Deniz Gokalp

The correlation between adiposity and adiponectin, tumor necrosis factor α, interleukin-6 and high sensitivity C-reactive protein levels. Is adipocyte size associated with inflammation in adults?

Objective: Hypertrophic obesity correlates with metabolic complications of obesity. We evaluated adipocyte volume and its relationship with tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), adiponectin and high sensitivity C-reactive protein (hs-CRP) levels. Subjects and methods: Patients were divided into 4 groups; lean healthy controls [body mass index (BMI): 24.2±1.4 kg/m2], non-diabetic obese patients (30.2±2.9), obese (30.1 ±3.2) and non-obese (22.2±1.5) Type 2 diabetic patients. TNF-α, hs-CRP, adiponectin and IL-6 levels were measured preoperatively and sc fat specimens were obtained during operation. Semi-thin sections were stained with toluidine-blue and evaluated by light microscopy. Fat volumes were calculated by Goldrick’s formulation. Results: Mean adipocyte volumes were higher in obese diabetic patients than in other groups (p<0.0001). Mean TNF-α, hs-CRP and IL-6 levels were higher in obese diabetic patients than in control subjects, obese non-diabetic and non-obese diabetic patients (p<0.0001, p<0.02 and p<0.01. respectively). Mean TNF-α levels of non-diabetic obese patients were higher than the control group (p<0.05). Mean IL-6 levels of diabetic and non-diabetic obese patients were higher than control subjects (p<0.02 and p<0.0001, respectively). Mean adiponectin levels of control subjects were higher than non-diabetic obese, non-obese diabetic and obese-diabetic subjects (p<0.0001). Mean adiponectin levels of obese diabetic patients were lower than non-diabetic obese subjects (p<0.008). Mean hs-CRP levels were higher in diabetic patients whether they were obese or not. There was a positive correlation between adipocyte size and TNF-α (p<0.01), IL-6 (p<0.03) and hs-CRP levels (p<0.004), and negative correlation between adipocyte size, adiponectin levels (p<0.0001). Conclusions: TNF-α, IL-6 and hs-CRP levels were positively, adiponectin negatively correlated with adipocyte size. Therefore, adiposity may be an inflammatory condition.

The evaluation of endothelial function with flow-mediated dilatation and carotid intima media thickness in young nonobese polycystic ovary syndrom patients; existence of insulin resistance alone may not represent an adequate condition for deterioration of endothelial function

OBJECTIVE To evaluate endothelial function with flow-mediated dilatation (FMD) and carotid intima media thickness (IMT) in young nonobese polycystic ovary syndrome (PCOS) patients. DESIGN Prospective case-control study. SETTING Healthy volunteers and nonobese young PCOS patients in clinical research. PATIENT(S) Thirty-nine PCOS patients with mean age of 22.82 +/- 5.53 years and 30 body mass index- and age-matched healthy controls were evaluated. INTERVENTION(S) Insulin resistance was calculated with area under the curve, quantitative insulin sensitivity check, and the Matsuda index. Endothelial function was assessed with FMD and carotid IMT by ultrasonography. MAIN OUTCOME MEASURE(S) Antropometric, hormonal, biochemical (insulin and glucose, tumor necrosis factor-alpha, hs-c-reactive protein, and homocysteine levels, and so forth), FMD, and IMT were measured. RESULT(S) There was a significant insulin resistance in PCOS patients. Serum FSH, total and free testosterone, cortisol, androstenedione, and DHEA-S levels of PCOS patients were also higher than control subjects, but we could not find any significant difference in terms of endothelial function determined with FMD. CONCLUSION(S) Existence of insulin resistance alone may not be an adequate factor for deterioration of endothelial function and carotid IMT in young, nonobese patients with PCOS. Other factors such as duration of insulin resistance, older age, presence of obesity, and inflammatory markers may play an important role in this process.

Mutations in the Amino-Terminal Region of Proopiomelanocortin (POMC) in Patients with Early-Onset Obesity Impair POMC Sorting to the Regulated Secretory Pathway

