Finding the right route for insulin delivery – an overview of implantable pump therapy

Abstract

Introduction Implantable pump therapy adopting the intraperitoneal route of insulin delivery has been available for the past three decades. The key rationale for implantable pump therapy is the restoration of the portal-peripheral insulin gradient of the normal physiology. Uptake in clinical practice is limited to specialized centers and selected patient populations. Areas covered Implantable pump therapy is discussed, including technical aspects, rationale for its use, and glycemic and non-glycemic effects. Target populations, summaries of clinical studies and issues related to implantable pump therapy are highlighted. Limitations of implantable pump therapy and its future outlook in clinical practice are presented. Expert opinion Although intraperitoneal insulin delivery appears closer to the normal physiology, technical, pharmacological, and costs barriers prevent a wider adoption. Evidence from clinical studies remains scarce and inconclusive. As a consequence, the use of implantable pump therapy will be confined to a small population unless considerable technological progress is made and well-conducted studies can demonstrate glycemic and/or non-glycemic benefits justifying wider application.

‘Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues

“…reservoirs of insulin (up to 3 months), catheter occlusion [62] remains a concern that has limited the feasibility of such systems in otherwise encouraging clinical trials [63]. Occlusions are often mediated by immunogenic and proinflammatory insulin-derived amyloid fibrils [64,65]. Insulin instability and fibrillation can also occur within the pump reservoir to inactivate the hormone and provide seeds for further cycles of fibrillation.…”

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

“…These technologies furthermore rely on sampling of subcutaneous fluid, which suffers from finite lag times associated with glucose diffusion/absorption from the bloodstream. Insulin and glucagon degradation or aggregation within pumps is another concern, as these hormones have notoriously poor solubility and are prone to amyloid‐like fibrillation . The presence of a transcutaneous sensor or device presents a greater risk for infection, and at the very least can be a source of discomfort for wearers.…”

Development of glucose-responsive ‘smart’ insulin systems

“…Despite their theoretical advantages and long-term reservoirs (up to three months), regulatory approval of IPIs in the United States has been withheld due to their susceptibility to catheter occlusion (49). Such occlusions are in part inflammatory, provoked by formation of immunogenic and pro-inflammatory amyloid fibrils (50, 51). In addition, fibrillation of insulin within the pump reservoir or catheter alters the flow properties of the solution and inactivates the hormone.…”

“…The challenge of insulin degradation in pumps, whether external (53) or implanted (50), may be addressed by development of ultra-stable, fibrillation-resistant insulin analogs. Two classes of insulin analogs have been shown to be refractory to fibrillation: single-chain insulins (SCIs) containing a foreshortened C domain (Fig.…”