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Decreased VMAT2 in the pancreas of humans with type 2 diabetes mellitus measured in vivo by PET imaging.

Authors :
Cline, Gary W.
Naganawa, Mika
Chen, Laigao
Chidsey, Kristin
Carvajal-Gonzalez, Santos
Pawlak, Sylvester
Rossulek, Michelle
Zhang, Yanwei
Bini, Jason
McCarthy, Timothy J.
Carson, Richard E.
Calle, Roberto A.
Source :
Diabetologia; Dec2018, Vol. 61 Issue 12, p2598-2607, 10p, 1 Diagram, 4 Charts, 3 Graphs
Publication Year :
2018

Abstract

Aims/hypothesis: The progressive loss of beta cell function is part of the natural history of type 2 diabetes. Autopsy studies suggest that this is, in part, due to loss of beta cell mass (BCM), but this has not been confirmed in vivo. Non-invasive methods to quantify BCM may contribute to a better understanding of type 2 diabetes pathophysiology and the development of therapeutic strategies. In humans, the localisation of vesicular monoamine transporter type 2 (VMAT2) in beta cells and pancreatic polypeptide cells, with minimal expression in other exocrine or endocrine pancreatic cells, has led to its development as a measure of BCM. We used the VMAT2 tracer [<superscript>18</superscript>F]fluoropropyl-(+)-dihydrotetrabenazine to quantify BCM in humans with impaired glucose tolerance (prediabetes) or type 2 diabetes, and in healthy obese volunteers (HOV).Methods: Dynamic positron emission tomography (PET) data were obtained for 4 h with metabolite-corrected arterial blood measurement in 16 HOV, five prediabetic and 17 type 2 diabetic participants. Eleven participants (six HOV and five with type 2 diabetes) underwent two abdominal PET/computed tomography (CT) scans for the assessment of test-retest variability. Standardised uptake value ratio (SUVR) was calculated in pancreatic subregions (head, body and tail), with the spleen as a reference region to determine non-specific tracer uptake at 3-4 h. The outcome measure SUVR minus 1 (SUVR-1) accounts for non-specific tracer uptake. Functional beta cell capacity was assessed by C-peptide release following standard (arginine stimulus test [AST]) and acute insulin response to the glucose-enhanced AST (AIRargMAX). Pearson correlation analysis was performed between the binding variables and the C-peptide AUC post-AST and post-AIRargMAX.Results: Absolute test-retest variability (aTRV) was ≤15% for all regions. Variability and overlap of SUVR-1 was measured in all groups; HOV and participants with prediabetes and with type 2 diabetes. SUVR-1 showed significant positive correlations with AIRargMAX (all groups) in all pancreas subregions (whole pancreas p = 0.009 and pancreas head p = 0.009; body p = 0.019 and tail p = 0.023). SUVR-1 inversely correlated with HbA<subscript>1c</subscript> (all groups) in the whole pancreas (p = 0.033) and pancreas head (p = 0.008). SUVR-1 also inversely correlated with years since diagnosis of type 2 diabetes in the pancreas head (p = 0.049) and pancreas tail (p = 0.035).Conclusions/interpretation: The observed correlations of VMAT2 density in the pancreas and pancreas regions with years since diagnosis of type 2 diabetes, glycaemic control and beta cell function suggest that loss of BCM contributes to deficient insulin secretion in humans with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
0012186X
Volume :
61
Issue :
12
Database :
Complementary Index
Journal :
Diabetologia
Publication Type :
Academic Journal
Accession number :
132880966
Full Text :
https://doi.org/10.1007/s00125-018-4624-0