Artificial Pancreas Control Strategies for Type 1 Diabetes

Artificial Pancreas Control Strategies for Type 1 Diabetes: Comparison

Please note this is a comparison between Version 1 by Abdul Majeed and Version 2 by Vivi Li.

This entry presents a comprehensive survey about the fundamental components of the artificial pancreas (AP) system including insulin administration and delivery, glucose measurement (GM), and control strategies/algorithms used for type 1 diabetes mellitus (T1DM) treatment and control.

type-1 diabetes mellitus
insulin
closed loop and open loop schemes
artificial pancreas
PID controller
β-cells
model predictive controller
and fuzzy logic controller

1. Introduction

1.1. What Is Diabetes?

Diabetes is a metabolic disease in which one’s blood sugar, or blood glucose (BG), levels are very high. Glucose comes from the foods one eats. Insulin is a hormone that helps the glucose enter human cells to provide them with energy, and it helps in maintaining the homeostatic BG levels. Insulin is produced by the specialized type of cells of the pancreas known as beta-cells (

β

-cells), which are necessary to exploit glucose as a source of energy from the digested food. Chronic hyperglycemia (high blood glucose concentration (BGC)) can lead to further complications such as microvascular and macrovascular damage leading to kidney disease, neuropathy, amputations, cardiac disease, stroke and retinopathy. Hence, diabetes includes a broad range of heterogeneous diseases [1]. Diabetes has been classified in to three major types based on the presumed etiology which are explained below:

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Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease in which the human body does not produce enough insulin while insulin inoculations are required on a daily basis. T1DM was further classified into two subgroups: immune mediated and idiopathic by the American Diabetes Association (ADA) in 2007. Meanwhile, the idiopathic type-1 diabetes is considered to be type-2 diabetes by several researchers and clinicians. Patients of T1DM become entirely dependent on externally administered insulin, and it is the only treatment available in medicine. However, the daily dose of insulin varies and depends heavily on a range of other factors including age, gender, daily exercise, and physique. However, an average daily dose is about 1-unit of insulin per kg weight per day [2].

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Type 2 diabetes mellitus (T2DM) also known as non-insulin dependent diabetes mellitus (NIDDM), it is characterized by the defect in both insulin secretion and insulin resistance. High levels of BG are managed with the reduced food intake, improved physical activity, and ultimately oral medications or insulin [3].

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Gestational diabetes (GD) can occur temporarily during pregnancy, and recent findings suggest that it can occur in 2~10% of the all pregnancies. During pregnancy, significant hormonal changes can lead to the blood sugar elevation in genetically predisposed individuals which is known as gestational diabetes (GD).

2. Physiological Methods of Insulin Delivery

2.1. Significance of First and Second Phase Insulin Secretion in Human Body

The immediate release of insulin after a meal is known as “first-phase insulin release”. The first-phase insulin secretion has a major effect on extinguishing hepatic glucose production ^[4][34]. Small change in the plasma insulin can have a significant effect on the hepatic glucose output ^[4][34]. Normally, insulin production in an early phase is actually less than the total insulin needed to yield a similar area under the glucose curve ^[5][6][33,35]. Improving first-phase response is related to glucose tolerance ^[7][36]. A person whose system is insulin-resistant without the variation in the insulin secretion becomes diabetic. Meanwhile, a person’s system which maintains the required level of glucose tolerance by adopting the “control gain” is regarded as a non-diabetic individual ^[5][33]. The first and second phases of insulin secretion occur all the time in the body. However, the second phase insulin secretion has a major effect on the glucose production as well as its utilization in a human body ^[4][34]. The importance of second phase insulin secretion cannot be ignored as it is necessary to maintain plasma glucose at a set point (i.e., normal range) ^[5][33]. In addition, the loss of first phase insulin secretion is the first indicator of the development of T2DM in a human body ^[8][37].

2.2. Hyperglycemia and Hypoglycemia

Insulin cannot be infused until the BG level exceeds 180–200 mg/dL. This condition is referred as hyperglycemia ^[9][38]. The condition of hyperglycemia is found to be common in intensive care units (ICU) ^[8][37]. According to existing surveys presented by Krinsley et al. ^[10][39], even a small level of hyperglycemia can lead to an increased rate of hospital mortality in ICUs ^[10][39]. Sugar level control with insulin infusion has a risk of hypoglycaemia. Sugar level which is <50 mg/dL is the called hypoglycemia. The hypoglycemia can be diagnosed by the Whipple’s triad, with three steps. (i) neuroglycemia symptoms, (ii) immediate glucose of <40 mg/dL, and (iii) symptoms of the relief after glucose intake ^[11][40].

