Overall symptom severity as a patient-reported outcome measure for chronic rhinosinusitis: what it reflects and how to measure it.

BACKGROUND: The objective of this study was to identify how - and to what extent - overall symptom severity (OSS) score reflects individual chronic rhinosinusitis (CRS) symptoms and whether it can be measured using alternatives to the standard visual analog scale (VAS). METHODS: CRS patients from four sites across three continents rated their OSS scores, severities of nasal obstruction, nasal drainage, decreased sense of smell, facial pain/pressure and sleep disturbance using a standard VAS, VAS with labeled tick marks at every 1 centimeter, and by writing down their OSS on a scale of 0 - 100 (which was divided by 10), all of which lead to severity scores ranging from 0 - 10 in 0.1 intervals. Quality of life was measured using the SNOT-22 and EQ-5D VAS. RESULTS: In 311 CRS patients, OSS score was significantly correlated with SNOT-22 and EQ-5D VAS. OSS score was most greatly associated with the mean of all individual symptom severity scores. From individual CRS symptoms, OSS was most greatly associated with nasal obstruction followed by nasal drainage and facial pain/pressure severities. These results held true for participants with and without nasal polyps. Measurement of OSS and individual symptom severity scores using a standard VAS, tick-marked VAS, and write-in option had near-perfect consistency. CONCLUSIONS: We demonstrate for the first time that OSS largely reflects the mean of individual CRS symptom severities, although OSS is=== most weighted by nasal obstruction severity. OSS and individual symptom severity scores can be measured using a standard VAS, tick-marked VAS or write-in prompt with near-perfect consistency.

Evaluation of Undiagnosed HIV Estimates Computed from the CD4 Depletion Model in a Rural, Medium-low HIV Prevalence State.

The CD4 depletion model estimates diagnosis delays by approximating infection date from CD4 T-cell count at diagnosis, and back-calculation can compute the proportion of undiagnosed PLWHA. The model assumes the immigration of PLWHA to the U.S. is negligible and counts as a transmission event, which may be impractical outside high prevalence states. Duration of U.S. residency among foreign-born PLWHA and diagnosis delays were compared. The impact on estimates of undiagnosed PLWHA was tested through simulation with different proportions of foreign-born people assumed to have acquired HIV abroad. In 67% of foreign-born people, the mean (SD) years of delay (9.9 (6.3)) exceeded the duration of U.S. residency (2.0 (1.9)). Additionally, inaccuracies in the estimates for proportions of undiagnosed PLWHA were pronounced when foreign-born people who acquired HIV abroad comprised 30% of diagnoses. The CD4 model inadvertently misclassified some diagnoses as in-state transmission events. Consequently, simulated results demonstrated inaccuracies and unstable calculations.

Alternatives to free flap surgery for maxillofacial reconstruction: focus on the submental island flap and the pectoralis major myocutaneous flap.

BACKGROUND: Microvascular tissue transfer (MTT) has been established as the gold standard in oral- and maxillofacial reconstruction. However, free flap surgery may be critical in multimorbid elderly patients and after surgery or radiotherapy, which aggravate microsurgery. This study evaluates indications and outcome of the submental island flap (SMIF) and the pectoralis major myocutaneous flap (PMMF) as alternatives to the free radial forearm flap (RFF). METHODS: This retrospective study included 134 patients who had undergone resection and reconstruction with SMIF, PMMF, or RFF at our department between 2005 and 2020. The level of comorbidity was measured with the Age-adjusted Charlson comorbidity index (ACCI). Primary outcome variables were flap success, complications, wound dehiscence, surgery duration, as well as time at the ICU and the ward (hospitalization). Chi-square tests, t-tests, and ANOVA were performed for statistics. RESULTS: 24 SMIFs, 52 RFFs, and 58 PMMFs were included in this study. The flap types did not significantly differ in terms of flap success, complications, and healing disorders. The SMIF presented a success rate of 95.8% and was significantly more often used in elderly patients (mean age = 70.2 years; p < 0.001) with increased comorbidities than the PMMF (p < 0.01) and RFF (p < 0.001). SMIF reconstruction reduced surgery duration (p < 0.001) and time at the ICU (p = 0.009) and the ward (p < 0.001) more than PMMF and RFF reconstructions. PMMF reconstruction was successful in 91.4% of patients and was more frequently used after head and neck surgery (p < 0.001) and radiotherapy (p < 0.001) than SMIF and RFF reconstructions. Patients undergoing PMMF reconstruction more frequently required segmental jaw resection and had presented with advanced tumor stages (both p < 0.001). Nicotine and alcohol abuse was more frequent in the RFF and PMMF groups (both p < 0.001) than in the SMIF group. CONCLUSIONS: The pedicled SMIF represents a valuable reconstructive option for elderly patients with increased comorbidity because of the shorter duration of surgery and hospitalization. On the other hand, the PMMF serves as a solid backup solution after head and neck surgery or radiotherapy. The rates of flap success, complications, and healing disorders of both pedicled flaps are comparable to those of free flap reconstruction.

