Studies on overnight insulin requirements and metabolic clearance rate of insulin in normal and diabetic man: relevance to the pathogenesis of the dawn phenomenon

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Abstract
In order to assess whether the metabolic clearance of insulin changes overnight, 11 patients with Type 1 (insulin-dependent) diabetes and low insulin antibody titre, and 6 nondiabetic subjects were studied. In these studies insulin was always infused by a Harvard pump. Initially, the nocturnal insulin requirements were assessed in the diabetic patients by an overnight feedback insulin infusion to maintain euglycaemia. The insulin requirements decreased continuously after midnight to a nadir of 0.115 ± 0.014 mU · kg−1 · min−1 at 04.30 hours, but after 05.00 hours the insulin requirements increased nearly 40 percent to a maximum of 0.16 ±0.012 mU · kg−1 · min−1 at 07.00 hours. To assess whether plasma insulin clearance changes overnight, the diabetic patients were studied on two different occasions, from 22.00–02.30 hours and from 04.00–08.30 hours. During each of these two studies insulin was infused in sequential steps of 90 min each at the rate of 0.13, 0.40 and 0.20 mU · kg−1 · min−1. Despite changes in plasma free insulin concentration, the metabolic clearance of insulin in the interval 22.00–02.30 hours (12.6±0.17 ml · kg−1 · min−1) was no different from that of the interval 04.00–08.30 hours (12.5 ± 0.19 ml · kg−1 · min−1). The nondiabetic subjects were studied on two different occasions to assess whether the metabolic clearance of insulin changes overnight. Somatostatin (0.25 mg/h) and insulin (0.3 mU kg−1 · min−1) were infused from 22.00–02.30 hours on one occasion, and from 04.00–08.30 hours on the other. The metabolic clearance of plasma free insulin in the interval 22.00–02.30 hours was no different from that of the interval 04.00–08.30 hours (12.6 ± 0.20 vs 12.9 ± 0.25 ml · kg−1 · min−1 nor was it different from that of the diabetic patients. It is concluded that, first, the metabolic clearance rate of insulin does not change overnight either in diabetic or in nondiabetic subjects; second, that it is independent of plasma insulin concentration; and third, that its value is comparable in nondiabetic subjects and in diabetic patients with a low titre of insulin antibodies. Thus, changes in insulin sensitivity rather than changes in insulin clearance are implicated in the pathogenesis of the dawn phenomenon.