Insulin transport across capillaries is rate limiting for insulin action in dogs

Abstract

This study examined the relationship between transcapillary insulin transport and insulin action in vivo. During euglycemic clamps (n = 7) in normal conscious dogs we simultaneously measured plasma and thoracic duct lymph insulin and glucose utilization (R(d)). Clamps consisted of an activation phase with constant insulin infusion (0.6 mU/kg per min) and a deactivation phase. [14C]Inulin was infused as a passively transported control substance. While [14C]inulin reached an equilibrium between plasma and lymph, steady-state (ss) plasma insulin was higher than lymph (P < 0.05) and the ratio of 3:2 was maintained during basal, activation, and deactivation phases: 18 ± 2 vs. 12 ± 1, 51 ± 2 vs. 32 ± 1, and 18 ± 3 vs. 13 ± 1 μU/ml. In addition, it took longer for lymph insulin to reach ss than plasma insulin during activation and deactivation: 11 ± 2 vs. 31 ± 5 and 8 ± 2 vs. 32 ± 6 min (P < 0.02). R(d) increased from 2.6 ± 0.1 to a ss of 6.6 ± 0.4 mg/kg per min within 50 ± 8 min. There was a remarkable similarity in the dynamics of insulin in lymph and R(d): the time to reach ss for R(d) was not different from lymph insulin (P > 0.01), and the relative increases of the two measurements were similar, 164 ± 45% and 189 ± 29% (P > 0.05). While there was only a modest correlation (r = 0.78, P < 0.01) between R(d) and plasma insulin, the dynamic changes of lymph insulin and R(d) showed a strong correlation (r = 0.95, P < 0.01). The intimate relationship between lymph insulin and R(d) suggests that the transcapillary insulin transport is primarily responsible for the delay in R(d). Thus, transcapillary transport may be rate limiting for insulin action, and if altered, it could be an important component of insulin resistance in obesity and diabetes mellitus.