2.3. Biological Perspective on How β-Cell Achieves Glucose Control and Energy Metabolism in Type 1 Diabetes Mellitus (T1DM)

The biological perspective on how a β-cell achieves glucose control can be summarized in four steps as: (i) after a person takes a meal, the small intestine absorbs glucose from the digested food. Consequently, the BG levels rise; (ii) increase in BG levels stimulate the β-cells in the pancreas to produce insulin; (iii) after that, insulin triggers liver, muscle, and fat tissue cells to absorb the glucose, where it is stored. As glucose is absorbed in the related parts, the BG levels fall; (iv) Once the glucose levels drop below a certain threshold, there is no longer a sufficient stimulus for insulin release, and the β-cells stop releasing further insulin. The conceptual overview of the whole process is shown in Figure 2. Due to the synchronization of the insulin release with the β-cells, basal insulin concentration oscillates in the blood following a meal. The oscillations are clinically important, since they are believed to help maintain sensitivity of insulin receptors in the target cells. The key role of the β-cells is to sense the BG levels, and regulate insulin accordingly. For example, when the BG increases following food intake, β-cells sense this change in concentration, and subsequently secrete insulin into the blood. On the other hand, when blood glucose levels are low, such as following a prolonged fasting period, the release of insulin from β-cells is inhibited ^[12][41].

Figure 2. Conceptual overview of the biological perspective on how a β-cell achieves glucose control.

Doctors have tried to help patients of T1DM to maintain their glucose values as close to the normal range as possible to delay the onset and slow the progression of long-term diabetes complications such as renal disease, retinopathy, neuropathy, and heart disease. Monitoring glucose levels is vital for achieving desirable glycemia and avoiding hypoglycemia. Continuous Glucose Monitoring (CGM) is a recent glucose monitoring device that assists to achieve these aims. CGM has been shown to improve glycemia without an increase in the hypoglycemia for adults with T1DM who wear it most days ^[13][14][15][42,43,44]. Furthermore, studies have reported the positive psychosocial changes such as decreased partners’ anxiety, vigilance and negative experiences surrounding hypoglycemia, and improved patients’ mood and general quality of life ^[16][17][45,46]. Currently, flash glucose monitoring is emerging as an innovative technology, it enables self-monitoring of blood glucose ^[18][47]. With the help of CGM and other related technologies, doctors and clinicians are able to gain more insight into the glucose variability, temporarily improved sense of control, reduced distress and reduced dependency on the others physical devices. However, some participants experienced confrontation with the CGM output as intrusive, whereas others reported frustration due to the technical failures and difficulty in trusting the devices. Active and passive self-management behaviours were reported by the participants, mirroring individual differences in attitudes and coping styles ^[19][48].

Insulin making and subsequent release from the β-cells is controlled by multiple players, including glucose, peptide hormones, neurotransmitters, and other related compounds ^[20][21][49,50]. Briefly, the rise in the BG levels that follows food intake is sensed by the β-cells, which subsequently take glucose up from the blood, and metabolize it to more fuel for the mitochondria to shunt towards adenosine triphosphate (ATP) production, increased levels of which result in the inhibition of the cell’s K_ATP channels. This ultimately leads to depolarization at the plasma membrane (PM), an electrical change that functions to activate the L-type Ca²⁺ channels, which allows an influx of Ca²⁺ into the β-cell. Finally, this wave of Ca²⁺ triggers the release of secretory granules containing insulin, to be released from the cell by exocytosis. The conceptual overview of the whole process is depicted in Figure 3. The flow is marked with red-arrows in Figure 3 for clarity.

Figure 3. Conceptual overview of the glucose-stimulated insulin secretion (GSIS) and brief excerpt of glucose sensing, oxidation into adenosine triphosphate (ATP) energy equivalents, potassium-ATP (K_ATP) channels working together, leading to calcium entry and insulin exocytosis in the pancreatic β-cells (shown with red arrow flow). (Adopted from ^[12][41]).

3. Open Loop Administration of an Insulin

The requirement/need of an automated AP system has been present since 1921, the time when insulin was discovered first time ^[5][33]. The produced insulin needs definition in terms of prehepatic insulin as well as portal insulin concentration in order to work as closely in a non-diabetic state ^[22][51].

