The future of open- and closed-loop insulin delivery systems

Abstract

We have analysed several aspects of insulin-dependent diabetes mellitus, including the glucose metabolic system, diabetes complications, and previous and ongoing research aimed at controlling glucose in diabetic patients. An expert review of various models and control algorithms developed for the glucose homeostasis system is presented, along with an analysis of research towards the development of a polymeric insulin infusion system. Recommendations for future directions in creating a true closed-loop glucose control system are presented, including the development of multivariable models and control systems to more accurately describe and control the multi-metabolite, multi-hormonal system, as well as in-vivo assessments of implicit closed-loop control systems.

Figure 1

Pharmacokinetic diagram of the minimal model. Solid lines represent material appearance or disappearance, and dashed lines represent contributions toward the kinetic appearance or disappearance. The k_i’s represent the rate coefficients for each term with respect to the kinetic process.

Figure 2

Pharmacokinetic diagram from Hovorka model [43]. Q₁ and Q₂ represent the mass of glucose in compartments 1 and 2, respectively. I represents plasma insulin, and x₁, x₂, and x₃ represent insulin action toward glucose uptake, production, and exchange between the two compartments. Solid lines represent kinetic appearance or disappearance. Dashed lines represent action by insulin. Large solid arrows represent a single non-continuous source of either glucose or insulin.

Figure 3

Flow diagram of the Sorensen glucose model [12].

Figure 4

Biphasic insulin response to step increase in glucose, as modeled by Nomura et al. [62]. At time zero the glucose concentration is increased from 80 mg/dL to 160 mg/dL and maintained at the new level. A basal insulin concentration of 15 mU/L was assumed, as the results of the model simulation are given as insulin levels above basal. At the time of the glucose change, a sharp spike in insulin occurs, known as first phase release. This response falls off rapidly, followed by a second delayed release phase that gradually increases to the steady state insulin value.

Figure 5

Schematic of mechanics of pH-responsive cationic hydrogels with glucose oxidase, based on the work of Podual [93]. Glucose appearance results in the production of gluconic acid, which decreases the system pH. pH-induced swelling results in increased diffusion of insulin from within the gel. As glucose is utilized, the mechanism is reversed.