Perhexiline Therapy in Patients with Type 2 Diabetes: Incremental Insulin Resistance despite Potentiation of Nitric Oxide Signaling

Abstract

Perhexiline (Px) inhibits carnitine palmitoyltransferase 1 (CPT1), which controls uptake of long chain fatty acids into mitochondria. However, occasional cases of hypoglycaemia have been reported in Px-treated patients, raising the possibility that Px may also increase sensitivity to insulin. Furthermore, Px increases anti-aggregatory responses to nitric oxide (NO), an effect which may theoretically parallel insulin sensitization. We therefore sought to examine these relationships in patients with stable Type 2 diabetes (T2D) and cardiovascular disease (n = 30). Px was initiated, and dosage was titrated, to reach the therapeutic range and thus prevent toxicity. Investigations were performed before and after 2 weeks, to examine changes in insulin sensitivity and, utilizing aggregometry in whole blood, platelet responsiveness to the anti-aggregatory effects of the NO donor sodium nitroprusside (SNP). Other parameters that affect may affect NO signalling were also evaluated. Px substantially potentiated inhibition of platelet aggregation by SNP (from 16.7 ± 3.0 to 27.3 ± 3.7%; p = 0.005). Px did not change fasting blood glucose concentrations but reduced insulin sensitivity (HOMA-IR score increased from median of 4.47 to 6.08; p = 0.028), and increased fasting plasma insulin concentrations (median 16.5 to 19.0 mU/L; p = 0.014). Increases in SNP responses tended (r = −0.30; p = 0.11) to be reciprocally related to increases in HOMA-IR, and increases in HOMA-IR were greater (p = 0.002) in patients without NO-sensitizing effects. No patient developed symptomatic hypoglycaemia, nor was there any other short-term toxicity of Px. Thus, in patients with stable T2D and cardiovascular disease, Px increases anti-aggregatory responsiveness to NO, but is not an insulin sensitizer, and does not induce hypoglycaemia. Absence of NO-sensitizing effect occurs in approximately 30% of Px-treated patients with T2D, and is associated with induction of insulin resistance in these patients.