Metabolic consequences of successful simultaneous pancreas kidney transplantation in humans

Currently, simultaneous pancreas-kidney transplantation or pancreas transpl antation alone are the only treatments that can pro,ide sufficient endogeno us insulin secretion and cessation of erogenous insulin administration in m ost patients with long standing type 1 diabetes and end stage nephropathy. However, posttransplant glucose metabolism mag not be entirely normalized b ecause 1) systemic insulin delivery results in peripheral: hyperinsulinemia , 2) only parts of the donor pancreas may be transplanted (segmental pancre as),3) immunosuppression, which is necessary to avoid rejection, causes ins ulin resistance and increases insulin secretory demand, and 4) the transpla nted pancreas is denervated. Despite systemic delivery of insulin, pancreas -kidney transplantation in diabetic patients results in a glucose metabolis m close to that of nondiabetic kidney transplant subjects receiving the sam e immunosuppressive treatment. The insulin secretory capacity of the pancre atic beta-cells of the graft is pivotal. Given changes in the kinetics of i nsulin and C-peptide, and in the glycemic responses and insulin resistance, insulin secretion is still relatively impaired in many recipients. Both qu antitative and qualitative defects in insulin secretion in response to beta -cell secretagogues are seen. The deficient insulin secretion is more commo n in segmental (versus whole) pancreas transplant recipients, inasmuch as t he number of beta-cells transplanted is the major determinant of glucose ho meostasis, Underlying insulin resistance, which is increased by 25-60%, is primarily attributable to mandatory immunosuppressive treatment and is by f ar the most important cause of the increased insulin secretory demand on th e pancreas graft. Insulin resistance is dominated by reduced peripheral glu cose uptake caused by impaired nonoxidative glucose metabolism in insulin-s ensitive tissues, primarily skeletal muscle. Hepatic glucose production and splanchnic glucose metabolism are largely normal. In response to hypoglyce mia, glucagon and epinephrine secretion improve substantially after pancrea s transplantation, but norepinephrine secretion does not. Further, pancreas transplantation has beneficial effects on lipids and lipoprotein profiles. Other studies have shown that pancreas transplantation seems to halt the p rogression in late diabetic complications to some extent and significantly improves quality of life. In the future, newer immunosuppressive agents may further improve patient and graft survival as well as improve graft functi on and limit side effects of the treatment.