RU2613272C1 - Method for determination type 1 diabetes compensation for adolescents - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention refers to medicine, namely to pediatrics, and concerns determination of type I diabetes compensation for adolescents. To do this, continuous monitoring of glucose and calculation of the average area under the glycemic curve in the hyper- and hypoglycemic range (AUC) during observation are performed. AUC values less than 1.18 mmol/l*h are regarded as compensation/subcompensation of T1D. At AUC level of 1.18 mmol/l*h and above T1D decompensation is diagnosed.

EFFECT: high accuracy evaluation of type 1 diabetes compensation for adolescents.

3 tbl, 2 ex

Description

The invention relates to medicine, namely to pediatrics, and will find application in pediatric endocrinology.

Achieving and maintaining the optimal level of glycemic control in children and adolescents with type 1 diabetes mellitus (T1DM) is an urgent problem in modern diabetology.

It has been proven that poor glycemic control and, as a result, decompensation of diabetes mellitus worsen the prognosis of the disease, leading to the development of both acute and chronic complications that reduce the quality of life and lead to early disability of young patients (Diabetes Control and Complications Trial (DCCT) Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med, 1993, 329: 977-986). In this regard, the timely diagnosis of CD1 decompensation is extremely relevant. Of great practical interest is the assessment of the degree of compensation of T1DM in adolescents, since they are characterized by a decrease in insulin sensitivity associated with a physiologically high concentration of contrainsular hormones (androgens, growth hormone, etc.), as well as a change in social behavior and a decrease in motivation for active management of diabetes (Greenbaum CJ. Insulin resistance in type 1 diabetes. Diabetes Metab Res Rev. 2002, 18: 192-200. [PubMed]). At present, to assess the degree of compensation of T1DM, along with clinical signs, glucose and ketone indicators are used in blood and urine during the day (Algorithms for the provision of specialized medical care for patients with diabetes mellitus, ed. II Dedova, MB Shestakova, ed. 7th, M., 2015, p. 79).

The disadvantages of the generally accepted recommendation of four to six-fold determination of blood glucose levels during the day include the difficulty in analyzing glycemia indicators and adjusting insulin doses by a doctor due to the fact that unmotivated patients do not bring a glucometer, do not keep a self-monitoring diary, which makes it impossible to assess the size and duration rises of postprandial glycemia, identify the presence of nocturnal hyper- and hypoglycemia.

Such methods of assessing the compensation of T1DM, such as monitoring the level of glucose and ketones in the blood and urine, are of limited use, due to the lack of a direct correlation of glucosuria and ketonuria with the level of glucose in the blood, which makes it difficult to choose further treatment tactics. In addition, the appearance of ketones in the urine, despite maintaining the target glycemic values, is possible in patients on a sub-calorie diet, with prolonged physical activity, various associated conditions (gastroenteritis, pregnancy).

It is important to note that routine point measurements of glucose during the day do not give a clear idea of the quality of glycemic control, while the use of long-term continuous glucose monitoring (NMH) provides the most complete information about the magnitude, duration and frequency of changes in blood glucose during the day, allowing a more adequate assessment of the degree of compensation of T1DM and rational adjustment of therapy. (Ametov A.S., Karpova E.V. Importance of continuous monitoring of glycemia in patients with diabetes. Breast cancer. 2008; 29: 1845-1849).

Currently, the following parameters are used to determine DM1 compensation according to the results of NMH: average glycemia, standard deviation (SD), mean amplitude of glycemic excursions: MAGE, and glycemic lability index (lability index: LI). Despite the simplicity of calculations, these criteria do not take into account the frequency of glucose fluctuations, the duration of stay in the hyper- and hypoglycemic ranges. To assess glycemic control, we also proposed the GRADE scale (glycaemic risk assessment diabetes equation), average daily risk range (ADRR) and its components: low blood glucose index (LBGI) and hyperglycemia (high blood glucose index) : HBGI). The disadvantages of these methods include the complexity and complexity of the analysis of the obtained data, which requires a doctor to spend time and a certain skill in working with charts, the lack of information of the listed indicators in determining the effectiveness of insulin therapy and the diagnosis of DM1 decompensation.