Precision Constraints for Three-Flavor Neutrino Oscillations from the Full MINOS+ and MINOS Dataset.

We report the final measurement of the neutrino oscillation parameters Δm_{32}^{2} and sin^{2}θ_{23} using all data from the MINOS and MINOS+ experiments. These data were collected using a total exposure of 23.76×10^{20} protons on target producing ν_{µ} and ν[over ¯]_{µ} beams and 60.75 kt yr exposure to atmospheric neutrinos. The measurement of the disappearance of ν_{µ} and the appearance of ν_{e} events between the Near and Far detectors yields |Δm_{32}^{2}|=2.40_{-0.09}^{+0.08}(2.45_{-0.08}^{+0.07})×10^{-3} eV^{2} and sin^{2}θ_{23}=0.43_{-0.04}^{+0.20}(0.42_{-0.03}^{+0.07}) at 68% C.L. for normal (inverted) hierarchy.

Health-related quality of life: a retrospective study on local vs. microvascular reconstruction in patients with oral cancer.

BACKGROUND: New medicinal and surgical oncological treatment strategies not only improve overall survival rates but continually increase the importance of Health-Related Quality of Life (HRQOL). The purpose of this retrospective cross-sectional study was to analyze HRQOL of patients with oral squamous cell carcinoma after ablative surgery and to evaluate predictive factors for HRQOL outcome. METHODS: The study included 88 patients with histologically confirmed oral squamous cell carcinoma of whom 42 had undergone local reconstruction (LR) and 46 microvascular reconstruction (MVR). During follow-up, all patients completed the University of Washington Quality of Life Questionnaire (UW-QOL) containing 12 targeted questions about the head and neck. Descriptive analyses were made for the tumor site, the T-stage, and adjuvant therapies. HRQOL was compared between the LR and the MVR group with parametric tests. Further analyses were impact of the tumor site, the T-status, and the time from surgery to survey on HRQOL. Statistics also included multivariate correlations and different interaction effects. RESULTS: HRQOL in the LR group was 'very good' with 84.3 ± 13.7 and 'good' in the MVR group with 73.3 ± 16.5 points. The physical domains swallowing (p = 0.00), chewing (p = 0.00), speech (p = 0.01), taste (p = 0.01), and pain (p = 0.04) were significantly worse in the MVR group. An increase in the T-status had a significant negative effect on swallowing (p = 0.01), chewing (p = 0.01), speech (p = 0.03), recreation (p = 0.05), and shoulder (p = 0.01) in both groups. Regarding the tumor site and subsequent loss of HRQOL, patients with squamous cell carcinoma on the floor of the mouth had significantly worse results in the categories pain (p = 0.002), speech (p = 0.002), swallowing (p = 0.03), activity (p = 0.02), and recreation (p = 0.01) than patients with tumors in the buccal mucosa. Speech (p = 0.03) and pain (p = 0.01) had improved 1 year after surgery. CONCLUSION: Patients with flap reconstruction because of oral squamous cell carcinoma showed very good overall HRQOL. Outcomes for microvascular reconstruction were good, even in the case of larger defects. The T-status is a predictor for HRQOL. Swallowing, chewing, speaking, taste, and pain were the most important issues in our cohort. Implementing HRQOL questionnaires for the assessment of quality of life could further increase the treatment quality of patients with oral cancer.

Adaptive changes in pancreas post Roux-en-Y gastric bypass induced weight loss.

