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JANUARY 1991

**A Semiclosed-Loop Algorithm for the Control of Blood Glucose Levels in Diabetics
**

Michael E. Fisher

Abstract-In this paper, a theoretical analysis of the control of plasma glucose levels in diabetic individuals is undertaken using a simple mathematical model of the dynamics of glucose and insulin interaction in the blood system. Mathematical optimization techniques are applied to the mathematical model to derive insulin infusion programs for the control of blood levels in diabetic individuals. Based on the results of the mathematical optimization, a semiclosed-loop algorithm is proposed for continuous insulin delivery to diabetic patients. The algorithm is based on three hourly plasma glucose samples. A theoretical evaluation of the effectiveness of this algorithm shows that it is superior to two existing algorithms in controlling hyperglycemia. A glucose infusion term representing the effect of glucose intake resulting from a meal is then introduced into the model equations. Various insulin infusion programs for the control of plasma glucose levels following a meal are then assessed. The theoretical results suggest that the most effective short-term control is achieved by an insulin infusion program which incorporates an injection to coincide with the meal.

I. INTRODUCTION HE past two decades has seen a great deal of effort expended in the design of insulin infusion devices for the control of blood glucose levels in insulin dependent diabetes mellitus patients. These devices deliver insulin either intravenously or subcutaneously, but both delivery methods have so far proved to be less than perfect [ 11. Intravenous infusion has suffered from problems with indwelling catheters while continuous subcutaneous infusion has yet to prove its superiority over more conventionally administered subcutaneous infusion. Nevertheless, we take the optimistic view that future research (see, for example, [2], [3]) promises the eventual resolution of problems associated with insulin delivery devices. The development of insulin infusion programs has generally proceeded along two fronts: open-loop methods and closed-loop methods. Open-loop programs deliver a predetermined amount of insulin to the patient and these have become increasingly more sophisticated in an attempt to obtain normality in a diabetic’s response to changing plasma glucose levels (see, for example, [4]-[SI). Along with the development of open-loop methods there has been a simultaneous development of closedloop methods [9]-[ll], sometimes referred to as an artificial beta cell or artificial pancreas. These devices require continuous monitoring of blood glucose levels and can involve quite sophisticated and costly apparatus. An alternative approach to open- or closed-loop methods are semiclosed-loop methods based on intermittent blood glucose sampling. In a sense, these are a compromise between openloop systems and fully closed-loop systems and are particularly

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appealing because of their simplicity and lack of expense. Such systems have been investigated in [ 121-[15]. Clinical studies with two of these systems, which are based on three hourly plasma glucose readings [ 131, [ 141, show them to be reasonably successful in practice. In this paper, we undertake a theoretical analysis of the control of plasma glucose levels in diabetic individuals using the simple mathematical model of the dynamics of glucose and insulin interaction in the blood system developed by Bergman er al. [ 161-[ 181. Mathematical optimization techniques are used to calculate optimal insulin infusion programs for the correction of hyperglycemia based on the theoretical model. The relative merits of various insulin infusion programs such as single injections, continuous infusion, and a combination of both single injection and continuous infusion for the control of blood glucose levels in diabetic individuals are then assessed. Based on the results of the mathematical optimization for the Bergman model, a semiclosed-loop algorithm is proposed for insulin delivery to diabetic patients. This algorithm is based on three hourly plasma glucose samples and combines a single injection with continuous infusion of insulin. Computer simulation is then used to theoretically evaluate the effectiveness of this algorithm. The results show that, in terms of the Bergman model, the algorithm compares favourably with the algorithms proposed by Chisolm er al. [13] and Furler et al. [14]. A glucose infusion term representing the effect of glucose intake resulting from a meal is then introduced into the model equations. Three insulin infusion programs incorporating single injections, continuous infusion, and a combination of both are assessed using mathematical optimization techniques. The theoretical results suggest that the most effective short term control is achieved by an insulin infusion program which incorporates an injection to coincide with the meal.

**11. THE MATHEMATICAL MODEL
**

The model we shall study is the so-called “minimal model” of Bergman er al. [16]-[18]. The model consists of a single glucose compartment, whereas plasma insulin is assumed to act through a “remote” compartment to influence net glucose uptake. Bergman er al. claim that among the models studied which satisfy certain validation criteria this model has the minimum number of parameters. While still classified as a very simple model of the dynamics of the interaction of blood glucose and insulin this model still retains some compatibility with known physiological facts and has now been validated in a number of clinical studies [18]-[20]. In this model, G ( r ) and Z ( t ) represent the differences of plasma glucose concentration and free plasma insulin concentration, respectively, from their basal val0 1991 IEEE

Manuscript received June 8, 1989; revised February 27, 1990. The author is with the Department of Mathematics, The University of Western Australia, Nedlands, Western Australia 6009. IEEE Log Number 9042378.

0018-9294/91/0100-0057$01.OO

This problem cannot. as the partition of [ 0. respectively. p 3 = 0. TI becomes finer and finer. G. = 4. in [17] in a study of diabetic and normal human subjects and in [16] for a group of dogs. is derived in [14] from the investigations of Home et al.29 4. For a discussion of optimal relaxed control problems the reader is referred to [26]. p 2 . The value of I. based on the model equations (2.X ( G + GB) + P ( t ) (2. if we remove the upper .Z. For example. = 15 mU/L. mU/min which.p2 = 0. For the Bergman model. However.4) together with a variety of initial conditions.5 mmol/L.39 4065 454 4. We have used the MISER program to solve the problem for the parameter sets (2. are basal values of plasma glucose concentration and free plasma insulin concentration. I . on U ( t ) . Fig.1) COMPARISONTHREE OF INSULIN INFUSIONPROGRAMS THE MODEL FOR (2. (2.025.. is a constant. = 12 L. The solution procedure used by this program partitions the interval [ 0. for correcting an initial state of hyperglycemia. The model equations are TABLE I G = -PIG . ii) optimal infusion. they use the values V. Values they use for normal subjects are pI = 0 .5) and 15 mmol/L (Go = 10. l(b) shows the insulin infusion rate profile for program iii) where the initial glucose level is 15 mmol/L. are estimated by Bergman et al. .91 7. and p 3 .ooOo13.3) The other model parameters are also discussed in [ 141 and. and X ( t ) is proportional to the concentration of insulin in the remote compartment. Furler et al.2) For diabetic (glucose resistant) subjects they argue that the value of pI is significantly reduced and so for theoretical purposes they use the set of values = 0.000013. T ] into equal subintervals and approximates the control u ( t ) by a constant function on each subinterval of the partition. 38.. The units of measurement will be taken as mmol per liter of plasma for G and mU per liter of plasma for 1. in general.1 - - . l ) .98 + 6 2219 1168 8. JANUARY 1991 ues. for all t E [O. is the insulin distribution volume and n is the fractional disappearance rate of insulin. X ( 0 ) = Xo and Z(0) = Io. I. Furler et al.5 mmol / L Go = 10. ~ ~0. P ( t ) and U ( t ) are the rates of infusion of exogeneous glucose and insulin. l). [22] and is typical of free insulin levels of controlled diabetic subjects under steady-state conditions.3) and (2. Fig. 111. closedloop solutions are not obtainable and (3. the total amount infused over the 6-h period for program ii). [ 141 yse the same equations with additional equations describing the effect of insulin antibodies on the insulin dynamics.4) The values of V. constant over hourly periods.) + u ( t ) / V I i) Injection/basal infusion ii) Optimal hourly infusion iii) Injection/hourly infusion Go = 5.10 1595 + where [0. In Table I we compare the values of the performance criterion J over a 6-h period resulting from three insulin infusion programs for the initial plasma glucose levels of 10 mmol/L (Go = 5. These three programs are i) a single injection at t = 0 plus infusion at the basal level of 1 U/h. n = (5/54)/min.57 4. where U.025. l(a) shows the plasma glucose responses for these three infusion programs for an initial glucose level of 15 mmol/L together with the plasma glucose response when only the basal insulin level ( 1 U / h ) is administered. the optimal control for this problem includes an impulse control at t = 0. for a person of average weight. give three alternative sets of values for p .89 3. As a means of comparing the effectiveness of the various programs we will use the performance criterion J ( u ) = i o T G 2 ( t dt ) (3. Values for the model parameters p l . corresponds to 1 U/h.1) seems to be an appropriate performance criterion. respectively. The insulin entries in Table I correspond to the initial injection plus 6 U for program i).33 +6 + 683 2. and 1. Swan [23] includes a term proportional to the square of the insulin infusion rate to obtain closed-loop solutions for the linear Ackerman model [24]. = (2.. p 2 .1) x = -p2x + p31 + I. Other performance criteria have been used in the literature. This is consistent with observations of the infusion rates that are required to maintain steady-state plasma glucose levels of severe diabetics at the basal values for normal subjects. Based on [17]. bound U. The constants G. A comparison of the three programs show that they all use similar total amounts of insulin while . One numerical algorithm which can be used to solve these problems is the general optimal control program MISER developed by Goh and Teo [25].. The model equations (2. In (2. for the parameter values (2.1) . (2. The steady state in the model corresponds to a constant insulin infusion rate of U = nV.TI (3. The problem we consider is the minimization of J ( U ) subject to the system equations (2.5). the corresponding initial conditions. This suggests that a combination of impulse control at t = 0 and continuous infusion is in fact the true optimal control for the optimal relaxed control problem in which the control is not bounded above. and n they use are obtained from [21]. 0 2 8 . while the value of Gs corresponds approximately to the basal plasma glucose concentration found in normal individuals.58 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING. iii) a single injection at t = 0 followed by optimal hourly infusion of insulin.1). p3 = O. V.2) 1. andp. NO.1) actually correspond to those used by Ollerton [ 151. and the initial injection plus the total amount infused following the injection over the 6-h period for program iii). be solved analytically. VOL.5 mmol/ L I = -n(I insulin ( U ) J ( u ) insulin ( U ) J ( u ) with initial conditions G ( 0 ) = Go. . TI is the time interval under consideration. OPTIMAL CONTROL IN THE ABSENCE GLUCOSE OF INFUSION In this section we examine various insulin infusion programs. open-loop solutions can be obtained using numerical techniques.4). and the constraints 0 5 u ( t ) 5 U. The numerical results show that.

