[The effect of genetic risk of diabetes on the correlations in bone and energy homeostasis]. / A genetikai diabeteskockázat hatása a csontanyagcsere-energia-háztartás kapcsolatokra.

INTRODUCTION: Type 2 diabetes is associated with increased risk of bone fractures, and the connection between bone remodeling and carbohydrate homeostasis is decoupled. It is not known whether these phenomena are the consequence of the deteriorating glucose metabolism, and the increasing insulin resistance or they belong to the genetic risk of type 2 diabetes. AIM: The aim of the authors was to clarify the impact of genetic risk on bone and carbohydrate homeostasis connections. METHOD: Hyperinsulinemic-normoglycemic clamps, and oral and iv. glucose loads were done to select 18 metabolically healthy females with first degree type 2 diabetic relatives -and 26 without diabetic relatives. RESULTS: The connections between total body glucose utilization and the activity of the bone metabolic unit were missing in healthy females with the genetic risk of type 2 diabetes, like in those with manifest diabetes. In this risk group the level of low-density-large molecular sized LDL lipids were decreased, while the high-density LDL group with low molecular size was increased. The latter change was in significant connection with increased interleukin-6 levels and increased bone resorption within the bone metabolic unit. CONCLUSIONS: These data suggest that the missing connection between glucose and bone metabolism is not the consequence of the developing insulin resistance and deteriorating glucose metabolism, but rather it belongs to the inherited diabetes risk. The etiology of this early alteration, which develops prior to glucose intolerance and insulin resistance is unknown and needs further investigations.

[Metabolic alteration in healthy men with first degree type 2 diabetic relatives]. / Anyagcsere-eltérések a 2-es típusú cukorbetegek egészséges, elso fokú férfi rokonaiban.

INTRODUCTION: The recognition of prediabetic patients with the genetic risk of type 2 diabetes is very important as prediabetes is the last stage when manifestation of diabetes could be prevented by life style modification or drug intervention. This suggests the need for diagnostic processes to trace the risk of patients in time. AIMS: The authors looked for metabolic differences between age and BMI in adjusted healthy men with or without first degree type 2 diabetic relatives. METHODS: The study included 73 healthy men (21 with and 52 without) first-degree relatives with type 2 diabetes. RESULTS: Total body and muscle tissue glucose utilization, glucose tolerance did not differ between the two groups, but free fatty acid levels were not suppressed by glucose load in subjects with diabetic relatives. In addition the body fat content, leptin and IL-6 levels were higher, while adiponectin and the free fatty acid/adiponectin ratio were significantly lover in healthy men with diabetic relatives. In this group HDL cholesterol, and the large buoyant LDL fraction were lower whereas the high density LDL - small molecular lipid fraction was higher than those measured in subjects without diabetic relatives. CONCLUSIONS: These data suggest that deteriorations of insulin sensitivity and glucose tolerance is preceded by disturbances of fatty acid metabolism. The observed alteration in free fatty acid/adiponectin ratio, and/or the absence of free fatty acid suppression during glucose tolerance tests could be a screening tool for diabetes risk among men.

[Metabolic differences in healthy first-degree female relatives of type 2 diabetic patients]. / Anyagcsere-eltérések a 2-es típusú cukorbetegek egészséges, elsofokú norokonaiban.

INTRODUCTION: Today the prevalence of type 2 diabetes reached an epidemic level. It is known that type 2 diabetes could only be prevented before the manifestation, during the "prediabetic" state, urging the development of diagnostic tests to recognize the group at risk in time. AIM: The authors explored metabolic differences between healthy, normal glucose tolerant, normal insulin resistant females having first degree relatives with and without type 2 diabetes. METHOD: Healthy, normal insulin sensitive females without (n = 26) and with (n = 18) type 2 diabetic relatives were investigated. RESULTS: Healthy females with first degree diabetic relatives had lower low density lipoproteins and higher high density lipoproteins as well as higher glucose and insulin levels at the 120 min of oral glucose test as compared to those without first degree diabetic relatives. CONCLUSIONS: These results suggest that the appearance of insulin resistance is preceded by hepatic insulin resistance and impaired lipid metabolism in the symptom-free prediabetic period of genetically susceptible females.

