Giacca A, McCall R, Chan B, Shi Z Q
Department of Physiology, University of Toronto, Ontario, Canada.
Metabolism. 1999 Feb;48(2):153-60. doi: 10.1016/s0026-0495(99)90026-4.
We have recently found that in nondiabetic dogs and humans, suppression of glucose production (GP) is mediated by both peripheral and hepatic effects of insulin. We have also found that both nonesterified fatty acids (NEFA) and glucagon are important determinants of the peripheral effect of insulin on GP. However, in moderately hyperglycemic depancreatized dogs, suppression of GP appeared to be mediated by peripheral but not hepatic insulin. In this latter study, insulin concentrations were in the high postprandial range (approximately 300 pmol/L) and suppression of GP may have been close to maximum. The aim of the present study was to determine whether GP can be regulated by hepatic insulin in depancreatized dogs at low insulin concentrations in the postabsorptive range. Depancreatized dogs were maintained at moderately hyperglycemic levels (approximately 10 mmol/L) by subbasal insulin infusions. In paired experiments, additional low-dose equimolar insulin infusions (0.75 pmol/kg x min) were administered peripherally (PER, n = 6) or portally (POR, n = 6) during glucose clamps. This resulted in a minimal increase in peripheral insulin levels, which was greater in PER versus POR, 29.0 +/- 3.7 versus 11.7 +/- 2.2 pmol/L. Also, we infused insulin peripherally at half this rate (1/2 PER, n = 6) to match the increase in peripheral insulin levels in POR (1/2 PER, 14.6 +/- 2.2) and thus obtain a selective POR versus 1/2 PER difference in hepatic sinusoidal insulin levels. PER suppressed GP more than POR (45.4% +/- 4.0% v 35.3% +/- 6.8%, P < .001), whereas POR did not suppress GP more than 1/2 PER (35.6% +/- 6.3%). Therefore, suppression of GP was proportional to peripheral rather than hepatic sinusoidal insulin levels, as in our previous study at higher insulin concentrations. In conclusion, during glucose clamps in moderately hyperglycemic depancreatized dogs, (1) suppression of GP was dominated by insulin's peripheral effects not only at postprandial but also postabsorptive insulin levels, and (2) we found no evidence for a hepatic effect of insulin in suppressing GP. We hypothesize that this effect is reduced in the depancreatized dog model of diabetes due to hepatic insulin resistance and/or hyperglycemia.
我们最近发现，在非糖尿病犬和人类中，葡萄糖生成（GP）的抑制是由胰岛素的外周和肝脏作用介导的。我们还发现，非酯化脂肪酸（NEFA）和胰高血糖素都是胰岛素对GP外周作用的重要决定因素。然而，在中度高血糖的去胰腺犬中，GP的抑制似乎是由外周胰岛素而非肝脏胰岛素介导的。在后者的研究中，胰岛素浓度处于餐后高值范围（约300 pmol/L），GP的抑制可能已接近最大值。本研究的目的是确定在吸收后范围内低胰岛素浓度下，去胰腺犬的GP是否可由肝脏胰岛素调节。通过亚基础胰岛素输注将去胰腺犬维持在中度高血糖水平（约10 mmol/L）。在配对实验中，在葡萄糖钳夹期间，外周（PER，n = 6）或门静脉（POR，n = 6）额外给予低剂量等摩尔胰岛素输注（0.75 pmol/kg·min）。这导致外周胰岛素水平最小程度升高，PER组升高幅度大于POR组，分别为29.0±3.7 pmol/L和11.7±2.2 pmol/L。此外，我们以该速率的一半外周输注胰岛素（1/2 PER，n = 6），以匹配POR组外周胰岛素水平的升高幅度（1/2 PER组为14.6±2.2），从而获得肝脏窦状隙胰岛素水平的选择性POR与1/2 PER差异。PER对GP的抑制作用大于POR（45.4%±4.0%对35.3%±6.8%，P <.001），而POR对GP的抑制作用不大于1/2 PER（35.6%±6.3%）。因此，与我们之前在较高胰岛素浓度下的研究一样，GP的抑制与外周而非肝脏窦状隙胰岛素水平成正比。总之，在中度高血糖的去胰腺犬进行葡萄糖钳夹期间，（1）GP的抑制不仅在餐后胰岛素水平而且在吸收后胰岛素水平时都以胰岛素的外周作用为主，（2）我们没有发现胰岛素对GP有肝脏作用的证据。我们推测，在糖尿病去胰腺犬模型中，由于肝脏胰岛素抵抗和/或高血糖，这种作用减弱。
