Nanomedicine and Insulin-Dependent Diabetes Mellitus
Xin Hui Sujata Liew UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland
Diabetes mellitus is a chronic condition that occurs when the body cannot synthesise or effectively utilise insulin. All patients with Type 1 Diabetes and many with long-standing Type 2 Diabetes require insulin therapy to achieve glycaemic control. Frequent monitoring of blood glucose levels is not only inconvenient and difficult to optimise, but also predisposes the patient to skin and soft tissue infections. Type 1 Diabetics are at increased risks of developing adverse complications owing to poor glucose control. This review article aims to discuss the limitations of current management approaches to diabetes. It will also explore and assess the plausibility of nanotechnology as a solution to our current challenges. Nanotechnology, the application of extremely small structures (known as nanoparticles), and nanotechnology-based approaches hold limitless potential for improving the care of patients with diabetes. Research in this field has facilitated the development of novel in vivo glucose measurement, monitoring, and insulin delivery modalities, all of which may dramatically improve the quality of life for individuals living with diabetes, however further investigation is required.
Introduction: What is diabetes?
Diabetes mellitus (DM) is defined as a constellation of metabolic abnormalities characterised broadly by hyperglycaemia. DM is a chronic condition caused by the lack or insufficiency of insulin, a hormone naturally produced by β cells in the pancreas. It acts to speed up the transfer of sugar from blood into tissues, where sugar is utilised as fuel or stored for use later.
There are two principal types of DM. Type 1 DM (T1DM) results from the complete lack of synthesis of insulin in the pancreas and is largely considered an autoimmune disease whereby β cells in the pancreas are attacked and destroyed by the immune system1. People with T1DM require exogenous insulin daily. Type 2 DM (T2DM) accounts for approximately 90% of diabetes worldwide2. In contrast with T1DM, individuals affected by T2DM can synthesise insulin. The pathophysiology lies in progressive reduction in insulin sensitivity in tissues, followed by deteriorating pancreatic β cell function. Hence, the amount of insulin produced in the pancreas becomes insufficient and hyperglycaemia results. If poorly controlled, pancreatic β cells become overworked and eventually atrophy, causing these patients to require exogenous insulin. The prevalence of DM is increasing worldwide. The International Diabetes Federation estimates that 366 million people had diabetes in 2011 and this is expected to rise to 552 million by 20303.
On an individual level, the affected person is noted to be at an increased risk psychosocial factors such as depression4 and unemployed5. At a community level, families caring for a diabetic person may experience high expenses due to costly treatment regimes. Futhermore, on a national level, poor population health leads to productivity losses and reduced economic output. DM is undoubtedly a costly disease that we must address its acceleration as a global pandemic.
Traditional approach to management of DM
Glucose monitoring is essential for the management of diabetes. Monitoring provides the data required for patients to make daily decisions related to food intake, insulin dose, and physical exercise, and can enable patients to prevent dangerous episodes of hypo- and hyperglycaemia.
For T1DM patients, injectable insulin replacement therapy is prescribed with the goal of mimicking natural pulsatile fluctuations in insulin levels throughout the day. Typical treatment includes subcutaneous injections of long-acting insulin to provide a basal level of insulin. This is supplemented with bolus injections of fast-acting insulin at mealtimes.
Initial treatment for T2DM focuses on delaying disease progression through lifestyle modifications, including standard exercise and dietary changes. Patients also receive oral and/ or injectable medications to improve insulin production and function.
Why can we not soley rely on the current treatment approaches for DM:
Current approaches for the management of DM have limitations. For patients who are insulin-dependent, injection of insulin can be painful, embarrassing or socially inconvenient, and time-consuming. Traditional approaches are associated with difficulty with accurate dosing, and eventually decreased compliance. An overdose of insulin can result in an event of severe hypoglycaemia, leading to coma, seizure, and even death6. Conversely, insulin under-dosing can result in severe dehydration by polyuria, resulting in a Hyperosmolar Hyperglycaemia State (HHS). Similarly, Diabetic Ketoacidosis (DKA) can occur. Not only is accurate judgement of insulin dose requirement challenging, but also there is often a discrepancy between the intended dose and the dose that is in fact delivered in 25% of patients7. A time lag exists between glucose measurement and insulin dosing, combined with delayed absorption of insulin following subcutaneous injection. These factors lead to imprecise doses of insulin loaded into the patient, limiting the effective mimicking of the body’s natural insulin levels.
Insulin pumps have been developed to maintain a basal level of insulin throughout the day. The pump is advantageous as it brings convenience to individuals who struggle on multiple daily injections and allows greater flexibility with food and exercise8. As such, lower insulin usage is required.
However, these pumps do not eliminate the inconvenience of requiring the individual to test their blood glucose level frequently. There is also an unavoidable risk of pump failure, and some evidence suggests that these pumps might in fact increase the risk of DKA and overall mortality9. Furthermore, intensive education is required to ensure users are well-informed on how to use the pumps effectively10.
