JPS5844382B2 - Device for controlling insulin injection amount in artificial pancreas - Google Patents

Description

Detailed Description of the Invention This invention relates to insulin injection in an artificial pancreas in which insulin is artificially injected into diabetic patients with impaired insulin dividing function of the pancreas to repeatedly control blood sugar levels at short intervals. The present invention relates to a quantity control device.

Conventionally, insulin therapy for diabetic patients is often performed by subcutaneously injecting devo insulin once a day.

However, because the blood sugar level or insulin distribution in the body fluctuates based on a certain biological rhythm, it is impossible to maintain normal blood sugar levels even if a large amount of insulin is administered once a day. .

Furthermore, with current treatments, blood sugar levels fluctuate widely;
At present, it is not possible to prevent the progression of diabetic vascular lesions.

Therefore, we continuously measure blood sugar using a glucose sensor, etc., calculate the appropriate amount of insulin to inject based on the obtained blood sugar level, and then, based on this data, administer insulin at a predetermined amount under the action of a metering pump. An artificial pancreas has been proposed that employs a so-called batch-type insulin injection amount control method in which insulin is injected at time intervals.

However, in this type of artificial pancreas, it is difficult to administer an appropriate amount of insulin based on the blood sugar level, which changes with the side. On the other hand, there is a drawback that glucose injection may be required.

Therefore, the inventors conducted extensive research in order to reproduce the same sugar metabolic state seen in normal people by injecting exogenous insulin into diabetic patients in response to ever-changing blood sugar levels. In humans, the total amount of insulin distributed in proportion to blood sugar levels and changes in blood sugar levels enters the systemic circulation, is distributed to insulin spaces throughout the body, is broken down in the liver, taken up into tissues, and distributed uniformly. After being diffused into the blood, it is reflected as insulin in the peripheral blood and serum, and it has been found that the relationship between these can be expressed as the following equation.

That is, peripheral blood and serum insulin levels IRI are objective variables, blood sugar level B S (1n9//l 00ml') and rate of change in blood sugar level I B S (Ing/l 00ml.m
The relational expression when i n ) is used as an independent variable is obtained by the following equation.

I B I = a X BS + b X JBS
+ c "" (II) However, a, b, and c are constant numbers, and are numerical values unique to each individual.

When exogenous insulin is administered intravenously to diabetic patients with low or absent endogenous insulin, the amount of insulin injected is 1.1. A, and peripheral blood and serum insulin levels I
The relationship between RI is as shown in the following equation.

d(θ-IRI) □, □, A-e.

, □RI-II) 011. -(III)t IRI: Peripheral blood, serum insulin level (p, U/ml θ: Insulin space - D: Rate of insulin uptake into tissues per minute (17m I n') K: Diffusion constant (dimensionless) 1.1.A,: Insulin injection amount (μU/min
Therefore, when calculating the injection amount of insulin by eliminating IRI, which cannot be measured in a shorter time than DIE, it was found that the following equation can be obtained since 12Bs is considered to be almost zero.

1.1. A.

θ(K, 1)XaXBS+(a+bXKl)lJBs+
cXKI))...(I) Accordingly, the present invention is equipped with a computer that measures the blood sugar level of a living body with a glucose sensor and calculates the amount of insulin to be injected based on the obtained measurement value. By using the calculation program for the newly developed controller as shown in the formula (1) above, we used the controller to calculate the appropriate amount of insulin to be injected and control the micropump for insulin infusion. It has been proven that blood sugar levels can be maintained within the normal range without causing hypoglycemia.

Therefore, the general object of the present invention is to continuously detect blood sugar levels in diabetic patients with impaired insulin dividing function of the pancreas, and to perform predetermined calculations corresponding to the detected blood sugar levels. An insulin injection amount control device for an artificial pancreas configured to calculate an appropriate insulin injection amount using a program and operate an insulin injection device to inject the required amount of insulin into a living body based on the calculated injection amount. It is on offer.

The main objects of the present invention are to provide a glucose sensor that continuously detects a blood sugar level, an arithmetic circuit that calculates an insulin injection amount in response to the detected blood sugar level, an insulin injection device, and a glucose sensor that continuously detects a blood sugar level. In an artificial pancreas device consisting of a controller that controls an insulin injection device based on a calculated value, the calculation circuit that calculates the insulin injection amount uses the following formula (%) (1) However, 1.1. A, ...Insulin injection amount (μU/min') θ ...Insulin space (rILl) D
...The rate at which insulin is taken up into tissues per minute (1
7min') K... Diffusion constant (dimensionless) BS ------- Blood sugar level (II1g/100rIl
l), (BS... Rate of change in blood sugar level (1nv)
/10077+4-m1n') a, b, c
- A control device for the amount of insulin injected into an artificial pancreas, characterized in that it is configured to perform a calculation consisting of a constant a: 100 μTJ/In9') (b 2100 μU -min/force; 7C:μ:U/ml) is to provide.

