Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas.

CONTEXT: Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. OBJECTIVE: To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. DESIGN: Retrospective cohort study. PATIENTS: Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. METHODS: Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). RESULTS: In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by -10 cm2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm2 decrease in mean total muscle mass (P = .002). CONCLUSIONS: The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas.

The role of ghrelin, neuropeptide Y and leptin peptides in weight gain after deep brain stimulation for Parkinson's disease.

BACKGROUND: The exact mechanism of weight gain (WG) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with idiopathic Parkinson's disease remains unknown. OBJECTIVES: To investigate a possible involvement of ghrelin, neuropeptide Y (NPY) and leptin in WG after DBS. METHODS: Twenty-three Parkinson patients were submitted for body composition measurements and blood sampling 3 days before, and 3 and 6 months after STN DBS. Peripheral concentrations of ghrelin, NPY, and leptin were determined, as well as the L-dopa equivalent daily dose. Patients were clinically evaluated using the Unified Parkinson's Disease Rating Scale. RESULTS: Three months after surgery, a significant WG was observed (3.09 ± 5.00 kg; p = 0.007) with no further increase at 6 months. Three months postoperatively, NPY circulating levels increased significantly (p = 0.05), while the increase of ghrelin levels reached statistical significance at 6 months (p = 0.001). WG was significantly associated with changes of ghrelin and leptin levels at 3 and 6 months, respectively. CONCLUSIONS: STN DBS seems to temporarily dysregulate the hypothalamic secretion of NPY and ghrelin. The variation of weight may be attributed to an increased production of ghrelin and leptin. A possible neuroprotective role of DBS, exerted through the increase of ghrelin levels, should be further studied.

Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21.

Fibroblast growth factor-21 (FGF21) is a pleiotropic protein involved in glucose, lipid metabolism and energy homeostasis, with main tissues of expression being the liver and adipose tissue. Brown adipose tissue (BAT) is responsible for cold-induced thermogenesis in rodents. The role of FGF21 in BAT biology has not been investigated. In the present study, wild-type C57BL/6J mice as well as a brown adipocyte cell line were used to explore the potential role of cold exposure and ß3-adrenergic stimulation in the expression of FGF21 in BAT. Our results demonstrate that short-term exposure to cold, as well as ß3-adrenergic stimulation, causes a significant induction of FGF21 mRNA levels in BAT, without a concomitant increase in FGF21 plasma levels. This finding opens new routes for the potential use of pharmaceuticals that could induce FGF21 and, hence, activate BAT thermogenesis.

Critical illness-related corticosteroid insufficiency in patients with cirrhosis and variceal bleeding.

BACKGROUND & AIMS: Relative adrenal insufficiency (AI) occurs in patients with cirrhosis with sepsis, but not with variceal bleeding. We evaluated adrenal function in cirrhotic patients with and without bleeding. METHODS: Twenty cirrhotic patients with variceal bleeding were evaluated using the short synacthen test (SST) and 10 using the low-dose synacthen test (LDSST) followed by SST. The control group included 60 stable cirrhotic patients, assessed by LDSST (n = 50) or SST (n = 10), and 14 healthy volunteers. AI was diagnosed using SST, based on peak cortisol levels ≤ 18 µg/dL in nonstressed patients or Δmax <9 µg/dL or a total cortisol level <10 µg/dL in stressed patients with variceal bleeding-the current criteria for critical illness-related corticosteroid insufficiency. Using LDSST, diagnosis was based on peak concentrations of cortisol ≤ 18 µg/dL in nonstressed patients and <25 µg/dL (or Δmax <9 µg/dL) in patients with variceal bleeding. We evaluated patients with levels of serum albumin >2.5 g/dL, to indirectly assess cortisol binding. RESULTS: All healthy volunteers had normal results from LDSSTs and SSTs. Patients with variceal bleeding had higher median baseline concentrations of cortisol (15.4 µg/dL) than stable cirrhotic patients (8.7 µg/dL, P = .001) or healthy volunteers (10.1 µg/dL, P = .01). Patients with variceal bleeding had higher median peak concentrations of cortisol than stable cirrhotic patients (SST results of 32.7 vs 21 µg/dL, P = .001; LDSST results of 9.3 vs 8.1 µg/dL; nonsignificant), with no differences in Δmax in either test. These differences were greater with variceal bleeding than in stable cirrhotic patients with AI. Subanalysis of patients with albumin levels >2.5 g/dL did not change these differences. CONCLUSIONS: Cirrhotic patients with variceal bleeding have AI. Despite higher baseline concentrations of serum cortisol and subnormal Δmax values, they did not have adequate responses to stress, and therefore had critical illness-related corticosteroid insufficiency.

