Vitamin D and new insights into pathophysiology of type 2 diabetes.

Deficiency in vitamin D plays a role in the onset and development of insulin resistance (IR) and type 2 diabetes (T2DM). A normal level of vitamin D is able to reduce low grade inflammation, which is a major process in inducing insulin resistance. It is also engaged in maintaining low resting levels of reactive species and radicals, normal Ca2+ signaling, a low expression of pro-inflammatory cytokines but increased formation of anti-inflammatory cytokines. Vitamin D is also able to prevent hypermethylation (of DNA) and consequent functional inactivation of many genes, as well as other epigenetic alterations in ß cells and in other insulin-sensitive peripheral tissues, mainly liver, adipose tissue and muscle. Vitamin D deficiency thus belongs to key factors accelerating the development of IR and consequently T2DM as well. However, vitamin D supplementation aimed at the control of glucose homeostasis in humans showed controversial effects. As a result, further studies are running to gain more detailed data needed for the full clinical utilization of vitamin D supplementation in the prevention and treatment of T2DM. Until new results are published, supplementation with high doses of vitamin D deficiency is not recommended. However, prevention of vitamin D deficiency and its correction are highly desired.

Relations of prediabetes and type 2 diabetes to the thyroid cancer.

OBJECTIVE: Patients with type 2 diabetes (T2DM) generally experience a higher incidence of cancer. However, the association between T2DM and thyroid cancer is inconclusive. METHODS: Case-control prospective study, 722 patients were screened for T2DM and prediabetes (PDM) and underwent thyroid ultrasound and biochemical tests. The patients were assigned to groups of PDM (n=55), T2DM (n=79) or a non-diabetes group (NDM) (n=588). Fine needle aspiration biopsy was carried out in 263 patients. Histological examinations were done for 109 patients after surgery, with findings of 52 benign (BS) and 57 malignant tumors (MS). RESULTS: 33 % of patients with T2DM and especially PDM were newly diagnosed by our screening: 6.5 % with T2DM and 72 % with PDM, respectively. The percentage of thyroid cancers did not significantly differ between the groups (χ2 test=0.461; p=0.794). Relevant positive thyroid predictors for T2DM (t-statistic=25.87; p<0.01) and PDM (21.69; p<0.01) contrary to NDM (-26.9; p<0.01) were thyroid volume (4.79; p<0.01), thyroid nodule volume (3.25; p<0.01) and multinodular thyroid gland (4.83; p<0.01), while negative relevant predictors included the occurrence of autoimmune thyroid disease (AITD) (-2.01; p<0.05). CONCLUSION: In general, we did not observe an increased risk for thyroid cancer in the diabetic and prediabetic groups in comparison to controls, in spite of well-established increased risk for other malignancies. Structural and benign changes such as larger and multinodular thyroid glands, in comparison to autoimmune thyroid disease, are present more often in diabetics.

Acipimox Administration With Exercise Induces a Co-feedback Action of the GH, PP, and PYY on Ghrelin Associated With a Reduction of Peripheral Lipolysis in Bulimic and Healthy-Weight Czech Women: A Randomized Study.

Objective: Anti-lipolytic drugs and exercise are enhancers of growth hormone (GH) secretion. Decreased circulating free fatty acids (FFA) have been proposed to exert ghrelin-GH feedback loop after administration of an anti-lipolytic longer-acting analog of nicotinic acid, Acipimox (OLB, 5-Methylpyrazine-2-carboxylic acid 4-oxide, molecular weight of 154.1 Da). OLB administration strongly suppresses plasma FFA during exercise. Neuroendocrine perturbations of the adipose tissue (AT), gut, and brain peptides may be involved in the etiopathogenesis of eating disorders including bulimia nervosa (BN) and anorexia nervosa. BN is characterized by binge eating, self-induced vomiting or excessive exercise. Approach: To test the hypothesis that treatment with OLB together with exercise vs. exercise alone would induce feedback action of GH, pancreatic polypeptide (PP), peptide tyrosine tyrosine (PYY), and leptin on ghrelin in Czech women with BN and in healthy-weight Czech women (HW). The lipolysis rate (as glycerol release) in subcutaneous abdominal AT was assessed with microdialysis. At an academic medical center, 12 BN and 12 HW (the control group) were randomized to OLB 500 mg 1 h before a single exercise bout (45 min, 2 W/kg of lean body mass [LBM]) once a week vs. identical placebo over a total of 2 weeks. Blood plasma concentrations of GH, PP, PYY, leptin, ghrelin, FFA, glycerol, and concentrations of AT interstitial glycerol were estimated during the test by RIA utilizing 125I-labeled tracer, the electrochemiluminescence technique (ECLIA) or colorimetric kits. Results: OLB administration together with short-term exercise significantly increased plasma GH (P < 0.0001), PP (P < 0.0001), PYY, and leptin concentrations and significantly decreased plasma ghrelin (P < 0.01) concentrations in both groups, whereas short-term exercise with placebo resulted in plasma ghrelin (P < 0.05) decrease exclusively in BN. OLB administration together with short-term exercise significantly lowered local subcutaneous abdominal AT interstitial glycerol (P < 0.0001) to a greater extent in BN. Conclusion: OLB-induced suppression of plasma ghrelin concentrations together with short-term exercise and after the post-exercise recovering phase suggests a potential negative co-feedback of GH, PP, PYY, and leptin on ghrelin secretion to a greater extent in BN. Simultaneously, the exercise-induced elevation in AT interstitial glycerol leading to a higher inhibition of peripheral lipolysis by OLB in BN. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03338387.

