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). Eighteen female patients with PBH were given placebo for 14 days followed by avexitide 30 mg twice daily and 60 mg once daily, each for 14 days in random order. The main outcome measures were glucose nadir and insulin peak during mixed-meal tolerance testing (MMTT) and hypoglycemic events captured by self-monitoring of blood glucose (SMBG), electronic diary, and blinded continuous glucose monitoring (CGM). RESULTS: Compared with placebo, avexitide 30 mg twice daily and 60 mg once daily raised the glucose nadir by 21% (P = .001) and 26% (P = .0002) and lowered the insulin peak by 23% (P = .029) and 21% (P = .042), corresponding to 50% and 75% fewer participants requiring rescue during MMTT, respectively. Significant reductions in rates of Levels 1 to 3 hypoglycemia were observed, defined, respectively, as SMBG <70 mg/dL, SMBG <54 mg/dL, and a severe event characterized by altered mental and/or physical function requiring assistance. CGM demonstrated reductions in hypoglycemia without induction of clinically relevant hyperglycemia. Avexitide was well tolerated, with no increase in adverse events. CONCLUSION: Avexitide administered for 28 days was well tolerated and resulted in robust and consistent improvements across multiple clinical and metabolic parameters, reinforcing the targeted therapeutic approach and demonstrating durability of effect. Avexitide may represent a first promising treatment for patients with severe PBH.

Hypoglycemia after gastric bypass: An emerging complication.

As the obesity epidemic worsens, more people are opting for weight-loss surgery, including gastric bypass. Of the possible complications associated with this procedure, hypoglycemia secondary to hyperinsulinemia is becoming a more common and therefore more relevant problem.

Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects.

CONTEXT: A substantial number of obese individuals are relatively insulin sensitive and the etiology for this variation remains unknown. OBJECTIVE: The primary objective was to detect factors in adipose tissue differentiating obese insulin-sensitive (OBIS) from obese insulin-resistant (OBIR) individuals and investigate whether adipose tissue hypoxia is a contributing factor in the pathogenesis of insulin resistance. DESIGN AND SETTING: This was a cross-sectional study in the general community. PARTICIPANTS: Subjects consisted of nondiabetic OBIS and OBIR subjects with similar body mass index, age, and total body fat but different insulin sensitivity index as well as lean insulin-sensitive subjects. INTERVENTIONS(S): There were no interventions. MAIN OUTCOME MEASURE(S): We examined adipocytokines and the expression of candidate genes regulating hypoxia, inflammation, and lipogenesis in adipose tissue and adipose tissue oxygenation. RESULTS: OBIS subjects had increased plasma adiponectin but similar plasma TNFα and leptin levels as compared with OBIR subjects. Genes regulating inflammation (CD68, MCP1, scavenger receptor A, and oxidized LDL receptor 1) were increased by 40%­60% (P < .05) in OBIR vs OBIS cohorts. In addition, genes involved in extracellular matrix formation such as collagen VI and MMP7 were up-regulated by 43% and 78% (P < .05), respectively, in OBIR vs OBIS. The expression of HIF1α and VEGF gene expression was increased by 37% and 52%, respectively, in OBIR vs OBIS (P < .01). Despite the differential expression in hypoxia-related genes, adipose tissue oxygenation measured by a Licox oxygen probe was not different between OBIS and OBIR subjects, but it was higher in lean subjects as compared with obese subjects. CONCLUSIONS: We confirmed that adipose tissue inflammation and fibrosis play an important role in the pathogenesis of insulin resistance independent of obesity in humans. Whether hypoxia is simply a consequence of adipose tissue expansion or is related to the pathogenesis of obesity-induced insulin resistance is yet to be understood.

A new immobilisation method to arrange particles in a gel matrix by ultrasound standing waves.

Ultrasonic forces may be used to manipulate particles in suspension. For example, a standing wave ultrasound (US) field applied to a suspension moves the particles toward areas of minimal acoustic pressure, where they are orderly retained creating a predictable heterogeneous distribution. This principle of ultrasonic retention of particles or cells has been applied in numerous biotechnological applications, such as mammalian cell filtering and red blood cell sedimentation. Here, a new US-based cell immobilisation technique is described that allows manipulation and positioning of cells/particles within various nontoxic gel matrices before polymerisation. Specifically, gel immobilisation was used to directly demonstrate that the viability of yeast cells arranged by an US standing wave is maintained up to 4 days after treatment. The versatility of this immobilisation method was validated using a wide range of acoustic devices. Finally, the potential biotechnological advantages of this US-controlled particle positioning method combined with gel immobilisation/encapsulation technology are discussed.