Development of glucose-responsive ‘smart’ insulin systems

Abstract

Purpose of Review The complexity of modern insulin-based therapy for Type I and Type II diabetes mellitus and the risks associated with excursions in blood-glucose concentration (hyperglycemia and hypoglycemia) have motivated the development of “smart insulin” technologies (glucose-responsive insulin; GRI). Such analogs or delivery systems are entities that provide insulin activity proportional to the glycemic state of the patient without external monitoring by the patient or healthcare provider. This review describes the relevant historical background to modern GRI technologies and highlights three distinct approaches: coupling of continuous glucose monitoring (CGM) to deliver devices (algorithm-based “closed-loop” systems), glucose-responsive polymer encapsulation of insulin and molecular modification of insulin itself. Recent Findings Recent advances in GRI research utilizing each of the three approaches are illustrated; these include newly developed algorithms for CGM-based insulin delivery systems, glucose-sensitive modifications of existing clinical analogs, newly-developed hypoxia-sensitive polymer matrices, and polymer-encapsulated, stem-cell-derived pancreatic β-cells. Summary Although GRI technologies have yet to be perfected, the recent advances across several scientific disciplines that are described in this review have provided a path towards their clinical implementation.

Biologically Inspired and Chemically Derived Methods for Glucose‐Responsive Insulin Therapy

“…For chronic hyperglycemia, micro‐ and macrovascular disease, renal disease, retinopathy (blindness), and neuropathy all arise as complications. Diabetic ketoacidosis in type‐1 diabetes and hyperglycemic coma in type‐2 diabetes are acute metabolic complications that can also arise . With hypoglycemia, there are relatively immediate signs and symptoms as compared to hyperglycemia, including adrenergic and neuroglycopenic effects that lead to anxiety, tremulousness, and altered mental state that can in the most severe cases result in life‐endangering hypoglycemic coma .…”

“…GOx has been commonly implemented in diagnostic technologies, notably in handheld glucose meters and more recently in the emergence of continuous glucose monitors (CGMs), which provide continuous readings of glucose levels from transcutaneously implanted electrodes. Recent advances in insulin delivery technology have coupled CGMs with mechanical insulin pumps, integrating these two devices with predictive control algorithms to tune insulin dosing based on projected future trends in blood glucose level . These systems are at the forefront of diabetes care and may soon replace conventional insulin injection as the standard therapy.…”

“…Therefore, with increasing diol concentration, the equilibrium between neutral PBA, charged PBA, and diol–boronate ester shifts toward the charged/ester forms, which favors enlarged network dimensions and enables diol concentration‐driven swelling . In certain cases, a dehydrated “skin” layer on the outer surface of the hydrogel material forms under hypo‐/normoglycemic conditions, acting as a barrier to diffusive “leakage” of encapsulated insulin and addressing a challenge faced by many technologies in this field (Figure C,D) . The reversible skin layer affords a sharper release profile that more closely approximates an “on–off switch” for insulin release, a long‐term goal in the field to ensure benefit from material‐based approaches relative to other methodologies (e.g., pumps or glucose‐responsive insulin variants).…”

Hope vs hype: where are we in type 1 diabetes?

“…The concept dates back to the late 1970s [69]. More recently, several groups have attempted to develop such an insulin [68], but no clinical trial results have yet been reported.…”

“…'Smart' insulins One potential approach for achieving glucose control is an insulin that can be administered but released in response to prevailing level of glucose, so-called 'smart' insulin [68]. The concept dates back to the late 1970s [69].…”