Insulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogs

Abstract

To determine whether the predominant effect of insulin in suppressing tracer-determined glucose production (Ra) is hepatic or peripheral, we infused insulin peripherally (PER) and portally (POR) at both low (0.75 pmol ⋅ kg−1 ⋅ min−1) and high physiological rates (2.7 pmol ⋅ kg−1 ⋅ min−1) during euglycemic clamps in normal dogs. We also infused insulin peripherally at one-half these rates (1/2 PER) to match the peripheral insulin levels in POR and thus obtain a selective POR vs. 1/2 PER difference in hepatic insulin levels. At the high-rate insulin infusion, peripheral insulin levels were greatest with PER (PER = 212 ± 10 pM, n = 5; POR = 119 ± 5 pM, n = 6; 1/2 PER = 122 ± 5 pM, n = 6). Calculated hepatic insulin levels were greatest with POR (POR = 227 ± 13 pM, PER = 206 ± 19 pM, 1/2 PER = 123 ± 8 pM). High-dose PER yielded a greater suppression of Ra than POR (79 ± 18 vs. 56 ± 6%, P < .001). Ra was only suppressed by 45 ± 6% with 1/2 PER ( P< 0.01 vs. POR on 6 paired experiments). Free fatty acid (FFA) was suppressed by 57 ± 8% with PER and only by 33 ± 5 and 37 ± 2% with POR and 1/2 PER, respectively. The low-dose PER and POR yielded an equal Ra suppression (PER = 46 ± 9%, POR = 43 ± 4%). Only 1/2 PER was associated with a lower suppression of Ra (36 ± 8, P < 0.05 vs. POR). FFA showed similar suppression in all three groups (∼25%). Using both insulin infusion rates, the percent Ra suppression per unit difference in peripheral insulin was approximately twofold greater than that per unit difference in hepatic insulin. These results suggest that, during euglycemic clamps without somatostatin in normal dogs, Ra suppression is mediated by both peripheral and hepatic effects of insulin and that peripheral insulin, at least at high physiological infusion rates, is more potent than hepatic insulin in suppressing Ra.

Insulin inhibits glucose production by a direct effect in diabetic depancreatized dogs during euglycemia

“…In this study in euglycemic depancreatized dogs, at matched peripheral insulin levels, portal insulin infusion (POR treatment) was more effective than half-rate peripheral insulin infusion (½ PER treatment) in suppressing GP during a hyperinsulinemic clamp, consistent with our previous findings in normal dogs (19) and humans (18). The ½ PER treatment, which only marginally suppressed GP, resulted in peripheral insulin levels equal to those of the POR treatment, but the hepatic sinusoidal insulin levels were presumably much lower than those in the POR treatment [Ն50% lower assuming a portal-peripheral gradient of 2.5 (10) and 72% contribution of the portal flow to hepatic blood flow (12)].…”

“…To address this question, the results of the present study should be compared with those from dogs maintained under tighter glycemic control throughout the treatment period. However, in the present study, the difference in GP suppression was comparable to that seen in our previous studies in nondiabetic dogs (19), suggesting that the acute effect of euglycemia may be sufficient to restore insulin's direct effect on GP.…”

“…However, in our studies in nondiabetic dogs, the direct effect of insulin was, if anything, less evident at high rather than low insulin levels (19). Also, during the clamp period, glucose was the only parameter that was markedly different from what it was in the previous study when the same additional insulin dose was infused portally or peripherally (9).…”

“…This inhibition is in part direct, i.e., due to hepatic sinusoidal insulin's interaction with the hepatocyte insulin receptor (18,19,28,29,31,32), and in part indirect, due to peripheral insulin's actions on extrahepatic tissues (1,18,19,23,28,29,31,32). These actions consist mainly of the antilipolytic effect of insulin in the adipose tissue (16,17,24,25,30).…”

Direct and indirect effects of insulin on hepatic glucose production in diabetic depancreatized dogs during euglycemia

“…The direct effect is due to interaction of hepatic sinusoidal insulin with the hepatocyte insulin receptor (Lewis et al 1996, Sindelar et al 1996, 1997, 1998, McCall et al 1998, Staehr et al 2001 and the indirect effect is due to insulin's actions on extrahepatic tissues, such as muscle and adipose tissue (Prager et al 1987, Ader & Bergman 1990, Lewis et al 1996, Sindelar et al 1996, 1997, 1998, McCall et al 1998, Staehr et al 2001), a cells (Giacca et al 1997), and brain (Obici et al 2002).…”