Simvastatin lowers reactive oxygen species level by Nrf2 activation via PI3K/Akt pathway.

The beneficial effects of HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) have been attributed not only to their cholesterol lowering effect but also to their pleiotropic actions and especially to their anti-oxidant activity. Nrf2 (NF-E2-related factor 2) is a transcription factor that orchestrates the transcriptional response of cells to oxidative stressors and electrophilic xenobiotics. In this study, primary mouse embryonic fibroblasts from wild type or Nrf2 knock out C57BL6J mice and ST-2 cells were used to investigate the implication of Nrf2 in the mediation of the anti-oxidant effects of statins and the possible involvement of PI3K/Akt pathway in this process. We show for the first time that simvastatin lowers reactive oxygen species (ROS) by activating Nrf2 through the PI3K/Akt pathway.

EMT Factors and Metabolic Pathways in Cancer.

The epithelial-mesenchymal transition (EMT) represents a biological program during which epithelial cells lose their cell identity and acquire a mesenchymal phenotype. EMT is normally observed during organismal development, wound healing and tissue fibrosis. However, this process can be hijacked by cancer cells and is often associated with resistance to apoptosis, acquisition of tissue invasiveness, cancer stem cell characteristics, and cancer treatment resistance. It is becoming evident that EMT is a complex, multifactorial spectrum, often involving episodic, transient or partial events. Multiple factors have been causally implicated in EMT including transcription factors (e.g., SNAIL, TWIST, ZEB), epigenetic modifications, microRNAs (e.g., miR-200 family) and more recently, long non-coding RNAs. However, the relevance of metabolic pathways in EMT is only recently being recognized. Importantly, alterations in key metabolic pathways affect cancer development and progression. In this review, we report the roles of key EMT factors and describe their interactions and interconnectedness. We introduce metabolic pathways that are involved in EMT, including glycolysis, the TCA cycle, lipid and amino acid metabolism, and characterize the relationship between EMT factors and cancer metabolism. Finally, we present therapeutic opportunities involving EMT, with particular focus on cancer metabolic pathways.

A shift to more targeted thyroidectomies increased the detection of thyroid cancer and in particular low-risk papillary tumors in Southwestern Greece the decade 2007 to 2016.

OBJECTIVES: Data regarding thyroid cancer (TC) epidemiology in Greece in the last decade are scarce, so we investigated the trends in TC detection during 2007 to 2016. METHODS: We retrospectively studied 2040 pathology reports of total thyroidectomies performed at our institution from 2007 to 2016. RESULTS: A number of 478 cases of TC were identified in the studied decade. The overall incidence of TC among thyroidectomies rose over the years. The proportion of papillary T1 tumors among thyroidectomies increased in the second period of our study (2012-2016), while that of papillary T2 to T4 tumors and other TC subtypes remained unchanged. Papillary T1 tumors represented 63.6% of all TC cases and 75.3% of them were low-risk microcarcinomas (papillary thyroid microcarcinoma). The strategy of fine needle aspiration (FNA) prior to surgery in the management of thyroid nodules was adopted by more clinical endocrinologists in the area of Southwestern (SW) Greece in the second period of our study (2012-2016:29.7% vs 2007-2011:18.4%, P < .001). Consequently, the indication for thyroidectomy was set by FNA more frequently in 2012 to 2016 than in 2007 to 2011 (42.5% vs 26.4% of cases, P < .001). CONCLUSIONS: The wider use of FNA in the triage of thyroid nodules led to increased rates of TC in thyroidectomies performed in SW Greece during the decade 2007 to 2016; low-risk, small papillary tumors represented the majority of TC cases.

Vitamin D-related immunomodulation in patients with liver cirrhosis.

