DIFFERENT ACUTE AND CHRONIC EFFECTS OF ACIPIMOX TREATMENT ON GLUCOSE AND LIPID-METABOLISM IN PATIENTS WITH TYPE-2 DIABETES

To study whether therapeutic reduction of non-esterified fatty acids (NEFA) can be used to improve glucose metabolism, we administered the antilipolytic agent, acipimox, 250 mg four times daily for 4 weeks in eight obese Type 2 diabetic patients. Glucose and NEFA metabolism were assessed before and after treatment with a two-step euglycaemic hyperinsulinaemic clamp (0.25 and 1 mU kg(-1) min(-1) insulin) combined with infusions of [3-H-3] glucose and [1_C-14] palmitate. Three days of acipimox treatment reduced 24-h serum NEFA levels by 10 %, but the difference disappeared after 4 weeks of treatment mainly due to a two-fold rise in morning NEFA concentrations (p< 0.01). After 3 days of acipimox treatment, fasting and 24-h plasma glucose and serum triglyceride concentrations were significantly reduced (p < 0.05), but no longer after 4 weeks of treatment. Despite the rebound rise in NEFA, acute administration of acipimox still inhibited both oxidative and non-oxidative NEFA metabolism in the basal state (p < 0.01 - 0.001) and during insulin infusion (p < 0.05 - 0.001). Inhibition of NEFA metabolism was associated with increased insulin-stimulated glucose uptake (from 3.56 +/- 0.28 to 5.14 +/- 0.67 mu mol kg(-1) min(-1), p < 0.05), mainly due to stimulation of non-oxidative glucose disposal (from 1.74 +/- 0.23 to 3.03 +/- 0.53 mu mol kg(-1) min(-1), p< 0.05). In conclusion, acipimox administered acutely inhibits NEFA appearance (lipolysis), which is associated with improved glucose uptake. However, after 4 weeks of treatment, the beneficial effects on NEFA and glucose metabolism are outweighed by a marked rebound rise in fasting NEFA concentrations. The results emphasize the problems using acipimox as a means to improve glucose tolerance in patients with Type 2 diabetes.