Drosophila limb development is organized by interactions between anterior and posterior compartment cells. Posterior cells continuously express and require engrailed (en) and secrete Hedgehog (Hh) protein. Anterior cells express the zinc-finger protein Cubitus interruptus (Ci). It is now shown that anterior cells lacking ci express hh and adopt posterior properties without expressing en. Increased levels of Ci can induce the expression of the Hh target gene decapentaplegic (dpp) in a Hh-independent manner. Thus, expression of Ci in anterior cells controls limb development (i) by restricting hh secretion to posterior cells and (ii) by conferring competence to respond to Hh by mediating the transduction of this signal.

Aims To investigate the pharmacokinetic/pharmacodynamic properties of fast‐acting insulin aspart (faster aspart) versus insulin aspart (IAsp) in people with type 2 diabetes (T2D). Materials and methods In a randomized, double‐blind, crossover design, 61 people with T2D usually treated with insulin ± oral antidiabetic drug(s) received single‐dose faster aspart and IAsp (0.3 U/kg) on separate visits. Blood samples for pharmacokinetic assessment were collected frequently until 12 hours post‐dose. Glucose‐lowering effect was determined in a euglycaemic clamp lasting up to 12 hours post‐dose (target 5.0 mmol/L). Results The serum IAsp pharmacokinetic profile and glucose‐lowering effect profile were shifted to the left for faster aspart versus IAsp. Least squares mean (± SE) onset of appearance was 3.3 ± 0.3 minutes for faster aspart, which was 1.2 minutes earlier than for IAsp (95% confidence interval [CI] −1.8;−0.5; P = .001). Onset of action for faster aspart was 8.9 minutes earlier (95% CI −12.1;−5.7; P < .001) than for IAsp. During the first 30 minutes after dosing, 89% larger IAsp exposure (ratio faster aspart/IAsp 1.89 [95% CI 1.56;2.28]; P < .001) and 147% greater glucose‐lowering effect (2.47 [95% CI 1.58;6.22]; P < .001) were observed for faster aspart compared with IAsp. Offset of exposure (time to 50% of maximum IAsp concentration in the late part of the pharmacokinetic profile) occurred earlier for faster aspart (difference faster aspart – IAsp −36.4 minutes [95% CI −55.3;−17.6]; P < .001). The treatment difference of faster aspart – IAsp in offset of glucose‐lowering effect (time to 50% of maximum glucose infusion rate in the late part of the glucose infusion rate profile) was −14.4 minutes (95% CI −34.4;5.5; P = .152). Conclusions In people with T2D, faster aspart was associated with earlier onset and greater initial exposure and glucose‐lowering effect compared with IAsp, as previously shown in people with type 1 diabetes.

The aim of the study was to find out whether the estimation of the baseline ovarian volume prior to stimulation would be a suitable predictor for the risk of ovarian hyperstimulation syndrome (OHSS). A total of 101 patients underwent in-vitro fertilization (IVF) and embryo transfer. They had a 3-D volumetric assessment of the ovaries and body weight estimations on the first day of hormonal stimulation. A second measurement was performed on the day of ovulation induction with human chorionic gonadotrophin (HCG) together with an oestradiol 17 beta estimation in serum. During the IVF programme 15 women developed OHSS and 86 did not. There was a significant correlation between the baseline ovarian volume and subsequent occurrence of OHSS (P = 0.03). Other significant relationships were found between the occurrence of OHSS and the number of follicles (P = 0.002), the number of oocytes retrieved (P = 0.0001) and the length of the cycle (P = 0.0001). The body weight before and after the stimulation was significantly lower in the group of women who did develop the syndrome (P = 0.011 resp. 0.03). The oestradiol 17 beta concentration on the day of HCG administration in the serum of the patients who had OHSS was significantly higher (P = 0.0001). In conclusion, volumetry of the ovaries could help to detect patients at risk and prevent the occurrence of OHSS by early adjustment of the hormonal dosage. Recent advances in ultrasound technology (3-D ultrasound) enable quick and highly accurate volumetric assessments. Furthermore, our study confirms previous observations that low body weight and long cycles seem to be additional risk factors for the development of OHSS.

