Rising Diabetes Rates and Challenges

1.0 Introduction

The development of diabetes is complex and once a patient is diagnosed, he or she embarks on a tasking and expensive care and management plan. Diabetes mellitus involves many organs of the body including the adipose tissue, kidneys, skeletal muscles, liver and intestinal duct. As such, care packages have to be coordinated. The condition affects about 382 million patients worldwide. The west pacific region tops for the area with highest cases of adults with diabetes mellitus. China falls in this region. Based on the rate at which the condition is being managed, by the year 2035, prevalence is estimated at 592 million in the planet. Diabetes has taken a toll on the finances of friends and relatives of patients. The worldwide cost of management and care of diabetes stands at $548 billion as at 2011. This is a lot of expenditure. Diabetes mellitus being the most prevalent type of diabetes affects about 7 organs and the corresponding systems they regulate in the body. Less sensitivity to insulin in the liver and other associated body parts, and reduced rate of insulin secreted as a result of dysfunction of beta-cells of the liver are the major causes of this condition. They lead to eventual hyperglycemia. Note that detection of insulin resistance is best done about 10- 20 years before those who are predisposed are eventually diagnosed. At this stage of moving from insulin resistance to diabetes mellitus, the patient is operating with less than 20% of the original volume of beta-cells which are at their peak performance. The Artificial Pancreas Device works by trying to copy the functioning of the pancreas. This system monitors glucose levels in the body and release measured quantities of insulin to; ensure hyperglycemia and hypoglycemia are avoided. All this is done with considerably less input from the patient or caregivers. Operation of these systems is a biotechnological improvement on the typical insulin pump. It uses a Continuous Glucose Monitor (CGM) to show real-time glucose level in the blood of patient. It makes use of a sensor which is strategically placed below a patient’s skin to compute glucose levels in interstitial fluid. The result is a reflection of glucose level in the blood. Diabetes patients are always advised to recalibrate blood Glucose Device Regularly (BGD) so that readings are correct reflection of glucose levels in interstitial fluid. APDs are therefore hybrid because they require human input for them to function optimally. Control algorithm is a code which is loaded into the APD to process data from interstitial fluids and output recommended amount of insulin to be introduced into the body. Finally, after determining correct periodic dosage, insulin pump is prompted by the controller to adjust insulin delivered. The science of artificial pancreas, diabetes type 2 patients and all related factors are analyzed in this study and the scope covers impact on biotechnology industry and economic bearing. Also addressed is the fate of other treatment and management plans of diabetes type 2 now that APDs have been developed. Guidelines that have been developed following artificial pancreas innovation underscore influence that APDs have had on governance and regulation. Finally, this study debunks effectiveness and economic viability of this innovation on the patient: and the future of advanced fully autonomous APDs to phase out the current hybrid systems.

2.0 Literature review

What is the impact of the artificial pancreas in managing diabetes mellitus?

Diabetes mellitus (DM) is a set of conditions associated with poor regulation of blood glucose levels secondary to deficient or ineffective levels of circulating insulin (Kharroubi and Darwish, 2015). Type 1 DM (T1DM) is a condition associated with beta-cell dysfunction following an autoimmune response at a young age (typically early childhood), leading to a lack of insulin production (Katsarou et al., 2017). In contrast, type 2 DM (T2DM) is associated with a reduction in insulin output from the pancreas and/or peripheral tissue resistance to insulin (DeFronzo et al., 2015). In both conditions, the lack of insulin activity leads to poorly controlled blood glucose levels, leading to prolonged periods of hyperglycaemia (Zaccardi et al., 2016). It is estimated that over 422 million people are diagnosed with DM across the globe, although under-diagnosis of DM is a significant problem, suggesting many more people are at-risk of affected by the condition (World Health Organization [WHO], 2018). The prevalence of DM has increased dramatically over time, from 4.7% in 1980 to 8.5% in 2014 (WHO, 2018). These trends are seen in all nations, including middle- and low-income countries and reflect an increasing burden of disease in adults and children (NCD Risk Factor Collaboration, 2016). In 2016, it was estimated that DM directly caused 1.6 million deaths, while high blood glucose was associated with a further 2.2 million deaths (WHO, 2018). Therefore, the burden of DM on the global population is significant and set to increase over time. As noted above, the pathogenesis of DM varies according to the specific type of condition affecting the individual. T1DM is typically diagnosed in childhood and presents as a constellation of symptoms reflecting persistent hyperglycaemia, including increased urination, thirst and weight loss (Katsarou et al., 2017). The autoimmune nature of the condition leads to a targeted destruction of pancreatic cells that produce insulin. In contrast, T2DM is associated more typically with a gradual increase in peripheral tissue insulin resistance, often associated with obesity and other cardiovascular risk factors (Morran et al., 2015; Zaccardi et al., 2016). Lifestyle factors are thought to be important in the development of T2DM, including diet and exercise (Kolb and Martin, 2017). These factors contribute to a complex pattern of metabolic risk that reduces the effect of insulin, while increasing the potential for hyperglycaemia and tissue damage. As individuals across the globe adopt a ‘Westernized’ lifestyle, including an increase in sedentary behaviors and a diet high in fat and sugar, the risk of T2DM has increased (Figure 1; Zheng et al., 2018). Although T1DM and T2DM are both importance clinical conditions with associated morbidity and mortality, the remainder of this paper will focus on T2DM as the most common form of the condition and is strongly associated with lifestyle factors relating to disease pathogenesis and outcomes (Zaccardi et al., 2016).

The impact of T2DM on the wellbeing of the individual is profound, including associations with quality of life, morbidity and mortality (Nwaneri et al., 2013). Patients are often diagnosed in adulthood, although childhood T2DM diagnoses are increasingly common (Chen et al., 2012). As there is no effective cure for the condition, this leads to a lifelong burden of disease, often with a deteriorating clinical course. Hyperglycaemia is as associated with a risk of blood vessel, nerve and kidney damage on a micro vascular level (Paneni et al., 2013). Consequently, patents are at risk of vision loss, renal disease and neurological symptoms, particularly affecting the distal limbs (e.g. hands and feet) (Paneni et al., 2013). Diabetic foot ulcers are an important source of morbidity in this group, reflecting the damage to peripheral tissue following interruption to the blood supply and an increased risk of damage secondary to poor sensation in the feet (Litwak et al., 2013). Ulceration and peripheral artery disease may lead to a risk of amputation in these patients (Litwak et al., 2013). In addition to micro vascular disease, micro vascular disease is also associated with the T2DM disease process. This comprises an increased risk of cardiovascular disease, including stroke and myocardial infarction, both of which are significant contributors to mortality (Nwaneri et al., 2013). Based on the risks associated with long-term T2DM, the introduction of effective clinical therapy is essential to reduce the risk of complications and prevent adverse events (Inzucchi et al., 2015). While insulin therapy is indicated for T1DM, to replace that which is not being produced by the pancreas, the treatment options for T2DM are more complicated (Davies et al., 2013). Initially, patients with early stage of T2DM or at high-risk for T2DM (i.e. prediabetes) may be advised to adopt a healthier lifestyle to manage their blood glucose levels (Inzucchi et al., 2015). However, it is often necessary for patients to engage in pharmacotherapy aimed at reducing blood sugar levels, including metformin (Bailey et al., 2013). A range of drugs may be used and each has a unique mechanism of action, promoting uptake of glucose into cells, increasing the secretion of insulin, or regulating the absorption of glucose from dietary sources (Bailey et al., 2013). Although these drugs may be effective in preventing episodes of hyperglycaemia, their use is necessary in the long-term and they do not correct the underlying metabolic problems leading to T2DM. Indeed, as pancreatic function reduces over time or insulin resistance increases substantially, these drugs may fail to maintain optimal glucose homeostasis (Chen et al., 2012).

In some patients with T2DM, the use of insulin therapy may be advisable where pancreatic insulin secretion is sufficiently low to justify exogenous insulin (Schliess et al., 2019). However, insulin therapy is associated with risks, including an increased risk of hypoglycaemic events in patients with DM (Ratner et al., 2013). Indeed, the advent of hypoglycaemic events in patients with T1DM (all of whom receive insulin therapy) often marks the greatest acute threat to life, as hypoglycaemia may be associated with loss of consciousness, seizures and mortality (Davies et al., 2013). Regulating insulin therapy in patients with T2DM carries similar risks, which need to be considered during the planning of therapy. One of the challenges with drug therapy in patients with T2DM is the needed to maintain glucose levels within an optimal range, which can be difficult to achieve without frequent blood glucose testing and drug dose adjustment. Although long-term markers of hyperglycaemia may be used (e.g. glycosylated haemoglobin) to guide treatment adjustment, this does not allow for acute control of blood glucose levels during treatment (Vigersky et al., 2012). In some situations, particularly when receiving insulin therapy in hospital, the need for closer monitoring of blood glucose and flexible dose adjustment is beneficial in these patients (Ratner et al., 2013). The artificial pancreas has emerged as an important treatment option in patients with DM in recent years (Thabit and Hovorka, 2016), following initial concept of the term in the 1970s. The artificial pancreas is essentially a system of closed-loop control of blood glucose levels, based on the use of continuous glucose monitoring technology (Kovatchev et al., 2016). While previous attempts to achieve an artificial pancreas were cumbersome systems, with poor achievement of target blood glucose and technical challenges in using throughout the day (Toschi and Wolpert, 2016), refinement of technology (particularly approaches to continuous glucose monitoring and regulation) have allow for these systems to be used in the long-term. Specifically, continuous glucose monitoring can be fed into an algorithm, based on a Smartphone or tablet, which is then used to control the delivery of insulin through a pump (Figure 2; Toschi and Wolpert, 2016).

