The PPARα/γ Agonist, Tesaglitazar, Improves Insulin Mediated Switching of Tissue Glucose and Free Fatty Acid Utilization In Vivo in the Obese Zucker Rat
Metabolic flexibility was assessed in male Zucker rats: lean controls, obese controls, and obese rats treated with the dual peroxisome proliferator activated receptor (PPAR) agonist, tesaglitazar, 3？μmol/kg/day for 3 weeks. Whole body glucose disposal rate ( ) and hepatic glucose output (HGO) were assessed under basal fasting and hyperinsulinemic isoglycemic clamp conditions using [3,3H]glucose. Indices of tissue specific glucose utilization ( ) were measured at basal, physiological, and supraphysiological levels of insulinemia using 2-deoxy-D-[2,6-3H]glucose. Finally, whole body and tissue specific FFA and glucose utilization and metabolic fate were evaluated under basal and hyperinsulinemic conditions using a combination of [U-13C]glucose, 2-deoxy-D-[U-14C]glucose, [U-14C]palmitate, and [9,10-3H]-(R)-bromopalmitate. Tesaglitazar improved whole body insulin action by greater suppression of HGO and stimulation of compared to obese controls. This involved increased insulin stimulation of in fat and skeletal muscle as well as increased glycogen synthesis. Tesaglitazar dramatically improved insulin mediated suppression of plasma FFA level, whole body turnover ( ), and muscle, liver, and fat utilization. At basal insulin levels, tesaglitazar failed to lower HGO or compared to obese controls. In conclusion, the results demonstrate that tesaglitazar has a remarkable ability to improve insulin mediated control of glucose and FFA fluxes in obese Zucker rats. 1. Introduction Impaired trafficking of fatty acids between oxidative disposal in nonadipose tissues and storage in adipose tissue, leading to ectopic lipid accumulation, may be causative in impaired glucose control [1], dyslipidemia [2], and inflammation [3], all important factors in the etiology of type 2 diabetes and cardiovascular disease. Metabolic flexibility is defined as the ability to switch from predominantly lipid metabolism, with high fluxes of fatty acids in the fasting state, to enhanced glucose uptake, oxidation and storage under hyperinsulinemic conditions [4]. Impaired metabolic flexibility could in theory induce ectopic lipid accumulation either via defective control of fatty acid availability due to insulin resistance [5, 6] or impaired fatty acid oxidation capacity [7, 8] or both. Whatever the precise pathophysiological mechanism, it has been shown that lowering fatty acid availability by suppressing 24？h FFA levels, using short term intensive treatment with the nicotinic acid analog acipimox, induced substantial improvements in blood glucose control in patients with type 2 diabetes [9].
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