3.1. Timing of Insulin Delivery

With the increase in the demand of the insulin infusion and its mechanism, it is recommended to take the dose with almost every meal ^[23][52]. However, one major concern is the timing of insulin delivery ^[24][53]. Depending on the type of insulin, rapid-acting insulin should be infused 15 min before the meal. Short-acting or regular insulin can be infused 30 min before the meal. Having food activity straight away after regular insulin can cause hypoglycemia (i.e., low sugar level) ^[24][53]. Changing the interval between insulin infusion and meal shows remarkable effect in the postprandial hyperglycemia in insulin dependent patients. Recent studies show that a near-normal glucose level can be achieved only when patient had their insulin administered 60 min before the meal ^[23][52]. Results infer that adjusting the time and the amount of insulin can be helpful in the management of the diabetes ^[12][41]. As shown in Figure 4, delayed insulin infusion before meals can be linked to greater hyperglycemia up to three hours after the meal ^[25][54].

Figure 4. Comparison of delayed and standard insulin delivery with the meal (adopted from ^[9][38]).

3.2. Manual Administration of the Insulin

The injection technique is the most common and early cure for a diabetic patient. Dosage is different for different individuals. People with T1DM do not produce enough insulin to meet the glucose level of a normal person so they need an external insulin. Most of the T2DM patients do not require external insulin. The timing of the insulin injection depends on the glucose level, and various other factors ^[24][53]. Injection site selection is important to yield appropriate results. Insulin can be injected into subcutaneous tissue of the upper arm or the anterior aspect of thighs and buttocks ^[25][54].

3.3. Subcutaneous Versus Inhaled Insulin

Inhaled insulin has been proven way more effective and reliable in the T1DM and T2DM. Infusion of regular insulin through lungs by inhalation has shown insulin absorption and lowering of the BG ^[26][55]. As shown in Figure 5, the maximum insulin concentration is more rapid in case of inhaled insulin as compared to the subcutaneous (SC) injection ^[27][56]. In subcutaneous insulin (SCI), the short-acting insulin driven by a mechanical force and delivered via a needle or soft cannula under the skin is undertaken on a continuous and constant basis ^[28][57]. Although SCI is expensive, but it provides greater flexibility for the individuals having diabetes in managing their condition, and it allows more precise insulin dosing than multiple daily injections (MDI) ^[29][58]. According to systematic reviews, potential benefits of SCI include improved glycaemic control, reduction in the hypoglycaemia unawareness, lower insulin doses, high absorption, and a lower frequency of severe hypoglycaemia ^[30][31][32][59,60,61]. Due to the development of sensor augmented insulin therapy with or without suspend functions ^[33][34][62,63], the T1DM control and quality of life for patients have significantly enhanced ^[35][36][64,65]. Moreover, SCI is most successful in individuals motivated to manage their condition and supported by a multidisciplinary team with expertise in the delivery of SCI ^[37][66]. In contrast, inhalable insulin is a powdered form of insulin, delivered with an inhaler into the lungs where it is absorbed ^[38][67].

Figure 5. Comparison of the inhaled insulin with the subcutaneous (SC) injection ^[16][45].

In general, inhaled insulins absorb more rapidly than SCI insulin, with faster peak concentration in serum and more rapid metabolism ^[39][68]. Sanofi-Aventis developed the first commercial inhaled insulin product (Exubera), which was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2006 and marketed by the Pfizer ^[40][69]. Although Exubera offered the advantage of painless insulin administration by the pulmonary route of administration, its pharmacokinetics (PK) and pharmacodynamics (PD) (i.e., PK/PD) characteristics were similar to the SCI injected rapid-acting insulin analogs (aspart, glulisine, and lispro) and, thus, offered no additional clinical benefit in postprandial glycemic control ^[41][70]. Furthermore, the inhaler device was large and the handling procedure for insulin administration was cumbersome ^[42][43][71,72]. Afrezza, an inhaled insulin with ultra-rapid PK/PD properties that enable improved postprandial glycemic control in adults with T1DM or T2DM has been suggested as a promising tool ^[44][73]. Improvements in the PK/PD characteristics of today’s SC insulins provide more physiological coverage of basal and prandial insulin requirements than inhaled insulin, that why SC is most widely used. Furthermore, the treatment with SC offers a safe and efficacious option for managing diabetes in patients with T1DM and T2DM ^[45][74]. The inhaled insulin delivery may cause safety issues in lungs. We refer interested readers for more detailed understanding about both these two insulin methods to the latest findings in recent studies ^{[46][47][48][49][50][51]}[75,76,77,78,79,80]. Pharmacokinetics deals with the absorption and distribution process of the insulin in a human body. Insulin is absorbed into the blood stream directly ^[52][81]. The rate of the absorption truly depends on the state of insulin, volume of the injection, and rate of the blood flow. It has been reported in literature that the absorption rate decreases with an increase in the concentration and the volume. Existing studies demonstrated that inhaled insulin can absorb faster in the human body ^[53][82]. Pharmacodynamics deals with effect of insulin on the human body. It is basically called the euglycaemic clamp study, and glucose infusion rate is used to represent the pharmacodynamics of an insulin ^[54][83].

