title: Effect of the GLP-1 Receptor Agonist Lixisenatide on Counterregulatory Responses to Hypoglycemia in Subjects With Insulin-Treated Type 2 Diabetes.
abstract: OBJECTIVE
  Counterregulatory responses are critical to prevent hypoglycemia in subjects with type 2 diabetes. This is particularly important in insulin-treated patients. This study explored the effect of the glucagon-like peptide 1 receptor agonist lixisenatide on the hormonal counterregulatory responses to insulin-induced hypoglycemia when added to basal insulin therapy in subjects with type 2 diabetes.
  
  
  METHODS
  The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 18 subjects with type 2 diabetes (11 males) with a mean age of 55 years, diabetes duration of 12 years, HbA1c level of 7.7%, fasting blood glucose (FBG) concentration of 9.7 mmol/L, and a BMI of 33 kg/m(2), who were treated with basal insulin (mean duration 7 years, daily dose 39 units/day) and metformin (mean daily dose 2.1 g). Subjects received treatment with lixisenatide or placebo for 6 weeks in random order, with a 4-week washout period in between. After 6 weeks of treatment, subjects underwent a two-step hyperinsulinemic hypoglycemic clamp at 3.5 and 2.8 mmol/L.
  
  
  RESULTS
  After 6 weeks of treatment, HbA1c and FBG levels were lower after lixisenatide therapy than after placebo therapy. At the hypoglycemic level of 3.5 mmol/L, glucagon and epinephrine levels were significantly lower during lixisenatide treatment than during placebo treatment, whereas at 2.8 mmol/L glucagon and epinephrine levels did not differ between the subjects. Cortisol, pancreatic polypeptide, and norepinephrine levels did not differ significantly between the treatments.
  
  
  CONCLUSIONS
  Glucagon and epinephrine levels are reduced by lixisenatide at a concentration of 3.5 mmol/L, but their counterregulatory responses to deep hypoglycemia at a concentration of 2.8 mmol/L are sustained during treatment with lixisenatide in combination with basal insulin.
authors.affiliation: Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Farngren
authors.affiliation: Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Margaretha
authors.initials: M
authors.lastname: Persson
authors.affiliation: Department of Clinical Sciences Lund, Lund University, Lund, Sweden bo.ahren@med.lu.se.
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005934:Glucagon / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D007003:Hypoglycemia; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D001786:Blood Glucose; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D006854:Hydrocortisone; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D010455:Peptides; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C517652:hemoglobin A1c protein, human; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor