I

nsulin Kinetics, Models, and Delivery Schedules

MONES BERMAN

Several insulin models are examined as to their responses to various insulin inputs and glucose utilization and production control. It is shown that the action of insulin on glucose utilization correlates best with model compartments having a 3050-min delay compared with plasma, whereas glucose production control is rapid. It is further shown that whereas the predicted plasma insulin response curves are nearly the same for various models, the responses at possible sites of action (e.g., receptors or slowly exchanging tissues) can differ considerably for the different models. By determining the parameter values for the glucose-insulin system in a patient through isotope kinetics studies, it is possible to use the patient's model either as a direct algorithm for insulin delivery or as a tool for studying glucose control under various conditions and thus aid in the design of appropriate algorithms or schedules for insulin delivery.
DIABETES CARE 3: 266-269, MARCH-APRIL 1980.

o program insulin delivery it is necessary to appreciate the modes of action of insulin both in relation to glucose and possibly other metabolic control processes. The information accumulated in recent years indicates that the processes of insulin control are more complex than was expected and a full understanding of the modes of action is still lacking. Although it is possible that simple insulin delivery algorithms may turn out to be adequate for routine treatment, this is not likely. Surely, this is not how the body seems to regulate insulin secretion in a normal physiologic state. I shall try to review some of the information that is presently available on the kinetic patterns of insulin and how they may relate to glucose control. In particular, I shall try to identify possible sites of action of the hormone and relate their insulin kinetic patterns there with those in the plasma and with the levels of glucose in plasma. Insulin controls glucose transport into cells of various tissues, some of which are readily accessible to plasma and others which are in slow exchange with it. It also controls the rate of glucose production in some tissues, such as liver, which are in rapid exchange with plasma. Its action is exerted through receptors which, in addition to their accessibility to plasma, also undergo conformational changes and diffusion on the cell surface. It has also been proposed that some insulin receptors exist in membranes inside the cell and that insulin has to enter the cell before these can be activated. In short, there is a time delay before an insulin

molecule in plasma can exert its action at the appropriate site. The timing is further complicated when trying to relate plasma insulin levels to plasma glucose, because of additional delays between plasma glucose and glucose at the sites of insulin action.
INSULIN KINETICS IN PLASMA AND POSSIBLE MODELS

When a bolus of insulin is injected into plasma in trace or physiologic amounts, the resulting plasma response (Figure 1) can be described by a sum of three exponentials. This seems to be the case for both labeled and nonlabeled insulins. The initial rapid exponential has a half-time of about 3 min and accounts for nearly 90% of the input, and the slowest has a half-time of about 30 min. Frequently, only the first component is paid attention to. Three-compartment models have been proposed by Silvers et al., 1 Sherwin et al., 2 and others to explain these data. The three-compartment model (Figure 2) suggests that, in addition to plasma, there are rapid and slow exchange compartments. The predicted kinetic patterns for these compartments are shown in Figure 1. The exchange compartments have not been identified physiologically, but it was shown by Sherwin et al.2 that the calculated response for the slow exchange compartment closely parallels the measured glucose utilization rates. More recently, we have studied insulin kinetics in the rabbit. The experiments were carried out by Zeleznik and Roth, 3 and the modeling was done by Berman and McGuire.4

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INSULIN KINETICS, MODELS, AND DELIVERY SCHEDULES/MONES BERMAN

1.09

p
V1
(PLASMR)

INSULIN RESPONSES IN MAM (MODEL GENERATED)

TCA Precipitable Activity

8.18

f VV
7
t

8.81 :

28

68 88 T I M E (MINUTES)

188

128

10

20

30

40

50

60

70

FIG. 1. Plasma insulin curve (Cl) derived by fitting experimental data for normal man after a bolus injection of insulin. C2 and C3 are model' B derived curves for fast and slow compartments, respectively, in exchange < with plasma.

