Klimes I, Mitková A, Gasperíková D, Ukropec J, Líska B, Bohov P, Stanek J, Seböková E
Diabetes and Nutrition Research Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Arch Physiol Biochem. 1998 Oct;106(4):325-32. doi: 10.1076/apab.106.4.325.4370.
A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown to improve blood glucose levels mainly due to the rapid and short term stimulation of insulin release. Nevertheless, a possible extrapancreatic action of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic hyperinsulinemic 6.4 mU.kg-1.min-1 clamp plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on either standard (BD) or high fat (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal (Rd) (C-BD: 32.3 +/- 1.9 vs C-HF: 25.5 +/- 1.9 mg.kg-1.min-1, p < 0.001) and glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 +/- 1.5 vs C-HF: 12.3 +/- 1.1 mmol.100 g-1.min-1, p < 0.001) were reduced by HF in control rats but were not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back their Rd (hHTg-HF: 23.5 +/- 1.3 vs hHTg-HF plus A-4166: 31.0 +/- 3.5 p < 0.03) and Rg' (Soleus muscle: hHTg-HF: 29.2 +/- 3.2 vs hHTg-HF plus A-4166: 41.3 +/- 4.0) to values of the control group on BD. In summary, a) a single bolus administration of A-4166 to the control or to the insulin resistant hHTg rats, fed either the BD or HF diets, did not abolish the reduction of GIR required to maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significant increase of the estimated plasma glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we suggest that A-4166 may have an extrapancreatic action but this needs to be proven using a long-term administration plan of A-4166.
A - 4166是一种苯丙氨酸衍生物，是一种降血糖药物，已证明其主要通过快速和短期刺激胰岛素释放来改善血糖水平。然而，A - 4166可能存在的胰腺外作用尚未得到研究。因此，在正常对照（C）或遗传性胰岛素抵抗（hHTg）大鼠中，在标准（BD）或高脂肪（HF）饮食喂养3周后，于钳夹开始60分钟后静脉注射单剂量A - 4166（10 mg/kg体重），研究胰岛素作用（正常血糖高胰岛素钳夹6.4 mU·kg⁻¹·min⁻¹加3H - 2 - 脱氧葡萄糖示踪剂给药）。HF喂养将维持正常血糖所需的葡萄糖输注率（GIR）降低至C组的约50%（p < 0.001）。在hHTg大鼠中，HF并未进一步加剧喂食BD的hHTg动物已有的GIR降低。A - 4166在C组和hHTg组中均未改变GIR。对照组大鼠中，HF降低了估计的葡萄糖处置（Rd）（C - BD：32.3 ± 1.9 vs C - HF：25.5 ± 1.9 mg·kg⁻¹·min⁻¹，p < 0.001）以及骨骼肌中的葡萄糖代谢指数（Rg'）（股四头肌：C - BD：25.6 ± 1.5 vs C - HF：12.3 ± 1.1 mmol·100 g⁻¹·min⁻¹，p < 0.001），且单次推注A - 4166未能使其恢复。然而，在喂食HF饮食的hHTg大鼠中，单剂量A - 4166使它们的Rd（hHTg - HF：23.5 ± 1.3 vs hHTg - HF加A - 4166：31.0 ± 3.5，p < 0.03）和Rg'（比目鱼肌：hHTg - HF：29.2 ± 3.2 vs hHTg - HF加A - 4166：41.3 ± 4.0）恢复到喂食BD的对照组水平。总之，a）对喂食BD或HF饮食的对照或胰岛素抵抗hHTg大鼠单次推注A - 4166，并未消除高胰岛素钳夹期间维持正常血糖所需的GIR降低；b）然而，A - 4166使喂食HF饮食的hHTG大鼠的估计血浆葡萄糖处置（Rd）和骨骼肌葡萄糖代谢指数（Rg'）显著增加；c）我们认为A - 4166可能具有胰腺外作用，但这需要通过A - 4166的长期给药方案来证实。
