JPH0817814B2 - Artificial pancreas device - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an insulin infusion device based on a fixed insulin infusion program and an artificial pancreas provided with a glucose infusion device based on a fixed glucose infusion program, and more particularly to The present invention relates to an artificial pancreas device that automatically converts a correction term of an arithmetic expression for creating a predetermined glucose infusion program in response to a change in blood glucose level over time and maintains and controls the blood glucose level at a predetermined value.

[Conventional technology]

Conventionally, as a device for artificially injecting insulin or glucose based on a certain program into a patient with insulin secretion dysfunction such as a diabetic patient, the present applicant has proposed “a device for controlling an insulin infusion amount in an artificial pancreas” ( Japanese Patent Publication No. 58-44382), "Improved artificial pancreas device" (Japanese Patent Publication No. 63-1059) and "Artificial pancreas device"
(Japanese Patent Publication No. 63-1060) and developed patent applications.

However, the calculation circuit for calculating the glucose infusion amount is
As shown in the above “improved artificial pancreas device”, 1
The glucose infusion amount per minute is expressed by the following formula GIR (t) = Cp {BGp−BG (t−τ)} + Cd {−ΔBG (t−τ)} where each symbol has the following meaning.

GIR (t): Glucose infusion amount per 1 kg body weight at time t (mg / min / kg) Cp: Coefficient (100 ml / min / kg) Cd: Coefficient (100 ml / kg) BGp: Control target blood sugar level (mg) / 100ml) BG (t-τ): Blood glucose level τ minutes before time t (mg / 1
00 ml) ΔBG (t−τ): Change rate of blood glucose level τ minutes before time t (mg / 100 ml / min) τ: It is configured to perform calculation based on time delay (min).

In the calculation formula of the glucose infusion amount, an infusion amount corresponding to the difference between the blood glucose level and the control target value (proportional action of blood glucose level) and an infusion amount corresponding to the rate of change of blood glucose (differential action of blood glucose level) The total glucose infusion amount per minute is calculated from the sum of the above.

In recent years, DeFronzo et al., "Glucose clamp method: Method for measuring insulin secretion and resistance" (Glucos
e clamp technique: a method for quantifying insulin
secretion and resistance, Am J Physiol 237: E214〜2
23, 1979), the glucose clamp method is often used. The glucose clamp method has the following two methods. First of all,
A method called hyperglycemic clamp, which aims to measure the sensitivity of pancreatic Langerhans islet β cells to glucose. In this method, a subject was given a predetermined amount of glucose priming for 14 minutes to raise the blood glucose level from the basal level to +125 mg / 100 ml, and then the glucose infusion amount was measured for about 2 hours to measure the blood glucose level. Is maintained at a constant value. Normally, the blood glucose level to be maintained is about 200 to 220 mg / 100 ml. Therefore, this method is based on the principle that the glucose infusion amount is equal to the glucose metabolism amount because the internal glucose production is completely suppressed under a certain blood glucose level, and the glucose metabolism amount depends on the glucose utilization. It serves as a quantitatively reflected index, and by measuring the plasma insulin concentration, the sensitivity of pancreatic Langerhans islet β cells to glucose load can be evaluated.

The second is Euglycemic insulin c
The purpose is to measure tissue sensitivity to exogenous insulin by a method called lamp). This method first performs insulin priming on a subject and maintains a predetermined insulin infusion amount after about 10 minutes. In order to keep the blood glucose level at the basal level for about 2 hours, glucose infusion is started after insulin priming and the glucose infusion amount is controlled. Normally, blood sugar levels maintained are about 80-90
It is mg / 100 ml. Therefore, this method is based on the principle that the glucose infusion amount matches the glucose metabolism amount under a constant blood glucose level, and the tissue sensitivity to exogenous insulin can be evaluated from the glucose metabolism amount.

[Problems to be Solved by the Invention]

However, in the above-mentioned glucose clamp method, since the fluctuation of the blood glucose level is kept as small as possible and kept at a predetermined value in principle, controlling the glucose infusion amount is a very important problem.