[Urinary iodine concentration in adult patients with type 1 diabetes mellitus]. / Jodurie u nemocných s diabetes mellitus 1. typu Vztahy k vybraným parametrum charakterizujícím diabetický syndrom.

INTRODUCTION: In patients with type 1 and 2 diabetes mellitus only rare data concerning the status of iodine supplementation and impact of possible iodine deficiency is available. AIM: To get basic information about (a) state of supply with iodine in patients with type 1 diabetes mellitus (DM1T), (b) the difference from non-diabetic population, (c) possible association of iodine saturation with some clinical and laboratory features of the diabetic syndrome, including the state of thyroid gland. SUBJECTS AND METHODS: We examined 54 men and 51 women treated with DM1T in a cross-sectional study. Age: median 42 years (25th quartil 31, 75th quartil 55), DM1T duration: 18 years (13, 23), BMI: 25.9 (23.3, 29.7), HbA1c: 61 mmol/mol (51, 71), creatinine: 71 µmol/l (61, 83), micro-albuminuria 4.3 µg/min (1.9, 11.8), TSH: 1.77 mIU/l (1.12, 2.80). The iodine saturation was evaluated using iodine concentration in a sample of first morning urine. RESULTS: Urinary iodine concentration in the whole group: median 152 µg/l, 25th quartile 117 µg/l, 75th quartile 219 µg/l. More than 50 % of the urinary iodine samples fell within range of optimal saturation (100-200 µg/l), 13 % within insufficient saturation (< 100 µg/l), 35 % of the samples showed increased saturation (> 200 µg/l), in which 2/3 were men. Using multiple regression analysis we found significant positive association of urinary iodine concentration and male gender, body weight, stature, and serum creatinine. No relation between urinary iodine and clinical and laboratory features of the diabetic syndrome was found. CONCLUSIONS: Iodine saturation in examined patients with DM1T was in accordance with ICCIDD (WHO) requirements for optimal/good saturation in non-diabetic population. With respect to the chosen normal urinary iodine concentration, eg. 100, resp. 150 µg/l the features of diabetic syndrome were not different. The question whether other factors than general measures taken in the past for solution of the iodine deficiency in the Czech Republic are involved in good level of iodine saturation in patients with DM1T should be addressed in further investigations comprising larger cohorts of patients.Key words: diabetes mellitus - urinary iodine concentration.

[Vitamin D and autoimmune thyroid diseases]. / Vitamin D a autoimunitní tyreopatie.

From the recent literature data it may be concluded that vitamin D deficiency is associated with increased risk of thyroid autoimmunity development and thus should be considered as an additional important risk factor for both chronic autoimmune thyroiditis (postpartum thyroiditis including) and Graves´ disease. A higher risk of Graves´ disease development is also associated with several polymorphisms in the gene encoding for vitamin D binding protein and for the specific receptor of active form of vitamin D - 1,25-(OH)2D3 in the respective target cells. Whether careful supplementation with vitamin D aimed to normalize low 25(OH)D levels brings preventive or therapeutic effect is subject to further research.Key words: autoimmune thyroiditis - D vitamin deficiency - D vitamin supplementation - Graves´disease.

