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Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels.

Abstract Neprilysin, a widely expressed peptidase, is upregulated in metabolically altered states such as obesity and type 2 diabetes. Like dipeptidyl peptidase-4 (DPP-4), neprilysin can degrade and inactivate the insulinotropic peptide glucagon-like peptide-1 (GLP-1). Thus, we investigated whether neprilysin deficiency enhances active GLP-1 levels and improves glycaemia in a mouse model of high fat feeding.
PMID
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Authors

Mayor MeshTerms
Keywords

DPP-4

GLP-1

Glucose tolerance

High fat diet

Insulin secretion

Mme

Mouse

Nep

Neprilysin

Journal Title diabetologia
Publication Year Start




PMID- 27933334
OWN - NLM
STAT- Publisher
DA  - 20161209
LR  - 20161231
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
DP  - 2016 Dec 08
TI  - Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with
      reduced DPP-4 activity and increased active GLP-1 levels.
AB  - AIM/HYPOTHESIS: Neprilysin, a widely expressed peptidase, is upregulated in
      metabolically altered states such as obesity and type 2 diabetes. Like dipeptidyl
      peptidase-4 (DPP-4), neprilysin can degrade and inactivate the insulinotropic
      peptide glucagon-like peptide-1 (GLP-1). Thus, we investigated whether neprilysin
      deficiency enhances active GLP-1 levels and improves glycaemia in a mouse model
      of high fat feeding. METHODS: Nep +/+ and Nep -/- mice were fed a 60% fat diet
      for 16 weeks, after which active GLP-1 and DPP-4 activity levels were measured,
      as were glucose, insulin and C-peptide levels during an OGTT. Insulin sensitivity
      was assessed using an insulin tolerance test. RESULTS: High-fat-fed Nep -/- mice 
      exhibited elevated active GLP-1 levels (5.8 +/- 1.1 vs 3.5 +/- 0.8 pmol/l, p <
      0.05) in association with improved glucose tolerance, insulin sensitivity and
      beta cell function compared with high-fat-fed Nep +/+ mice. In addition, plasma
      DPP-4 activity was lower in high-fat-fed Nep -/- mice (7.4 +/- 1.0 vs 10.7 +/-
      1.3 nmol ml-1 min-1, p < 0.05). No difference in insulin:C-peptide ratio was
      observed between Nep -/- and Nep +/+ mice, suggesting that improved glycaemia
      does not result from changes in insulin clearance. CONCLUSIONS/INTERPRETATION:
      Under conditions of increased dietary fat, an improved glycaemic status in
      neprilysin-deficient mice is associated with elevated active GLP-1 levels,
      reduced plasma DPP-4 activity and improved beta cell function. Thus, neprilysin
      inhibition may be a novel treatment strategy for type 2 diabetes.
FAU - Willard, Joshua R
AU  - Willard JR
AD  - Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way (151), 
      Seattle, WA, 98108, USA.
FAU - Barrow, Breanne M
AU  - Barrow BM
AD  - Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way (151), 
      Seattle, WA, 98108, USA.
FAU - Zraika, Sakeneh
AU  - Zraika S
AD  - Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way (151), 
      Seattle, WA, 98108, USA. [email protected]
AD  - Division of Metabolism, Endocrinology & Nutrition, Department of Medicine,
      University of Washington, Seattle, WA, USA. [email protected]
LA  - eng
GR  - P30 DK017047/DK/NIDDK NIH HHS/United States
GR  - R00 DK080945/DK/NIDDK NIH HHS/United States
GR  - R01 DK098506/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20161208
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
OTO - NOTNLM
OT  - DPP-4
OT  - GLP-1
OT  - Glucose tolerance
OT  - High fat diet
OT  - Insulin secretion
OT  - Mme
OT  - Mouse
OT  - Nep
OT  - Neprilysin
EDAT- 2016/12/10 06:00
MHDA- 2016/12/10 06:00
CRDT- 2016/12/10 06:00
PHST- 2016/10/25 [received]
PHST- 2016/11/16 [accepted]
AID - 10.1007/s00125-016-4172-4 [doi]
AID - 10.1007/s00125-016-4172-4 [pii]
PST - aheadofprint
SO  - Diabetologia. 2016 Dec 8.

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