title: Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: unraveling the role of gut hormonal and pancreatic endocrine dysfunction.
abstract: BACKGROUND
  Profound hypoglycemia occurs rarely as a late complication after Roux-en-Y gastric bypass (RYGB). We investigated the role of glucagon-like-peptide-1 (GLP-1) in four subjects who developed recurrent neuro-glycopenia 2 to 3 y after RYGB.
  
  
  METHODS
  A standardized test meal (STM) was administered to all four subjects. A 2 h hyperglycemic clamp with GLP-1 infusion during the second hour was performed in one subject, before, during a 4 wk trial of octreotide (Oc), and after 85% distal pancreatectomy. After cessation of both glucose and GLP-1 infusion at the end of the 2 h clamp, blood glucose levels were monitored for 30 min. Responses were compared with a control group (five subjects 12 mo status post-RYGB without hypoglycemic symptoms).
  
  
  RESULTS
  During STM, both GLP-1 and insulin levels were elevated 3- to 4-fold in all subjects, and plasma glucose-dependent insulinotropic peptide (GIP) levels were elevated 2-fold. Insulin responses to hyperglycemia ± GLP-1 infusion in one subject were comparable to controls, but after cessation of glucose infusion, glucose levels fell to 40 mg/dL. During Oc, the GLP-1 and insulin responses to STM were reduced (>50%). During the clamp, insulin response to hyperglycemia alone was reduced, but remained unchanged during GLP-1. Glucagon levels during hyperglycemia alone were suppressed and further suppressed after the addition of GLP-1. With the substantial drop in glucose during the 30 min follow-up, glucagon levels failed to rise. Due to persistent symptoms, one subject underwent 85% distal pancreatectomy; postoperatively, the subject remained asymptomatic (blood glucose: 119-220 mg/dL), but a repeat STM showed persistence of elevated levels of GLP-1. Histologically enlarged islets, and β-cell clusters scattered throughout the acinar parenchyma were seen, as well as β-cells present within pancreatic duct epithelium. An increase in pancreatic and duodenal homeobox-1 protein (PDX-1) expression was observed in the subject compared with control pancreatic tissue.
  
  
  CONCLUSIONS
  A persistent exaggerated hypersecretion of GLP-1, which has been shown to be insulinotropic, insulinomimetic, and glucagonostatic, is the likely cause of post-RYGB hypoglycemia. The hypertrophy and ectopic location of β-cells is likely due to overexpression of the islet cell transcription factor, PDX-1, caused by prolonged hypersecretion of GLP-1.
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA.
authors.forename: Atoosa
authors.initials: A
authors.lastname: Rabiee
authors.forename: J Trent
authors.initials: JT
authors.lastname: Magruder
authors.forename: Rocio
authors.initials: R
authors.lastname: Salas-Carrillo
authors.forename: Olga
authors.initials: O
authors.lastname: Carlson
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
authors.forename: Frederic B
authors.initials: FB
authors.lastname: Askin
authors.forename: Dariush
authors.initials: D
authors.lastname: Elahi
authors.forename: Dana K
authors.initials: DK
authors.lastname: Andersen
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D004703:Endocrine System / Q000503:physiopathology*; D005260:Female; D015390:Gastric Bypass / Q000009:adverse effects*; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000503:physiopathology*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000209:etiology* / Q000503:physiopathology; D007003:Hypoglycemia / Q000209:etiology* / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D008875:Middle Aged; D009765:Obesity / Q000601:surgery*; D010179:Pancreas / Q000503:physiopathology*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D006003:Glycogen