World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease

INSULIN RESISTANCE: LIPID EFFECTS—Ronald Krauss (Berkley, CA) discussed lipid effects of peroxisome proliferator–activated receptors (PPARs). PPARa activation reduces triglyceriderich lipoproteins as a consequence of combined intrahepatic actions increasing fatty acid oxidation, increasing apolipoprotein (apo)A-5, and decreasing apoC-3. The LDL phenotype B, defined by small dense LDL cholesterol with low peak particle size, may be considered a specific marker for atherogenic dyslipidemia or, as Krauss termed it, “a fingerprint for this dyslipidemic phenotype”with high triglyceride, low HDL cholesterol, and high levels of apoB for a given LDL cholesterol concentration. A study of lipoprotein particle size and concentration as assessed using nuclear magnetic resonance spectroscopy among 26,836 nondiabetic women in the Women’s Health Study showed that LDL cholesterol was not associated with the pattern B phenotype and that both LDL particle concentration and size were strongly and independently associated with diabetes to nearly the same degree as the A1C level (1). HDL size, HDL cholesterol, triglyceride, and VLDL size also displayed the association with the small dense LDL cholesterol phenotype, suggesting that all these measures reflect the interplay between fatty acids and lipid metabolism as they relate to insulin resistance. PPARa activation decreases VLDL cholesterol, changes LDL cholesterol from smaller to larger size, and raises HDL cholesterol, while the lipoprotein effects of PPARd are less well understood. Both are reported to be activated by hydrolyzed VLDL lipids, although endogenous factors activating these receptors have not been well characterized. In an in vitro study in the absence of albumin, cellular fatty acid uptake determined PPARa activation but at fatty acid levels not achievable in plasma because of the effect of albumin binding (2). One therefore needs then to look for sources of endogenous PPAR activation by fatty acid; Krauss suggested “that’s where VLDL comes in. ” Local VLDL lipolysis may present high concentrations of fatty acid to tissues. Supporting this hypothesis, treatment with P-407, a fatty acid clearance inhibitor, reverses the activation of PPARa target genes occurring with fasting, implying that endogenous PPARa activation relies on VLDL triglyceride lipolysis. ApoC3, which inhibits lipoprotein lipase (LPL), can be seen as regulating access to lipoproteinderived PPARa ligands. Lipolysis of VLDLderived fatty acid then can be thought of as an important process for activation of PPARa both in the liver and in the periphery. Use of the relatively specific pharmacologic PPARd activator MBX-8025 (Metabolex), in a phase 2 proof-of-concept study of obese individuals with elevated levels of triglyceride and LDL cholesterol and HDL cholesterol,60 mg/dL, decreased triglyceride and fatty acid levels, and increased HDL cholesterol, with a fall in apoB and with reduction in insulin and in homeostasis model assessment of insulin resistance (HOMA-IR)—an effect beyond what one would expect from a typical PPARa agonist. With use of direct lipoprotein particle measurement by ion mobility, reduction in LDL cholesterol and increase in HDL cholesterol levels were seen independent of effects on HOMAIR, with an increase in LDL cholesterol peak diameter, leading to an almost complete conversion of phenotype B to phenotype A associated with reduction in VLDL triglyceride (3). Another PPARd agonist, GW501516, led to 20% reduction in liver fat, which correlated with change in triglyceride levels (4). Krauss speculated that PPARd may complement the effect of PPARa, reducing peripheral delivery of fatty acid to the liver and perhaps increasing hepatic fatty acid oxidation as is seen with PPARa. “Time will tell,” he commented, “whether agents such as this will pass muster for clinical efficacy and safety, as well as outcome. ”