Effects of obesity, pneumoperitoneum, and body position on mechanical power of intraoperative ventilation: an observational study.

Mechanical power can describe the complex interaction between the respiratory system and the ventilator and may predict lung injury or pulmonary complications, but the power associated with injury of healthy human lungs is unknown. Body habitus and surgical conditions may alter mechanical power but the effects have not been measured. In a secondary analysis of an observational study of obesity and lung mechanics during robotic laparoscopic surgery, we comprehensively quantified the static elastic, dynamic elastic, and resistive energies comprising mechanical power of ventilation. We stratified by body mass index (BMI) and examined power at four surgical stages: level after intubation, with pneumoperitoneum, in Trendelenburg, and level after releasing the pneumoperitoneum. Esophageal manometry was used to estimate transpulmonary pressures. Mechanical power of ventilation and its bioenergetic components increased over BMI categories. Respiratory system and lung power were nearly doubled in subjects with class 3 obesity compared with lean at all stages. Power dissipated into the respiratory system was increased with class 2 or 3 obesity compared with lean. Increased power of ventilation was associated with decreasing transpulmonary pressures. Body habitus is a prime determinant of increased intraoperative mechanical power. Obesity and surgical conditions increase the energies dissipated into the respiratory system during ventilation. The observed elevations in power may be related to tidal recruitment or atelectasis, and point to specific energetic features of mechanical ventilation of patients with obesity that may be controlled with individualized ventilator settings.NEW & NOTEWORTHY Mechanical power describes the complex interaction between a patient's lungs and the ventilator and may be useful in predicting lung injury. However, its behavior in obesity and during dynamic surgical conditions is not understood. We comprehensively quantified ventilation bioenergetics and effects of body habitus and common surgical conditions. These data show body habitus is a prime determinant of intraoperative mechanical power and provide quantitative context for future translation toward a useful perioperative prognostic measurement.

The neuroendocrine stress response compensates for suppression of insulin secretion by volatile anesthetic agents: An observational study.

Alterations in perioperative metabolic function, particularly hyperglycemia, are associated with increased post-operative complications, even in patients without preexisting metabolic abnormalities. Anesthetic medications and the neuroendocrine stress response to surgery may both contribute to altered energy metabolism through impaired glucose and insulin homeostasis but the discrete pathways involved are unclear. Prior human studies, though informative, have been limited by analytic sensitivity or technique, preventing resolution of underlying mechanisms. We hypothesized that general anesthesia with a volatile agent would suppress basal insulin secretion without altering hepatic insulin extraction, and that surgical stress would promote hyperglycemia through gluconeogenesis, lipid oxidation, and insulin resistance. In order to address these hypotheses, we conducted an observational study of subjects undergoing multi-level lumbar surgery with an inhaled anesthetic agent. We measured circulating glucose, insulin, c-peptide, and cortisol frequently throughout the perioperative period and analyzed the circulating metabolome in a subset of these samples. We found volatile anesthetic agents suppress basal insulin secretion and uncouple glucose-stimulated insulin secretion. Following surgical stimulus, this inhibition disappeared and there was gluconeogenesis with selective amino acid metabolism. No robust evidence of lipid metabolism or insulin resistance was observed. These results show that volatile anesthetic agents suppress basal insulin secretion, which results in reduced glucose metabolism. The neuroendocrine stress response to surgery ameliorates the inhibitory effect of the volatile agent on insulin secretion and glucose metabolism, promoting catabolic gluconeogenesis. A better understanding of the complex metabolic interaction between anesthetic medications and surgical stress is needed to inform design of clinical pathways aimed at improving perioperative metabolic function.

Coordinated regulation of gene expression and microRNA changes in adipose tissue and circulating extracellular vesicles in response to pioglitazone treatment in humans with type 2 diabetes.

