JPS631059B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an improved artificial pancreas device that not only controls the amount of insulin injected, but also allows the amount of glucose injected to be controlled based on a fixed glucose infusion program. Various methods and devices are known for artificially injecting insulin into patients with insulin secretion dysfunction, such as diabetic patients, based on a fixed program. Japanese Patent Application Publication No. 53-47195 of the present applicant
No. (Special Publication No. 58-44382) is one example.
This patent application forms the basis of the present invention;
References will be made in detail throughout the specification below. Traditionally, insulin therapy for diabetic patients consists of 1
This is often done by subcutaneously injecting depot insulin once a day. However, since blood sugar levels or insulin secretion in living bodies fluctuate based on certain biorhythms, it is impossible to maintain normal blood sugar levels even if a large amount of insulin is administered once a day. Furthermore, with current treatment methods, blood sugar levels fluctuate widely, and the progress of diabetic vascular lesions cannot be prevented. 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. Various artificial pancreases have been proposed that employ a so-called batch method of insulin injection amount control method in which insulin is injected at time intervals. However, in this type of artificial pancreas,
It has been difficult to administer an appropriate amount of insulin based on ever-changing blood sugar levels. Therefore, in the above-mentioned Japanese Patent Publication No. 58-44382, the present applicant injected exogenous insulin into diabetic patients in response to ever-changing blood sugar levels, in order to reproduce the same sugar metabolic state as observed in normal subjects. We proposed a method for injecting insulin based on a specific program or formula. In other words, peripheral blood and serum insulin levels IRI are the objective variables, and blood sugar level BS (mg/
100ml) and rate of change in blood sugar level ΔBS (mg/100ml・
The relational expression when min) is used as an independent variable is obtained by the following equation. =a×+b×Δ+c () [However, a, b, and c are constant numbers and are unique values for each individual. ] When exogenous insulin is administered intravenously to a diabetic patient who has little or no endogenous insulin, the relationship between the insulin injection amount IIA and peripheral blood and serum insulin values is as shown in the following equation. d(θ・IRI)/dt=IIA−K・θ・・〓 ………(): Peripheral blood, serum insulin level (μU/ml) θ: Insulin space (body weight x 15.7/100 (ml)) 〓: Rate of insulin uptake into tissues per minute (1/
min) K: Diffusion constant (dimensionless) IIA: Insulin injection amount (μU/min) Therefore, if we eliminate the impossibility of measurement in a short time from the above formulas () and () and calculate the insulin injection amount, we get the following: The formula is obtained. IIA=θ{K〓×a×+(a+b×K〓)Δ
+c×K〓}……()

[During the ceremony, I.I.A.…Insulin injection amount (μU/min) θ...Insulin space (body weight x 15.7/100 (ml)) 〓…Rate of insulin taken into tissues per minute (1/min) K...Diffusion constant (dimensionless) …Blood sugar level (mg/100ml) Δ… Rate of change in blood sugar level (mg/100ml・min) a, b, c...constants specific to the patient's medical condition]

Discloses a method for controlling the amount of insulin injected in an artificial pancreas configured to perform calculations consisting of the following: In addition, in the above calculation formula (), the amount of insulin injected IIA is set to 30 times the basal insulin injected amount required for normal glucose metabolism. It was also disclosed that insulin consumption can be greatly reduced by setting the maximum value. Furthermore, various coefficients in the arithmetic expression () were calculated as follows. That is, a pulsed glucose load is administered to a normal dog;
When Δ<0 and 20mg/Kgmin of glucose
Regarding the case of Δ>0 after continuous infusion for 60 minutes,
