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The role of puberty and normal variations in pubertal timing for the development of obesity in men is unclear. The aim of the current study was to investigate the impact of pubertal timing and prepubertal BMI (kg/m(2)) for young adult BMI and fat mass distribution. Detailed growth charts from birth to age 18-20 years were retrieved for the men participating in the population-based Gothenburg Osteoporosis and Obesity Determinants study. Age at peak height velocity (PHV) and BMI at age 10 years were estimated for 579 subjects, and PHV was used as an assessment of pubertal timing. The fat mass characterization and distribution were analyzed using dual X-ray absorptiometry and peripheral as well as abdominal computed tomography at age 18.9 +/- 0.5 years. We demonstrate that age at PHV is an independent negative predictor of young adult BMI and whole-body fat mass. Interestingly, age at PHV is an independent negative predictor of central, but not peripheral, fat mass. In contrast, BMI at 10 years of age predicts both central and peripheral subcutaneous fat mass. In conclusion, we demonstrate that early pubertal onset specifically predicts a central fat mass distribution, while a predominantly subcutaneous obese phenotype is strongly predicted by a high prepubertal BMI. [ABSTRACT FROM AUTHOR]

Aims To study the effect of exogenous i.m. glucagon on recovery from controlled insulin-induced hypoglycaemia in patients with type 2 diabetes treated with the novel glucokinase activator AZD1656, in combination with metformin. Methods This was a single-centre randomized, open, two-way crossover phase I, automated glucose clamp (Biostator®; Life Science Instruments, Elkhart, MD, USA) study ( NCT00817271) in eight patients (seven men and one woman, mean age 58.6 years, body mass index 28.1 kg/m2). All patients received a stable dose of metformin twice daily, ranging from 1000 to 2250 mg. A 2-day titration phase commenced with 40 mg AZD1656 twice daily, escalating to 80 mg twice daily if tolerated. This was followed by a single dose of 80 or 160 mg AZD1656, administered on days 5 and 8 when metabolic studies were performed. After an overnight fast on days 5 and 8, controlled hypoglycaemia was induced using an exogenous i.v. infusion of insulin. Plasma glucose was lowered in a stepwise fashion over 3 h to attain a target nadir of 2.7 mmol/l. This was sustained for 30 min, at the end of which the hypoglycaemic clamp was released. In random sequence, patients either received an i.m. injection of 1 mg glucagon or were allowed to recover from hypoglycaemia by endogenous counter-regulation. To avoid prolonged hypoglycaemia, a reverse glucose clamp was applied from 4 to 6 h post-dose. Results Three patients received 40 mg AZD1656 twice daily and five patients 80 mg twice daily. Mean plasma glucose at 20 min after release of the hypoglycaemic clamp was significantly lower (3.1 ± 0.3 mmol/l) for AZD1656 alone than for AZD1656 + glucagon (4.9 ± 0.8 mmol/l; p < 0.001 between the groups). Catecholamine and cortisol responses were similar on the AZD1656 + glucagon and AZD alone study days. Growth hormone response was 18% lower for AZD1656 alone (p = 0.01), consistent with the effect of a pharmacological dose of glucagon on growth hormone secretion. No safety or tolerability concerns were observed during treatment with AZ1656. Conclusions Exogenous glucagon was effective as a rescue treatment for hypoglycaemia induced during treatment with AZD1656, given in combination with metformin in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamic effects of the glucokinase activator ( GKA) AZD6370 in non-diabetic subjects, using the euglycaemic clamp to avoid the risk of hypoglycaemia. Methods Oral single ascending doses of AZD6370 10-650 mg or subcutaneous short-acting insulin 4 or 12 U were given to healthy fasting subjects. AZD6370 safety, tolerability and pharmacokinetics were assessed. Pharmacodynamic effects on serum (S)-insulin and glucose infusion rate ( GIR) were investigated with euglycaemic clamp. AZD6370 10-20 mg was also assessed when taken with food without euglycaemic clamp. Results AZD6370 was well tolerated and no safety concerns were raised. AZD6370 was rapidly absorbed and eliminated, and plasma concentration was proportional to dose. Both S-insulin and GIR increased following AZD6370 administration. The observed increase in GIR correlated with increasing AZD6370 area under the plasma concentration vs. time curve, demonstrating a dose-concentration-dependent pharmacodynamic effect. AZD6370 at doses of 50 and 80 mg had similar effects to short-acting insulin 4 U on peripheral S-insulin levels but greater effects on GIR, suggesting an effect beyond the increase of peripheral S-insulin levels at lower doses. In the food interaction part of the study, performed without euglycaemic clamp, dose escalation was stopped at a low dose (20 mg) because of hypoglycaemia. Conclusion The euglycaemic clamp was successfully used to avoid hypoglycaemia and to demonstrate pharmacodynamic effects, that is, markedly increased insulin secretion and glucose utilisation, following administration of AZD6370 in healthy fasting subjects. In addition to the effect on pancreatic insulin secretion, the data support an extra-pancreatic (hepatic) component of GKA action. [ABSTRACT FROM AUTHOR]

