Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure

Stimulation of lipolysis and the induction of resistance to insulin's actio ns on glucose metabolism are well-recognized effects of growth hormone (GH) . To evaluate whether these two features are causally linked, we studied th e impact of pharmacologically induced antilipolysis in seven GH-deficient p atients (mean [+/- SE] age 37 +/- 4 years). Each subject was studied under four different conditions: during continuation of GH replacement alone (A), after discontinuation of GH replacement for 2 days (B), after GH replaceme nt and shortterm coadministration of acipimox (250 mg, p.o., b.i.d., for 2 days) (C), and after administration of acipimox alone (D). At the end of ea ch study, total and regional substrate metabolisms were assessed in the bas al state and after a 3-h hyperinsulinemic/euglycemic clamp. Serum levels of free fatty acids (FFAs) were elevated with GH alone (A) and suppressed wit h acipimox (C and D). Basal rates of lipid oxidation were highest with GH a lone (A), and suppressed by 50% with acipimox (B versus D, P < 0.01; A vers us C, P < 0.05). Basal glucose oxidation rates were lowest with GH alone (A ) and highest with acipimox (C and D) (P = 0.01). Insulin-stimulated rates of total glucose turnover were significantly lower with GH alone as compare d with all other conditions (P = 0.004). Insulin sensitivity as assessed by the M value (rate of glucose infusion) was reduced with GH alone as compar ed with all other conditions M value in mg . kg(-1) . min(-1): GH alone [A] , 2.55 +/- 0.64; discontinuation of GH [B], 4.01 +/- 0.70; GH plus acipimox [C], 3.96 +/- 1.34; acipimox alone [D], 4.96 +/- 0.91; P < 0.01). During p harmacological antilipolysis, GH did not significantly influence insulin se nsitivity (C versus D; P = 0.19). From our results, we reached the followin g conclusions: 1) Our data strongly suggest that the insulin antagonistic a ctions of GH on glucose metabolism are causally linked to the concomitant a ctivation of lipolysis. 2) In addition, GH may induce residual insulin resi stance through non-FFA-dependent mechanisms. 3) The cellular and molecular mechanisms subserving the insulin antagonistic effects of GH remain to be e lucidated.