As the artificial pancreas represents a method of replacing normal pancreatic function, the research base supporting its use has largely been derived from patients with T1DM. However, there is evidence to suggest that this approach may also benefit individuals with T2DM, including theoretical data and small studies. Thabit et al., (2017) performed a randomized, parallel-group trial in adults with T2DM managed with insulin therapy. A total of 40 participants were included in the trial, which compared the use of the artificial pancreas (closed-loop insulin delivery) versus conventional subcutaneous insulin, as per local guidelines. The proportion of time spent in the target blood glucose range was assessed for both groups over a 72-hour treatment period, noting that 59.8% of patients on artificial pancreas therapy versus 38.1% in the control group achieved this outcome, a finding that was statistically significant (P=0.0004). No significant adverse events were noted in either group and the authors concluded that the artificial pancreas is a safe and effective means of optimizing insulin delivery in these patients. This study is limited by a number of factors including the small sample size and the use of patients from a single centre, limiting generalizability of the findings. Furthermore, these patients had a disproportionately high rate of foot ulceration compared to the general T2DM population, further affecting generalizability of the findings. Finally, the patients in the artificial pancreas group also received basal insulin glargine in an attempt to prevent ketogenesis if the pump was disconnected. While may have been a prudent safety measure, the use of basal insulin may have influenced the interpretation of the efficacy of the artificial pancreas method (Bergenstal et al., 2012). Therefore, the findings of this study do not necessarily support the use of artificial pancreas protocols in patients with T2DM in hospital unless additional basal insulin is provided. There are also emerging studies that suggest the utility of the artificial pancreas for managing patients with T2DM in specific contexts. For instance, Taleb et al., (2019) recently performed a randomized crossover pilot trial of artificial pancreas use in patients with T2DM requiring intensive insulin therapy. It is known that intensive insulin therapy can be difficult to treat and the use of continuous glucose monitoring presents an effective means of regulating blood glucose levels (Kramer et al., 2013). The findings of the study by Taleb et al., (2019) suggested that the use of an artificial pancreas in this context is feasible in a controlled setting and allowed for a better level of glucose control compared to the use of multiple daily insulin injections. However, this was only a pilot study and included a small sample (n=15), while the efficacy of treatment was not compared to alternative approaches, including ultra-long-acting basal insulin or other medications. As the study was in a controlled setting, rather than free-living patients, the effectiveness of the artificial pancreas and the cost-effectiveness of the approach in general blood glucose control is uncertain (Taleb et al., 2019).

It has also recently been proposed that the use of artificial pancreas systems may be beneficial in patients with T2DM who are receiving haemodialysis, a common intervention needed in patients with T2DM and renal failure (Thomas et al., 2016). Bally and colleagues (2019) found that the use of an artificial pancreas was superior to subcutaneous insulin in patients receiving haemodialysis, without increasing the risk of hypoglycaemia. As with the other studies of artificial pancreas use in patients with T2DM, this study was based on a small sample size from a single centre, limiting generalizability. Therefore, there is a need for further research to support the indications for artificial pancreas use in patients with T2DM, as well as direct comparisons of this approach with other treatment options or adjuncts. Pending the results of such studies, the use of artificial pancreas systems in patients with T2DM remains limited to specific clinical contexts (haemodialysis or intensive insulin therapy) of patients whose beta-cell mass is still secreting insulin. In addition to these studies, there is a need to ensure that artificial pancreas use is optimized according to the use of an appropriate algorithm (Pinsker et al., 2016). The algorithm in place dictates the degree of sensitivity to blood glucose fluctuations as well as the insulin pump response, which can dramatically influence glycaemic control (Weisman et al., 2017). There is no clear consensus regarding the optimal algorithm in artificial pancreas systems and the development of new algorithms suggests the need for further refinement and direct comparisons of the risk or benefits of these parameters (Pinsker et al., 2016). Therefore, there remain a number of gaps in the evidence base regarding the application of artificial pancreas systems in patients with T2DM.

Installation and coordination of APD

This section addresses how different parts of an artificial pancreas device are connected and work together. We have 4 basic components of this system.

Continuous glucose monitor (CGM)

Control algorithm

Insulin pump

The patient

The continuous Glucose Monitor (CGM) functions by displaying consistent data to show glucose levels in the blood of a patient. A sensor is designed to be embedded under the skin in the adipose fat tissue where it can measure glucose levels in the interstitial fluid. This directly related to blood sugar levels. The information which is now in form of a signal is transmitted and can be intercepted by a matched receiver (Van Reenen, J., 2002). A blood glucose monitor (BCM) is used to regularly recalibrate the CGM for accurate reading. There is hope that with time, improvement in the APDs will help do away with BCM.

The receiver which intercepts the transmitted signal is usually located in an external processing machine e.g. Smartphone. The phone receives information from CGM and since it contains the algorithm that performs mathematical computations, it releases commands onto the controller instructing it on the dosage to be given at the pump. It is the regulation that the algorithm can never be run on the pump.

The insulin pump makes changes on insulin delivery to tissue under the skin based on commands dispatched from controller.

The patient is an integral part of APD functionality. He or she plays a large part in variation of glucose levels in the blood by changing physical activity and diet. The body could also fail to respond to insulin produced. The patient houses all the components of APD on his or her body and is directly involved in regular recalibration of CGM using BCM (Van Reenen, J., 2002).

Beta cell mass in people with diabetes mellitus

When diagnosing type 2 diabetes, one critical pointer is the early onset of dysfunction of beta-cells of the pancreas. This development highlights progression of this condition. Note that dysfunction of the said beta-cells may be brought about by their insufficiency, their outright dysfunction or a mix of both. Diabetes mellitus patients’ beta-cells are always associated with hypertrophy (Uc, A. and Fishman, D.S., 2017). Due to this, any significant loss of beta-cells should be noted. When considering patients who have impaired fasting glucose, their beta-cells are consequently reduced in number. Reduction in number of beta-cells involving such happenings could be attributed to higher apoptosis as opposed to the common insufficiency in production of beta-cells. This is called neogenesis. The average maximum beta-cells an individual has at one point in his or her life is always determined at an early age. The number is bound to drop with time as the individual is exposed to different conditions (Hovorka et al 2017). The two major causes of reduced productivity of beta-cells have been associated with type 2 diabetes patients (Hovorka et al 2017). Whether or not either one of the two factors leads to the development of the other has not been studied. Therefore, the scope of this research is concerned will dwell on beta-cell mass of diabetes mellitus patients. Condition of a specific aspect of the gene determines both the beta-cell insufficiency and dysfunction. The most significant cause of beta-cell deterioration is called chronic hyperglycemia and very high free fatty acid (FFA) quantities. Relationship has been established between increase in inflammatory cytokines and destruction of insulin-coordination channels in the beta-cells. Also, the cytokines could be linked to destruction of fibroid islets among others (Teoh, S.H., 2004).

When computing the beta-cell mass specifically in diabetes mellitus patients, we factor in the rare of replication, hypertrophy and neogenesis before subtracting the rate of apoptosis. The added factors are three major ways in which beta-cells are packed by pregnancy, obesity and more resistance to insulin. One certain fact however, is that the eventual progression from insulin resistance to diabetes type 2 is as a result of beta cell reduction and reduced mass of beta-cell. Saito et al 2010 found in a study that the beta-cell mass on diabetes patients is always generally lower than that of non-diabetes patients. A study by Wilander and Westermark reported that the eventual volume of the islets of diabetes patients is about 70% that of non-diabetes patients, also in the same year. Islet volume for patients stood at about 1.01 cubic centimeters while that of non-patients stood at 1.6 cubic centimeters. They both had a margin of error of about 10%. A comparison between beta-cell mass of diabetes mellitus patients with obesity versus those patients who were lean was done. It reported about 63% of insufficiency in beta-cell volume for obese humans whereas the figure stood at about 41% for lean diabetes humans. Relative volume was increased in obese patients than in lean patients. Of all study variations conducted, it could be established that there is an approximated 30-60 % relative insufficiency of beta-cell mass. There is a spectrum of findings on beta-cells when considering heterogeneity of each patient subjects (Gittes et al., 2017). However, there is relationship between body mass index (BMI) and beta-cell mass strictly found in type 2 diabetes patients and normal humans (non patients). As far as the two groups are concerned, the need to adjust one’s BMI is entirely dependent on beta-cell mass (Davies et al 2016). Indication of regeneration of beta-cell after a series of injuries in the pancreas is not sufficient and note that apoptosis as an accelerator beta-cell loss has been captured before. The significance of insufficiency in beta-cell mass happens in the onset of T2DM (D'Alessio et al 2008). As such, it is a pointer that it plays a more primary role instead of assuming that it comes about secondary to hyperglycemia. Based on these observations, it is safe to assume that peak beta-cell mass occurs at an early in life because of genetic and healthy nutrition conditions and may drop later due to any number of reasons such as compromised environmental conditions. Assessment of beta-cell mass was done by taking measurements of beta-cell area in the islets. Note that size of each beta-cell was not considered. It makes sense to assume that a larger size of beta-cell means that beta-cell number their-in is reduced for the same volume under consideration. We can conclude that reduction in volume of beta-cell leads to reduction in number of individual beta-cell. Reduction in number of beta-cell in the pancreas necessitates for compensation to cover for the need of the body. This causes a strain on each beta-cell as they function to offset the insufficiency. The result is loss in beta-cell mass in T2DM patients (Benesch et al., 2018).

