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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.

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.

In summary, this article briefly reviews the evidence that three separate autonomic inputs to the islet are capable of stimulating glucagon secretion and that each is activated during IIH. We have reviewed our evidence that these autonomic inputs mediate the glucagon response to IIH, both in non-diabetic animals and humans. Finally, we outline our new preliminary data suggesting an eSIN in an autoimmune animal model of T1DM. We conclude that the glucagon response to IIH is autonomically mediated in non-diabetic animals and humans. We further suggest that at least one of these autonomic inputs, the sympathetic innervation of the islet, is diminished in autoimmune T1DM. These data raise the novel possibility that an autonomic defect contributes to the loss of the glucagon response to IIH in T1DM.

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.

Our laboratory has investigated the role of the neuropeptide galanin in the sympathetic neural control of both the canine endocrine pancreas and liver. Galanin mRNA and peptide were found in the neuronal cell bodies of the celiac ganglion, which projects fibers to both organs. Galanin fibers formed dense networks around the islets. Galanin was released from these nerves and the amount released appeared sufficient to markedly inhibit basal insulin secretion. We therefore propose that galanin is a sympathetic neurotransmitter in canine endocrine pancreas. Galanin was also found in hepatic nerves usually co-localized with tyrosine hydroxylase, a sympathetic marker. Further, intraportal administration of the sympathetic neurotoxin, 6-hydroxydopamine, abolished galanin staining in the hepatic parenchyma. We evaluated the role of galanin in mediating the actions of sympathetic nerves to increase hepatic glucose production and decrease hepatic arterial conductance. Local infusion of synthetic galanin had little effect by itself, but it did potentiate the action of norepinephrine to stimulate hepatic glucose production, demonstrating a neuromodulatory action. In contrast, galanin had no effect on hepatic arterial blood flow. We therefore propose that in the liver galanin functions as a neuromodulator of norepinephrine's metabolic action.

Mechanisms regulating circulating leptin are incompletely understood. We developed a radioimmunoassay for mouse leptin to examine the influence of age, dietary fat content, and fasting on plasma concentrations of leptin in the background strain for the ob/ob mouse, the C57BL/6J mouse. Plasma leptin increased with age [5.3 +/- 0.6 ng/ml at 2 mo (n = 23) vs. 14.2 +/- 1.6 ng/ml at 11 mo (n = 15), P < 0.001]. Across all age groups (2-11 mo, n = 160), log plasma leptin correlated with body weight (r = 0.68, P < 0.0001), plasma insulin (r = 0.38, P < 0.001), and amount of intra-abdominal fat (r = 0.90, P < 0.001), as revealed by magnetic resonance imaging. Plasma leptin was increased by a high-fat diet (58% fat for 10 mo) and reduced by fasting for 48 h. The reduction of plasma leptin was correlated with the reduction of plasma insulin (r = 0.43, P = 0.012) but not with the initial body weight or the change in body weight. Moreover, the reduction in plasma leptin by fasting was impaired by high-fat diet. Thus plasma leptin in C57BL/6J mice 1) increases with age or a high-fat diet; 2) correlates with body weight, fat content, and plasma insulin; and 3) is reduced during fasting by an action inhibited by high-fat diet and related to changes of plasma insulin.