OBJECTIVE(S): Increasing evidence indicates that vitamin D status is linked to severity of liver cirrhosis and patients' survival. However, the potential role of vitamin D-related immunomodulation in hepatic decompensation and patients' mortality in relation to vitamin D deficiency remains unknown. The aim of the current study is to evaluate the association between vitamin D status and vitamin D binding protein (VDBP) levels with serum cytokine and lipopolysaccharide binding protein (LBP) and to examine their role on disease severity and cirrhotics' mortality. METHODS: One hundred consecutive Caucasian patients with liver cirrhosis were enrolled in the study. 25(OH)D, VDBP, and LBP concentrations were assessed by ELISA. Cytokine tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), IL-1ß, IL-8, IL-10, and IL-12 levels were determined by Cytometric Bead Array. RESULTS: 25(OH)D levels were inversely correlated with CP score, MELD, IL-6, and CP stage and VDBP levels with CP score, MELD, IL-6, IL-8, LBP, and CP stage. Cirrhotics with 25(OH)D deficiency and severe deficiency had significantly higher CP score, increased IL-6 levels and lower VDBP levels. In the multivariate analysis, the independent prognostic factors associated with patients' survival were CP stage B [hazard ratio = 6.75; 95% confidence interval (CI) 1.32, 34.43; P = 0.022], CP stage C (hazard ratio = 7.39; 95% CI 1.41, 38.81; P = 0.018), the presence of hepatocellular carcinoma (hazard ratio = 4.50; 95% CI 1.54, 13.13; P = 0.006) and 25(OH)D levels (hazard ratio = 0.87; 95% CI 0.80, 0.95; P = 0.002). CONCLUSION: The results show that vitamin D status and VDBP levels are associated with liver cirrhosis severity and patients' mortality, possibly through a proinflammatory immune response.

Simvastatin activates Keap1/Nrf2 signaling in rat liver.

Some of the statins' pleiotropic actions have been attributed to their antioxidant activity. The Nrf2 transcription factor controls the expression of a number of protective genes in response to oxidative stress. In the present study, wistar rats, primary hepatocytes as well as ST2 cells, were employed to explore the potential role of Nrf2 in mediating the reported antioxidant effects of statins. Simvastatin triggered nuclear translocation of Nrf2 in rat liver and in primary rat hepatocytes in a mevalonate-dependent and cholesterol-independent way. In liver, nuclear extracts from simvastatin-treated rats, the DNA-binding activity of Nrf2, was significantly increased and the mRNA of two known targets of Nrf2 (HO-1 and GPX2) was induced. In ST2 cells stably transfected with constructs bearing Nrf2-binding site (antioxidant responsive element), simvastatin enhanced Nrf2-mediated transcriptional activity in a mevalonate-dependent and cholesterol-independent fashion. In conclusion, activation of Keap1/Nrf2 signaling pathway by simvastatin might provide effective protection of the cell from the deleterious effects of oxidative stress.

Glucose levels and insulin secretion in surgery-induced hyperglycemia in normoglycemic obese patients.

BACKGROUND: Transient hyperglycemia is commonly observed in non-diabetic subjects during surgery. We undertook this study to investigate (1) insulin secretion pattern and glucose levels during elective surgery, and (2) the role of pre-operative fasting in the development of surgery-induced hyperglycemia. METHODS: We examined 21 severely obese normal glucose tolerant patients, who underwent bariatric surgery. From the 21 operated subjects, 14 remained fasted while seven patients received 75 g glucose the preoperative night. They sampled at baseline and from the onset of operation frequently for 9 h thereafter, for measuring serum insulin and glucose. RESULTS: Hyperglycemia developed within 1 h from the onset of operation and lasted 9 h. The administration of 75 g glucose the preoperative night prevented surgery-induced hyperglycemia. Insulin profile analyzed by deconvolution analysis was similar between fasted patients and those who received 75 g glucose. Serum insulin was suppressed at the beginning of the surgery and reached baseline values 4 h thereafter. CONCLUSION: Hyperglycemia occurred within 1 h from the beginning of surgery and sustained for at least 9 h while insulin levels are suppressed or unaltered compared to baseline values in euglycemia. The administration of 75 g glucose the preoperative night prevents surgery-induced hyperglycemia without altering the profile of insulin secretion.