[Glucagon antagonists open a new way in treatment of type 2 diabetes Mellitus]. / Antagonisté glukagonu otevírají novou cestu v lécbe diabetu 2. typu.

UNLABELLED: Excessive hepatic glucose production resulting from dysregulated glucagon secretion associated with inappropriate fasting and postprandial hyperglucagonemia is common feature in type 2 diabetes (DM2T). The effects of some currently widely used anti-diabetic agents, especially concerning metformin, GLP1 agonists and inhibitors of DPP4, comprise partial supression of glucagon secretion and/or action. Complete supression of glucagon action is recently widely investigated in experiments, and also results of phase 1 and 2 of the clinical trials are available. The experimental studies proved expected therapeutical potential of this approach. Blockade of glucagon action in diabetic animals resulted in decreased hepatic glucose production, reduction of fasting and prandial hyperglycemia, and improved glucose tolerance. On the other hand, the complete supression of glucagon action is associated with possible risk of pancreatic A-cell hyperplasia, hyperglucagonemia, increased sensitivity to the development of liver steatosis or other liver damage, higher risk of hypoglycemia and other potential side effects. Thus evaluation of safety profile must represent the high priority in the development of new molecules affecting glucagon secretion and intracellular action. A number of molecules antagonising glucagon action were prepared in recent years; some of them are already reviewed successfully in phase 2 of clinical testing; however no molecule is used in clinical practice so far. The presented article briefly sums up contemporary knowledge about glucagon dysregulation in T2DM, and gained experience with pharmacological supression of glucagon action in those patients. Anti-sense oligo-nucleotides, and monoclonal anti-bodies against glucagon and glucagon receptor are mentioned. The glucagon receptor antagonists are discussed in a greater detail as well. KEY WORDS: glucagon antagonism - potential side effects - type 2 diabetes mellitus.

How Does Energy Intake Influence the Levels of Certain Steroids?

The influence of steroid hormones on food intake is well described. However, there are only a few studies on the effect of food intake on steroid levels. The study involved eight non-smoker women (average age 29.48±2.99 years; average BMI 21.3±1.3 kg/m2); they did not use any kind of medication affecting steroidogenesis. We analysed the influence of four various stimuli on the levels of steroid hormones and melatonin. During their follicular phase of menstrual cycle, each woman had an oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), a standard breakfast and psyllium (a non-caloric fibre). Cortisol declined during each test, which is a physiological decline in the morning hours. In all tests (except of the application of the non-caloric fibre, psyllium), however, this decline was modified. After the standard breakfast there was an increase in cortisol at 40th minute. The OGTT and IVGTT tests led to a plateau in cortisol levels. Testosterone levels and those of other steroid hormones showed no relationships to tested stimulations. Oral and intravenous glucose have influenced physiological decline of melatonin levels. During the IVGTT test, melatonin levels started to increase at 20th minute, reaching a maximum at 40th minute. The OGTT test led to a delayed increase in melatonin levels, compared to IVGTT. Despite the fact that we performed the tests in the morning hours, when steroid hormone levels physiologically start to change due to their diurnal rhythm, we still found that food intake influences some of the hormone levels.

How smoking cessation influence hormonal levels in postmenopausal women?

Smoking represents the most widespread substance dependence in the world. Nicotine alters women hormonal homeostasis. Women smokers have higher testosterone and lower estradiol levels throughout life compared to nonsmokers. We monitored the effect of smoking discontinuation on steroid spectrum with 25 postmenopausal women smokers. They had been examined before discontinuation of smoking and after 6, 12, 24 and 48 weeks of abstinence. Blood was collected to determine steroid spectrum (measured by GC-MS), luteinizing hormone, follicle stimulating hormone and sex hormone binding globulin (measured by IRMA). Repeated measures ANOVA model was used for evaluation of the data. In postmenopausal women, an increase in testosterone, dihydrotestosterone, dehydroepiandrosterone and other androgens occurred. Neither nicotine replacement therapy nor weight changes nor age play a role in androgen level increase. The higher androgens levels correlated with failure in smoking cessation. Women smokers have higher androgen levels, which might play a role in smoking dependence development. Women successful in smoking cessation, compared to the non-successful ones, have lower androgen levels initially and also after smoking discontinuation.

The role of "mixed" orexigenic and anorexigenic signals and autoantibodies reacting with appetite-regulating neuropeptides and peptides of the adipose tissue-gut-brain axis: relevance to food intake and nutritional status in patients with anorexia nervosa and bulimia nervosa.

