Mechanism of action of insulin in diabetic patients: a dose-related effect on glucose production and utilisation

Abstract

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.

Mechanism of action of insulin and insulin analogues

“…Compensating mechanisms to combat hypoglycaemia later modified this pattern. Similar results have been reported by Issekutz et al [21] in diabetic dogs and more recently by Brown et al [22] in diabetic human subjects. These workers found that low insulin infusion rates affected only hepatic glucose production whereas at higher infusion rates both production and utilisation were affected.…”

Covalently-linked insulin dimers: their metabolism and biological effects in vivo as partial competitive antagonists of insulin clearance

“…Insulin has been shown to control NEFA concentration primarily by modulating output from peripheral stores [14]. On the other hand, the hepatic effect of insulin on glucose production is the predominant determinant of peripheral glucose concentration at low insulin concentrations, with a further effect in increased peripheral uptake only at high physiological levels [15,16]. A bolus of insulin alone (173 or 700 pmol/kg) caused an immediate rapid fall in plasma NEFA and glucose.…”

Insulin, growth hormone and sport

“…In fact this is NOT the case and is another error arising from extrapolating from in vitro rat data. It has been shown quite unequivocally that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting hepatic glucose production (Ra) without stimulating peripheral glucose uptake (Brown et al 1978). As hepatic glucose output is 'switched off' by the chalonic action of insulin, glucose concentration falls and glucose uptake actually decreases.…”