1. The metabolism of unlabelled monocomponent human insulin and porcine proinsulin was studied in ten normal subjects (five males and five females) by using a priming dose-constant-infusion technique. In each subject, the metabolic clearance rate (MCR) was measured at four separate steady-state hormone concentrations averaging 16-21 6 punitslml (insulin) and 4-2-42.8 ng/ml (proinsulin).2. For insulin the MCR fell progressively from 34 ml kg-' min-' at a mean fasting insulin concentration of 3.8 punitslml to 11.4 ml kg-' min-' at the highest concentration achieved (280 punits/ml); for proinsulin MCR averaged 3.7 ml kg -' min-' at a mean plasma concentration of 4.2 ng/ml and fell to 2.71 ml kg-' min-' at 10.7 ng/ml, remaining constant thereafter at concentrations up to 71 ng/ml.3. The half-disappearance time (T+) from the plasma, after the end of the infusion, averaged 4.3 min for insulin and 25.6 min for proinsulin.4. The apparent distribution space (DS) was similar for both hormones (83 ml/kg of insulin and 98.9 ml/kg of proinsulin).5. There was a direct correlation between T+ and DS for both hormones. 6. Although the higher MCR of insulin was reflected in its shorter T+, there was, for each hormone, no relationship between MCR and T+.7. The biological potency of porcine proinsulin, as judged by its effect on plasma glucose, was approximately 5% of that of insulin.8. The responses of serum growth hormone and cortisol were shown to be directly related to the degree of hypoglycaemia induced.
Abstract. The metabolic clearance rate (MCR), half‐disappearance time (T½ and apparent distribution space (DS) of unlabelled human growth hormone (HGH) have been studied using the priming dose – constant infusion technique. In 11 normal subjects MCR averaged 2.99 ml/kg/min., T½ 19.0 min. and DS 79.3 ml/kg. There were no differences between males and females and MCR was constant at HGH levels ranging from 5 to 50 ng/ml. In 10 out of 17 patients with chronic liver disease of varying severity MCR/kg was reduced below the lower limit of normal. TV2 was prolonged in 15 of these patients. There was a very close correlation between MCR/kg and DS/kg in liver disease (r = 0.8219). Increased DS/kg accounted for the normal MCR/kg seen in some patients with severe hepatocellular failure. MCR/kg was markedly reduced in three patients'with chronic renal failure. T72 and DS/kg were both significantly increased in this group (48.0 min. and 117.0 ml/kg, respectively). MCR/kg and T72 were normal in one patient with the nephrotic syndrome but normal glomerular filtration rate. MCR/kg was not significantly different from normal in patients with thyrotoxicosis, myxoedema and uncontrolled diabetes mellitus, despite the fact that T½ shorter than normal in thyrotoxicosis and longer than normal in myxoedema. It is suggested that HGH does not normally diffuse freely from the vascular to extravascular extracellular fluid, and that normally a substantial concentration gradient exists between the vascular and extravascular compartments; under these circumstances, the liver and kidneys are the major sites of HGH metabolism. In hepatic and renal failure, this gradient is reduced and extravascular degradation sites may assume more importance in the metabolism of growth hormone. Acute fluctuations in the peripheral blood concentrations of growth hormone indicate alterations in secretion rate and not alterations in metabolism.
1239hydrate diet, reduced physical activity, and obesity may be the important factors implicated. And all these factors seem to operate in the Nauruan population.8This work was supported in part by a grant from the National Health and Medical Research Council of Australia. We thank the government of the Republic of Nauru for allowing the study to proceed, and Miss Roma Swan for typing the manuscript. ReferencesIPrior, I A M, et al, Lancet, 1966, 1, 333. 2 West, K M, Diabetes, 1974, 23, 841. 3 Zimmet, P, et al, Diabetologia, 1977 DeBoer, W, Collins, J, and Zimmet, P, Di'abetologi 'a, 1977, 13, 388. 5 Prior, I A M, and Davidson, F, New Zealand Journal of Medicine, 1966, 65, 375. 6 Bennett, P H, Burch, T A, and Miller, M, Lancet, 1971, 2, 125. 7 Summary and conclusions Six insulin-requiring diabetics were studied after insulin had been withheld for 24 hours. On three separate occasions each received a two-hour infusion of insulin at a low dose (2-6 U/h) and a high dose (10 6 U/h) and an infusion of saline as control. The rates of production and utilisation of glucose were measured isotopically. The rate of fall of plasma glucose concentration was faster on the hightdose infusion of insulin than on the low, whereas the fall in plasma free fatty acids, glycerol, and keton bodies was the same on both insulin infusions. The mechanism whereby the two rates of insulin administration lowered plasma glucose concentration differed: during the low-dose infusion the decrease in the glucose concentration was produced entirely by a fall of hepatic glucose output, whereas during the high-dose insulin infusion the glucose concentration fell because both the rate of glucose production fell and the rate of glucose utilisation rose. In all experiments there was a direct relation between a fall in serum potassium concentration and the fall in plasma glucose concentration irrespective of the mechanism that reduced the glucose concentration. These results indicate that in uncontrolled diabetics low-dose insulin infusions lower the blood glucose concentration entirely by reducing glucose production from the liver and that the effect of insulin on potassium transport is independent of its effect on glucose uptake.
Summary.A [14C]~glucose tracer infusion method was used to compare the effects of insulin infusion on glucose metabolism with the effects of infusion of three semisynthetic modified insulins and of proinsu= lin. Insulin produced hypoglycaemia in the anaesthetised dog by decreasing hepatic glucose production and increasing peripheral glucose utilisation. Compensatory antihypoglycaemic mechanisms eventually modified these responses. A1, Be9-Diacetyl insulin exerted an hypoglycaemic effect entirely by stimulation of peripheral glucose uptake. A1-B29 crosslinked insulins and proinsulin produced hypoglycaemia almost entirely by decreasing hepatic glucose production and had little effect on tissue uptake. These observations suggest that insulin analogues may have actions in vivo that are qualitatively different from those of native insulin and suggest that certain analogues have a predominant action on the liver. This has important therapeutic implications concerning the development of semisynthetic insulins for clinical use.
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