11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls

Type 2 vesicular monoamine transporter (VMAT2), found in the brain, is also expressed by P-cells of the pancreas in association with insulin. Preclinical experiments suggested that C-11-dihydrotetrabenazine PET-measured VMAT2 binding might serve as a biomarker of P-cell mass. We evaluated the feasibility of C-11- dihydrotetrabenazine PET quantification of pancreatic VMAT2 binding in healthy subjects and patients with long-standing type 1 diabetes. Methods: C-11-Dihydrotetrabenazine PET was performed on 6 patients and 9 controls. VMAT2 binding potential (BPND) was estimated voxelwise by using the renal cortex as reference tissue. As an index of total pancreatic VMAT2, the functional binding capacity (the sum of voxel BPND x voxel volume) was calculated. Pancreatic BPND, functional binding capacity, and stimulated insulin secretion measurements were compared between groups. Results: The pancreatic mean BPND was decreased in patients (1.86 +/- 0.05) to 86% of control values (2.14 +/- 0.08) (P = 0.01). In controls, but not in patients, BPND correlated with stimulated insulin secretion (r(2) = 0.50, P = 0.03). The average functional binding capacity was decreased by at least 40% in patients (P = 0.001). The changes in functional binding capacity and BPND were less than the near-complete loss of stimulated insulin secretion observed in patients (P = 0.001). Conclusion: These results suggest that C-11-dihydrotetrabenazine PET allows quantification of VMAT2 binding in the human pancreas. However, BPND and functional binding capacity appear to overestimate beta-cell mass given the near-complete depletion of p-cell mass in long-standing type 1 diabetes, which may be due to higher nonspecific binding in the pancreas than in the renal cortex.