Aims: To assess the safety, pharmacokineti'cs and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus (T2DM). Methods: This randomized, single-blind, placebo-controlled, monotherapy study was carried out in two parts. In part A, 32 patients received AZD1656 (7,20, 40 or 80 mg) twice daily or placebo for 8 days in hospital. In part B, another 20 patients received, as outpatients, individually titrated AZD1656 15-45mg twice daily or placebo for 28days. Safety, pharmacokinetics and pharmacodynamic variables were evaluated. Results: AZD16S6 was generally well tolerated. Pharmacokinetics of AZD1656 were virtually dose- and time-independent. AZD1656 was rapidly absorbed and eliminated. An active metabolite was formed which had a longer half-life than AZD1656, but showed ~15% of the area under the plasma concentration versus time curve from 0 to 24 h compared with that of AZD1656. Renal excretion of AZD1656 and the metabolite was low. In part A, fasting plasma glucose (FPG) was reduced by up to 21% and mean 24-h plasma glucose was reduced by up to 24% with AZD1656 versus placebo, depending on dose. No dose-related changes in serum insulin or C-peptide were observed with AZD1656 at the end of treatment. Results in part B confirmed the glucose-lowering effect of AZD1656 versus placebo. Conclusions: AZD1656 was well tolerated with predictable pharmacokinetics in patients with T2DM. Dose-dependent reductions in plasma glucose were observed. [ABSTRACT FROM AUTHOR]

Objective Vaginal estradiol is considered contraindicated in aromatase inhibitor (AI)-treated patients because of the risk of elevated estrogen levels. This leaves limited treatment options for patients experiencing gynecological symptoms. However, in clinical practice, no precise estimation has been performed of circulating estrogens and aromatase index in postmenopausal breast cancer patients on long-lasting AI or tamoxifen treatment. Methods Steroid hormones were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) and extraction radioimmunoassay (RIA). Postmenopausal AI-treated patients ( n =33) were compared with tamoxifen-treated patients ( n =34) and controls without vaginal treatment ( n =56), with vaginal estradiol ( n =25), or with estriol ( n =11) treatment. Results By use of LC-MS/MS, median (range) estradiol plasma concentrations were 16.7 (2.4-162.6), 31.0 (13.4-77.1), 27.2 (7.8-115.8) and 33.3 (20.3-340.1) pmol/l in AI-treated breast cancer patients, tamoxifen-treated breast cancer patients, postmenopausal controls and postmenopausal controls on vaginal estradiol, respectively. The AI-treated group and subgroups had significantly lower estradiol and estrone concentrations than all other groups ( p <0.05). There was extensive interindividual variation in estradiol concentration within the AI-treated group, measured using both LC-MS/MS (2.3-182.0 pmol/l) and extraction RIA (2.4-162.6 pmol/l). The AI-treated group had lower aromatase index compared to all other groups ( p <0.05-0.001). Conclusion Circulating estrogen levels may have been underestimated in previous longitudinal studies of AI-treated breast cancer patients. Additional studies are required to further evaluate the role of circulating estrogens in breast cancer patients suffering from gynecological symptoms. [ABSTRACT FROM AUTHOR]

Objective: The amount of visceral adipose tissue is a risk factor for the metabolic syndrome. It is unclear how BMI changes during childhood and adolescence predict adult fat distribution. We hypothesized that there are critical periods during development for the prediction of adult subcutaneous and visceral fat mass by BMI changes during childhood and adolescence.Research Design and Methods: Detailed growth charts were retrieved for the men participating in the population-based Gothenburg Osteoporosis and Obesity Determinants (GOOD) Study (n = 612). Body composition was analyzed using dual-energy X-ray absorptiometry and adipose tissue areas using abdominal computed tomography at 18 to 20 years of age.Results: The main finding in the present study was that subjects with increases in BMI Z score of more than 1 SD during adolescence had, independent of prepubertal BMI, both larger subcutaneous (+138%; P < 0.001) and visceral adipose tissue areas (+91%; P < 0.001) than subjects with unchanged BMI Z-score. In contrast, subjects with increases in BMI Z score of more than 1 SD during late childhood had a larger amount of adult subcutaneous adipose tissue (+83%; P < 0.001) than subjects with unchanged BMI Z score but an unaffected amount of visceral adipose tissue. BMI changes during adolescence predict both visceral and subcutaneous adipose tissue of the abdomen, whereas BMI changes during late childhood predict only the subcutaneous adipose tissue.Conclusions: The amount of visceral adipose tissue in young adult men was associated with BMI changes specifically during adolescence, whereas the amount of subcutaneous adipose tissue was associated with BMI changes during both late childhood and adolescence. [ABSTRACT FROM AUTHOR]