Continuous glucose monitors
A recent alternative to self-monitoring of blood glucose are continuous glucose monitors (CGMs). These are sensors inserted subcutaneously to measure blood glucose levels (BGLs) in the interstitial fluid. CGMs undoubtedly bring convenience by avoiding multiple finger pricks required daily and facilitating effective treatment. CGMs are less invasive and work 24 hours a day. However, CGMs are associated with high rates of discontinuation resulting from unique psychological concerns11, as false alarms of hypoglycaemia can cause frustration.
In summary, not only are insulin pumps and CGMs expensive, but also increase the patient’s risk of infection, fibrosis, and scarring. Owing to the foreign body response, frequent maintenance and replacement of the device increase effort and cost to patients, limiting their effectiveness.
Nanomedicine: A ROLE in DIabetes management
The application of nanotechnology to medicine, commonly referred to as 'nanomedicine', has the potential to transform our approach to human health and disease. Nanotechnology is the application of extremely small structures (known as nanoparticles) which are invisible to the naked eye. Over the past 20 years, nanomedicine has been a rapidly growing field and has an impact on cancer diagnosis, cardiovascular disease, and targeted drug delivery.
Nanomedicine offers glucose nanosensors, oral insulins, the artificial pancreas, and nanopumps to overcome challenges such as blood glucose monitoring and insulin injection. The nanoparticulate system aims to create an ideal and complete “closed system” which ultimately mimics the physiological role of a pancreas: alter insulin levels in the blood according to the fluctuation of blood glucose level in real time12.
Nanomedicine in diagnosis of diabetes: quantifying beta cell mass
Pancreatic β cell mass closely correlates with β cell function and is a parameter commonly examined in studies of islet biology and DM13. Early detection of DM and identification of disease progression are critical aspects of disease management. To date, direct measurement of β cell mass is only possible in post-mortem autopsy or by means of invasive procedures, through excision of tissue and imaging β cells after the addition of contrast dyes14.
Non-invasive methods of assessment of β cell mass may be possible with nanotechnology. Nanoprobes with β cell specificity and high contrast are currently being developed. These novel technologies include superparamagnetic iron oxide nanoparticles (SPIONS), a technique which allows nanoparticles to be targeted using magnetism, tracked using MRI and used as magnetic triggers for drug release, mainly used as a tool to monitor immune cell infiltration and subsequent pancreatitis which could detect early stage diabetes15. A high concentration of carrier and drug can be achieved as an external magnetic field can be applied locally to the target organ. This allows accumulation of magnetic nanoparticles in the preferred site of action. Considering that many promising drugs are limited by their ability to reach the target site, the concept of advanced drug delivery in SPIONS is particularly compelling16. However, the pharmacokinetics and in vivo fate of SPIONS are not yet fully understood. Potential adverse effects arising from off-target drug carriage and incomplete understanding of the drug release profile are issues that must be considered17.
Nanomedicine technology in glucose sensing and insulin delivery:
Glucose meters are universally utilised in the management of glucose homeostasis in a variety of settings. However, obtaining accurate readings from these devices can be challenging as glucose meters can only analyse whole blood, despite the instability of glucose in whole blood18. Nanotechnology might provide a more trustworthy alternative to current glucose-sensing methods. Next-generation sensors provide high accuracy for prolonged periods and are patient-friendly.
Further, glucose-responsive nanoparticles can be developed to meet physiological needs for insulin19. In other words, when there is a rapid increase in blood glucose, nanosensors detect this surge and respond accordingly by releasing insulin.
While nanomaterials greatly enhance biosensor performance, limitations exist. Nanosensors could display the same drawbacks as current sensors. Though a closed system, there is still a time lag between when elevated blood glucose is detected and when insulin is released from nanoparticles. Also, since the particles are mostly composed of polysaccharides for biocompatibility, they will eventually degrade in the body making routine replacement necessary. Additionally, concerns over the nanoparticle toxicity limit the application of these devices for in vivo sensing20.
Noninvasive methods of insulin delivery:
To counter the adverse effects associated with insulin pumps and multiple daily injections, non-invasive methods of administering insulin are also being explored. Oral, inhalable, and transdermal delivery can provide pain-free and convenient options for diabetic patients21. However, such methods of delivering insulin are not yet successful. Poor and unpredictable bioavailability has limited the success of insulin delivery via such alternative routes. Insulin, a large peptide molecule, has poor epithelial permeability22 and is consequently not well-absorbed in the gastrointestinal tract, lungs, and skin.
Nevertheless, oral insulin has been increasingly investigated. To protect insulin from premature degradation in the gastrointestinal tract, efforts in nanomedicine have focused primarily on utilising nanoparticles as protective carriers23. Recently, insulin-loaded polymeric Poly(lactic-co-glycolic acid) nanoparticles which targeted neonatal Fc receptor in the intestinal epithelium were reported to enhance epithelial transport of insulin24. Even though these findings are promising, the use of oral insulin nanoparticles may be limited to replacing injections of long-acting insulin. Short or fast-acting insulin require more predictable insulin absorption profiles, which alternative non-invasive methods of insulin delivery have yet to achieve.
DM remains a pervasive global health threat. There is a need for improved insulin therapy and treatment optimisation for diabetic patients. There is no cure for DM and it has contributed greatly to high costs in healthcare systems globally. To date, lifestyle interventions only modulate risk factors. Pharmaceutical therapies, on the other hand, can produce unfavourable side effects. Stem cell transplantation that aims to create and replace failing β cells of the pancreas is a potential cure for diabetes, but this is unavoidably a costly and high-risk surgical procedure. Progress in closed loop insulin delivery with the use of nanoparticles has been encouraging and shows promise for the treatment of DM. This is not to say that nanomedicine will replace current treatment options; instead, nanomedicine can potentially exist as an adjunct and improve modern treatment strategies. Nanomedicine provides a plethora of possibilities for the diagnosis and treatment of DM. Based on current developments in nanoscale glucose sensing, one can expect increasing clinical applications of this technology in the future.
1. Us A, Us C. Types Of Diabetes: Diabetes Education Online [Internet]. Dtc. ucsf.edu. 2018.
2. National Diabetes Statistics Report, 2017: Estimates of Diabetes and Its Burden in the United States. CDC. 2018.
3. IDF Diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. 2018.
4. Egede LE, Zheng d & Simpson k. Comorbid depression is associated with increased health care use and expenditures in individuals with diabetes. Diabetes Care 2002; 25:464–470.
5. Gannon B & Nolan B. disability and labor force participation in Ireland. the Economic and Social review 2004; 35:135–155
6. Insulin Overdose - Symptoms, Causes, Treatments & Prevention. Diabetes. co.uk. 2018.
7. Pfutzner A, Asakura T, Sommavilla B, et al. Insulin delivery with FlexPen®: dose accuracy, patient preference and adherence. Exp Opin. 2008;5:915-925.
8. Pros and cons of insulin pumps. 2018.
9. Diabetic Ketoacidosis - Causes, Symptoms and Treatment of DKA. Diabetes. co.uk. 2018.
10. After Intensive Education, Insulin Pump Slightly Better Than Multiple Daily Injections in Type 1 Diabetes. Practice Update. 2018.
11. Block J, Buckingham B. Use of real-time continuous glucose monitoring technology in children and adolescents. Diabet Spectr. 2008;21:84–90.
12. Rao PV, Gan SH. Recent Advances in Nanotechnology-Based Diagnosis and Treatments of Diabetes. Curr Drug Metab. 2015;16(5):371-5.
13. Kahn SE, Carr DB, Faulenbach MV, Utzschneider KM. An examination of beta-cell function measures and their potential use for estimating beta-cell mass. Diabetes Obes Metab. 2008 Nov;10 Suppl 4:63-76.
14. Reiner T, Thurber G, Gaglia J, Vinegoni C, Liew CW, Upadhyay R, Kohler RH, Li L, Kulkarni RN, Benoist C, Mathis D, Weissleder R. Accurate measurement of pancreatic islet beta-cell mass using a second-generation fluorescent exendin-4 analog. Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12815-20.
15. Sun C, Lee J, Zhang M. Magnetic nanoparticles in MR imaging and drug delivery. Advanced Drug Delivery Reviews. 2008];60(11):1252-1265.
16. Veiseh O, Gunn J, Zhang M. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Advanced Drug Delivery Reviews. 2010;62(3):284-304.
17. Laurent S, Saei A, Behzadi S, Panahifar A, Mahmoudi M. Superparamagnetic iron oxide nanoparticles for delivery of therapeutic agents: opportunities and challenges. Expert Opinion on Drug Delivery. 2014;11(9):1449-1470.
18. Tonyushkina K, Nichols JH. Glucose Meters: A Review of Technical Challenges to Obtaining Accurate Results. Journal of diabetes science and technology. 2009;3(4):971-980.
19. Veiseh O, Tang B, Whitehead K, Anderson D, Langer R. Managing diabetes with nanomedicine: challenges and opportunities. Nature Reviews Drug Discovery. 2014;14(1):45-57.
20. Taguchi M, Ptitsyn A, McLamore E, Claussen J. Nanomaterial-mediated Biosensors for Monitoring Glucose. Journal of Diabetes Science and Technology. 2014;8(2):403-411.
21. Owens D. New horizons — alternative routes for insulin therapy. Nature Reviews Drug Discovery. 2002;1(7):529- 540.
22. Kumar V, Choudhry I, Hurkat P, Jain A, Jain D. Oral Insulin: Myth or Reality. Current Diabetes Reviews. 2017.
23. Bakhru S, Furtado S, Morello A, Mathiowitz E. Oral delivery of proteins by biodegradable nanoparticles. Advanced Drug Delivery Reviews. 2013;65(6):811-821.
24. Pridgen E, Alexis F, Kuo T, Levy- Nissenbaum E, Karnik R, Blumberg R et al. Transepithelial Transport of Fc-Targeted Nanoparticles by the Neonatal Fc Receptor for Oral Delivery. Science Translational Medicine. 2013;5(213):213ra167-213ra167.