BACKGROUND: Obesity has been shown to trigger adaptive increases in pancreas parenchymal and fat volume. Consecutively, pancreatic steatosis may lead to beta-cell dysfunction. However, it is not known whether the pancreatic tissue components decrease with weight loss and pancreatic steatosis is reversible following Roux-en-Y gastric bypass (RYGB). Therefore, the objective of the study was to investigate the effects of RYGB-induced weight loss on pancreatic volume and glucose homeostasis. METHODS: Eleven patients were recruited in the Obesity Centre of the University Medical Centre Hamburg-Eppendorf. Before and 6 months after RYGB, total GLP-1 levels were measured during oral glucose tolerance test. To assess changes in visceral adipose tissue and pancreatic volume, MRI was performed. Measures of glucose homeostasis and insulin indices were assessed. Fractional beta-cell area was estimated by correlation with the C-peptide-to-glucose ratio; beta-cell mass was calculated by the product of beta-cell area and pancreas parenchymal weight. RESULTS: Pancreas volume decreased from 83.8 (75.7-92.0) to 70.5 (58.8-82.3) cm3 (mean [95% CI], P = .001). The decrease in total volume was associated with a significant decrease in fat volume. Fasting insulin and C-peptide were lower post RYGB. HOMA-IR levels decreased, whereas insulin sensitivity increased (P = .03). This was consistent with a reduction in the estimated beta-cell area and mass. CONCLUSIONS: Following RYGB, pancreatic volume and steatosis adaptively decreased to "normal" levels with accompanying improvement in glucose homeostasis. Moreover, obesity-driven beta-cell expansion seems to be reversible; however, future studies must define a method to more accurately estimate functional beta-cell mass to increase our understanding of glucose homeostasis after RYGB.

Paradoxical ulcerative colitis during adalimumab treatment of psoriasis resolved by switch to ustekinumab.

Here we report the case of a patient with psoriasis who developed ulcerative colitis most likely caused by adalimumab. After cessation of adalimumab, colitis improved significantly. However, as psoriasis worsened, the patient was switched to ustekinumab, which resulted in complete cessation of colitis. During the 2-year follow-up under ustekinumab therapy, no further gastrointestinal complaints occurred. Paradoxical psoriasis manifestations in inflammatory bowel disease (IBD) under tumour necrosis factor (TNF)-inhibitor therapy have been reported and paradoxical IBD occurred rarely (mostly Crohn disease) in patients with rheumatological conditions treated with infliximab or etanercept. Due to the highly probable association of adalimumab with the onset of colitis in this case, we would like to suggest the term 'paradoxical ulcerative colitis' (PUC) for this as yet extremely rarely reported phenomenon. To the best of our knowledge this is the first description of PUC in a patient with psoriasis and in adalimumab treatment. Our observation suggests that ustekinumab is an effective treatment option in patients with paradoxical anti-TNF-driven inflammatory reactions like psoriasis or IBD.

[Severe atypical ketoacidosis due to SGLT2-inhibitor therapy : Two case reports]. / Schwere atypische Ketoazidose durch SGLT2-Inhibitor-Therapie : Zwei Fallberichte.

Two female patients were admitted due to ketoacidosis. Serum glucose was moderately elevated. The patients exhibited abdominal and neurologic symptoms. Treatment consisted of metformin, insulin glargin and empagliflozin, as well as glimepiride, insulin detemir and empagliflozin, respectively. Treatment with intravenous fluid replacement, insulin, glucose, potassium and buffer solution led to a normalisation of pH and serum glucose levels. Our report describes two cases of atypical ketoacidosis with moderately elevated serum glucose during sodium-glucose co-transporter-2 (SGLT2) inhibitor therapy.

The epidemic spreading model and the direction of information flow in brain networks.

The interplay between structural connections and emerging information flow in the human brain remains an open research problem. A recent study observed global patterns of directional information flow in empirical data using the measure of transfer entropy. For higher frequency bands, the overall direction of information flow was from posterior to anterior regions whereas an anterior-to-posterior pattern was observed in lower frequency bands. In this study, we applied a simple Susceptible-Infected-Susceptible (SIS) epidemic spreading model on the human connectome with the aim to reveal the topological properties of the structural network that give rise to these global patterns. We found that direct structural connections induced higher transfer entropy between two brain regions and that transfer entropy decreased with increasing distance between nodes (in terms of hops in the structural network). Applying the SIS model, we were able to confirm the empirically observed opposite information flow patterns and posterior hubs in the structural network seem to play a dominant role in the network dynamics. For small time scales, when these hubs acted as strong receivers of information, the global pattern of information flow was in the posterior-to-anterior direction and in the opposite direction when they were strong senders. Our analysis suggests that these global patterns of directional information flow are the result of an unequal spatial distribution of the structural degree between posterior and anterior regions and their directions seem to be linked to different time scales of the spreading process.

