Intraportal islet oxygenation

Abstract

Islet transplantation (IT) is a promising therapy for the treatment of diabetes. The large number of islets required to achieve insulin independence limit its cost-effectiveness and the number of patients who can be treated. It is believed that >50% of islets are lost in the immediate post-IT period. Poor oxygenation in the early post-IT period is recognized as a possible reason for islet loss and dysfunction but has not been extensively studied. Several key variables affect oxygenation in this setting, including (1) local oxygen partial pressure (pO(2)), (2) islet oxygen consumption, (3) islet size (diameter, D), and (4) presence or absence of thrombosis on the islet surface. We discuss implications of oxygen-limiting conditions on intraportal islet viability and function. Of the 4 key variables, the islet size appears to be the most important determinant of the anoxic and nonfunctional islet volume fractions. Similarly, the effect of thrombus formation on the islet surface may be substantial. At the University of Minnesota, average size distribution data from clinical alloislet preparations (n = 10) indicate that >150-µm D islets account for only ~30% of the total islet number, but >85% of the total islet volume. This suggests that improved oxygen supply to the islets may have a profound impact on islet survivability and function since most of the β-cell volume is within large islets which are most susceptible to oxygen-limiting conditions. The assumption that the liver is a suitable islet transplant site from the standpoint of oxygenation should be reconsidered.

Keywords: anoxia; hypoxia; intraportal transplant; islet transplant; oxygenation.

Figure 1.

Sketch illustrating an islet in the native pancreas (left) and an islet that has been intraportally transplanted (right). The native islet is well perfused with arterial blood, whereas the transplanted islet obtains oxygen from the surrounding intraportal blood and relies solely on oxygen diffusion from its surface before it becomes revascularized and possibly indefinitely if not revascularized well.

Figure 2.

Schematic depicting the effect of different variables on intraportal islet oxygenation and anoxic core formation. The ideal case in terms of oxygenation involves a small diameter (D) islet with minimal metabolic demand (or low oxygen consumption rate [OCR]), high local oxygen partial pressure (pO₂) (>40 mmHg) and no thrombosis. Unfortunately, most cases are likely to be worse in terms of oxygenation and involve unfavorable changes to some of these key variables. Cases 1 to 4 depict approximate and relative sizes of the anoxic core that would form if 1 of the key variables were unfavorably adjusted within a realistic range of values. Case 1 involves a small D islet under conditions of low pO₂ (<10 mmHg). Case 2 involves a small D islet with a high OCR. Case 3 involves a small D islet with formation of a thrombus on the surface of the islet. Case 4 involves a large D islet. Finally, if all variables are affected unfavorably, then most of the islet would be anoxic; the worst case would involve a large D islet with high OCR, low local pO₂, and thrombus formation on its surface.

Figure 3.

Islet size distribution as stratified by ranges of islet diameter, D (A). Mean (± standard error, SE) number fractions are representative data averaged from 10 human alloislet preparations (high-purity, cultured fractions) produced at the University of Minnesota from February 2011 to January 2012. Mean (± SE) volume fractions are estimated from number fraction data by calculating the mean islet volumes under the assumption that the islets are spherical with a median D for that size range. Of the total number of islets, 32% were >150-µm in D, but these islets account for 86% of the total transplantable volume of islet tissue.