Proportion of participants with type 2 diabetes achieving a metabolic composite endpoint with once-weekly semaglutide treatment versus comparators: Post hoc pooled analysis from SUSTAIN 1-5, 7-10 and SUSTAIN China.

AIM: To compare the proportion of participants with type 2 diabetes (T2D) treated with once-weekly (OW) subcutaneous (SC) semaglutide versus comparators who achieved a composite metabolic endpoint. MATERIALS AND METHODS: SUSTAIN 1-5, 7-10 and SUSTAIN China trial data were pooled. Participants with T2D (aged ≥18 years) and glycated haemoglobin ≥7.0% (≥53 mmol/mol) who had been randomized to OW SC semaglutide (0.5 or 1.0 mg) or comparator in addition to background medication. Using patient-level data pooled by treatment, proportions of participants achieving the metabolic composite endpoint, defined as glycated haemoglobin <7% (<53 mmol/mol), blood pressure <140/90 mmHg and non-high-density lipoprotein cholesterol <130 mg/dl (<3.37 mmol/L), were evaluated following baseline adjustments. Endpoints were analysed per trial using a binomial logistic regression model with treatment, region/country and stratification factor as fixed effects and baseline value as covariate. Pooled analysis used logistic regression with treatment and trial as fixed effects and baseline value as covariate. RESULTS: This post hoc analysis included data from 7633 participants across 10 trials. The proportion of participants who achieved the metabolic composite endpoint was significantly higher with OW SC semaglutide 0.5 and 1.0 mg versus comparators (23.7% and 32.0% vs. 11.5%, respectively; p < .0001). Likewise, when the OW SC semaglutide doses were pooled, significantly higher proportions of patients receiving semaglutide achieved the composite metabolic endpoint versus comparators (29.1% vs. 11.4%, respectively; p < .0001). CONCLUSIONS: Treatment with OW SC semaglutide versus comparators was associated with increased proportions of participants with T2D meeting the composite metabolic endpoint.

Anger, race, and the neurocognition of threat: attention, inhibition, and error processing during a weapon identification task.

This study measured event-related brain potentials (ERPs) to test competing hypotheses regarding the effects of anger and race on early visual processing (N1, P2, and N2) and error recognition (ERN and Pe) during a sequentially primed weapon identification task. The first hypothesis was that anger would impair weapon identification in a biased manner by increasing attention and vigilance to, and decreasing recognition and inhibition of weapon identification errors following, task-irrelevant Black (compared to White) faces. Our competing hypothesis was that anger would facilitate weapon identification by directing attention toward task-relevant stimuli (i.e., objects) and away from task-irrelevant stimuli (i.e., race), and increasing recognition and inhibition of biased errors. Results partially supported the second hypothesis, in that anger increased early attention to faces but minimized attentional processing of race, and did not affect error recognition. Specifically, angry (vs. neutral) participants showed increased N1 to both Black and White faces, ablated P2 race effects, and topographically restricted N2 race effects. Additionally, ERN amplitude was unaffected by emotion, race, or object type. However, Pe amplitude was affected by object type (but not emotion or race), such that Pe amplitude was larger after the misidentification of harmless objects as weapons. Finally, anger slowed overall task performance, especially the correct identification of harmless objects, but did not impact task accuracy. Task performance speed and accuracy were unaffected by the race of the face prime. Implications are discussed.

Ageing-related changes in nap neuroscillatory activity are mediated and moderated by grey matter volume.

Ageing-related changes in grey matter result in changes in the intensity and topography of sleep neural activity. However, it is unclear whether these findings can be explained by ageing-related differences in sleep pressure or circadian influence. The current study used high-density electroencephalography to assess how grey matter volume differences between young and older adults mediate and moderate neuroscillatory activity differences during a midday nap following a motor sequencing task. Delta, theta, and sigma amplitude were reduced in older relative to young adults, especially over frontocentral scalp, leading to increases in relative delta frontality and relative sigma lateral centroposteriority. Delta reductions in older adults were mediated by grey matter loss in frontal medial cortex, primary motor cortex, thalamus, caudate, putamen, and pallidum, and were moderated by putamen grey matter volume. Theta reductions were mediated by grey matter loss in primary motor cortex, thalamus, and caudate, and were moderated by putamen and pallidum grey matter volume. Sigma changes were moderated by putamen and pallidum grey matter volume. Moderation results suggested that across frequencies, young adults with more grey matter had increased activity, whereas older adults with more grey matter had unchanged or decreased activity. These results provide a critical extension of previous findings from overnight sleep in a midday nap, indicating that they are not driven by sleep pressure or circadian confounds. Moreover, these results suggest brain regions associated with motor sequence learning contribute to sleep neural activity following a motor sequencing task.