A case series of verrucae vulgares mimicking hyperkeratosis in individuals with diabetic foot ulcers.

BACKGROUND: Diabetic foot ulcers are a common complication in the advanced stages of diabetes mellitus. Certain lesions may be refractory to usual treatments with prolonged healing. In these cases, differential diagnoses to classical ulcers should be considered. Although plantar warts are a common and easy-to-diagnose finding in the general population, diagnosis can be challenging in people with diabetic foot ulcers, as they mimic hyperkeratosis in these people. CASE REPORT: We report seven cases of people with diabetic foot ulcers and verrucae vulgares mimicking treatment-refractory hyperkeratosis, presenting to our centre between 2014 and 2016. Diagnosis was aided by the clinical presentation, followed by dermoscopy and punch biopsy. Treatment included topical application of 5-fluoruracil and salicylic acid (four people), cryotherapy (three people) and surgical excision (three people), all in combination with local pressure offloading. In five people, the verrucae were completely removed after a mean treatment period of 9.4 months; two individuals were lost to follow-up. CONCLUSION: Verrucae may be more common in people with diabetic foot lesions and polyneuropathy than generally assumed. Typical findings include small, pinhead-sized bleedings within and surrounding hyperkeratous lesions. These findings should alert the clinician for the potential presence of a verruca. In such cases, biopsy should be performed to enable specific diagnosis and treatment.

Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.

Relation between growth rate and structure of graphene grown in a 4″ showerhead chemical vapor deposition reactor.

The chemical vapor deposition (CVD) growth of graphene on copper is controlled by a complex interplay of substrate preparation, substrate temperature, pressure and flow of reactive gases. A large variety of recipes have been suggested in literature, often quite specific to the reactor, which is being used. Here, we report on a relation between growth rate and quality of graphene grown in a scalable 4″ CVD reactor. The growth rate is varied by substrate pre-treatment, chamber pressure, and methane to hydrogen (CH4:H2) ratio, respectively. We found that at lower growth rates graphene grains become hexagonal rather than randomly shaped, which leads to a reduced defect density and a sheet resistance down to 268 Ω/sq.

Operation of an anaerobic filter compared with an anaerobic moving bed bioreactor for the treatment of waste water from hydrothermal carbonisation of fine mulch.

This experimental study investigates the anaerobic digestion of waste water from hydrothermal carbonisation of fine mulch (wood chips) in combination with a co-substrate for the first time. Two anaerobic reactors, an anaerobic filter (AF) and an anaerobic moving bed bioreactor (AnMBBR), were operated over a period of 131 days at mesophilic conditions. The organic loading rate was increased to a maximum of 8.5 g L-l d-1 in the AF and the AnMBBR. Both reactors achieved similarly efficient chemical oxygen demand removal rates of 80% approximately (approx.) and high methane production rates of approx. 2.7 L L-1 d-1. Nevertheless, signs of an inhibition were observed during the experiments.

Predicting haemodynamic networks using electrophysiology: The role of non-linear and cross-frequency interactions.

Understanding the electrophysiological basis of resting state networks (RSNs) in the human brain is a critical step towards elucidating how inter-areal connectivity supports healthy brain function. In recent years, the relationship between RSNs (typically measured using haemodynamic signals) and electrophysiology has been explored using functional Magnetic Resonance Imaging (fMRI) and magnetoencephalography (MEG). Significant progress has been made, with similar spatial structure observable in both modalities. However, there is a pressing need to understand this relationship beyond simple visual similarity of RSN patterns. Here, we introduce a mathematical model to predict fMRI-based RSNs using MEG. Our unique model, based upon a multivariate Taylor series, incorporates both phase and amplitude based MEG connectivity metrics, as well as linear and non-linear interactions within and between neural oscillations measured in multiple frequency bands. We show that including non-linear interactions, multiple frequency bands and cross-frequency terms significantly improves fMRI network prediction. This shows that fMRI connectivity is not only the result of direct electrophysiological connections, but is also driven by the overlap of connectivity profiles between separate regions. Our results indicate that a complete understanding of the electrophysiological basis of RSNs goes beyond simple frequency-specific analysis, and further exploration of non-linear and cross-frequency interactions will shed new light on distributed network connectivity, and its perturbation in pathology.