The odyssey of nontoxic nodular goiter (NTNG) in Greece under suppression therapy, and after improvement of iodine deficiency.

BACKGROUND: Nontoxic nodular goiter (NTNG) is common in endemic goiter regions. Thyroxine (T4) is often used to treat NTNG. There is little information regarding T4 treatment in regions that have recently become iodine sufficient. We studied the effect of T4 treatment on thyroid function tests in southwestern Greece (SWG), a recently iodine-sufficient area. METHODS: We studied 827 residents of SWG (group A) to determine goiter prevalence, thyroid function, and urinary iodine concentration (UIC). Group B: 385 consecutive patients with thyroid dysfunction. Of these, 89 had NTNG and followed for 10 years on T4 treatment, and 296 had hyperthyroidism. Group C: 29 patients with NTNG, treated with triiodothyronine (T3) 50 mug/day and followed for 6 months. Measurements included serum T4 and 24-hour radioactive iodine uptake (RAIU) before and at the end of T3 administration. RESULTS: The median UIC in group A was 114 microg/L. In group B (89 patients), the incidence of newly diagnosed hyperthyroidism was 5-7% per year with a cumulative percentage of 33% at the 10th year. The initial thyrotropin (TSH) was lower (0.78 +/- 0.51 mIU/L) in those who developed thyrotoxicosis compared to those who remained euthyroid (1.17 +/- 0.74 mIU/L) (p < 0.05). In 296 thyrotoxic patients, the incidence of autoimmune hyperthyroidism and toxic multi-nodular goiter (TMNG) was similar. In group C, 10/29 patients remained euthyroid and the 24-hour RAIU decreased by 49% during T3 treatment. Similarly, serum T4 decreased by 49%. In the remaining patients who developed hyperthyroidism, 24-hour RAIU and T4 were decreased by 19% and 22%, respectively. CONCLUSIONS: In SWG, a recently iodine-sufficient region, the risk of developing hyperthyroidism in patients with NTNG after administration of 100-150 microg T4 is relatively high in those whose serum TSH before T4 treatment is in the lower normal range. Therefore, T4 treatment should be avoided in these patients.

Stress-induced hyperglycemia in patients with severe sepsis: a compromising factor for survival.

OBJECTIVE: To study the clinical and laboratory characteristics of patients with severe sepsis and baseline hyperglycemia and investigate the impact of hyperglycemia on the final outcome. PATIENTS: A total of 265 patients admitted with severe sepsis in 3 major hospitals in South-Western Greece, during a 1-year period, were included in the study. Patients were divided in 3 groups according to their glycemic profile at admission: patients with stress hyperglycemia (group SH, n=47), with diabetes mellitus (group DM, n=65), and with normal glucose level (group NG, n=153). Hyperglycemia was defined as an admission or in-hospital fasting glucose level of >or=126 mg/dL or a random blood glucose level of >or=200 mg/dL on >or=2 determinations. RESULTS: A total of 42.2% of patients with severe sepsis had baseline hyperglycemia with 17.7% having sepsis-induced stress hyperglycemia. No family history was noted in the SH group. A higher percentage of septic patients with stress hyperglycemia died compared with patients with normal glucose levels (42.5% versus 13.7%) and diabetics (42.5% versus 24.6%). Group DM had also a poorer prognosis than group NG (24.6% versus 13.7%). A positive correlation was detected between the fasting blood glucose levels of group SH and the severity of sepsis indicated by sepsis-related organ failure assessment score. CONCLUSION: Baseline hyperglycemia, including stress-induced hyperglycemia, is common in patients with severe sepsis. Stress-induced hyperglycemia is related to a more severe disease and poorer prognosis.

Prognostic significance of vitamin D receptor (VDR) gene polymorphisms in liver cirrhosis.

