The incidence of gestational diabetes mellitus before and after the introduction of HAPO diagnostic criteria.

INTRODUCTION: During the years 2014-2015 new diagnostic criteria for gestational diabetes mellitus (GDM) were gradually adopted by the Czech professional societies, which emerged from the results of the large prospective multicenter HAPO study (The Hyperglycemia and Adverse Pregnancy Outcome). The adoption of the new criteria was accompanied by concerns about the increase in the number of women with GDM. The paper deals with epidemiological results of GDM incidence in the first three years since the introduction of new criteria. METHODS AND RESULTS: In the years 2013-2014 GDM screening was performed at 1,594 pregnant woman at the General Teaching Hospital in Prague. According to that time valid diagnostic criteria (fasting glucose 5.6 mmol/g and/or 8.9 mmol/l in 60 min and/or 7.7 mmol/l in 120 min 75 g OGTT) GDM was found in 324, i.e. 20 % of women. In the years 2016-2018 were 2,629 pregnant women examined. GDM based on the new criteria (fasting blood glucose 5.1 mmol/l and/or 10 mmol/l in 60 min and/or 8.5 mmol/l in 120 min OGTT) was diagnosed in significantly less women - in 375, i.e. 14.3% (p < 0.0001). Overt diabetes, i.e. fasting glucose 7.0 mmol/l and/or 11.1 mmol/l in 120 min OGTT, was newly detected in 6 pregnant women, i.e. 0.2 %. Gestational diabetes was found in 62% cases based on repeated fasting fasting blood glucose and in 38% on the basis of higher blood glucose at 60 min and/or 120 min OGTT. GDM was significantly more prevalent in the age category over 30 years. Among women aged under 25 years GDM was present at 9.9%, aged 25-29.9 years at 9.6%, aged 30-34.9 years at 14.2% and aged 35 years at 18.6 %. Hypoglycaemia < 3.5 mmol/l experienced 2.9% of women during OGTT. When the screening in 2016-2018 was evaluated according to the previous diagnostic criteria, diabetes would be diagnosed in 16.2% of pregnant women. The result of the test would be falsely negative in 6% of all pregnant women, i.e. these women have repeatedly higher fasting glucose (5.1-5.5 mmol/l) according to the current criteria which was evaluated as physiological according to the previous criteria. However, in the HAPO, these values were already associated with a significant increase of complications. A total of 50% of women with GDM diagnosed according to the previous criteria would have a false positive result of OGTT (8.9-9.9 mmol/l in 60 min and/or 7.7-8.4 mmol/l in 120 min OGTT). These values are not considered to be significantly at risk under the new criteria. CONCLUSION: Our data do not confirm the increase in GDM incidence following the introduction of new diagnostic criteria which, according to current knowledge, better reflect the real risks of complications for the child and the mother. Applying the previous criteria has led to a number of false negative and positive results, so we consider the adoption of better-funded new criteria a step in the right direction. The incidence of diabetes was significant in all age categories and significantly increased in women over 30 years of age.

Body composition is associated with bone and glucose metabolism in postmenopausal women with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is associated with increased fracture risk; the underlying mechanism remains unexplained. This study aimed to investigate the relationships between body composition and bone and glucose metabolism in postmenopausal women with T2DM. Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) and body composition. A total of 68 postmenopausal women with T2DM and 71 controls were eligible for the study. In contrast to normal BMD in T2DM, a similar prevalence of low-trauma fractures was observed in both groups. T2DM women had significantly higher Trunk fat% and A/G ratio and significantly lower Legs LM% and Legs FM%. Legs LM% was significantly lower in fractured T2DM group and negatively correlated with glycaemia and HbA1c (p<0.01). Serum osteocalcin was significantly lower in T2DM and inversely correlated with FM%, Trunk FM% and A/G ratio (p<0.01) and positively correlated with Legs FM% and total LM% (p<0.05). In conclusion, abdominal obesity and decrease in muscle mass may contribute to low bone formation in T2DM women. Further research is needed to unravel underlying pathophysiological mechanisms and to determine whether maintenance of muscle mass, especially in the lower extremities and/or reduction of central fat mass can prevent fractures.

Fructosamine 3-kinase and glyoxalase I polymorphisms and their association with soluble RAGE and adhesion molecules in diabetes.