CONTEXT Mutations in the proopiomelanocortin (POMC) gene that impair the synthesis or structure of POMC-derived peptides predispose to human obesity. OBJECTIVE Our objective was to identify and characterize novel mutations in the POMC gene found in patients with early-onset obesity. DESIGN AND PATIENTS The POMC gene was screened in 500 patients with severe early-onset obesity. The biosynthesis, processing, sorting, and secretion of wild-type POMC and two newly identified POMC mutants was studied using metabolic labeling, Western blotting, and immunoassay analysis of lysates and conditioned media of transiently transfected beta-TC3 cells. RESULTS Two novel heterozygous missense mutations in POMC (C28F and L37F) were identified in unrelated probands with early-onset obesity and their overweight or obese family members. Both mutations lie in a region of the N terminus of POMC that has been suggested to be involved in its sorting to the regulated secretory pathway. Metabolic labeling studies indicate that whereas the mutations do not reduce intracellular levels of POMC, both mutations (C28F>L37F) impair the ability of POMC to be processed to generate bioactive products. Studies of the secretion of POMC products suggest, particularly with C28F, that the impaired propeptide processing of these mutations results, at least in part, from a mistargeting of mutant POMC to the constitutive rather than the regulated secretory pathway. CONCLUSION These mutations in patients with early-onset obesity represent a novel molecular mechanism of human POMC deficiency whereby naturally occurring mutations in its N-terminal sequence impair the ability of POMC to enter the trafficking pathway in which serial propeptide processing normally occurs.

Insulin Resistance in Type 2 Diabetes Mellitus May Be Related to Bone Mineral Density

The mechanism of bone mineral density (BMD) changes in type 2 diabetes mellitus is not clear. We aimed to investigate the effect of insulin resistance in type 2 diabetics on BMD. Insulin resistance was determined using the homeostasis model assessment index (HOMA-IR). Nineteen type 2 diabetic patients with a HOMA-IR <2.7 (mean age, 51.5±9.6yr; body mass index [BMI], 27.3±5.1kg/m(2); duration of diabetes, 10.5±7.3yr) were included in Group A, and 30 BMI- and age-matched type 2 diabetic patients with a HOMA-IR ≥2.7 were included in Group B. The BMD was measured with dual-energy X-ray absorptiometry. Independent t-test was used for statistical analysis. The Group A values for mean fasting glucose and insulin levels were 160.1±77.0mg/dL and 4.79±2.89μU/L, respectively, whereas the Group B values were 195.1±58.9mg/dL (p>0.05) and 19.30±16.89μU/L (p=0.0001). Significantly higher total lumbar vertebra T-score (p=0.02) and total lumbar vertebra BMD in Group A were determined than Group B (p=0.033). The lumbar vertebra total Z-score was significantly lower in Group B (p=0.042). Marked insulin resistance may have a negative effect on BMD in type 2 diabetics, while the presence of hyperinsulinemia may be associated with the low BMD.

Serum resistin and adiponectin levels in young non-obese women with polycystic ovary syndrome

Introduction. Although polycystic ovary syndrome (PCOS) was described more than half a century ago, the underlying cause of PCOS is still unknown. The aim of our study was to evaluate whether serum resistin and adipocytokine levels alter and its changes relate with low grade inflammation in non-obese young women with PCOS. Subjects and methods. Newly diagnosed 31 young non-obese women with PCOS (mean age 21.8 ± 5.4 years; body mass index (BMI): 23.8 ± 6.6 kg/m2) and 25 BMI- and age-matched, regular-cycling, healthy women (mean age 24.9 ± 5.7 years; BMI: 23.1 ± 5.8 kg/m2) were included the study Anthropometric measurements were evaluated. Resistin, adiponectin, glucose, insulin, hormone profiles, Lipoprotein (Lp)(a), high sensitive C reactive protein (hs-CRP), and homocysteine levels were measured in the beginning of oral glucose tolerance test. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Results. Non-obese young women with PCOS had high adiponectin levels (28.01 ± 6.47 ng/ml in PCOS vs. 23.89 ± 7.70 ng/ml in control subjects, p = 0.034), whereas serum resistin levels were not significantly different compared with healthy controls (14.14 ± 6.6 ng/ml in PCOS vs. 13.78 ± 4.26 ng/ml in control subjects). There were no significant differences between two groups in terms of fasting insulin, Lp(a), homocysteine, and hs-CRP levels. Mean HOMA-IR value of patients with PCOS was similar with control subjects (1.93 ± 0.73 in PCOS; 1.15 ± 0.54 in control group). Conclusions. Resistin levels did not change in non-obese young women with PCOS whereas adiponectin level in non-obese young women with PCOS was significantly higher than control subjects, perhaps, because of no insulin resistance. Circulating resistin levels may not be candidate to play a role in pathogenesis of PCOS without insulin resistance or obesity.

