Peroxisome Proliferator–Activated Receptor-α Agonist Treatment in a Transgenic Model of Type 2 Diabetes Reverses the Lipotoxic State and Improves Glucose Homeostasis

Abstract

Abnormalities in insulin action are the characteristics of type 2 diabetes. Dominant-negative muscle-specific IGF-I receptor (MKR) mice exhibit elevated lipid levels at an early age and eventually develop type 2 diabetes. To evaluate the role of elevated lipids in the progression of the diabetic state, MKR mice were treated with WY14,643, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist. WY14,643 treatment markedly reduced serum fatty acid and triglyceride levels within a few days, as well as muscle triglyceride levels, and subsequently normalized glucose and insulin levels in MKR mice. Hyperinsulinemic-euglycemic clamp analysis showed that WY14,643 treatment enhanced muscle and adipose tissue glucose uptake by improving whole-body insulin sensitivity. Insulin suppression of endogenous glucose production by the liver of MKR mice was also improved. The expression of genes involved in fatty acid oxidation was increased in liver and skeletal muscle, whereas gene expression levels of hepatic gluconeogenic enzymes were decreased in WY14,643-treated MKR mice. WY14,643 treatment also improved the pattern of glucose-stimulated insulin secretion from the perfused pancreata of MKR mice and reduced the beta-cell mass. Taken together, these findings suggest that the reduction in circulating or intracellular lipids by activation of PPAR-alpha improved insulin sensitivity and the diabetic condition of MKR mice.

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

“…FENO and gemfibrozil) for the treatment of hypertriacylglycerolaemia in type 2 diabetic patients, their effect on insulin sensitivity in humans has not been rigorously examined and conflicting results have been reported [9][10][11][12][13][14]. Studies in rodents conclusively demonstrate that PPAR-α activation with FENO and other more potent PPAR-α agents enhances peripheral (muscle) and hepatic insulin sensitivity [4][5][6][7][8]. Although PPAR-α-null mice do not manifest any obvious alteration in insulin sensitivity [42], PPAR-α activation in nutritional (high-fat diet), genetic (Zucker obese fa/fa rat), and lipoatrophic (A-ZIP/ F-1) models of insulin resistance markedly improves insulin sensitivity [4,7,43] and reduces visceral fat in the two former models.…”

“…Intracellular fatty acids and their derivatives interfere with insulin-stimulated glucose metabolism, through an effect on the insulin-signalling pathway, possibly by activating protein kinase C [1,44]. In rodents it has been suggested that PPAR-α activation increases fatty acid oxidation, thus decreasing intramyocellular lipid content and improving insulin sensitivity [4][5][6][7]. In contrast, PPAR-α-null mice are protected from high-fat diet-induced insulin resistance [42].…”

“…PPAR-α agonists have been used to treat hypertriacylglycerolaemia and reduce cardiovascular risk [2,3]. Studies in rodents clearly demonstrate that PPAR-α agonists improve hepatic and muscle insulin resistance, decrease hepatic and intramuscular fat content, reduce plasma NEFA and enhance adiponectin (AD) expression [4][5][6][7][8]. Some [9][10][11], but not all [12][13][14], studies in humans with hypertriacylglycerolaemia and/or type 2 diabetes suggest that PPAR-α agonists, i.e.…”

Modest PGC-1α Overexpression in Muscle in Vivo Is Sufficient to Increase Insulin Sensitivity and Palmitate Oxidation in Subsarcolemmal, Not Intermyofibrillar, Mitochondria

“…In one study from our laboratory (69) and in several others by Muoio and co-workers (2,66,70), the rates of fatty acid oxidation have been shown to be greater in mitochondria obtained from red muscle than in mitochondria obtained from white muscle. These studies suggest that there are intrinsic differences in the capacities to oxidize fatty acids by red and white muscle mitochondria.…”

Weight Loss–Associated Induction of Peroxisome Proliferator–Activated Receptor-α and Peroxisome Proliferator–Activated Receptor-γ Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice

“…A reduction in circulating or intracellular lipids by activation of PPAR-␣ improved insulin sensitivity and the diabetic condition of mice. 34 In adipocytes, skeletal muscle, and pancreatic ␤-cells, lipids are mobilized by the hormone-sensitive lipase, which deficiency results in a moderate impairment of insulin sensitivity. 35 …”