Advanced glycation end-products (AGEs) are key players in pathogenesis of long-term vascular diabetes complications. Several enzymes such as fructosamine 3-kinase (FN3K) and glyoxalase I (GLO I) are crucial in preventing glycation processes. The aim of our study was to evaluate an association of FN3K (rs1056534, rs3848403) and GLO1 rs4746 polymorphisms with parameters of endothelial dysfunction and soluble receptor for AGEs (sRAGE) in 595 diabetic and non-diabetic subjects. Genotypic and allelic frequencies of mentioned polymorphisms did not differ between subgroups. In diabetic patients significant differences were observed in sRAGE concentrations according to their rs1056534 and rs3848403 genotype. While GG and CG genotypes of rs1056534 with mutated G allele were associated with significant decrease of sRAGE (GG: 1055+/-458 and CG: 983+/-363 vs. CC: 1796+/-987 ng/l, p<0.0001), in rs3848403 polymorphism TT genotype with mutated T allele was related with significant sRAGE increase (TT: 1365+/-852 vs. CT: 1016+/-401 and CC: 1087+/-508 ng/l, p=0.05). Significant differences in adhesion molecules were observed in genotype subgroups of GLO1 rs4746 polymorphism. In conclusion, this is the first study describing significant relationship of FN3K (rs1056534) and (rs3848403) polymorphisms with concentration of sRAGE in patients with diabetes.

Skin autofluorescence relates to soluble receptor for advanced glycation end-products and albuminuria in diabetes mellitus.

The aim of this study was to compare skin autofluorescence caused by advanced glycation end-products (AGEs) with biochemical markers of endothelial dysfunction and soluble receptor for AGEs (sRAGE) in patients with diabetes. Skin autofluorescence (AF) assessed by AGE-Reader was evaluated with sRAGE and other biochemical parameters in 88 patients with diabetes (47 Type 1/T1DM/ and 41 Type 2/T2DM/) and 20 controls. Skin AF was significantly higher in T1DM and T2DM in comparison to controls (2.39 ± 0.54, 2.63 ± 0.73 versus 1.96 ± 0.33 AU; P < 0.0001). Positive correlation of AF with sRAGE was detected in T1DM and T2DM (r = 0.37, P < 0.02 and r = 0.60, P < 0.0001), but not in controls. Significantly higher AF values were found in patients with positive albuminuria as compared to those with normal albuminuria. Similarly, higher AF was detected in patients with endothelial dysfunction expressed by vWF, ICAM-1, and VCAM-1. Multiple regression analysis revealed independent association of skin AF with age, sRAGE, and albumin-creatinine ratio in patients with diabetes (R (2) = 0.38). Our study confirms that AF is elevated in patients with diabetes, especially with positive albuminuria and endothelial dysfunction. The strong and independent relationship between AF and sRAGE supports the idea that AF may reflect AGEs/RAGE interactions. The exact mechanism remains to be established.

[Present and future of insulin treatment]. / Soucasnost a perspektivy lécby inzulinem.

The main goal of modern insulin treatment is to bring diabetes control to physiological regulation as close as possible. We move from human insulin to insulin analogues which may due to their properties reduce glucose excursions (glucose variability) with hypoglycemic and hyperglycemic episodes. Besides short acting insulin analogues diminishing extension of hyperinsulinemia and postprandial hypoglycemia observed by human insulin treatment, the long-acting analogues are used to create stabilized insulin level and to prevent nocturnal hypoglycemia. Individualized insulin treatment is the basement for modern trends in diabetology.

Pheochromocytoma and markers of oxidative stress.

High levels of catecholamines in pheochromocytoma (PHEO) are associated with risk of cardiovascular complications. In this study, we looked for potential differences in markers of oxidative stress - vitamin C, superoxide dismutase (SOD) and malondialdehyde (MDA) in PHEO before and after the operation. We studied 18 subjects with PHEO who were examined before and approximately one year after the successful tumor removal (free of disease). All subjects had elevated urinary epinephrine and/or norepinephrine levels before the operation. Vitamin C levels increased significantly after the operation from 61+/-27 to 77+/-20 micromol/l (P=0.02), and MDA decreased significantly after the tumor removal from 2.6+/-0.4 to 2.0+/-0.6 micromol/l (P=0.01). However, no changes were found in SOD activity before and after the operation. In conclusion, increased catecholamine production in PHEO is accompanied by decreased levels of vitamin C and increased levels of MDA which may indicate the activation of oxidative stress in PHEO. Successful operation was associated with lowering of oxidative stress by using both biomarkers. On the contrary, no changes in SOD activity before and after the tumor removal were noted.