3.4. Multiple Daily Insulin Therapy

The most renowned method of insulin therapy consists of the regular periodic injection of basal (baseline) insulin multiple times in a day—known as multiple daily insulin injections (MDI)—supported by the additional insulin doses (boluses), and oral glucose or glucagon as required to maintain normoglycemic conditions (e.g., at mealtimes) ^[55][84]. While calculating the required basal and bolus insulin doses, practical guidelines need to be followed. Due to the significant complications, there is now an array of options/factors that allow for the personalization and situational evaluation of the treatments ^[55][84]. MDI using short- and long-acting doses are currently the main strategies of the insulin administration in this population. Depending upon the scenarios, some injections are developed as a mix of rapid acting (i.e., quick onset and peak times with short duration) and long acting (i.e., delayed onset time, low or no peak, and long duration) insulin to provide both basal and bolus action from a single injection, thereby reducing the number of injections required per day ^[56][57][85,86]. In addition, in some cases, it may be helpful to perform islet transplantation or that of the pancreas, in place of insulin therapy to significantly lower the treatment costs ^[56][85].

Generally, MDI comprise of three or more injections per day. It contains one injection of long-acting (LA) insulin in the evening, and an injection of the short-acting (SA) insulin ahead of every meal. LA insulin is drafted in such a way that it delivers insulin steadily and remains in the body for around 24 h. Meanwhile, the SA insulin needs to be adjusted to match the meal using the insulin-to-carbohydrate ratio ^[58][87]. The presentation of MDI and its use in diabetes control and complications trials (DCCT) study has been the ideal case to protect the patients with T1DM. The recent evolution of automated bolus calculations for the MDI is available to help patients to perform complex calculations that are required for functional insulin therapy (FIT) ^[59][60][88,89]. But there are some limitations of MDI to be considered: those patients who use very small amount of insulin doses or are insulin-sensitive may conflict with the MDI as it comes up with the limitations and accuracy’s issues. Similarly, for patients who require large doses, the use of continuous subcutaneous insulin infusion (CSII) may be very helpful from the pharmacodynamics aspect. Continuous infusion works better on delivery of basal insulin rather than using a large subcutaneous depot. MDI is not very effective on those who eat frequently or living soft lifestyle, demanding a large number of injections of the SA insulin, and it becomes difficult to manage through MDI ^[59][88]. The Hypo-Ana research study shows that using an analogue-based regimen decreases the severe hypoglycemia in patients with impaired knowledge of hypoglycemia ^[59][60][88,89]. Data also suggests it is being taught already as a way of adjusting the insulin, but many patients ignore the fact and underestimate the insulin doses face difficulty while calculating appropriate amount of insulin adjustments and which acts like a barrier. In early study, the use of bolus calculator recommended reduced errors of insulin and fear hypoglycemia ^[61][62][90,91]. The use of a bolus automated calculator is linked with revised Hba1c and reduced glycemic fluctuations even in the younger patients with T1DM on MDI ^[63][92]. The list of distinct categories of the insulin available in medicine (adopted from ^[64][93]) is summarized in Table 1.

Table 1. Description about distinct types of the insulin available in medicine for T1DM treatment.

Type of Insulin	Time Action Profile	Dose
Short acting	Begins from the 30-min after the subcutaneous with reaching peak action in 2–4 h	3 times in a day, 30 min before taking a meal
Long acting	Beyond 24 h and up to 36 h	Once daily subcutaneous, at the same time with at least 8h interval between consecutive doses
Rapid acting	Generally, 4–20 min after subcutaneous injection with peak at 20–30 min.	Three times a day up to 15 min before food intake
Intermediate acting	Peak onset from 4–6 h, with the duration of action until 14–16 h	1 or 2 time daily subcutaneous

3.5. Continuous Subcutaneous Insulin Therapy

Insulin pump therapy also known as continuous subcutaneous insulin infusion (CSII) is a way of providing intensive insulin therapy which consistently leads to enhances glucose and reduced hypoglycemia. CSII was developed about 40 years ago. CSII systems are portable pump therapy devices that are generally constructed as a combination of an onboard insulin reservoir, an infusion apparatus (tubing and cannula), and an electromechanical infusion pump ^[65][66][94,95]. According to numerous studies, these systems can be operated easily using the synthetic human insulin or rapid-acting insulin analogs (RAIA), with the help of RAIA, it provides superior performance to the synthetic human insulin ^[65][94]. In most cases, CSII uses the same basal dosage as MDI, with the basal insulin dosage applied more consistently over the day in CSII ^[66][95].