The technique of glucose clamp by Deflonzo et al. Collects the blood of the subject every 5 minutes using a syringe,
The blood glucose level is measured using the blood, and the infusion setting dial of the glucose infusion pump is adjusted based on the obtained blood glucose level to adjust the glucose infusion amount. Therefore, there is a large variation in the blood glucose level that should be kept constant in principle, and further, a series of operations cannot be completed by one operator, which is very complicated.

Therefore, when the artificial pancreas device having an arithmetic circuit having the above-mentioned formula for calculating the glucose infusion amount is adapted to the glucose clamp method to control the glucose infusion amount in order to maintain a predetermined blood glucose level, glucose infusion Since the calculation formula of the volume consists of the addition sum of the proportional action and the differential action of the blood glucose level, that is, because of the PD control, there is no effect of correcting and controlling the glucose infusion amount when the blood glucose level slightly fluctuates. There was a flaw.

Therefore, an object of the present invention is to provide a conventional artificial pancreas device equipped with an arithmetic circuit having an arithmetic expression for calculating the glucose infusion amount, when the metabolism amount when the glucose infusion amount and the metabolism amount are matched is determined by the subject. It is an object of the present invention to provide an artificial pancreas device that can perfectly balance both of these fluctuating functions of the blood glucose level of the human body and that can obtain a simple and accurate metabolic rate.

[Means for solving the problem]

An artificial pancreas device according to the present invention is a glucose sensor that continuously measures a blood glucose level, an arithmetic circuit that calculates an insulin infusion amount and a glucose infusion amount according to a measured blood glucose level, an insulin infusion device and a glucose infusion device, and the above computation. In an artificial pancreas device consisting of an insulin infusion device and a controller that controls a glucose infusion device based on the operation value calculated by the circuit, the operation circuit for calculating the glucose infusion amount calculates the glucose infusion amount per unit time by the following equation ( 1), GIR (t) = GA {GD−BG (t)} − GB · ΔBG (t) + GC
(1) However, In the formula, each symbol has the following meaning.

GIR (t): Glucose infusion amount per unit time and unit weight (mg / min / kg) BG (t): Blood glucose level per unit time (mg / 100ml) ΔBG (t): Change rate of blood glucose level per unit time (Mg / 100
ml / min) GA: Proportional coefficient of operation (100 ml / min / kg) GB: Differential coefficient of operation (100 ml / kg) GC: Correction term (mg / min / kg) GC ₁ : Correction term value before a certain time before time t (Mg / min / kg) GD: glucose control target blood glucose level (mg / 100 ml) a, b: characterized in that the calculation is performed based on a coefficient (dimensionless) that determines the degree of correction.

[Action]

According to the artificial pancreas device of the present invention, the arithmetic circuit, the glucose infusion amount corresponding to the difference between the measured blood glucose level and the glucose control target blood glucose level, the glucose amount corresponding to the rate of change of the blood glucose level, unit time before Correction term value (for example, 1 minute before) (GC
Value) and the amount of glucose infusion in the correction term consisting of the difference between the value obtained based on the rate of change of the blood glucose level measured at the current time, and from the sum of the three terms, per unit time (for example, per minute) The total glucose infusion of

Accordingly, even if a slight change in blood glucose level occurs, the correction term immediately responds to automatically convert the glucose injection amount, and the blood glucose level can be maintained and controlled to be constant. It should be noted that various correction calculations can be performed by changing each parameter in the calculation formula of glucose infusion amount, and a sufficient function can be exhibited for maintaining and controlling the blood glucose level in the glucose clamp method at a constant level. .

〔Example〕

Next, an embodiment of the artificial pancreas device according to the present invention will be described in detail below with reference to the accompanying drawings.

FIG. 1 is a system diagram showing the basic configuration of the artificial pancreas device of the present invention. That is, in FIG. 1, the blood glucose level signal measured by the glucose sensor 12 for the subject 10 is transferred to the controller 14. Next, the output of the controller 14 operates the arithmetic circuit 16 in which a program for calculating the insulin infusion amount and the glucose infusion amount based on the blood glucose level is operated to calculate the glucose infusion amount to be infused into the subject 10. , And is configured to transfer the calculation result to the controller 14 again. Therefore, the controller 14 drives and controls the glucose infusion pump 18 for injecting glucose into the subject 10,
The glucose reservoir 20 is configured to inject an appropriate amount of glucose into the subject 10.