One way to assess the compensation of T1DM is to study fructosamine (FA), an indicator that characterizes the glycation of blood serum proteins, mainly albumin. FA is a complex of glucose with blood proteins, which disappears from the blood after 2-3 weeks, when the protein breaks down. FA reflects the parameters of blood glucose in the previous 2-3 weeks.

The disadvantage of this method is the dependence of the results of measuring the FA from various factors. Thus, in addition to diabetes mellitus, an increase in the concentration of FA in the blood is observed in patients with renal failure, with hypothyroidism, myeloma, and acute inflammatory diseases due to an increase in the level of immunoglobulins of class A, due to the use of drugs such as heparin, L-methyldopa. On the other hand, a decrease in the level of FA in the blood is noted with nephrotic syndrome, diabetic nephropathy, accompanied by a loss of plasma albumin, with hyperthyroidism. In addition, this indicator characterizing the state of carbohydrate metabolism during the previous 2-3 weeks is not informative for the diagnosis of DM1 decompensation in a specific period of time. Untimely detection of DM1 decompensation can lead to the development of ketoacidosis and the need for inpatient treatment.

A study of FA can be useful in monitoring glycemia in people with abnormal red blood cell survival (hemolytic anemia, hemoglobinopathies) who have uninformative determination of glycated hemoglobin (HbA1c) (ISPAD Clinical Practice Consensus Guidelines 2009 Compendium. Pediatric Diabetes. 2009; 10 (Suppl . 12): 210).

Closest to the claimed method for evaluating the compensation of T1DM is determining the level of HbA1c in the blood (Peacock I. Glycosylated haemoglobin: measurement and clinical use. J. Clin Pathol. 1984 Aug; 37 (8): 841-851). Until recently, the dominant goal of T1DM therapy was to lower HbA1c, a blood count that reflects the average blood glucose in the previous period to 3 months. The essence of this method is to determine the percentage of hemoglobin A, irreversibly bound to glucose molecules, present in red blood cells. The degree of glycation of hemoglobin depends on the average concentration of blood glucose over the life of the red blood cell (on average 120 days). Thus, HbA1c reflects the level of compensation of T1DM during the previous 3 months.

The disadvantage of this method is that the standard approach to assessing the effectiveness of DM1 therapy by the level of HbA1c involves monitoring the average daily glycemia, but does not take into account the amplitude of glucose fluctuations, the frequency and severity of hypoglycemic conditions. Meanwhile, a decrease in the level of HbA1c in children and adolescents can be associated with an increase in the number and duration of episodes of severe hypoglycemia, leading to impaired central nervous system activity, which is an additional risk factor for the development and progression of diabetes complications.

Determination of HbA1c has leading diagnostic value in assessing long-term disease compensation (over the previous 3-4 months). It should be borne in mind that according to generally accepted studies (DCCT, 1983-1993 and Epidemiology of Diabetes Interventions and Complications, EDIC, 1994-2005), HbA1c values of more than 9% confirm the presence of DM1 decompensation and a high risk of diabetic complications in patients. However, normal HbA1c levels do not necessarily indicate satisfactory (optimal) glycemic control and are often recorded in decompensated patients.

It should be noted that the changing social aspects of adolescent life, as well as the physiological decrease in insulin sensitivity at this age, require intensive glycemic self-control, with possible quick and simultaneous adjustment of doses and regimen of insulin therapy. In this situation, it is not possible to assess the quality of glycemic control, make an informed decision about the need to change the treatment according to the HbA1c criterion. Normalization of HbA1c occurs within 4-6 weeks after the change of therapy, and therefore this parameter is used only for long-term monitoring of the course of diabetes.

A drawback of the HbA1c study is also its unreliable measurement in people with various forms of anemia or hemoglobinopathy.

These disadvantages are eliminated in the claimed invention.

The objective of the invention is to develop a method by which patients can evaluate the compensation of T1DM in real time, which will allow to choose an adequate treatment tactic and prevent the development of diabetic complications.