The CSII is an efficient self-management tool for T1DM patients. It is recommended that insulin therapy should initiate at the start of the week, it is because patient has access to the clinical help for the rest of the week ^[67][96]. In fact, across Europe, there are less than 30% T1DM patients which are using insulin pumps, while in the USA, the use of insulin pump is relatively higher ^[68][97]. The key dominance of insulin pumps is the additional flexibility, allowing patients to adjust basal insulin in response to the requirement changes due to illness, alcohol and exercise. Many pumps also provide on-board automated bolus calculators, allowing persistent boluses for corrections by the day. Moreover, wellbeing and increased flexibility using CSII in patients may increase their attachment to intensified therapy ^[69][98]. A short randomized trial revealed that increased glucose in the target but too short to report HbA1c levels ^[70][99]. Despite the fact that CSII is effective, it must be appropriately maintained and used, as device performance heavily depends on proper operation (i.e., timely replacement of consumables) to avoid failure modes such as impeded or clogged infusion pathways, which can lead to the insulin deficiency and hyperglycemia. The tools used by the T1DM subjects for insulin dosing are summarized in Figure 6, and the detailed description about each method/tool, and their advantages and disadvantages are summarized by Rima et al. ^[71][100].

Figure 6. Overview of the tools used by T1DM subjects for insulin dosing (adopted from ^[71][100]).

4. Closed Loop Administration of Insulin

Current treatment methods such as SC injections and continuous delivery of insulin can result in frequent variations in the BG levels due to their open-loop nature ^[72][101]. In order to keep a stable basal glycemia with the continuous insulin infusion, we require a feedback system ^[73][102]. The main aim of the feedback system is to maintain a set point which is predefined. Variable transfer functions like proportional, integral or derivative terms are used to implement a feedback system ^[73][102]. The diabetes control and complications trial (DCCT) published in 1993 showed that it is very important to tightly control the BG in a human body ^[74][103]. The trial showed that there is an increased risk of hypoglycemia by combining the results of SC injections and insulin pumps ^[74][103]. A person with T1DM has always a long-term risk related to hyperglycemia, and short-term risks of the hypoglycemia, so they need to have a tight BG control. However, the T2DM patients’ needs an insulin treatment when oral anti-diabetic agent and changing lifestyle do not provide glucose control ^[75][104]. A closed-loop AP system shown in Figure 7a,b requires three main things: (i) a glucose sensor or continuous glucose monitor (CGM), (ii) an insulin pump, and (iii) a control device that receives CGM values and uses a control algorithm to convey signal to the insulin pump for appropriate amount of insulin delivery ^[75][104].

Figure 7. Example of the closed loop insulin delivery system using artificial pancreas (AP) ^[75][104]. (a) Abstract overview of AP system components. (b) Detailed overview of the AP system.

Different control algorithms have been proposed in literature for closed loop administration of insulin so far, but two of the most commonly used algorithms are: (i) proportional integral control (PID)- it regulates insulin by noticing variations from the target glucose levels, and (ii) model predictive control (MPC)- it regulates the insulin by minimizing the difference of forecasted and target glucose levels ^[76][105]. The different control challenges which need to be considered for the APs ^[77][106] are: (i) in the closed loop system, insulin is delivered when there is only glucose deviation without consideration of information about the meal size, and timing; (ii) the hypoglycemia condition is risky as it can cause coma, seizures, and mental illness. Also, hyperglycemia is not good as it causes cardiovascular disease and other chronic diseases. Therefore, these conditions must be considered; (iii) different treatments for diabetes patients have different requirements. In some cases, rapid insulin delivery is required, and vice versa. Exercise can also create the hypoglycemia condition, so all of these physical factors are important to consider while designing an AP system; (iv) when creating a rapid insulin delivery control algorithm mostly the maximum BG lowering effect occur after up to 90–120 min. When designing control algorithm this time range should be considered. Furthermore, sometimes there occurs noise in the sensor measurements so different estimation techniques should be employed for compensating these noise values. Also, the self-calibration methods with self/auto correction ability are required for the success of the APs.