Kinetic Models for Plasma Disappearance of Insulin in Normal Subjects (original) (raw)
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Insulin Kinetics in Type-1 Diabetes: Continuous and Bolus Delivery of Rapid Acting Insulin
IEEE Transactions on Biomedical Engineering, 2005
We investigated insulin lispro kinetics with bolus and continuous subcutaneous insulin infusion (CSII) modes of insulin delivery. Seven subjects with type-1 diabetes treated by CSII with insulin lispro have been studied during prandial and postprandial conditions over 12 hours. Eleven alternative models of insulin kinetics have been proposed implementing a number of putative characteristics. We assessed 1) the effect of insulin delivery mode, i.e., bolus or basal, on the insulin absorption rate, the effects of 2) insulin association state and3) insulin dose on the rate of insulin absorption, 4) the remote insulin effect on its volume of distribution, 5) the effect of insulin dose on insulin disappearance, 6) the presence of insulin degradation at the injection site, and finally 7) the existence of two pathways, fast and slow, of insulin absorption. An iterative two-stage parameter estimation technique was used. Models were validated through assessing physiological feasibility of parameter estimates, posterior identifiability, and distribution of residuals. Based on the principle of parsimony, best model to fit our data combined the slow and fast absorption channels and included local insulin degradation. The model estimated that 67(53-82)% [mean (interquartile range)] of delivered insulin passed through the slow absorption channel [absorption rate 0.011(0.004-0.029) min 1 ] with the remaining 33% passed through the fast channel [absorption rate 0.021(0.011-0.040) min 1 ]. Local degradation rate was described as a saturable process with Michaelis-Menten characteristics [V MAX = 1 93(0 62 6 03) mU min 1 , K M = 62 6(62 6 62 6) mU]. Models representing the dependence of insulin absorption rate on insulin disappearance and the remote insulin effect on its volume of distribution could not be validated suggesting that these effects are not present or cannot be detected during physiological conditions. Index Terms-Biological systems modeling, identification, insulin kinetics, parameter estimation, type-1 diabetes. I. INTRODUCTION I NSULIN therapy in people with type-1 diabetes aims to mimic the pattern of endogenous insulin secretion present in healthy subjects. This pattern can be achieved to some ex-Manuscript
Modeling absorption kinetics of subcutaneous injected soluble insulin
Journal of Pharmacokinetics and Biopharmaceutics, 1989
Absorption of subcutaneously injected soluble insulin deviates markedly from simple first-order kinetics and depends both on the volume and concentration of the injected solution. This paper presents a model of the absorption process in which insulin is presumed to be present in subcutis in a low molecular weight form, a high molecular weight form, and an immobile form where the molecules are bound to the tissue. The model describes how diffusion and absorption gradually reduce the insulin concentrations in the subcutaneous depot and thereby shift the balance between the three forms in accordance with usual laws of chemical kinetics. By presuming that primarily low molecular weight insulin penetrates the capillary walls, the model can account for experimentally observed variations in the absorption rate over a wide range of volumes and of concentrations. The model is used to determine the effective diffusion constant D for insulin in subcutis, the absorption rate constant B for low molecular weight insulin, the equilibrium constant Q between high and low molecular weight insulin, the binding capacity C for insulin in the tissue, and the average life time T for insulin in its bound state. Typical values for a bolus injection in the thigh of fasting type I diabetic patients are D=0.9 × 10−4 cm2/min, B=1.3 × 10−2/min, and Q=0.13 (ml/IU)2. Binding of insulin in the tissue is significant only at small concentrations. The binding capacity is of the order of C=0.05 IU/cm3 with a typical average life time in the bound state of T=800 min. Combined with a simplified model for distribution and degradation of insulin in the body, the absorption model is used to simulate variations in plasma free insulin concentrations with different delivery schedules, i.e., bolus injection and dosage by means of an infusion pump. The simulations show that a pump repetition frequency of 1–2 per hr is sufficient to secure an almost constant plasma insulin concentration.
A Model of the Kinetics of Insulin in Man
Journal of Clinical Investigation, 1974
We suggest that the combined use of glucose-clamp and kinetic-modeling techniques should aid in the delineation of pathophysiologic states affecting glucose and insulin metabolism.
