Glucose uptake and pulsatile insulin infusion: euglycaemic clamp and [33H] glucose studies in healthy subjects

Abstract

To test the hypothesis that insulin has a greater effect on glucose metabolism when given as pulsatile than as continuous infusion, a 354-min euglycaemic clamp study was carried out in 8 healthy subjects. At random order soluble insulin was given intravenously either at a constant rate of 0.45 mU/kg \ m=. \min or in identical amounts in pulses of 1\m=1/2\ to 2\m=1/4\ min followed by intervals of 10\m=1/2\to 9\m=3/4\min. Average serum insulin levels were similar during the two infusion protocols, but pulsatile administration induced oscillations ranging between 15 and 62 \g=m\U/ml. Glucose uptake expressed as metabolic clearance rate (MCR) for glucose was significantly increased during pulsatile insulin delivery as compared with continuous administration (270\p=n-\294 min: 8.7 \ m=+-\ 0.7 vs 6.8 \ m=+-\ 0.9 ml/kg \ m=. \min, P < 0.01, and 330\p=n-\354 min: 8.9 \ m=+-\0.5 vs 7.4 \m=+-\0.9 ml/kg \ m=. \ min, P <0.05). The superior efficacy of pulsatile insulin delivery on glucose uptake was not consistently found until after 210 min of insulin administration. In both infusion protocols, endogenous glucose production as estimated by the [3-3H]glucose infusion technique was suppressed to insignificant values. Finally, the effect of insulin on endogenous insulin secretion and lipolysis as assessed by changes in serum C-peptide and serum FFA was uninfluenced by the infusion mode. In conclusion, insulin infusion resulting in physiological serum insulin levels enhances glucose uptake in peripheral tissues in healthy subjects to a higher degree when given in a pulsed pattern mimicking that of the normal endocrine pancreas than when given as a continuous infusion. In man basal plasma insulin oscillates regularly with a mean period of 13 min (Lang et al. 1979). The frequency of oscillations remains stable after intravenous glucose or tolbutamide challenge al¬ though the amplitude increases (Matthews et al. 1983). This contrasts insulin secretion in type II diabetics in whom brief and irregular oscillations are superimposed on fluctuations of long dura¬ tion (Lang et al. 1981). The role of this disorgan¬ ized insulin secretion in the insulin resistance of type II diabetes needs to be determined. Recently, Matthews et al. (1983) demonstrated an aug¬mented hypoglycaemic effect of insulin applied as pulsatile infusion compared with continuous infu¬ sion. It is uncertain whether the improved insulin action was due to effects in the liver or in peri¬ pheral tissues.The present study was performed mainly to determine the impact of pulsatile insulin adminis¬ tration on glucose uptake in healthy subjects. The effect of insulin on lipolysis and endogenous insu¬ lin secretion was also measured. We aimed at insulin levels similar to those observed in the postprandial state and in type I diabetics supplied with insulin through conventional routes. Subjects and Methods SubjectsEight healthy males participated in the study. Mean age was 26 years (range 23 to 33 years) and mean weight

Measurement of pulsatile insulin secretion in the rat: direct sampling from the hepatic portal vein

“…These data imply that an insulin concentration oscillatory profile of ϳ400 -600 pmol/l is optimal for hepatic insulin signaling in all three species and suggests that the high amplitude portal vein insulin oscillations do have physiological importance. Prior studies (5,10,14,19,28,36) have revealed an apparent enhanced action of pulsatile vs. nonpulsatile insulin delivery for suppression of hepatic glucose release, but these studies used much smaller insulin oscillations than those present in the portal vein delivered into the systemic circulation. One negative study (8) reproduced the portal vein pulse amplitude observed in vivo in the dog but at a frequency less than half of that in vivo and to quantify hepatic glucose uptake rather than suppression of hepatic glucose release .…”

The conscious Göttingen minipig as a model for studying rapid pulsatile insulin secretion in vivo

“…In addition, insulin action is markedly impaired in diabetes and prediabetes [44]. The impaired pulsatile insulin release has been linked to impaired insulin action [4,5,6,7] but the causes and implications need to be fully established. Mechanistic studies in animal models are an important tool for evaluating this relation in vivo.…”

“…This problem can, to some extent, be circumvented by studying first degree relatives of diabetic patients who are at risk of the disease but are still not affected by the effects of hyperglycaemia [9]. However, animal models are a valuable research tool for examining the relation between beta-cell mass, function and morphology on the one hand and insulin It is well documented that insulin concentrations show large amplitude oscillations in the peripheral circulation with a periodicity of 5 to 15 min [1,2,3], and it has been shown that these oscillations are of importance for insulin action in liver [4], muscle [5,6] and adipose tissues [7]. Since Type II (non-insulin-depenresistance on the other, because carefully controlled studies can involve surgical [10,11,12] or toxicological [10,13,14,15,16,17] induction of diabetes and long-term maintenance on experimental diets can induce insulin resistance and lipotoxicity [18,19,20,21].…”

Pattern of insulin delivery affects hepatic insulin sensitizing substance (HISS) action and insulin resistance

“…Studies in the fasted state have shown greater glucose uptake (Schmitz et al 1986), faster inhibition of endogenous insulin, prolonged decrease in glucagon (Ward et al 1989), and greater inhibition of hepatic glucose production (Paolisso et al 1991) with pulsatile compared with continuous insulin administration. Pulsatile insulin infusions have a greater hypoglycemic effect, which is only observed after several hours of infusion (Matthews et al 1983;Ward et al 1989).…”