Symptoms of T2DM and testing

Looking out for signs and symptoms helps people find a way of avoiding the condition by seeking early treatment. While polyuria, polydypsia and polyphagia are commonly associated with T1DM, hyperglycaemia is associated with both types of diabetes. Just like T1DM, T2DM could progress steadily and lead to great loss of body weight only when it is not detected for long. Main problem with diabetes diagnosis is mildness of the early onset stage of the disease which could make it hard to pick on. Other pointers to look out for are fatigue, restlessness and sudden unexplained loss of body weight (Shichiri et al., 2009).

Based on the risk factors explained above, people who think they are predisposed to the condition should undergo screening. The relevant authority prefers using oral glucose tolerance test (OGTT). Testing can reveal presence of T2DM when fasting> 126 and 2h glucose >200 mg/dl. Recent developments where glycosylated haemoglobin has been suggested during the testing for diabetes show that HbA1c reading above 6.5% confirms presence of diabetes. Pre-diabetes as a result is present when the reading is between 5.7-6.4 % (Nijhoff, M.F. and de Koning, E.J., 2018).

Pregnant women who have reported to a hospital for the first time are advised to take diabetes screening to help the prenatal care. Screening for gestational diabetes should be done around 24-28 week of the pregnancy using the standard diagnosis. Gestational diabetes is complex to the point that it could be asymptomatic at that period in the pregnancy and women who have no prior history of diabetes are advised to take the screening seriously.

Awareness of symptoms of diabetes and regular testing could help curb the menace of diabetes. Pre-diabetes stage is very important because it gives patients and their health assistants get ample time to tackle it through adjusting ones health choices (diet and physical activities). Awareness on the need for regular screening is possible through empowerment. (Shichiri et al., 2009).

Management of T2DM

We could consider what constitutes proper clinic visit by a diabetes or pre-diabetes patient. They should carry their medical history which will capture; symptoms of hypoglycaemia or hyperglycaemia, assessment of lifestyle and psychosocial aspects, assessment of all medications they are currently taking, conclusive assessment of meal plans, any mild or chronic complications and prior result of HbA1c screenings (Damiano et al., 2014).

A patient’s physical examination must include weight and height, oral examination, examination of any form of retinopathy, cardiovascular inspection, abdominal examination, the complete neurological examination and foot assessment (Damiano et al., 2014).

Diagnostic studies involve; quarterly HbA1c, fasting and 2h postprandial glucose, thyroid stimulating hormone, analysis of the urine and micro albumin screening of the urine.

Following consultation among the team of specialists from different disciplines on how to go about treatment of diabetes at the stage of diagnosis, they could include; noting and treating risk factors of diabetes, controlling the blood sugar using appropriate tools and regiments and addressing complications associated with care of T2DM. A follow up during care and or diagnosis phases is important especially when making referrals to; dietician, neurologist, cardiologist, diabetes educator (who helps with assessing the capability of patient to take care of himself or herself during treatment) and ophthalmologist for regular retinal checkups (Hernando et al., 2018).

Diabetes care is encrusted on healthy living by adopting good diet and habitual exercise. Treatment package for T2DM include education, adherence to strict nutrition guidelines, regular exercise, insulin therapy, general management of complications linked with T2DM (Zinman et al., 2013).

When using nutritional care for a patient, guiding goals include ensuring that the level of glucose in the blood is within the recommended range. Also, it seeks to ensure that the level of lipid in the body does not compromise macro vascular integrity of the body and maintain normal blood pressure. We achieve most of these goals by tailor-making a T2DM patient’s diet to best fit him or her. Proper diet prevents the need to treat complications by making sure they are not developed in the first place. Therapeutic methods of addressing T2DM involve use of insulin secretagogues, alpha-glucosidase inhibitors and insulin therapy. The problem of insulin resistance may be solved by using oral agents and improve beta-cell glucose sensing and eventual insulin secretion at the same time. In the cases where monotherapy have proved futile, combination of oral agents such as thiazolidinediones plus metformin have come handy. Another combination is metformin plus sulfonylureas (O’Donnell, M. 2018).

T1DM patients are advised against taking part in Ramadan fasting. T2DM patients must always seek permission from their physician for the appropriate course of action. Poorly managed T2DM patients should not fast because they are at a risk of dehydration as a result of hyperglycaemia. Treatment plans will always be adjusted for patients who are taking oral medication. Fast-breaking meals must be thoroughly monitored lest one develops postprandial hyperglycaemia (Skyler et al., 2014).

Biotechnology and tissue engineering in T2DM

As stated before, diabetes is caused mainly by insufficiency and or resistance to insulin which is normally produced by the islet cells. Here, we study biotechnology and tissue engineering as tools used to help with tissue transplant and general treatment mechanisms before innovation of APDs. We focus on how their success or failure has helped shape the future of APDs. T1DM is characterized by destruction of most of the beta-cells by autoimmune response. T2DM involves secretion of insulin which is probably not being utilized properly. It can thus be regulated by changes in health choices or even use of drugs. Interestingly, T2DM may be uncontrollable by not responding to insulin or other treatment regimens. This forms the backbone for the study of biotechnology and tissue engineering relationship with T2DM (Li, J. and Halal, W.E., 2002).

When attempting to treat T1DM and some adverse postprandial hyperglycaemia as in T2DM, surgeries to replace islet cells have been done. Cases involving whole transplant of pancreas or parts of islet cells have been reported. In 2000, seven diabetes patients were fully dependent on regular dosage if insulin were operated on to transplant islets from cadavers. Despite being a success, the procedure which was done in Canada reports that the patients became insulin independent for 1 year after the procedure but later developed complications due to immune-suppressant drugs they were using to prevent tissue rejection. The high dosages used exposed them to risk of getting cancer and contracting infection due to compromised immunity (Huang et al., 2012).

The need to circumvent donation from humans led to using tissues from pigs (xenotransplantation). One instance of biotechnology and tissue engineering is seen when the desire to mask tissues donated by the pigs from attack by human body immunity is achieved by encapsulation technology. This is done by covering islet cells by alginate capsules. Implementation of this idea has proved difficult for researchers involved. Islet cells used have poor survival chances after transplant. Also, the capsules which are made of alginate cannot stand the test of time. When ability of capsules to protect islet cells has been compromised, the immune system of the body can thereafter attack it. Destruction of capsules produces resultant material which prompts the immune system to respond. This threat could cause a devastating reaction. Variables of tubular and planar protective devices are designed to house islet cells before being transplanted into the body. They are convenient in the sense that they can always be retrieved and replaced. They are advantageous in that they are compatible (tubular chambers) with the immune system of the body. However, they could rupture and leak contents (islet cells) exposing them to immune system of body. Planar chambers on the other hand could cause immune-reaction hence cause failure (Hovorka et al., 2014).

Use of microcapsules is simple. It is easily manufactured and can be easily introduced into a patient’s body with a minor surgery. In 1994, micro capsulated islet cells were first used on a diabetic patient while on immune-suppressants. This treatment plan guaranteed insulin independence for about 9 months. Extensive biotechnological research on this treatment has not guaranteed long-term insulin independence in T2DM patients whose immunity is not suppressed.

As a guideline, objective of bio-artificial pancreas development is to develop treatment for T1DM and T2DM patients who are insulin dependent. The theory is to encapsulate patients’ cells that are genetically modified to produce, store and secrete insulin depending on blood glucose levels. As an alternative to using human liver, the idea is to encapsulate stem cells and beta-cell harvested from humans. Encapsulation for this undertaking is done with the help of appropriate editing technology (Cell-in-a-Box) (Del Favero et al., 2015).

Using this tool, cells that produce insulin are encapsulated with the help of sodium cellulose sulfate technology which can be found in prescribed technology. The first step shows that encapsulation does not interfere with insulin secretion or the beta-cells. Note that encapsulated cells were capable of noticing changes in glucose concentration of a given solution and appropriately address it. This encapsulating tool used is more compatible with immunity of patient (Kowalski, A. 2015).

University of Technology in Australia has licensed PharmaCyte to use genetically edited human liver beta-cells named Melligen; for treatment of T1DM and T2DM (case of insulin-dependence). This innovation can be said to ‘heal’ diabetes because in a trial on a mice, it normalized glucose level. Their discovery is welcome as they can be produced limitlessly in tissue culture. They are not affected with pro-inflammatory cytokines as much as islet cells. Further development can ensure that they replace islet beta-cells with a promise of being used as suitable permanent graft (Ganguly et al, 2018).