However, in the present invention, the glucose infusion amount is calculated by the following equation in the arithmetic circuit 16 based on the blood glucose level measured by the glucose sensor 12.

GIR (t) = GA {GD−BG (t)} − GB · ΔBG (t) + GC
(1) However, In the formula, each symbol has the following meaning.

GIR (t): Glucose infusion amount per unit time and unit weight (mg / min / kg) BG (t): Blood glucose level per unit time (mg / 100ml) ΔBG (t): Change rate of blood glucose level per unit time (Mg / 100
ml / min) GA: Proportional coefficient of operation (100 ml / min / kg) GB: Differential coefficient of operation (100 ml / kg) GC: Correction term (mg / min / kg) GC ₁ : Correction term value before a certain time before time t (Mg / min / kg) GD: glucose control target blood glucose level (mg / 100 ml) a, b: coefficient that determines the degree of correction (dimensionless) Thus, in the present invention, glucose injection by conventional PD control is performed. In the calculation formula GIR (t) of the amount, by providing a constant term GC and adding it, the modulation of the human body of the subject in the case of PD control, that is, the insulin infusion amount for maintaining the target blood glucose level is changed over time. Changing to
It is possible to reduce the steady-state deviation (offset amount) caused by.

However, in the artificial pancreas device according to the present invention, since the glucose metabolism of the subject changes with time, that is, the offset amount changes with time, the constant term
It is necessary to update the optimum value of GC one after another.

Therefore, in the present invention, the glucose metabolism level of the subject is measured by keeping the blood glucose level of the subject constant. In this case, in order to quickly adjust this to the target value for a fluctuating target, adjustment will be made with a coefficient, but if it is attempted to adjust quickly, hunting (overshoot) will increase, and if the blood glucose level is below a certain level. When measuring glucose metabolism in, the reliability of the measured value becomes a problem. In order to solve this problem, in the present invention, the constant term GC is provided and the constant term GC
It is configured to correct itself from past measurement values.

Therefore, in order to obtain this constant term GC, for example, the correction term value GC ₁ one minute before is required, and in order to obtain this correction term value GC ₁ , the correction term value GC ₂ one minute before is required. It is necessary to set the initial value somewhere. Therefore, for example, the conventional average value is set as the initial value GC ₅ , the blood glucose level change rate ΔBG (t) is set as 0, and the blood glucose level BG (t) and the blood glucose level change rate are set every 1 minute. ΔBG
With the measured value of (t), change the setting four times,
Find the constant term GC. Note that the initial value is not limited to the above case, and for example, an expected value, a final value of the previous measured value, or the like can be used.

In this way, by automatically changing the constant term GC every 1 minute, the constant term GC that provides an optimal glucose infusion amount for keeping the blood glucose level of the subject constant after a few minutes.
A feedback system having a learning function of changing (correcting) the value of is constructed.

The constants a and b are determined by the subject from the balance between hunting and the convergence speed to the target value.
= 10, b = 12) to (a = 2, b = 128). In addition, PD control type proportional operation coefficient GA and differential operation coefficient GB
Is determined based on the usual PD control concept.

In the embodiment shown in FIG. 1, the applicant previously proposed "a device for controlling the amount of insulin infused in the artificial pancreas" (Japanese Patent Publication No. 58-44382) and an "artificial pancreas device" (Japanese Patent Publication No. 63). -1060) to apply the arithmetic expression for calculating the insulin infusion amount to the arithmetic circuit 16 and control the insulin infusion pump 22 via the controller 14 to inject an appropriate amount of insulin from the insulin storage tank 24 into the subject 10. Can be configured. In addition, the “improved artificial pancreas device” previously proposed by the applicant (Japanese Patent Publication No. 63-1059)
It is also possible to control the glucose injection amount by applying the arithmetic expression for calculating the glucose injection amount in.

