11C-dihydrotetrabenazine PET of the Pancreas in Subjects with Long-standing Type 1 Diabetes and in Healthy Controls

Overview

Journal J Nucl Med

Specialty Nuclear Medicine

Date 2009 Feb 19

PMID 19223416

Citations 58

Authors

Robin Goland

Matthew Freeby

Ramin Parsey

Yoshifumi Saisho

Dileep Kumar

Norman Simpson

Joy Hirsch

Martin Prince

Antonella Maffei

J John Mann

Peter C Butler

Ronald Van Heertum

Rudolph L Leibel

Masanori Ichise

Paul E Harris

Affiliations

Soon will be listed here.

Abstract

Unlabelled: 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.

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References

de Vries E, van Waarde A, Buursma A, Vaalburg W . Synthesis and in vivo evaluation of 18F-desbromo-DuP-697 as a PET tracer for cyclooxygenase-2 expression. J Nucl Med. 2003; 44(10):1700-6. View

Parsey R, Ojha A, Ogden R, Erlandsson K, Kumar D, Landgrebe M . Metabolite considerations in the in vivo quantification of serotonin transporters using 11C-DASB and PET in humans. J Nucl Med. 2006; 47(11):1796-802. View

Wajchenberg B . beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007; 28(2):187-218. DOI: 10.1210/10.1210/er.2006-0038. View

Erickson J, Schafer M, Bonner T, Eiden L, Weihe E . Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci U S A. 1996; 93(10):5166-71. PMC: 39426. DOI: 10.1073/pnas.93.10.5166. View

Kung M, Hou C, Lieberman B, Oya S, Ponde D, Blankemeyer E . In vivo imaging of beta-cell mass in rats using 18F-FP-(+)-DTBZ: a potential PET ligand for studying diabetes mellitus. J Nucl Med. 2008; 49(7):1171-6. DOI: 10.2967/jnumed.108.051680. View

DaSilva J, Kilbourn M . In vivo binding of [11C]tetrabenazine to vesicular monoamine transporters in mouse brain. Life Sci. 1992; 51(8):593-600. DOI: 10.1016/0024-3205(92)90228-h. View

McCulloch D, Koerker D, Kahn S, Bonner-Weir S, Palmer J . Correlations of in vivo beta-cell function tests with beta-cell mass and pancreatic insulin content in streptozocin-administered baboons. Diabetes. 1991; 40(6):673-9. DOI: 10.2337/diab.40.6.673. View

Kilbourn M, Lee L, Vander Borght T, Jewett D, Frey K . Binding of alpha-dihydrotetrabenazine to the vesicular monoamine transporter is stereospecific. Eur J Pharmacol. 1995; 278(3):249-52. DOI: 10.1016/0014-2999(95)00162-e. View

Vander Borght T, Kilbourn M, Desmond T, Kuhl D, Frey K . The vesicular monoamine transporter is not regulated by dopaminergic drug treatments. Eur J Pharmacol. 1995; 294(2-3):577-83. DOI: 10.1016/0014-2999(95)00594-3. View

10.

Tsai E, Sherry N, Palmer J, Herold K . The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia. 2006; 49(2):261-70. DOI: 10.1007/s00125-005-0100-8. View

11.

Dotta F, Censini S, van Halteren A, Marselli L, Masini M, Dionisi S . Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A. 2007; 104(12):5115-20. PMC: 1829272. DOI: 10.1073/pnas.0700442104. View

12.

Mehvar R, Jamali F, Watson M, Skelton D . Pharmacokinetics of tetrabenazine and its major metabolite in man and rat. Bioavailability and dose dependency studies. Drug Metab Dispos. 1987; 15(2):250-5. View

13.

Butler A, Galasso R, Meier J, Basu R, Rizza R, Butler P . Modestly increased beta cell apoptosis but no increased beta cell replication in recent-onset type 1 diabetic patients who died of diabetic ketoacidosis. Diabetologia. 2007; 50(11):2323-31. DOI: 10.1007/s00125-007-0794-x. View

14.

Pick A, Clark J, Kubstrup C, Levisetti M, Pugh W, Bonner-Weir S . Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes. 1998; 47(3):358-64. DOI: 10.2337/diabetes.47.3.358. View

15.

Maffei A, Liu Z, Witkowski P, Moschella F, Del Pozzo G, Liu E . Identification of tissue-restricted transcripts in human islets. Endocrinology. 2004; 145(10):4513-21. DOI: 10.1210/en.2004-0691. View

16.

Kloppel G, Drenck C, Oberholzer M, Heitz P . Morphometric evidence for a striking B-cell reduction at the clinical onset of type 1 diabetes. Virchows Arch A Pathol Anat Histopathol. 1984; 403(4):441-52. DOI: 10.1007/BF00737292. View

17.

Raffo A, Hancock K, Polito T, Xie Y, Andan G, Witkowski P . Role of vesicular monoamine transporter type 2 in rodent insulin secretion and glucose metabolism revealed by its specific antagonist tetrabenazine. J Endocrinol. 2008; 198(1):41-9. PMC: 2712213. DOI: 10.1677/JOE-07-0632. View

18.

Meier J, Butler A, Saisho Y, Monchamp T, Galasso R, Bhushan A . Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes. 2008; 57(6):1584-94. PMC: 3697779. DOI: 10.2337/db07-1369. View

19.

Ichise M, Liow J, Lu J, Takano A, Model K, Toyama H . Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab. 2003; 23(9):1096-112. DOI: 10.1097/01.WCB.0000085441.37552.CA. View

20.

Kim J, Ichise M, Sangare J, Innis R . PET imaging of serotonin transporters with [11C]DASB: test-retest reproducibility using a multilinear reference tissue parametric imaging method. J Nucl Med. 2006; 47(2):208-14. View