Because PharmeCyte has also acquired the exclusive license for use of Cell-in-a-box tool in researching treatment of T2DM, encapsulation of Melligen therein is advantageous. When compared to alginate, the licensed tool is more durable. Cellulose which is used for encapsulation is bio-inert. They are not responsible for any known occurrence of immune response unlike alginate encapsulation. The encapsulation of choice has also not hindered Melligen from insulin secretion in any way. This outline shows correct structuring of cell-in-a-box encapsulation and melligen innovations will form a recipe for T1DM and associated T2DM permanent one-time treatment. This section addresses the ideal form of artificial pancreas device (APD) which is fully self-sufficient. It will be called a bio-artificial pancreas.

Why this device is not yet implemented despite having all the technology at our disposal? Some critical issues need to be addressed before we achieve such a milestone. We have the problem of foreign-body response which is guaranteed once an alien body is introduced into the body. Such an attack kills islet cells. Also, such bio-artificial devices do not allow ample supply of oxygen to beta-cells based on the penetration of the material used. The implementation phase of the production sees a lot of beta-cells get destroyed resulting in few cells than had been planned. Such an undertaking is therefore not feasible. There is little understanding on the perfect way of positioning bio-artificial pancreas such that all constitutive beta-cells get nutrients and oxygen for them to stay alive and function properly (Kundu, S. ed., 2014).

Insulin therapy

Persons suffering from type II diabetes either suffer because of insufficient production of insulin from the pancreas/ or from the failure of the body cells to take up the insulin produced. This ends up destroying the cells of the pancreas and therefore leads to the stoppage of the preparation of insulin. In the early stages of type ii diabetes it can be fully managed by increasing physical activity and making changes in the lifestyle of an individual. As the stages advance it may be necessary to carry out insulin therapy for the patient to be able to function optimally and achieve daily fasting glucose levels. Insulin therapy also reduces the risk of diabetic individual suffering from type ii diabetes developing both micro vascular and macro vascular complications related to their condition. Several insulin analogues have been developed. These insulin analogues are modifications of the human insulin where the amino acid sequences have been modified (Janson et al., 2016). These have been developed to overcome the challenges which were faced with the administration of the human insulin.

The human insulin has a slow absorption across the subcutaneous tissue. It is also characterized by a long period of time before the onset of its metabolic activity. These limitations of the human insulin are the causes of post meal hyperglycemia and nocturnal hypoglycemia. There are three rapid acting insulin analogues and these are aspart, glulisine, lispro. These analogues only take 15 minutes to start their action following their subcutaneous injection and are characterized by a faster and greater action peak. Long acting insulin analogues are also available, examples are detemir and glargine. Since type two diabetes is a progressive disease insulin therapy is often initiated later during the patient’s life and more so after the failure of oral glucose lowering agents and lifestyle changes. However an early onset of insulin therapy has marked benefits. It can maintain and restore the functionality of β cells of the pancreas thus leading to the achievement of prolonged glucose remission (Farrington, 2018). Patients suffering from T2DM are sometimes also reluctant to start insulin therapy because of fears like suffering hypoglycemia, painful injections, gain of weight and psychological fears such as the permanence of insulin treatment, the restrictiveness that results from its use, low self-efficacy and increased illness severity.

In type 1diabetes the use of an artificial pancreas is linked to better control of blood sugar levels in comparison with other standard treatments in which insulin therapy is used. Artificial pancreas has shown ability to provide about two additional hours of normoglycemia in a day. This has reduced the amount of time patients spent in hyperglycemia and hypoglycemia. The use of artificial pancreas for the management of diabetes is also safe and effective based on evidence from several studies. A study conducted by Bekiari and colleagues involving a review of 41 trials which involved 41 trials in which 1000 diabetic patients were participants found out the use of artificial pancreas was more effective for the management of type diabetes as compared to other techniques which involve insulin therapy (Bekiari et al., 2018). Many other studies which have tested the strength of association of different devices in different settings were also found to be consistent.

“Closed-loop system”

The closed loop system is advantageous over sensor augmented pumps in that they are able to perform a gradual modulation of the infusion of basal insulin in response to variations in glycaemic levels (Donner, 2015). It thus increases the time spent in the target levels of glucose range and automatically acts to reduce the level of glucose without exposing the patient to risks of hypoglycemia. El Khatib et al reported the efficacy and safety of using a dual hormone pancreas following a study which involved six adults using the device for 48 hrs. These together with many other studies (citations) have shown the use of artificial pancreas to be safe and effective even for the pediatric age group (Esposito et al. 2018). Patients using the artificial pancreas have reported lower levels of glycosylated haemoglobin (HbAIc) levels as compared to controls (Soloway, 2018).

On the 5th of April 2014, an article published in the New York Times stated that “Even Small Medical Advances Can Mean Big Jumps in Bills”. This article claimed that technologies aimed at managing diabetes are overpriced but only hold a limited potential in terms of the value they add on the care of this patients (Davies, 2013). This is an echo of the all-important question on whether there is a real need for the introduction of such a technology at an extra cost while there are other available methods of delivery of insulin. The question therefore is does an artificial pancreas offer more advantages over other types of insulin therapy which can offset the additional cost of making the system. One of the main reasons of developing an artificial pancreas was to improve metabolic control without exposing the patient to hypoglycemia. The connection of the continuous glucose monitoring device to Smartphone has enabled the patients and their caregivers to get alerted in case of hyperglycemia or hypoglycemia. Fully automated closed loop systems are able to automatically adjust the levels of insulin delivery and establish insulin doses for meals without the intervention of the patient.

The closed loop system has a limitation in that it has a lag time which could be an average of about 20 minutes. This lag time results from the fact that the continuous glucose monitor systems of the closed loop system measures the concentration of glucose in the interstitial fluid rather than blood glucose (Ann, 2009). The accuracy of continuous glucose monitor measurements are also influenced by factors such as movement, pressure and skin temperature (Nijhoff, Koning, 2018). Even though the continuous glucose monitor is able to provide readings of glycaemic levels every five minutes, regardless of whether it is daytime or at night and subsequently administer the correct amount of basal insulin together with long acting insulin, the patient still need to check his or her blood sugar levels using a glucose meter a few times a day. This is to determine if there is any need to adjust the amount of insulin through correction doses.

Persons with type 2 diabetes require physical activity as integral part of their treatment plan. Persons who stay fit throughout their life are able to achieve a better control of glucose levels and this is beneficial as it prevents long term complications (Amy, 2017). The reduction of blood glucose levels is achieved through the utilization of the glucose by the muscles. This helps even one has insulin resistance or does not have enough insulin. For insulin resistant case exercise reduces insulin resistance helping the cells to achieve a better utilization of insulin. In type two diabetes exercises can prevent the onset of secondary complications such as cardiovascular diseases.

People with diabetes need to take precaution when choosing the type of exercise activity to undertake. This is because improper choice of exercise can result into adverse problems such as hypoglycemia. For persons taking medications which lower their sugar levels they should eat small quantities of carbohydrates relative exercise and drink plenty of drinking water before during and after the exercise. Drinking a lot of water ensures they remain hydrated. For diabetic patients on insulin therapy, they need to take a carbohydrate snack before beginning exercise if their sugar levels are below 100mg/dl and if above this level they should just go ahead and exercise. After the exercise they must check their blood sugar levels and if it dips below 70mg/dl they should snack a carbohydrate. If one is engaged in exercise activities that may take a long period of time they are advised to plan for a carbohydrate snack (Atlas, 2015). The person must carry a fast acting carbohydrate for example glucose tablets just in case they experience huge drops of blood sugar levels causing hypoglycemia when in the exercise session. If the person is exercising alone they should carry an item which identifies them to be diabetic so that other people can help in case of the happening of unexpected events. This helps solve problems of persons with diabetes fearing to exercise as a result of fear of experiencing hypoglycemia.

Insulin replacement regimen

The fact that a patient must always refill his or her APD necessitates mentioning this subject. Knowledge on insulin replacement regimens equips the nurse practitioners and other diabetes caregivers the necessary tools of selecting the appropriate method of insulin regimen modalities, be capable of defining the main components of therapy of insulin replacement, be able to guide patients on the initiation and titration procedures for the series of daily injections and the associated insulin pump therapy and be able to discuss the insulin replacement therapy and correctly select the appropriate candidates for this healthcare management program. This therapy is an essential aspect of treatment for type 2 diabetes patients with aggravated failure of the beta-cell (Cobelli et al, 2016). The proposed therapy is the kind that copies the process that the human body delivers the insulin. The insulin therapy addressed here is also known as the basal-bolus therapy or intensive insulin therapy. It is a comprehensive care package that functions according to the comprehension of the immediate data and understanding of the processes that revolve around glucose homeostasis to help patients with their insulin dosing. The effectiveness of this therapy is its ability to be in sync with the activities of the diabetes type 2 patients (Bally et al., 2018). Diabetes patients have two ways in which their care packages secrete insulin; the prandial and background patterns.

