Defining clinically important hypoglycemia in patients with postbariatric hypoglycemia.

Background: Postbariatric hypoglycemia (PBH) is a rare but growing complication of bariatric surgery. Many aspects have yet to be established, including the blood glucose threshold which represents clinically important hypoglycemia in affected patients.

Objective: To confirm the glucose threshold below which neuroglycopenic (NG) symptoms arise in patients with PBH during provoked and real-world hypoglycemia as an indicator of clinically important hypoglycemia.

PREVENT: A Randomized, Placebo-controlled Crossover Trial of Avexitide for Treatment of Postbariatric Hypoglycemia.

Context: Postbariatric hypoglycemia (PBH), characterized by enteroinsular axis overstimulation and hyperinsulinemic hypoglycemia, is a complication of bariatric surgery for which there is no approved therapy.

Objective: To evaluate efficacy and safety of avexitide [exendin (9-39)], a glucagon-like peptide-1 antagonist, for treatment of PBH.

Methods: A multicenter, Phase 2, randomized, placebo-controlled crossover study (PREVENT).

Guidelines for gastrostomy tube placement and enteral nutrition in patients with severe, refractory hypoglycemia after gastric bypass.

Background: Postbariatric hypoglycemia (PBH) affects up to 38% of Roux-en-Y gastric bypass (RYGB) patients. Severe cases are refractory to diet and medications. Surgical treatments including bypass reversal and pancreatectomy are highly morbid and hypoglycemia often recurs.

Safety, efficacy and pharmacokinetics of repeat subcutaneous dosing of avexitide (exendin 9-39) for treatment of post-bariatric hypoglycaemia.

Aim: To evaluate the safety, efficacy and pharmacokinetics of repeat dosing of two formulations of subcutaneous (SC) avexitide (exendin 9-39) in patients with post-bariatric hypoglycaemia (PBH).

Methods: In this phase 2, multiple-ascending-dose study conducted at Stanford University, 19 women with PBH underwent a baseline oral glucose tolerance test (OGTT), with metabolic and symptomatic assessments. Fourteen were then sequentially assigned to receive one of four ascending-dose levels of twice-daily lyophilized (Lyo) avexitide by SC injection for 3 days.

Longitudinal multi-omics of host-microbe dynamics in prediabetes.

Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2D better, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability.

Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia.

Background: Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB.

High-frequency actionable pathogenic exome variants in an average-risk cohort.

Exome sequencing is increasingly utilized in both clinical and nonclinical settings, but little is known about its utility in healthy individuals. Most previous studies on this topic have examined a small subset of genes known to be implicated in human disease and/or have used automated pipelines to assess pathogenicity of known variants. To determine the frequency of both medically actionable and nonactionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multiomics profiling study.

Metabolic markers, regional adiposity, and adipose cell size: relationship to insulin resistance in African-American as compared with Caucasian women.

Background/objectives: African-American women have the greatest prevalence of obesity in the United States, and higher rates of type 2 diabetes than Caucasian women, yet paradoxically lower plasma triglycerides (TG), visceral fat and intrahepatic fat, and higher high-density lipoprotein (HDL)-cholesterol. Visceral fat has not been evaluated against insulin resistance in African-American women, and TG/HDL-cholesterol has been criticized as a poor biomarker for insulin resistance in mixed-sex African-American populations. Adipocyte hypertrophy, reflecting adipocyte dysfunction, predicts insulin resistance in Caucasians, but has not been studied in African-Americans.

Integrative Personal Omics Profiles during Periods of Weight Gain and Loss.

Advances in omics technologies now allow an unprecedented level of phenotyping for human diseases, including obesity, in which individual responses to excess weight are heterogeneous and unpredictable. To aid the development of better understanding of these phenotypes, we performed a controlled longitudinal weight perturbation study combining multiple omics strategies (genomics, transcriptomics, multiple proteomics assays, metabolomics, and microbiomics) during periods of weight gain and loss in humans. Results demonstrated that: (1) weight gain is associated with the activation of strong inflammatory and hypertrophic cardiomyopathy signatures in blood; (2) although weight loss reverses some changes, a number of signatures persist, indicative of long-term physiologic changes; (3) we observed omics signatures associated with insulin resistance that may serve as novel diagnostics; (4) specific biomolecules were highly individualized and stable in response to perturbations, potentially representing stable personalized markers.

Efficacy and pharmacokinetics of subcutaneous exendin (9-39) in patients with post-bariatric hypoglycaemia.

