Factors associated with diabetic foot ulcers and lower limb amputations in type 1 and type 2 diabetes supported by real-world data from the German/Austrian DPV registry.

AIMS: Diabetic foot ulcer (DFU) is a leading cause of lower limb amputations in people with diabetes. This study was aimed to retrospectively analyze factors affecting DFU using real-world data from a large, prospective central-European diabetes registry (DPV [Diabetes-Patienten-Verlaufsdokumentation]). MATERIALS AND METHODS: We matched adults with type 1 (T1D) or type 2 diabetes (T2D) and DFU to controls without DFU by diabetes type, age, sex, diabetes duration, and treatment year to compare possible risk factors. Cox regression was used to calculate hazard ratios for amputation among those with DFU. RESULTS: In our cohort (N = 63 464), male sex, taller height, and diabetes complications such as neuropathy, peripheral artery disease, nephropathy, and retinopathy were associated with DFU (all p < .001). Glycated hemoglobin (HbA1c) was related to DFU only in T1D (mean with 95% confidence interval [CI]: 7.8 [6.9-9.0] % vs 7.5 [6.8-8.5] %, p < .001). High triglycerides and worse low-density lipoprotein/high-density lipoprotein ratio were also associated with DFU in T1D, whereas smoking (14.7% vs 13.1%) and alcohol abuse (6.4% vs 3.8%, both p < .001) were associated with DFU in T2D. Male sex, higher Wagner grades, and high HbA1c in both diabetes types and insulin use in T2D were associated with increased hazard ratios for amputations. CONCLUSIONS: Sex, body height, and diabetes complications were associated DFU risk in adults with T1D and T2D. Improvement in glycemic control and lipid levels in T1D and reduction of smoking and drinking in T2D may be appropriate interventions to reduce the risk for DFU or amputations.

Common procedures and conditions leading to inpatient hospital admissions in adults with and without diabetes from 2015 to 2019 in Germany : A comparison of frequency, length of hospital stay and complications.

OBJECTIVE: To evaluate common surgical procedures and admission causes in inpatient cases with diabetes in Germany between 2015 and 2019 and compare them to inpatient cases without diabetes. METHODS: Based on the German diagnosis-related groups (G-DRG) statistics, regression models stratified by age groups and gender were used to calculate hospital admissions/100,000 individuals, hospital days as well as the proportion of complications and mortality in inpatient cases ≥ 40 years with or without a documented diagnosis of diabetes (type 1 or type 2). RESULTS: A total of 14,222,326 (21%) of all inpatient cases aged ≥ 40 years had a diagnosis of diabetes. More middle-aged females with vs. without diabetes/100,000 individuals [95% CI] were observed, most pronounced in cases aged 40-< 50 years with myocardial infarction (305 [293-319] vs. 36 [36-37], p < 0.001). Higher proportions of complications and longer hospital stays were found for all procedures and morbidities in cases with diabetes. CONCLUSION: Earlier hospitalizations, longer hospital stays and more complications in inpatient cases with diabetes together with the predicted future increase in diabetes prevalence depict huge challenges for the German healthcare system. There is an urgent need for developing strategies to adequately care for patients with diabetes in hospital.

Clinical characteristics and cardiovascular risk profile in children and adolescents with latent autoimmune diabetes: Results from the German/Austrian prospective diabetes follow-up registry.

