649 research outputs found
Marked hyperleptinemia after high-fat diet associated with severe glucose intolerance in mice
We asked whether the likelihood for mice of the C57BL/6J strain to develop glucose intolerance when fed a high-fat diet is related to the increase in circulating levels of leptin or free fatty acids (FFA). We therefore administered a high-fat diet (58% fat) or a control diet (11% fat) for 1.5 years. NMRI mice were used as a more glucose-tolerant control group. After a high-fat diet, the area under the glucose curve following an intraperitoneal glucose challenge (1g/kg) increased more markedly in C57BL/6J mice (by 42 +/- 8%) than in NMRI mice (by 21 +/- 3%, P = 0.007). Plasma levels of insulin, leptin and FFA increased in both strains of mice, whereas plasma glucose levels were elevated after the high-fat diet only in C57BL/6J mice. The slope of the relationship between body weight and plasma leptin was higher in C57BL/6J mice than in NMRI mice, suggesting leptin insensitivity. Circulating leptin correlated to circulating insulin in both strains of mice, whereas plasma FFA correlated to plasma insulin in NMRI mice but not in C57BL/6J mice. These correlations remained significant after adjustment for body weight. The results show that elevated leptin and FFA levels evolve after high-fat feeding in mice, in conjunction with evolvement of glucose intolerance and hyperglycemia
Changes in Prandial Glucagon Levels After a 2-Year Treatment With Vildagliptin or Glimepiride in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy
OBJECTIVE - To determine if the dipeptidyl peptidase-4 inhibitor vildagliptin more effectively inhibits glucagon levels than the sulfonylurea glimepiride during a meal. RESEARCH DESIGN AND METHODS - Glucagon responses to a standard meal were measured at baseline and study end point (mean 1.8 years) in a trial evaluating add-on therapy to metformin with 50 mg vildagliptin bid. compared with glimepiride up to 6 mg q.d. in type 2 diabetes (baseline MC 7.3 +/- 0.6%). RESULTS - A1C and prandial glucose area under the curve (AUC)(0-2 h) were reduced similarly in both groups, whereas prandial insulin AUC(0-2 h) increased to a greater extent by glimepiride. Prandial glucagon AUC(0-2 h) (baseline 66.6 +/- 2.3 pmol . h(-1) . l(-1)) decreased by 3.4 +/- 1.6 pmol . h(-1) . l(-1) by vildagliptin (n = 137) and increased by 3.8 +/- 1.7 pmol . h(-1) . l(-1) by glimepiride (n = 121). The between-group difference was 7.3 +/- 2.1 pmol . h(-1) . l(-1) (P < 0.001). CONCLUSIONS - Vildagliptin therapy but not glimepiride improves postprandial a-cell function, which persists for at least 2 years
Effects of glucagon-like peptide-I on glucose turnover in rats
The influences of glucagon-like peptide-I-(7-36) amide (GLP-I; 15 pmol . kg(-1). min(-1)) on glucose turnover were studied in freely moving Wistar rats. In fed rats, GLP-I reduced plasma glucose (from 7.3 +/- 0.2 to 5.6 +/- 0.3 mmol/l; P = 0.017), increased plasma insulin (from 20 +/- 3 to 89 +/- 11 mU/l; P = 0.002), and reduced plasma glucagon (from 44 +/- 1 to 35 +/- 2 pg/ml; P = 0.009) and glucose appearance rate (R(a); from 3.9 1 0.2 to 1.7 +/- 0.7 mu mol . min(-1). 100 g(-1) after 30 min; P = 0.049) without affecting glucose disappearance rate (R(d)). The glucose clearance rate (MCR) was increased (P = 0.048). In 48-h-fasted rats, GLP-I reduced plasma glucose (from 5.0 +/- 0.2 to 4.4 +/- 0.3 mmol/l; P = 0.035) and increased plasma insulin (from 4 +/- 1 to 25 +/- 10 mU/l; P = 0.042) and plasma glucagon (from 43 +/- 3 to 61 +/- 7 pg/ml; P = 0.046). R(a) and R(d) were not significantly affected, although R(a) was lower than R(d) after 15-30 min (P = 0.005) and MCR was increased (P = 0.049). Thus GLP-I reduces R(a) in fed rats and increases MCR in fed and fasted rats. The reduced R(a) seems mediated by an increased insulin-to-glucagon ratio; the increased glucose clearance seems dependent on insulin and a peripheral effect of GLP-I
β- and α-Cell Dysfunction in Subjects Developing Impaired Glucose Tolerance: Outcome of a 12-Year Prospective Study in Postmenopausal Caucasian Women
OBJECTIVE— This study assessed insulin and glucagon secretion in relation to insulin sensitivity in Caucasian women who develop impaired glucose tolerance (IGT) versus those who maintain normal glucose tolerance (NGT) over a 12-year period
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
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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
Accelerating Drug Development Using Biomarkers: A Case Study with Sitagliptin, A Novel DPP4 Inhibitor for Type 2 Diabetes
The leveraged use of biomarkers presents an opportunity in understanding target engagement and disease impact while accelerating drug development. For effective integration in drug development, it is essential for biomarkers to aid in the elucidation of mechanisms of action and disease progression. The recent years have witnessed significant progress in biomarker selection, validation, and qualification, while enabling surrogate and clinical endpoint qualification and application. Biomarkers play a central role in target validation for novel mechanisms. They also play a central role in the learning/confirming paradigm, particularly when utilized in concert with pharmacokinetic/pharmacodynamic modeling. Clearly, these attributes make biomarker integration attractive for scientific and regulatory applications to new drug development. In this review, applications of proximal, or target engagement, and distal, or disease-related, biomarkers are highlighted using the example of the recent development of sitagliptin for type 2 diabetes, wherein elucidation of target engagement and disease-related biomarkers significantly accelerated sitagliptin drug development. Importantly, use of biomarkers as tools facilitated design of clinical efficacy trials while streamlining dose focus and optimization, the net impact of which reduced overall cycle time to filing as compared to the industry average
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