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

Abstract

Type 2 vesicular monoamine transporter (VMAT2), found in the brain, is also expressed by beta-cells of the pancreas in association with insulin. Preclinical experiments suggested that (11)C-dihydrotetrabenazine PET-measured VMAT2 binding might serve as a biomarker of beta-cell mass. We evaluated the feasibility of (11)C-dihydrotetrabenazine PET quantification of pancreatic VMAT2 binding in healthy subjects and patients with long-standing type 1 diabetes.

Methods: (11)C-Dihydrotetrabenazine PET was performed on 6 patients and 9 controls. VMAT2 binding potential (BP(ND)) 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 BP(ND) x voxel volume) was calculated. Pancreatic BP(ND), functional binding capacity, and stimulated insulin secretion measurements were compared between groups.

Results: The pancreatic mean BP(ND) 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, BP(ND) 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 BP(ND) were less than the near-complete loss of stimulated insulin secretion observed in patients (P = 0.001).

Conclusion: These results suggest that (11)C-dihydrotetrabenazine PET allows quantification of VMAT2 binding in the human pancreas. However, BP(ND) and functional binding capacity appear to overestimate beta-cell mass given the near-complete depletion of beta-cell mass in long-standing type 1 diabetes, which may be due to higher nonspecific binding in the pancreas than in the renal cortex.

Figures

Figure 1

Representative time–activity curves of 11C-dihydrotetrabenazine uptake in pancreas and left renal cortex of study subjects. Time–activity curves are shown with circles and squares for pancreas and left renal cortex, respectively, and open and solid symbols indicate 1 control and 1 patient, respectively.

Figure 2

Transverse 11C-dihydrotetrabenazine PET images of patients (top row) and controls (bottom row). Summed dynamic PET images were obtained 0–90 min after injection of approximately 481–555 MBq of 11C-dihydrotetrabenazine (left). Corresponding tissue segmentation images are also shown (middle), with different colors being used to represent different organs. Voxelwise parametric images of VMAT2 binding potential (BPND) are shown (right) using another color scale (right bottom). These BPND images are fused onto segmentation image using gray scale, with pancreatic ROI boundary shown using dotted blue outlines (right). L = liver; K = kidney; S = stomach; P = pancreas.

Figure 3

Association between binding potential and glucose-stimulated insulin secretion in controls. BPND values and AUC c-peptide measures for each control were evaluated for strength of association by linear correlation. Regression line (BPND = 0.001 · AUC c-peptide + 1.504) yielded r2 of 0.50 and P value of 0.03. x- and y-intercepts were −1.504 and 1.504, respectively.

Figure 4

VMAT2 functional binding capacity of controls and patients. This histogram plots product of BPND and voxel (Vox.) volume at each BPND interval for controls and patients. Functional binding capacity is sum of all columns for each population. Percentage functional binding capacity of patients relative to controls is shown above histogram. Inset shows another histogram considering only BPND values greater than 2.5 as representative of β-cell mass. Percentage functional binding capacity of patients relative to controls is also shown. Error bars represent SEM.

Figure 5

Histogram summary of voxel BPND in controls and patients. (Top) Average number of voxels at each BPND interval is displayed for controls (n = 9) (white bars) and patients (n = 6) (black bars). Error bars represent SEM. (Bottom) Number of voxels at each BPND interval was normalized to total number of voxels in ROI for each individual and displayed as mean for controls and patients (i.e., this is a frequency histogram). Asterisks indicate statistically significant differences (P < 0.05, Student t test) between controls and patients.