Despite evidence that the autonomic nervous system (ANS) makes a significant contribution to increased glucagon secretion during insulin-induced hypoglycemia in several animal species, including a recent study in nonhuman primates, the role of the ANS in mediating this important counterregulatory response in humans remains controversial. Therefore, glucagon responses to insulin-induced hypoglycemia were examined in seven nondiabetic women (BMI, 28.0 +/- 2.0 kg/m2) with and without the presence of the ganglionic nicotinic receptor antagonist trimethaphan. Trimethaphan impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia and in the adrenal medulla and, therefore, markedly impairs autonomic activation during insulin-induced hypoglycemia. The studies were performed in random order at least 4 weeks apart. Trimethaphan was infused at a variable rate (0.3-0.6 mg/min) to modestly lower blood pressure (approximately 10 mmHg) without producing hypotension. Regular human insulin was infused (0.28 pmol x m(-2) x min(-1)) with a variable rate glucose infusion to lower the plasma glucose from 4.9 +/- 0.2 to 2.6 +/- 0.2 mmol/l in the control study and from 4.9 +/- 0.2 to 2.5 +/- 0.2 mmol/l in the trimethaphan study. Trimethaphan impaired parasympathetic and sympathoadrenal activation during insulin-induced hypoglycemia as assessed by 70% reductions of the plasma pancreatic polypeptide response and epinephrine response (both P < 0.05 vs. control study). Glucagon secretory responses during insulin-induced hypoglycemia were assessed as peak responses and as the area under the curve (AUC) above baseline values during insulin-induced hypoglycemia. Plasma glucagon increased in the control study from 44 +/- 5 ng/l to a peak of 76 +/- 9 ng/l (delta = 32 +/- 8 ng/l; P < 0.005 vs. baseline) and in the trimethaphan study from 41 +/- 3 to 50 +/- 7 ng/l (delta = 10 +/- 5 ng/l; P < 0.02 vs. control subjects). The glucagon response to insulin-induced hypoglycemia as assessed by the AUC was 948 +/- 272 ng x 1(-1) x 45 min(-1) in the control study (P < 0.01 vs. baseline), but was reduced by 75% in the trimethaphan study (AUC = 203 +/- 94 ng x 1(-1) x 45 min(-1); P < 0.02 vs. control subjects). Trimethaphan did not affect the glucagon response to arginine administration. These results demonstrate that the ANS mediates the majority of the glucagon response to insulin-induced hypoglycemia of 2.5 mmol/l in postmenopausal nondiabetic women.

Neural control of pancreatic polypeptide (PP) release has not been previously investigated in the mouse. In addition, it is not known to what extent increased glucagon secretion during hypoglycemia in mice is neurally mediated vs. an effect of hypoglycemia to directly stimulate glucagon secretion at the level of the islet. Feeding or the cholinergic agonist carbachol increased plasma PP levels in conscious mice (+74 +/- 18 pg/ml vs. fasted mice and +141 +/- 17 pg/ml vs. control, respectively). Neuroglucopenia induced by 2-deoxy-D-glucose or insulin-induced hypoglycemia also increased plasma PP (+79 +/- 18 and +89 +/- 11 pg/ml vs. control, respectively). These increases were abolished by hexamethonium and reduced by atropine methylnitrate (atropine). Hypoglycemia-induced hyperglucagonemia (+1,243 +/- 275 pg/ml) was reduced to 31 +/- 7% of control by atropine (+382 +/- 85 pg/ml), to 48 +/- 9% of control by combined adrenergic blockade (+601 +/- 112 pg/ml), and nearly abolished by atropine plus combined blockade (+143 +/- 41 pg/ml; 11 +/- 3% of control) or hexamethonium (+151 +/- 38 pg/ml; 12 +/- 3% of control). We conclude the following in the mouse. 1) Feeding or cholinergic agonists increase plasma PP. 2) During neuroglucopenia or hypoglycemia, plasma PP is increased via nicotinic and muscarinic mechanisms. 3) The glucagon response to hypoglycemia is predominantly the result of autonomic activation and is mediated by both muscarinic and adrenergic mechanisms.

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.

Bo AhrénDepartment of Clinical Sciences, Lund University, Lund, SwedenAbstract: Inhibition of dipeptidyl peptidase-4 (DPP-4) prevents the inactivation of glucagonlike peptide-1 (GLP-1). This increases circulating levels of active GLP-1, stimulates insulin secretion and inhibits glucagon secretion, which results in lowering of glucose levels and improvement of the glycemic control in patients with type 2 diabetes. This review summarizes experiences with DPP-4 inhibition in the treatment of type 2 diabetes, with a focus on sitagliptin. Sitagliptin has in several clinical studies been shown to improve metabolic control in type 2 diabetes, both when used as monotherapy and when used in combination with metformin, sulfonylurea, thiazolidinediones or insulin. The reduction in HbA1c is ≈0.6% to 1.0% from baseline levels of 7.5% to 8.7% over 6 to 12 months therapy. Sitagliptin has a favorable safety profile, is highly tolerable, and there is a minimal risk of hypoglycemia. Furthermore, sitagliptin is body weight neutral or induces a slight body weight reduction. Sitagliptin may be used in the early stages of type 2 diabetes in combination with metformin or other treatments in subjects with inadequate glycemic control on these treatments alone. Sitagliptin may also be used in monotherapy and, finally, sitagliptin may be used in combination with insulin in more advanced stages of the disease.Keywords: glucagon-like peptide-1, dipeptidyl peptidase-4, type 2 diabetes, sitagliptin, treatment

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. To inform these issues, 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.