Based on the calculation formula (1) described above, for example, the measured blood glucose level BG
Fig. 2 shows the calculation result of glucose injection GIR per minute when the value decreases from 80mg / 100ml at a rate of 1mg / 100ml per minute, if it is shown on the graph according to the setting example of each parameter. Is. As is clear from FIG.
It will be appreciated that the amount of glucose infused changes rapidly in response to extremely small changes in blood glucose level.

Although the preferred embodiments of the present invention have been described above, the present invention is not limited to the above-described embodiments, and it goes without saying that various design changes can be made without departing from the spirit of the present invention. .

〔The invention's effect〕

As is apparent from the above-described examples, when a specific metabolic rate in which the glucose infusion rate and the metabolic rate are matched is obtained, the conventional PD is used for the subject's fluctuating blood glucose level adjusting function.
With control, you can't completely balance the two,
According to the present invention, the constant term GC is provided and the constant term GC is automatically adjusted to follow the modulation of the human body of the subject, while the human labor and accurate metabolism were not obtained. The constant term GC
More accurate measurements of can be obtained.

Usually, this measurement is performed over 2 to 3 hours, but the initial value is set, during which the blood glucose level is measured continuously,
The measured value is sampled at fixed time intervals (for example, 1 minute, but this time may be shorter or longer), and the constant term GC is sequentially replaced during the measurement period to Even if there is a modulation, it is possible to follow a place that cannot be followed only by PD control, and an accurate metabolic rate can be obtained.

Therefore, according to the present invention, it is particularly effective when the glucose clamp method is carried out for a diabetic patient, and it is easy to automatically maintain the measured blood glucose level at a predetermined value. The effect of reducing the work effort for controlling the motion of the device is extremely large.

[Brief description of drawings]

FIG. 1 is a system diagram showing an embodiment of an artificial pancreas device according to the present invention, and FIG. 2 is a response characteristic diagram of glucose infusion amount with respect to fluctuations in measured blood glucose level based on an arithmetic expression of glucose infusion amount in the present invention device. Is. 10 …… Subject 12 …… Glucose sensor 14 …… Controller 16 …… Computing circuit 18 …… Glucose injection pump 20 …… Glucose storage tank 22 …… Insulin injection pump 24 …… Insulin storage tank

Front page continuation (72) Inventor Tatsuo Suzuki 3-43-2, Ebisu, Shibuya-ku, Tokyo Within Nikkiso Co., Ltd. (56) Reference JP-A-52-135599 (JP, A) JP-A-55-21905 (JP, A) JP-A-56-28765 (JP, A) JP-A-58-175566 (JP, A)

Claims (1)

[Claims] 1. A glucose sensor for continuously measuring a blood glucose level, an arithmetic circuit for calculating an insulin infusion amount and a glucose infusion amount according to the measured blood glucose level, an insulin infusion device and a glucose infusion device, and an arithmetic circuit for calculating the blood glucose level. In an artificial pancreas device that includes an insulin infusion device and a controller that controls a glucose infusion device based on the calculated value, the arithmetic circuit that calculates the glucose infusion amount calculates the glucose infusion amount per unit time by the following equation (1), GIR (T) = GA {GD−BG (t)} − GB · ΔBG (t) + GC
(1) However, In the formula, each symbol has the following meaning. GIR (t): Glucose infusion amount per unit time and unit weight (mg / min / kg) BG (t): Blood glucose level per unit time (mg / 100ml) ΔBG (t): Change rate of blood glucose level per unit time (Mg / 100
ml / min) GA: Proportional coefficient of operation (100 ml / min / kg) GB: Differential coefficient of operation (100 ml / kg) GC: Correction term (mg / min / kg) GC ₁ : Correction term value before a certain time before time t (Mg / min / kg) GD: glucose control target blood glucose level (mg / 100 ml) a, b: artificial pancreas characterized by being configured to perform calculation based on a coefficient (dimensionless) that determines the degree of correction apparatus.