Z. [13] and Furler et al. three hourly plasma glucose readings is especially appealing. Secondly. In all cases. the development of a simple semiclosed-loop system based on.5 U/h for levels above 12 mmol/L.FISHER: CONTROL OF BLOOD GLUCOSE LEVELS IN DIABETICS I GO) 59 basal infusion / TABLE I1 OF CRITERIONU ) FOR ALGORITHMS2. .5 mmol/L and T = 6 h. 1. U = nV. Algorithm 3 was found to be vastly superior to the other two. The systems of Chisolm et al. Firstly. These two algorithms have been evaluated theoretically in [ 141 using the Bergman model and Algorithm 2 was found to be superior in controlling hyperglycemia.). which are shown in Table 11. say. J( 1. (a) Plasma glucose profiles for three insulin infusion programs.bG) U IV. Go = 10.). l) was used as a means of comparing the performances of this algorithm with those of Algorithms l and 2. The algorithms on which these systems are based supply a constant insulin infusion rate over a three hour period calculated from a simple piecewise linear graph on the basis of a three hourly plasma glucose reading. delivers insulin at the rate of 0. with a linear transition between these rates for plasma glucose levels from 2 to 12 mmol/L.1 ) This formula was obtained by a least-squares fit of the expression U = G(u . which we shall call Algorithm 3. This algorithm. The effectiveness of Algorithm 3 was then assessed from a theoretical viewpoint using the model and the parameter values (2. with a linear transition between these rates for plasma glucose to the data obtained from solving the optimal control problem for various initial values of plasma glucose levels. The first algorithm (Chisolm et ul. The size of the injection is given by the formula U = giving different plasma glucose profiles. if the plasma glucose reading is below 6 mmol/L then insulin is delivered at a constant rate over the next 3 h which is (4.5 U/h for plasma glucose levels below 4 mmol/L and 2.3) This formula is very close to that obtained from linear regression based on solving the optimal control problem for various initial values of plasma glucose levels. although an interesting feature of program iii) is that it fails to retum the plasma glucose level to the basal level inside 6 h. which we shall refer to as Algorithm 2 .41 - 0.5 U/h for plasma glucose levels below 2 mmol/L and 2. levels from 4 to 8 mmol/L.5 1 insulin infusion rate (U/hour) time (hours) 0 3 6 (b) ' Fig. The performance criterion (3. Based on the results from solving this optimal control problem for various initial values of plasma glucose levels we have constructed a simple semiclosed loop algorithm for plasma glucose control.3) which correspond to a patient with relatively severe diabetes. VALUES THE PERFORMANCE AND 3 Initial Plasma Glucose Level (mmol/L) 8 10 12 6563 5041 1197 15 8347 8134 2213 20 17092 16790 4375 0 II \\\ \'\ injection +optimal hourly infusion Algorithm 1 Algorithm 2 Algorithm 3 5284 1220 294 7600 2859 672 d . (b) Insulin infusion rate profile for program iii). (4. and Furler et al. In both cases.0094G) U. The time period considered was 24 h. [14] with the insulin delivered by a computer-assisted insulin infusion system. uses the glucose reading in the beginning of each three hour period and consists of two parts. 2(a) and (b) shows the theoretical plasma glucose profiles re- ---1 - 1 . G(0. if the plasma glucose reading is greater than or equal to 6 mmol/L (a somewhat arbitrary amount) then an injection is given followed by constant infusion for the 3-h period at the rate required to maintain plasma insulin at its basal value in the steady state. The results of solving the optimal control problem formulated in the previous section clearly show that a combination of an impulse with infusion held constant over fixed time periods results in a far superior correction of a hyperglycemic state than control based purely on constant infusion. The two programs incorporating an injection are far superior in terms of the objective function J ( U ) . The second algorithm (Furler et al. delivers insulin at the rate of 0. mU/min. not only in the values of J obtained.5 U/h for levels above 8 mmol/L. but also in the increased stability (speed with which any oscillations are damped out) of plasma glucose levels. Such systems have been developed by Chisolm et al. that is. Fig. have been used with some success for short term therapy of diabetic inpatients. which we shall refer to as Algorithm 1. Ollerton [15] has also used theoretical techniques to derive semiclosed-loop insulin infusion algorithms based on three hourly and 10 min plasma glucose readings. A SEMICLOSED-LOOP ALGORITHM Because of the complexity and expense of fully closed-loop insulin infusion devices.