Relationship of soluble RAGE and RAGE ligands HMGB1 and EN-RAGE to endothelial dysfunction in type 1 and type 2 diabetes mellitus.

Receptor for advanced glycation end-products (RAGE) plays the essential role in the pathogenesis of diabetic vascular complications. The aim of the study was to compare concentration of soluble RAGE and its ligands (EN-RAGE and HMGB1) with different biochemical parameters in Type 1 (T1DM) and Type 2 (T2DM) diabetes mellitus.Total number of 154 persons (45 T1DM, 68 T2DM, 41 controls) was examined and concentrations of sRAGE, EN-RAGE and HMGB1 were measured and compared to diabetes control, albuminuria, cell adhesion molecules and metalloproteinases (MMPs).Mean serum sRAGE concentration was higher in T1DM as compared to controls (1137±532 ng/l vs. 824±309 ng/l, p<0.01). Similarly, EN-RAGE was significantly higher in both diabetic groups (p<0.001) and HMGB1 concentrations were elevated in T2DM patients (p<0.01). Significant relationship was found between MMP9 and HMGB1 and EN-RAGE in diabetic patients. Inverse relationship was observed between MMP2 and MMP9 in both types of diabetic patients (r= - 0.602, p<0.002 and r= - 0.771, p<0.001). Significant positive correlation was found between sRAGE and ICAM-1, VCAM-1 or vWF (p<0.01 to p<0.001).We conclude that serum sRAGE and RAGE ligands concentrations reflect endothelial dysfunction developing in diabetes.

[A recommended approach to evaluate cardiovascular risk and to prevent cardiovascular diseases and type 2 diabetes mellitus in women with polycystic ovary syndrome]. / Doporucený postup k posouzení kardiovaskulárního rizika a prevenci kardiovaskulárních onemocnení a diabetes mellitus 2. typu u zen se syndromem polycystických ovarií

Polycystic ovary syndrome is one of the most common endocrinopathy in women of fertile age. It is commnoly accompanied by an increased occurence of cardiovascular risk factors. This association led to a consensus statement of Androgen Excess Society for screening of cardiovascular risk factors. We present the recommendations of Czech Endocrine and Czech Diabetological Societies for the screening and primary prevention of cardiovascular diseases and diabetes mellitus.

[Pathogenesis of type 1 and type 2 diabetes in 2011--the unifying model of glucoregulation disorder]. / Patogeneze diabetes mellitus 1. a 2. typu v roce 2011--jednotící model poruchy glykoregulace.

Present knowledge on pathogenic mechanisms in type 1 and type 2 diabetes mellitus may offer the identical scheme of the cascade steps disturbing B-cell and its organells. The only one difference is based in the initiation of the whole cascade by cytokines activated in previous infection (Type 1 DM) or by increased concentration of free fatty acids (Type 2 DM) in the individuals with different genetic background for both types of diabetes. Impaired function and structure of mitochondria causes cell failure and its following apoptosis. The elucidation of the cause of changes in developed diabetes enables to suggest some perspective therapeutic approaches and/or preventive ways.

Glucose and its metabolites have distinct effects on the calcium-induced mitochondrial permeability transition.