Eating disorders such as anorexia (AN) and bulimia nervosa (BN) are characterized by abnormal eating behavior. The essential aspect of AN is that the individual refuses to maintain a minimal normal body weight. The main features of BN are binge eating and inappropriate compensatory methods to prevent weight gain. The gut-brain-adipose tissue (AT) peptides and neutralizing autoantibodies play an important role in the regulation of eating behavior and growth hormone release. The mechanisms for controlling food intake involve an interplay between gut, brain, and AT. Parasympathetic, sympathetic, and serotoninergic systems are required for communication between brain satiety centre, gut, and AT. These neuronal circuits include neuropeptides ghrelin, neuropeptide Y (NPY), peptide YY (PYY), cholecystokinin (CCK), leptin, putative anorexigen obestatin, monoamines dopamine, norepinephrine (NE), serotonin, and neutralizing autoantibodies. This extensive and detailed report reviews data that demonstrate that hunger-satiety signals play an important role in the pathogenesis of eating disorders. Neuroendocrine dysregulations of the AT-gut-brain axis peptides and neutralizing autoantibodies may result in AN and BN. The circulating autoantibodies can be purified and used as pharmacological tools in AN and BN. Further research is required to investigate the orexigenic/anorexigenic synthetic analogs and monoclonal antibodies for potential treatment of eating disorders in clinical practice.

Short-term exercise combined with Acipimox administration induces an increase in plasma ACTH and its subsequent fall in the recovery phase in bulimic women.

OBJECTIVE: Free fatty acids (FFA)-adrenocorticotropin (ACTH) feedback loop between adipose tissue and the hypothalamic-pituitary centers in the brain has been suggested to be affected by the exercise and by administration of anti-lipolytic drugs. Also leptin may be affected by exercise. Dysfunction of FFA-leptin-ACTH secretion might be involved in binge eating and subsequent purging as is the case in bulimia nervosa (BN). METHODS: In the present single-blind, randomized study, we explored responses of plasma ACTH, leptin and FFA concentrations to exercise (45 min, 2 W/kg of lean body mass [LBM]) with Acipimox (Aci), an anti-lipolytic nicotinic acid analog, or placebo randomly received in nine women with BN and nine healthy women. RESULTS: The exercise with Aci administration resulted in plasma ACTH (p<0.001) and leptin increase higher in BN patients and a decrease in the plasma FFA levels in both groups. The falling of plasma ACTH (p<0.01) levels in the post-exercise recovering phase (90-minute) with Aci administration is more expressed in BN patients. The exercise induced an increase in plasma ACTH (p<0.05) and FFA levels and a decrease in the plasma leptin level in both groups. CONCLUSIONS: We demonstrated that the Aci-induced elevation in plasma ACTH (p<0.001) levels after the exercise higher in BN patients and that the falling of plasma ACTH (p<0.01) levels in the post-exercise recovering phase (90-minute) with Aci administration is suppressed only in BN patients, while Aci increased plasma leptin levels in this recovering phase more in BN patients. Therefore, these observations led us to suggesting that FFA-leptin-ACTH are involved in the dysregulation of neuroendocrine profile in this syndrome and that Aci affects a FFA-independent mechanism. In conclusion, Aci can be considered acceptable in the treatment of eating disorders, and it may also serve as an alternative low-dose dexamethasone suppression test (LDDST) in these patients. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12612000309886.

[Will vitamin D become a new antidiabetic?]. / Stane se vitamin D novým antidiabetikem?

Based on experience from experimental and human studies, vitamin D can be considered an important factor lowering the risk of diabetes mellitus type 1 and 2. The mechanism consists in the direct influence of vitamin D via nuclear receptors on genes coding proteins associated with normal function of B cells of Langerhans islands and genes coding proteins ensuring normal function of the immune system. There is also an indirect influence via regulation of homeostasis of calcium. Clinical observation and cross-sectional studies show an inverse relationship between vitamin D deficiency and appearance of diabetes mellitus type 2. A major deficit of vitamin D in diabetes mellitus type 2 appears to be an independent factor able to predict an increased risk of future cardiovascular mortality. Deficiency in early periods of life was shown to precede autoimmune diabetes mellitus type 1 in an experiment as well as in humans. Prevention of vitamin D deficiency in early as well as later periods of life is a basic pre-requisites of successful preventive measures against diabetes mellitus type 1. Explicit evidence for the significance of the correction of vitamin D deficiency for improvement of metabolic control in diabetics is still missing mainly due to a low number of intervention, placebo-controlled and randomized trials. On the other side, intervention studies often showed positive influence on the conditions accompanying diabetes, such as systolic hypertension or endothelial dysfunction. Unlike in diabetics, the intervention trials showed positive results in non-diabetics with high risk of type 2 diabetes and impaired fasting glycaemia or insulin resistance. One can conclude that existing knowledge already indicate that maintaining the level of 25-hydroxyvitamin D > 30 ng/ml during the year without seasonal variations will be have multiple real as well as potential health benefits. A great promise for clinical practice are the structural analogs of vitamin D tested experimentally, which maintain the influence on the immune system, effect of insulin and B cells function, but have suppressed influence on bone and calcium metabolism.