Several polymorphisms in the vitamin D receptor (VDR) are associated with the occurrence of chronic liver disease. Here, we investigated the association between BsmI, ApaI, TaqI and FokI VDR polymorphisms and the severity of liver cirrhosis in relation to serum cytokine and lipopolysaccharide binding protein (LBP) levels and their role on survival in cirrhotic patients. We found that patients harboring the BB genotype had higher MELD score, and they were mainly at CP stage C; patients harboring the AA genotype had increased LBP, IL-1ß and IL-8 levels, and they were mostly at CP stage C; TT genotype carriers had higher MELD score and they were mainly at CP stage C and FF genotype carriers had lower IL-1ß levels when compared to Bb/bb, Aa/aa, Tt/tt and Ff/ff genotypes respectively. In the multivariate analysis ApaI, BsmI and TaqI polymorphisms were independently associated with liver cirrhosis severity. In the survival analysis, the independent prognostic factors were CP score, MELD and the FF genotype. Our results indicate that the ApaI, TaqI and BsmI polymorphisms are associated with the severity of liver cirrhosis, through the immunoregulatory process. Survival is related to the FF genotype of FokI polymorphism, imparting a possible protective role in liver cirrhosis.

Thyroid function in humans with morbid obesity.

Morbidly obese subjects may present with abnormal thyroid function tests but the reported data are scarce. Therefore, we studied the thyroid parameters in 144 morbidly obese patients, 110 females and 34 males, to assess the prevalence of hypothyroidism. Eleven percent (11.8%) carried the diagnosis of hypothyroidism and were undergoing levothyroxine (LT4) replacement therapy, 7.7% had newly diagnosed subclinical hypothyroidism, 0.7% had subclinical hyperthyroidism and 7.7% were euthyroid with positive antibodies (anti-thyroid peroxidase antibodies [TPOAb]). From the 144 subjects, we selected a cohort of 78 euthyroid subjects with negative TPOAb, who did not receive LT4 replacement or suppression therapy (the experimental group) and compared them to 77 normal-weight euthyroid subjects, TPOA-negative, matched for age and gender who served as controls. The experimental group had higher serum levels of triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and thyrotropin (TSH) compared to the control group. Serum TSH concentration was associated with fasting serum insulin levels and insulin resistance but not with serum leptin levels, body mass index (BMI), fat mass, and lean body mass. In conclusion, in morbidly obese individuals, the prevalence of overt and subclinical hypothyroidism was high (19.5%). The morbidly obese subjects have higher levels of T3, FT3, T4, and TSH, probably the result of the reset of their central thyrostat at higher level.

Fibrocalculous pancreatic diabetes in patient residing in the Mediterranean region.

A 40-year old male residing in the Mediterranean region and afflicted with chronic pancreatitis and diabetes is presented. This is a case of chronic calcific non-alcoholic pancreatitis with characteristic intraductal calculi on abdominal X-ray. Five years following the initial episode of pancreatitis, the patient developed insulin-requiring diabetes mellitus. This case accords with the criteria for fibrocalculous pancreatic diabetes with the unique feature of the patient having been born in Greece and being a resident of Greece.

Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice.

Fibroblast growth factor 21 (Fgf21) is a hormone with emerging beneficial roles in glucose and lipid homeostasis. The interest in Fgf21 as a potential antidiabetic drug and the factors that regulate its production and secretion is growing. Statins are the most widely prescribed drug for the treatment of dyslipidemia. However, the function of statins is not limited to the lowering of cholesterol as they are associated with pleiotropic actions such as antioxidant, anti-inflammatory and cytoprotective effects. The recently described effect of statins on mitochondrial function and the induction of Fgf21 by mitochondrial stress prompted us to investigate the effect of statin treatment on Fgf21 expression in the liver. To this end, C57BL6J male mice and primary mouse hepatocytes were treated with simvastatin, and Fgf21 expression was subsequently assessed by immunoblotting and quantitative real-time PCR. Hepatic Fgf21 protein and mRNA and circulating levels of FGF21significantly decreased in mice that had received simvastatin in their food (0.1% w/w) for 1 week. This effect was also observed with simvastatin doses as low as 0.01% w/w for 1 week or following 2 intraperitoneal injections within a single day. The reduction in Fgf21 mRNA levels was further verified in primary mouse hepatocytes, indicating that the effect of simvastatin is cell autonomous. In conclusion, simvastatin treatment reduced the circulating and hepatic Fgf21 levels and this effect warrants further investigation with reference to its role in metabolism.