AIMS: To characterize children and adolescents with latent autoimmune diabetes of the young (LADY), and to assess the utility of classifying individuals as LADYs regarding their cardiovascular (CV) risk factors. METHODS: Data from 25,520 individuals (age at diagnosis <18 years) of the Prospective Diabetes Follow-up Registry Diabetes-Patienten Verlaufsdokumentation (DPV) were analyzed. LADY was defined as positivity of ≥one islet autoantibody (iAb+) and an insulin-free interval of ≥6 months upon diabetes diagnosis. LADYs were compared to iAb+ individuals immediately requiring insulin ("immunologically confirmed" type 1 diabetes, T1DM), iAb-/Ins- individuals ("classical" T2DM) and to those clinically defined as T2DM (iAbs not measured). RESULTS: Clinical characteristics of LADYs (n = 299) fell in between those with T1DM (n = 24,932) and T2DM (iAb-/Ins-, n = 152) or suspected T2DM (iAB not measured, n = 137). Stratifying LADYs according to their clinical diagnosis however revealed two distinct populations, highly resembling either T1DM or T2DM. Particularly, CV risk profile, precisely prevalence rates of arterial hypertension and dyslipidemia, was significantly higher in LADYs clinically classified as T2DM compared to LADYs classified as T1DM, and did not differ from those with "classical" T2DM. CONCLUSIONS: In terms of CV risk, classifying children and adolescents with diabetes as LADYs provides no additional benefit. Instead, clinical diagnosis seems to better assign individuals to appropriate risk groups for increased CV risk profiles.

Intranasal oxytocin attenuates the effects of monetary feedback on procedural learning.

Procedural learning is a vital brain function that allows us to acquire motor skills during development or re-learn them after lesions affecting the motor system. Procedural learning can be improved by feedback of different valence, e.g., monetary or social, mediated by dopaminergic circuits. While processing motivationally relevant stimuli, dopamine interacts closely with oxytocin, whose effects on procedural learning, particularly feedback-based approaches, remain poorly understood. In a randomized, double-blind, placebo-controlled trial, we investigated whether oxytocin modulates the differential effects of monetary and social feedback on procedural learning. Sixty-one healthy male participants were randomized to receive a placebo or oxytocin intranasally. The participants then performed a modified serial reaction time task. Oxytocin plasma concentrations were measured before and after applying the placebo or verum. Groups did not differ regarding general reaction times or measures of procedural learning. For the placebo group, monetary feedback improved procedural learning compared to a neutral control condition. In contrast, the oxytocin group did not show a differential effect of monetary or social feedback despite a significant increase in oxytocin plasma levels after intranasal application. The data suggest that oxytocin does not influence procedural learning per se. Instead, oxytocin seems to attenuate the effects of monetary feedback on procedural learning specifically.

Comorbidities in Recent-Onset Adult Type 1 Diabetes: A Comparison of German Cohorts.

Aims: Restrictive exclusion criteria from different study populations may limit the generalizability of the observations. By comparing two differently designed German cohorts, we assessed the prevalence of cardiovascular risk factors and diabetes-related complications in recent-onset adult type 1 diabetes. Methods: This study evaluated 1511 persons with type 1 diabetes of the prospective diabetes follow-up registry (DPV) and 268 volunteers of the prospective observational German Diabetes Study (GDS) with a known diabetes duration <1 year. Participants had similar age (36 years), sex distribution (41% female) and BMI (26 kg/m2) in both cohorts. Results: The average HbA1c was 6.4 ± 0.8% in the GDS and 7.0 ± 1.1% in the DPV. Prevalence of hypertension (24%) was similar, while more DPV participants had dyslipidemia and lipid-lowering medication than GDS participants (77% vs. 41% and 7% vs. 2%, respectively; p<0.05). Prevalence of retinopathy and nephropathy was higher in DPV compared to GDS participants (10% vs. 3% and 18% vs. 7%, respectively; p<0.001). Conclusions: Diabetic nephropathy and retinopathy are the most frequent complications in type 1 diabetes, affecting up to every 10th patient within the first year after diagnosis, underlining the need for more stringent risk factor management already at the time of diagnosis of type 1 diabetes.

Diabetes in the Hospital­A Nationwide Analysis of all Hospitalized Cases in Germany With and Without Diabetes, 2015-2017.