Prandial pattern of insulin secretion involves fast production which is proportional to glucose distribution and this is mainly caused by sudden ingestion of glucose into the body. The effects involve quick ingestion of the glucose by body tissues. The background pattern on the other hand involves insignificantly small amount of secretions at constant time intervals. This limits production of glucose from the body tissues. The pattern named above is related to variations in glycaemia. This replacement therapy of insulin is suitable for some cases of type 2 diabetes patients and all the type 1 diabetes patients. This method is recommended when the preliminary interventions such as lifestyle modification have failed to improve the patient’s quality of health. The guidelines include effective planning of meals, regular glucose monitoring, and guidance on self-care and enhanced support of the patients (Bakiari et al., 2018).

The overall remedies stem from guided meditation to traditional herbs to natural remedies. The relevant authority (The National Centre for Complementary and Alternative medicine) defines alternative medicine as a series of broad heath care packages and processes that are not currently regarded as conventional medicine. It should be noted that alternative medicine as described above cannot work alongside the conventional medicine hence it is a substitute according to the preference of the diabetes type 2 patients (Bouwens et al., 2005). Complementary medicine on the other hand is used alongside the conventional medicine practices for better results.

Alternative and complementary medicine and other treatment.

The alternative and complementary medicine has a varying opinion on safety varying from patient to patient and consulting with the doctor before committing to a given practice is recommended. One such method is the acupuncture which involves the practitioner pinning thin needles to certain positions of the skin. The argument is that this practice causes the body to release its natural painkillers into the system. This helps suppress pain commonly among the diabetes type 2 patients who have developed neuropathy. This defect leads to pain in the nerves. The other method is Biofeedback that works by making patient more cognizant of his or her body pain, how their body interprets it and thereby learn to embrace it. The underlying factor is relaxation and proper stress management. Natural dietary supplements involve use of chromium to develop glucose tolerance factor which enhances the functioning of insulin. Still, another natural product is the ginseng whose benefits are noticed in fasting (Haudich et al., 2018). It regulates the spiking after meal blood sugar levels. Use of plant foods such as cinnamon, clover, okra, broccoli and other greens, fenugreek seeds and sage; which are rich in minerals, vitamins and fiber helps those with T2DM diabetes by aiding the body to get rid of inflammation, trigger release of insulin and to initiate the working of insulin among others.

Pancreas of a living donor is a probable treatment. Of course, there is the risk of surgery on both the donor and the recipient in the early stages of the treatment. There is little or no report of long-term surgical risks. In the time spanning from 1996 to 2005, following the 8918 transplants involving the pancreas as is the scope of this study, more than 99% of donations were from dead donors. The living pancreas transplant are more favorable statistically with advantages ranging from limited case of immune-suppression, reduced probability if rejection by the recipient, reduced post-transplant malignancy and reduced risk of infection. It is noted that of the perioperative deaths reported, none was as a result of living pancreas donor transplanted. In the living pancreas donor cases, substantial perioperative complications such as fistula and or abscess have occurred in less than 5%. It is reported that splenectomy due to bleeding and reoperation and abscess occur in about 5% to 15%. When reviewing probable donors for selection, the candidates undergo a tasking evaluation so that those with glucose tolerance abnormalities are sidelined. Living pancreas donors are not common in the United States of America same as other parts of the world. Published documents show that the most recent case of living pancreas donation is as recent as 2015 I South Korea. The comprehension of outcomes that follow the process of donation helps the prospective living pancreas donor make relevant informed decisions. The data from the registry of the United States was integrated to try to capture the understanding of the donor candidate on the long-term impact of their decision to donate (Collin et al., 2000). Such decisions ensure show why the human pancreas cannot be depended on as much as artificial pancreas for treatment.

Diabetes mellitus diagnosis is on the rise and this happening has put an unnecessary strain on the healthcare systems worldwide. The guidelines for diabetes type 2 management is well documented and is premised on a prescribed glycaemic control without causing further harm to the patient. Continuous advancement of the diabetic technology through continuous subcutaneous insulin infusion (CSII) and other related mathematical models and computer simulations of the bodily functions has been helpful. They have led to development of real-time continuous glucose monitoring (CGM) systems (Atlas, 2015). All the above stated achievements have been anchored on engineering inputs and development in bio-electronic components. The American Diabetes Association (ADA) reported in its findings back in march 2013 that as at 2012 the total sum of monies spent on management of diabetes stood at $245 billion. This was an additional sum of $71 billion from the amount spent in the year 2007 (Davies et al., 2013). The costs are only rising. The finding shows that this disease is a major hazard which can be solved by a concerted effort on the fronts of research in bioengineering and behavioral change, and proper interactive drug delivery. Diabetes is a common ailment directly affecting millions of patients worldwide and their families in other aspects hence it is a viable investment which needs a lot of effort to ensure maximum help and support reaches those in need. The multinationals invest fortune in scientific research to come up with ways and methods of curbing the scourge of type 2 diabetes (Collin et al., 2000). This alone should be a pointer on how much people need the most effective care. In September 2016, Medtronics Minimed 670G was introduced into the market with the approval of the US FDA. No other improved version of this or other tool has seen the light of day thereafter. There are several promising systems under review in the field of artificial pancreas development (Ho, 2009). Aside from the hardware aspect being developed, there is the associated open-source algorithm which can be accessed by interested parties in the development of better systems. Some are in the advanced stage of testing and could hit the market soon. Close mentions of companies that are few steps shy of securing approval for launching their products include Tandem Inc.

Their system is based on its own insulin pump but borrowing on the operating code written at the University of Virginia. This startup could break through the measures put aside for approval and following the good test results in the trial that employed continuous glucose monitoring device (Dexcom G6). Such system updates and hardware improvements are the desired steps in the fight against type 2 diabetes. When studying the competition such systems pose on the current methods. Improved will include a system of about 4 holistic solutions to address comprehensive closed-loop control product (Chouvarda et al 2017). There will be several mixes of structures unlike the current solutions which are not fully dependent and must be augmented to help patients successfully. The development of diabetes proceeded well and the parent review document shows that from the 1970s when the advancement took shape, additional tools of mathematical models and computer aided simulations running the human body have shown that the employed criteria for diabetes type 2 management is viable and that poses no danger to the patients. It is intended for them. The artificial pancreases that have been developed have not been tinkered into reality. They have been designed based on biomedical engineering that are found on engineering principles and best engineering practice. Analyzing the concept of diabetes in the ecosystem construct, initialization of the construct starts with the identification of the diabetes and then based on the financial capability and nature of the disease, determination of the choice of treatment is the next step. Now, the routines revolving around how the patient takes care of himself or herself will be addressed as dynamic process that present disturbances on the metabolism of the ecosystem. These perturbations directly affect the treatment of the disease. The aspect of treatment mostly affected by these concerns is the technology. These unfolding shows that despite being the most efficient way of diabetes management, it could also be affected. Thus, the way out as far as treatment is concerned is a more holistic method which must involve varying approaches that check and complement each other (Kumar et al., 2018).

History of artificial pancreas (APD) development

Artificial pancreas is a system that combines a control algorithm, a device of insulin infusion and a glucose sensor (Amy, 2017). Development of AP can be traced fifty years back when the possibility of regulating blood glucose was set up by studies in persons living with type 1 diabetes, through the use of insulin and glucose infusion and measurement of intravenous glucose. Shortly after the pioneering work achieved by Kidish, the expectations for effective closure of the loop were initiated by teams who worked simultaneously to report results of the artificial pancreas between the years 1974 and 1978 (Crasto et al., 2009). In 1978, the Biostator, first commercial device, emerged from one of these realizations. This was then followed by another system of in-patient known as the Nikkiso STG-22 currently being used in Japan (Donner, 2015). According to Wood (2000), glucose sensing intravenous route and infusion of insulin is not recommended for outpatient use. However, these devices facilitated further advancement in technology and equally proved external glucose control feasibility. In 1979, Tambort et al and Pickup et al denoted that subcutaneous route is viable for the delivery of insulin continuously. Shichiri et al. later tested wearable AP prototype, which then developed into subsequent research on the same. In 1980, the implantable system came into phase through the use of intravenous glucose sensing and infusion of intraperitoneal insulin. There was further development of this technology resulting in long term use and clinical trials. However, it should be noted that its clinical usage became limited due to surgical procedures that were required for implantation of pump and sensor (Nishida et al., 2009).

In all early intraperitoneal and intravenous systems of AP, the artificial pancreas algorithms belonged to a class referred to as controllers of proportional-derivatives, that applied values of blood glucose and rate of change of blood glucose in calculating insulin dose in a relatively straightforward manner. According to Teoh (2004), proportional-derivative control and proportional-integral-derivative control, the enhanced version, contains the inherent demerits that bar their application in subcutaneous systems. This is due to the inevitable time lags present in insulin action and sense of the subcutaneous glucose. The newer controller commonly referred to as model-predictive control (MPC), does not experience these disadvantages due to the fact that it uses a metabolic system mathematical model of the individual under controlled in their calculation. Notably, many of these algorithms of MPC are generally based on 1979 milestone, the Glucose Kinetics minimal model (Setty et al., 2016). Therefore, since the earlier years of advancement of AP, technologies of insulin delivery and glucose sensing were accompanied by simulation and computer modeling. In 1999, the new subcutaneous AP was commercially introduced by the Minimed continuous glucose monitoring system. The project of Minimed closed-loop was the first to produce evidence for the viability of the route of subcutaneous-subcutaneous for the blood glucose control that was fully automated in patients with type 1 diabetes (Hillard et al., 2004). ADICOL project which was funded by the European Commission demonstrated the viability of applying improved MPC strategies to shut the loop. The Juvenile Diabetes Research Foundation International (JDRF) established AP project in September 2006 and financed consortium of centers in order to carry out a research on closed-loop control. Notably, inspiring outcomes have been reported by several centers. The JDRF established a currently operating multicenter, multinational trial in adolescents and adults with type 1 diabetes (Russell et al., 2014).