Intraoperative transfusion practices in Europe.

BACKGROUND: Transfusion of allogeneic blood influences outcome after surgery. Despite widespread availability of transfusion guidelines, transfusion practices might vary among physicians, departments, hospitals and countries. Our aim was to determine the amount of packed red blood cells (pRBC) and blood products transfused intraoperatively, and to describe factors determining transfusion throughout Europe. METHODS: We did a prospective observational cohort study enrolling 5803 patients in 126 European centres that received at least one pRBC unit intraoperatively, during a continuous three month period in 2013. RESULTS: The overall intraoperative transfusion rate was 1.8%; 59% of transfusions were at least partially initiated as a result of a physiological transfusion trigger- mostly because of hypotension (55.4%) and/or tachycardia (30.7%). Haemoglobin (Hb)- based transfusion trigger alone initiated only 8.5% of transfusions. The Hb concentration [mean (sd)] just before transfusion was 8.1 (1.7) g dl(-1) and increased to 9.8 (1.8) g dl(-1) after transfusion. The mean number of intraoperatively transfused pRBC units was 2.5 (2.7) units (median 2). CONCLUSION: Although European Society of Anaesthesiology transfusion guidelines are moderately implemented in Europe with respect to Hb threshold for transfusion (7-9 g dl(-1)), there is still an urgent need for further educational efforts that focus on the number of pRBC units to be transfused at this threshold. CLINICAL TRIAL REGISTRATION: NCT 01604083.

[Treatment of type 2 diabetes]. / Therapie des Typ-2-Diabetes.

New glucose-lowering drugs have raised the complexity of diabetes treatment in recent years. While metformin is still the first choice in monotherapy for most cases, various options exist for dual combination therapy. In addition, combinations of three different oral glucose-lowering drugs are increasingly used. Insulin therapy is typically initiated using once daily administration of a long-acting insulin. If basal insulin alone is no longer sufficient, treatment can be intensified by adding short-acting insulin at mealtime or by combining basal insulin with oral glucose-lowering drugs or a glucagon-like peptide (GLP)-1 analogue. The choice of the most appropriate glucose-lowering drug should take into account not only the glucose-lowering efficacy, but also the side effect profile of the respective agents; economic factors must be considered as well. Modern treatment of type 2 diabetes should aim for near-normal glucose control.

[Recurrent hypoglycemia due to an occult insulinoma]. / Okkultes Insulinom als Ursache rezidivierender Hypoglykämien.

A 64-year-old woman presented with a history of recurrent hypoglycemia. A prolonged fasting test revealed an increased "amended" insulin-glucose ratio. Transabdominal ultrasound (US), computed tomography (CT) scan, and magnetic resonance imaging (MRI) did not show abnormal results. An insulinoma was suspected based on a contrast-enhanced endoscopic US examination as well as a (68)gallium-DOTA-exendin-4 positron-emission tomography (PET)/CT. The diagnosis of an insulinoma was confirmed histologically after surgical removal of the tumor. Hypoglycemia did not occur during the postoperative period. The prolonged fasting test is the gold standard for the diagnosis of an insulinoma. Novel imaging procedures, such as contrast-enhanced endoscopic US or (68)gallium-DOTA-exendin-4 PET/CT are valuable additions to the diagnostic workup.

Role of operative airway evaluation in children with recurrent croup: a retrospective cohort study.

OBJECTIVE: Determine which risk factors in children with recurrent croup warrant bronchoscopic evaluation. DESIGN: Retrospective cohort study. SETTING: Tertiary paediatric hospital. PARTICIPANTS: Children with recurrent croup who underwent a rigid bronchoscopy between 2001 and 2013. MAIN OUTCOME MEASURES: Bronchoscopy findings, classified as normal, mildly abnormal or significantly abnormal. RESULTS: Two hundred and thirty-five children underwent a rigid bronchoscopy and 110 underwent a flexible oesophagoscopy. One hundred and forty-five children (61.7%) had a mildly abnormal exam, and 27 children (11.5%) had significant findings that required a surgical intervention or grade 2 or greater subglottic stenosis. The significantly abnormal group included 4 children with laryngomalacia, 2 with a subglottic cyst, 8 with grade 2 or 3 subglottic stenosis and 13 children who underwent a surgical procedure for subglottic stenosis. Sixty-seven children had a preoperative diagnosis of asthma, 62 were atopic and 78 had symptoms of gastro-oesophageal reflux. Oesophagoscopy was diagnostic of gastro-oesophageal reflux in 19 of 110 cases, and 106 children (45.1%) had bronchoscopic findings suggestive of GERD. Eight children had eosinophilic oesophagitis. After multivariate analysis, significantly abnormal bronchoscopy was significantly associated with chronic cough (P = 0.02), have a previous intubation (P = 0.002) or be younger than 3 years old (P = 0.01). CONCLUSION: Significant findings on bronchoscopy that warranted further surgical intervention were uncommon in this cohort. Nearly half of the patients had evidence of gastro-oesophageal reflux. In patients without risk factors for significant abnormalities, empiric medical management may be beneficial prior to endoscopy.