However, it is clear that the arithmetic expression (1) basically includes the arithmetic expression (1), and also includes arithmetic expressions to which various constant terms and the like are added.

In addition, in the above calculation formula (I), the insulin injection amount is 1.1.30 times the basal insulin injection amount B necessary for normal glucose metabolism. It is preferable to set it as the maximum value of A.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Next, embodiments of the insulin injection amount splitting device according to the present invention will be described in detail with reference to the accompanying drawings.

Figure 1 shows the basic configuration of the device of the present invention, which is used for diabetic patients IO who have impaired insulin distribution function of the pancreas.
The glucose sensor 12 is used to measure the amount of blood sugar.

The blood sugar level signal measured by the glucose sensor is transmitted to the controller 14, which operates the arithmetic circuit 16 programmed to calculate the appropriate amount of insulin to be injected into the body, thereby calculating the amount of insulin to be injected into the living body. In order to calculate and inject insulin that matches the calculated value, the insulin injection pump 18 is driven and controlled to inject an appropriate amount of insulin from the insulin reservoir 20 to the living body 10.

However, in the present invention, the calculation circuit 16 that calculates the appropriate amount of insulin to be injected based on the blood sugar level measured by the glucose sensor 12 is set to perform the calculation of the following equation.

1.1. A.

θ(KIDXaXBs+(a+bXKD), !1fBS
+CXKI))...(I) However, 1.1. A, ...Insulin infusion amount (μU/min) θ ...Insulin space - D ......Rate of insulin taken into tissues per minute (17 m1 n) K ...Diffusion constant (dimensionless) BS ...Blood sugar level (mvloor/ll),
(BS... Rate of change in blood sugar level (m9/100
rnA' min ') a p l) x C...
・・・Constants specific to the patient's medical conditionNext, in order to calculate the above coefficients, normal dogs were subjected to pulsed glucose loading.1.
(Peripheral blood, serum insulin, and blood sugar were measured and subjected to multiple regression analysis for the case of BS<0 and the case of JBS>O after continuous infusion of glucose at 20/kg min for 60 minutes, and by statistical processing, IBs>O...=・a=0.137, b=4.10
, c--1,95JB S<O"-・a=0.08
8 jb--1,29, c=2.20 was obtained.

However, the constants a and bs c shown here are just examples.
This arithmetic expression should be changed and set arbitrarily according to the user's judgment.

Insulin space θ is Sherwine, etc.
According to the method of inet al), θ=0.15X body weight g
) was sought.

D was determined as I) = 0.14817min by Stimler's method.

As a result of statistically processing the relationship between the amount of insulin injected and the peripheral blood insulin level using pancreatectomized dogs, K=1.
I asked for 46.

However, it was also confirmed that 1.2 is clinically appropriate.

However, in actual use, both θ and ID are ±5%.
There is no problem even if there are fluctuations in the numbers within.

Next, an example using a pancreatectomized dog will be described regarding the suitability of the above formula (1) for calculating the amount of insulin to be injected.

Experimental Example 1 Intravenous Pulse Glucose Tolerance Test 0, 33 g/kg body weight of glucose was injected into the jugular vein of a pancreatectomized dog for 10 seconds, and the blood sugar level was then measured over 80 minutes.

Next, insulin injections were stopped for at least 24 hours in the pancreatectomized dog.
And after fasting for 16 hours, 5000μU/
kgmin of insulin was continuously infused, and the blood sugar level was 120.
When the level decreased to 111g/100ml, the continuous infusion amount was increased to 2.
The amount was set at 25 μU/'q min (this is defined as the basal insulin injection amount, hereinafter abbreviated as B).

However, when insulin infusion was stopped after intravenous glucose loading, the blood glucose level decreased to approximately 170 In9/100 m after 40 to 60 minutes.
Although it decreased to 1, it was observed that it rose again after that.

Next, under similar conditions, 100
When 10XB of insulin was injected in the first minute and 10XB of insulin was continuously injected thereafter, the glucose disappearance curve was slightly delayed compared to that of a normal dog, but the glucose utilization constant (K value) was normal (3.1±0.3).