BACKGROUND: Comprehensive data on the frequency of diabetes mellitus among hospitalized patients in Germany have not been published to date. METHODS: Among all inpatient cases aged ≥20 years that were documented in the German DRG statistics for 2015-2017, we analyzed the frequencies of five types of diabetes (type 1, type 2, other/pancreatic diabetes, "rare diabetes" with an ICD code of E12 or E14, gestational diabetes) and of prediabetes, stratified by sex and age group. The presence of any of these conditions was ascertained from the corresponding ICD-10 code among the main diagnoses (reasons for admission) or secondary diagnoses. We also compared the length of hospital stay, in-hospital mortality, and the frequency of various categories of main diagnosis in cases with and without diabetes in each age group. RESULTS: In the period 2015-2017, approximately 18% of the 16.4 to 16.7 million inpatient cases carried a main or secondary diagnosis of diabetes (in 2017: type 2, 17.1%; type 1, 0.5%). Diabetes was more common in male cases than in female cases (in 2017: type 2, 19.7% vs. 14.8%; type 1, 0.5% vs. 0.4%). In 2017, the greatest difference in length of hospital stay between patients with and without diabetes was for patients with type 1 diabetes aged 40-49 (7.3 vs. 4.5 days), while the greatest difference in in-hospital mortality was for patients with type 2 diabetes aged 70-79 (3.7% vs. 2.8%). From the age of 30 (age category 30-39), diseases of the cardiovascular system, and from the age of 50 (age category 50-59), diseases of the respiratory or urogenital systems were more frequently listed as a reason for admission in cases with than in those without diabetes. CONCLUSION: The fact that diabetes is twice as prevalent in hospitalized cases as in the general population underscores the high morbidity associated with the disease and the greater need of persons with diabetes for in-hospital care, as the population of multimorbid diabetes patients continues to grow older.

Immune-checkpoint inhibitor-associated diabetes compared to other diabetes types - A prospective, matched control study.

BACKGROUND: To describe checkpoint inhibitor-induced diabetes mellitus (CPI-DM) and to compare with regular type 1 (T1DM), type 2 (T2DM), and medication-induced diabetes mellitus (MI-DM). METHODS: We included 88 177 adult patients from the Diabetes Patient Follow-Up (DPV) registry with diabetes manifestation between 2011 and 2020. Inclusion criteria were T1DM, T2DM, MI-DM, or CPI-DM. Because of the heterogeneity between the groups, we matched patients by age, sex, and diabetes duration using propensity scores. Patient data were aggregated in the respective first documented treatment year. RESULTS: The matched cohort consisted of 24 164 patients; T1DM: 29, T2DM: 24000, MI-DM: 120, CPI-DM: 15 patients. Median age at manifestation of CPI-DM patients was 63.6 (57.2-72.8) years (53.3% male). Body mass index in CPI-DM patients was significantly lower (26.8 [23.9-28.1] kg/m2 ) compared with T2DM patients (29.8 [26.2-34.3] kg/m2 , P = 0.02). At manifestation, HbA1c was significantly higher in CPI-DM compared with MI-DM, but there was no difference during follow-up. Diabetic ketoacidosis (DKA) was documented in six CPI-DM patients (T1DM: 0%, T2DM: 0.4%, MI-DM: 0.0%). Fourteen CPI-DM patients were treated with insulin, and three received additional oral antidiabetics. The most common therapy in T2DM was lifestyle modification (38.8%), insulin in MI-DM (52.5%). Concomitant autoimmune thyroid disease was present in four CPI-DM patients (T1DM: 0.0%, T2DM: 1.0%, MI-DM: 0.8%). CONCLUSIONS: The data from this controlled study show that CPI-DM is characterized by a high prevalence of DKA, autoimmune comorbidity, and metabolic decompensation at onset. Structured diagnostic monitoring is warranted to prevent DKA and other acute endocrine complications in CPI-treated patients.

Adults' Adherence to Growth Hormone Replacement in Relation to Medication-Related Beliefs, Coping and Quality of Life - An Exploratory Analysis.