Thyroid and celiac diseases autoantibodies in patients with adult chronic idiopathic thrombocytopenic purpura

The association of chronic idiopathic thrombocytopenic purpura (cITP) and thyroid autoimmune diseases (TAD) is a known but an uncommon condition. Celiac disease (CD), which is characterized by malabsorption and villous atrophy that occur as a consequence of the ingestion of wheat gluten may also be related to other autoimmune disorders. In this study, we investigated the prevalence of thyroid anti-microsomal (TAMA) and anti-thyroglobulin (TATA) auto antibodies, anti-gliadin (AGA) IgG, IgA, anti-endomisium (EMA) IgG and IgA antibodies in 74 patients with cITP and in 162 healthy controls. TATA positivity was found in 29, and TAMA positivity in 19 out of 74 patients; and in 16 and 18 out of 162 controls respectively (p < 0.0001 and p = 0.005, respectively). TAD was diagnosed in 29 of cITP patients. AGA IgG positivity was found in 17, and IgA was present in five out of 74 patients; and AGA IgG was found in 19, and IgA was detected in 4 out of 162 controls (p = 0.032 and p = 0.143, respectively). EMA IgG positivity was found in six out of 74 patients and in nine out of 162 control subjects (p = 0.566). EMA IgA positivity was found in two out of 74 patients and in one out of 162 controls (p = 0.232). We showed that the prevalence of TAD and related autoantibodies are higher in patients with cITP. We suggest that, patients with cITP should be followed up for development of TAD. In addition, all CD related auto antibodies were found to be more frequent in patients with cITP, but only the AGA IgG reached to the clinical significance. None of the CD related auto antibody positive patients developed clinically manifested CD. Large-scale designed studies are needed to clarify the long-term impact and importance of these CD related auto antibodies in patients with cITP.

Sheehan’s syndrome as a rare cause of anaemia secondary to hypopituitarism

Although its exact mechanism is unclear, anaemia is well recognised as a feature of hypopituitarism; and anaemia is associated with Sheehan’s syndrome (SS). We aimed to evaluate the frequency and severity of anaemia and other haematological changes among patients with Sheehan’s syndrome, in comparison with healthy controls. Sixty-five SS patients and 55 age-matched female healthy controls were included. Biochemical and hormonal assessments and haematological evaluations were carried out, and groups were compared. The mean number of red blood cells, as well as mean haemoglobin, iron and erythropoietin levels, total iron-binding capacity and transferrin saturation were all significantly lower in SS patients compared to controls. SS patients had significantly higher rates of anaemia (80.0% vs. 25.5%, p = 0.0001), iron deficiency (44.6% vs. 5.4%, p = 0.001), leukopenia (20.0% vs. 5.4%, p = 0.015), thrombocytopenia (9.2% vs. 0.0%, p = 0.028) and bicytopenia (21.5% vs. 1.8%, p = 0.001) compared to controls. Anaemic SS patients had normochromic-normocytic anaemia (55%) or hypochromic-microcytic anaemia (45%). Anaemia is frequently associated with Sheehan’s syndrome and responds to appropriate replacement therapy. Hypopituitarism should be considered as a possible cause of anaemia, and a hormone examination should be undertaken promptly, particularly in patients with anaemia resistant to therapy and/or with a history suggestive of Sheehan’s syndrome.

Serum tumour necrosis factor‐alpha and interleukin‐8 levels in acromegalic patients: acromegaly may be associated with moderate inflammation