Mitochondrial production of reactive oxygen species (ROS) due to up-regulated glucose oxidation is thought to play a crucial, unifying role in the pathogenesis of chronic complications associated with diabetes mellitus. Mitochondrial permeability transition (MPT) is an interesting phenomenon involved in calcium signalling and cell death. We investigated the effects of glucose and several of its metabolites on calcium-induced MPT (measured as mitochondrial swelling) in isolated rat liver mitochondria. The presence of glucose, glucose 1-phosphate (both at 30 mM) or methylglyoxal (6 mM) significantly slowed calcium-induced mitochondrial swelling. Thirty mM glucose also resulted in a significant delay of MPT onset. In contrast, 30 mM fructose 6-phosphate accelerated swelling, whereas glucose 6-phosphate did not influence the MPT. The calcium binding potentials of the three hexose phosphates were tested and found similar. In vitro hydrogen peroxide production by mitochondria respiring on succinate in the presence of rotenone was independent of mitochondrial membrane potential and increased transiently during calcium-induced MPT. Inhibition of MPT with cyclosporine A resulted in decreased mitochondrial ROS production in response to calcium. In contrast, inhibition of MPT by methylglyoxal was accompanied by increased ROS production in response to calcium. In conclusion, we confirm that methylglyoxal is a potent inhibitor of MPT. In addition, high levels of glucose, glucose 1-phosphate and fructose 6-phosphate can also affect MPT. Methylglyoxal simultaneously inhibits MPT and increases mitochondrial ROS production in response to calcium. Our findings provide a novel context for the role of MPT in glucose sensing and the cellular toxicity caused by methylglyoxal.

[Coeliac disease and diabetes]. / Celiakie a diabetes.

Coeliac disease is associated with type 1 diabetes mellitus more than ten times more frequently than it is present in nondiabetic population. It often exists with minimal signs or without them. It may cause different complications if it would remain without treatment. Active screening of coeliac disease and similarly of autoimmune thyreopathy is therefore an integral part of examination in type 1 diabetic patients.

Meal test for glucose-dependent insulinotropic peptide (GIP) in obese and type 2 diabetic patients.

Glucose-dependent insulinotropic peptide (GIP) contributes to incretin effect of insulin secretion which is impaired in Type 2 diabetes mellitus. The aim of this study was to introduce a simple meal test for evaluation of GIP secretion and action and to examine GIP changes in Type 2 diabetic patients. Seventeen Type 2 diabetic patients, 10 obese non-diabetic and 17 non-obese control persons have been examined before and after 30, 60 and 90 min stimulation by meal test. Serum concentrations of insulin, C-peptide and GIP were estimated during the test. Impaired GIP secretion was found in Type 2 diabetic patients as compared with obese non-diabetic and non-obese control persons. The AUCGIP during 90 min of the meal stimulation was significantly lower in diabetic patients than in other two groups (p<0.03). Insulin concentration at 30 min was lower in diabetic than in non-diabetic persons and the GIP action was delayed. The deltaIRI/deltaGIP ratio increased during the test in diabetic patients, whereas it progressively decreased in obese and non-obese control persons. Simple meal test could demonstrate impaired GIP secretion and delayed insulin secretion in Type 2 diabetic patients as compared to obese non-diabetic and non-obese healthy control individuals.

Levels of circulating biomarkers at rest and after exercise in coronary artery disease patients.

As traditional risk factors are unable to fully explain the pathogenesis of coronary artery disease (CAD), novel mechanisms became a target of many investigations. Our aim was to study the response of selected markers to physical exercise. High-sensitive C-reactive protein (hs-CRP), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), advanced oxidation protein products (AOPP), soluble receptor for advanced glycation end-products (sRAGE), pregnancy-associated plasma protein A (PAPP-A), E-selectin, vascular endothelial growth factor (VEGF) and B-type natriuretic peptide (BNP) levels were measured in serum of 21 CAD patients and in 22 healthy controls at rest and after exercise bicycle stress test performed up to the maximal tolerated effort. At rest, hs-CRP, AOPP, MMP-9 and BNP were significantly elevated in the CAD patients as compared with controls. In contrast, P-selectin was significantly lower in CAD patients and a tendency to lower levels of sRAGE was noted. After exercise MMP-9 and BNP, increased significantly in both groups. In conclusions, CAD patients have elevated hs-CRP, AOPP, MMP-9 and BNP--novel markers related to cardiovascular risk or left ventricular overload. MMP-9 and BNP increase significantly with exercise in both healthy individuals and CAD patients.

[Diagnostics and treatment of organic hyperinsulinism--experience in 105 cases]. / Diagnostika a lécba organického hyperinzulinismu--zkusenosti u 105 pacientu.