Cortisol in tissue and systemic level as a contributing factor to the development of metabolic syndrome in severely obese patients.

CONTEXT: Adrenal and extra-adrenal cortisol production may be involved in the development of metabolic syndrome (MetS). OBJECTIVE: To investigate the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the expression of HSD11B1, nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptors) α (NR3C1α) and ß (NR3C1ß) in the liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of severely obese patients with and without MetS. METHODS: The study included 37 severely obese patients (BMI ≥ 40 kg/m(2)), 19 with MetS (MetS+ group) and 18 without (MetS- group), studied before and during bariatric surgery. Before the day of surgery, urinary free cortisol (UFC) and diurnal variation of serum and salivary cortisol were estimated. During surgery, biopsies of the liver, VAT and SAT were obtained. The expression of HSD11B1, NR3C1α and NR3C1ß was evaluated by RT-PCR. RESULTS: UFC and area under the curve for 24-h profiles of serum and salivary cortisol were lower in the MetS- group. In the MetS- group, mRNA levels of HSD11B1 in liver exhibited a negative correlation with liver NR3C1α (LNR3C1α) and VAT expression of HSD11B1 was lower than the MetS+ group. CONCLUSIONS: We observed a downregulation of the NR3C1α expression and lower VAT mRNA levels of HSD11B1 in the MetS- group, indicating a lower selective tissue cortisol production and action that could protect these patients from the metabolic consequences of obesity. In the MetS- group, a lower activity of the HPA axis was also detected. Taken together, cortisol in tissue and systematic level might play a role in the development of MetS in severely obese patients.

Autonomously functioning thyroid nodules in a former iodine-deficient area commonly harbor gain-of-function mutations in the thyrotropin signaling pathway.

BACKGROUND: Somatic activating mutations of the thyrotropin (thyroid-stimulating hormone (TSH)) receptor (TSHR) and G(alphas) protein have been detected in solitary toxic adenomas and toxic multinodular goiters, but their role in the pathogenesis of autonomous nodules is debated. The frequency of mutations is highly variable among populations and is inversely proportional to iodine intake. DESIGN AND PATIENTS: We screened 28 clinically and histologically heterogeneous autonomous nodules from 24 Greek patients for the presence of TSHR and G(alphas) mutations. RESULTS: By direct sequencing of genomic DNA, we detected 11 somatic heterozygous gain-of-function mutations in TSHR and one in G(alphas). Forty-three percent (12 of 28) of all nodules and 57% (four of seven) of solitary toxic adenomas harbored an activating mutation. Typical adenomas and hyperplastic nodules did not differ in mutation frequency. Substitutions I568T and T632I were detected in both histological types of nodules. CONCLUSIONS: Our findings indicate that activating somatic mutations in the TSH signaling pathway are frequent in autonomous nodules in Greece. This may be due to earlier exposure of the population to iodine deficiency, which was corrected in Greece only over the past two decades. Gain-of-function mutations are shared by nodules with varying histological and clinical presentations. Thus, they may represent a common molecular mechanism underlying the pathogenesis of non-autoimmune thyroid autonomy.

Insulin sensitivity and Lp(alpha) concentrations in normoglycemic offspring of type 2 diabetic parents.

BACKGROUND: Offspring of at least 1 parent with type 2 diabetes are more resistant to the insulin action, exhibit higher incidence of dyslipidemia and are more prone to cardiovascular diseases. The association between Lp(alpha) and coronary heart disease is well established. An association between Lp(alpha) concentration and insulin sensitivity was examined in this study. We investigated the serum LP(alpha) in 41 offspring of 41 families of type 2 diabetic subjects (group I) with normal glucose tolerance, compared to 49 offspring who their parents had no history of type 2 diabetes, matched for sex, age, BMI, WHR and blood pressure (group II). Serum Lp(alpha), triglycerides, insulin resistant index, HDL, LDL-cholesterol and insulin were measured. RESULTS: The offspring of type 2 diabetic subjects had higher fasting serum triglycerides (mean +/- SD 199.3 +/- 184.2 vs. 147.1 +/- 67.9 ng/dl, p < 0.05) lower HDL-cholesterol (37.3 +/- 9.0 vs. 44.6 +/- 7.8, p < 0.001) and particularly higher Insulin resistance Index (HOMA-IR) (2.84 +/- 1.39 vs. 1.67 +/- 0.77, p < 0.001). They also had higher serum LP(alpha) concentration (15.4 +/- 6.7 vs. 8.6 +/- 6.0, p < 0.001). By simple linear analysis in the offspring of type 2 diabetic parents there was no correlation of Lp(alpha) concentration with insulin resistance index Homa-IR (r = 0,016 p = NS). CONCLUSIONS: We conclude that serum LP(alpha) is significantly increased in offspring of type 2 diabetic subjects but was not related to insulin sensitivity.