A higher response of plasma neuropeptide Y, growth hormone, leptin levels and extracellular glycerol levels in subcutaneous abdominal adipose tissue to Acipimox during exercise in patients with bulimia nervosa: single-blind, randomized, microdialysis study.

BACKGROUND: Neuropeptide Y (NPY) is an important central orexigenic hormone predominantly produced by the hypothalamus, and recently found to be secreted in adipose tissue (AT). Acipimox (Aci) inhibits lipolysis in AT and reduces plasma glycerol and free fatty acid (FFA) levels. Exercise and Aci are enhancers of growth hormone (GH) and NPY secretion and exercise may alter leptin levels. We expect to find abnormal neuropeptidergic response in plasma and AT in patients with bulimia nervosa (BN). We hypothesize that Aci influences these peptides via a FFA-independent mechanism and that Aci inhibits lipolysis through a cyclic adenosine monophosphate (cAMP)-dependent pathway. Dysregulations of the AT-brain axis peptides might be involved in binge eating as is the case in BN. METHODS: The objective of this study was to determine the responses of plasma NPY, GH, leptin, FFA and glycerol levels to exercise in BN patients and healthy women (C) given the anti-lipolytic drug Aci or placebo. The secondary objective of this study was to compare the responses of extracellular glycerol levels and plasma glycerol levels to exercise alone or together with Aci administration in BN patients and C women. Extracellular glycerol was measured in vivo in subcutaneous (sc) abdominal AT using microdialysis. Eight BN and eight C women were recruited for this single-blind, randomized study. Aci or placebo was given 1 hour before the exercise (45 min, 2 W/kg of lean body mass [LBM]). NPY, GH, leptin, FFA, glycerol plasma and AT glycerol levels were measured using commercial kits. RESULTS: The primary outcome of this study was that the exercise with Aci administration resulted in plasma NPY and GH increase (after a 45-minute exercise) and leptin (after a 90-minute post-exercise recovering phase) increased more in BN patients. The secondary outcomes of this study were that the exercise with Aci administration induced a higher decrease of extracellular glycerol in BN patients compared to the C group, while the exercise induced a higher increase of glycerol concentrations in sc abdominal AT of BN patients. Plasma glycerol levels decreased more in BN patients and plasma FFA levels were depressed in both groups after the exercise with Aci administration. The exercise induced similar increases in plasma NPY, GH, FFA and glycerol levels, and a similar decrease in the plasma leptin level in both groups. CONCLUSIONS: We confirm the results of a single-blind, randomized, microdialysis study, i.e. that the Aci-induced elevation in plasma NPY and GH levels during the exercise is higher in BN patients and that Aci increased plasma leptin levels in the post-exercise recovering phase (90-minute) more in BN patients. The post-exercise rise (45-minute) in AT glycerol is much more attenuated by acute Aci treatment in BN patients. Simultaneously, we found facilitated turnover of plasma glycerol after the exercise together with Aci administration in BN. Our results support the hypotheses that Aci exerts an effect on the FFA-independent and cAMP-dependent mechanism. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000955910.

Acipimox during exercise points to an inhibitory feedback of GH on ghrelin secretion in bulimic and healthy women.