[Effects of catalase gene (RS769217) polymorphism on energy homeostasis and bone status are gender specific]. / Nemhez kötött a katalázgén-polimorfizmus (RS769217) hatása az energia-háztartásra és a csontok állapotára.

The pathogenic role of oxidative stress has already been proven both in energy homeostasis and bone metabolism. The effects of +22348C>T (RS769217) polymorphism of catalase (EC 1.11.1.6, hydrogenperoxid-hydrogenperoxid oxidoreduktase) gene were investigated on glucose disposal and bone mineral density in groups of healthy (n = 24) and glucose intolerant (n = 27) females and healthy (n = 64) and glucose intolerant (n = 26) males. Glucose intolerant groups included IFG, IGT and non-treated type 2 diabetic patients. There were no differences in allele frequencies between the genders and groups in this transdanubian Hungarian population. The effects of CAT gene polymorphisms on glucose metabolism and bone status were gender specific. Females with mutant CAT (CT+TT) gene had better HOMA-IR (CC: 2.95+/-1.8 versus CT+TT: 2.06+/-0.9, p<0.05), but bone density did not differ between the CC and CT+TT haplotypes. The homozygote TT females had significantly better whole body glucose disposal. (M-1 mg/kg/min: CC: 9,43+/-4,4 versus TT: 13,23+/-1,6mg/kg body weight/min, p<0.05). The appearance of T allel among males caused lower femur density (CC: 1,11+/-0,17 versus CT+TT: 1,03+/-0,16, p<0.05 g/cm 2 ) and better HOMA-IR (CC: 2.42+/-2.3 versus CT+TT: 1.50+/-0.2, p<0.05), with no change in whole body glucose disposal. Osteocalcin - which has been proven to be the connection between energy homeostasis and bone metabolism - had identical serum levels in both haplotypes, but the significant correlation between muscle tissue glucose utilization and osteocalcin levels (r = +0.4424, p<0.05, n = 23) disappeared in the presence of T allele. Multiple correlation showed significant connection between leptin/adiponectin and femur BMD in CC female group, and between leptin/adiponectin and lumbar BMD in CC male group. The correlations disappeared with the appearance of T allele. Our results differ from the data obtained in Korean postmenopausal women and stress the need of population/ethnic specific replication of genetic data.

[Occurrence of GRB10 (+11275G > A) polymorphism in Hungarian population and its relationship to glucose metabolism]. / A GRB10 gén (+11275G > A) polimorfizmusának hazai elôfordulása és kapcsolata a cukoranyagcserével.

In our backstage experiment with differential display method among the differentially expressed genes we found the gene of GRB10 (Growth factor Receptor-Bound protein 10). The GRB10 protein binds to insulin and insulin-like growth factor receptors and acts as a negative regulatory protein. Besides, GRB10 gene polymorphisms are connected to the development of type 2 diabetes mellitus. In this experiment we investigated the allele frequency of RS 2237457, +11275G > A polymorphism in Hungarian healthy and type 2 diabetic populations (healthy: n = 77, diabetics: n = 85). We also searched for the connections between the genotype and glucose homeostasis measured by hyperinsulinemic - normoglycemic clamps in healthy volunteers (n = 88), glucose intolerant (IFG n = 15; IGT n = 29) and non-treated type 2 diabetic patients (n = 9). We did not find significant differences in allele frequencies between the Hungarian healthy and diabetic populations (healthy: g vs. a: 62% vs. 38%; 2DM g vs. a: 70% vs. 30%). In case of females, glucose utilization did not depend on GRB10 gene polymorphisms. Insulin production after oral glucose load was increased among males with gg alleles, and not after iv. glucose administration. The glucose disposal in muscle tissue was lower and the metabolic clearance rate was also lower calculated either for total body or muscle tissue in this group. In both genders gg alleles were associated with a disadvantageous lipid profile of decreased levels of large, buoyant LDL molecules and HDL levels in females. Metabolic changes related to the polymorphism of GRB10 gene support a gender specific role of this gene in insulin sensitivity and insulin signal transduction. It may be hypothesized on the basis of the differences in insulin release after oral and iv. glucose loads that GRB10 is involved in incretin signaling pathway.

