title: Rapid Elevation in CMPF May Act As a Tipping Point in Diabetes Development.
abstract: Prediabetes, a state of mild glucose intolerance, can persist for years before a sudden decline in beta cell function and rapid deterioration to overt diabetes. The mechanism underlying this tipping point of beta cell dysfunction remains unknown. Here, the furan fatty acid metabolite CMPF was evaluated in a prospective cohort. Those who developed overt diabetes had a significant increase in CMPF over time, whereas prediabetics maintained chronically elevated levels, even up to 5 years before diagnosis. To evaluate the effect of increasing CMPF on diabetes progression, we used obese, insulin-resistant models of prediabetes. CMPF accelerated diabetes development by inducing metabolic remodeling, resulting in preferential utilization of fatty acids over glucose. This was associated with diminished glucose-stimulated insulin secretion, increased ROS formation, and accumulation of proinsulin, all characteristics of human diabetes. Thus, an increase in CMPF may represent the tipping point in diabetes development by accelerating beta cell dysfunction.
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3352, Toronto, ON M5S 1A8, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3352, Toronto, ON M5S 1A8, Canada.
authors.forename: Kacey J
authors.initials: KJ
authors.lastname: Prentice
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3352, Toronto, ON M5S 1A8, Canada.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Eversley
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3352, Toronto, ON M5S 1A8, Canada.
authors.forename: Battsetseg
authors.initials: B
authors.lastname: Batchuluun
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3360, Toronto, ON M5S 1A8, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Leavey
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3352, Toronto, ON M5S 1A8, Canada.
authors.forename: Jakob B
authors.initials: JB
authors.lastname: Hansen
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3352, Toronto, ON M5S 1A8, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Wei
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3360, Toronto, ON M5S 1A8, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Cox
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3352, Toronto, ON M5S 1A8, Canada.
authors.forename: Feihan F
authors.initials: FF
authors.lastname: Dai
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: wpjia@sjtu.edu.cn.
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 3352, Toronto, ON M5S 1A8, Canada. Electronic address: michael.wheeler@utoronto.ca.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D005663:Furans / Q000097:blood* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000032:analysis; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D011236:Prediabetic State / Q000378:metabolism / Q000473:pathology*; D011422:Propionates / Q000097:blood* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C468134:3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; D005663:Furans; D017127:Glycation End Products, Advanced; D007328:Insulin; D011422:Propionates; D017382:Reactive Oxygen Species; D005947:Glucose