Encoding and consolidation of motor sequence learning in young and older adults.

Sleep benefits motor memory consolidation in young adults, but this benefit is reduced in older adults. Here we sought to understand whether differences in the neural bases of encoding between young and older adults contribute to aging-related differences in sleep-dependent consolidation of an explicit variant of the serial reaction time task (SRTT). Seventeen young and 18 older adults completed two sessions (nap, wake) one week apart. In the MRI, participants learned the SRTT. Following an afternoon interval either awake or with a nap (recorded with high-density polysomnography), performance on the SRTT was reassessed in the MRI. Imaging and behavioral results from SRTT performance showed clear sleep-dependent consolidation of motor sequence learning in older adults after a daytime nap, compared to an equal interval awake. Young adults, however, showed brain activity and behavior during encoding consistent with high SRTT performance prior to the sleep interval, and did not show further sleep-dependent performance improvements. Young adults did show reduced cortical activity following sleep, suggesting potential systems-level consolidation related to automatization. Sleep physiology data showed that sigma activity topography was affected by hippocampal and cortical activation prior to the nap in both age groups, and suggested a role of theta activity in sleep-dependent automatization in young adults. These results suggest that previously observed aging-related sleep-dependent consolidation deficits may be driven by aging-related deficiencies in fast learning processes. Here we demonstrate that when sufficient encoding strength is reached with additional training, older adults demonstrate intact sleep-dependent consolidation of motor sequence learning.

Aging-Related Changes in Cortical Sources of Sleep Oscillatory Neural Activity Following Motor Learning Reflect Contributions of Cortical Thickness and Pre-sleep Functional Activity.

Oscillatory neural activity during sleep, such as that in the delta and sigma bands, is important for motor learning consolidation. This activity is reduced with typical aging, and this reduction may contribute to aging-related declines in motor learning consolidation. Evidence suggests that brain regions involved in motor learning contribute to oscillatory neural activity during subsequent sleep. However, aging-related differences in regional contributions to sleep oscillatory activity following motor learning are unclear. To characterize these differences, we estimated the cortical sources of consolidation-related oscillatory activity using individual anatomical information in young and older adults during non-rapid eye movement sleep after motor learning and analyzed them in light of cortical thickness and pre-sleep functional brain activation. High-density electroencephalogram was recorded from young and older adults during a midday nap, following completion of a functional magnetic resonance imaged serial reaction time task as part of a larger experimental protocol. Sleep delta activity was reduced with age in a left-weighted motor cortical network, including premotor cortex, primary motor cortex, supplementary motor area, and pre-supplementary motor area, as well as non-motor regions in parietal, temporal, occipital, and cingulate cortices. Sleep theta activity was reduced with age in a similar left-weighted motor network, and in non-motor prefrontal and middle cingulate regions. Sleep sigma activity was reduced with age in left primary motor cortex, in a non-motor right-weighted prefrontal-temporal network, and in cingulate regions. Cortical thinning mediated aging-related sigma reductions in lateral orbitofrontal cortex and frontal pole, and partially mediated delta reductions in parahippocampal, fusiform, and lingual gyri. Putamen, caudate, and inferior parietal cortex activation prior to sleep predicted frontal and motor cortical contributions to sleep delta and theta activity in an age-moderated fashion, reflecting negative relationships in young adults and positive or absent relationships in older adults. Overall, these results support the local sleep hypothesis that brain regions active during learning contribute to consolidation-related neural activity during subsequent sleep and demonstrate that sleep oscillatory activity in these regions is reduced with aging.

Metric Structure and Rhyme Predictability Modulate Speech Intensity During Child-Directed and Read-Alone Productions of Children's Literature.