[The role of osteocalcin in the connection of bone and glucose metabolism in humans]. / Az osteocalcin helye a humán cukor- és csontanyagcsere kapcsolatában.

UNLABELLED: The lack of osteoblast derived osteocalcin in mice causes reduced pancreatic beta-cell proliferation, decreased expression of insulin gene and adiponectin gene in adipocytes as well. METHODS: The relationship between insulin sensitivity, osteocalcin and bone state in 45 healthy (20 females, 25 males) and 92 glucose intolerant (51 females, 41 males) subjects was examined. Body composition, bone density, markers of bone resorption and formation as well as glucose uptake (M value for insulin sensitivity) measured by hyperinsulinemic normoglycemic clamp were determined separately in males and females. RESULTS: Osteocalcin levels were similar in the two genders, however, glucose intolerant men had lower osteocalcin levels than healthy men (24.5+/-11 vs. 18.1+/-9 ng/ml, p < 0.05). In the healthy group, we found positive correlation between osteocalcin and muscle M values (females: r = +0.319, p < 0.05, males: r = 0.481, p < 0.01), although this relationship disappeared in the glucose intolerant groups. Osteocalcin did not show correlation with adiponectin level in any of the genders. Based on a multivariate regression analysis, in all females significant independent predictors of osteocalcin level were fasting blood glucose, whole and lean body mass glucose uptake, metabolic clearance rate, estradiol and LDL-cholesterol levels (determined 92% of its value), while in all men these were serum calcium, OGTT glucose area under the curve, free fatty acid levels, insulogenic index, HOMA-R and waist/hip ratio (determined 95% of its value). The BMU index characterizing bone resorption/formation correlated significantly with the M values only in women. CONCLUSION: This study confirmed the relationship between insulin sensitivity and osteocalcin in healthy human population, although basic difference was found between the two genders which was not related to osteocalcin.

Steady-state pharmacokinetics of roflumilast and roflumilast N-oxide in patients with mild and moderate liver cirrhosis.

BACKGROUND: Roflumilast and its primary N-oxide metabolite are targeted phosphodiesterase 4 (PDE4) inhibitors with similar in vivo potency. Roflumilast is being developed for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease and asthma. OBJECTIVE: To investigate the effects of mild and moderate liver cirrhosis on the steady-state pharmacokinetics of roflumilast and roflumilast N-oxide. METHODS: Patients with mild (n = 8, Child-Pugh A) and moderate (n = 8, Child-Pugh B) liver cirrhosis and healthy subjects (n = 8) matched with patients with cirrhosis with regard to sex, age and bodyweight received oral roflumilast 250 microg once daily for 14 days. Blood samples were collected for 24 hours after the last dose on day 14. Steady-state plasma concentrations of roflumilast and roflumilast N-oxide were determined using a validated high-performance liquid chromatography with tandem mass spectrometry assay. The pharmacokinetics were compared between groups using ANOVA. RESULTS: In patients with liver cirrhosis, the average total exposure (area under the plasma concentration-time curve from 0 to 24 hours [AUC(24)]) of roflumilast was approximately 51% (Child-Pugh A) and 92% (Child-Pugh B) higher than in healthy subjects. In contrast, roflumilast maximum plasma concentration (C(max)) was unaltered in Child-Pugh A patients and was increased by 27% in Child-Pugh B patients. Changes in the AUC(24) of roflumilast N-oxide were less distinct, with 24% and 41% increases and corresponding C(max) increases of 26% and 40% in Child-Pugh A and B patients, respectively, compared with healthy subjects. Overall, changes in average potency-corrected exposure to the sum of the free fractions of both compounds were estimated to result in approximately 26% and 46% increases in total PDE4 inhibitory capacity (tPDE4i) in Child-Pugh A and B patients, respectively, relative to healthy subjects. Roflumilast was well tolerated. CONCLUSIONS: Mild and moderate liver cirrhosis resulted in distinct alterations of exposure to roflumilast but only in modest alterations of exposure to roflumilast N-oxide. The integrated exposure-weighted assessment of the observed pharmacokinetic changes of roflumilast and roflumilast N-oxide (tPDE4i) indicates modest average exposure increases to the sum of both compounds. These findings and the favourable tolerability profile suggest that roflumilast can be safely used in patients with mild and moderate liver cirrhosis without special precautions or dose adjustment.