Introduction: Little is known about psychological reasons associated with adherence to growth hormone (GH) replacement therapy (GHRx) in adults. As in other chronic diseases, medication-related beliefs, coping strategies and disease impact on quality of life (QoL) might play an important role. We thus explored these psychological factors in relation to adherence in patients with GH deficiency (GHD) in order to find leverage points for the improvement of adherence. Patients and Methods: Cross-sectional analysis including 107 adult GHD patients on GHRx who completed self-assessment inventories on health-related QoL (Short-Form SF-36), coping style (Freiburg questionnaire on coping with illness, FKV-LIS) and medication beliefs (Beliefs about Medicine questionnaire, BMQ). Results were correlated to general and GH-specific adherence to medication. Results: In the BMQ, 92.5% of the patients (n=99) reported a strong belief in the need for their medication, which correlated significantly with general adherence (rs = 0.325). Active coping was significantly related to general (rs = 0.307) and GH-specific adherence (rs = 0.226). Better mental QoL (rs = 0.210) but worse physical QoL (rs = -0.198; all p < 0.05) were related to higher GH-specific adherence. Older age was associated with a higher degree of active coping, a higher belief in the necessity of medication and worse physical QoL. Conclusion: We provide preliminary data that most GHD patients on GHRx are strongly convinced of their need for medication and that adherence to GHRx is influenced by coping strategies and QoL. Patients with impaired psychological QoL are less able to translate their convictions into good adherence, a phenomenon to be addressed in future research.

Characteristics of Patients with Type 1 Diabetes and Additional Autoimmune Disease in the DPV Registry.

CONTEXT: Autoimmune diseases affect ~8% of the population. Type 1 diabetes mellitus (T1DM) is linked to other autoimmune diseases (AIDs), such as autoimmune thyroid disease or Addison's disease (AD), that may impact diabetes therapy and outcome. OBJECTIVE: To analyze demographic and clinical characteristics of other AIDs in T1DM from a large standardized registry, the Prospective Diabetes Follow-up Registry (DPV). METHODS: We searched the registry for T1DM with the additional diagnosis of Hashimoto's thyroiditis (HT), Graves' disease (GD), and/or AD. T1DM with other AIDs (n = 6166, 5.4%) were compared with isolated T1DM (n = 107 457). For group comparisons, we used multivariable regression models with age, sex, diabetes duration, migration background, and type of insulin regimen as basic adjustments (microvascular endpoints: additionally adjusted for glycated hemoglobin). RESULTS: Patients with additional AIDs were more often female (54.7 vs 32.0%, P < .001) and had a longer diabetes duration (7.9 [4.2-12.5] vs 6.7 [2.7-12.9] years, P < .001). After adjustment, daily insulin dosage was higher in AD and HT than in isolated T1DM (0.858 ±â€…0.032 and 0.813 ±â€…0.005 vs 0.793 ±â€…0.001 IU/kg per day). Retinopathy was less common in HT (1.5%), whereas it was more frequent in GD (3.1%) than in isolated T1DM (1.8%). In both GD and HT, microalbuminuria occurred less often (10.6% and 14.3% vs 15.5%) and neuropathy (2.1% and 1.8% vs 0.8%) was more common than in isolated T1DM. All P < .05. CONCLUSION: T1DM with additional AIDs show heterogeneous differences compared with isolated T1DM. T1DM plus AD or HT requires more insulin. Further, the rate of neuropathy is higher in HT or GD, whereas the rate of microalbuminuria is lower.

Comparing diabetes due to diseases of the exocrine pancreas to type 1 and type 2 diabetes using propensity score matching.

