title: Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study.
abstract: OBJECTIVE
  Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (-7.7% vs -3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.
  
  
  METHODS
  This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40-70 years old, overweight (BMI 27-40 kg/m(2)) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n = 35) or matching placebo (n = 33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.
  
  
  RESULTS
  Liraglutide treatment (n = 24) significantly (p ≤ 0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs -4% [-11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs -0.5% (-15, 14]), and decreased insulin clearance rate (-3.5% [-11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n = 25). The liraglutide-treated group also had significantly (p ≤ 0.03) lower day-long glucose (-8.2% [-11, -6] vs -0.1 [-3, 2]) and NEFA concentrations (-14 [-20, -8] vs -2.1 [-10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p ≤ 0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.
  
  
  CONCLUSIONS
  A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01784965 FUNDING: The study was funded by the ADA.
authors: Department of Medicine, Stanford University School of Medicine, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA, 94305-5103, USA, sunhkim@stanford.edu.
authors: Sun H
authors: SH
authors: Kim
authors: Alice
authors: A
authors: Liu
authors: Danit
authors: D
authors: Ariel
authors: Fahim
authors: F
authors: Abbasi
authors: Cindy
authors: C
authors: Lamendola
authors: Kaylene
authors: K
authors: Grove
authors: Vanessa
authors: V
authors: Tomasso
authors: Gerald
authors: G
authors: Reaven
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose; D004038:Diet, Reducing; D004311:Double-Blind Method; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D000069450:Liraglutide; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000517:prevention & control*; D011236:Prediabetic State / Q000097:blood / Q000188:drug therapy*; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1