k t ) . prior to which plasma glucose and insulin are at their fasting The simple algorithm we have proposed here for the correclevels. The time period chosen was 6 h and the parameter values were again given by (2. In the model we shall assume that oral glucose infusion commences at t = 0 appropriate method of treatment for diabetes ketoacidosis is to give a bolus of insulin followed by infusion [9].2) was now solved numerically using the basal values of plasma glucose and insulin as the initial conditions. then. t 2 0 ( 5 .60 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING. [28]. CONTROL PLASMA OF GLUCOSE LEVELSFOLLOWING a theoretical analysis of the linear Ackerman model [24]. 2. vary from subject to subject. The algorithm suffers from glucose level rising quite rapidly (from the rest level) to a maxthe same deficiency as these earlier algorithms in that it is based imum in less than 30 min and then falling to the base level after on fixed values of the model parameters p l . (b) Fig. JANUARY 1991 I 2 - injection + optimal hourly infusion rime (hours) 6 I 0 -2L Fig. A function which produces the dequire some means of compensating for differences between sired behavior in the model is diabetic subjects. If we use the values within it a mechanism for handling meals.05 have incorporated an open-loop meal program into their overall sulting from the three algorithms for initial glucose values of 10 mmol/L (Go = 5 . the most effective short term control is achieved by an insulin infusion program which incorporates an injection coincident with the meal. VI. 3. I . These about 2-3 h.5 k = 0.1). of course.2) which represent normal subjects. and iii) a single injection at t = 0 followed by optimal hourly infusion of insulin. with the parameter values (2. (a) Gn = 5. p 2 .5 mmol/L.1) will be taken to represent the rate at nation of injections and constant infusion which are determined which glucose enters the blood from intestinal absorption folby three hourly plasma glucose readings. 5 ) and 15 mmol/L (Go = 10. ii) optimal infusion. A theoretical comlowing a meal. 1 ) rameters p l . Similar results were also obtained in [27] from V. and 3. subject to (3.5 mmol/L. Chisolm et al. This could be achieved by estimating the paP ( t ) = B exp ( . we obtain the desired effect. The optimal control problem to minimize (3. (b) Gn = 10. Plasma glucose profiles over a 24-h period for Algorithms 1 . AlA MEAL though the present conclusions are based only on a theoretical analysis of the Bergman model. VOL. the parison using the Bergman model shows it to be superior to the aim is for the model to produce the desired effect of the plasma algorithms proposed in [ 131 and [ 141. These three programs are i) a single injection at t = 0 plus infusion at the basal level of 1 U/h.3). constant over hourly periods. tion of hyperglycemia in the absence of a meal uses a combiThe term P ( t ) in (2. The results of three insulin infusion programs are illustrated in Fig. The results clearly show that. and p 3 for each patient or by incorporating a “patient factor” into the algorithm as in [14]. An form of P ( t ) for nondiabetics is not important provided the preeffective implementation of the algorithm would therefore reviously stated aim is met. they are consistent with many Here we examine means of controlling the plasma glucose clinical studies published in the literature which suggest that an level following an infusion of exogenous glucose. program would need to include k . p 2 . 2. 3. NO. and p 3 . There is some evidence to suggest that the exact parameters will. Plasma glucose profiles for 6 h following a meal for three insulin infusion programs. provided appropriate values are chosen for the constants B and A complete insulin infusior.5). 38. The results obtained in this paper suggest that the most effective insulin infusion programs are those which include an insulin injection. respectively. [13] B = 0. DISCUSSION . of the three programs considered. In oral glucose tests with normal subjects.

M. pp. Toffolo. Olefsky. vol. E. Zinman. 419-420. V. [24] E.Sc. N. Marliss. 91. vol. Rosevear. A. “Optimal insulin infusion resulting from a mathematical model of blood glucose dynamics. to our understanding of P-cell function?. vol. Principles of Optimal Control Theory. 0. Bergman. R. Salem. 1985. 1977. “Insulin responses to varying profiles of subcutaneous insulin infusion: Kinetic modelling studies.. 32. Home. N. vol. Clin. vol. 1983. “Control of blood glucose in diabetics using an artificial pancreas. vol. [20] A. 101. W. 51. Gatewood. “Normalization of plasma glucose of unstable diabetes: Studies under ambulatory. Avogaro. Med. M. M. A. B. [I51 R. Ider. M. and G. L. 479-486. 13. S. H. Kraegen. “A new phase of insulin secretion: How will it contribute [30] -. 30. and A. Skor. Bergman. J . “Model studies of blood glucose regulation. J. He received the B. vol. and A. E. vol. Furler. Res. Genuth and P. E. Invest. J . Michael E. 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Lab. “Quantitative estimation of insulin sensitivity. Murray. Applications of Optimal Control Theory in Biomedicine. vol. Aust. REFERENCES J. together with the results of Section IV. Campbell. “Waveform requirements for metabolic normalization with continuous intravenous insulin delivery in man. Massi-Benedetti. pp. 141. 13. “Normalization of glycemia in diabetics during meals with insulin and glucagon delivery by the artificial pancreas. Clemens. Y. 784-789. 339-342.” Aust. W. 2503-2522. degree with first class honors in 1967. Kraegen. 1984. pp. the grey present and the rosy future. Eng. Lazarus. Intern. Cobelli. J. [17] R. England. Bristow. pp. [26] R. Fisher and K. A. H. and C. Nat. “Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. 1989. Clin. 208-213. 1965. 97. Cobelli. Singapore: Applied Research Corporation. 6. C .” Ann. Capaldo. Meler. 50. Invest. New York: Plenum. 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N . R. fed conditions with pumped intravenous insulin. and J. Clin. . vol. [28] J . 1985. D. J . Alberti.” Brit. . pp. C. “Blood glucose control by intermittent loop closure in the basal mode: Computer simulation studies with a diabetic model. Bergman. in mathematics from The University of Western Australia. 1982. 1982. 7. Molnar. E. F.. vol. pp. Parsons. pp. pp. Service. Chisolm. Claremont.. Bowden. [25] C. G. M. however. D.” J. Mirouze. Chia. Perlman. pp. vol. 1974. “The artificial beta cell-a continuous control of blood sugar by external regulation of insulin (glucose controlled insulin infusion system). Kraegen and D. Bergman. respectively. Teo. 571581. and the M. W. N Z J. Y . pp. Leibel. L. [27] M. 30. 1987. 1972. M. pp. Swan. Filler. Metab. pp. R. 51-65. McNamara. We acknowledge that these results are still very much at the preliminary stage and require further investigation before they can be implemented. S. W. pp. vol. first as a Teaching Assistant. 1983. vol. 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