Mithat Bahceci

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.

Insulin sensitivity and hyperprolactinemia.

It has been shown that prolactin (PRL) induces glucose intolerance, hyperinsulinemia and insulin resistance in several animal species. In women with microprolactinomas, the sensitivity to insulin is lower in hyperprolactinemia than in normoprolactinemia. Thirty non-obese women with hyperprolactinemia and 30 healthy non-obese women were included into the study. Age, body weight (bw), height, body mass index (BMI), waist circumference, hip circumference and waist to hip ratio of both patients with hyperprolactinemia and control sub-jects were not different. Mean serum prolactin level was higher in hyperprolactinemic patients than in control group (84.5±51.1 ng/ml and 13.8±5.3 ng/ml respectively, p<0.002). Mean HOMA-(%B) index of hyperprolactinemic patients was higher than in control subjects (121±49 and 84±38, respectively, p<0.02). Mean HOMA-(%S) index was lower in hyper-prolactinemic patients (56±39 and 105±55, respectively, p<0.006). Serum total testosterone, free testosterone, androstenedione, estradiol, cortisol, sex hormone binding globulin and DHEA-S levels in both hyperprolactinemic women and healthy subjects, statistically did not show any difference between the two groups. The present data indicate that hyperpro-lactinemia is associated with an insulin-resistant state. This resistant state may not be a result of obesity, androgenic hormones, and SHBG or pregnancy. It may be the result of serum free fatty acids (FFA) levels, decrement in the number of insulin receptors (by a down-regulation of insulin receptors) or post-binding defect in insulin action or more.

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.

Is serum C-reactive protein concentration correlated with HbA1c and insulin resistance in Type 2 diabetic men with or without coronary heart disease?

Background and aims: C-reactive protein (CRP) is an inflammatory marker that predicts coronary heart disease (CHD) risk. Diabetes mellitus (DM) counts as a CHD risk equivalent. We aimed to compare serum high sensitivity CRP (hs-CRP) levels in Type 2 diabetic (T2DM) men without CHD, non-diabetic CHD patients and T2DM patients with CHD. Subjects and methods: Four groups were formed; Group 1 [DM(+) CHD(−), no.=25], Group 2 [DM(−), CHD(+) no.=25], Group 3 [DM(+), CHD(+), no.=25], and Group 4 (controls, no.=30). Serum hs-CRP, insulin, glucose, total, HDL-, LDL- and VLDL-cholesterol, triglyceride levels and homeostasis model assessment for insulin resistance (HOMA-IR) index were determined. Results: Mean hs-CRP level of Group 1 (0.6±0.29) was not different statistically from Group 2 (1.44±0.97). Mean hs-CRP levels were higher in men with CHD, whether they were diabetic (Group 3; 3.83±2.01 mg/dl) or non-diabetic (Group 4), than in control subjects (0.16±0.15; p=0.0001 and p<0.004, respectively). Mean hs-CRP level of Group 3 was also higher than Group 2 (p=0.0001). There was a positive correlation between serum hs-CRP and glycated hemoglobin (HbA1c; r=0.277, p<0.01), fasting insulin (r=0.336, p<0.02) and HOMA-IR (r=0.348, p<0.02) in T2DM men with or without CHD. Conclusions: T2DM men without CHD had similar CRP levels with non-diabetic CHD patients, whereas CRP levels of T2DM men with CHD were higher than non-diabetic men with CHD. Because of a positive correlation between serum hs-CRP and HbA1c, fasting insulin and HOMA-IR, inflammation, insulin resistance and hyperglycemia jointly contribute to the cardiovascular risk in T2DM men.