OBJECTIVE: Ghrelin is predominantly produced by the stomach and the growth hormone (GH)-ghrelin feedback loop between the stomach and the pituitary gland has recently been suggested. The disruption of the gut-brain axis might be involved in bulimia nervosa (BN). METHODS: We investigated responses of plasma GH, ghrelin, and neuropeptide Y (NPY) concentrations to exercise or to exercise after the administration of the antilipolytic drug Acipimox (Aci) in seven BN patients and seven healthy women (C). Aci was administered 1h before exercise (45 min, 2 W/kg of lean body mass/LBM/). Ghrelin, GH, NPY, free fatty acids (FFA) and glycerol plasma levels were measured during the test using commercial kits. RESULTS: The exercise induced an increase in plasma GH, NPY and FFA in both groups and a decrease in plasma ghrelin levels only in BN patients. Exercise after Aci administration resulted in an increase in plasma GH, and a decrease in plasma ghrelin in both groups; NPY increased more in BN patients. Exercise-induced FFA increase was depressed after Aci. CONCLUSIONS: We conclude that the Aci-induced suppression in plasma ghrelin levels during exercise in both groups suggests a negative feedback of GH on ghrelin secretion. Observed changes in plasma FFA levels were not related to changes in GH and ghrelin levels.

[Adrenocortical insufficiency and diabetes mellitus type 1]. / Adrenokortikální insuficience a diabetes mellitus typu 1.

Adrenocortical disorders represents an important problem in patients with type 1 diabetes mellitus and therefore many physicians are concerned with this issue. The causes of adrenocortical insufficiency include both autoimmunity and dysregulation related to insufficiently compensated diabetes. Early diagnosis of hypocorticism remains doubtful. Diagnostic approaches are not standardized or unified and especially their evaluation and interpretation are a matter of discussion. Treatment of proven hypocorticism, notably of the subclinical form in diabetic patients, remains questionable. Modes of substitution used presently cannot mimic fully diurnal rhythm of glucocorticoid secretion in spite of newly developed drug forms. The risk of glucocorticoid overdose persists, and insulinotherapy need to be adjusted permanently.

Adrenocortical function in young adults with diabetes mellitus type 1.

In 75 young adults with diabetes mellitus type 1 (DM 1) we have performed a cross-sectional study to gain more information about their adrenocortical function. We have found in a surprisingly large portion of patients (25%) a subnormal response (<500 nmol/L, low responders) of the serum cortisol during low-dose Synacthen test, accompanied by significantly decreased stimulated values of aldosterone and salivary cortisol. Basal serum cortisol, aldosterone, and dehydroepiandrosterone sulphate (in women only) were significantly reduced in low responders as well, while ACTH, cortisol binding globulin, plasma renin activity, urinary free cortisol/24h, and salivary cortisol did not differ. The results indicate that the disorder of adrenocortical function in low responders occurs in all adrenocortical zones. The patients with the highest risk in respect to revealed hypocorticalism were DM 1 with autoimmune thyroiditis, 13 out of 36 in contrast to 5 out of 39 suffered from isolated form of DM 1, with onset around 30 years, independently on sex. The biorhythm of salivary cortisol in low responders under real-life conditions did not significantly differ from normal responders, except of the decreased values in the morning. Antibodies against 21-hydroxylase and adrenal cortex were negative in the entire group of diabetics studied. In conclusion, this is the first study to demonstrate in as much as 25% of young adults with DM 1 patients without any signs of adrenal autoimmunity decreased both basal and stimulated serum cortisol and aldosterone levels, implying existence of subclinical primary hypocorticalism.

[(TTTTA), polymorphism in the promoter of the CYP11A1 gene in the pathogenesis of polycystic ovary syndrome]. / Promotorový polymorfismus (TTTTA)n genu CYP11A1 v patogenezi syndromu polycystických ovarií.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrinopathy which is characterized by ovarian androgen excess. PCOS has a strong genetic component but the pathogenetic mechanisms responsible for hyperandrogenemia are still unknown. The CYP11A1 encodes the cholesterol side-chain cleavage enzyme that catalyzes the first and rate-limiting step of steroidogenesis. A promoter polymorphism (TTTTA)n CYP11A1 has been reported to be related to the risk of PCOS but the results were controversial. METHODS AND RESULTS: We determined this polymorphism in a cohort of 256 PCOS and 109 healthy control women. Using two models (dominant model for allele with 4 repeats and dominant model for long alleles, i.e. 7 and more repeats) we did not find either the difference in allele and genotype distribution between PCOS and controls or the influence of polymorphism on serum testosterone and androstendione levels. However, the PCOS carriers of long alleles had lower FSH, total- and LDL-cholesterol compared to the carriers of short alleles (p = 0.007; p = 0.02; p = 0.02, ANOVA). In controls, the non-carriers of allele with 4 repeats had significantly higher DHEA-S (p = 0.02, ANOVA) levels than the carriers of allele with 4 repeats. CONCLUSIONS: Despite of some associations found, it seems that the promoter variability of CYP11A1 does not play a key role in the pathogenesis of PCOS.