OBJECTIVE: To estimate the prevalence of diabetes due to diseases of the exocrine pancreas (DEP) using data of the multicentre diabetes patient follow-up registry. Moreover, we aimed at comparing individuals with diabetes due to DEP to individuals with type 1 and type 2 diabetes. METHODS: Individuals with DEP, type 1 or type 2 diabetes ≥18 years of age were studied. We aggregated the most recent treatment year per patient and used propensity scores to match diabetes due to DEP to type 1 and type 2 diabetes. Matching was conducted one-to-one with sex, age, diabetes duration, migration background and the German index of socioeconomic deprivation as covariates. RESULTS: We identified 7,093 (1.6%) individuals with diabetes due to DEP. In the matched cohort DEP-type 1 diabetes we observed a similar daily insulin dose (0.62 IU/kg (95% confidence interval:0.60-0.63), 0.60 IU/kg (0.58-0.62)) and significant differences regarding microvascular (41.0% (39.7-42.2), 45.3% (44.0-46.6)), and macrovascular disease (16.6% (15.7-17.6), 14.7% (13.8-15.6)). HbA1c (8.2% (8.1-8.3), 7.9% (7.8-8.0)), daily insulin dose (0.60 IU/kg (0.58-0.62), 0.56 IU/kg (0.54-0.58)) and event rates of severe hypoglycemia (23.9 events/100 PY (21.4-26.8), (9.5 events/100 PY (8.0-11.2)) were significantly higher in individuals with diabetes due to DEP compared to type 2 diabetes. CONCLUSIONS: Using registry data, rare diabetes types such as diabetes due to DEP can be studied with a significant sample size. Our study identified differences and similarities between adult individuals with DEP related diabetes and type 1 or type 2 diabetes.

Motivation for and adherence to growth hormone replacement therapy in adults with hypopituitarism: the patients' perspective.

INTRODUCTION: While reasons for non-adherence in children requiring growth hormone (GH) replacement (GH-Rx) are well researched, few studies have investigated adherence in adult GH deficient patients. Against the background of the adverse medical sequelae of untreated severe GH deficiency (GHD) in adults, we explored adherence to GH-Rx and associated factors in this patient group. METHOD: Cross-sectional analysis including 107 adult patients with severe GHD on GH-Rx, 15 untreated GDH patients and 19 who had discontinued therapy. Patients completed self-developed ad hoc surveys on adherence to medication and GH-Rx, specific beliefs about GH-Rx, side effects and burden of injection, reasons for never receiving or dropping out of therapy, respectively. RESULTS: Adherence to GH-Rx was high (mean 15.8/18 points on the self-developed adherence score) and significantly correlated with general medication adherence. Higher age was significantly associated with better adherence to GH-Rx, while injection side effects, duration of treatment or device used were not. The most frequent reasons for not being on GH-Rx apart from medical reasons included fear of side effects, lack of belief in treatment effects and dislike of injections. In patients not on GH-Rx, the proportion of patients in employment was significantly smaller than in the treatment group, despite similar age and comorbidities. CONCLUSIONS: Adherence to GH-Rx was high for those patients on therapy. Instead of focusing on improving adherence in those adults already on GH-Rx, efforts should be undertaken to ally fear of side effects and provide education on positive treatment effects for those eligible but not receiving therapy.

Undertreatment of cardiovascular risk factors in the type 1 diabetes exchange clinic network (United States) and the prospective diabetes follow-up (Germany/Austria) registries.

