In addition to their benefits on glycemia, the specific actions of insulin analogs on glucose and lipid metabolism should be depicted. Here we analyzed the effects of Lispro (LIS) and Glulisine (GLU) insulin-analogs in diabetic rats. Diabetes was induced in Wistar male rats following an i.v. injection of streptozotocin (STZ) at 60mg/kg. Conscious rats underwent a 2-hour hyperinsulinemic (LIS or GLU at 0.8U/kg/h) euglycemic clamp with a constant infusion of 3H-glucose (4µCi/kg/min), with n=8 rats per each group. Glycemia was monitored continuously to adjust glucose infusion rate (GIR) to maintain euglycemia during the LIS or GLU perfusion. Blood, muscle and liver samples were collected for biochemical and radioactivity analysis. Compared to GLU, mean GIR was 51% higher in LIS treated rats (LIS: 18 +/- 1mg/kg/min, GLU: 12 +/- 1 mg/kg/min, p<0.01). Importantly, the higher GIR observed with LIS was associated with a strong inhibition of hepatic glucose production, which remained elevated in rats treated with GLU (LIS: 0.4 +/- 0.9mg/kg/min, GLU: 6.4 +/-1.6 mg/kg/min, p<0.01). Whole body glycolysis, glycogen, as well as liver and muscle glycogen synthesis rates remain similar between groups. Compared with LIS, rats treated with GLU showed a better reduction in plasma free fatty acids and glycerol levels during the clamp experiment, with a 50% and 139% lower plasma free fatty acids and glycerol area under the curve (p<0.and p<0.01 vs. LIS, respectively). 3H-glucose incorporation in muscle and liver lipid stores was not different, indicating that lipolysis rather than lipogenesis was differentially impacted.
In conclusion, hyperinsulinemic euglycemic clamps in STZ rats enabled to detect a strong inhibition of hepatic glucose production by LIS, while GLU better suppresses lipolysis. Our experimental setting should help to differentiate other insulin analogs and dissect their mechanisms of action.
F. Briand: Employee; Self; Physiogenex S.A.S.. Stock/Shareholder; Self; Physiogenex S.A.S. E. Brousseau: Employee; Self; Physiogenex S.A.S. R. Burcelin: Stock/Shareholder; Self; Physiogenex S.A.S. T. Sulpice: Employee; Self; Physiogenex S.A.S.. Stock/Shareholder; Self; Physiogenex S.A.S..