The problem is solved in that a teenager with T1DM carries out three to six-day continuous glucose monitoring using long-term monitoring devices, analyzes the area indicator under the AUC glycemic curve (Area under curve), which characterizes the average glucose concentration in the hyper- and hypoglycemic ranges, and at AUC values of less than 1.18 mmol / L * H, compensation / subcompensation of T1DM (optimal / suboptimal glycemic control) is diagnosed, and at AUC levels of 1.18 mmol / L * H and above, decomputer satsiyu T1D.

A new technical result obtained using this method is that it is possible to diagnose DM1 decompensation with high accuracy in real time in order to make a decision on the correction of insulin therapy regimens.

Studies of the last decade have demonstrated that glycemic variability plays an important role in assessing the level of glycemic control, since sharp rises and decreases in blood glucose levels negatively affect the body of patients with type 1 diabetes, increasing the risk of developing diabetic complications. The widespread use of long-term LMWH, in contrast to routine point measurements of glucose during the day, provides the most complete information about the magnitude, duration and frequency of changes in blood glucose during the day, allowing a more adequate assessment of the compensation of T1DM and rational adjustment of therapy (A. Ametov, Karpova EV The value of continuous monitoring of glycemia in patients with diabetes. Breast cancer. 2008; 29: 1845-1849).

The method for evaluating the compensation of T1DM that we propose involves analyzing the area under the concentration-time glycemic curve (AUC; mmol / L * H), an integral indicator characterizing the total glucose concentration outside the target values for the studied time period (24 h - 36 h - 72 h ) and standardly used for analysis of glucose measurement results by the sensor. The AUC value is calculated automatically by the device as an integral of the function of the blood glucose concentration versus time and is equal to the area of the figure bounded by the glycemic curve and the upper / or lower limit of the reference boundaries (3.9-7.8 mmol / L).

Our studies, including the analysis of clinical, laboratory data, the results of NMH in 94 adolescents with T1DM using modern methods of statistical analysis (the method of choosing alternatives - the “decision tree” method), allowed us to choose the AUC indicator as the most informative and affordable criterion for assessing T1DM compensation.

In a monitor study of the state of carbohydrate metabolism in adolescents, the target parameters of glucose level fluctuations were set in the device memory: the lower limit at the level of 3.9 mmol / l, the upper limit - 7.8 mmol / l - reference values.

Deviations of glycemia above the acceptable threshold (> 7.8 mmol / L) were regarded as the hyperglycemic range, deviations of glycemia below the minimum threshold (<3.9 mmol / L) as the hypoglycemic range.

Using the methods of statistical analysis (discriminant one-dimensional division by categorical predictors - “decision tree method”) it was found that the average total AUC value for glucose monitoring time less than 1.18 mmol / l * H testified to compensation / subcompensation of T1DM, and the level of AUC, equal to 1.18 mmol / l * H or more, corresponded to the stage of DM1 decompensation.

Our proposed method takes into account the duration, severity of hypo- and hyperglycemia, the amplitude of glucose fluctuations, eliminates the influence of concomitant factors that distort the true picture of the course of the disease, and thereby allows us to judge the degree of compensation of T1DM.

Moreover, the parallel (simultaneous) determination of HbA1c and AUC - in its accuracy in assessing the decompensation of T1DM in adolescents, exceeds the indicator properties of all other methods.

AUC values of less than 1.18 mmol / L * H in combination with normal HbA1c values confirm CD1 compensation / subcompensation, while AUC of 1.18 mmol / L * H and higher is a clear indicator of CD1 decompensation, even in cases when HbA1c is normal.

The proposed marker is extremely important for practical endocrinology, as it contributes to the assessment of diabetes compensation and the selection of adequate insulin therapy, which will delay and prevent the development of chronic diabetic complications.

The data presented give reason to believe that the use of such a method of evaluating compensation as determining AUC is a promising tool for an individualized assessment of glycemic control, the risk of developing vascular complications and hypoglycemia.

A detailed description of the method and examples of its clinical implementation.

The method is carried out standardly as follows.

