<p>Type 1 diabetes mellitus affects millions of people worldwide. Islet transplantation is a minimal invasive surgical procedure that restores euglycemia and halts the progression of diabetic complications. However, despite transplantation of islets from multiple donors most patients reverse to hyperglycemia within five years. New strategies to improve long-term outcome of islet transplantation are indispensable. This thesis studied differences in the microvasculature between endogenous and transplanted pancreatic islets, and investigated means to improve islet graft revascularization and function. Islet graft microvessels were similar to endogenous islets responsive to adenosine, angiotensin II and nitric oxide (NO). Recipient hyperglycemia induced a higher basal islet graft blood flow, which also was less dependent on NO than in normoglycemic recipients. Transplantation of freshly isolated instead of cultured islets improved graft revascularization, oxygenation and function. Pretreatment of islets with vascular endothelial growth factor decreased their expression of matrix metalloproteinase-9 (MMP-9) and impaired graft revascularization. Moreover, MMP-9 pretreatment <i>per se</i> improved graft revascularization. <i>In vivo</i>, 20-25% of all endogenous rat islets was low oxygenated (pO₂ <10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Interestingly, oxygenation was related to metabolism, since well oxygenated islets <i>in vivo</i> had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis. In intraportally transplanted islets, the low oxygenated fraction of islets was markedly increased one day post-transplantation, and the oxygenation remained low following revascularization. In summary, these data suggest that a better revascularization of transplanted islets can improve graft function. Furthermore, the oxygenation and metabolism of endogenous islets is tightly regulated. This regulation seems to be disturbed following transplantation, which may contribute to long-term islet graft failure. </p>

Type 1 diabetes mellitus affects millions of people worldwide. Islet transplantation is a minimal invasive surgical procedure that restores euglycemia and halts the progression of diabetic complications. However, despite transplantation of islets from multiple donors most patients reverse to hyperglycemia within five years. New strategies to improve long-term outcome of islet transplantation are indispensable. This thesis studied differences in the microvasculature between endogenous and transplanted pancreatic islets, and investigated means to improve islet graft revascularization and function. Islet graft microvessels were similar to endogenous islets responsive to adenosine, angiotensin II and nitric oxide (NO). Recipient hyperglycemia induced a higher basal islet graft blood flow, which also was less dependent on NO than in normoglycemic recipients. Transplantation of freshly isolated instead of cultured islets improved graft revascularization, oxygenation and function. Pretreatment of islets with vascular endothelial growth factor decreased their expression of matrix metalloproteinase-9 (MMP-9) and impaired graft revascularization. Moreover, MMP-9 pretreatment per se improved graft revascularization. In vivo, 20-25% of all endogenous rat islets was low oxygenated (pO2 &lt;10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Interestingly, oxygenation was related to metabolism, since well oxygenated islets in vivo had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis. In intraportally transplanted islets, the low oxygenated fraction of islets was markedly increased one day post-transplantation, and the oxygenation remained low following revascularization. In summary, these data suggest that a better revascularization of transplanted islets can improve graft function. Furthermore, the oxygenation and metabolism of endogenous islets is tightly regulated. This regulation seems to be disturbed following transplantation, which may contribute to long-term islet graft failure.

<p>Transplanting pancreatic islets into the liver through the portal vein is currently the most common procedure in clinical islet transplantations for treating patients with brittle type 1 diabetes. However, most islet grafts fail within a 5-year period necessitating retransplantation. The vascular connections are disrupted at islet isolation and implanted islets depend on diffusion of oxygen and nutrients in the immediate posttransplantation period. Rapid and efficient revascularization is of utmost importance for the survival and long-term function of transplanted islets. </p><p>In this thesis, the influence of the implantation microenvironment for islet engraftment and function was studied. Islets were transplanted into the liver, the renal subcapsular site or the pancreas. Islets implanted into the liver contained fewer glucagon-positive cells than islets implanted to the kidney and endogenous islets. Intraportally transplanted islets responded with insulin and glucagon release to secretagogues, but only when stimulated through the hepatic artery. Thus, the intrahepatic grafts were selectively revascularized from the hepatic artery. The vascular density in human islets transplanted into the liver of athymic mice was markedly lower when compared to human islets grafted to the kidney. Islets implanted into their physiological environment, the pancreas, were markedly better revascularized. Insulin content, glucose-stimulated insulin release, (pro)insulin biosynthesis and glucose oxidation rate were markedly decreased in transplanted islets retrieved from the liver, both when compared to endogenous and transplanted islets retrieved from the pancreas. Only minor changes in metabolic functions were observed in islets implanted into the pancreas when compared to endogenous islets. </p><p>The present findings demonstrate that the microenvironment has a major impact on the engraftment of transplanted islets. Elucidating the beneficial factors that promote engraftment would improve the survival and long-term function of transplanted islets. Ultimately, islet transplantation may be provided to an increased number of patients with type 1 diabetes.</p>

Transplanting pancreatic islets into the liver through the portal vein is currently the most common procedure in clinical islet transplantations for treating patients with brittle type 1 diabetes. However, most islet grafts fail within a 5-year period necessitating retransplantation. The vascular connections are disrupted at islet isolation and implanted islets depend on diffusion of oxygen and nutrients in the immediate posttransplantation period. Rapid and efficient revascularization is of utmost importance for the survival and long-term function of transplanted islets. In this thesis, the influence of the implantation microenvironment for islet engraftment and function was studied. Islets were transplanted into the liver, the renal subcapsular site or the pancreas. Islets implanted into the liver contained fewer glucagon-positive cells than islets implanted to the kidney and endogenous islets. Intraportally transplanted islets responded with insulin and glucagon release to secretagogues, but only when stimulated through the hepatic artery. Thus, the intrahepatic grafts were selectively revascularized from the hepatic artery. The vascular density in human islets transplanted into the liver of athymic mice was markedly lower when compared to human islets grafted to the kidney. Islets implanted into their physiological environment, the pancreas, were markedly better revascularized. Insulin content, glucose-stimulated insulin release, (pro)insulin biosynthesis and glucose oxidation rate were markedly decreased in transplanted islets retrieved from the liver, both when compared to endogenous and transplanted islets retrieved from the pancreas. Only minor changes in metabolic functions were observed in islets implanted into the pancreas when compared to endogenous islets. The present findings demonstrate that the microenvironment has a major impact on the engraftment of transplanted islets. Elucidating the beneficial factors that promote engraftment would improve the survival and long-term function of transplanted islets. Ultimately, islet transplantation may be provided to an increased number of patients with type 1 diabetes.