Pioglitazone, a PPARγ agonist, is used to treat type 2 diabetes (T2D). PPARγ is highly expressed in adipose tissue (AT), however the effects of pioglitazone to improve insulin sensitivity are also evident in other tissues and PPARγ agonism has been shown to alter cancer derived extracellular vesicle (EV)-miRNAs. We hypothesized that pioglitazone modifies the cargo of circulating AT-derived EVs to alter interorgan crosstalk in people with diabetes. We tested our hypothesis in a 3-month trial in which 24 subjects with T2D were randomized to treatment with either pioglitazone 45 mg/day or placebo (NCT00656864). Levels of 42 adipocyte-derived EV-miRNAs were measured in plasma EVs using low density TaqMan arrays. Levels of differentially expressed EV-miRNAs and their most relevant target genes were also measure in adipose tissue from the same participants, using individual TaqMan assays. Levels of 5 miRNAs (i.e., miR-7-5p, miR-20a-5p, miR-92a-3p, miR-195-5p, and miR-374b-5p) were significantly downregulated in EVs in response to pioglitazone treatment relative to placebo. The opposite occurred for miR-195-5p in subcutaneous AT. Changes in miRNA expression in EVs and AT correlated with changes in suppression of lipolysis and improved insulin sensitivity, among others. DICER was downregulated and exosomal miRNA sorting-related genes YBX1 and hnRNPA2B1 displayed a downregulation trend in AT. Furthermore, analysis of EV-miRNA targeted genes identified a network of transcripts that changed in a coordinated manner in AT. Collectively, our results suggest that some beneficial pharmacologic effects of pioglitazone are mediated by adipose-specific miRNA regulation and exosomal/EV trafficking. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00656864.

Body Habitus and Dynamic Surgical Conditions Independently Impair Pulmonary Mechanics during Robotic-assisted Laparoscopic Surgery.

BACKGROUND: Body habitus, pneumoperitoneum, and Trendelenburg positioning may each independently impair lung mechanics during robotic laparoscopic surgery. This study hypothesized that increasing body mass index is associated with more mechanical strain and alveolar collapse, and these impairments are exacerbated by pneumoperitoneum and Trendelenburg positioning. METHODS: This cross-sectional study measured respiratory flow, airway pressures, and esophageal pressures in 91 subjects with body mass index ranging from 18.3 to 60.6 kg/m2. Pulmonary mechanics were quantified at four stages: (1) supine and level after intubation, (2) with pneumoperitoneum, (3) in Trendelenburg docked with the surgical robot, and (4) level without pneumoperitoneum. Subjects were stratified into five body mass index categories (less than 25, 25 to 29.9, 30 to 34.9, 35 to 39.9, and 40 or higher), and respiratory mechanics were compared over surgical stages using generalized estimating equations. The optimal positive end-expiratory pressure settings needed to achieve positive end-expiratory transpulmonary pressures were calculated. RESULTS: At baseline, transpulmonary driving pressures increased in each body mass index category (1.9 ± 0.5 cm H2O; mean difference ± SD; P < 0.006), and subjects with a body mass index of 40 or higher had decreased mean end-expiratory transpulmonary pressures compared with those with body mass index of less than 25 (-7.5 ± 6.3 vs. -1.3 ± 3.4 cm H2O; P < 0.001). Pneumoperitoneum and Trendelenburg each further elevated transpulmonary driving pressures (2.8 ± 0.7 and 4.7 ± 1.0 cm H2O, respectively; P < 0.001) and depressed end-expiratory transpulmonary pressures (-3.4 ± 1.3 and -4.5 ± 1.5 cm H2O, respectively; P < 0.001) compared with baseline. Optimal positive end-expiratory pressure was greater than set positive end-expiratory pressure in 79% of subjects at baseline, 88% with pneumoperitoneum, 95% in Trendelenburg, and ranged from 0 to 36.6 cm H2O depending on body mass index and surgical stage. CONCLUSIONS: Increasing body mass index induces significant alterations in lung mechanics during robotic laparoscopic surgery, but there is a wide range in the degree of impairment. Positive end-expiratory pressure settings may need individualization based on body mass index and surgical conditions.

Effects of Pioglitazone on Glucose-Dependent Insulinotropic Polypeptide-Mediated Insulin Secretion and Adipocyte Receptor Expression in Patients With Type 2 Diabetes.