1. Determination of compensation for T1DM is carried out using the MiniMed Paradigm Real-Time 522/722 or MiniMed Paradigm Veo 554/754 (Medtronic Minimed, USA) systems equipped with a continuous glucose monitoring device by measuring glucose every 5 minutes for three to six days. 2 hours before the expected meal (11 ⁰⁰ ), the patient is injected with an MMT-7008 Enlite glucose sensor using the automatic device Serter Enlite MMT-7510 in the subcutaneous fat of the recommended area (lateral sections of the abdominal wall, upper buttocks, shoulder muscles ), connect the transmitter MiniLink Transmitter and secure with a special waterproof adhesive. After a 2-hour initialization period, the sensor registers and transmits glucose values to a transmitter that sends this data to the insulin pump. The principle of operation of the sensor is based on an electrochemical reaction with glucose contained in the interstitial fluid of the patient, which corresponds to the level of glucose in the capillary blood.

2. On the screen of the MiniMed Paradigm Real-Time or MiniMed Paradigm Veo systems, the speed and direction of change of glucose level in real time, the current glucose level (in mmol / l or in mg / dl), as well as glucose graphs for the last 3, 6 are displayed , 12 or 24 hours. Throughout the study, a continuous monitoring system is regularly calibrated, which includes entering into the device data on the level of glucose of capillary blood, measured with an glucose meter on an empty stomach and 2 hours after eating at least 2 times a day.

3. After the study is completed, the sensor is removed from the body.

4. The glucose data stored in the memory of the MiniMed Paradigm Real-Time or MiniMed Paradigm Veo systems is transferred to a personal computer using the CareLink USB MMT-7305 data transfer device and processed by CareLink Pro Therapy Management Software. The results are displayed in the form of graphs and tables.

5. Assess the AUC values. The AUC value is analyzed, which is equal to the sum of the average values during observation in the hyperglycemic (Avg AUC> 7.8) and hypoglycemic (Avg AUC <3.9) ranges. For AUC values less than 1.18 mmol / L * H, compensation / subcompensation of T1DM is diagnosed, and for AUC values of 1.18 mmol / L * H and higher, T1DM decompensation.

The efficiency of the invention is confirmed by the following examples.

Example 1

Patient Aeva, 14 years old, has been observed in the children's endocrinology department of RNIIAP for 2.5 years about type 1 diabetes mellitus. He has been on insulin pump therapy for 2 years. The girl does not make complaints. The daily need for insulin is 0.65 U / kg body weight; receives 6-7 XE per day. Self-monitoring is regular. Diagnosis: Type 1 diabetes mellitus, stage of compensation.

NMG and analysis of the results of the study allowed us to calculate the AUC value equal to 1.17 mmol / l * H. According to our data, this indicated optimal glycemic control of the disease and the absence of decompensation of T1DM.

A 6.3% HbA1c level indicated DM1 compensation. With a 6-fold measurement of glycemia during the course of the day using a glucometer, the fluctuations in glycemia were 4.1-7.2 mmol / L. There was a lack of glucosuria, ketones in urine and blood. An additional clinical and laboratory examination, including examination by a neurologist, registration of electroneuromyography, ophthalmoscopy, determination of the level of microalbuminuria, did not reveal chronic diabetic complications in the patient.

The baseline bolus regimen scheme was left unchanged. With planned hospitalization after 8 months, the child's condition remained stable, and no clinical or laboratory manifestations of chronic diabetic complications were detected. Thus, from this example it follows that AUC1 less than 1.18 mmol / L * H indicates optimal / suboptimal glycemic control.

Example 2

Patient B-s, 13 years old, is observed in the children's endocrinology department of RNIAP for type 1 diabetes. Receives FDI for 1 year. The course of the disease is labile, accompanied by pronounced diurnal fluctuations in glycemia. Self-control of the disease is irregular, hypoglycemic conditions 1-2 times a week. The diary of self-control does not lead. The daily insulin requirement is 0.83 units / kg body weight. The optimal level of HbA1c was recorded - 5.8%. The boy does not make complaints.

Continuous monitoring of glycemia for 72 hours revealed an AUC value of 1.18 mmol / L * H, indicated by our data on DM1 decompensation and required a change in the baseline bolus regimen of insulin therapy, as well as nutrition correction.