Artificial Pancreas Device System Market struggle

Food and Drug Administration (FDA) has collaborated with government and private research institutions ad-lib clinical research to speed up the advancement of the artificial pancreas device systems. Food and Drug Administration released a document that listed clinical studies requirements and approval for a premarket application meant for the production of the APDS (Nijhoff et al., 2018). Notably, this is expected to steer up the manufacturing and global growth of APDS. The FDA has noted down specific issues of concern in the insulin infusion pumps software and components. According to Nissen et al (2016), the current insulin used in the Artificial Pancreas Device System absorbs for a very long period of time. Such factors have significantly reduced the global growth of Artificial Pancreas Devices.

Artificial Pancreas Devices Competitiveness with key market players

The key players are innovations that are highly focused on production technologies to enhance shelf life and efficiency. Some of these key players are:

Pancreum- The CoreMD

Pancreum provides a powerful infrastructure and wireless communication for an exchangeable wearable medical device. The CoreMd is able to perform various functions such as sensing body condition and alerting the user that a given threshold has been reached. It also assists in the injection of drugs delivered subcutaneously (glucagon, insulin, vasopressors and amylin) (Atlas, 2015). Pancreum has remained a competitive market player due to these exemplary key functions. Currently, Pancreum is mainly applied in an insulin pump module, glucagon pump module, pancreas Genesis artificial pancreas system a continuous glucose monitoring module ( Crasto et al., 2009). The CoreMD contains a highly performing CPU, 32-bit. This outstanding feature makes it smarter as compared to other wearable devices used in the management of diabetes in the market. Notably, Pancreum is not disposable and has a coin-bell battery. Its battery is rechargeable and therefore no electronic boards are thrown away after some time. This implies, for instance, that its fixed exchangeable insulin pump exclusively contains the mechanism and the reservoir to insert the cannula and give out the insulin (Davies et al., 2013).

The Bigfoot Biomedical, Inc.

Bigfoot Biomedical was first founded by a group of individuals with personal networks to type 1 diabetes. Through its injected and loop systems, the company seeks to cut down the depression of people living with insulin-requiring diabetes. It also seeks to enhance the health care providers leverage through connectivity, automation, data and artificial intelligence. Bigfoot came out of the shadows in 2015, looking for ways to improve their artificial pancreas system through the aid of Bryan Mazlish. In 2014, a wired article covering information on home diabetes device referred to Mazlish as Bigfoot in order to conceal his identity. The name later stuck. Since then, the Bigfoot moved forward winning support from various foundations such as the Juvenile Diabetes Research Foundation. In mid-2015, the Bigfoot purchased the assets from the maker of shuttered insulin pump and relocated into Silicon Valley headquarters citing planned integration of Asante's insulin pump into its own system. After one year, the Bigfoot established a clinical trial of the smart loop platform.

Medtronic Insulin pump

Medtronic was initially founded in 1949 as a form of the medical device repair shop. The first insulin pump, the Minimed 502, was released into the market in 1983. After several years, updates to infusion sets and sites of insertion that enabled for temporary separation from the system of the pump (Heinemann et al., 2016). In 2003, BolusWizard was introduced which shared the value of glucose in a wireless manner from the glucometer integrated system and recommended the correct dosage of the insulin. Later in 2006, the MiniMed real-time system was released in the market. MiniMed helped in integrating the CGM data in order to help in proper viewing when displayed. MiniMed 530G was then approved by the FDA in 2013, with the enlite for persons above 16 years of age. In 2016, Medtronic 670G system was launched into the market and this was promptly followed by Medtronic 670G (Honka et al., 20114).

Medtronic plc stands to be the world's biggest medical device company that makes a lot of its profits and sales from the healthcare system. Medtronic headquarter is located in the Republic of Ireland. Medtronic has an executive and operational headquarters in Minesota and Fridley in the U.S. Medtronic operates in several nations across the globe with about 87000 employees. In 2018, Medtronic was rated as the largest medical device company (Kumar et al., 2014). According to Polak (2008), Medtronic remain to be a great player in the global healthcare market, it holds competitive and powerful ranks in quite a big number of diseases such as spinal surgery, cardiac care among others.

However, the long term growth driver for Medtronic remains to be its diabetes franchise. This is due to the fact that the diabetes market is large. Currently, Medtronic poses a stiff competition against artificial pancreas devices; it takes a leading position in selling medical devices that assist patients in controlling the level of their blood sugar. In 2015, Medtronic recorded net sales of more than €1.6 billion from the diabetes branch (O’Donnell et al., 2008). This was 9% per cent up the previous year which indicated a faster growth in diabetes division. The company has dominated the market for a very long time, its biggest advantage against other competitors has stemmed due to the fact that its continuous glucose controlling system and insulin pump communicate with each other (Ratner et al., 2013). This is an exclusive feature that is liked by majority of its users. The CGM enables patients to continuously measure the levels of their blood sugar throughout the day, which is bound to change due to various reasons (Setty et al., 2016). The continuous glucose monitoring device enables the patients to observe emerging trends in their blood sugar levels thus they can take action to curb lows and highs (Taylor et al., 2000). Importantly, they are highly performing compared to traditional glucose meters that solely give a single point in time number. However, the highly advanced technology that has placed Medtronic devices at the forefront is ultimately eroding. Other competitors can now catch up and even supersede the company's potential. Currently, Medtronic has come up with a new system referred to as the 640G. The system is enjoying large sales overseas and it is set to revamp the companies look in the 21st century. It has outstanding features that its clients will find appealing. One of the exclusive features of this new device is that it is able to suspend insulin delivery as the individual’s glucose gets low. The pumping will only resume once the level of glucose starts to recover (Zinman et al., 2015). The device is currently trading overseas however it has not been submitted for approval by the FDA, because the clinical trial of phase 3 of the device is still ongoing.

Johnson & Johnson' Animas

The Animas Corporation specializes in designing and making of insulin pumps used by patients with diabetes. This company is one of the key players in the struggle to dominate the world market for people with diabetes. The company has design various pumps such as animas vibe and the animas 2020. Johnson & Johnson's animas was ahead of the curve in 2013 when it was first tested, however, the company is yet to update the status of its system since then. It was reported that the company was developing a pump which contains hypoglycemia-hyperglycemia minimizer algorithm built inside it. This made the device ahead over a key competitor Medtronic during its early stages of development (Ratner et al., 2013). Notably, two feasibility studies were produced on the device. Unfortunately, the company became reluctant to work on the project. Earlier in 2018, it was reported that Johnson & Johson was giving a chance to strategic options for its diabetes business. Such strategic options may entail operating partnership formation, strategic alliance or joint ventures, while reporting the full-year earning and the 4th-quarter, the healthcare conglomerate reiterated that all possible options will be assessed in order to determine the best option that can facilitate future growth and maximization of shareholders value. It assured for future hopes and that the process would result in strategic alternatives of whichever kind.

Other competitive players

According to Zinman et al (2015), insulin pump global market is greatly rising and will gain more prominence in the coming years. The insulin pump market is approximated to raise up €8000 million by the end of 2024. The insulin pump market is gaining market dominance with a rapid rate due to the rise in diabetic population prevalence. According to American Diabetes Association, about 1.5 million people worldwide use an insulin pump for the management of diabetes. Artificial pancreas system continues to face stiff competition against other market players. Some of these players have been discussed in this chapter.

Cellnovo insulin pumps

Cellnovo insulin pump was the first insulin pump to be introduced in the UK market with touch-screen controls (American Diabetes Association, 2016). Cellnovo insulin pump is light and small in size, it can be worn either as a tethered pump or as a parch pump. When this pump is worn as a patch pump, its tubing can be removed. In this case, both the pump and the cannula strongly stick on the skin (Chen et al., 2017). This device enjoys a large market proportion due to its outstanding feature, touch-screen technology. The touch-screen feature gives the handset a catchy appearance to the eyes of its users. This handset has a number of uses such as monitoring of insulin delivery, logging of essential data, calculation of boluses and taking levels of blood glucose as a monitor of blood glucose. The touch screen enables patients to add food to the database as well as typing notes into the pump. Key advantages of this system are that it enables for logging, viewing and analyzing a wider range of data. Such data include results of blood glucose, physical activity, insulin delivery and intake of carbohydrates. The main innovation in the cellnovo pump which has enabled disposable insulin reservoir, low cost and component miniaturization is the micro fluidics that has been built around a micro-actuator (Crasto et al., 2009). The micro-pump has shown an accurate drop-by-drop insulin controlled delivery. In taking a leading position in terms of the state-of-art trial of IDCL, Barate believes in years to come Cellnovo will be one of the major players in the market once the market is ready to accept the AP for the delivery of insulin. Currently, cellnovo is collaborating with other major players in the market in order to stretch their market and even improve the system further.

