Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes

• Published in: Cell metabolism 2018-01, Vol.27 (1), p.210-217.e3
• Main Authors: Perry, Rachel J., Peng, Liang, Cline, Gary W., Wang, Yongliang, Rabin-Court, Aviva, Song, Joongyu D., Zhang, Dongyan, Zhang, Xian-Man, Nozaki, Yuichi, Dufour, Sylvie, Petersen, Kitt Falk, Shulman, Gerald I.
• Format: Article
• Language: English
• Subjects: Acetyl Coenzyme A - metabolism; acetyl-CoA; Animals; Caloric Restriction; Diabetes Mellitus, Type 2 - pathology; Diet; Disease Models, Animal; Fasting; gluconeogenesis; Glucose - metabolism; Glycogenolysis; Hyperglycemia - pathology; Lipid Metabolism; Liver - metabolism; Male; Oxidation-Reduction; Rats, Sprague-Dawley; T2D; type 2 diabetes; very low calorie diet
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.10.004

Caloric restriction rapidly reverses type 2 diabetes (T2D), but the mechanism(s) of this reversal are poorly understood. Here we show that 3 days of a very-low-calorie diet (VLCD, one-quarter their typical intake) lowered plasma glucose and insulin concentrations in a rat model of T2D without altering body weight. The lower plasma glucose was associated with a 30% reduction in hepatic glucose production resulting from suppression of both gluconeogenesis from pyruvate carboxylase (VPC), explained by a reduction in hepatic acetyl-CoA content, and net hepatic glycogenolysis. In addition, VLCD resulted in reductions in hepatic triglyceride and diacylglycerol content and PKCɛ translocation, associated with improved hepatic insulin sensitivity. Taken together, these data show that there are pleotropic mechanisms by which VLCD reverses hyperglycemia in a rat model of T2D, including reduced DAG-PKCɛ-induced hepatic insulin resistance, reduced hepatic glycogenolysis, and reduced hepatic acetyl-CoA content, PC flux, and gluconeogenesis. [Display omitted] •A 3-day, very-low-calorie diet (VLCD) reverses T2D in rats by multiple mechanisms•A VLCD lowers hepatic acetyl-CoA, glycogenolysis, and TAG-DAG-PKCɛ activation•A VLCD markedly improves hepatic, not peripheral, insulin sensitivity in T2D rats Perry et al. show that short-term (3 days) low-calorie diet improves glucose metabolism before weight loss in a rat model of T2 diabetes and trace the beneficial metabolic effects to improved liver metabolism due to reductions in hepatic glycogenolysis, acetyl-CoA-driven pyruvate carboxylase flux, and TAG-DAG-PKCɛ-mediated insulin resistance.