Measurement Of Beta-cell Mass Research Articles

Editorial introductions.

Current Opinion in Endocrinology and Diabetes was launched in 1994, with Obesity added to the title in 2007. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The fields of endocrinology and diabetes are divided into 9 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editor and Section Editors for this issue. EDITOR IN CHIEF David M. HarlanDavid M. HarlanDr David M. Harlan is a graduate of the University of Michigan (Bachelor of Science) and the Duke University School of Medicine, USA. He completed his internal medicine internship and residency at the Duke University Medical Center. This was before serving for 4 years as a staff internist at the Navy Hospital, San Diego, CA, USA. He then returned to Duke for his fellowship training in diabetes, endocrinology, and metabolism. In 1991 he established his laboratory at the Navy Medical Research Institute, USA, where he rose to become the Director of Combat Casualty Care. He was then appointed to the faculty of the Uniformed Services University of the Health Sciences. In 1999, he moved his laboratory to the National Institutes of Health, where he became the Diabetes Branch Chief within the National Institute of Diabetes, Digestive, and Kidney Diseases. In 2010, he moved to the University of Massachusetts School of Medicine, USA, where he is the William and Doris Krupp Professor of Medicine and Diabetes Division Chief. Dr Harlan also co-directs the UMass Diabetes Center of Excellence. His research interests all relate to diabetes and include the immunopathogenesis underlying type 1 diabetes and improved care delivery models for the disease. SECTION EDITORS Matthew FreebyMatthew FreebyMatthew Freeby, MD, is Health Sciences Associate Clinical Professor of Medicine in the Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine at the University of California Los Angeles, USA. Dr Freeby received his MD from Virginia Commonwealth University, USA and completed his internal medicine internship and residency training at the University of California San Diego. He subsequently completed training in an endocrinology fellowship at Columbia University Medical Center in New York, USA. Dr Freeby is involved in community leadership for the American Diabetes Association and serves on planning committees for the Endocrine Society's annual meetings. His research has focused on a number of diabetes related topics including non-invasive in vivo measurement of beta cell mass as well as the evaluation of general care and complications. He has also collaborated with researchers evaluating iPS as a method for beta cell replacement in type 1 and other rare forms of diabetes. Lynne L. LevitskyLynne L. LevitskyDr Lynne L. Levitsky is a graduate of Bryn Mawr College and Yale Medical School, USA. She received her pediatric training at the Albert Einstein College of Medicine in New York, USA, and at the Children's Hospital of Philadelphia, USA. She was trained in pediatric endocrinology at the University of Maryland in Baltimore, USA. She was a Pediatric Endocrinologist and Professor of Pediatrics at the Pritzker School of Medicine, University of Chicago, USA, until 1990. She then came to Massachusetts General Hospital, USA, as Chief of the Pediatric Endocrine Unit and Associate Professor of Pediatrics at Harvard Medical School. She is now Emeritus Chief and co-director of the Turner Syndrome Wellness Center, USA. Her research interests in carbohydrate metabolism span laboratory studies of transcriptional control of beta cell function, and a role as an investigator in the NIH-sponsored TODAY treatment study of type 2 diabetes in the young. She is a past President of the Pediatric Endocrine Society and was the first head of the Education Council for that organization.

Editorial introductions

Current Opinion in Endocrinology and Diabetes was launched in 1994, with Obesity added to the title in 2007. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The fields of endocrinology and diabetes are divided into 9 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editor in chief and Section Editors for this issue. EDITOR IN CHIEF David M. HarlanDavid M. HarlanDr David M. Harlan is a graduate of the University of Michigan (Bachelor of Science) and the Duke University School of Medicine, USA. He completed his internal medicine internship and residency at the Duke University Medical Center. This was before serving for 4 years as a staff internist at the Navy Hospital, San Diego, CA, USA. He then returned to Duke for his fellowship training in diabetes, endocrinology, and metabolism. In 1991 he established his laboratory at the Navy Medical Research Institute, USA, where he rose to become the Director of Combat Casualty Care. He was then appointed to the faculty of the Uniformed Services University of the Health Sciences. In 1999, he moved his laboratory to the National Institutes of Health, where he became the Diabetes Branch Chief within the National Institute of Diabetes, Digestive, and Kidney Diseases. In 2010, he moved to the University of Massachusetts School of Medicine, USA, where he is the William and Doris Krupp Professor of Medicine and co-directs the UMass Diabetes Center of Excellence. His research interests all relate to diabetes and include the immunopathogenesis underlying type 1 diabetes and improved care delivery models for the disease. SECTION EDITORS Matthew J. FreebyMatthew J. FreebyMatthew J. Freeby, MD, is Health Sciences Associate Clinical Professor of Medicine in the Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine at the University of California Los Angeles, USA. Dr Freeby received his MD from Virginia Commonwealth University, USA and completed his internal medicine internship and residency training at the University of California San Diego. He subsequently completed training in an endocrinology fellowship at Columbia University Medical Center in New York, USA. Dr Freeby is involved in community leadership for the American Diabetes Association and serves on planning committees for the Endocrine Society's annual meetings. His research has focused on a number of diabetes related topics including non-invasive in vivo measurement of beta cell mass as well as the evaluation of general care and complications. He has also collaborated with researchers evaluating iPS as a method for beta cell replacement in type 1 and other rare forms of diabetes. Lynne L. LevitskyLynne L. LevitskyDr Lynne L. Levitsky is a graduate of Bryn Mawr College and Yale Medical School, USA. She received her pediatric training at the Albert Einstein College of Medicine in New York, USA, and at the Children's Hospital of Philadelphia, USA. She was trained in pediatric endocrinology at the University of Maryland in Baltimore, USA. She was a Pediatric Endocrinologist and Professor of Pediatrics at the Pritzker School of Medicine, University of Chicago, USA, until 1990. She then came to Massachusetts General Hospital, USA, as Chief of the Pediatric Endocrine Unit and Associate Professor of Pediatrics at Harvard Medical School. She is now Emeritus Chief and co-director of the Turner Syndrome Wellness Center, USA. Her research interests in carbohydrate metabolism span laboratory studies of transcriptional control of beta cell function, and a role as an investigator in the NIH-sponsored TODAY treatment study of type 2 diabetes in the young. She is a past President of the Pediatric Endocrine Society and was the first head of the Education Council for that organization.