Do current incretin mimetics exploit the full therapeutic potential inherent in GLP-1 receptor stimulation?

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are incretin-derived glucose-lowering agents that have been used for the treatment of type 2 diabetes since 2007. Agents such as exenatide (short-acting and once weekly preparations), liraglutide, taspoglutide, albiglutide and lixisenatide lower fasting glucose and HbA1c upon subcutaneous injection, leading to glycaemic control that is equivalent to, or better than, that observed with other oral glucose-lowering agents or bedtime insulin. However, varying proportions of patients report nausea and vomiting, adverse events that typically narrow the therapeutic dose range. Furthermore, GLP-1 RAs reduce fasting glucose to a clinically meaningful extent, but not into the normal range. In contrast, where GLP-1 is administered as a short-term intravenous infusion, a full normalisation of glucose concentrations (approximately 5 mmol/l) has been observed without any risk of gastrointestinal side effects. Subcutaneous infusions or injections of GLP-1 are much less effective. The present analysis relates the proportion of patients who report nausea following treatment with GLP-1 and GLP-1 RAs to the clinical effectiveness of the treatment (represented by the fasting glucose concentration achieved with treatment). The results suggest that GLP-1 RAs injected into the subcutaneous compartment do not exploit the full potential inherent in GLP-1 receptor activation. Reasons for this may include modifications of the peptide molecules in the subcutaneous environment or high local concentrations triggering side effects through GLP-1 receptors on autonomic nerves in subcutaneous adipose tissue. Elucidation of the mechanisms underlying differential responses to GLP-1/GLP-1 RAs administered intravenously vs subcutaneously may help to develop improved agents or modes of administration that are more effective and have fewer side effects.

Hyperglycaemia is associated with impaired pulsatile insulin secretion: effect of basal insulin therapy.

AIM: Postprandial insulin pulsatility is impaired in patients with type 2 diabetes, but the effects of exogenous insulin therapy on pulsatile insulin secretion are not known. We addressed, whether pulsatile insulin secretion is related to glycaemic control, whether basal insulin supplementation increases postprandial insulin secretion, and if so, is this accomplished by a specific improvement in pulsatile insulin secretion? METHODS: Fourteen patients with type 2 diabetes underwent a mixed meal test before and after an 8-week treatment period with insulin glargine. Glucose, insulin and C-peptide levels were measured, and insulin pulsatility was determined by deconvolution analysis. RESULTS: Insulin treatment lowered fasting glycaemia from 179.6 ± 7.5 mg/dl to 117.6 ± 6.5 mg/dl (p < 0.001). Postprandial insulin and C-peptide levels increased significantly after the treatment period (p < 0.0001). The total calculated insulin secretion rate increased with insulin treatment (p = 0.0039), with non-significant increases in both pulsatile and non-pulsatile insulin secretion. Insulin pulse frequency was unchanged by the intervention. There was an inverse relationship between fasting and postprandial glycaemia and insulin pulse mass (r(2) = 0.51 and 0.56, respectively), whereas non-pulsatile insulin secretion was unrelated to either fasting or postprandial glucose concentrations (r(2) = 0.0073 and 0.031). CONCLUSIONS: Hyperglycaemia in type 2 diabetes is associated with a reduction in postprandial insulin secretion, specifically through a reduction in insulin pulsatility. Reducing chronic hyperglycaemia by basal insulin therapy enhances endogenous ß-cell function in the postprandial state. These data support the use of basal insulin regimens in the pharmacotherapy of overtly hyperglycaemic patients with type 2 diabetes.