Incretin hormone dysregulation contributes to reduced insulin secretion and hyperglycemia in patients with type 2 diabetes mellitus (T2DM). Resistance to glucose-dependent insulinotropic polypeptide (GIP) action may occur through desensitization or downregulation of ß-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator-activated receptor γ (PPARγ) response elements (PPREs). Whether this occurs in humans is unknown. To test this, we conducted a randomized, double-blind, placebo-controlled trial of pioglitazone therapy on GIP-mediated insulin secretion and adipocyte GIP-R expression in subjects with well-controlled T2DM. Insulin sensitivity improved, but the insulinotropic effect of infused GIP was unchanged following 12 weeks of pioglitazone treatment. In parallel, we observed increased GIP-R mRNA expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPARγ binding to GIP-R PPREs. These results show PPARγ agonists regulate GIP-R expression through PPREs in human adipocytes, but suggest this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Because GIP has antilipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPARγ agonists.

Thromboelastography Before Epidural Placement in a Thrombocytopenic Parturient With Gaucher Disease Treated With Imiglucerase: A Case Report.

Gaucher disease is a common inborn error of metabolism leading to widespread chronic inflammation and often thrombocytopenia. Here we discuss assessment of coagulation in a parturient with Gaucher disease treated with imiglucerase, who presented with thrombocytopenia and requested epidural analgesia for planned vaginal delivery. We used thromboelastography to determine the safety of placing an epidural catheter and to plan for potential peripartum bleeding. The patient had a normal coagulation profile by thromboelastography and had uncomplicated epidural analgesia for a successful spontaneous vaginal delivery.

Effects of glucose and insulin on secretion of amyloid-ß by human adipose tissue cells.

OBJECTIVE: Obesity and type 2 diabetes mellitus are risk factors for developing Alzheimer disease. Overlapping patterns of metabolic dysfunction may be common molecular links between these complex diseases. Amyloid-ß (Aß) precursor protein and associated ß- and γ-secretases are expressed in adipose tissue. Aß precursor protein is up-regulated with obesity and correlated to insulin resistance. Aß may be secreted by adipose tissue, its production may be regulated through metabolic pathways, and Aß may exert effects on adipose tissue insulin receptor signaling. METHODS: Human stromal-vascular cells and differentiated adipocytes were cultured with different combinations of glucose and insulin and then assayed for Aß in conditioned media. Aß was measured in vivo using adipose tissue microdialysis. RESULTS: Aß secretion was increased by glucose and insulin in vitro. Adipose tissue microdialysates contained Aß. Adipocytes treated with Aß had decreased expression of insulin receptor substrate-2 and reduced Akt-1 phosphorylation. CONCLUSIONS: Aß was made by adipose tissue cells in vitro at concentrations similar to in vivo measurements. Regulation of Aß production by glucose and insulin and effects of Aß on the insulin receptor pathway suggest similar cellular mechanisms may exist between neuronal dysfunction in Alzheimer disease and adipose dysfunction in type 2 diabetes.

Adipose tissue natriuretic peptide receptor expression is related to insulin sensitivity in obesity and diabetes.

OBJECTIVE: Cardiac natriuretic peptides (NPs) bind to two receptors (NPRA-mediator of signaling; NPRC-clearance receptor) whose ratio, NPRR (NPRA/NPRC), determines the NP bioactivity. This study investigated the relationship of NP receptor gene expression in adipose tissue and muscle with obesity and glucose intolerance. Prospectively, the study also assessed whether changes in NP receptor expression and thermogenic gene markers accompanied improvements of insulin sensitivity. METHODS: A cross-sectional study of subjects with a wide range of BMI and glucose tolerance (n = 50) was conducted, as well as a randomized 12-week trial of subjects with type 2 diabetes mellitus (T2DM) treated with pioglitazone (n = 9) or placebo (n = 10). RESULTS: NPRR mRNA was significantly lower in adipose tissue of subjects with obesity when compared with lean subjects (P ≤ 0.001). NPRR decreased with progression from normal glucose tolerance to T2DM (P < 0.01) independently of obesity. Treatment of subjects with T2DM with pioglitazone increased NPRR in adipose tissue (P ≤ 0.01) in conjunction with improvements in insulin sensitivity and increases of the thermogenic markers PPARγ coactivator-1α and uncoupling protein 1 (P ≤ 0.01). CONCLUSIONS: Decreased adipose tissue NPRR was associated with obesity, glucose intolerance, and insulin resistance. This relationship was not observed for skeletal muscle NPRR. Pharmacological improvement of insulin sensitivity in subjects with T2DM was tied to improvement in NPRR and increased expression of genes involved in thermogenic processes.

