In general, inhaled insulins absorb more rapidly than SCI insulin, with faster peak concentration in serum and more rapid metabolism
[68][39]. 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
[69][40]. 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
[70][41]. Furthermore, the inhaler device was large and the handling procedure for insulin administration was cumbersome
[71,72][42][43]. 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
[73][44]. 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
[74][45]. 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
[75,76,77,78,79,80][46][47][48][49][50][51]. Pharmacokinetics deals with the absorption and distribution process of the insulin in a human body. Insulin is absorbed into the blood stream directly
[81][52]. 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
[82][53]. 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
[83][54].
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)
[84][55]. 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
[84][55]. 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
[85,86][56][57]. 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
[85][56].
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
[87][58]. 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)
[88,89][59][60]. 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
[88][59]. The Hypo-Ana research study shows that using an analogue-based regimen decreases the severe hypoglycemia in patients with impaired knowledge of hypoglycemia
[88,89][59][60]. 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
[90,91][61][62]. 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
[92][63]. The list of distinct categories of the insulin available in medicine (adopted from
[93][64]) 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
[94,95][65][66]. 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
[94][65]. In most cases, CSII uses the same basal dosage as MDI, with the basal insulin dosage applied more consistently over the day in CSII
[95][66].
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
[96][67]. 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
[97][68]. 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
[98][69]. A short randomized trial revealed that increased glucose in the target but too short to report HbA1c levels
[99][70]. 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.
[100][71].
Figure 6. Overview of the tools used by T1DM subjects for insulin dosing (adopted from
[100][71]).
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
[101][72]. In order to keep a stable basal glycemia with the continuous insulin infusion, we require a feedback system
[102][73]. 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
[102][73]. 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
[103][74]. The trial showed that there is an increased risk of hypoglycemia by combining the results of SC injections and insulin pumps
[103][74]. 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
[104][75]. 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
[104][75].
Figure 7. Example of the closed loop insulin delivery system using artificial pancreas (AP)
[104][75]. (
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
[105][76]. The different control challenges which need to be considered for the APs
[106][77] 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.