Effect of intravenous glucose infusion on plasma insulin removal rate
Metabolism, 1974
We have studied the effects of different intravenous glucose loads on the plasma insulin removal rates of constantly infused porcine insulin in dogs. Insulin removal was studied during infusions of exogenous insulin at rates of 20, 50, and 150 mU/min, and three different glucose loads were given during each of the three insulin infusions. Endogenous insulin secretion was suppressed by the constant administration of epinephrine and propranolol, and thus the resulting plasma insulin concentrations were entirely a function of entry and removal of the exogenously infused insulin. Consequently, at steady-state conditions, any change in rate of insulin removal would result in a reciprocal change in plasma insulin concentration.
A minimal model of insulin secretion and kinetics to assess hepatic insulin extraction
AJP: Endocrinology and Metabolism, 2005
The liver is the principal site of insulin degradation, and assessing its ability to extract insulin is important to understand several pathological states. Noninvasive quantification of hepatic extraction (HE) in an individual requires comparing the profiles of insulin secretion (ISR) and posthepatic insulin delivery rate (IDR). To do this, we propose here the combined use of the classical C-peptide minimal model with a new minimal model of insulin delivery and kinetics. The models were identified on insulin-modified intravenous glucose tolerance test (IM-IVGTT) data of 20 healthy subjects. C-peptide kinetics were fixed to standard population values, whereas insulin kinetics were assessed in each individual, along with IDR parameters, thanks to the presence of insulin decay data observed after exogenous insulin administration. From the two models, profiles of ISR and IDR were predicted, and ISR and IDR indexes of β-cell responsivity to glucose in the basal state, as well as during ...
Acta Diabetologica, 2007
The liver plays a pivotal role in determining postprandial insulin levels because it is responsible for the extraction of a large (approximately 50%) fraction of the newly secreted insulin by the pancreas. Evidence exists that hepatic insulin extraction is not constant during a meal, but is inhibited because of saturable receptor-mediated mechanisms and/or increase in hepatic blood flow. The aim of the present study was to exploit the ability of mathematical model simulation to shed light on the role of a variable hepatic insulin extraction during a meal. Mathematical models of insulin secretion and kinetics were coupled to provide predictions for the concentration of insulin in plasma following a meal under the assumptions of either a constant or a time-varying hepatic insulin clearance. Our results indicate that a 20% inhibition in hepatic clearance is able to remarkably enhance the plasma insulin level following a meal. These results emphasise the need for simple and accurate methods to measure the time course of hepatic insulin extraction under nonsteady-state conditions.
Human insulin dynamics in women: a physiologically based model
American journal of physiology. Regulatory, integrative and comparative physiology, 2015
Currently available models of insulin dynamics are mostly based on the classical compartmental structure and thus their physiological utility is limited. In this work, we describe the development of a physiological-based model and its application to data from 154 patients who underwent an insulin modified intravenous glucose tolerance test (IM IVGTT). In order to determine the time profile of endogenous insulin delivery without using C peptide data and to evaluate the transcapillary transport of insulin, the hepatosplanchnic, renal and peripheral beds were incorporated into the circulatory model as separate subsystems. Physiologically reasonable population mean estimates were obtained for all estimated model parameters, including plasma volume, interstitial volume of the peripheral circulation (mainly skeletal muscle), uptake clearance into the interstitial space, hepatic and renal clearance, as well as total insulin delivery into plasma. The results indicate that, at a population l...
Effect of insulin on the distribution and disposition of glucose in man
1985
Understanding the influence of insulin on glucose turnover is the key to interpreting a great number of metabolic situations. Little is known, however, about insulin's effect on the distribution and exchange of glucose in body pools. We developed a physiological compartmental model to describe the kinetics of plasma glucose in normal man in the basal state and under steady-state conditions of euglycemic hyperinsulinemia.
Journal of diabetes science and technology, 2015
Pharmacokinetic (PK) models describing the transport of insulin from the injection site to blood assist clinical decision making and are part of in silico platforms for developing and testing of insulin delivery strategies for treatment of patients with diabetes. The ability of these models to accurately describe all facets of the in vivo insulin transport is therefore critical for their application. Here, we propose a new model of fast-acting insulin analogs transport from the subcutaneous and intradermal spaces to blood that can accommodate clinically observed biphasic appearance and delayed clearance of injected insulin, 2 phenomena that are not captured by existing PK models. To develop the model we compare 9 insulin transport PK models which describe hypothetical insulin delivery pathways potentially capable of approximating biphasic appearance of exogenous insulin. The models are tested with respect to their ability to describe clinical data from 10 healthy volunteers which re...