Kaleido Insulin pumps

Kaleido Insulin pump is a new system in the European market. The pump has several unique features that will give it a lead advantage over other systems in the market. Such features include an option used in placing the infusion site with varied tubing length to contain various locations on the body (Heinemann, 2016). The pump can be stuck on the skin with adhesive. Additionally, the system has two interchangeable and rechargeable pumps, and a handset that regulates delivery of Insulin through Bluetooth technology. These pumps are water-resistant to approximate depth of 3.0 feet. However, the handset and the pump charging station must be maintained dry (Honka et al., 2014). The Kaleido equally provides options of ten colors for the Insulin pump. Kaleido has been designed in a simple way to use by all its clients. It does not have any unnecessary intricate functionality; it only contains features that are essential for the Insulin therapy (Laiteerapong et al., 2008). The two major elements of Kaleido are bolus dosing and bolus profiles: The basal menu provides clients with the chance to set up seven profiles that can be easily copied and modified (Rigla et al., 2018). The initial process is simple and easy to partake, with twenty-four-hour segments shown on the screen and the option to press down or up per hour, leading to an overview of patterns and daily total dose. The basal menu provides rates from 15 per cent of the latest profit up to 20 per cent. This can be controlled for a period of three hours in an increment of thirty minutes (Ratner et al., 2013). Kaleido is slowly rising into the market ranks and with the impressive and appealing features it has, it will soon dominate the world market.

Sooil Dana Diabecare Insulin Pumps

The Sooil Company produces two Insulin pumps that are in the market, Dana Diabecre RS and Dana Diabecre. These two pumps are found in multiple countries in Asia and Europe. The Dana Diabecare R model features a lightweight design and a connected glucometer (Setty et al., 2016). This system also enables for control of pumps settings remotely via an Android-based smartphone application. In 2018, the Dana Diabecre RS system was launched into the market and connected with applications of smartphone for both iOS and Android through Bluetooth technology. Sooil has been producing insulin pumps in the world market since 1981. In 2000, their newest pump, the DANA Diabecre II, was given approval by the FDA. After a year later, it started distributing in the U.S and other nations across the globe (Uc et al., 2017).

OmniPod Insulin Pumps

Omnipod first received its clearance with the FDA in 2005 after it was founded in 2000 by the Insulate cooperation. This system was the first to be developed from patch insulin pump containing two components: Personal Diabetes Manager (PDM) of Omnipod and a dischargeable OmniPod infusion pump. The PDM is a portable device with a powered battery that regulates delivery of insulin from a dischargeable infusion pump (Thabit et al., 2017).

The insulin pod is specifically designed to last for 3 days before it is replaced. The pump is stuck to the body with adhesive. The PDM is essential for every function and in case it is lost, the current rate of basal will still be delivered (Setty et al., 2016). Patients use PDM to deliver boluses, program the alarm and to change the rates of the basal. Omnipod is particularly designed in a way that it doesn't require tubing. This is because the Pod is directly fixed to the skin. The Omnipod is waterproof; this special feature enables users to put on the pump even while swimming (Kumar et al., 2018). Notably, many insulin pumps can be disconnected while at the insertion site, Omnipod cannot be disconnected. Omnipod is slowly rising and the company is hopeful it will soon take the lead in the market.

How inequalities in NHS affect T2DM

This study will address various aspects of inequalities affecting the National Health System (NHS). This body is the largest single-payer healthcare system in the world and therefore studying inequalities inside it helps identify loopholes on how to improve quality of health for T2DM patients. The impact that this organization has had is remarkable. It was once considered remarkably free and all the people could access quality health care. The benefit it once brought to the poor with T2DM is in jeopardy.

Misrepresentation of masses in NHS

The NHS has come up with many ways of enlightening the masses with calls to make them closely monitor their health. It is their responsibility. The NHS as currently constituted is more complicated than it was a couple of years ago (Wender et al., 2015). Communities are not as involved in development of policies as they once used to do. There has been little to no involvement from them and this has negatively impacted the health system. The resultant healthcare provided is not as tailor-made to the needs of the society as it should be. Therefore, such systems should not be imposed on the people but their help, input and expertise however little must be sought for successful healthcare.

Health inequality

The burden of emotional and psychological health of a patient is an underlying problem affecting all patients with terminal illnesses. T2DM patients qualify to be included as people living with long-term conditions. One with such conditions is more likely to suffer from depression (about three times) than those who are not diagnosed with such illnesses. That is only for those with one long term condition. For those with three long term conditions, they have an even harder time as they are seven times more likely to suffer depression (Lawrence, 2008). Such mental issues explained increase the probability of a patient to develop a physical illness. Co morbid depression increases risk of any of the many types of heart disease by 100%. Diabetes patients who have reached the working age and have psychological problems are by far less likely to be employed. As such, they are at a disadvantage because this may make them not able to fend for themselves and or afford APD medication. Also, they are not as likely to benefit from public health programs and mainstream screening because they do not integrate well into the society. Other health complications they are more likely to suffer from include obesity, cardiovascular issues and abnormal lipid levels.

Housing inequality

Proper housing equality among the patients is known to improve health of T2DM patients. (Marso et al., 2016). It is related with community wellbeing. Housing inequalities vary from the quality of homes the patient is residing in terms of value, the function of homes as a stage for which community integration of the patients and affordability of the homes. Disparity in incomes does not favor the poor as all the demerits of owning inhabitable homes befall them. Government strategy and guidelines on housing recommend that everyone must among other things have housing that is both affordable and appropriately serving their needs. T2DM patients should have his or her home that is dry, warm and effective when handling energy. Finally, their homes must have health support that ensures their wellbeing through accessible healthcare centers close to their homes (Nishida et al., 2009). One should note that adequate housing is a fundamental that is founded within the Universal Declaration of Human rights. The relevant administrative body within the United Nations underscore that the major aspects of housing are habitability, affordability, security of stay, and non-discrimination in admittance to the housing. The amount of money one earns or can access have a direct bearing on the type of housing and the place it is located and the type and level of medication one can afford. The poor people are therefore on the receiving end of housing inequalities since they could be barred from staying in some localities near to the wellbeing centers (Roberts et al, 2008). Cold weather and climate conditions could exacerbate the effects of diabetes type 2. Therefore, a patient must be able to afford to heat their homes. Fuel poverty is directly linked with the built environment and the patient’s ability to afford it.

Welfare inequality

Welfare inequality in the NHS is substantial. Healthcare specialists have voiced concern over social inequality and the accompanying effects this has in all the aspects of a patient’s wellbeing (Taylor et al., 2000). They include the life expectancy, the mental health and the physical health. Poverty is rampant in the United Kingdom and no age group is exempt from it. People from lower socio-economic groupings are more predisposed to T2DM. Poverty can hit hard on the diet and other feeding projects among the poor and this further affects the way they respond to treatment. Other related factors are unemployment and some types of employments which are low paying. There is a vicious cycle involving poverty and T2DM. For instance, a poor person cannot afford better healthcare which can in turn improve their quality of life. Alternatively, T2DM patient who is already in poverty cannot competitively go to work or seek better employment to improve their income. Therefore, one who is already in this pool is damned.

3.0 Methodology

This research seeks to find out impact of APDS in treatment and management of T2DM. It does this by addressing a number of questions. What convenience does artificial pancreas have over the use of insulin pumps? Is the convenience of the system absolute to the point of eliminating other complementary treatment and management plans? What is the economic feasibility of this management plan? What has hindered development of absolute bio-artificial pancreas?

This study will address the APDS as closed loop systems despite needing regular input from patient when recalibrating the device after taking meals and refilling the device with dose of insulin whenever necessary. A perfect independent artificial pancreas is hard to implement for any number of reasons stated before (Devries et al, 2016). The research understands that care and management of diabetes is expensive and could take psychological to on friends and family. This study focuses on T2DM which is mainly caused by production of insufficient insulin or failure of body cells to respond to the same.

This methodological approach taken for this study will be mixture of both qualitative and quantitative approach. The research is keen on response of all key stakeholders of the industry on how the development of the condition has impacted them economically, emotionally, physically and psychologically hence the qualitative approach. The research would also want to study the development of this condition from analyzing competition of key players in design and sale of APDS. We would also like to know why APDS is amongst the most commonly used treatments and why it has not been fully automated.

A survey was conducted on T2DM patients using carefully structured questionnaires to understand the exact impact this condition has had on their life. 10 respondents were requested to take at most 20 minutes of their time to respond to questionnaires readout to them. Respondents were reached on mail to request their cooperation. The researcher opted for online survey to get opinions of respondents from comfort of their home. This helped with avoiding illegible responses and the ease respondents had to ensured highest degree of truthfulness. A sample of questionnaire administered is attached at the appendix.

The secondary data forming basis for quantitative analysis are gotten from literature documented in the references. (Farrington, C 2018) is specifically instrumental in relaying the innovations of Melligen and cell-in-a-box technologies which have highlighted potential of development of self-sustaining bio-artificial pancreas.

