GLUCOREGULATION AFTER CANINE ISLET TRANSPLANTATION - CONTRIBUTION OF INSULIN SECRETORY CAPACITY, INSULIN ACTION, AND THE ENTEROINSULAR AXIS

The physiological glucoregulatory mechanisms after islet transplantati on have been incompletely investigated, We studied the insulin secreto ry capacity (ISC) by intravenous arginine stimulation during 35-mM glu cose clamps, insulin action during hyperinsulinemic euglycemic clamps, and mixed-meal stimulation at 6-9 mo after intrasplenic islet autotra nsplantation in 8 dogs, as compared with 30 controls, The enteroinsula r axis in the recipients was examined by infusion of porcine glucose-d ependent insulinotropic polypeptide (GIP) and human glucagon-like pept ide-1 (GLP-1) (7-36 amide) under 8.5-mM glycemic clamp conditions in o rder to mimic the postprandial glycemia after transplantation. The gra fts comprised 25% of the native islet mass, and the ISC likewise avera ged 25% of the control value, The postprandial insulin response, in co ntrast, had increased to 140% after transplantation-albeit with a conc omitant glucose excursion to approximately 8.5 mM, Insulin action decl ined on average by 45% posttransplant. The ISC correlated both with th e postprandial glucose excursion and insulin action in the grafted dog s, Insulin action did not correlate with the postprandial glucose excu rsion, Infusion of GIP had no effect, but GLP-1 nearly doubled glucose -stimulated insulin, Thus, a hyperglycemia-enhanced insulinotropic eff ect of GLP-1, and perhaps other gut hormones, may account for the diff erence in the insulin response to the intravenous and oral challenges, Because the ISC reflects the engrafted islet mass and appears to be t he primary determinant of glucose tolerance, transplantation of higher islet doses should allow prolonged near-normal glucoregulation-at lea st, in the autotransplant setting. (C) 1997 Elsevier Science Inc.