Decompensation of carbohydrate metabolism was confirmed by high daily variability of glycemia in the range of 3.0-17.5 mmol / L, glucosuria up to 4% in portions and up to 37 mg in daily urine. Screening for complications revealed distal symmetric polyneuropathy (stage 1B), diabetic neuroosteoarthropathy. Despite an HbA1 level of less than 9%, the patient was diagnosed with type 1 diabetes mellitus, the stage of decompensation, and changes were made to the schedule of insulin therapy.

Thus, from this example it follows that an AUC of 1.18 mmol / L * H and higher allows you to diagnose DM1 decompensation and requires correction of treatment tactics.

We examined 94 adolescents with T1DM who are on gtpii at the age from 14 to 18 years, who underwent LMW for 3-6 days. We analyzed the level of HbA1c, daily fluctuations in glucose, the frequency and severity of hypoglycemic and ketoacidotic conditions, and patient self-monitoring diaries.

Assessment of glycemic profiles obtained on the basis of NMH allowed us to divide adolescents into 2 groups. The first group included 39 (41.5%) patients without clinical manifestations of ketoacidosis with fluctuations in blood glucose corresponding to optimal / suboptimal glycemic control according to the Algorithms for the provision of specialized medical care for patients with diabetes mellitus, 2015 (Algorithms for the provision of specialized medical care for patients with diabetes mellitus ", Under the editorship of II Dedov, MB Shestakova, ed. 7th, M., 2015, p. 79). The second group consisted of 55 (58.5%) adolescents with glycemic indicators that go beyond the reference values and / or have clinical manifestations of DM1 decompensation. Both groups were comparable in terms of tender composition, duration of the disease, duration of pump therapy and the presence of complications.

According to the results of the study, in 38 (97.4%) adolescents of group 1, the AUC indicator was in the range from 0 to 1.18 mmol / L * H, which corresponded to compensation / subcompensation of T1DM, and in 52 (94.5%) patients of group 2 this indicator was 1.18 mmol / l * H and higher — SD1 decompensation. This testified to the high sensitivity and specificity of this method of assessing compensation for T1DM.

To study the correspondence of the proposed new method for assessing compensation of T1DM to the currently generally accepted level of glycated hemoglobin, we used the mathematical method for evaluating the results - constructing a four-table table (O. Yu. Rebrova. Statistical analysis of medical data. O. Yu. Rebrova - M .: Media Sphere, 2003 .-- 305).

In adolescents on PPII, HbA1c levels and areas under the glycemic curve in the hyper- and hypoglycemic range (AUC) were determined. To construct a four-field table, the AUC values from 0 to 1.18 mmol / L * H and HbA1c of less than 9% were set as the reference interval, which was regarded as compensation / subcompensation of T1DM, i.e. "negative result". Decompensation of T1DM was diagnosed with an AUC level of 1.18 mmol / L * H or more, and HbA1c values exceeding 9.0% - a “positive result” (Table 1, Table 2).

The diagnostic value of both putative tests was calculated, their comparative analysis was carried out by indicators of sensitivity, specificity, and prognosticity of positive and negative results (Table 3).

An assessment of the compliance of the new test with the reference one showed that the sensitivity of the diagnostic test in terms of the area under the AUC glycemic curve (94.5%>) is 2 times higher than the sensitivity for HbA1c (41%), with almost the same high specificity of both methods (97.4% and 84.6%, respectively).

Based on the foregoing, the claimed method for evaluating the compensation of T1DM in patients with T1DM compared with existing has the following advantages:

1. The proposed method is highly accurate.

2. Determination of AUC is an adequate indicator of the effectiveness of insulin therapy aimed at achieving the target level of glycemia.

Claims (1)

A method for determining compensation for type 1 diabetes mellitus by determining glucose levels, characterized in that patients undergo continuous glucose monitoring, calculate the average area under the glycemic curve in the hyper- and hypoglycemic ranges (AUC) and at AUC values less than 1.18 mmol / l * H diagnose the compensation / subcompensation of T1DM, and with AUC values of 1.18 mmol / l * H and above - the decompensation of T1DM.