Physiological and Pharmacological Stimulation of Pancreatic Islet Hormone Secretion in Type I Diabetic Pancreas Allograft Recipients

Abstract

Successful heterotopic and denervated pancreas allograft transplantation (PAT) often results in normoglycemia and peripheral hyperinsulinemia in insulin-dependent (type I) diabetic recipients. The contribution of altered hepatic insulin extraction (HIE) to the resulting hyperinsulinemia in such patients remains uncertain. Furthermore, whether the denervated pancreas allografts exhibit β-cell hyperresponsiveness to physiological and pharmacological stimulation is controversial. We evaluated β-cell function and HIE after successful whole cadaveric PAT with systemic venous drainage in 13 type I diabetic patients before and after mixed-meal and intravenous glucose and glucagon administration. The results were compared with those of 5 nondiabetic patients with kidney transplantation only, who had native innervated pancreases with portal insulin delivery and were receiving an equivalent triple immunosuppressive therapy (cyclosporin, azathioprine, and prednisone), and 7 healthy control subjects with no family history of diabetes. After PAT, fasting and poststimulation serum glucose concentrations were normalized. PAT was associated with marked basal hyperinsulinemia (3- to 8-fold) as assessed by immunoreactive insulin (IRI) levels in type I diabetic patients (mean ± SE 345 ± 43 pM) compared with control subjects (43 ± 14 pM) and nondiabetic kidney-transplantation patients (129 ± 38 pM). After mixed-meal ingestion, the mean incremental integrated insulin area was similar in PAT patients (18 ± 3 nM · min) compared with kidneytransplantation patients (20 ± 4 nM · min) and healthy control subjects (21 ± 3 nM · min). Basal serum Cpeptide levels were significantly greater in PAT (1.72 ± 0.13 nM) and kidney-transplantation (2.15 ± 0.33 nM) patients than in healthy control subjects (0.50 ± 0.10 nM; P < 0.01). In contrast, the post-mixed-meal incremental integrated C-peptide area was significantly lower in PAT (95 ± 20 nM · min) than in kidneytransplantation (304 ± 42 nM · min; P < 0.001) patients, but it was similar to that of healthy control subjects (100 ± 14 nM · min). Although the acute first and second phases of insulin response were greater in PAT patients after intravenous glucose, the corresponding C-peptide responses were not different among the three groups. The mean basal steady-state molar ratios of C-peptide and insulin that reflect basal HIE were significantly reduced by 70 and 60% in PAT patients compared with kidney-transplantation patients and healthy control subjects, respectively (P < 0.01). In summary, successful heterotopic PAT results in normalization of glycemic control at basal conditions and after physiological and pharmacological stimulations in type I diabetic patients; however, the normalized glucose concentrations occur at the expense of markedly elevated basal IRI that could be ascribed to severe insulin resistance and decreased HIE caused by direct systemic venous drainage that bypasses the liver rather than β-cell hyperresponsiveness.