Intraoperative Lung-Protective Ventilation Trends and Practice Patterns: A Report from the Multicenter Perioperative Outcomes Group.

BACKGROUND: The use of an intraoperative lung-protective ventilation strategy through tidal volume (TV) size reduction and positive end-expiratory pressure (PEEP) has been increasingly investigated. In this article, we describe the current intraoperative lung-protective ventilation practice patterns and trends. METHODS: By using the Multicenter Perioperative Outcomes Group database, we identified all general endotracheal anesthetics from January 2008 through December 2013 at 10 institutions. The following data were calculated: (1) percentage of patients receiving TV > 10 mL/kg predicted body weight (PBW); (2) median initial and overall TV in mL/kg PBW and; (3) percentage of patients receiving PEEP ≥ 5 cm H2O. The data were analyzed at 3-month intervals. Interinstitutional variability was assessed. RESULTS: A total of 330,823 patients met our inclusion criteria for this study. During the study period, the percentage of patients receiving TV > 10 mL/kg PBW was reduced for all patients (26% to 14%) and in the subpopulations of obese (41% to 25%), short stature (52% to 36%), and females (39% to 24%; all P values <0.001). There was a significant reduction in TV size (8.90-8.20 mL/kg PBW, P < 0.001). There was also a statistically significant but clinically irrelevant difference between initial and overall TV size (8.65 vs 8.63 mL/kg PBW, P < 0.001). Use of PEEP ≥ 5 cm H2O increased during the study period (25%-45%, P < 0.001). TV usage showed significant interinstitutional variability (P < 0.001). CONCLUSIONS: Although decreasing, a significant percentage of patients are ventilated with TV > 10 mL/kg PBW, especially if they are female, obese, or of short stature. The use of PEEP ≥ 5 cm H2O has increased significantly. Creating awareness of contemporary practice patterns and demonstrating the efficacy of lung-protective ventilation are still needed to optimize intraoperative ventilation.

Adapting simultaneous analysis phylogenomic techniques to study complex disease gene relationships.

The characterization of complex diseases remains a great challenge for biomedical researchers due to the myriad interactions of genetic and environmental factors. Network medicine approaches strive to accommodate these factors holistically. Phylogenomic techniques that can leverage available genomic data may provide an evolutionary perspective that may elucidate knowledge for gene networks of complex diseases and provide another source of information for network medicine approaches. Here, an automated method is presented that leverages publicly available genomic data and phylogenomic techniques, resulting in a gene network. The potential of approach is demonstrated based on a case study of nine genes associated with Alzheimer Disease, a complex neurodegenerative syndrome. The developed technique, which is incorporated into an update to a previously described Perl script called "ASAP," was implemented through a suite of Ruby scripts entitled "ASAP2," first compiles a list of sequence-similarity based orthologues using PSI-BLAST and a recursive NCBI BLAST+ search strategy, then constructs maximum parsimony phylogenetic trees for each set of nucleotide and protein sequences, and calculates phylogenetic metrics (Incongruence Length Difference between orthologue sets, partitioned Bremer support values, combined branch scores, and Robinson-Foulds distance) to provide an empirical assessment of evolutionary conservation within a given genetic network. In addition to the individual phylogenetic metrics, ASAP2 provides results in a way that can be used to generate a gene network that represents evolutionary similarity based on topological similarity (the Robinson-Foulds distance). The results of this study demonstrate the potential for using phylogenomic approaches that enable the study of multiple genes simultaneously to provide insights about potential gene relationships that can be studied within a network medicine framework that may not have been apparent using traditional, single-gene methods. Furthermore, the results provide an initial integrated evolutionary history of an Alzheimer Disease gene network and identify potentially important co-evolutionary clustering that may warrant further investigation.

