title: Mechanisms of Action of Liraglutide in Patients With Type 2 Diabetes Treated With High-Dose Insulin.
abstract: The mechanisms of action of incretin mimetics in patients with long-standing type 2 diabetes (T2D) and high insulin requirements have not been studied.
  
  
  
  To evaluate changes in β-cell function, glucagon secretion, and fat distribution after addition of liraglutide to high-dose insulin.
  
  
  
  A single-center, randomized, double-blind, placebo-controlled trial.
  
  
  
  University of Texas Southwestern and Parkland Memorial Hospital clinics.
  
  
  
  Seventy-one patients with long-standing (median, 17 years) T2D requiring high-dose insulin treatment (>1.5 U/kg/d; average, 2.2 ± 0.9 U/kg/d).
  
  
  
  Patients were randomized to liraglutide 1.8 mg/d or matching placebo for 6 months.
  
  
  
  We measured changes in insulin and glucagon secretion using a 4-hour mixed-meal challenge test. Magnetic resonance-based techniques were used to estimate sc and visceral fat in the abdomen and ectopic fat in the liver and pancreas.
  
  
  
  Glycosylated hemoglobin improved significantly with liraglutide treatment, with an end-of-trial estimated treatment difference between groups of −0.9% (95% confidence interval, −1.5, −0.4%) (P = .002). Insulin secretion improved in the liraglutide group vs placebo, as measured by the area under the curve of C-peptide (P = .002) and the area under the curves ratio of C-peptide to glucose (P = .003). Insulin sensitivity (Matsuda index) and glucagon secretion did not change significantly between groups. Liver fat and sc fat decreased in the liraglutide group vs placebo (P = .0006 and P = .01, respectively), whereas neither visceral nor pancreatic fat changed significantly.
  
  
  
  Treatment with liraglutide significantly improved insulin secretion, even in patients with long-standing T2D requiring high-dose insulin treatment. Liraglutide also decreased liver and sc fat, but it did not alter glucagon secretion.
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Anna
authors.initials: A
authors.lastname: Vanderheiden
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Harrison
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Warshauer
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Beverley
authors.initials: B
authors.lastname: Adams-Huet
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Xilong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Keith
authors.initials: K
authors.lastname: Hulsey
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dimitrov
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yokoo
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Jaster
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Daniella F
authors.initials: DF
authors.lastname: Pinho
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Ivan
authors.initials: I
authors.lastname: Pedrosa
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lenkinski
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Laurentiu M
authors.initials: LM
authors.lastname: Pop
authors.affiliation: Department of Internal Medicine (A.V., L.B.H., J.T.W., B.A.-H., L.M.P., I.L.), Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Texas Diabetes & Endocrinology (L.B.H.), Austin, Texas 78749; Departments of Clinical Sciences (B.A.-H., X.L., I.L.) and Radiology (Q.Y., K.H., T.Y., A.W.J., D.F.P., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Philips Medical Systems (I.D.), Cleveland, Ohio 44143; and Advanced Imaging Research Center (T.Y., I.P., R.E.L.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Lingvay
mesh_terms: D000273:Adipose Tissue / Q000000981:diagnostic imaging; D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005934:Glucagon / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D000069450:Liraglutide / Q000494:pharmacology / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged
chemical_list: D001786:Blood Glucose; D005934:Glucagon; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide