The aim of this study was to investigate the role of plasma glucagon levels on the blood glucose response to intravenous insulin administered continuously or in a pulsatile manner. Six type I diabetic patients proven to have no residual insulin secretion were investigated. Endogenous glucagon secretion was inhibited by a continuous intravenous infusion of somatostatin (100 μg/h) and replaced by exogenous infusions of the hormone at three different rates (7.5, 4.5, and 2.5 μg/h), resulting in three different plasma glucagon steady-state levels (i.e., ≃200, ≃130, and ≃75 pg/ml, respectively). Each subject, in random order and on different days, was infused intravenously with regular human insulin either continuously (0.17 mU · kg−1 · min−1) or with the same amount of insulin infused in a pulsatile manner (0.85 mU · kg−1 · min−1 during 2 min followed by 8 min during which no insulin was infused). At plasma glucagon levels ≃200 pg/ml, blood glucose rose from ∼10 to ∼13 mM without any difference between the two modalities of insulin infusion. For plasma glucagon levels ≃130 pg/ml, plasma glucose remained steady throughout the experiments, but during the last 40 min, plasma glucose levels were significantly lower when insulin was administered intermittently. This greater blood glucose-lowering effect of pulsatile insulin occurred earlier and was more pronounced for plasma glucagon levels averaging 75 pg/ml. We conclude that the greater hypoglycemic effect of insulin administered intravenously in a pulsatile manner in type I diabetics critically depends on plasma glucagon circulating levels.

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