Measurement of interstitial insulin in human adipose and muscle tissue under moderate hyperinsulinemia by means of direct interstitial access.

Insulin's action to stimulate glucose utilization is determined by the insulin concentration in interstitial fluid (ISF) of insulin-sensitive tissues. The concentration of interstitial insulin has been measured in human subcutaneous adipose tissue and skeletal muscle, however, never in parallel. The aim of this study was to compare interstitial insulin levels between both tissue beds by simultaneous measurements and to verify and quantify low peripheral ISF insulin fractions as found during moderate hyperinsulinemia. Nine healthy subjects (27.2 +/- 0.8 yr) were investigated. A euglycemic-hyperinsulinemic clamp was started with a primed-constant intravenous insulin infusion of 1 mU x kg(-1) x min(-1). For direct access to ISF, macroscopically perforated open-flow microperfusion catheters were inserted in both tissues. During steady-state conditions (9.5 h), interstitial effluents were collected in 30-min fractions using five different insulin concentrations in the inflowing perfusates ("no net flux" protocol). Regression analysis of insulin concentrations in perfusates and effluents yielded the relative recovery and the perfusate insulin concentration, which was in equilibrium with the surrounding tissue. Thus, in subcutaneous adipose tissue and skeletal muscle, the mean ISF-to-serum insulin level was calculated as 21.0% [95% confidence interval (CI) 17.5-24.5] and 26.0% (95% CI 19.1-32.8; P = 0.14), respectively. Recoveries for insulin averaged 51 and 64%, respectively. The data suggest that the concentrations of insulin arising in healthy subjects at the level of ISF per se are comparable between subcutaneous adipose and skeletal muscle tissue. The low interstitial insulin fractions seem to confirm reports of low peripheral insulin levels during moderate insulin clamps.

Insulin kinetics in type-I diabetes: continuous and bolus delivery of rapid acting insulin.

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 and 3) 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 [VMAX = 1.93(0.62 - 6.03) mU min(-1), KM = 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.

Interstitial glucose kinetics in subjects with type 1 diabetes under physiologic conditions.

We investigated the dynamic relationship between interstitial glucose (IG) in the subcutaneous adipose tissue and plasma glucose (PG) during physiologic conditions in type 1 diabetes mellitus (T1DM). Nine subjects with T1DM (5/4 M/F; age, 33 +/- 13 years; body mass index, 26.6 +/- 4.3 kg/m(2); glycosylated hemoglobin [HbA(1c)], 8.6% +/- 0.9%; mean +/- SD) treated by continuous subcutaneous insulin infusion (CSII) with insulin lispro were studied over 12 hours after a standard meal (40 g carbohydrate [CHO]) and prandial insulin. IG was measured by open flow microperfusion. Nine compartment models were postulated to account for temporal variations in the IG/PG ratio. The models differed in the inclusion of physiologically motivated alterations of pathways entering/leaving the IG compartment in the adipose tissue. The best model included zero order (constant) glucose disposal from the interstitial fluid (ISF) and insulin-stimulated glucose transfer from plasma to the ISF. The former effect is expressed by a positive association between the IG/PG ratio and PG, eg, a decrease in PG from 9 to 3.3 mmol/L lowers the IG/PG ratio by 0.1. The latter effect results in the IG/PG ratio to be increased by 0.03 per 10 mU/L of plasma insulin. We were not able to detect the stimulatory effect of insulin on glucose disappearance from the ISF. In conclusion, we developed and quantified a model of IG kinetics in the adipose tissue applicable to physiologic conditions in subjects with T1DM.

Nonlinear model predictive control of glucose concentration in subjects with type 1 diabetes.

A nonlinear model predictive controller has been developed to maintain normoglycemia in subjects with type 1 diabetes during fasting conditions such as during overnight fast. The controller employs a compartment model, which represents the glucoregulatory system and includes submodels representing absorption of subcutaneously administered short-acting insulin Lispro and gut absorption. The controller uses Bayesian parameter estimation to determine time-varying model parameters. Moving target trajectory facilitates slow, controlled normalization of elevated glucose levels and faster normalization of low glucose values. The predictive capabilities of the model have been evaluated using data from 15 clinical experiments in subjects with type 1 diabetes. The experiments employed intravenous glucose sampling (every 15 min) and subcutaneous infusion of insulin Lispro by insulin pump (modified also every 15 min). The model gave glucose predictions with a mean square error proportionally related to the prediction horizon with the value of 0.2 mmol L(-1) per 15 min. The assessment of clinical utility of model-based glucose predictions using Clarke error grid analysis gave 95% of values in zone A and the remaining 5% of values in zone B for glucose predictions up to 60 min (n = 1674). In conclusion, adaptive nonlinear model predictive control is promising for the control of glucose concentration during fasting conditions in subjects with type 1 diabetes.

Closing the loop: the adicol experience.

The objective of the project Advanced Insulin Infusion using a Control Loop (ADICOL) was to develop a treatment system that continuously measures and controls the glucose concentration in subjects with type 1 diabetes. The modular concept of the ADICOL's extracorporeal artificial pancreas consisted of a minimally invasive subcutaneous glucose system, a handheld PocketPC computer, and an insulin pump (D-Tron, Disetronic, Burgdorf, Switzerland) delivering subcutaneously insulin lispro. The present paper describes a subset of ADICOL activities focusing on the development of a glucose controller for semi-closed-loop control, an in silico testing environment, clinical testing, and system integration. An incremental approach was adopted to evaluate experimentally a model predictive glucose controller. A feasibility study was followed by efficacy studies of increasing complexity. The ADICOL project demonstrated feasibility of a semi-closed-loop glucose control during fasting and fed conditions with a wearable, modular extracorporeal artificial pancreas.