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.

No abstract

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.

Context Post-bariatric 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 GLP-1 antagonist, for treatment of PBH. Design Phase II, randomized, placebo-controlled crossover study (PREVENT). Setting Multicenter. Participants Eighteen female patients with PBH. Intervention Placebo for 14 days followed by avexitide 30 mg BID and 60 mg QD, each for 14 days in random order. Main Outcome Measures 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 monitor (CGM). Results Compared to placebo, avexitide 30 mg BID and 60 mg QD raised the glucose nadir by 21% (p=0.001) and 26% (p=0.0002) and lowered the insulin peak by 23% (p=0.029) and 21% (p=0.042), corresponding to 50% and 75% fewer participants requiring rescue during MMTT, respectively. Significant reductions in rates of Levels 1-3 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. Conclusions 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.

We read with interest the recent article by Ahmad et al. on the prevalence of late dumping syndrome (DS) [1]. They used the Sigstad scoring system to diagnose subjects with DS. Subjects that met the 3.26 cutoff score were determined to have early DS versus late DS dependent on timing of symptoms, occurring within 1 h or 1-3 h post-prandially. The Sigstad scoring system does not effectively discern for the presence of hypoglycemia. For example, if a patient developed dizziness (1.5pts), nausea (1 pt), and abdominal cramping (1 pt) over 1 h post-prandially, the cutoff score is exceeded and the patient would be classified as late DS, regardless of the fact that none of the symptoms are reflective of hypoglycemia. Since the hallmark of late DS is hypoglycemia, this indicates the need for updated nomenclature. Post-bariatric hypoglycemia (PBH) is an increasingly recognized complication of bariatric surgery, occurring particularly after surgical procedures creating anatomy in which ingested foods bypass the pylorus (e.g., Roux-en-Y gastric bypass (RYGB)) or alter gastric emptying (e.g., sleeve gastrectomy). Although the precise pathophysiology is unknown, rapid transit of glucose to the intestine in this setting leads to increased gastrointestinal peptide secretion including GLP-1, excess insulin release, and subsequent hypoglycemia. In addition, patients with PBH also have an attenuated glucagon response, reduced insulin clearance, and impaired β cell secretory suppression during hypoglycemia [2]. Diagnostic criteria for PBH include (1) neuroglycopenic symptoms with post-prandial plasma glucose < 54 mg/dL (SI, 3.0 mmol/L), (2) occurrence ≥ 6 months after bariatric surgery, and (3) no fasting hypoglycemia [2]. Yet, a barrier to advancing scientific knowledge and understanding the true prevalence of this disease is the obsolete terminology of late dumping syndrome (DS) [3]. Both late DS and PBH are often used interchangeably to refer to post-prandial hyperinsulinemic hypoglycemia; sometimes late DS is used to refer to mild presentations of PBH [3-5].