TIME (minutes)

TCA Soluble Activity

Briefly, iodinated high affinity (pork) and low affinity (guinea pig) insulins were injected simultaneously into the rabbit, and plasma levels were determined over a 90-min interval. TCA precipitable, TCA soluble, and antibody precipitable radioactivity measurements were made for both plasma insulins under a variety of conditions: tracer injections, preloading with various levels of cold insulin before the administration of the tracer, and washouts with cold insulin at various times after the administration of the tracer. The plasma curves for the various conditions are shown in Figure 3. Without going through the details here, one can propose a possible model for insulin kinetics as shown in Figure 4. Although the details of the model may not be correct, certain important features emerge: (1) slow and fast distribution compartments in the body, (2) slow and fast receptor compartments in exchange with plasma, (3) partial degradation of the insulin molecule, probably associated with the receptors, and (4) delayed degradation pathways for insulin, probably associated with internalization. An important consequence of the modeling was the conclusion that the labeled plasma insulin was not fully homogeneous. About 10-15% of the labeled insulin seems to behave differently from the rest.
ENDOGENOUS INSULIN

Low affinity insulin

A ft u a *
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T> -&-0-5 High affinity insulin

10

20

30

40

50

60

70

TIME (minutes)

CO Q.

TCA Precipitable Activity 7 Minute Washout Study

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Q

Low affinity insulin

a
UJ

High affinity Insulin

o o

2
IO-*

8L

10

20

30

40

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60

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TIME (minutes)

FIG. 2. Three-compartment model for insulin kinetics in man.2 Mean SD; rate constants in minutes'1.

FIG. 3. Plasma curves for high affinity (pork) and low affinity (guinea pig) radioactivities in the rabbit after a bolus injection of a tracer3: (A) TCA precipitable activities, (B) TCA soluble activities, and (C) TCA precipitable activities when a large load of cold insulin was administered 7 min after the tracer.

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INSULIN KINETICS, MODELS, AND DELIVERY SCHEDULES/MONES BERMAN

L(l,13)-1.00 100 r 'O . . -0.20 \ s TCA-Ab , 0.04__X

RABBIT MODEL PLASMA INSULIN (COMPARTMENT 1) (MICRO-UNITS/fL)

1
10 -

I . I . I

12 T i l t IN H O U R S

16

TCA Soluble

FIG. 6. Predicted plasma response curves for three rates of absorption of a bolus of insulin: e~\ e~02t, and e~004t. Litl3 represents the absorption rate constants in units of hours'1.

FIG. 4. An insulin kinetics model compatible with all the experimental data obtained in rabbit studies.4 Compartments 1, 8, and 23 represent "body" distributions of insulin. Compartments 3 and 12 represent rapid and slow receptor'Ossociated compartments. Compartments 7, 10, and 17 represent partially degraded insulins. Compartments 2, 15, and 13 are introduced to account for about 10% of non-insulin-like activities necessary to explain the data. The Ly are fractional turnover rates in units of minutes'1. The quantities in brackets are model-predicted, steady state flow rates and masses derived from a constant unit infusion rate (Uj) of insulin into plasma.

INSULIN RESPONSES AND INSULIN INPUT ALGORITHMS

T
Since

he insulin responses at various sites due to a particular insulin input can be calculated mathematically by convoluting the model responses to a unit bolus injection (Figure 5) with the desired input, nsulin input into plasma varies considerably
, C12 SLOW RECEPTOR RABBITT INSULIN

depending on the form of the insulin and its site and mode of administration, I chose to examine the range of responses by selecting three typical exponential absorption rates e"', e~0%2<, and e~ 004 '. These have mean absorption times of 1, 5, and 25 h, respectively. Figure 6 shows the plasma responses for the three exponential inputs. As may be expected, the shape of plasma response curves closely follow the shape of the input function with a delay of a few minutes, reflecting the turnover of insulin in the plasma. To examine how the plasma response curves may differ for the different models, a comparison between a single-compartment and a three-compartment model for the most apparent case (e~') was calculated and is shown in Figure 7. For most practical cases, the responses are nearly indistinguishable, although differences would emerge under steady state conditions.

PLASMA INSULIN CONCENTRATIONS (MICRO-UNITS/fL) ABSORPTION RATE L(l,4) - 1.00

100

1 COMPARTMENT MODEL 3 COMPARTMENT MODEL

40 TIME

60 (MINUTES)

80

6 8 TIME IN HOURS

FIG. 5. Responses of rabbit insulin model to bolus injection of insulin in the plasma.

FIG. 7. Comparison of model-predicted plasma response curves for a one-and three-compartment model.

