Insulin sensitivity of glucose disposal and lipolysis: No influence of common genetic variants in IRS-1 and CAPN10

Abstract

Aims/hypothesis. This study aimed to assess the physiologic relationships between insulin sensitivity of lipolysis and that of glucose disposal and whether two common genetic polymorphisms associated with insulin resistance partially explained the remaining variation. Methods. We measured suppression of lipolysis (isotopically [primed-continuous infusion of d5 glycerol] measured glycerol rate of appearance) and glucose disposal during a three-step (n = 24) or standard (n = 57) hyperinsulinaemic euglycaemic clamp in 81 healthy subjects. We also compared insulin sensitivity of lipolysis in carriers (vs. wildtype controls) of the CAPN10 UCSNP43 G/A and IRS-1 Gly972Arg polymorphisms. Results. We observed a significant correlation between insulin sensitivity of glucose disposal and insulin sensitivity of lipolysis (r = -0.39, p < 0.001) which was retained, albeit weaker, after adjusting for BMI (r = -0.27, p = 0.002). No significant difference in insulin sensitivity of lipolysis was found between Gly/Gly compared with X/Arg (IRS-1) and G/G compared with G/A +A/A (CAPN10) (all p values > 0.15). Conclusion/interpretation. Insulin sensitivity of lipolysis has a considerable variation in healthy human beings and independently explains about 10% of the variation in insulin sensitivity of glucose disposal (or vice versa). It is possible that mediated through NEFAs, insulin resistance of glucose disposal is secondary to that of lipolysis. Alternatively, the biological variation in insulin sensitivity, to some extent, affects both systems in parallel. Neither of the two putatively insulin resistance-related polymorphisms that were tested contributed measurably to the biological variation of insulin sensitivity of lipolysis.