However, when the insulin injection of 10XB was continued, hypoglycemia occurred after 80 minutes (see Figure 2 a s b).

Therefore, when injecting insulin, the maximum amount of insulin to be injected was defined as 30XB, and the injection was performed according to a certain program, and the results shown in FIGS. 3a and 3b were obtained.

In other words, in the first minute, the absolute value of blood sugar and the rate of change in blood sugar are low due to the rapid and large amount of glucose infusion, and 177XB of insulin is required according to the calculation based on formula (〇), but according to the program, 30XB When insulin was injected, an average injection amount of 3XB was sufficient after 1 minute, and the sugar disappearance curve (see Figure 3a) showed no significant difference compared to the sugar disappearance curve shown in Figure 2a. .

The glucose utilization constant (K value) is 3.2 ± 0.2, which is normal, and the amount of insulin injected after 80 minutes is B, making it possible to maintain blood sugar within the normal range without causing hypoglycemia. did it.

Therefore, in this case, it was found that the amount of insulin injected could be saved by 50% or less.

Experimental Example 2 Oral Glucose Tolerance Test After pancreatectomy, a positive blood glucose level was maintained by continuous injection of insulin amount B using the same method as in Example 1, and then 2.0, ! ? /
9 body weight of glucose was injected.

Changes in blood sugar were measured for 3 hours while continuously injecting insulin dose B, and the results shown in FIG. 4 a s b were obtained.

On the other hand, when insulin was administered according to a fixed program, blood sugar levels could be controlled within the normal range for 4 hours with an insulin dose of about 3XB (see Figures 5a and b).
.

Experimental Example 3 Treatment Test for Diabetic Coma Conventionally, in the treatment of diabetic coma and diabetic ketoacidosis, large doses of insulin have been the principle.

Pancreatectomized dogs were stopped from insulin treatment for 3 to 9 days to reach severe diabetic ketoacidosis, and treated with an insulin solution prepared by adding insulin actravit to physiological saline supplemented with 0.5% gelatin to the final insulin concentration. 5xB
- When the blood sugar lowering rate was measured by continuous infusion of tooxB insulin for at least 3 hours, the average blood sugar lowering rate was the highest at 121 m97di/h with an insulin dose of 30XB, and was better in cases where larger amounts of insulin were administered. No significant effect could be observed.

From the above results, the basis for setting the maximum amount of injected insulin to 30×B in the insulin injection program for the artificial pancreas was obtained.

As is clear from the above practical example, the device of the present invention maintains the blood sugar level within the normal range without causing hypoglycemia by calculating the amount of insulin to be injected according to a specific calculation program in the calculation circuit. The amount of insulin injected can be saved.

Although the preferred embodiments of the present invention have been described above, it goes without saying that various design changes can be made without departing from the spirit of the present invention.

[Brief explanation of the drawing]

Fig. 1 is a system diagram of an artificial pancreas implementing the device of the present invention;
Figures a, b to 5 a, b show blood glucose response characteristic curves and insulin injection amount curves of experimental examples in which the device of the present invention was applied to a large pancreas. 10...Patient, 12...Glucose sensor, 14...Controller, 16...
・Arithmetic circuit, 1881611. Insulin injection pump, 20... Insulin storage tank.

Claims (1)

[Scope of Claims] 1. A glucose sensor that continuously detects a blood sugar level, a calculation circuit that calculates an insulin injection amount in response to the detected blood sugar level, an insulin injection device, and a calculation value calculated by the calculation circuit. In an artificial pancreas device consisting of four parts, a controller that controls the insulin injection device based on the following formula % formula % (1) However, 1.1. A...Insulin injection amount (μU/min) θ...Insulin space (ml) Movement...
・・Rate of incorporation per minute into the composition of insulin (1/rT1
in) K... Diffusion constant (dimensionless) BS... Blood sugar level (■/rooml) ABS...
... Rate of change in blood sugar level (rn9y100rrLl-min) a s b z C ... Constant a: loOμψ
~J'b: lOOμU-minArL9(c:
A device for controlling the amount of insulin injected into an artificial pancreas, characterized in that it is configured to perform calculations consisting of and including equations μ:U, 41'. 2 In the above equation (1), the insulin injection amount 1. is 30 times the basal insulin injection amount B required for normal glucose metabolism. 2. The device for controlling the amount of insulin injected into an artificial pancreas according to claim 1, wherein LA and O are set as maximum values.