Aim: To evaluate the efficacy, pharmacokinetic (PK) profile and tolerability of subcutaneous (s.c.).

Adipose tissue macrophages impair preadipocyte differentiation in humans.

Aim: The physiologic mechanisms underlying the relationship between obesity and insulin resistance are not fully understood. Impaired adipocyte differentiation and localized inflammation characterize adipose tissue from obese, insulin-resistant humans. The directionality of this relationship is not known, however.

Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia.

Aims/hypothesis: Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry.

Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans.

Obesity is associated with insulin resistance, but significant variability exists between similarly obese individuals, pointing to qualitative characteristics of body fat as potential mediators. To test the hypothesis that obese, insulin-sensitive (IS) individuals possess adaptive adipose cell/tissue responses, we measured subcutaneous adipose cell size, insulin suppression of lipolysis, and regional fat responses to short-term overfeeding in BMI-matched overweight/obese individuals classified as IS or insulin resistant (IR). At baseline, IR subjects exhibited significantly greater visceral adipose tissue (VAT), intrahepatic lipid (IHL), plasma free fatty acids, adipose cell diameter, and percentage of small adipose cells.

In vivo 2H2O administration reveals impaired triglyceride storage in adipose tissue of insulin-resistant humans.

Indirect evidence suggests that impaired triglyceride storage in the subcutaneous fat depot contributes to the development of insulin resistance via lipotoxicity. We directly tested this hypothesis by measuring, in vivo, TG synthesis, de novo lipogenesis (DNL), adipocyte proliferation, and insulin suppression of lipolysis in subcutaneous adipose tissue of BMI-matched individuals classified as insulin resistant (IR) or insulin sensitive (IS). Nondiabetic, moderately obese subjects with BMI 25-35 kg/m(2), classified as IR or IS by the modified insulin suppression test, consumed deuterated water ((2)H2O) for 4 weeks.

Time-domain ab initio study of charge relaxation and recombination in dye-sensitized TiO2.

In order to investigate the electron dynamics at the alizarin/I2-/TiO2 interface this study uses a novel state-of-the-art quantum-classical approach that combines time-dependent density functional theory with surface hopping in the Kohn-Sham basis. Representing the dye-sensitized semiconductor Grätzel cell with the I-/I3- mediator, the system addresses the problems of an organic/inorganic, molecule/bulk interface that are commonly encountered in molecular electronics, photovoltaics, and photoelectrochemistry. The processes studied include the relaxation of the injected electron inside the TiO2 conduction band (CB), the back electron transfer (ET) from TiO2 to alizarin, the ET from the surface to the electrolyte, and the regeneration of the neutral chromophore by ET from the electrolyte to alizarin.

Time-domain ab initio simulation of electron and hole relaxation dynamics in a single-wall semiconducting carbon nanotube.

The electron and hole relaxation in the (7, 0) zigzag carbon nanotube is simulated in time domain using a surface-hopping Kohn-Sham density functional theory. Following a photoexcitation between the second van Hove singularities, the electrons and holes decay to the Fermi level on characteristic subpicosecond time scales. Surprisingly, despite a lower density of states, the electrons relax faster than the holes.

Trajectory surface hopping in the time-dependent Kohn-Sham approach for electron-nuclear dynamics.

The mean-field treatment of electron-nuclear interaction results in many qualitative breakdowns in the time-dependent Kohn-Sham (TDKS) density functional theory. Examples include current-induced heating in nanoelectronics, charge dynamics in quantum dots and carbon nanotubes, and relaxation of biological chromophores. The problem is resolved by the trajectory surface-hopping TDKS approach, which is illustrated by the photoinduced electron injection from a molecular chromophore into TiO2, and the excited-state relaxation of the green fluorescent protein chromophore.

Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function.

During normal development Notch receptor signaling is important in regulating numerous cell fate decisions. Mutations that truncate the extracellular domain of Notch receptors can cause aberrant signaling and promote unregulated cell growth. We have examined two types of truncated Notch oncoproteins that arise from proviral insertion into the Notch4 gene (Notch4/int-3) or a chromosomal translocation involving the Notch1 gene (TAN-1).

Electron, hydride, and fluoride affinities of silicon-containing species: computational studies.

The distance dependence of silicon substitution on the electron affinity (EA) of carbon radicals has been studied using computational methods in SiH3(CH2)nCH2 (A) and SiH2F(CH2)nCH2 (B). Large EAs result when n = 0 for both A and B. The result for A is compared with the experimental EA value of (CH3)3SiCH2.