BACKGROUND: Organic hyperinsulinism causes hypoglycaemia manifesting mainly in the fasting state. We summarize our experience with diagnosis and treatment of 105 patients with organic hyperinsulinism. METHODS AND RESULTS: The diagnosis was confirmed in all patients by spontaneous hypoglycemia and neuroglycopenic symptoms, both developed during fasting test. Endoscopic ultrasonography was the most reliable method for the insulinoma localization (77% of insulinomas confirmed by surgery in the same location within the pancreas), less positive results were obtained by digital subtraction angiography (29%) and still less was found by computed tomography (18%). The localization remains unclear in about 20-25% of insulinomas despite of combined different exploring techniques. Surgical removal of insulinoma by enucleation is the best way of treatment, in some cases laparoscopic removal is a method of choice. From total number of 95 surgically treated patients the successful removal of insulinoma was performed in 84 patients (88%) and another 3 had histopathology diagnosis of micronodular polyadenomatosis. CONCLUSIONS: Insulinoma was not found during surgery and subsequent thorough histopathology investigation of the whole resecate in 8 patients which have to be treated like other non-surgically treated patients by diazoxide together with diabetic diet.

Microvascular Reactivity and Endothelial Function in Type 2 Diabetic Patients with Hyperlipidemia Treated with Simvastatin: 3-year Follow-up.

Aim of this study was to evaluate microvascular reactivity (MVR) by laser Doppler flowmetry in Type 2 diabetes mellitus (T2DM) with hyperlipidemia during three years of simvastatin treatment. Additionally, markers of endothelium and fibrinolysis were evaluated. Twenty patients with T2DM and hyperlipidemia were treated with 20 mg of simvastatin daily for 3 months, treatment was then interrupted for 3 months (wash-out) and again started and maintained continually up to total of 36 months of follow-up. Maximal perfusion (max), velocity of perfusion increase (max/t) and percent increase of perfusion compared to baseline (%) was measured during post-occlusive reactive hyperemia (PORH) and thermal hyperemia (TH). VCAM-1, ICAM-1, E-selectin and P-selectin were used as markers of endothelium, tissue plasminogen activator (tPA) and its inhibitor (PAI-1) as markers of fibrinolysis. Baseline MVR in diabetic patients was comparable to controls. MVR decreased at months 3, 12, and 36 compared to baseline (PORHmax 26+/-12, 35+/-17, 26+/-11 vs. 56+/-30 PU, p<0.05, THmax 67+/-19, 81+/-37, 58+/-24 vs. 134+/-70 PU, p<0.01, PORHmax/t 2.0+/-1.4, 2.8+/-1.7, 1.9+/-1.3 vs. 7.7+/-7.4 PU/s, p<0.05, THmax/t 1.1+/-0.6, 1.0+/-0.4, 0.7+/-0.4 vs. 1.5+/-0.7 PU/s, p<0.05.

[Education in medical specialties in the Czech Republic]. / Specializacní vzdelávání lékaru v Ceské Republice.

This overview describes actual status of education in specialties for physicians, stomatologists and pharmacists who may be trained in ground specialties and subspecialties, as well. Resident positions becoming available just in this year were created as a part of the education system. Final design and stabilization of the whole system structure including financial support is proposed in the future.

Paraoxonase 1 gene polymorphisms and enzyme activities in diabetes mellitus.

Paraoxonase 1 (PON1), an antioxidant enzyme closely associated with HDL (high-density lipoproteins), preserves LDL (low-density lipoproteins) against oxidation. Less protection may be therefore supposed by decreased PON1 activity. This study was undertaken to investigate the association of PON1 gene polymorphisms with diabetic angiopathy and to evaluate the relationship of these polymorphisms with PON1 activity. Total of 86 Type 1 (T1DM) and 246 Type 2 (T2DM) diabetic patients together with 110 healthy subjects were examined. DNA isolated from leukocytes was amplified with polymerase chain reaction (PCR) followed by restriction enzyme digestion. The products were analyzed for L55M and Q192R polymorphisms in coding region and for -107 C/T and -907 G/C in promotor sequence of PON1. Serum enzyme activity was measured spectrophotometrically. Significant differences were found between T1DM or T2DM and control persons in L55M polymorphism (allele M more frequent in T1DM and T2DM vs. controls, p<0.05) and Q192R polymorphism (R allele less frequent in T1DM and T2DM vs. controls, p<0.01) of the PON1 gene. Serum PON1 activity was significantly decreased in T1DM (110+/-68 nmol/ml/min) and T2DM patients (118+/-69 nmol/ml/min) compared to the control persons (203+/-58 nmol/ml/min), both p<0.01. The presence of MM and QQ genotypes was accompanied by lower PON1 activity than of LL and RR genotypes (p<0.05), respectively. Better diabetes control was found in patients with LL than with MM genotypes and similarly in RR genotype than QQ genotype with p<0.05. Significantly different allele frequencies were found in diabetic patients with macroangiopathy than in those without it (M: 0.59 vs. 0.44. R: 0.12 vs. 0.19, p<0.01). The association of PON1 polymorphisms, lower PON1 activity and poorer diabetes control found in patients with macroangiopathy further support the idea of genetic factors contributing to the development of vascular disorders in diabetes.