Temporal and phonological predictability in children's literature may support early literacy acquisition. Realization of predictive structure in caregiver prosody could guide children's attention during shared reading, thereby supporting reading subskill development. However, little is known about how predictive structure is realized prosodically during child-directed reading. We investigated whether speakers use word intensity to signal predictive metric and rhyme structure in child-directed and read-alone productions of The Cat in the Hat (Dr. Seuss, 1957), by modeling maximum intensity (dB) of monosyllabic words as a function of metric strength, rhyme predictability, and a set of control parameters. In the control model, intensity increased with lower lexical frequency, capitalization, first mention, and likelihood of a syntactic boundary. Metric structure predicted word intensity beyond these control factors in a hierarchical manner: words aligned with beat one in a 6/8 metric structure were produced with highest intensity, words aligned with beat four were produced with intermediate intensity, and words aligned with all other beats were produced with the lowest intensity. Additionally, phonologically predictable rhyme targets were reduced in intensity. The effects of meter and rhyme were not moderated by the presence of a child audience. These results demonstrate that predictability along multiple dimensions is encoded during reading of poetic children's literature, and that metric structure is realized hierarchically in word intensity. Further, the manner by which predictability is encoded in word intensity differs from that previously reported for word duration in this corpus (Breen, 2018), demonstrating that intensity and duration present nonidentical prosodic information channels.

Event-Related Potential Evidence of Implicit Metric Structure during Silent Reading.

Under the Implicit Prosody Hypothesis, readers generate prosodic structures during silent reading that can direct their real-time interpretations of the text. In the current study, we investigated the processing of implicit meter by recording event-related potentials (ERPs) while participants read a series of 160 rhyming couplets, where the rhyme target was always a stress-alternating noun-verb homograph (e.g., permit, which is pronounced PERmit as a noun and perMIT as a verb). The target had a strong-weak or weak-strong stress pattern, which was either consistent or inconsistent with the stress expectation generated by the couplet. Inconsistent strong-weak targets elicited negativities between 80-155 ms and 325-375 ms relative to consistent strong-weak targets; inconsistent weak-strong targets elicited a positivity between 365-435 ms relative to consistent weak-strong targets. These results are largely consistent with effects of metric violations during listening, demonstrating that implicit prosodic representations are similar to explicit prosodic representations.

Effect of liraglutide on anthropometric measurements, sagittal abdominal diameter and adiponectin levels in people with type 2 diabetes treated with multiple daily insulin injections: evaluations from a randomized trial (MDI-liraglutide study 5).

AIM: Use of the glucagon-like peptide 1 receptor agonist liraglutide has been shown to reduce weight. Different types of anthropometric measurements can be used to measure adiposity. This study evaluated the effect of liraglutide on sagittal abdominal diameter, waist circumference, waist-to-hip ratio and adiponectin levels in people with type 2 diabetes (T2D) treated with multiple daily insulin injections (MDI). MATERIALS AND METHODS: In the multicentre, double-blind, placebo-controlled MDI-liraglutide trial, 124 individuals with T2D treated with MDI were randomized to either liraglutide or placebo. Basal values of weight, waist circumference, waist-to-hip ratio, sagittal abdominal diameter and adiponectin were compared with measurements at 12 and 24 weeks after randomization. RESULTS: Baseline-adjusted mean weight loss was 3.8 ± 2.9 kg greater in liraglutide than placebo-treated individuals (p < 0.0001). Waist circumference was reduced by 2.9 ± 4.3 cm and 0.2 ± 3.6 cm in the liraglutide and placebo groups, respectively, after 24 weeks (baseline-adjusted mean difference: 2.6 ± 4.0 cm, p = 0.0005). Corresponding reductions in sagittal abdominal diameter were 1.1 ± 1.7 cm and 0.0 ± 1.8 cm (baseline-adjusted mean difference: 1.1 ± 1.7 cm, p = 0.0008). Hip circumference was reduced in patients randomized to liraglutide (baseline-adjusted mean difference between treatment groups: 2.8 ± 3.8 cm, p = 0.0001), but there was no significant difference between the groups in either waist-to-hip ratio (baseline-adjusted mean difference: 0.0 ± 0.04 cm, p = 0.51) or adiponectin levels (baseline-adjusted mean difference: 0.8 ± 3.3 mg L-1, p = 0.17). Lower HbA1c and mean glucose levels measured by masked continuous glucose monitoring at baseline were associated with greater effects of liraglutide on reductions in waist circumference and sagittal abdominal diameter. CONCLUSIONS: In patients with T2D, adding liraglutide to MDI may reduce abdominal and hip obesity to a similar extent, suggesting an effect on both visceral and subcutaneous fat. Liraglutide had greater effects on reducing abdominal obesity in patients with less pronounced long-term hyperglycaemia but did not affect adiponectin levels.

Emotional Memory Moderates the Relationship Between Sigma Activity and Sleep-Related Improvement in Affect.