Origins of amyloid-ß.

BACKGROUND: Amyloid-ß plaques are a defining characteristic of Alzheimer Disease. However, Amyloid-ß deposition is also found in other forms of dementia and in non-pathological contexts. Amyloid-ß deposition is variable among vertebrate species and the evolutionary emergence of the amyloidogenic property is currently unknown. Evolutionary persistence of a pathological peptide sequence may depend on the functions of the precursor gene, conservation or mutation of nucleotides or peptide domains within the precursor gene, or a species-specific physiological environment. RESULTS: In this study, we asked when amyloidogenic Amyloid-ß first arose using phylogenetic trees constructed for the Amyloid-ß Precursor Protein gene family and by modeling the potential for Amyloid-ß aggregation across species in silico. We collected the most comprehensive set of sequences for the Amyloid-ß Precursor Protein family using an automated, iterative meta-database search and constructed a highly resolved phylogeny. The analysis revealed that the ancestral gene for invertebrate and vertebrate Amyloid-ß Precursor Protein gene families arose around metazoic speciation during the Ediacaran period. Synapomorphic frequencies found domain-specific conservation of sequence. Analyses of aggregation potential showed that potentially amyloidogenic sequences are a ubiquitous feature of vertebrate Amyloid-ß Precursor Protein but are also found in echinoderm, nematode, and cephalochordate, and hymenoptera species homologues. CONCLUSIONS: The Amyloid-ß Precursor Protein gene is ancient and highly conserved. The amyloid forming Amyloid-ß domains may have been present in early deuterostomes, but more recent mutations appear to have resulted in potentially unrelated amyloid forming sequences. Our results further highlight that the species-specific physiological environment is as critical to Amyloid-ß formation as the peptide sequence.

Obesity and asthma: an inflammatory disease of adipose tissue not the airway.

RATIONALE: Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese. OBJECTIVES: To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity. METHODS: We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time. MEASUREMENTS AND MAIN RESULTS: Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P < 0.01), with increased expression of leptin (P < 0.01) and decreased adiponectin (p < 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho = -0.8; P < 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery. CONCLUSIONS: Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation.

Measurement of altered AßPP isoform expression in frontal cortex of patients with Alzheimer's disease by absolute quantification real-time PCR.

Enzymatic cleavage of amyloid-ß protein precursor (AßPP) produces amyloid-ß (Aß) peptides which form the insoluble cortical plaques characteristic of Alzheimer's disease (AD). AßPP is post-transcriptionally processed into three major isoforms with differential cellular and tissue expression patterns. Changes in AßPP isoform expression may be indicative of disease pathogenesis in AD, but accurately measuring AßPP gene isoforms has been difficult to standardize, reproduce, and interpret. In light of this, we developed a set of isoform specific absolute quantification real time PCR standards that allow for quantification of transcript copy numbers for total AßPP and all three major isoforms (AßPP695, AßPP751, and AßPP770) in addition to glyceraldehyde-3-dehydrogenase (GAPDH) and examined expression patterns in superior frontal gyrus (SFG) and cerebellar samples from patients with (n = 12) and without AD (n = 10). Both total AßPP and AßPP695 transcripts were significantly decreased in SFG of patients with AD compared to control (p = 0.037 and p = 0.034, respectively). AßPP751 and AßPP770 transcripts numbers were not significantly different between AD and control (p > 0.15). There was trend for decreased percentage AßPP695 (p = 0.051) and increased percentage AßPP770 (p = 0.013) expression in SFG of patients with AD. GAPDH transcripts levels were also decreased significantly in the SFG of patients with AD compared to control (p = 0.005). Decreasing total AßPP and AßPP695 copy number was associated with increased plaque burden and decreased cognitive function. In this study we describe a simple procedure for measuring AßPP isoform transcripts by real-time PCR and confirm previous studies showing altered AßPP isoform expression patterns in AD.

