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Arachnoiditis ossificans is a rare disease, characterized by intradural ossifications, representing the end stage of chronic adhesive arachnoiditis. We describe the case of a 55-year-old patient who developed symptoms of a cauda equina syndrome after an open microdiscectomy at the L5 to S1 segment. A subsequent exploratory surgery revealed an intradural concentric bony structure with partly incorporated and partly adherent nerve roots. A partial removal of the intradural calcifications was performed. Postoperatively, the patient showed neurological improvement. The removed intradural calcifications were submitted for histological analysis and proved to be normal bone tissue, notably containing yellow bone marrow. To our knowledge, the presence of yellow bone marrow within bony cavities of arachnoiditis ossificans has not previously been reported.

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

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.

Evidence is accumulating that prolonged fasting (PL) might evoke improvements in metabolic health. Since fasting is accompanied by numerous endogenous processes to equilibrate blood glucose concentration, its feasibility is disputable in people with type 1 diabetes (PWT1D). We aimed to assess the safety and efficacy of PL in c-peptide negative (^< 0.9 ng/mL) PWT1D. Methods: Glucose metabolism was assessed during the fasting period (CGM) and via a 75 g OGTT accompanied with the same bolus insulin dose after 12 (shortF) and 36 hours of fasting (longF). Area under the curve (AUC) was calculated following the trapezoidal rule. Safety was assessed by the number of hypoglycemic episodes (< 70 mg/dL) during fasting. Data were analysed using a paired sample t-test or Mann-Whitney-U-test (p≤0.05). Results: In total, 17 PWT1D (6 women, aged 37 ± 11 years, BMI 24.9 ± 2.9 kg/m2, 10 MDI) were included. 13 episodes of mild hypoglycemia occurred in 9 participants during the shortF versus 27 in 15 participants during the longF. Incidence of hypoglycemia per hour was similar in both arms (median [IQR] shortF: 0.08 [0 - 0.08] vs. longF: 0.06 [0.03 - 0.07], p=0.62). Conclusion: PL did not increase the risk of hypoglycemia in PWT1D. Intriguingly, the AUC for glucagon was significantly higher after longF compared to shortF, potentially explaining the numerically lower number of hypoglycemic events during longF. Disclosure O. Moser: Other Relationship; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi. N.J. Tripolt: None. P.N. Pferschy: None. A. Obermayer: None. H. Kojzar: None. J.K. Mader: Advisory Panel; Self; Becton, Dickinson and Company, Eli Lilly and Company, Medtronic, Prediktor Medical, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis. M. Brunner: None. A. Mueller: None. H. Yildirim: None. C. Sourij: None. M.L. Eckstein: Research Support; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi-Aventis. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi.

Objectives: To evaluate the effect of SGLT2i on the development of DKA during insulin depletion in T1DM. Methods: Sixteen male, C-peptide negative T1DM subjects were enrolled in this open, randomized, crossover, bicentric trial with two 7-day treatment periods (with/without SGLT2i). At the end of each treatment period, insulin was withdrawn for a maximum of 12h, followed by recovery phase (12h). Results: SGLT2i led to significantly lower plasma glucose (PG) values during insulin depletion (PGmax with/without SGLT2i: 174±40 (mean±SD) vs. 302±48 mg/dL; 95% CI for ratio: 0.51-0.60), but to higher beta-hydroxybutyrate (BHB) values (Figure) and a steeper BHB increase (delta BHB: 8.1±2.0 vs. 6.0±1.7 µmol/L/min; 95% CI for ratio: 1.22-1.49). pH, bicarbonate and base excess during insulin depletion were comparable. Baseline glucagon (7.8±2.5 vs. 5.0±1.6 pmol/L; 95% CI for ratio: 1.26-1.95) and FFA levels (0.65±0.27 vs. 0.43±0.31 mmol/L; 95% CI for ratio: 1.08-2.28) were higher with SGLT2i, but data indicate that after increase during insulin depletion comparable concentrations were reached for both. Conclusions: SGLT2i keeps PG in near normal ranges during DKA development and recovery, potentially impeding DKA diagnosis. While SGLT2i leads to higher ketone levels, increased baseline glucagon and FFA, an effect on pH and acidosis was not demonstrated. Disclosure I. Mursic: None. E. Svehlikova: None. W. Regittnig: None. T. Augustin: None. C. Magnes: None. A. Eberl: None. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. O. Klein: None. M. Wolf: None. M. Urschitz: None. M. Brunner: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S, Roche Diagnostics K.K.