AIM: To examine the control of cardiovascular risk factors in type 1 diabetes (T1D) registries from the United States and Germany/Austria. MATERIALS AND METHODS: Data on individuals aged ≥12 years with T1D for ≥1 year, from the T1D Exchange Clinic Network (T1DX, United States) and the Prospective Diabetes Follow-up Registry (DPV, Germany/Austria) from 1 January 2016 to 31 March 2018 were analysed. Linear and logistic regression models adjusted for age groups, sex, duration of diabetes and minority status were used to compare clinical characteristics and achievement of diabetes management targets between registries. RESULTS: The cohort consisted of 47 936 patients (T1DX, n = 19 442; DPV, n = 28 494). Achievement of HbA1c goals (<7.0%, ages 18-65 years; all others, <7.5%) was better in the DPV for those aged <65 years (all P < .001). However, more older adults (aged ≥65 years) in the T1DX achieved an HbA1c goal of <7.5% compared with DPV (70% vs. 50%, P < .001). The frequency of patients with overweight (53% vs. 51%, P < .001) and obesity (19% vs. 9%, P < .001) was higher in T1DX. The frequency of meeting blood pressure goals (84% vs. 66%, P < .001) and lipid goals (73% vs. 62%, P < .001) was higher in T1DX; this was observed across all age groups (all P < .001). Few young adults aged <26 years received antihypertensive and lipid-lowering medications, respectively, despite indications in both registries (T1DX: 5% and 3%, DPV: 3% and 1%). CONCLUSION: A minority of patients with T1D achieve glycaemic targets and the majority are inadequately treated for hypertension and dyslipidaemia. This highlights the need for improved diabetes and cardiovascular risk management strategies in T1D.

Q fever: Evidence of a massive yet undetected cross-border outbreak, with ongoing risk of extra mortality, in a Dutch-German border region.

BACKGROUND: Following outbreaks in other parts of the Netherlands, the Dutch border region of South Limburg experienced a large-scale outbreak of human Q fever related to a single dairy goat farm in 2009, with surprisingly few cases reported from neighbouring German counties. Late chronic Q fever, with recent spikes of newly detected cases, is an ongoing public health concern in the Netherlands. We aimed to assess the scope and scale of any undetected cross-border transmission to neighbouring German counties, where individuals unknowingly exposed may carry extra risk of overlooked diagnosis. METHODS: (A) Seroprevalence rates in the Dutch area were estimated fitting an exponential gradient to the geographical distribution of notified acute human Q fever cases, using seroprevalence in a sample of farm township inhabitants as baseline. (B) Seroprevalence rates in 122 neighbouring German postcode areas were estimated from a sample of blood donors living in these areas and attending the regional blood donation centre in January/February 2010 (n = 3,460). (C) Using multivariate linear regression, including goat and sheep densities, veterinary Q fever notifications and blood donor sampling densities as covariates, we assessed whether seroprevalence rates across the entire border region were associated with distance from the farm. RESULTS: (A) Seroprevalence in the outbreak farm's township was 16.1%. Overall seroprevalence in the Dutch area was 3.6%. (B) Overall seroprevalence in the German area was 0.9%. Estimated mean seroprevalence rates (per 100,000 population) declined with increasing distance from the outbreak farm (0-19 km = 2,302, 20-39 km = 1,122, 40-59 km = 432 and ≥60 km = 0). Decline was linear in multivariate regression using log-transformed seroprevalence rates (0-19 km = 2.9 [95% confidence interval (CI) = 2.6 to 3.2], 20 to 39 km = 1.9 [95% CI = 1.0 to 2.8], 40-59 km = 0.6 [95% CI = -0.2 to 1.3] and ≥60 km = 0.0 [95% CI = -0.3 to 0.3]). CONCLUSIONS: Our findings were suggestive of widespread cross-border transmission, with thousands of undetected infections, arguing for intensified cross-border collaboration and surveillance and screening of individuals susceptible to chronic Q fever in the affected area.

Once-weekly Somapacitan is Effective and Well Tolerated in Adults with GH Deficiency: A Randomized Phase 3 Trial.

CONTEXT: Growth hormone (GH) replacement requires daily GH injections, which is burdensome for some adult patients with GH deficiency (AGHD). OBJECTIVE: To demonstrate efficacy and safety of somapacitan, a once-weekly reversible albumin-binding GH derivative, versus placebo in AGHD. DESIGN: Randomized, parallel-group, placebo-controlled (double-blind) and active-controlled (open-label) phase 3 trial, REAL 1 (NCT02229851). SETTING: Clinics in 17 countries. PATIENTS: Treatment-naïve patients with AGHD (n = 301 main study period, 272 extension period); 257 patients completed the trial. INTERVENTIONS: Patients were randomized 2:2:1 to once-weekly somapacitan, daily GH, or once-weekly placebo for 34 weeks (main period). During the 52-week extension period, patients continued treatment with somapacitan or daily GH. MAIN OUTCOME MEASURES: Body composition measured using dual-energy x-ray absorptiometry (DXA). The primary endpoint was change in truncal fat percentage to week 34. Insulin-like growth factor 1 (IGF-I) standard deviation score (SDS) values were used to dose titrate. RESULTS: At 34 weeks, somapacitan significantly reduced truncal fat percentage (estimated difference: -1.53% [-2.68; -0.38]; P = 0.0090), demonstrating superiority compared with placebo, and it improved other body composition parameters (including visceral fat and lean body mass) and IGF-I SDS. At 86 weeks, improvements were maintained with both somapacitan and daily GH. Somapacitan was well tolerated, with similar adverse events (including injection-site reactions) compared with daily GH. CONCLUSIONS: In AGHD patients, somapacitan administered once weekly demonstrated superiority over placebo, and the overall treatment effects and safety of somapacitan were in accordance with known effects and safety of GH replacement for up to 86 weeks of treatment. Somapacitan may provide an effective alternative to daily GH in AGHD. A short visual summary of our work is available (1).

Peripheral Oxytocin Predicts Higher-Level Social Cognition in Men Regardless of Empathy Quotient.

INTRODUCTION: Pharmaceutical oxytocin (OT) administration is being tested as a novel treatment for social deficits in various psychiatric populations. However, little is known about how naturally occurring variation in peripheral OT relates to differences in social cognition. This study investigates whether healthy individuals with very high or very low levels of empathy differ in endogenous OT and whether OT plasma levels can predict performance in a mentalizing task. METHODS: 40 healthy men were included based upon their score above the 85th or below the 15th percentile of the empathy quotient inventory 1. Participants' abilities to interpret social information was assessed via the Social Detection Task 2. Plasma OT levels were analyzed using enzyme immunoassay. RESULTS: OT plasma levels predicted mentalizing performance for more ambiguous social scenes (i. e., difficult items) for all participants. We found no group differences in OT plasma levels between subjects with high and low empathy. DISCUSSION: These findings confirm a link between peripheral OT and the ability to read subtle nonverbal social cues in healthy individuals, which is independent of self-reported empathy.

Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial.

Reduced social motivation is a hallmark of individuals with autism spectrum disorders (ASDs). Although the exact neural mechanisms are unclear, oxytocin has been shown to enhance motivation and attention to social stimuli, suggesting a potential to augment social reinforcement learning as the central mechanism of behavioral interventions in ASD. We tested how reinforcement learning in social contexts and associated reward prediction error (RPE) signals in the nucleus accumbens (NAcc) were modulated by intranasal oxytocin. Male adults with a childhood diagnosis of ASD (n = 15) and healthy controls (n = 24; aged 18-26 years) performed a probabilistic reinforcement learning task during functional magnetic resonance imaging in a single-center (research center in Germany), randomized double-blind, placebo-controlled cross-over trial. The interventions were intranasal oxytocin (Syntocinon®, Novartis; 10 puffs = 20 international units (IUs) per treatment) and placebo spray. Using computational modeling of behavioral data, trial-by-trial RPE signals were assessed and related to brain activation in NAcc during reinforcing feedback in social and non-social contexts. The order of oxytocin/placebo was randomized for 60 participants. Twenty-one participants were excluded from analyses, leaving 39 for the final analysis. Behaviorally, individuals with ASD showed enhanced learning under oxytocin when the learning target as well as feedback was social as compared to non-social (social vs. non-social target: 87.09% vs. 71.29%, 95% confidence interval (CI): 7.28-24.33, p = .003; social vs. non-social feedback: 81.00% vs. 71.29%, 95% CI: 2.81-16.61, p = .027). Correspondingly, oxytocin enhanced the correlation of the RPE signal with NAcc activation during social (vs. non-social) feedback in ASD (3.48 vs. -1.12, respectively, 95% CI: 2.98-6.22, p = .000), whereas in controls, this effect was found in the placebo condition (2.90 vs. -1.14, respectively, 95% CI: 1.07-7.01, p = .010). In ASD, a similar pattern emerged when the learning target was social (3.00 vs. -0.64, respectively, 95% CI: -0.13 to 7.41, p = .057), whereas controls showed a reduced correlation for social learning targets under oxytocin (-0.70 vs. 2.72, respectively, 95% CI: -5.86 to 0.98, p = .008). The current data suggest that intranasal oxytocin has the potential to enhance social reinforcement learning in ASD. Future studies are warranted that investigate whether oxytocin can potentiate social learning when combined with behavioral therapies, resulting in greater treatment benefits than traditional behavior-only approaches.

Investigating the impact of overnight fasting on intrinsic functional connectivity: a double-blind fMRI study.

The human brain depends mainly on glucose supply from circulating blood as an energy substrate for its metabolism. Most of the energy produced by glucose catabolism in the brain is used to support intrinsic communication purposes in the absence of goal-directed activity. This intrinsic brain function can be detected with fMRI as synchronized fluctuations of the BOLD signal forming functional networks. Here, we report results from a double-blind, placebo controlled, cross-over study addressing changes in intrinsic brain activity in the context of very low, yet physiological, blood glucose levels after overnight fasting. Comparison of four major resting state networks in a fasting state and a state of elevated blood glucose levels after glucagon infusion revealed altered patterns of functional connectivity only in a small region of the posterior default mode network, while the rest of the networks appeared unaffected. Furthermore, low blood glucose was associated with changes in the right frontoparietal network after cognitive effort. Our results suggest that fasting has only limited impact on intrinsic brain activity, while a detrimental impact on a network related to attention is only observable following cognitive effort, which is in line with ego depletion and its reliance on glucose.

QT prolongation caused by insulin-induced hypoglycaemia - An interventional study in 119 individuals.

AIMS: Hypoglycaemia is associated with increased risk of cardiovascular events and mortality in patients with diabetes, but the extent and mechanisms of this link are ill defined. We here prospectively studied cardiac repolarization abnormalities during insulin-induced hypoglycaemia in humans. METHODS: 119 individuals (69 males, age 47.5±13.4years, range 18-82years) were assessed during hypoglycaemia after the injection of 0.1-0.25units/kg human insulin. Corrected QT intervals (QTc) and QT dispersion (QTd) were calculated from serially recorded twelve lead electrocardiograms, and plasma glucose and other endocrine markers were studied. RESULTS: QTc increased from 415.1±21.9ms (mean±standard deviation) at baseline to 444.9±26.5ms during hypoglycaemia (plasma glucose nadir, 1.6±0.5mmol/L, p=0.001), accompanied by an increase of QTd from 45.0±22.7ms to 64.1±40.0ms (p<0.001). Hypoglycaemia-induced abnormal QTc prolongation (defined as ⩾460ms in females and ⩾450ms in males) occurred in 17% (9/54) of females and 26% (17/65) of males. 97 of 119 of individuals (82%) developed transient hypokalaemia (K+ ⩽3.6mmol/L), and plasma epinephrine increased from 220.4±169.5pmol/L at baseline to 2945.6±2421.4pmol/L during hypoglycaemia. Baseline QTc, but not age or gender, was a significant predictor of hypoglycaemia-induced QTc prolongation (p=0.001). CONCLUSIONS: Insulin-induced hypoglycaemia frequently causes abnormal QT prolongation and is associated with hypokalaemia and sympathoadrenal activation, thereby increasing the potential risk for ventricular arrhythmias, particularly in individuals with pre-existing high normal QTc.