The cause of high cardiovascular risk in acromegaly is unclear, although inflammation may play an important role in the progression of atherosclerosis. 1 Long-term exposure to high levels of GH and IGF-1 may influence cardiovascular risk factors associated with atherosclerosis. We aimed to evaluate inflammatory markers such as high-sensitive C-reactive protein (hs-CRP), homocysteine and cytokine [interleukin (IL)-1 β , IL-2 receptor, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)α ] levels in patients with acromegaly and to determine any possible relationships between these markers and GH/IGF-1 levels. This cross-sectional study was performed in 22 newly diagnosed acromegalic patients [eight females, 14 males, mean age 32·8 ± 11·0 years, range 17–62 years; body mass index (BMI) 28·5 ± 3·4 kg/m 2 ] and 26 age-matched healthy controls (11 females, 15 males, mean age 32·9 ± 12·6 years, range 23–69 years; BMI 26·2 ± 5·3 kg/m 2 ). Diagnosis of acromegaly was made if the GH level of the patient could not be suppressed below 1 μ g/l during a standard oral glucose tolerance test (OGTT) and IGF-1 was elevated. Serum glucose, insulin, GH, IGF-1 and IGFBP-3 were measured just before the beginning of the OGTT. In addition, hs-CRP, homocysteine, TNFα and cytokines (IL-1 β , IL-2 receptor, IL-6, IL-8, IL-10) were measured at baseline. During the OGTT (at 30, 60, 90 and 120 min), the area under the curve for glucose (AUC glu 120) and insulin (AUC ins 120) were calculated. Patients with known coronary heart disease or receiving any medication for cardiovascular disease were excluded. Waist circumference was measured. BMI, body fat mass (FM), fat ratio (F percentage) and fat free mass (kg) were determined by bioelectrical impedance. Insulin resistance was calculated as HOMA-IR (homeostasis model assessment of insulin resistance) by using the formula: fasting insulin ( μ U/l) × fasting glucose (mmol/l)/22·5. Serum TNFα levels were measured by a solid-phase competitive chemiluminescent enzyme immunoassay. IL-8 and GH levels were assessed by a solid-phase, two-site chemiluminescent immunometric assay using an IMMULITE 2000 analyser. Serum IGF-1 levels were measured with a solid-phase, enzyme-labelled chemiluminescent immunometric assay. In the statistical analysis, a nonparametric Mann–Whitney U -test was used for the comparison of groups. Relationships between variables were examined by Pearson’s correlation test. The clinical characteristics of the study population are shown in Table 1. Mean serum TNFα and IL-8 levels were higher in patients with acromegaly, compared to controls (20·3 ± 25·8 vs. 8·3 ± 3·0 ng/l, P = 0·023 and 143·2 ± 255 vs. 79·9 ± 204·1 ng/l, P = 0·012, respectively). hs-CRP, homocysteine, IL-1 β , IL-2R, IL-6, IL-10 levels and HOMA-IR values in patients were similar to those in controls. Mean AUC glu120 was higher in the acromegalic than in the control group (940 ± 272 vs. 661 ± 93 mmol min/l, P = 0·0001) whereas mean AUC ins120 levels were similar (4011 ± 3675 vs. 4027 ± 392 mU min/l, P > 0·05). No correlation was found between TNFα , GH, IGF-1 levels and anthropometrical parameters, nor between serum IL-8, TNFα , GH, IGF-1 and IGFBP-3 levels. There was a positive correlation between TNFα and IL-8 levels ( r = 0·463, P = 0·007). We found higher mean serumTNFα and IL-8 levels in newly diagnosed acromegalic patients compared to control subjects, whereas hs-CRP, homocysteine, IL-1 β , IL-6, IL-8, IL-10 and IL-2 receptor levels were not significantly different from those of the control subjects. These results imply a possible association between acromegaly and inflammation, at least in part. To the best of our knowledge, this is the first study to evaluate TNFα in patients with acromegaly. There are conflicting results on the interaction between TNFα and GH. Bozzola et al . 2 evaluated serum IL-6 and TNFα levels in GH-deficient children and found a significant increase in IL-6 and TNFα levels 6 h after rhGH administration. However, Andiran and Yordam 3 demonstrated a possible inhibitory action of GH on TNFα release after long-term treatment with rhGH. The explanation of such these findings is not straightforward. Both of the abovementioned studies included GH-deficient subjects and all subjects were being treated with replacement dose GH, whereas our patients were acromegalic and were chronically exposed to excess GH. Such chronic exposure may lead to increasing TNFα levels in acromegaly. However, it is well known that GH levels decline with increased Table 1. Anthropometric characteristics, inflammatory cytokine levels and biochemical risk factors for cardiovascular disease in the study population

Hyperthyroidism may affect serum N‐terminal pro‐B‐type natriuretic peptide levels independently of cardiac dysfunction

Background and aim  It is known that NT‐proBNP levels increase in cardiac failure. However, NT‐proBNP levels in different thyroid states are still unclear. We aimed to evaluate serum NT‐proBNP levels in both hyperthyroid and hypothyroid patients without cardiac insufficiency.

Assessment of bleeding disorders in Sheehan's syndrome: are bleeding disorders the underlying cause of Sheehan's syndrome?

Sheehans syndrome (SS) is an adenopituitary insufficiency caused by hypovolemia secondary to excessive blood loss during or after childbirth. However, the mechanism of postpartum hemorrhage and ischemia is not clear. We aimed to evaluate the bleeding disorders among patients with SS, in comparison with healthy controls. In addition, we investigated underlying causes in postpartum hemorrhage that begin the event. The present study was conducted at the Dicle University School of Medicine. Forty-eight patients with SS and 50 age-matched female healthy controls were included. Biochemical and hormonal variables were measured, as was platelet function by means of closure times (PFA-100 testing using collagen plus epinephrine and collagen plus ADP), von Willebrand factor (vWF) level, prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), and coagulation factors. Although PT and INR were significantly higher in patients with SS (both P < 0.01), aPTT and levels of fibrinogen, vWF, and factors II, V, VII, VIII, IX, X, XI, and XII did not differ significantly. Closure times with collagen/epinephrine and collagen/ADP also did not differ significantly between patients with SS and control patients. The nonspecific etiology and presence of excessive postpartum hemorrhage in patients with SS suggest that coagulation disorders may play a role in their predisposition to bleeding. The increased PT and INR noted might implicate bleeding diathesis as the underlying etiology, although no significant decreases were noted in factor levels. Further studies are needed to elucidate this complex mechanism of this disorder.