Aims To investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D). Methods In this double-blind, placebo-controlled, single-centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L). Results The mean (range) participant age was 54.2 (41-64) years, body mass index 29.4 (23.3-36.1) kg/m2 , glycated haemoglobin 60.8 (44.3-83.6) mmol/mol (7.7 [6.2-9.8]%), and diabetes duration 4.5 (0.3-13.2) years. A total of 35 participants completed the trial and were included in the analyses. During the hypoglycaemic clamp from 5.5 mmol/L PG to nadir, the absolute change in mean glucagon concentration was similar for semaglutide vs placebo: 88.3 vs 83.1 pg/mL (estimated difference 5.2 pg/mL [95% confidence interval -7.7 to 18.1]). Concentrations of other counterregulatory hormones increased with both treatments, with a statistically significantly lower increase for noradrenaline and cortisol with semaglutide vs placebo. The glucose infusion rate to maintain constant clamp levels was similar for each treatment group, suggesting an overall similar counterregulatory response. The mean hypoglycaemic symptom score and proportion of participants recognizing hypoglycaemia during the study were lower for semaglutide vs placebo treatment at nadir, but cognitive function test results were similar. No new safety issues were observed for semaglutide. Conclusions Semaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D.

Objective: Although hypoglycemia is associated with increased risk for subsequent cardiovascular events, experimental data investigating the effect of hypoglycemia on coagulation and platelet activation in type 2 diabetes are limited. Research Design and Methods: This monocentric, open, single arm, trial included 14 subjects with type 2 diabetes (10 male/4 female, age 55±7 years, HbA1c 51±7 mmol/mol, diabetes duration 5±4 years) and metformin treatment only. A stepwise hyperinsulinemic hypoglycemic clamp was performed, aiming to investigate parameters of platelet function during predefined plateaus of hypoglycemia (at 63 and 45 mg/dl, for 30 minutes respectively), 24 hours and 7 days later. Additionally, all subjects underwent a hyperinsulinemic euglycemic clamp experiment. Results: While platelet activation assessed by light transmittance aggregometry did not significantly increase following a hypoglycemic clamp, flow cytometry based platelet activation assessment demonstrated a significant increase 24 hours (PAC1CD62PCD63pos p Conclusions: One single event of insulin induced hypoglycemia led to an increase in markers of platelet activation and coagulation, however, the activation occurred with a delay and was evident 24 hours and 7 days after the actual hypoglycemia. Disclosure F. Aberer: None. P.N. Pferschy: None. N.J. Tripolt: None. C. Sourij: None. H. Kojzar: None. B. Prietl: None. S. Kofler: None. M. Brunner: None. R. Riedl: None. E. Novak: None. A.M. Obermayer: None. P. Reitbauer: None. T. Stojakovic: None. F. Aziz: None. A. Oulhaj: None. F. Pruller: None. H. Scharnagl: Research Support; Self; Abbott, Amgen Inc. Speaker's Bureau; Self; Sanofi-Aventis Deutschland GmbH. H. Sourij: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Novo Nordisk A/S, Sanofi-Aventis. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis.

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 (PAC1pos CD62Ppos , PAC1pos CD63Ppos and PAC1pos CD62Ppos CD63pos ; P

Introduction A 60-cm endoscopically implantable duodenal–jejunal bypass liner (Endobarrier™, GI Dynamics, Lexington, MA, USA) has been introduced as a therapeutic option to support weight loss for a selected group of obese subjects with type 2 diabetes mellitus (T2DM). The sleeve prevents contact between chyme and the intestinal mucosa of the upper gastrointestinal tract. The primary aim of this study is to elucidate the changes in insulin sensitivity and beta-cell function after EndoBarrier™ implantation in obese patients with T2DM; changes in gut permeability and gut microbiome are also to be examined. Methods This is an open, single-center, prospective trial in which ten obese subjects with T2DM and suboptimal glycemic control (glycosylated hemoglobin A1c (HbA1c) level > 48 mmol/mol) are investigated with regards to EndoBarrier™ implantation. The Endobarrier™ is implanted shortly after baseline and left in situ for a period of 36 weeks. Dual-energy X-ray absorptiometry measurement, assessment of beta-cell function and insulin sensitivity as measured by a Botnia clamp procedure, and a mixed-meal tolerance test are performed prior to implantation and at 4, 36, and 64 weeks after implantation. The composition of the gut microbiota is characterized from stool using 454 pyrosequencing of 16S rRNA genes. Gut permeability is assessed by a differential sugar absorption method. Planned outcome This study will give mechanistic insights in particulr into changes of insulin sensitivity, beta-cell function or microbiome changes over time in subjects implanted with an EndobarrierTM device. Trial registration NCT02769728, Registered 12 May 2016. Current Protocol Date/Version: 04 September 2017/Version 1.9.

