Lewis G F, Carpentier A, Vranic M, Giacca A
Department of Medicine, University of Toronto, Ontario, Canada.
Diabetes. 1999 Mar;48(3):570-6. doi: 10.2337/diabetes.48.3.570.
We and others have shown that insulin acutely suppresses glucose production in fasting nondiabetic humans and dogs, by both a direct hepatic effect and an indirect (extrahepatic) effect, and in diabetic dogs by an indirect effect alone. In type 2 diabetes, there is resistance to insulin's ability to suppress hepatic glucose production, but it has not previously been determined whether the resistance is primarily at the level of the hepatocyte or the peripheral tissues. To determine whether the diabetic state reduces the direct effect of insulin in humans, we studied nine patients with untreated type 2 diabetes who underwent three studies each, 4-6 weeks apart. 1) Portal study (POR): intravenous tolbutamide was infused for 3 h with calculation of pancreatic insulin secretion from peripheral plasma C-peptide. 2) Peripheral study (PER): equidose insulin was infused by peripheral vein. 3) Half-dose peripheral insulin study (1/2 PER): matched peripheral insulin levels with study 1. In all studies, glucose was clamped at euglycemia, glucose turnover was measured with the constant specific activity method, and 3-[3H]glucose was purified by high-performance liquid chromatography. Peripheral insulin was lower in POR versus PER but slightly higher in POR versus 1/2 PER, although most of the difference could be accounted for by higher proinsulin levels in POR (stimulated by tolbutamide). Calculated portal insulin was approximately 1.3-fold higher in POR versus PER and approximately 2.2-fold higher in POR versus 1/2 PER. In the final 30 min of the clamp, glucose production reached a lower steady-state level in PER than in POR (4.0 +/- 0.4 vs. 5.3 +/- 0.5 pmol(-1) x kg(-1) x min(-1), P < 0.05), despite the higher hepatic insulin level in POR. In contrast with our studies in nondiabetic individuals, glucose production was not more suppressed at steady state in POR versus 1/2 PER (5.3 +/- 0.4 micromol x kg(-1) x min(-1)), despite much higher hepatic insulin levels in POR. In conclusion, this is the first study in patients with type 2 diabetes to characterize insulin resistance to the acute direct suppressive effect of insulin on hepatic glucose production.
我们和其他研究人员已经表明，胰岛素可通过直接肝脏效应和间接（肝外）效应，在空腹的非糖尿病人类和犬类中急性抑制葡萄糖生成；在糖尿病犬类中，胰岛素仅通过间接效应抑制葡萄糖生成。在2型糖尿病中，存在对胰岛素抑制肝脏葡萄糖生成能力的抵抗，但此前尚未确定这种抵抗主要是在肝细胞水平还是外周组织水平。为了确定糖尿病状态是否会降低胰岛素对人类的直接作用，我们研究了9例未经治疗的2型糖尿病患者，每位患者间隔4 - 6周进行三项研究。1）门静脉研究（POR）：静脉输注甲苯磺丁脲3小时，根据外周血浆C肽计算胰腺胰岛素分泌量。2）外周研究（PER）：通过外周静脉输注等量胰岛素。3）半量外周胰岛素研究（1/2 PER）：使胰岛素水平与研究1匹配。在所有研究中，将血糖钳定在正常血糖水平，采用恒定比活性法测量葡萄糖周转率，并用高效液相色谱法纯化3 - [3H]葡萄糖。与PER相比，POR中的外周胰岛素水平较低，但与1/2 PER相比，POR中的外周胰岛素水平略高，尽管大部分差异可归因于POR中较高的胰岛素原水平（由甲苯磺丁脲刺激）。计算得出，与PER相比，POR中的门静脉胰岛素约高1.3倍，与1/2 PER相比，POR中的门静脉胰岛素约高2.2倍。在钳夹的最后30分钟，尽管POR中的肝脏胰岛素水平较高，但PER中的葡萄糖生成达到的稳态水平低于POR（4.0±0.4对5.3±0.5 pmol(-1)×kg(-1)×min(-1)，P<0.05）。与我们在非糖尿病个体中的研究相反，尽管POR中的肝脏胰岛素水平高得多，但在稳态时，POR中的葡萄糖生成与1/2 PER相比并未受到更明显的抑制（5.3±0.4 μmol×kg(-1)×min(-1)）。总之，这是首次在2型糖尿病患者中进行的研究，旨在描述胰岛素对胰岛素急性直接抑制肝脏葡萄糖生成作用的抵抗情况。