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RABBIT MODEL INSULIN RESPONSES IN PLASMA AND RECEPTOR SPACES (MICRO-tJNITS/fl.)

quired for the individual patient. These can be obtained through preliminary isotope kinetic studies.5 Thus, the model can either serve directly as the algorithm for insulin delivery or provide guidelines for generating delivery algorithms or schedules. Studies of insulin kinetics in man 9>1 show that plasma responses do not vary greatly between populations (normal, diabetic, obese, etc.). Hence, a model for normal subjects can serve as a reasonable predictive tool for plasma responses to various inputs in most cases. If, however, insulin responses at sites other than plasma are of concern, additional studies to define these for different populationssimilar to those carried out in the rabbits3'4are yet to be done. From the Laboratory of Theoretical Biology, DCBD, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205.
REFERENCES
1 Silvers, A., Swenson, R. S., Farquhar, J. W., and Reaven, G. M.: Derivation of three compartment model describing disappearance of plasma insulin-131I in man. J. Clin. Invest. 48: 1461-69, 1969. 2 Sherwin, R. S., Kramer, K. J., Tobin, J. D., Insel, P. A., Liljenquist, J. E., Berman, M., and Andres. R.: A model of the kinetics of insulin in man. J. Clin. Invest. 53: 1481-92, 19743 Zeleznik, A. J., and Roth, J.: Demonstration of the insulin receptor in vivo in rabbits and its possible role as a reservoir for the plasma hormone. J. Clin. Invest. 61: 1363-74, 1978. 4 Berman, M., McGuire, E. A., Roth, J., and Zeleznik, A. J.: A kinetic model of insulin binding to receptors and its degradation in vivo in the rabbit. Diabetes 29: 51-59, 1980. 5 Insel, P. A., Liljenquist, J. E., Tobin, J. D., Sherwin, R. S., Watkins, P., Andres, R., and Berman, M.: Insulin control of glucose metabolism in man: a new kinetic analysis. J. Clin. Invest. 55: 1057-66, 1975. 6 Pilo, A., Ferrannini, E., andNavalesi, R.: Measurement of glucose-induced insulin delivery rate in man by deconvolution analysis. Am. J. Physiology. 233: E500-08, 1977. 7 Berman, M.: A deconvolution scheme. Math. Biosci. 40: 31923, 1978. 8 Pilo, A., Navalesi, R., and Ferrannini, E.: Insulin kinetics after portal and peripheral injection of [125I]insulin. I. Data analysis and modeling. Am. J. Physiol. 230: 1626-29, 1976. 9 McGuire, E. A., Tobin, J. D., Berman, M., and Andres, R.: Kinetics of native insulin in diabetic, obese, and aged men. Diabetes 28: 110-20, 1979. 10 Navalesi, R., Pilo, A., and Ferrannini, E.: Kinetic analysis of plasma insulin disappearance in nonketotic diabetic patients and in normal subjects: a tracer study with 125I-insulin. J. Clin. Invest. 61: 197-208, 1978.

4 5 TIME IN HOURS

FIG. 8. Model'generated insulin response curves for plasma (Cl), a fast receptor state (C3), and a slow receptor state (C12) in the rabbit, for a bolus injection of insulin having an absorption rate constant of I h" 1 .

To examine responses at other sites, the rabbit model was used. Response curves are shown in Figure 8 for plasma (Cl), a rapidly accessible receptor state (C3), and a slowly equilibrating receptor state (C12). As can be seen, plasma (Cl) and a rapidly equilibrating receptor compartment (C3) have nearly the same responses. The slow receptor state (C12), however, shows a delay of about 30-50 min in reaching a peak and, therefore, is not quite comparable to plasma responses. These response curves suggest that insulin control of glucose utilization at the slow receptor state (C12) is compatible with the delayed action of insulin observed by Sherwin et al.2 Should it be important that insulin delivery be scheduled to fit a certain pattern in various sites of action (including plasma), then the model could be used directly as the algorithm for an insulin delivery system. In practice it would be necessary to determine experimentally the parameter values of the insulin model and the control parameters of glucose production and utilization by insulin for each patient.2'5 Knowing these, one can calculate, using deconvolution techniques (e.g., Pilo,6 Berman7) what the insulin input into plasma should be in order to generate the desired responses at the sites of interest. In theory, one can go one step further by incorporating the glucose subsystem as well. By specifying a desired glucose plasma response curve for a given glucose input, one can calculate the insulin input function necessary to generate that response. To accomplish this the parameter values for both the glucose and insulin subsystems are re-

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