Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France
Department of Internal MedicineErasmus University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The NetherlandsLilly Research LaboratoriesLilly Corporate Center, Indianapolis, Indiana 46285, USAAlizé Pharma69 130 Ecully, France.
Eur J Endocrinol. 2014 Jun;170(6):799-807. doi: 10.1530/EJE-13-0347. Epub 2013 Jul 17.
The objective of this study was to assess the effects of a continuous overnight infusion of des-acyl ghrelin (DAG) on acylated ghrelin (AG) levels and glucose and insulin responses to a standard breakfast meal (SBM) in eight overweight patients with type 2 diabetes. Furthermore, in the same patients and two additional subjects, the effects of DAG infusion on AG concentrations and insulin sensitivity during a hyperinsulinemic-euglycemic clamp (HEC) were assessed.
A double-blind, placebo-controlled cross-over study design was implemented, using overnight continuous infusions of 3 and 10 μg DAG/kg per h and placebo to study the effects on a SBM. During a HEC, we studied the insulin sensitivity.
We observed that, compared with placebo, overnight DAG administration significantly decreased postprandial glucose levels, both during continuous glucose monitoring and at peak serum glucose levels. The degree of improvement in glycemia was correlated with baseline plasma AG concentrations. Concurrently, DAG infusion significantly decreased fasting and postprandial AG levels. During the HEC, 2.5 h of DAG infusion markedly decreased AG levels, and the M-index, a measure of insulin sensitivity, was significantly improved in the six subjects in whom we were able to attain steady-state euglycemia. DAG administration was not accompanied by many side effects when compared with placebo.
DAG administration improves glycemic control in obese subjects with type 2 diabetes through the suppression of AG levels. DAG is a good candidate for the development of compounds in the treatment of metabolic disorders or other conditions with a disturbed AG:DAG ratio, such as type 2 diabetes mellitus or Prader-Willi syndrome.
本研究旨在评估持续 overnight 输注去酰基 ghrelin（DAG）对 8 例超重 2 型糖尿病患者酰基 ghrelin（AG）水平以及对标准早餐餐（SBM）的葡萄糖和胰岛素反应的影响。此外，在相同的患者和另外 2 名受试者中，评估了 DAG 输注对 DAG 输注对高胰岛素正常血糖钳夹（HEC）期间 AG 浓度和胰岛素敏感性的影响。
采用双盲、安慰剂对照交叉研究设计， overnight 连续输注 3 和 10μg DAG/kg per h 和安慰剂，以研究对 SBM 的影响。在 HEC 期间，我们研究了胰岛素敏感性。
与安慰剂相比， overnight DAG 给药显著降低了餐后血糖水平，无论是在连续血糖监测还是在峰值血清葡萄糖水平时。血糖改善程度与基线血浆 AG 浓度相关。同时，DAG 输注显著降低了空腹和餐后 AG 水平。在 HEC 期间，2.5 h 的 DAG 输注明显降低了 AG 水平，并且在我们能够达到稳态正常血糖的 6 名受试者中，胰岛素敏感性的 M 指数得到显著改善。与安慰剂相比， DAG 给药没有伴随许多副作用。
DAG 给药通过抑制 AG 水平改善了肥胖 2 型糖尿病患者的血糖控制。DAG 是开发用于治疗代谢紊乱或其他 AG：DAG 比值失调的化合物的良好候选物，例如 2 型糖尿病或 Prader-Willi 综合征。
