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Identification and Characterization ...

Prentice, Kacey June.

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Identification and Characterization of the Role of the Circulating Metabolite 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropanoic Acid (CMPF) in Diabetes.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Identification and Characterization of the Role of the Circulating Metabolite 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropanoic Acid (CMPF) in Diabetes./
Author:	Prentice, Kacey June.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2015,
Description:	262 p.
Notes:	Source: Dissertation Abstracts International, Volume: 77-07(E), Section: B.
Contained By:	Dissertation Abstracts International77-07B(E).
Subject:	Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10015125
ISBN:	9781339490267

Identification and Characterization of the Role of the Circulating Metabolite 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropanoic Acid (CMPF) in Diabetes.
Prentice, Kacey June.

Identification and Characterization of the Role of the Circulating Metabolite 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropanoic Acid (CMPF) in Diabetes. - Ann Arbor : ProQuest Dissertations & Theses, 2015 - 262 p.

Source: Dissertation Abstracts International, Volume: 77-07(E), Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2015.

This item is not available from ProQuest Dissertations & Theses.

Both gestational diabetes (GDM) and type 2 diabetes (T2D) are caused by a failure of the pancreatic beta cell to compensate for increased insulin demand. The underlying cause of this failure, particularly the rapid transition from prediabetes to diabetes, and between GDM and T2D is largely unknown. To identify circulating factors that may play a causal role in beta cell dysfunction we performed global metabolomics profiling on the plasma of GDM and T2D patients compared to normal glucose tolerant controls. We identified the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) as being highly elevated in diabetic plasma. In vivo and in vitro assays demonstrated that CMPF induces glucose intolerance by impairing glucose-stimulated insulin secretion (GSIS), suggesting CMPF may play a causal role in diabetes. Analysis of human patients showed that rapid elevation in CMPF is associated with a significantly increased risk of diabetes development, consistent with elevated CMPF being the "tipping point" in the progression from prediabetes to overt diabetes. The mechanism underlying this dysfunction involves increasing reactive oxygen species (ROS), resulting in altered gene expression, inhibition of beta cell transcription factor activity, as well as uncoupling of glucose metabolism to ATP production, thus reducing insulin biosynthesis and secretion. Additionally, CMPF induces a state of preferential fatty acid utilization, which persists for months following treatment. This suggests that CMPF exposure during GDM may be responsible for the extremely high rate of progression to T2D postpartum. While detrimental for beta cell function, this ability of CMPF to drive fatty acid oxidation has beneficial effects for hepatic insulin sensitivity due to the prevention of steatosis. CMPF induces beta-oxidation, simulating a "fasting-like" state and promoting expression of FGF21, which is required to impair triglyceride synthesis and promote beta-oxidation long-term. Overall, CMPF is significantly elevated in human diabetes and has direct effects on beta cell function and insulin sensitivity in rodent models.

ISBN: 9781339490267Subjects--Topical Terms:

518431
Physiology.

Identification and Characterization of the Role of the Circulating Metabolite 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropanoic Acid (CMPF) in Diabetes.
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