Background/Objectives: Dietary addition of either conjugated linoleic acid (CLA) or n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) has been shown to alter adiposity and circulating lipids, risk markers of cardiovascular diseases. However, CLA may decrease insulin sensitivity, an effect that may be reversed by n-3 LC-PUFA. Thus, the potential of CLA plus n-3 LC-PUFA to affect insulin secretion and sensitivity in non-diabetic young and old, lean and obese subjects was tested. Subjects/Methods: CLA (3g daily) plus n-3 LC-PUFA (3g daily) or control oil (6g daily) was given to lean (n = 12; BMI 20-26 kg/[m.sup.2]) or obese (n = 10; BM I 29-35 kg/[m.sup.2]) young (20-37 years old) or lean (n = 16) or obese (n = 11) older men (50-65 years) for 12 weeks. The study had a double-blind, placebo-controlled randomized crossover design, and primary end points were insulin secretion and sensitivity during a standardized meal test, evaluated by modeling glucose, insulin and C-peptide data. Results: The combination was well tolerated. There was no significant difference in fasting levels of glucose, insulin or C-peptide after CLA/n-3 LC-PUFA treatment compared with control oil. Neither insulin secretion nor estimated sensitivity was affected by CLA/n-3 LC-PUFA in lean or obese young subjects or in older lean subjects. However, in older obese subjects, estimated insulin sensitivity was reduced with CLA/n-3 LC-PUFA compared with control (P = 0.024). Conclusions: The results do not support beneficial effects of CLA/n-3 LC-PUFA for [beta]-cell dysfunction or insulin resistance in humans but suggest that insulin sensitivity in older obese subjects is reduced. doi:10.1038/ejcn.2008.45; published online 3 September 2008 Keywords: CLA; n-3 LC-PUFA; humans; insulin secretion; insulin sensitivity; obesity, Introduction There is considerable interest in conjugated linoleic acid (CLA) and n-3 polyunsaturated fatty acids (n-3 LC-PUFAs) due to their reported beneficial effects on energy metabolism and insulin sensitivity associated [...]

Syntactic violations in speech and music have been shown to elicit an anterior negativity (AN) as early as 100 ms after violation onset and a posterior positivity that peaks at roughly 600 ms (P600/LPC). The language AN is typically reported as left-lateralized (LAN), whereas the music AN is typically reported as right-lateralized (RAN). However, several lines of evidence suggest syntactic processing of language and music rely on overlapping neural systems. The current study tested the hypothesis that syntactic processing of speech and music share neural resources by examining whether musical proficiency modulates ERP indices of linguistic syntactic processing. ERPs were measured in response to syntactic violations in sentences and chord progressions in musicians and nonmusicians. Violations in speech were insertion errors in normal and semantically impoverished English sentences. Violations in music were out-of-key chord substitutions from distantly and closely related keys. Phrase-structure violations elicited an AN and P600 in both groups. Harmonic violations elicited an LPC in both groups, blatant harmonic violations also elicited a RAN in musicians only. Cross-domain effects of musical proficiency were similar to previously reported within-domain effects of linguistic proficiency on the distribution of the language AN; syntactic violations in normal English sentences elicited a left-lateralized AN in musicians and a bilateral AN in nonmusicians. The late positivities elicited by violations differed in latency and distribution between domains. These results suggest that initial processing of syntactic violations in language and music relies on shared neural resources in the general population, and that musical expertise results in more specialized cortical organization of syntactic processing in both domains.