Peripheral blood, serum insulin, and blood sugar were measured, multiple regression analysis was performed, and statistical processing revealed the following results: Δ>0...a=0.137, b=4.10, c=-1.95 Δ<0...a=0.088, b=-1.29, c=2.20 was obtained. Insulin space θ was determined by the method of Sherwin et al. as θ=0.157×body weight (g). = 0.1481/min was determined by Stimmler'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 = 1.46 was obtained. However, we also demonstrated that K=1.2 is clinically appropriate. This time, the present invention provides an artificial pancreas device that has a wide range of clinical applications and can be applied to patients with unstable diabetes or various types of hypoglycemia, as well as to prepare for the unlikely event of an accident in the insulin injection system. It is something to do. The present inventors have conducted intensive research to improve this type of artificial pancreas device by directly injecting glucose without using glucagon. If the total amount of glucose to be injected is calculated from the sum of the amount (proportional action of blood sugar level) and the injection volume corresponding to the rate of change in blood sugar (differential action of blood sugar level), an extremely satisfactory glucose infusion program can be obtained. I found out. SUMMARY OF THE INVENTION Accordingly, the main objects of the present invention are to provide a glucose sensor that continuously measures blood sugar levels, a calculation circuit that calculates an insulin injection amount and a glucose injection amount according to a measured blood sugar level, an insulin injection device, a glucose injection device, and the calculation circuit. In an artificial pancreas device comprising an insulin infusion device and a controller that controls the glucose infusion device based on the calculated value calculated by An object of the present invention is to provide an improved artificial pancreas device characterized in that the total glucose injection amount is controlled based on the sum of the glucose injection amount corresponding to the rate of change of the value. In the improved artificial pancreas device of the present invention, the controller controls the glucose infusion device to inject the calculated glucose infusion amount into the patient with a fixed time delay. This time-delayed injection is important in the present invention. Generally, under physiological conditions, when hypoglycemia occurs, various hormones with anti-insulin effects are rapidly secreted and act on the liver and peripheral tissues to increase glucose production and limit glucose uptake, resulting in decreased blood sugar levels. It takes a certain amount of time before an increase is recognized. Time delay injection, which is a feature of the present invention, is based on this knowledge. The above object of the present invention is achieved by calculating the amount of glucose injected per minute using the following formula as a glucose infusion program. GIR(t)=Cp{BGp−BG(t−τ)}+Cd{−ΔBG(
t-τ)} In the formula, each signal has the following meaning. GIR (t): Glucose injection amount per minute kg body weight at time t (mg/min・Kg) Cp: Coefficient (1/min) Cd: Coefficient (dimensionless) BGp: Control target blood sugar level (mg/100ml) BG (t-τ): Blood sugar level τ minutes before time t (mg x 100ml) ΔBG (t-τ): Rate of change in blood sugar level τ minutes before time t (mg/100ml・min) τ: Time Delay (min) However, in the above formula, GIR(t)≠0. By incorporating a glucose infusion program based on the above formula into the artificial pancreas device, the improved artificial pancreas device of the present invention can control hypoglycemia in various ways by changing each parameter, thereby improving the safety of the artificial pancreas as a medical device. Not only is it useful for improving sexual performance, but it also fully exerts its function against unstable diabetes and various types of hypoglycemia. Furthermore, compared to the glucagon injection method, the glucose injection method according to the present invention has a rapid and reliable blood sugar elevating effect, and can be applied even to patients with low glucagon reactivity, so its clinical application can be greatly expanded. You can expect it. Hereinafter, the present invention will be described by way of example with reference to the accompanying drawings. FIG. 1 shows the basic configuration of an artificial pancreas device for carrying out the method of the present invention, which measures the blood sugar level of a diabetic or hypoglycemic patient 10 with insulin secretion dysfunction using a glucose sensor 12. The blood glucose level signal measured by the glucose sensor 12 is configured to be transmitted to the controller 14. Next, the output of the controller 14 operates an arithmetic circuit 16 incorporating a program for calculating the amount of insulin and glucose to be injected based on the blood sugar level signal, and calculates the amount of glucose to be injected into the living body. The results are communicated again to the controller 14. Therefore, the controller 14 is configured to inject an appropriate amount of glucose from the glucose storage tank 26 into the living body 10 by driving and controlling the glucose injection pump 22 for injecting the amount of glucose. However, in the present invention, based on the blood sugar level measured by the glucose sensor 12, the amount of glucose injected is calculated using the formula GIR(t)=Cp{BGp-BG(t-τ)}+Cd{-ΔBG(
