Preservation of the incretin effect after orthotopic pancreas transplantation in inbred rats

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To establish whether the incretin effect is under neural control, insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) responses and hepatic insulin clearance were investigated after oral and “isoglycemic” intravenous glucose in 12 inbred rats after denervation of the pancreas by orthotopic transplantation with portal venous drainage (Tx group) and in 12 laparotomized controls (sham group). Effective pancreas denervation was documented by a decreased pancreatic polypeptide (PP) response to insulin-induced hypoglycemia and by decreased levels of norepinephrine and calcitonin gene—related peptide (CGRP) in pancreatic tissue. Basal and incremental arterial plasma glucose integrated over 180 minutes did not differ between oral and intravenous glucose, but the integrated insulin response (mean ± SEM) was significantly greater with oral versus intravenous glucose (Tx group, 104.9 ± 22.0 v 31.0 ± 4.9 nmol · L −1 · min, P < .01; sham group, 79.5 ± 10.6 v 36.6 ± 5.8 nmol · L −1 · min, P < .01). The integrated response of C-peptide was similar during both tests (Tx group, 105 ± 14 v 79 ± 8 pmol · mL −1 · min; sham group, 112 ± 10 v 121 ± 12 pmol · mL −1 · min). Hepatic insulin clearance was significantly decreased in both groups by oral compared with intravenous glucose administration (Tx group, 1.3 ± 0.2 v 3.3 ± 0.6 mmol/mmol, P < .01; sham group, 1.6 ± 0.1 v 3.9 ± 0.6 mmol/mmol, P < .02). The incretin effects for insulin (Tx group, 5.6 ± 2.7; sham group, 3.0 ± 0.8) and C-peptide (Tx group, 1.4 ± 0.2; sham group, 1.1 ± 0.2), calculated as the ratio of the integrated oral response and integrated intravenous response, and GIP responses to oral and intravenous glucose were not significantly different between the two groups. We conclude that there is preservation of the incretin effect in rats with orthotopically transplanted and hence extrinsically denervated pancreas, thus ruling out the possibility that the autonomic nervous system substantially contributes. Hepatic insulin clearance and insulinotropic hormones such as GIP appear to be more important.