Impaired glucose metabolism in women with polycystic ovary syndrome.

BACKGROUND: To compare the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in lean and overweight/obese women with polycystic ovary syndrome (PCOS), with the data from a normal population sample. METHODS: PCOS-affected women fulfilling ESHRE diagnostic criteria underwent an oral glucose tolerance test. Prevalence of IGT and T2DM in control sample of white healthy females was extracted from the published data from NHANES II. RESULTS: In 225 women with PCOS, IGT was present in 6/104 (5.8%) lean and in 15/121 (12.4%) overweight/obese women. T2DM was present in 1/104 (1.0%) lean and in 3/121 (2.5%) overweight/obese PCOS women. In a sample of 643 women from NHANES II, the crude rate of IGT was 5.9%. IGT was significantly more common only in the overweight/obese PCOS subgroup as compared to the NHANES II cohort (chi(2) = 5.99, p < 0.01). CONCLUSIONS: IGT was found significantly more frequently only in overweight/obese PCOS subjects in comparison with healthy controls.

Beta cell function and insulin sensitivity in women with polycystic ovary syndrome: influence of the family history of type 2 diabetes mellitus.

AIM: To study the impact of family history (FH) of type 2 diabetes mellitus on beta-cell compensatory mechanism in women with polycystic ovary syndrome (PCOS). SUBJECTS AND METHODS: A total of 70 women with PCOS, 14 with first-degree relative with type 2 diabetes mellitus (T2DM) (FH+), 56 with negative FH of T2DM (FH-) and 72 age and BMI matched control healthy women (CNT) underwent oral glucose tolerance test (OGTT). Insulin resistance was evaluated as oral glucose index (OGIS); insulin and C-peptide secretion as the insulinogenic index in 30th min of OGTT. RESULTS: Fasting blood glucose levels were significantly higher in FH+ than in FH- (p < 0.05). Fasting insulin was higher in FH+ than in CNT (p < 0.05). Fasting C-peptide was significantly higher in both FH- and FH+ than in CNT (p < 0.05 and p < 0.01, respectively). OGIS was lower in FH+ than in FH- or in CNT (p < 0.05). Insulinogenic index calculated from C-peptide values (II-Cp) was lower in FH+ than in CNT (p < 0.05). Adaptation index calculated from the values of OGIS and insulinogenic index was significantly lower in FH+ than in CNT or in FH- (p < 0.0001 and p < 0.01, respectively). CONCLUSIONS: Insulin resistance and defective early-phase insulin secretion is present only in those PCOS-affected subjects who had positive FH of T2DM.

Incretin levels in polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) has been linked to a high risk of type 2 diabetes mellitus. Disturbances in the secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been observed in states with impaired glucose regulation. This paper considers the secretion of GIP and GLP-1 after oral glucose load in a group of lean, glucose-tolerant PCOS women in comparison with age- and body mass index (BMI)-matched healthy women. DESIGN: Case control. METHODS: PCOS (n=21, 25.8+/-4.1 years, BMI 21.6+/-1.7 kg/m(2)) and control healthy women (CT, n=13, 28.5+/-7.2 years, BMI 20.3+/-2.5 kg/m(2)) underwent oral glucose tolerance test (OGTT) with blood sampling for glucose, insulin, C-peptide, total GIP, and active GLP-1. Insulin sensitivity was determined both at fasting and during the test. STATISTICS: Repeated measures ANOVA. RESULTS: Glucose levels and insulin sensitivity did not differ between PCOS and CT. PCOS had significantly higher levels of C-peptide (P<0.05) and tended to have higher insulin levels. The levels of total GIP were significantly higher in PCOS than in CT (P<0.001). Active GLP-1 levels exhibited a significantly different time-dependent pattern in PCOS (P<0.002 for PCOS versus time interaction). GLP-1 concentrations were similar in PCOS and CT in the early phase of OGTT and then reached significantly lower levels in PCOS than in CT at 180 min (P<0.05). CONCLUSIONS: Increased total GIP and lower late phase active GLP-1 concentrations during OGTT characterize PCOS women with higher C-peptide secretion in comparison with healthy controls, and may be the early markers of a pre-diabetic state.