PMID- 33140542
OWN - NLM
STAT- MEDLINE
DCOM- 20210705
LR  - 20220202
IS  - 1463-1326 (Electronic)
IS  - 1462-8902 (Print)
IS  - 1462-8902 (Linking)
VI  - 23
IP  - 2
DP  - 2021 Feb
TI  - Effect of the glucagon-like peptide-1 analogue liraglutide versus placebo 
      treatment on circulating proglucagon-derived peptides that mediate improvements 
      in body weight, insulin secretion and action: A randomized controlled trial.
PG  - 489-498
LID - 10.1111/dom.14242 [doi]
AB  - AIM: To examine how circulating glucagon-like peptide-1 (GLP-1) concentrations 
      during liraglutide treatment relate to its therapeutic actions on glucose and 
      weight, and to study the effects of liraglutide on other proglucagon-derived 
      peptides (PGDPs), including endogenous GLP-1, glucagon-like peptide-2, glucagon, 
      oxyntomodulin, glicentin and major proglucagon fragment, which also regulate 
      metabolic and weight control. MATERIALS AND METHODS: Adults who were 
      overweight/obese (body mass index 27-40 kg/m(2) ) with prediabetes were 
      randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used 
      specific assays to measure exogenous (liraglutide, GLP-1 agonist [GLP-1A]) and 
      endogenous (GLP-1E) GLP-1, alongside five other PGDP concentrations during a 
      mixed meal tolerance test (MMTT) completed at baseline and at week 14 
      (liraglutide, n = 16; placebo, n = 19). Glucose during MMTT, steady-state plasma 
      glucose (SSPG) concentration for insulin resistance and insulin secretion rate 
      (ISR) were previously measured. MMTT area-under-the-curve (AUC) was calculated 
      for ISR, glucose and levels of PGDPs. RESULTS: Participants on liraglutide versus 
      placebo had significantly (P </= .004) decreased weight (mean -3.6%, 95% CI [-5.2% 
      to -2.1%]), SSPG (-32% [-43% to -22%]) and glucose AUC (-7.0% [-11.5% to -2.5%]) 
      and increased ISR AUC (30% [16% to 44%]). GLP-1A AUC at study end was 
      significantly (P </= .04) linearly associated with % decrease in weight (r = -0.54) 
      and SSPG (r = -0.59) and increase in ISR AUC (r = 0.51) in the liraglutide group. 
      Treatment with liraglutide significantly (P </= .005) increased exogenous GLP-1A 
      AUC (median 310 vs. 262 pg/mL x 8 hours at baseline but decreased endogenous 
      GLP-1E AUC [13.1 vs. 24.2 pmol/L x 8 hours at baseline]), as well as the five 
      other PGDPs. Decreases in the PGDPs processed in the intestines are independent 
      of weight loss, indicating a probable direct effect of GLP-1 receptor agonists to 
      decrease their endogenous production in contrast to weight loss-dependent changes 
      in glucagon and major proglucagon fragment that are processed in pancreatic alpha 
      cells. CONCLUSIONS: Circulating GLP-1A concentrations, reflecting liraglutide 
      levels, predict improvement in weight, insulin action and secretion in a linear 
      manner. Importantly, liraglutide also downregulates other PGDPs, normalization of 
      the levels of which may provide additional metabolic and weight loss benefits in 
      the future.
CI  - (c) 2020 John Wiley & Sons Ltd.
FAU - Kim, Sun H
AU  - Kim SH
AUID- ORCID: 0000-0003-0895-7491
AD  - Division of Endocrinology, Gerontology and Metabolism, Department of Medicine, 
      Stanford University School of Medicine, Stanford, California, USA.
AD  - Stanford Diabetes Research Center, Stanford University School of Medicine, 
      Stanford, California, USA.
FAU - Abbasi, Fahim
AU  - Abbasi F
AD  - Stanford Diabetes Research Center, Stanford University School of Medicine, 
      Stanford, California, USA.
AD  - Division of Cardiovascular Medicine, Department of Medicine, Stanford University 
      School of Medicine, Stanford, California, USA.
FAU - Nachmanoff, Clara
AU  - Nachmanoff C
AD  - Division of Endocrinology, Gerontology and Metabolism, Department of Medicine, 
      Stanford University School of Medicine, Stanford, California, USA.
FAU - Stefanakis, Konstantinos
AU  - Stefanakis K
AD  - Department of Medicine, Boston VA Healthcare System and Department of Medicine, 
      Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 
      Massachusetts, USA.
FAU - Kumar, Ajay
AU  - Kumar A
AD  - Ansh Labs, Webster, Texas, USA.
FAU - Kalra, Bhanu
AU  - Kalra B
AD  - Ansh Labs, Webster, Texas, USA.
FAU - Savjani, Gopal
AU  - Savjani G
AD  - Ansh Labs, Webster, Texas, USA.
FAU - Mantzoros, Christos S
AU  - Mantzoros CS
AUID- ORCID: 0000-0003-3755-8158
AD  - Department of Medicine, Boston VA Healthcare System and Department of Medicine, 
      Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 
      Massachusetts, USA.
LA  - eng
GR  - K24 DK081913/DK/NIDDK NIH HHS/United States
GR  - P30 DK116074/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20201119
PL  - England
TA  - Diabetes Obes Metab
JT  - Diabetes, obesity & metabolism
JID - 100883645
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Insulin)
RN  - 0 (Peptides)
RN  - 55963-74-1 (Proglucagon)
RN  - 839I73S42A (Liraglutide)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
SB  - IM
MH  - Adult
MH  - Body Weight
MH  - *Glucagon-Like Peptide 1
MH  - Glucagon-Like Peptide-1 Receptor
MH  - Humans
MH  - Insulin/metabolism
MH  - Insulin Secretion
MH  - *Liraglutide/therapeutic use
MH  - Peptides
MH  - Proglucagon
PMC - PMC7856054
MID - NIHMS1644262
OTO - NOTNLM
OT  - clinical trial, control, GLP-1, GLP-1 analogue, glucagon, glycaemic, liraglutide
COIS- Conflict of interest statement AK, BK, GS work for Ansh Labs. CSM has been a 
      shareholder of and reports grants through his institution and personal consulting 
      fees from Coherus Inc and personal consulting fees from Pangea Inc, reports 
      grants through his institution and personal consulting fees from Eisai and Novo 
      Nordisk, reports personal consulting fees and in kind support with research 
      reagents from Ansh Labs, reports personal consulting fees from Genfit, P.E.S., 
      Loumos, Intercept, Astra Zeneca, Aegerion and Regeneron, reports in kind support 
      (educational activity meals at and through his institution) from Amarin, Janssen, 
      Boehringer Ingelheim and travel support and fees from TMIOA, the California 
      Walnut Commission and the Cardiometabolic Health Conference.
EDAT- 2020/11/04 06:00
MHDA- 2021/07/06 06:00
PMCR- 2022/02/01
CRDT- 2020/11/03 05:51
PHST- 2020/09/20 00:00 [received]
PHST- 2020/10/15 00:00 [revised]
PHST- 2020/10/29 00:00 [accepted]
PHST- 2020/11/04 06:00 [pubmed]
PHST- 2021/07/06 06:00 [medline]
PHST- 2020/11/03 05:51 [entrez]
PHST- 2022/02/01 00:00 [pmc-release]
AID - 10.1111/dom.14242 [doi]
PST - ppublish
SO  - Diabetes Obes Metab. 2021 Feb;23(2):489-498. doi: 10.1111/dom.14242. Epub 2020 
      Nov 19.