Sleep is essential for regulating mood and affect, and it also consolidates emotional memories. The mechanisms underlying these effects may overlap. Here, we investigated whether the influence of sleep on affect may be moderated by emotional memory consolidation. Young adults viewed 45 negative and 45 neutral pictures before taking an afternoon nap measured with polysomnography. Following the nap period, participants viewed the same pictures intermixed with novel ones and indicated whether they remembered each picture. Affect was measured with the Positive and Negative Affect Schedule (PANAS) at baseline before the initial picture viewing task, immediately following the initial picture viewing task, and following the nap. The ratio of positive to negative affect declined over the task period and recovered over the nap period. When controlling for pre-nap affect, NREM sigma activity significantly predicted post-nap affect. Memory for negative pictures moderated this relationship such that a positive association between sigma activity and affect occurred when memory was low but not when memory was high. These results indicate that emotional memory consolidation influences the relationship between nap physiology and mood.

Incorporation of feedback during beat synchronization is an index of neural maturation and reading skills.

Speech communication involves integration and coordination of sensory perception and motor production, requiring precise temporal coupling. Beat synchronization, the coordination of movement with a pacing sound, can be used as an index of this sensorimotor timing. We assessed adolescents' synchronization and capacity to correct asynchronies when given online visual feedback. Variability of synchronization while receiving feedback predicted phonological memory and reading sub-skills, as well as maturation of cortical auditory processing; less variable synchronization during the presence of feedback tracked with maturation of cortical processing of sound onsets and resting gamma activity. We suggest the ability to incorporate feedback during synchronization is an index of intentional, multimodal timing-based integration in the maturing adolescent brain. Precision of temporal coding across modalities is important for speech processing and literacy skills that rely on dynamic interactions with sound. Synchronization employing feedback may prove useful as a remedial strategy for individuals who struggle with timing-based language learning impairments.

Mixed meal ingestion diminishes glucose excursion in comparison with glucose ingestion via several adaptive mechanisms in people with and without type 2 diabetes.

AIMS: To study the integrative impact of macronutrients on postprandial glycaemia, ß-cell function, glucagon and incretin hormones in humans. METHODS: Macronutrients were ingested alone (glucose 330 kcal, protein 110 kcal or fat 110 kcal) or together (550 kcal) by healthy subjects (n = 18) and by subjects with drug-naïve type 2 diabetes (T2D; n = 18). ß-cell function and insulin clearance were estimated by modelling glucose, insulin and C-peptide data. Secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured, and paracetamol was administered to estimate gastric emptying. RESULTS: In both groups, the mixed-meal challenge diminished glucose excursion compared with glucose challenge alone, and insulin levels, but not C-peptide levels, rose more than after the mixed meal than after glucose alone. ß-cell function was augmented, insulin clearance was reduced and glucagon levels were higher after the mixed meal compared with glucose alone. GLP-1 and GIP levels increased after all challenges and GIP secretion was markedly higher after the mixed meal than after glucose alone. The appearance of paracetamol was delayed after the mixed-meal challenge compared with glucose alone. CONCLUSIONS: Adding protein and fat macronutrients to glucose in a mixed meal diminished glucose excursion. This occurred in association with increased ß-cell function, reduced insulin clearance, delayed gastric emptying and augmented glucagon and GIP secretion. This suggests that the macronutrient composition regulates glycaemia through both islet and extra-islet mechanisms in both healthy subjects and in subjects with T2D.

Longitudinal maturation of auditory cortical function during adolescence.

Cross-sectional studies have demonstrated that the cortical auditory evoked potential (CAEP) changes substantially in amplitude and latency from childhood to adulthood, suggesting that these aspects of the CAEP continue to mature through adolescence. However, no study to date has longitudinally followed maturation of these CAEP measures through this developmental period. Additionally, no study has examined the trial-to-trial variability of the CAEP during adolescence. Therefore, we longitudinally tracked changes in the latency, amplitude, and variability of the P1, N1, P2, and N2 components of the CAEP in 68 adolescents from age 14 years to age 17 years. Latency decreased for N1 and N2, and did not change for P1 or P2. Amplitude decreased for P1 and N2, increased for N1, and did not change for P2. Variability decreased with age for all CAEP components. These findings provide longitudinal support for the view that the human auditory system continues to mature through adolescence. Continued auditory system maturation through adolescence suggests that CAEP neural generators remain plastic during this age range and potentially amenable to experience-based enhancement or deprivation.

Musical Meter Modulates the Allocation of Attention across Time.

Dynamic attending theory predicts that attention is allocated hierarchically across time during processing of hierarchical rhythmic structures such as musical meter. ERP research demonstrates that attention to a moment in time modulates early auditory processing as evidenced by the amplitude of the first negative peak (N1) approximately 100 msec after sound onset. ERPs elicited by tones presented at times of high and low metric strength in short melodies were compared to test the hypothesis that hierarchically structured rhythms direct attention in a manner that modulates early perceptual processing. A more negative N1 was observed for metrically strong beats compared with metrically weak beats; this result provides electrophysiological evidence that hierarchical rhythms direct attention to metrically strong times during engaged listening. The N1 effect was observed only on fast tempo trials, suggesting that listeners more consistently invoke selective processing based on hierarchical rhythms when sounds are presented rapidly. The N1 effect was not modulated by musical expertise, indicating that the allocation of attention to metrically strong times is not dependent on extensive training. Additionally, changes in P2 amplitude and a late negativity were associated with metric strength under some conditions, indicating that multiple cognitive processes are associated with metric perception.

Continued maturation of auditory brainstem function during adolescence: A longitudinal approach.

OBJECTIVE: Considerable attention has been devoted to understanding development of the auditory system during the first few years of life, yet comparatively little is known about maturation during adolescence. Moreover, the few studies investigating auditory system maturation in late childhood have employed a cross-sectional approach. METHODS: To better understand auditory development in adolescence, we used a longitudinal design to measure the subcortical encoding of speech syllables in 74 adolescents at four time points from ages 14 through 17. RESULTS: We find a developmental decrease in the spectral representation of the evoking syllable, trial-by-trial response consistency, and tracking of the amplitude envelope, while timing of the evoked response appears to be stable over this age range. CONCLUSIONS: Subcortical auditory development is a protracted process that continues throughout the first two decades of life. Specifically, our data suggest that adolescence represents a transitional point between the enhanced response during childhood and the mature, though smaller, response of adults. SIGNIFICANCE: That the auditory brainstem has not fully matured by the end of adolescence suggests that auditory enrichment begun later in childhood could lead to enhancements in auditory processing and alter developmental profiles.

Physiological aspects of the combination of insulin and GLP-1 in the regulation of blood glucose control.

Combining insulin with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors as glucose-lowering therapy for type 2 diabetes is a promising strategy that has gained considerable interest over the past few years. One advantage of this combination is the complementary mechanistic actions of insulin and GLP-1. Insulin increases glucose utilization and retards hepatic glucose production through direct actions in muscle, adipose tissue and the liver. On the other hand, GLP-1 stimulates insulin secretion, inhibits glucagon secretion and retards gastric emptying. Combining these effects results in powerful reductions in both fasting and postprandial glucose through diminished glucose entry into the bloodstream after food consumption, reduced hepatic production of glucose and increased glucose utilization. In addition, GLP-1 receptor agonists induce satiety, leading to decreases in food intakes and body weight, thereby preventing the weight gain often seen with insulin therapy. Clinical trials have verified that these physiological effects as a result of combining insulin with GLP-1 receptor agonists or DPP-4 inhibitors can indeed result in improved glycaemia, with limited risks of hypoglycaemia and weight gain.

Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4), which cleaves and inactivates glucagon-like peptide 1 (GLP-1), is a glucose-lowering strategy in type 2 diabetes. Since DPP-4 is a ubiquitously distributed enzyme, we examined whether it is expressed in islets and whether an islet effect to inhibit DPP-4 may result in stimulated insulin secretion. METHODS: We investigated DPP-4 expression and activity in the islets of mouse models of obesity as well as human islets from non-diabetic and type 2 diabetic donors. We further investigated whether inhibition with DPP-4 inhibitors could promote insulin secretion via islet GLP-1 in isolated islets. RESULTS: DPP-4 was readily detected in mouse and human islets with species-specific cellular localisation. In mice, DPP-4 was expressed predominantly in beta cells, whereas in humans it was expressed nearly exclusively in alpha cells. DPP-4 activity was significantly increased in islets from diet-induced obese mice compared with mice fed a control diet. In humans, DPP-4 activity was significantly lower in islets from type 2 diabetic donors than in non-diabetic donors. In human islets, there was a significant positive correlation between DPP-4 activity and insulin secretory response to 16.7 mmol/l glucose. Treatment of mouse islets with the DPP-4 inhibitors, NVPDPP728 and vildagliptin, resulted in a significant potentiation of insulin secretion in a GLP-1-dependent manner, as this was inhibited by the GLP-1 receptor antagonist, Exendin (9-39), and was retained in glucose-dependent insulinotropic polypeptide (GIP) receptor-deficient mice but lost in mice lacking GLP-1 receptors or both incretin receptors. Human islets treated with the DPP-4 inhibitor, vildagliptin, showed increased secretion of insulin and intact GLP-1. CONCLUSIONS/INTERPRETATION: We conclude that DPP-4 is present and active in mouse and human islets, is regulated by the disease state, and that inhibition of islet DPP-4 activity can have direct effects on islet function. Inhibiting islet DPP-4 activity may therefore contribute to the insulin-secretory and glucose-lowering action of DPP-4 inhibition.

Pronounced reduction of postprandial glucagon by lixisenatide: a meta-analysis of randomized clinical trials.

AIM: Glucagon-like peptide-1 (GLP-1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aimed to investigate the effects of the once-daily prandial GLP-1 receptor agonist lixisenatide on postprandial plasma glucose (PPG), glucagon and insulin levels. METHODS: Six randomized, placebo-controlled studies of lixisenatide 20 µg once daily were included in this analysis: lixisenatide as monotherapy (GetGoal-Mono), as add-on to oral antidiabetic drugs (OADs; GetGoal-M, GetGoal-S) or in combination with basal insulin (GetGoal-L, GetGoal-Duo-1 and GetGoal-L-Asia). Change in 2-h PPG and glucose excursion were evaluated across six studies. Change in 2-h glucagon and postprandial insulin were evaluated across two studies. A meta-analysis was performed on least square (LS) mean estimates obtained from analysis of covariance (ANCOVA)-based linear regression. RESULTS: Lixisenatide significantly reduced 2-h PPG from baseline (LS mean difference vs. placebo: -4.9 mmol/l, p < 0.001) and glucose excursion (LS mean difference vs. placebo: -4.5 mmol/l, p < 0.001). As measured in two studies, lixisenatide also reduced postprandial glucagon (LS mean difference vs. placebo: -19.0 ng/l, p < 0.001) and insulin (LS mean difference vs. placebo: -64.8 pmol/l, p < 0.001). There was a stronger correlation between 2-h postprandial glucagon and 2-h PPG with lixisenatide than with placebo. CONCLUSIONS: Lixisenatide significantly reduced 2-h PPG and glucose excursion together with a marked reduction in postprandial glucagon and insulin; thus, lixisenatide appears to have biological effects on blood glucose that are independent of increased insulin secretion. These effects may be, in part, attributed to reduced glucagon secretion.

Glucagon dynamics during hypoglycaemia and food-re-challenge following treatment with vildagliptin in insulin-treated patients with type 2 diabetes.

AIMS: To determine the effects of dipeptidyl peptidase-4 (DPP-4) inhibition on glucagon dynamics in patients with insulin-treated type 2 diabetes (T2D). METHODS: The study was a single-centre, double-blind, randomized, placebo controlled crossover study in patients with T2D, mean age 59 ± 6 (s.d.) years and mean haemoglobin A1c 7.7 ± 0.8%, treated with exogenous insulin with or without oral antihyperglycaemic agents. Patients received vildagliptin (50 mg BID) or placebo as add-on to insulin for 4 weeks in random order with a 4-week washout in-between. On day 28 of the respective treatment, patients were served a standard meal (500 kcal) followed by a hyperinsulinaemic hypoglycaemic clamp (target 2.5 mmol/l) and a subsequent food re-challenge (700 kcal). The completers population (n = 29) was analysed. RESULTS: Glucose levels were lower with vildagliptin than with placebo during the meal [areas under the curve (AUC) 1.23 ± 0.07 vs. 1.46 ± 0.05 mol/l min, P < 0.001] and similar between the groups during the clamp. During the meal, glucagon levels were lower with vildagliptin (AUC 1.98 ± 0.15 vs. 2.15 ± 0.17 nmol/l min, P = 0.016). In contrast, the glucagon counter-regulation to the insulin-induced hypoglycaemia was sustained by vildagliptin (6.05 ± 1.20 pmol/l during vildagliptin vs.6.94 ± 1.09 pmol/l during placebo, NS). During the food re-challenge after hypoglycaemia, glucagon levels were, again, significantly lower after vildagliptin (AUC 1.30 ± 0.11 vs. 1.52 ± 0.12 nmol/l min, P < 0.039). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels were significantly elevated by vildagliptin compared to placebo during meal, hypoglycaemia and food re-challenge. CONCLUSIONS: Vildagliptin action to block GLP-1 and GIP inactivation by DPP-4 improves glucagon dynamics during hypoglycaemia, hyperglycaemia and food re-challenge.