Impaired microvascular reactivity and endothelial function in patients with Cushing's syndrome: influence of arterial hypertension.

The aim of the study was to evaluate skin microvascular reactivity (MVR) and possible influencing factors (fibrinolysis, oxidative stress, and endothelial function) in patients with Cushing's syndrome. Twenty-nine patients with active Cushing's syndrome (ten of them also examined after a successful operation) and 16 control subjects were studied. Skin MVR was measured by laser Doppler flowmetry during post-occlusive (PORH) and thermal hyperemia (TH). Malondialdehyde and Cu,Zn-superoxide dismutase were used as markers of oxidative stress. Fibrinolysis was estimated by tissue plasminogen activator (tPA) and its inhibitor (PAI-1). N-acetyl-beta-glucosaminidase, E-selectin, P-selectin, and ICAM-1 were used as markers of endothelial function. Oxidative stress and endothelial dysfunction was present in patients with hypercortisolism, however, increased concentration of ICAM-1 was also found in patients after the operation as compared to controls (290.8+/-74.2 vs. 210.9+/-56.3 ng.ml(-1), p<0.05). Maximal perfusion was significantly lower in patients with arterial hypertension during PORH and TH (36.3+/-13.0 vs. 63.3+/-32.4 PU, p<0.01, and 90.4+/-36.6 vs. 159.2+/-95.3 PU, p<0.05, respectively) and similarly the velocity of perfusion increase during PORH and TH was lower (3.2+/-1.5 vs. 5.2+/-3.4 PU.s(-1), p<0.05, and 0.95+/-0.6 vs. 1.8+/-1.1 PU.s(-1), p<0.05, respectively). The most pronounced impairment of microvascular reactivity was present in patients with combination of arterial hypertension and diabetes mellitus.

Influence of PPAR-alpha agonist fenofibrate on insulin sensitivity and selected adipose tissue-derived hormones in obese women with type 2 diabetes.

PPAR-alpha agonists improve insulin sensitivity in rodent models of obesity/insulin resistance, but their effects on insulin sensitivity in humans are less clear. We measured insulin sensitivity by hyperinsulinemic-isoglycemic clamp in 10 obese females with type 2 diabetes before and after three months of treatment with PPAR-alpha agonist fenofibrate and studied the possible role of the changes in endocrine function of adipose tissue in the metabolic effects of fenofibrate. At baseline, body mass index, serum glucose, triglycerides, glycated hemoglobin and atherogenic index were significantly elevated in obese women with type 2 diabetes, while serum HDL cholesterol and adiponectin concentrations were significantly lower than in the control group (n=10). No differences were found in serum resistin levels between obese and control group. Fenofibrate treatment decreased serum triglyceride concentrations, while both blood glucose and glycated hemoglobin increased after three months of fenofibrate administration. Serum adiponectin or resistin concentrations were not significantly affected by fenofibrate treatment. All parameters of insulin sensitivity as measured by hyperinsulinemic-isoglycemic clamp were significantly lower in an obese diabetic group compared to the control group before treatment and were not affected by fenofibrate administration. We conclude that administration of PPAR-alpha agonist fenofibrate for three months did not significantly affect insulin sensitivity or resistin and adiponectin concentrations in obese subjects with type 2 diabetes mellitus. The lack of insulin-sensitizing effects of fenofibrate in humans relative to rodents could be due to a generally lower PPAR-alpha expression in human liver and muscle.