Serum c-reactive protein (CRP) levels and insulin resistance in non-obese women with polycystic ovarian syndrome, and effect of bicalutamide on hirsutism, CRP levels and insulin resistance

Background/Aims: Insulin resistance is associated with serum C-reactive protein (CRP) levels. We aimed to evaluate the effect of bicalutamide on insulin resistance and serum CRP levels in non-obese polycystic ovarian syndrome (PCOS) patients. Methods: 40 non-obese patients (BMI ≤25 kg/m2) with PCOS and, 40 age- and BMI-matched healthy women were studied. Patients received bicalutamide orally at the dose of 25 mg/day. Serum CRP levels were measured with immunometric assay. Homeostasis model assessment (HOMA-IR) index was used for insulin resistance. Results: Mean Ferriman-Gallwey score (FGS) (p = 0.001), insulin (p = 0.001), serum glucose (p = 0.001), prolactin (p < 0.003), total (p < 0.04) and free testosterone (p = 0.001) and free androgen index (FAI) levels (p = 0.001) of PCOS subjects were higher than in the control group. Mean HOMA-IR of PCOS patients was higher than in control subjects (2.43 ± 1.2 and 0.94 ± 0.37, p = 0.001). CRP levels in subjects with PCOS was also higher than in control subjects (4.27 ± 1.33 and 0.98 ± 0.19, p = 0.001). After bicalutamide treatment, FGS, free and total testosterone and FAI decreased (p = 0.001). HOMA-IR, prolactin and CRP levels did not show any statistical difference with bicalutamide treatment. Conclusions: PCOS patients had insulin resistance and a high CRP level. Bicalutamide treatment did not influence insulin resistance and CRP level in PCOS, and this ineffectiveness of bicalutamide on CRP levels may be the result of insulin resistance and/or high prolactin levels at this time.

Is hyperprolactinemia associated with insulin resistance in non-obese patients with polycystic ovary syndrome?

Insulin resistance is common in polycystic ovary syndrome (PCOS). Moderate elevations in serum PRL concentration may contribute to insulin resistance in PCOS. The aim of this study was to determine PRL on development of insulin resistance in non-obese hyperprolactinemic patients with PCOS. Ninety-eight non-obese subjects with PCOS and 100 non-obese healthy control were accepted in the study. Serum glucose, lipids, androgens, free androgen index (FAI), gonadotropins, fat mass and percentage, SHBG, and insulin levels were measured. Homeostasis model assessment (HOMA) was used as index of pancreatic β-cell function and tissue insulin sensitivity. Independent t-test was used in comparison of results. In patients with PCOS, FAI and mean HOMA-(%B) level were higher than in the control group (p<0.0001), whereas mean HOMA-(%S) in subjects with PCOS was lower than in the control group (p<0.0001). Patients with PCOS were divided into subgroups according to their serum prolactin level (<24 or ≥24 ng/ml). Although FAI was not different, mean insulin and HOMA-(%B) levels in hyperprolactinemic patients were higher than in normoprolactinemic subjects (p<0.001). HOMA-(%S) in hyperprolactinemic patients with PCOS was lower than in normoprolactinemic patients (p<0.002). In conclusion, PCOS is associated with insulin resistance; non-obese hyperprolactinemic PCOS patients may be more insulin-resistant than normoprolactinemics and there may be an association between hyperprolactinemia and insulin resistance in PCOS.

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.

The prevalence of non-classic adrenal hyperplasia among Turkish women with hyperandrogenism

The prevalence of non-classic adrenal hyperplasia (NCAH) among Turkish women with hirsutism has not been established so far. Thus, we aimed to evaluate the prevalence of 21-hydroxylase (21-OH) deficiency by ACTH stimulation test among hirsute women. The study population consisted of 285 premenopousal women, aged 16–46 years (mean: 23.2 ± 0.3). All were hirsute and hyperandrogenic. Androgen secreting tumors of the ovaries and the adrenal glands were excluded as well as thyroid dysfunction and hyperprolactinemia. All the patients were evaluated by 0.25 mg (i.v.) ACTH stimulation test and 17-OHP responses were obtained at 30 and 60 min. The diagnosis of NCAH due to 21-OH deficiency was considered in patients with the poststimulation 17-OHP level exceed 10 ng/ml. Six (2.1%) of the patients had NCAH due to 21-OH deficiency confirmed by genotyping. The rest of the patients were polycystic ovary syndrome (n = 166, 58.2%) and idiopathic hyperandrogenemia (n = 113, 39.7%). There were no patients with idiopathic hirsutism because patients with normal serum androgen levels were excluded. This first and most extensive national study investigating NCAH prevalence among Turkish population showed that NCAH is not prevalent in this population.