BackgroundManagement of diabetes in elderly patients is complicated by the elevated risk of insulin-induced hypoglycaemia. This is the first study to report the pharmacodynamic and pharmacokinetic characteristics of IDegAsp (insulin degludec [IDeg]/insulin aspart [IAsp]), a soluble co-formulation of a long-acting basal insulin analogue (IDeg) and a rapid-acting insulin analogue (IAsp) in a single injection, in elderly and younger adult subjects with type 1 diabetes using a glucose clamp.MethodsIn this randomised, single-centre, double-blind, single-dose (SD), two-period, crossover trial, 15 elderly subjects (aged ≥65 years) and 13 younger adults (aged 18–35 years) with type 1 diabetes were randomly assigned to two SD administrations of 0.5 U/kg IDegAsp or biphasic insulin aspart 30 (control) followed by a 26-h euglycaemic glucose clamp and 120-h pharmacokinetic blood sampling. The glucose infusion rate (GIR) profiles were extrapolated to simulated steady-state (SS) conditions using pharmacodynamic models.ResultsIDegAsp GIR profiles showed a distinct peak and rapid onset of action from IAsp followed by a separate and flat basal action from IDeg. Mean 24-h area under the GIR curve was similar in elderly subjects vs. younger adults (mean ratio 1.01 [95 % confidence interval 0.69–1.47]). Simulated SS pharmacodynamic profiles with once-daily IDegAsp showed a parallel upshift in GIR profiles vs. SD profiles. The shape of the IDegAsp pharmacodynamic profile was retained with twice-daily dosing under simulated SS conditions. IDegAsp was well tolerated.ConclusionsThe distinct prandial and basal pharmacodynamics of IDegAsp observed in younger adults were preserved in elderly subjects with type 1 diabetes. The glucose-lowering effect of IDegAsp was similar in elderly subjects and younger adults with type 1 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s40266-015-0272-y) contains supplementary material, which is available to authorized users.

Glucagon concentrations and EGP during hypoglycemia were more pronounced in C-pos than in C-neg patients, which indicates that preserved β-cell function may contribute to counterregulation during hypoglycemia in patients with T1DM.

Aims To investigate the effect of hypoglycaemia on platelet and coagulation activation in people with type 2 diabetes. Materials and methods This monocentric, open, single‐arm, mechanistic trial included 14 people with established type 2 diabetes (four women, 10 men, age 55 ± 7 years, glycated haemoglobin concentration 51 ± 7 mmol/mol) receiving metformin monotherapy. A stepwise hyperinsulinaemic‐hypoglycaemic clamp experiment (3.5 and 2.5 mmol/L, for 30 minutes respectively) was performed, aiming to investigate platelet and coagulation activity during predefined plateaus of hypoglycaemia, as well as 1 day and 7 days later. Results While platelet activation assessed by light transmittance aggregometry did not significantly increase after the hypoglycaemic clamp procedure, the more sensitive flow cytometry‐based measurement of platelet surface activation markers showed hypoglycaemia‐induced activation 24 hours (PAC1posCD62Ppos, PAC1posCD63Ppos and PAC1posCD62PposCD63pos; P < .01) and 7 days after the hypoglycaemic clamp (P < .001 for PAC1posCD63pos; P < .01 for PAC1posCD62Ppos and PAC1posCD62PposCD63pos) in comparison to baseline. Coagulation markers, such as fibrinogen, D‐dimer, plasminogen activator inhibitor‐1, von Willebrand factor activity and factor VIII, were also significantly increased, an effect that was most pronounced 24 hours after the hypoglycaemic clamp. Conclusion A single event of insulin‐induced hypoglycaemia led to an increase in markers of platelet activation and coagulation in people with early stages of type 2 diabetes on metformin therapy. However, the activation occurred with a delay and was evident 24 hours and 7 days after the actual hypoglycaemic episode.

A novel liquid chromatography-mass spectrometry (LC-MS) approach for analysis of oxidized phosphatidylcholines by an Orbitrap Fourier Transform mass spectrometer in positive electrospray ionization (ESI) coupled to hydrophilic interaction liquid chromatography (HILIC) was developed. This method depends on three selectivity criteria for separation and identification: retention time, exact mass at a resolution of 100,000 and collision induced dissociation (CID) fragment spectra in a linear ion trap. The process of chromatography development showed the best separation properties with a silica-based Kinetex column. This type of chromatography was able to separate all major lipid classes expected in mammalian samples, yielding increased sensitivity of oxidized phosphatidylcholines over reversed phase chromatography. Identification of molecular species was achieved by exact mass on intact molecular ions and CID tandem mass spectra containing characteristic fragments. Due to a lack of commercially available standards, method development was performed with copper induced oxidation products of palmitoyl-arachidonoyl-phosphatidylcholine, which resulted in a plethora of lipid species oxidized at the arachidonoyl moiety. Validation of the method was done with copper oxidized human low-density lipoprotein (LDL) prepared by ultracentrifugation. In these LDL samples we could identify 46 oxidized molecular phosphatidylcholine species out of 99 possible candidates.

The EndoBarrier™ medical device is a duodenal-jejunal bypass liner designed to mimic the effects of gastric bypass surgery to induce weight loss and glycaemic improvement. In this study, 10 participants with type 2 diabetes mellitus (T2DM), a mean body mass index (BMI) of 43.3 ± 5.0 (kg/m2) and a mean glycated haemoglobin A1c (HbA1c) of 60.6 ± 8.6 mmol/mol were examined at baseline (before implantation of EndoBarrier™), 4 weeks after implantation, at 36 weeks (right before explantation) and 24 weeks after the removal of the device to explore the short and long-term effects on glucose metabolism. Besides a significant reduction in body weight and fat mass, EndoBarrier™ treatment significantly improved insulin sensitivity during Botnia clamp investigations after four weeks of implantation. The beneficial effects decreased over time but remained significant 24 weeks after removal of the device.