Rapid Elevation in CMPF May Act As a Tipping Point in Diabetes Development

• Published in: Cell reports (Cambridge) Vol. 14; no. 12; pp. 2889 - 2900
• Main Authors: Liu, Ying, Prentice, Kacey J., Eversley, Judith A., Hu, Cheng, Batchuluun, Battsetseg, Leavey, Katherine, Hansen, Jakob B., Wei, David W., Cox, Brian, Dai, Feihan F., Jia, Weiping, Wheeler, Michael B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.03.2016; Elsevier
• Subjects: Adult; Aged; Animals; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress - genetics; Female; Furans - blood; Furans - metabolism; Gene Expression Regulation - drug effects; Glucose - pharmacology; Glycation End Products, Advanced - analysis; Glycolysis - drug effects; Humans; Insulin - metabolism; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Logistic Models; Male; Membrane Potential, Mitochondrial - drug effects; Mice; Middle Aged; Obesity - etiology; Obesity - metabolism; Oxidative Stress - drug effects; Oxidative Stress - genetics; Pancreas - metabolism; Pancreas - pathology; Prediabetic State - metabolism; Prediabetic State - pathology; Propionates - blood; Propionates - metabolism; Reactive Oxygen Species - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.02.079

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. [Display omitted] •CMPF is significantly elevated in both prediabetes and type 2 diabetes•Rapid elevation in circulating CMPF may accelerate diabetes development•CMPF impairs glucose metabolism by introducing preferential fatty acid oxidation•CMPF induces beta cell dysfunction shown as impaired insulin secretion Liu et al. show that CMPF is significantly elevated in both prediabetes and type 2 diabetes. Rapid elevation in CMPF may represent the tipping point in beta cell function, playing a causal role in the conversion from prediabetes to type 2 diabetes.