Changes in glucose and fat metabolism in response to the administration of a hepato-preferential insulin analog

Abstract

Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Because subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeutic benefits. The effects of recombinant human insulin (HI) delivered intraportally or peripherally were compared with an acylated insulin model compound (insulin-327) in dogs. During somatostatin and basal portal vein glucagon infusion, insulin was infused portally (PoHI; 1.8 pmol/kg/min; n = 7) or peripherally (PeHI; 1.8 pmol/kg/min; n = 8) and insulin-327 (Pe327; 7.2 pmol/kg/min; n = 5) was infused peripherally. Euglycemia was maintained by glucose infusion. While the effects on liver glucose metabolism were greatest in the PoHI and Pe327 groups, nonhepatic glucose uptake increased most in the PeHI group. Suppression of lipolysis was greater during PeHI than PoHI and was delayed in Pe327 infusion. Thus small increments in portal vein insulin have major consequences on the liver, with little effect on nonhepatic glucose metabolism, whereas insulin delivered peripherally cannot act on the liver without also affecting nonhepatic tissues. Pe327 functionally restored the physiologic portal-arterial gradient and thereby produced hepato-preferential effects.

Figure 1

Arterial and portal vein insulin concentrations in conscious dogs fasted overnight during the basal (−40 to 0 min) and experimental periods (0–300 min) in the PoHI (A), PeHI (B), and Pe327 groups (C) (mean ± SEM; n = 7, 8, 5 for arterial insulin in the 3 groups, respectively; portal insulin also was measured in a subset of 4 animals from each group).

Figure 2

Arterial plasma glucose concentration (A) and peripheral vein glucose infusion rate (B) in conscious dogs fasted overnight during the basal (−40 to 0 min) and experimental periods (0–300 min) in the PoHI, PeHI, and Pe327 groups (mean ± SEM; n = 7, 8, 5 in the 3 groups, respectively).

Figure 3

Tracer-determined endogenous glucose production (A) and whole-body glucose uptake (B) in conscious dogs fasted overnight during the basal (−40 to 0 min) and experimental periods (0–300 min) in the PoHI, PeHI, and Pe327 groups (mean ± SEM; n = 7, 8, 5 in the 3 groups, respectively). Panel A: P < 0.05 for PeHI vs. PoHI at 90 min and for PeHI vs. Pe327 between 120 and 180 min. Panel B: P < 0.05 for PeHI vs. PoHI between 120 and 300 min, for PeHI vs. Pe327 between 90 and 210 min, and for PoHI vs. Pe327 between 240 and 300 min.

Figure 4

Net hepatic glucose balance (A) and nonhepatic glucose uptake (B) in conscious dogs fasted overnight during the basal (−40 to 0 min) and experimental periods (0–300 min) in the PoHI, PeHI, and Pe327 groups (mean ± SEM; n = 4, 4, 4 in the 3 groups, respectively). Panel A: P < 0.05 for PeHI vs. Pe327 at 180 min. Panel B: P < 0.05 for PeHI vs. PoHI between 180 and 300 min, for PeHI vs. Pe327 between 180 and 210 min, and for PoHI vs. Pe327 at 300 min.

Figure 5

Arterial plasma NEFAs (A) and arterial blood glycerol (B) in conscious dogs fasted overnight during the basal (−40 to 0 min) and experimental periods (0–300 min) in the PoHI, PeHI, and Pe327 groups (mean ± SEM; n = 7, 8, 5 in the 3 groups, respectively). Panel A: P < 0.05 for PeHI vs. PoHI between 30 and 270 min, for PeHI vs. Pe327 between 30 and 60 min, and for PoHI vs. Pe327 between 120 and 240 min. Panel B: P < 0.05 for PeHI vs. PoHI between 15 and 240 min, for PeHI vs. Pe327 between 15 and 45 min, and for PoHI vs. Pe327 between 120 and 240 min.

Figure 6

Change from basal tracer-determined glucose uptake relative to change from basal endogenous glucose production in conscious dogs fasted overnight between 90 and 150 min (A) and 240 and 300 min (B) of the experimental period in the PoHI (solid regression line), PeHI (medium dashed line), and Pe327 groups (large dashed line) (mean ± SEM; n = 7, 8, 5 in the 3 groups, respectively).