The Effect of Transplantation Site and Islet Mass on Long-Term Survival and Metabolic and Hormonal Function of Canine Purified Islet Autografts

Abstract

Determination of the long-term function of islet transplantation in relation to the implantation site and the numbers of islets is of scientific interest and, with human islet transplant trials in progress, is a pressing clinical question. In this study, highly purified canine islets were isolated by collagenase digestion and Ficoll purification, and autotransplanted into either the spleen (in 10 dogs) or the liver (in 12 dogs). Dogs transplanted with islets into the spleen or liver received 264,300 +/- 20,300 (mean +/- SEM) and 158,600 +/- 15,000 islet equivalents (150-microns-sized islets) respectively. Graft survival at 1 yr was 86% in intrasplenic islet autografts (ISTx) and 50% in intraportal islet autografts (IPTx). Intravenous glucose tolerance tests and mixed meal-oral glucose tests were performed 1-12 mo from islet transplantation. Compared to controls, ISTx and IPTx dogs showed a similar decrease of glucose tolerance after both intravenous glucose tolerance tests and mixed meal-oral glucose tests. On intravenous glucose tolerance tests, plasma insulin levels were lower in ISTx than in IPTx dogs and controls. On mixed meal-oral glucose tests, insulin values were higher in IPTx dogs than in controls. There was a positive correlation (r = .56, p < 0.05) between the number of transplanted islet equivalents and the K values. These results demonstrate that, in dogs with islet transplant: 1) long-term islet survival can be achieved in the spleen better than in the liver; 2) islet survival is related to the mass of transplanted islets in the spleen, but not in the liver, where other factors probably affect islet survival; 3) the ability of metabolizing glucose is reduced after both intrasplenic and intraportal islet autografts; 4) both reduced insulin secretion (predominant in ISTx dogs on intravenous glucose tolerance testing) and insulin resistance (predominant in IPTx dogs on mixed meal-oral glucose tests) are the probable causes of the decreased glucose tolerance.

The Defective Glucagon Response From Transplanted Intrahepatic Pancreatic Islets During Hypoglycemia Is Transplantation Site–Determined

“…In searching for the cause of this abnormality, a generalized defect in acell secretory function can be excluded, because glucagon responses to intravenous arginine, although reduced in magnitude after both intrahepatic and intraperitoneal islet transplant, were present in both the human and canine studies. This is consistent with the observed presence of immunostainable glucagon in a-cells that have been obtained in liver biopsies (12,15,22) and with reports that intrahepatic islet autografts secrete glucagon after the ingestion of a mixed meal (11) and during exercise (23). The reduced magnitude of the arginine-induced glucagon response following islet transplantation is likely the result of an overall reduction in islet cell mass.…”

“…The introduction of transplanted islets into the portal vein with subsequent engraftment in the liver has been the most common method of PICT. Whether the hepatic environment is as conducive for the long-term function of islet grafts as other sites of islet transplantation, notably the spleen and kidney, has been increasingly questioned (7)(8)(9)(10)(11).…”

“…While many studies have focused on the longevity and function of pancreatic-islet (3-cells that have been engrafted in the liver (6,(10)(11)(12)(13)(14)(15), the assessment of a-cell function after intrahepatic islet transplantation is very limited. In the first human study of a-cell function, Pyzdrowski et al (15) demonstrated that islets transplanted in the liver failed to secrete glucagon in response to hypoglycemia that was induced by a bolus of intravenous insulin, yet retained responses to intravenous arginine.…”

Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study

“…Experimentally, many different sites have been proposed as suitable locations for Islet transplantation. These vary from the metabolically logical, such as the liver (16) and spleen (17), to the convenient, such as the kidney capsule (18) and omental pouch (19), to immunologically privileged, such as the testis (20). Locating the islets subcutaneously has also been advocated (21,22).…”

Imaging Islets Labeled With Magnetic Nanoparticles at 1.5 Tesla

“…A number of alternate sites have been proposed as more suitable locations for islet transplantation. These include the spleen (8,9), the kidney capsule (9,10), the omental pouch (11), the gall bladder (12), intracerebrally (13), the rectum (14), mammary fat pads (15), and the testis (16). Locating the islets subcutaneously has also been advocated (17,18).…”