The modern understanding of sleep is based on the classification of sleep into stages defined by their electroencephalography (EEG) signatures, but the underlying brain dynamics remain unclear. Here we aimed to move significantly beyond the current state-of-the-art description of sleep, and in particular to characterise the spatiotemporal complexity of whole-brain networks and state transitions during sleep. In order to obtain the most unbiased estimate of how whole-brain network states evolve through the human sleep cycle, we used a Markovian data-driven analysis of continuous neuroimaging data from 57 healthy participants falling asleep during simultaneous functional magnetic resonance imaging (fMRI) and EEG. This Hidden Markov Model (HMM) facilitated discovery of the dynamic choreography between different whole-brain networks across the wake-non-REM sleep cycle. Notably, our results reveal key trajectories to switch within and between EEG-based sleep stages, while highlighting the heterogeneities of stage N1 sleep and wakefulness before and after sleep.

IMPORTANCEIt is unclear whether a lifestyle intervention can maintain glycemic control in patients with type 2 diabetes. OBJECTIVE To test whether an intensive lifestyle intervention results in equivalent glycemic control compared with standard care and, secondarily, leads to a reduction in glucose-lowering medication in participants with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Randomized, assessor-blinded, single-center study within Region Zealand and the Capital Region of Denmark (April 2015-August 2016). Ninety-eight adult participants with non-insulin-dependent type 2 diabetes who were diagnosed for less than 10 years were included. Participants were randomly assigned (2:1; stratified by sex) to the lifestyle group (n = 64) or the standard care group (n = 34).INTERVENTIONS All participants received standard care with individual counseling and standardized, blinded, target-driven medical therapy. Additionally, the lifestyle intervention included 5 to 6 weekly aerobic training sessions (duration 30-60 minutes), of which 2 to 3 sessions were combined with resistance training. The lifestyle participants received dietary plans aiming for a body mass index of 25 or less. Participants were followed up for 12 months.MAIN OUTCOMES AND MEASURES Primary outcome was change in hemoglobin A 1c (HbA 1c ) from baseline to 12-month follow-up, and equivalence was prespecified by a CI margin of ±0.4% based on the intention-to-treat population. Superiority analysis was performed on the secondary outcome reductions in glucose-lowering medication. RESULTS Among 98 randomized participants (mean age, 54.6 years [SD, 8.9]; women, 47 [48%]; mean baseline HbA 1c , 6.7%), 93 participants completed the trial. From baseline to 12-month follow-up, the mean HbA 1c level changed from 6.65% to 6.34% in the lifestyle group and from 6.74% to 6.66% in the standard care group (mean between-group difference in change of −0.26% [95% CI, −0.52% to −0.01%]), not meeting the criteria for equivalence (P = .15). Reduction in glucose-lowering medications occurred in 47 participants (73.5%) in the lifestyle group and 9 participants (26.4%) in the standard care group (difference, 47.1 percentage points [95% CI, 28.6-65.3]). There were 32 adverse events (most commonly musculoskeletal pain or discomfort and mild hypoglycemia) in the lifestyle group and 5 in the standard care group.CONCLUSIONS AND RELEVANCE Among adults with type 2 diabetes diagnosed for less than 10 years, a lifestyle intervention compared with standard care resulted in a change in glycemic control that did not reach the criterion for equivalence, but was in a direction consistent with benefit. Further research is needed to assess superiority, as well as generalizability and durability of findings.

Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY, resulted in concomitant increased secretion of the other, probably explaining the absent effect on food intake on these experimental days. Combined blockade of GLP-1 and PYY actions increased food intake after RYGB, supporting that these hormones have a role in decreased food intake postoperatively.

We aimed to study the relationship between pain perception and cytokine release during systemic inflammation. We present a randomized crossover trial in healthy volunteers (n = 17) in 37 individual trials. Systemic inflammation was induced by an i.v. bolus of Escherichia coli LPS (2 ng/kg) on two separate trial days, with or without a nicotine patch applied 10 h previously. Pain perception at baseline, and 2 and 6 h after LPS was assessed by pressure algometry and tonic heat stimulation at an increasing temperature (45-48℃) during both trials. Compared with baseline, pain pressure threshold was reduced 2 and 6 h after LPS, while heat pain perception was accentuated at all testing temperatures after 2 but not 6 h. The magnitude of changes in pain perception did not correlate to cytokine release. No effect of transdermal nicotine or training status was observed. In conclusion, LPS administration in healthy human volunteers leads to reduction in pain pressure threshold and an increase in pain perception to heat stimuli, supporting a relationship between acute systemic inflammation and pain perception.

BackgroundLevodopa‐induced dyskinesias are a common side effect of dopaminergic therapy in PD, but their neural correlates remain poorly understood.ObjectivesThis study examines whether dyskinesias are associated with abnormal dopaminergic modulation of resting‐state cortico‐striatal connectivity.MethodsTwelve PD patients with peak‐of‐dose dyskinesias and 12 patients without dyskinesias were withdrawn from dopaminergic medication. All patients received a single dose of fast‐acting soluble levodopa and then underwent resting‐state functional magnetic resonance imaging before any dyskinesias emerged. Levodopa‐induced modulation of cortico‐striatal resting‐state connectivity was assessed between the putamen and the following 3 cortical regions of interest: supplementary motor area, primary sensorimotor cortex, and right inferior frontal gyrus. These functional connectivity measures were entered into a linear support vector classifier to predict whether an individual patient would develop dyskinesias after levodopa intake. Linear regression analysis was applied to test which connectivity measures would predict dyskinesia severity.ResultsDopaminergic modulation of resting‐state connectivity between the putamen and primary sensorimotor cortex in the most affected hemisphere predicted whether patients would develop dyskinesias with a specificity of 100% and a sensitivity of 91% (P < .0001). Modulation of resting‐state connectivity between the supplementary motor area and putamen predicted interindividual differences in dyskinesia severity (R 2 = 0.627, P = .004). Resting‐state connectivity between the right inferior frontal gyrus and putamen neither predicted dyskinesia status nor dyskinesia severity.ConclusionsThe results corroborate the notion that altered dopaminergic modulation of cortico‐striatal connectivity plays a key role in the pathophysiology of dyskinesias in PD. © 2016 International Parkinson and Movement Disorder Society

