Decreased VMAT2 in the pancreas of humans with type 2 diabetes mellitus measured in vivo by PET imaging
- 378 Downloads
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 [18F]fluoropropyl-(+)-dihydrotetrabenazine to quantify BCM in humans with impaired glucose tolerance (prediabetes) or type 2 diabetes, and in healthy obese volunteers (HOV).
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.
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 HbA1c (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).
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.
KeywordsBeta cell mass Pancreas PET imaging Type 2 diabetes VMAT2
Arginine stimulus test
Acute insulin response to arginine for the standard AST
Acute insulin response to the glucose-enhanced AST
Absolute test–retest variability
Beta cell mass
Coefficient of variation
Fasting blood glucose
Healthy obese volunteer
Magnetic resonance imaging
Pfizer Clinical Research Unit
Positron emission tomography
Pancreatic polypeptide (cells)
Region of interest
Standardised uptake value
Standardised uptake value ratio
Vesicular monoamine transporter type 2
The authors appreciate the excellent technical assistance of staff at the Yale University PET Center, especially PET Technologists D. Ruggiero and E. Hidalgo, and the New Haven PCRU.
Some of the data were presented as an abstract at the ADA 76th Scientific Sessions, 10–14 June 2016, New Orleans, LA, USA.
All authors contributed to the conception and design of the study/protocol. LC, KC, SC-G, MR and JB researched data and contributed to discussion. GWC, MN and REC wrote the manuscript and researched data. All authors contributed to discussion and reviewed/edited the manuscript. All authors approved the final version of the manuscript. GWC is the guarantor of this work, had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.
This work was supported by the Yale-Pfizer Bioimaging Research Alliance and National Institutes of Health (NIH) grant 1S10OD010322-01. This publication was also made possible by Clinical and Translational Science Award Grant Number UL1 TR000142 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript. The sponsor, Pfizer Worldwide R&D, was involved in study design and data collection and provided editorial assistance.
- 20.Shankar SS, Vella A, Raymond RH et al (2016) Standardized mixed-meal tolerance and arginine stimulation tests provide reproducible and complementary measures of beta-cell function: results from the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series. Diabetes Care 39:1602–1613CrossRefGoogle Scholar