Relative iron "overload" in offspring of patients with type 2 diabetes mellitus: a new component in the conundrum of insulin resistance syndrome?

There are a few reports suggesting that subtle disturbances of iron metabolism are frequently found in patients with type 2 diabetes (DM2), but it is not known if these disturbances precede or accompany the diabetic state. We investigated the serum iron indices in 41 offspring of DM2 parents (group I) with normal glucose tolerance, and in 49 offspring whose parents had no history of DM2 and were matched for sex, age, body mass index (BMI), waist to hip ratio (WHR) and blood pressure (group II). Serum iron, ferritin, total iron binding capacity (TIBC), transferrin saturation, serum triglycerides, cholesterol, Apo-B, high density lipoprotein (HDL) and glucose and insulin values during an oral glucose tolerance test were measured. Insulin resistance was assessed using the homeostasis model assessment (HOMA - Insuline resistence index-IRI). In comparison to controls (group II), the offspring of DM2 subjects (group I) had higher fasting serum triglycerides (mean +/- SD 2.25+/-2.08 vs. 1.6+/-0.8 mmol/L, p<0,05), lower HDL cholesterol (0.96 +/- 0.2 vs. 1.1 +/- 0.2 mmol/L, p<0.001), higher total cholesterol (5.5 +/- 1.1 vs. 5.1 +/- 0.8 mmol/L, p < 0.05), higher apo-B-lipoprotein (133.2+/-34.3 vs. 125.5+/-30.5 mg/dl, p<0.05), higher LDL-C (3.7 +/- 0.8 vs. 3.2 +/- 0.6 mmol/L), higher gamma-GT (28+/-10 vs. 17+/-5.6 iu/L, p<0.01) higher insulin in the Area Under the Curve (204.7+/-140.8 v. 153.1 +/- 63.0 microU/ml, p<0.05) and higher HOMA-IRI (2.84+/-1.39 vs. 1.67+/-0.77, p<0.001), higher serum ferritin concentrations (98.3+/-57.7 vs. 62.0+/-41.1 ng/ml, p<0.01), higher serum iron concentration (20.2+/-6.0 micromol/L vs. 14.5+/-4.3, p<0.001) and higher transferrin saturation index (31.3+/-8.4 vs. 22.6+/-7.3, p<0.0001). By single linear analysis in the offspring of DM2 parents, there was a positive correlation of IRI with transferrin saturation (r=0.400, p<0.01), fibrinogen (r=0.377, p=0.025) and ferritin concentration (r=0.344, p=0.041), and a negative correlation with TIBC (r=-0.477, p < 0.0001), while stepwise multiple regression analysis, IRI showed a positive correlation with fibrinogen (b=0.64, t=3.746, p<0.001), triglycerides (b=0.37, t=2.619, p<0.01) and ferritin (b=0.20, t=1.827, p=0.05). No correlation of IRI, with any of the above parameters was seen in the offspring of normal parents. By logistic regression analysis the parameters characterizing the offspring of parents with DM2 were IRI (OR 14.9 CI 2.4-91.0) serum iron (OR 44.2 CI 6.9-281), TIBC (OR 6.1 CI 1.01-37.0 and gamma-GT (OR 29.6 CI 5.0-174). In conclusion, the data indicate that the iron load, is significantly increased in offspring of DM2 subjects with unaffected glucose tolerance. Furthermore, ferritin concentration is related to insulin resistance. Hence, the relative iron "overload" in offspring of type 2 diabetics is present along with insulin resistance and might worsen the hepatic insulin insensitivity already present in these patients.