For the quantitative approach, the choice of literature to be used depended on their ability to capture necessary information on T2DM research expenditure, structural and functional aspects of beta-cells, history of search for cheap and convenient treatment T2DM and how APDS fair against other treatment methods. Qualitative approach involved surveying patients who were carefully selected. The researcher maintained courtesy from requesting their participation which was done with their utmost privacy in mind. All participants had to be suffering from T2DM and UK Citizen staying in any part of the country because the survey was administered online. The time and monetary resources allocated for this project limited number of participants to 10.

Whereas the need to put all participants at ease by filling questionnaires they agreed to fill out, two surveys were incomplete and this could be attributed to lost connectivity and or loss of interest. In some case with secondary sources of data, the text made reference to diabetes instead of being explicitly clear on the type (Namikawa et al., 2016). Whereas T2DM is the more common of the two (about 90%) conditions, one cannot be certain of consistency of data when analyzing statistical patterns in such cases. Therefore, assumptions are made to make sense of such data. In the case where two questionnaires were incomplete, the researcher was forced to analyze completed surveys; establish sets of patterns and compare them with those which were not completed. As such, the researcher could make informed guesses based on data at hand.

Instead of using online surveys which have their advantages and disadvantages, use of alternative such as moving around physically would have solved the problem of incomplete questionnaires. Personal appeal works when the administer is present in person. It is very important as it helps him or her make decisions go his or her way.

In the qualitative approach, a theoretical analysis was used whereas for quantitative approach, statistical and theoretical analyses were used. The data from respondents were used to build on, reinforce and improve on knowledge of problems facing T2DM patients. Secondary data on pharmaceutical multinationals were used to understand change in patterns of expenditure and profit margin with the development of APDs. It also shows the edge APDs have over other treatment plans.

Analysis shows how far we have come in development of APDs and how much more needs to be done to obtain a working prototype of bio-artificial pancreas. The research shows the various aspects of life changing impacts the plight for T2DM treatment has had on the patient. Most of ways in which major stakeholders are affected is documented. Since how concerned parties are affected is the subject of this research, findings should be able to be used to improve their quality of life.

4.0 Results

APDs have come about as valuable tools and the experience they offer during treatment has been described as both cost effective and tailor-made to the needs of patient. One study reported that if candidates are selected properly such that technologies designed best suit their needs, then clinical trials have shown that using insulin pump therapy (OpT2mise) together with glucose monitoring system (DiaMonD) has a great potential of asserting better glycaemic control among T2DM patients. The array of T2DM patients helps in understanding how APD management provides different results for different patients. Patients who were introduced early into APD treatment as soon as they were diagnosed had fewer chances of developing early onset of diabetic complications. T2DM patients that had been under care and with the help of insulin pump viewed APDs as a better option and thought it would help with consistency in care. This is due to additional functionality that helped with monitoring and automatic adjustment of insulin pump. This hope of better functionality could mean better glycaemic control.

Usage of APDs reduces the burden of care on both caregivers and patients when it comes to insulin administration. Patients are specifically protected from frailty and aggravated physical impairments as a result of sudden occurrences of massive dysglycemia, by using this technology. These patients who would otherwise need constant emergency hospitalization find a way of saving more money and live quality life while doing so. Development of the ultimate APDs which is cost effective is a multidisciplinary undertaking. Cost effectiveness and value for money can guarantee a higher rate of acceptability among T2DM patients.

Based on CLOSE’s approach to APD usage in T2DM management, their experts responsible for design state that a slight tweak in TIDM algorithm would reinforce the vigor of glycaemic control among T2DM patients. Such a move to improve acceptability hits a snag when we realize the heterogeneity of patients reduces the possibility of a single APD design to serve such a variety (Namikawa et al, 2016).

However, despite the bottleneck of lack of APD plus to suit all users, creation of one such package has a probability of increasing commitment from all players in the industry. 8 participants took part in the survey as a mere courtesy and because they had time. The other two said that they had had enough of the scourge and that they would do anything in their power however little to curb it. All participants were using APD therapy at the time of survey. 2 participants upgraded from use of insulin pumps and another 2 were on complementary management. The effectiveness APDs stood out as the reason for which patients that had used other alternative methods before preferred it. Whereas the cost of insulin pumps is high ($2600-$3900) with some of it being offset by the NHS, the cost of APDs is higher with an annual subscription of about $10000 incurred by private T2DM patients. Such high costs make insurance against a number of risks very important (Howard et al, 2008). One patient who had insight into the condition stated that the high cost of APDs was justifiable because the sophistication of its systems helped T2DM patients avert risk of severe hyperglycaemia without even understanding their exposure in the first place. All 10 subjects agreed that development of working prototype that could be fully autonomous would be priceless.

Based on the high charges for APDs five participants believed that designers were doing a good job and that they needed more time to get it all right. The other five differed. Two pointed out that markup from their current services marked the end of their research. Another two think that a different approach would shed more light. All participants agreed that with the advent of APDs, they have been able to take part in intense sports and be safe always. These systems have actually helped them hit the gym and take regular exercises.

5.0 Discussion

T2DM is the most prevalent type of diabetes accounting for about 85% of new diagnosis when compared with T1DM. It is not as severe as T1DM despite its commonality. It is a multi-organ condition affecting many parts of the body and therefore needs a coordinated treatment at best. This study seeks to establish the impact of use of APDs for management of T2DM.

Insulin therapy is prescribed for TIDM patients and T2DM patients with complications. Before onset of the diabetes, healthy lifestyle is advised for those who are predisposed to these conditions and such patients are enrolled in pharmacotherapy to help keep blood sugar levels in check. Drugs such as metformin are taken. Such drugs however, have are long-term solutions which may expose patients to health risks associated with metabolic imbalance despite keeping hyperglycaemia at bay. This is where insulin therapy is important in T2DM treatment.The usage of insulin pumps arise therefore because relatively, patients’ glucose level is more stable and within range. The need to maintain even more stable range of blood glucose necessitates closer monitoring and self-adjusting systems that give dosage accordingly. APDs are more suitable in this respect that insulin pumps (Ho, Y., 2019).

APDs could be beneficial to T2DM patients who are on haemodialysis. Bally his colleagues in 2019 found out that this treatment was way better than subcutaneous insulin and did not pose as great a danger as of developing hyperglycaemia.

Evolution of treatments up until development has largely been due to failure of previous treatments to be wholly effective. It is important to know that promise of self-sufficient bio-artificial pancreas is hinged on two innovations. The use of Cell-In-a-Box technology as an editing tool that encapsulates beta-cells primed for transplant thereby protecting them from immune response from host is important for this breakthrough. The other innovation is genetically edited beta-cell coined as Melligen. Together, with more research, they guarantee permanent treatment for T2DM (Hartnell et al 2018).

Use of APDs is quite popular that in developed nations where T2DM patients have the funds to seek quality healthcare, they are shadowed most treatments including alternative methods. The zeal with which participants came out to take part in an online survey shows how much the condition has taken from them and the desire to tackle it. Effectiveness of APDs is seen when all participants who happen to be T2DM patients use it instead of other alternatives. The cost of acquiring, maintaining and safeguarding APDs is a lot and arrangements with NHS have helped subsidize such costs. They have found their way into the insurance industry as they are insured against any number of risks a patient prefers to cover (Speier et al 2017). One particular patient who had a better understanding of T2DM prognosis says that as currently designed, APDs are a blessing as they tackle and solve conditions patients do not even appreciate are lurking. Such risks include severe hyperglycaemia. Research to find fully autonomous artificial pancreas is welcome.

In struggle for market share, APDs developers have forced out insulin pumps designers to evolve and catch up with them. Such companies include Pancreum- the CoreMD, The Bigfoot Biomedicak Inc and Medtronic insulin pump. Small players like cellnovo insulin pumps have been competitive. They’ve make additional improvements such as touch screen user interface which is appealing to users. Kaleido insulin pumps have introduced water-resistant systems to stay afloat and can stand pressure of utmost the depth of 3 ft (Hughes, 2013)

6.0 Conclusion

What is the convenience and effectiveness of APDs over other alternative methods of T2DM management? Is the effectiveness strong enough to phase out other methods of treatment? It the economic impact of APDs in the market significant? This paper answers these questions. As stated before, T2DM is more common of the two types of diabetes but less severe (Speier et al 2017). Methodology uses both qualitative and quantitative approaches which form the backbone of analysis of impact of APDs in T2DM care. These devices are effective and their suitability has sparked a race in fight for market share of loyalty from diabetes patients. Limitation of insulin pumps to maintain a suitable range of blood glucose is compensated for by enhancing customer experience such as double rechargeable pumps and or standalone systems with attractive graphic user interface (Broedl, et al, 2015). T2DM patients have complained about high pricing of APDs but have called for more research to find bio-artificial pancreas which would be self-sufficient. The objective of achieving self-sufficient APDs is within sight because of two great medical innovations (encapsulation editing tools and “Melligen” engineered beta-cell).

High pricing of cost of APDs in the UK is the reason, according to some patients interviewed, that the discipline is growing faster. Every T2DM patient would dream of having such improvised devices to help with hyperglycaemia (Speier et al 2017).

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