Sexually dimorphic diet-induced insulin resistance in obese tissue inhibitor of metalloproteinase-2 (TIMP-2)-deficient mice.

Circulating levels of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitor of metalloproteinases (TIMPs), are altered in human obesity and may contribute to its pathology. TIMP-2 exerts MMP-dependent (MMP inhibition and pro-MMP-2 activation) and MMP-independent functions. To assess the role of TIMP-2 in a murine model of nutritionally induced obesity, weight gain in wild-type and TIMP-2 deficient [knockout (KO)] mice fed a chow or high-fat diet (HFD) was determined. The effects of diet on glucose tolerance and insulin sensitivity, as well as pancreatic ß-cell and adipocyte physiology, were assessed. Chow-fed TIMP-2 KO mice of both sexes became obese but maintained relatively normal glucose tolerance and insulin sensitivity. Obesity was exacerbated on the HFD. However, HFD-fed male, but not female, TIMP-2 KO mice developed insulin resistance with reduced glucose transporter 2 and pancreatic and duodenal homeobox 1 levels, despite increased ß-cell mass and hyperplasia. Thus, although ß-cell mass was increased, HFD-fed male TIMP-2 KO mice develop diabetes likely due to ß-cell exhaustion and failure. TIMP-2 mRNA, whose expression was greatest in sc adipose tissue, was down-regulated in HFD-fed wild-type males, but not females. Furthermore, HFD increased membrane type 1-MMP (MMP-14) expression and activity in male, but not female, sc adipose tissue. Strikingly, MMP-14 expression increased to a greater extent in TIMP-2 KO males and was associated with decreased adipocyte collagen. Taken together, these findings demonstrate a role for TIMP-2 in maintaining extracellular matrix integrity necessary for normal ß-cell and adipocyte physiology and that loss of extracellular matrix integrity may underlie diabetic and obesogenic phenotypes.

Plasma amyloid-beta peptide levels correlate with adipocyte amyloid precursor protein gene expression in obese individuals.

BACKGROUND/AIMS: Several studies have demonstrated that midlife obesity increases the risk for dementia and Alzheimer's disease. Moreover, plasma 42-amino-acid amyloid-beta (Abeta42) levels appear to correlate with BMI. We recently demonstrated that adipocyte amyloid precursor protein (APP) expression is upregulated in obesity and correlates with insulin resistance and adipose tissue inflammation. In this study, we aimed to investigate the relation between adipocyte APP expression and plasma Abeta peptide levels. METHODS: We conducted a pilot study in which we measured adipocyte APP gene expression and the circulating plasma levels of Abeta40 in 10 obese individuals before and after a 6-month behaviorally based weight loss intervention. Subjects had an oral glucose tolerance test with measurement of insulin levels, Abeta40 levels measured by ELISA and transcript levels of APP in subcutaneous abdominal adipocytes measured by quantitative real-time PCR. RESULTS: At baseline, adipocyte APP expression correlated significantly with plasma Abeta40 levels and with 2-hour insulin concentrations. Following the 6-month weight loss intervention, body weight and BMI decreased significantly. Fasting plasma concentrations of glucose and insulin were improved. Adipocyte APP expression was significantly decreased (p < 0.001) after weight loss. Changes in adipocyte APP expression correlated with changes in plasma Abeta40 levels (R = 0.74, p = 0.01) and changes in 2-hour insulin (R = 0.75, p = 0.01). CONCLUSION: The results of this pilot study suggest that increased circulating plasma levels of Abeta peptides in obesity may be due to increased adipocyte APP gene expression. While these results suggest a possible mechanism linking midlife obesity with the later development of Alzheimer's disease, further research is necessary to elucidate the regulation and functional significance of APP in adipocytes.

Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes.

CONTEXT: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state. OBJECTIVE: The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function. DESIGN: We conducted a randomized, double-blind, placebo-controlled trial. SETTING: The study was performed in General Clinical Research Centers at two University Hospitals. SUBJECTS: Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2-7.5%. INTERVENTION: Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout. Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout. RESULTS: There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P < 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023). CONCLUSION: Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.