Abstract

K-111, formerly BM 17.0744, (2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid) is a new insulin-sensitizer with peroxisome proliferator-activated receptor (PPAR) alpha activity but without PPAR gamma activity. We determined the efficacy of K-111 in non-human primates in increasing insulin-stimulated glucose uptake and improving metabolic syndrome, assessing the general health-related effects. Six adult male obese normoglycemic prediabetic and insulin-resistant rhesus monkeys were studied on vehicle and following K-111 treatment (four-week chronic dosing each of 3 doses: 1, 3, and 10 mg/kg/d) with assessment of changes in substrate, hormone, and blood pressure measurements and alterations in insulin sensitivity using the euglycemic, hyperinsulinemic clamp technique. K-111 led to significantly decreased body weight and improved hyperinsulinemia, insulin sensitivity, hypertriglyceridemia, and HDL-cholesterol levels without adipogenesis or significant effects on fasting glucose, 24-hour urine glucose excretion, systolic or diastolic blood pressure, plasma fibrinogen, total cholesterol, or chemistry and hematology profile. These benefits are similar to the health-improving effects of calorie restriction, providing preliminary evidence that K-111 has excellent potential as a calorie-restriction mimetic agent. These results indicate the necessity of future study of K-111 for metabolic syndrome in humans, and suggest potential in reducing the risks of diabetes and cardiovascular disease.