t-τ)} In the formula, each signal has the following meaning. GIR (t): Glucose injection amount per minute kg body weight at time t (mg/min・Kg) Cp: Coefficient (1/min) Cd: Coefficient (dimensionless) BGp: Control target blood sugar level (mg/100ml) BG (t-τ): Blood sugar level τ minutes before time t (mg x 100ml) ΔBG (t-τ): Rate of change in blood sugar level τ minutes before time t (mg/100ml・min) τ: Time Calculated by delay (min). The improved artificial pancreas device of the present invention is a device that has been improved to control the amount of glucose injected as described above. Of course, the quantity can also be controlled at the same time. Next, an experimental example using a pancreatectomized dog will be described to examine the validity of the glucose injection amount calculation formula. Experimental Example 1 After controlling the blood sugar of a pancreatectomized dog to the normoglycemic range by intravenous insulin injection, hypoglycemia was induced by intravenously injecting 0.1 U/Kg of insulin actrapid, and insulin was administered according to the program of the present invention. Glycemic control was performed using glucose infusion and glucose infusion. (1) Figure 2 shows the results of injecting glucose with Cp=0.2, Cd=0, and τ=20. The blood sugar response curve of the pancreatectomized dog closely matched the blood sugar response curve of five normal dogs shown with diagonal lines after insulin loading. That is, pancreatectomized dog 5
No statistically significant difference was observed between the blood sugar response curves of these cases and those of the five normal dogs. (2) Figure 3 shows the results of injecting glucose with Cp=0.5, Cd=0.5, and τ=4. The blood sugar of pancreatectomized dogs showed a rapid recovery from hypoglycemia compared to the blood sugar response curve of normal dogs, and there was less fluctuation in blood sugar levels after recovery, resulting in good blood sugar control. The present invention has been described above with reference to preferred embodiments, but
Of course, the glucose infusion program of the present invention can be used in combination with any other insulin infusion program, and various improvements and 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 the improved artificial pancreas device of the present invention;
FIGS. 2 and 3 are blood sugar response characteristic curve diagrams of glucose infusion according to the program of the present invention. 10...patient, 12...glucose sensor, 1
4... Controller, 16... Insulin amount and glucose amount calculation circuit, 20... Insulin infusion pump, 22... Glucose infusion pump, 24
...Insulin storage tank, 26...Glucose storage tank.

Claims (1)

[Claims] 1. A glucose sensor that continuously measures blood sugar levels;
A calculation circuit that calculates an insulin injection amount and a glucose injection amount according to a measured blood sugar level, an insulin injection device and a glucose injection device, and controls the insulin injection device and the glucose injection device based on the calculation value calculated by the calculation circuit. In an artificial pancreas device consisting of a controller, an arithmetic circuit that calculates the amount of glucose injected per minute calculates the amount of glucose injected per minute using the following formula: GIR(t)=Cp{BGp−BG(t−τ)}+Cd{−ΔBG(
t-τ)} In the formula, each signal has the following meaning. GIR (t): Glucose injection amount per minute kg body weight at time t (mg/min・Kg) Cp: Coefficient (1/min) Cd: Coefficient (dimensionless) BGp: Control target blood sugar level (mg/100ml) BG (t-τ): Blood sugar level τ minutes before time t (mg x 100ml) ΔBG (t-τ): Rate of change in blood sugar level τ minutes before time t (mg/100ml・min) τ: Time An artificial pancreas device characterized in that it is configured to perform calculations based on delay (min).