 7-19 and 21, following standard procedures. RESULTS The mutation was found in both index patients and in 6 out of 12 family members (50%). Three of them were biochemically affected with histologically proven medullary thyroid carcinoma in two of them while there are no certain clues regarding the other three members as they declined further evaluation. CONCLUSION Patients with MEN2A should be also searched in exon 8 while positive carriers of this mutation should be screened annually for pheochromocytoma or other components of the syndrome.

Bone density patterns after normal and premature menopause

OBJECTIVES The investigation of the effect of time and type of menopause on bone mineral density (BMD) at different ages. METHODS Five hundred and fourteen women, who had never received any hormonal substitution were studied in a cross-sectional design: 177 with normal (NMP), 210 with surgical (SUMP) and 127 with premature natural (EMP) menopause. Age at menopause was 49.1+/-3.9, 38.3+/-4.7 and 38.1+/-4.2 years (mean+/-1 S.D.), respectively. BMD was measured at L2-L4 vertebrae and proximal femur by the DEXA method. RESULTS EMP women presented significantly lower vertebral BMD than NMP women in the 45-55-years segments (P<0.001), but did not differ from SUMP women. This group exhibited lower vertebral BMD than NMP between 45 and 50 years (P<0.001). Regarding femoral neck, EMP women exhibited lower values than SUMP in the 45-50 and 55-65 age segments (P<0.001) whereas SUMP women presented significantly higher BMD values than NMP women after 55 years of age (P<0.001). The percentages of women with vertebral BMD (T-score values) in the osteoporotic range were significantly greater in EMP compared with either NMP or SUMP groups (both P<0.001) whereas in femoral neck lower in SUMP than the other two categories. CONCLUSIONS Women with either natural or surgical premature menopause exhibit lower BMD of trabecular bone compared with normal menopause women at the age segments 45-55 and 45-50, respectively. However, surgical menopause women exceed normal menopause women in their mixed bone BMD values after 60 years as well as premature natural menopause women at almost all age segments.

IGF-I increases the recruitment of GLUT4 and GLUT3 glucose transporters on cell surface in hyperthyroidism

OBJECTIVE In hyperthyroidism, tissue glucose disposal is increased to adapt to high energy demand. Our aim was to examine the regulation of glucose transporter (GLUT) isoforms by IGF-I in monocytes from patients with hyperthyroidism. DESIGN AND METHODS Blood (20 ml) was drawn from 21 healthy and 10 hyperthyroid subjects. The abundance of GLUT isoforms on the monocyte plasma membrane was determined in the absence and presence of IGF-I (0.07, 0.14, and 0.7 nM) using flow cytometry. Anti-CD14-phycoerythrin monocional antibody was used for monocyte gating. GLUT isoforms were determined after staining the cells with specific antisera to GLUT3 and GLUT4. RESULTS In monocytes from the euthyroid subjects, IGF-I increased the abundance of GLUT3 and GLUT4 on the monocyte surface by 25 and 21% respectively (P<0.0005 with repeated measures ANOVA). Hyperthyroidism increased the basal monocyte surface GLUT3 and GLUT4; in these cells, IGF-I had a marginal but highly significant effect (P=0.003, with repeated measures ANOVA) on GLUT3 (11%) and GLUT4 (10%) translocation on the plasma membrane. CONCLUSIONS In hyperthyroidism: 1) basal abundance of GLUT3 and GLUT4 on the plasma membrane is increased and 2) the sensitivity of the recruitment of GLUT3 and GLUT4 transporters on the plasma membrane in response to IGF-I is increased. These findings may contribute to the understanding of the mechanism by which hyperthyroidism increases glucose disposal in peripheral tissues.

24-h blood glucose pattern in type I and type II diabetics after oral treatment with pentoxifylline as assessed by artificial endocrine pancreas

SummaryBased on the known action of xanthine derivatives on the insulin secretion, the effect of pentoxifylline on carbohydrate homeostasis of type I (IDDM) and type II (NIDDM) diabetics was investigated. Pentoxifylline is known to exert a favorable influence on hemorheological disturbances in such patients. Twenty-four hour blood glucose pattern and insulin requirements were evaluated in type I and type II diabetics by the use of the artificial pancreas before and after a 14-day treatment with pentoxifylline 400 mg p.o. (Trental 400®) t.i.d. During the stabilization period before treatment with pentoxifylline, NIDDM patients required 10.1±3.8 U of insulin and the IDDM 35±13.7 U. After 2 weeks on pentoxifylline, NIDDM required only 6.3±2.8 U (p<0.05) and IDDM 28.5±9.7 U (n.s.). Average blood glucose during the 24h decreased by 15.8±3.5% in NIDDM and by 10.3±2.5% in IDDM. Moreover, a significant smoothing of glucose fluctuations during the 24h was noted in both groups. It is concluded that pentoxifylline administered concurrently to any antidiabetic type of treatment leads to better blood glucose control as well as to prevention or delay of vascular complications.