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ENDOCRINE PHYSIOLOGY AND METABOLISM

The impact of obesity, sex, and diet on hepatic glucose production in cats

¹Department of Physiology and Pharmacology, University of Georgia College of Veterinary Medicine. Athens; ²Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia; ³Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; ⁴Nestle Purina Research, Lausanne, Switzerland; ⁵Department of Veterinary Biosciences, University of Illinois College of Veterinary Medicine, Urban-Champaign, Illinois; ⁶Emory NMR Research Center, Emory University, Atlanta; and ⁷Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

Submitted 15 September 2008 ; accepted in final form 27 January 2009

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using ²H₂O, [U-¹³C₃]propionate, and [3,4-¹³C₂]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin (P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats (P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP (P < 0.003). Female obese cats had 1.5 times higher fluxes through phosphoenolpyruvate carboxykinase (P < 0.02) and citrate synthase (P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold (P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

nuclear magnetic resonance spectroscopy; diabetes mellitus; pyruvate cycling; thyroxine; polyunsaturated fatty acids