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GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products.

Abstract The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes and, recently, of obesity. The insulinotropic activity of the native incretin hormone GLP-1(7-36)amide, which is mainly exerted through a unique G protein-coupled receptor (GLP-1R), is terminated via enzymatic cleavage by dipeptidyl peptidase-IV that generates a C-terminal GLP-1 metabolite GLP-1(9-36)amide, the major circulating form in plasma. GLP-1(28-36)amide and GLP-1(32-36)amide are further cleavage products derived from GLP-1(7-36)amide and GLP-1(9-36)amide by the action of a neutral endopeptidase known as neprilysin. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive. However, emerging evidence indicates that GLP-1 byproducts have insulinomimetic activities that may contribute to the pleiotropic effects of GLP-1 independently of the canonical GLP-1R. The recent studies reporting the beneficial effects of the administration of these metabolites in vivo and in vitro are the focus of this review. Collectively, these results suggest that GLP-1 metabolites inhibit hepatic glucose production, exert antioxidant cardio- and neuroprotective actions, reduce oxidative stress in vasculature and have both anti-apoptotic and proliferative effects in pancreatic β-cells, putatively by the modulation of mitochondrial functions. These findings have implication in energy homeostasis, obesity and its associated metabolic and cardiovascular complications as well as incretin-based therapies for the treatment of diabetes and obesity.
PMID
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Authors

Mayor MeshTerms
Keywords

Dipeptidyl peptidase IV

GLP-1 metabolites

GLP-1(28–36)amide

GLP-1(32–36)amide

GLP-1(9–36)amide

Neprilysin

Journal Title eating and weight disorders : ewd
Publication Year Start




PMID- 28040864
OWN - NLM
STAT- Publisher
DA  - 20170101
LR  - 20170104
IS  - 1590-1262 (Electronic)
IS  - 1124-4909 (Linking)
DP  - 2016 Dec 31
TI  - GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1
      breakdown products.
LID - 10.1007/s40519-016-0352-y [doi]
AB  - The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic
      target for the treatment of type 2 diabetes and, recently, of obesity. The
      insulinotropic activity of the native incretin hormone GLP-1(7-36)amide, which is
      mainly exerted through a unique G protein-coupled receptor (GLP-1R), is
      terminated via enzymatic cleavage by dipeptidyl peptidase-IV that generates a
      C-terminal GLP-1 metabolite GLP-1(9-36)amide, the major circulating form in
      plasma. GLP-1(28-36)amide and GLP-1(32-36)amide are further cleavage products
      derived from GLP-1(7-36)amide and GLP-1(9-36)amide by the action of a neutral
      endopeptidase known as neprilysin. Until recently, GLP-1-derived metabolites were
      generally considered metabolically inactive. However, emerging evidence indicates
      that GLP-1 byproducts have insulinomimetic activities that may contribute to the 
      pleiotropic effects of GLP-1 independently of the canonical GLP-1R. The recent
      studies reporting the beneficial effects of the administration of these
      metabolites in vivo and in vitro are the focus of this review. Collectively,
      these results suggest that GLP-1 metabolites inhibit hepatic glucose production, 
      exert antioxidant cardio- and neuroprotective actions, reduce oxidative stress in
      vasculature and have both anti-apoptotic and proliferative effects in pancreatic 
      beta-cells, putatively by the modulation of mitochondrial functions. These
      findings have implication in energy homeostasis, obesity and its associated
      metabolic and cardiovascular complications as well as incretin-based therapies
      for the treatment of diabetes and obesity.
FAU - Guglielmi, Valeria
AU  - Guglielmi V
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier
      1, 00133, Rome, Italy.
AD  - Internal Medicine Unit and Obesity Center, University Hospital Policlinico Tor
      Vergata, Rome, Italy.
FAU - Sbraccia, Paolo
AU  - Sbraccia P
AD  - Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier
      1, 00133, Rome, Italy. [email protected]
AD  - Internal Medicine Unit and Obesity Center, University Hospital Policlinico Tor
      Vergata, Rome, Italy. [email protected]
LA  - eng
PT  - Review
PT  - Journal Article
DEP - 20161231
PL  - Germany
TA  - Eat Weight Disord
JT  - Eating and weight disorders : EWD
JID - 9707113
OTO - NOTNLM
OT  - Dipeptidyl peptidase IV
OT  - GLP-1 metabolites
OT  - GLP-1(28-36)amide
OT  - GLP-1(32-36)amide
OT  - GLP-1(9-36)amide
OT  - Neprilysin
EDAT- 2017/01/04 06:00
MHDA- 2017/01/04 06:00
CRDT- 2017/01/02 06:00
PHST- 2016/11/15 [received]
PHST- 2016/12/15 [accepted]
AID - 10.1007/s40519-016-0352-y [doi]
AID - 10.1007/s40519-016-0352-y [pii]
PST - aheadofprint
SO  - Eat Weight Disord. 2016 Dec 31. doi: 10.1007/s40519-016-0352-y.

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