-Exaggerated secretion of glucagon-like peptide 1 (GLP-1) is important for postprandial glucose tolerance after Roux-en-Y gastric bypass (RYGB), whereas the role of glucose-dependent insulinotropic polypeptide (GIP) remains to be resolved. We aimed to explore the relative importance of endogenously secreted GLP-1 and GIP on glucose tolerance and ␤-cell function after RYGB. We used DPP-4 inhibition to enhance concentrations of intact GIP and GLP-1 and the GLP-1 receptor antagonist exendin-(9 -39) (Ex-9) for specific blockage of GLP-1 actions. Twelve glucose-tolerant patients were studied after RYGB in a randomized, placebo-controlled, 4-day crossover study with standard mixed-meal tests and concurrent administration of placebo, oral sitagliptin, Ex-9 infusion, or combined Ex-9-sitagliptin. GLP-1 receptor antagonism increased glucose excursions, clearly attenuated ␤-cell function, and aggravated postprandial hyperglucagonemia compared with placebo, whereas sitagliptin had no effect despite two-to threefold increased concentrations of intact GLP-1 and GIP. Similarly, sitagliptin did not affect glucose tolerance or ␤-cell function during GLP-1R blockage. This study confirms the importance of GLP-1 for glucose tolerance after RYGB via increased insulin and attenuated glucagon secretion in the postprandial state, whereas amplification of the GIP signal (or other DPP-4-sensitive glucose-lowering mechanisms) did not appear to contribute to the improved glucose tolerance seen after RYGB.Roux-en-Y gastric bypass; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; exendin-(9 -39); dipeptidyl peptidase-4 inhibition ROUX-EN-Y GASTRIC BYPASS (RYGB) is an effective treatment of severe obesity and induces large and sustainable weight loss, which is superior to diet, intensive lifestyle, or pharmaceutical interventions (47, 51). Moreover, RYGB improves glycemic control within days after surgery, before major weight loss (24), and induces remission of type 2 diabetes in the majority of patients (5, 47). Patients with preoperative normal glucose tolerance (NGT) also display changed postprandial glycemic profile after RYGB with increased peak plasma glucose, followed by a lower nadir (24,45). A combination of improved hepatic insulin sensitivity induced by hypocaloric postoperative diet (18), rapid glucose absorption (19), and exaggerated postprandial insulin secretion seems to be responsible for the early changes in glucose metabolism after RYGB in patients with NGT and type 2 diabetes (3).The postprandial gastrointestinally induced stimulation of insulin secretion, the incretin effect, is due to the insulinotropic effects of the two hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (38,56). In glucose-tolerant subjects, GLP-1 and GIP contribute nearly equally to the incretin effect, which explains up to 70% of the postprandial insulin secretion (36,38,56). The incretin effect is severely impaired in type 2 diabetes (35) but is also reduced in obese people with NGT ...

Breaking up prolonged sitting with nonambulatory standing across 9 h acutely reduced postprandial glycemic response during and the day after the intervention independent of insulin levels, whereas a 30-min MVPA bout did not.

Postprandial secretion of glucagon‐like peptide‐1 (GLP‐1) is enhanced after Roux‐en‐Y gastric bypass (RYGB), but the precise molecular mechanisms explaining this remain poorly understood. Plasma concentrations of bile acids (BAs) increase after RYGB, and BAs may act as molecular enhancers of GLP‐1 secretion through activation of TGR5‐receptors. We aimed to evaluate GLP‐1 secretion after oral administration of the primary bile acid chenodeoxycholic acid (CDCA) and the secondary bile acid ursodeoxycholic acid (UDCA) (which are available for oral use) in RYGB‐operated participants. Eleven participants (BMI 29.1 ± 1.2, age 37.0 ± 3.2 years, time from RYGB 32.3 ± 1.1 months, weight loss after RYGB 37.0 ± 3.1 kg) were studied in a placebo‐controlled, crossover‐study. On three different days, participants ingested (1) placebo (water), (2) UDCA 750 mg, (3) CDCA 1250 mg (highest recommended doses). Oral intake of CDCA increased plasma concentrations of GLP‐1, C‐peptide, glucagon, peptide YY, neurotensin, total bile acids, and fibroblast growth factor 19 significantly compared with placebo (all P < 0.05 for peak and positive incremental area‐under‐the‐curve (piAUC)). All plasma hormone concentrations were unaffected by UDCA. Neither UDCA nor CDCA changed glucose, cholecystokinin or glucose‐dependent insulinotropic polypeptide (GIP) concentrations. In conclusion, our findings demonstrate that the primary bile acid chenodeoxycholic acid is able to enhance secretion of gut hormones when administered orally in RYGB‐operated patients—even in the absence of nutrients.