We previously reported a striking similarity between the dynamics of both glucose turnover and thoracic duct lymph insulin during euglycemic clamps (J Clin Invest 84:1620, 1989), which suggested that transendothelial insulin transport (TET) is rate-limiting for insulin action in vivo. Thoracic duct lymph, however, is primarily derived from insulin-insensitive tissues, which raises questions as to the physiological significance of this relationship. The relationship between glucose turnover and TET was thus examined in insulin-sensitive tissues by the simultaneous measurement of insulin in plasma, thoracic duct lymph, and hindlimb lymph during euglycemic clamps in normal anesthetized dogs (n = 8). Clamps consisted of two 3-h phases: a 0.6 mU · min−1 · kg−1 insulin infusion (activation phase) followed by termination of the insulin infusion (deactivation phase). Lymph insulin was < plasma insulin during both phases (P < 0.01) with steady-state hindlimb (120 ± 12 pM) and thoracic duct lymph insulin (138 ± 12 pM) 38 and 45%, respectively, lower than steady-state plasma insulin (222 ± 24 pM) at the end of the activation phase (P < 0.05). Also, the rate of increase of lymph insulin was slower than plasma insulin during hormone infusion; half-time to steady-state was 8.8 ± 2.0 min for plasma insulin, but longer for thoracic (25.8 ± 3.5) and hindlimb lymph insulin (40.7 ± 5.7 min). A very close relationship was observed during activation between the rate of increase of glucose uptake (Rd) and the increase in hindlimb lymph insulin (r2 = 0.92); this relationship was weaker for thoracic lymph (r2 = 0.74) and much weaker between glucose uptake and plasma insulin (r2 = 0.35). These data support the concept that interstitial insulin (represented by hindlimb lymph) is the signal that determines glucose uptake by insulin-sensitive tissues and that the rate of increase of glucose uptake is determined by transendothelial insulin transport into insulin-sensitive tissue. Also, during activation, hindlimb lymph insulin was a very strong predictor of the rate of suppression of hepatic glucose output (HGO) (r2 = 0.96), and the correlation with HGO was stronger than that for thoracic lymph (r2 = 0.85). The evidence that the rate of increase of Rd and the rate of suppression of HGO during insulin infusion are very strongly predicted by the time course of insulin in hindlimb lymph is consistent with the single-gateway hypothesis: the insulin transport rate across endothelium in insulin-sensitive tissue (skeletal muscle) determines the rate of glucose utilization and the suppression of hepatic glucose output. It is suggested that there is a yet-undefined signal that controls HGO generated at the level of insulin-sensitive peripheral tissues.

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