Objective
Individuals with T1D often face the challenge of dangerously low blood glucose events even when using an insulin pump or weekly insulin injections. Hypoglycaemia and injections with needles are two major hurdles for people living with T1D. Based on the recent progress we made using advanced material engineering, we will use our patented, glucose-responsive (GR) insulin delivery glycogen nano-system, combined with a clinical used capric acid (CA) and tannic acid (TA) protective layer, to develop a new, oral nano-system that functions as a gastrointestinal tract (GIT) insulin reservoir. This ‘gut-resistant artificial pancreas will permit a prolonged and sustained insulin release through the portal vein in response to food-derived glucose. Firstly, with the support from co-PI Cavalieri, I will engineer a glucose-sensing 'oral glycogen insulin' formulation for improved insulin oral bioavailability via the GIT. Secondly, I will test the glucose-lowering effects of the oral glycogen-insulin in diabetic mouse models. Lastly, I will assess the biodistribution and bioavailability of the oral glycogen-insulin by an ultrasensitive positron emission tomography (PET).
Background Rationale
The GTI is considered as a harsh environment due to acidic gastric pH and digestive proteases destroying insulin. The low bioavailability of current oral insulin delivery technology is still the biggest challenge. Capric acid-based permission enhancer technology helped the success of OI338, an expensive engineered insulin analogue that is currently in phase II clinical trial. The low bioavailability of OI338 and the cost-effectiveness issues stopped its further development. Therefore, commercial oral formulation of insulin for T1D is not available, and preclinical studies are limited. In particular, there is a need to design new nontoxic nanomaterials entirely made of biodegradable biopolymers to enable effective, safe and, importantly, hypoglycaemia-free insulin delivery by oral administration. Our rationale is to engineer gut-resistant glucose-responsive glycogen nanoparticles by coating them with CA and a tannic acid protective layer. Based on our advanced material engineering technology, we will develop an oral gut-resistant artificial pancreas that has a long retention time that enables it to transform the gut into a glucose-responsive insulin reservoir. This ‘gut-resistant artificial pancreas’ will permit a prolonged and sustained insulin release through the portal vein in response to food-derived glucose.
Description of Project
Type 1 diabetes (T1D) is the most common chronic disease of childhood, although it can develop at any age. T1D patients are often poorly managed, especially during puberty, when glucose levels are not always monitored by the parents as adolescents transition to adulthood. Prolonged periods of high blood sugar levels can lead to severe life-threatening events, but their main effect is an increased risk for long-term issues in blood circulation that affect sensitive organs, like the eyes and kidneys. The opposite problem, a treatment-induced severe hypoglycaemia in which assistance from another person is required, affects more than one-third of people with T1D. Not surprisingly, the fear of hypoglycaemia is extremely common and for many individuals with T1D, avoidance of hypoglycaemia dominates their self-management at the cost of additional exposure to hyperglycaemia and higher risk of long-term complications. Collectively, people with T1D still face daily challenges in managing their blood glucose levels and suffer the fear of moderate to severe, life-threatening hypoglycemia, even when using an insulin pump, weekly insulin or oral insulin. The introduction of a glucose-responsive insulin release systems (also known as ‘closed-loop insulin systems’) represents a ground-breaking advancement in treating T1D. This system functions as an ‘artificial pancreas’, releasing insulin precisely when the body needs it, leading to significantly improved and more reliable blood glucose control. Furthermore, T1D patients undoubtedly have a strong preference for oral insulin intake if such treatment becomes available. However, as gastric acidity and digestive enzymes destroy insulin once swallowed, insufficient levels of insulin are available for absorption after ingestion of current oral insulin, representing a major challenge for this breakthrough technology. Overall, there is a real need for an innovative oral insulin delivery system for people living with T1D. The revolutionary nanotechnology that I developed offers an engineered, gut-resistant ‘artificial pancreas’ that provides an improved availability of insulin by oral intake with a reduced risk for experiencing low blood glucose events.
Anticipated Outcome
My research holds promising and impactful outcomes for the treatment of type 1 diabetes (T1D). First, it is expected to successfully engineer a few types of oral, gut-resistant ‘artificial pancreas’ materials and confirm in vitro (in artificial systems) their fundamental properties, including their ability to respond to glucose by insulin release, resist the tough gut environment and pass intestinal epithelial cells.
Furthermore, we anticipate these medication candidates to achieve an excellent blood glucose control after oral administration in two T1D mouse models. This feasible outcome is expected due to the gut resistance of the particles, which are protected by a shell made of non-toxic materials that allows them to remain in the gut for prolonged periods of time. Overall, our nanoparticles will essentially transform the gut into a glucose-responsive insulin reservoir, which can respond to glucose fluctuations by precise release of insulin.
In summary, the efforts I lead for development of an oral, gut-resistant ‘artificial pancreas’ system aim to yield highly positive outcomes and offer capacities for improved blood glucose control, glucose responsiveness and improved bioavailability - all by a medication taken orally. These anticipated outcomes hold great promise for enhancing the quality of life and care of individuals living with type 1 diabetes, without fearing needle injections and dangerous hypoglycaemic episodes.
Relevance to T1D
My research on oral delivery of gut-resistant and glucose-responsive insulin holds significant promise for people living with type 1 diabetes (T1D) and addresses critical aspects of their care, including the following points:
Improved Blood Glucose Control: My research is focused on developing innovative nanotechnology that transforms the gut into a glucose-responsive insulin reservoir, achieved as the material remains stable in the digestive system for prolonged periods of time.
Prevention of Hypoglycemia: The glucose-responsive nanosugar not only controls high blood sugar levels, but also prevents dangerously low blood sugar episodes (hypoglycemia). This advantage is crucial for T1D patients, who face this challenge on a daily basis.
Reduced Treatment Burden, resulting from potentially offering an oral treatment that provides injection-free and hypoglycemia-free insulin at an improved cost. The latter is achieved since the oral, gut-resistant ‘artificial pancreas’ system can be loaded with cheap and commercially available insulin, while enhancing its action duration. My work aims to reduce the daily treatment burden on individuals with T1D. This can lead to a better quality of life, fewer interruptions, and improved adherence to treatment regimens.
In summary, my research is directly relevant to T1D as it addresses key challenges and offers innovative solutions that will positively impact those affected by the condition. Ultimately, I aspire to develop a user-friendly and safe oral medication, which can be taken without injections, to reduce the overall treatment burden and improve the way we manage blood glucose control in T1D.