The relative contribution of insulin secretory capacity, insulin action, and incretins to metabolic control after islet transplantation in dogs

Adequate metabolic control is central to the concept of islet transplantati on, but has received limited attention. We studied metabolic control in 8 d ogs at 6-9 months after intrasplenic autografting of similar to 25% of the normal mass islets - as compared to 30 controls. A similar posttransplant r eduction to similar to 25% of the insulin secretory capacity as assessed by intravenous arginine stimulation during 35 mM glucose clamps, mirrored the reduction of the islet mass. Postprandially, in contrast, the insulin resp onse had increased to 140% in the islet recipients - with a concomitant ris e of glycemia to similar to 8.5 mM, Posttsansplant, the insulin secretory c apacity correlated both with the index of insulin action (which averaged 55 % of the normal value) as assessed by euglycemic hyperinsulinemic clamps;an d - inverse - with the postprandial glucose excursions. Because insulin act ion did not correlate with postprandial glucose, the insulin secretory capa city appears to be the primary determinant of the impaired glucose toleranc e. Marked postprandial hyperglucagonemia, and a virtually absent pancreatic polypeptide response in the grafted animals, may also have contributed to the impaired glucose tolerance. Posttransplant, infusion of a physiological dose of the gut hormone glucagon-like peptide-1 during 8.5 mM glucose clam ps,mimicking the postprandial glycemia - potentiated glucose-stimulated ins ulin 175%. Thus, after transplantation of a suboptimal islet mass, postpran dial glucose excursions are restrained by hyperglycemic potentiation of the entero-insular axis, which may account for the difference in the insulin r esponse to the intravenous and oral challenges. Because, the insulin secret ory capacity reflects the islet mass and appears to be the major determinan t of glucoregulation, transplantation of a larger islet mass may allow near -normal glycemic control.