[Effect of progressive insulin resistance on the correlation of glucose metabolism and bone status]. / A progrediáló inzulinrezisztencia hatása a glükózanyagcsere csontállapot kapcsolatokra.

A paradox is hidden in the increasing number of patients with insulin resistance, Type 2 diabetes and osteoporosis, as the world wide diabetes epidemic is driven by the same obesity which protects the bones in the obese females. Our aim was to investigate the connection between the early glucose intolerance, insulin resistance and bone density and metabolism. After metabolic status of matched 20 healthy and 51 glucose intolerant women (age: 49 +/- 9 y.) was determined, hyperinsulinemic-euglycemic clamps were done, while adipo- and cytokine levels were measured. Bone mineral density over lumbar spine and the femur neck were measured by DEXA. No differences in bone density were observed between groups at any sites measured. Tight correlations were found between total body glucose utilization and bone density in healthy group (lumbar spine r = -0.4921, p < 0.05, femur neck: r = -0.4972, p < 0.05), while with deterioration of glucose metabolism this correlation disappeared (lumbar spine: r = -0.022, ns; femur neck: r = -0.3136, ns). The adiponectin was the only adipokine which correlated with lumbar spine density in both groups ( r = -0.5081, p < 0.05; -0.2804, p < 0.05), but not with femur density, where this connection disappeared with glucose intolerance ( r = -0.6742, p < 0.01; -0.1723, ns). Relations of bone metabolic markers indicated that bone resorption decreases with worsening of insulin resistance. In conclusion inverse correlations were found between bone density and glucose metabolism, or insulin sensitivity in healthy women in perimenopause, but this connection disappeared with the deterioration of glucose metabolism and progression of insulin resistance measured by the "gold standard" insulin-glucose clamps. Decreasing insulin sensitivity of bones and escape from "metabolic control" may result in frequently observed hyperdensity in Type 2 diabetics.

[The cognitive effect of alprazolam in healthy volunteers]. / Az alprazolam kognitív funkciókra gyakorolt hatásának vizsgálata egészséges önkénteseken.

Randomised, double blind placebo controlled crossover study has been performed to evaluate the effect of single dose of anxiolytic alprazolam on the cognitive function in 18 healthy male volunteers. The subject received a single dose of 0.75 mg, 1.75 mg alprazolam or placebo in randomised order. Performances on cognitive tests (immediate and delayed word recall test, digit symbol substitution test, critical fusion frequency and multiple choice reaction test) and subjective rating of the drug effect have been evaluated before and at several occasions after the administration of alprazolam or placebo. According to the results of the statistical analysis alprazolam impaired the performance in cognitive tests dose dependently and induced subjective sedation. The applied test battery proved to be capable to measure the effect of the drugs on the cognitive function in pharmacodynamic studies.