Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions

Abstract

Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin-deficient diabetes. Recent progress in techniques for islet isolation, islet culture, and peritransplant management of the islet transplant recipient has resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or subtotal pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate postsurgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality of life is substantially improved. For patients with type 1 diabetes or insulin-deficient forms of pancreatogenic (type 3c) diabetes, isolation of islets from a deceased donor pancreas with intrahepatic transplantation of allogeneic islets can ameliorate problematic hypoglycemia, stabilize glycemic lability, and maintain on-target glycemic control, consequently with improved quality of life, and often without the requirement for insulin therapy. Because the metabolic benefits are dependent on the numbers of islets transplanted that survive engraftment, recipients of autoislets are limited to receive the number of islets isolated from their own pancreas, whereas recipients of alloislets may receive islets isolated from more than one donor pancreas. The development of alternative sources of islet cells for transplantation, whether from autologous, allogeneic, or xenogeneic tissues, is an active area of investigation that promises to expand access and indications for islet transplantation in the future treatment of diabetes.

Figure 1.

Procedure for total pancreatectomy with islet autotransplantation. The diseased pancreas is resected during total pancreatectomy together with the duodenum and the spleen, which both share their arterial blood supply with the pancreas. While gastrojejunostomy and choledochojejunostomy Roux-en-Y reconstruction is performed, the pancreas is brought to a cGMP or cGTP islet isolation facility where it is digested by collagenases and undergoes variable centrifuge purification that separates the acinar from the endocrine cells with the goal of maximizing islet recovery while minimizing the transplanted tissue volume. The final islet product is transplanted intraportally via the splenic vein stump, a mesenteric vein, or recannulation of the umbilical vein. If excessive portal pressure is caused by a high tissue volume, a portion of the islet product may be placed in the peritoneal cavity or other nonhepatic site.

Figure 2.

Procedure for islet allotransplantation. A pancreas is procured from a deceased donor without diabetes and brought to a cGMP islet isolation facility where it is digested by collagenases and purified by centrifugation with the final islet product placed in culture for up to 72 h prior to intraportal delivery in a recipient with type 1 diabetes. Shown here is percutaneous, transhepatic access to the main portal vein via a right portal branch vein identified under ultrasound and fluoroscopic guidance. Alternatively, access to the main portal vein can be achieved via a mesenteric vein identified by direct visualization during minilaparotomy.

Figure 3.

Peritransplant management for islet autotransplantation. At the time of pancreatectomy, insulin therapy is initiated IV according to a modified hospital protocol targeting normoglycemia, and at the time of islet infusion anticoagulation is initiated with unfractionated heparin. Once stable postoperatively and as oral intake is advanced, IV insulin and heparin are transitioned to subcutaneous regimens, antiplatelet therapy with aspirin is added, instruction in a carbohydrate-controlled diet is provided, and pancreatic enzyme replacement and acid-blocking therapy is initiated or resumed.

Figure 4.

Peritransplant management for islet allotransplantation. At the time a compatible islet preparation is available and enters culture, induction and maintenance immunosuppression is initiated in the hospital where intensive insulin therapy is maintained targeting normoglycemia. At the time of islet infusion, anti-inflammatory therapy (e.g., etanercept) and anticoagulation are initiated, with unfractionated heparin transitioned to a subcutaneous regimen with antiplatelet therapy using low-dose aspirin added by the second day. [Shown is the B7 protocol from Hering BJ, Clarke WR, Bridges ND, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 2016;39:1230–1240; other approaches may vary.]

Figure 5.

Functional islet β-cell mass estimated from the β-cell secretory capacity. β-Cell secretory capacity is measured as the acute insulin response to glucose-potentiated arginine and shown for insulin-independent autoislet and alloislet recipients as the percentage of nondiabetic control values. Although in both groups a functional islet β-cell mass of ~40% to 50% of normal is achieved, when corrected for the number of islet equivalents transplanted (and assuming 1 million islets are present in the controls), there remains an ~25% loss of islet β-cell mass in the alloislet recipients.

Figure 6.

Potential mechanisms explaining the risk for hypoglycemia experienced by recipients of intrahepatic autoislets following total pancreatectomy, as well as the amelioration of hypoglycemia experienced by type 1 diabetic recipients of intrahepatic alloislets. [Includes data from Rickels MR, Liu C, Shlansky-Goldberg RD, et al. Improvement in beta-cell secretory capacity after human islet transplantation according to the B7 protocol. Diabetes 2013; 62:2890-2897; and from Robertson RP, Bogachus LD, Oseid E, et al. Assessment of beta-cell mass and alpha- and beta-cell survival and function by arginine stimulation in human autologous islet recipients. Diabetes 2015;64:565–572.]