Glucagon-like peptide-1 (GLP-1) plays a significant role in glucose homeostasis through its incretin effect on insulin secretion. However, GLP-1 also exhibits extrapancreatic actions, and in particular its possible influences on insulin sensitivity are controversial. To study the dynamic action of GLP-1 on insulin sensitivity, we applied advanced statistical modeling methods to study glucose disappearance in mice that underwent intravenous glucose tolerance test with administration of GLP-1 at various dose levels. In particular, the minimal model of glucose disappearance was exploited within a population estimation framework for accurate detection of relationships between glucose disappearance parameters and GLP-1. Minimal model parameters were estimated from glucose and insulin data collected in 209 anesthetized normal mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). Insulin secretion markedly increased, as expected, with increasing GLP-1 dose. However, minimal model-derived indexes, i.e., insulin sensitivity and glucose effectiveness, did not significantly change with GLP-1 dose. Instead, fractional turnover rate of insulin action [[P.sub.2] = 0.0207 [+ or -] 24.3% (min) at zero GLP-1 dose] increased steadily with administered GLP-1 dose, with significant differences at 10.4 nmol/kg ([P.sub.2] = 0.040 [+ or -] 15.5%, P = 0.0046) and 31.2 nmol/kg ([P.sub.2] = 0.050 [+ or -] 29.2%, P = 0.01). These results show that GLP-1 influences the dynamics of insulin action by accelerating insulin action following glucose challenge. This is a novel mechanism contributing to the glucose-lowering action of GLP-1. glucose kinetics; insulin secretion; insulin sensitivity; mathematical modeling; minimal model doi:10.1152/ajpendo.00303.2006.

In phenotype experiments in mice, determination of dynamic insulin sensitivity often uses the insulin tolerance test. However, the interpretation of this test is complicated by the counterregulation occurring at low glucose. To overcome this problem, we determined the dynamic insulin sensitivity after inhibition of endogenous insulin secretion by diazoxide (25 mg/kg) in association with intravenous administration of glucose plus insulin (the DSGIT technique). Estimation of insulin sensitivity index ([S.sub.r]) by this technique showed good correlation to [S.sub.1] from a regular intravenous glucose tolerance test (r = 0.87; P < 0.001; n = 15). With DSGIT, we evaluated dynamic insulin sensitivity in mice with a rat insulin promoter ([beta]-cell-targeted) dominant-negative mutation of hepatic nuclear factor (HNF)-l[alpha] [RIP-DN HNF-l[alpha] (Tg) mice]. When insulin was administered exogenously at the same dose in Tg and wild-type (WT) mice, plasma insulin levels were higher in WT, indicating an increased insulin clearance in Tg mice. When the diazoxide test was used, different doses of insulin were therefore administered (0.1 and 0.15 U/kg in WT and 0.2 and 0.25 U/kg in Tg) to achieve similar insulin levels in the groups. Minimal model analysis showed that [S.sub.I] was the same in the two groups (0.78 [+ or -] 0.21 x [10.sup.-4] min*[pmol.sup.-1]*[l.sup.-1] in WT vs. 0.60 [+ or -] 0.11 in Tg; P = 0.45) as was the glucose elimination rate (P = 0.27). We conclude that 1) the DSGIT technique determines the in vivo dynamic insulin action in mice, 2) insulin clearance is increased in Tg mice, and 3) chronic islet dysfunction in RIP-DN HNF-l[alpha] mice is not compensated with increased insulin sensitivity. glucose effectiveness; glucose tolerance; minimal modeling; diazoxide; insulin action

Feed replacement at weaning plays an important role in the induction of pancreatic maturation. To understand the changes in the exocrine pancreas at weaning and the relation to postweaning problems, we studied the function of the exocrine pancreas and changes of intestinal hemolytic Escherichia coli in four pigs. The pigs were chronically fitted with pancreatic duct catheters and T-shaped cannula inserted into the duodenum for reintroduction of pancreatic juice. One day before weaning (at 30 d of age), pancreatic juice was collected for 1 h before and 1 h after a morning and an evening suckling. The pigs were not creep fed, but from weaning the pigs received a standard weaning diet ad libitum. On d 1, 2, 3, and 5 after weaning, pancreatic juice was collected continuously for the 24-h period. The total pancreatic secretion was 'measured at hourly intervals,1.5-mL samples were taken for analysis, and the remaining juice was returned to the animal. On these days, samples from the duodenum, ileum, and rectum were also taken for analyses of hemolytic E. coli. From the day before to 5 d after weaning, a gradual increase in pancreatic secretion was observed concerning volume (P < .001) and protein (P < .01) and trypsin (P < .02) levels. An increase (P < .01) in hemolytic E. coli in the duodenal contents was also documented during this period. We assume that the gradual increase in the measured variables of pancreatic secretion is related to the increasing consumption of solid feed. However, the appearance of E. coli and disappearance of milk components from the gastrointestinal tract could be other factors stimulating the exocrine pancreas. Key Words: Pancreas, Pigs, Weaning, Trypsin, Escherichia coli