Based on the lack of accurate methods for glucagon analysis, it has been suggested that glucagon levels are elevated in subjects with type 1 diabetes. The availability of more specific methods for the determination of glucagon has indicated that actual glucagon levels are lower than previously assumed. This study aimed to characterize fasting glucagon levels in subjects with type 1 diabetes (T1D) and type 2 diabetes (T2D) compared to their nondiabetic counterparts using two different assays. We recruited 20 healthy, 20 T1D and 20 T2D subjects for the trial. Glucagon samples were obtained using BD P800 blood collection tubes and measured with a double-antibody sandwich ELISA (Mercodia) and a RIA (MP Biomedicals). Using the ELISA, healthy subjects had similar glucagon levels compared to T1D. ELISA based glucagon measurements demonstrated significantly higher fasting glucagon levels in T2D as compared to healthy subjects, while RIA measurements tend to be numerically higher, albeit not statistically different (p=0.201). Median glucagon values obtained by RIA were significantly (p=0.0001) higher than those measured by ELISA in a pooled analysis. In conclusion, T2D show fasting hyperglucagonaemia, whereas T1D present with similar fasting glucagon levels compared to nondiabetic subjects. Furthermore, this study highlights the importance of selective analysis methods in endocrine research. Disclosure M. Brunner: None. M. Haberlander: None. E. Svehlikova: None. K. Eberhard: None. E. Stach: None. R. Lipp: None. B.M. Obermayer-Pietsch: None. T.R. Pieber: Consultant; Self; Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Employee; Self; CBmed. Research Support; Self; Novo Nordisk A/S, AstraZeneca. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc..

Context Complete loss of β-cell function in patients with type 1 diabetes mellitus (T1DM) may lead to an increased risk of severe hypoglycemia. Objective We aimed to determine the impact of C-peptide status on glucagon response and endogenous glucose production (EGP) during hypoglycemia in patients with T1DM. Design and Setting We conducted an open, comparative trial. Patients Ten C-peptide positive (C-pos) and 11 matched C-peptide negative (C-neg) patients with T1DM were enrolled. Intervention Plasma glucose was normalized over the night fast, and after a steady-state (baseline) plateau all patients underwent a hyperinsulinemic, stepwise hypoglycemic clamp with glucose plateaus of 5.5, 3.5, and 2.5 mmol/L and a recovery phase of 4.0 mmol/L. Blood glucagon was measured with a specific and highly sensitive glucagon assay. EGP was determined with a stable isotope tracer technique. Main Outcome Measure Impact of C-peptide status on glucagon response and EGP during hypoglycemia. Results Glucagon concentrations were significantly lower in C-pos and C-neg patients than previously reported. At baseline, C-pos patients had higher glucagon concentrations than C-neg patients (8.39 ± 4.6 vs 4.19 ± 2.4 pmol/L, P = 0.016, mean ± standard deviation) but comparable EGP rates (2.13 ± 0.2 vs 2.04 ± 0.3 mg/kg/min, P < 0.391). In both groups, insulin suppressed glucagon levels, but hypoglycemia revealed significantly higher glucagon concentrations in C-pos than in C-neg patients. EGP was significantly higher in C-pos patients at hypoglycemia (2.5 mmol/L) compared with C-neg patients. Conclusions 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.

Background Management 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. Methods In 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. Results IDegAsp 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. Conclusions The 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 material The online version of this article (doi:10.1007/s40266-015-0272-y) contains supplementary material, which is available to authorized users.