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

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 4h 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 3-4h. 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.

Age-Corrected Beta Cell Mass Following Onset of Type 1 Diabetes Mellitus Correlates with Plasma C-Peptide in Humans

BackgroundThe inability to produce insulin endogenously precipitates the clinical symptoms of type 1 diabetes mellitus. However, the dynamic trajectory of beta cell destruction following onset remains unclear. Using model-based inference, the severity of beta cell destruction at onset decreases with age where, on average, a 40% reduction in beta cell mass was sufficient to precipitate clinical symptoms at 20 years of age. While plasma C-peptide provides a surrogate measure of endogenous insulin production post-onset, it is unclear as to whether plasma C-peptide represents changes in beta cell mass or beta cell function. The objective of this paper was to determine the relationship between beta cell mass and endogenous insulin production post-onset.Methods and FindingsModel-based inference was used to compare direct measures of beta cell mass in 102 patients against contemporary measures of plasma C-peptide obtained from three studies that collectively followed 834 patients post-onset of clinical symptoms. An empirical Bayesian approach was used to establish the level of confidence associated with the model prediction. Age-corrected estimates of beta cell mass that were inferred from a series of landmark pancreatic autopsy studies significantly correlate (p>0.9995) with contemporary measures of plasma C-peptide levels following onset.ConclusionsGiven the correlation between beta cell mass and plasma C-peptide following onset, plasma C-peptide may provide a surrogate measure of beta cell mass in humans. The clinical relevance of this study is that therapeutic strategies that provide an increase in plasma C-peptide over the predicted value for an individual may actually improve beta cell mass. The model predictions may establish a standard historical “control” group - a prior in a Bayesian context - for clinical trials.

VMAT2 quantitation by PET as a biomarker for β‐cell mass in health and disease

The common pathology underlying both type 1 and type 2 diabetes (T1DM and T2DM) is insufficient beta-cell mass (BCM) to meet metabolic demands. An important impediment to the more rapid evaluation of interventions for both T1DM and T2DM lack of biomarkers of pancreatic BCM. A reliable means of monitoring the mass and/or function of beta-cells would enable evaluation of the progression of diabetes as well as the monitoring of pharmacologic and other interventions. Recently, we identified a biomarker of BCM that is quantifiable by positron emission tomography (PET). PET is an imaging technique which allows for non-invasive measurements of radioligand uptake and clearance, is sensitive in the pico- to nanomolar range and of which the results can be deconvoluted into measurements of receptor concentration. For BCM estimates, we have identified VMAT2 (vesicular monoamine transporter type 2) as a biomarker and [(11)C] DTBZ (dihydrotetrabenazine) as the transporter's ligand. VMAT2 is highly expressed in beta-cells of the human pancreas relative to other cells of the endocrine and exocrine pancreas. Thus measurements of [(11)C] DTBZ in the pancreas provide an indirect measurement of BCM. Here we summarize our ongoing efforts to validate the clinical utility of this non-invasive approach to real-time BCM measurements.

Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas

Vesicular monoamine transporter 2 (VMAT2) is expressed in pancreatic beta cells and has recently been proposed as a target for measurement of beta cell mass in vivo. We questioned, (1) What proportion of beta cells express VMAT2? (2) Is VMAT2 expressed by other pancreatic endocrine or non-endocrine cells? (3) Is the relationship between VMAT2 and insulin expression disturbed in type 1 (T1DM) or type 2 diabetes (T2DM)? Human pancreas (7 non-diabetics, 5 T2DM, 10 T1DM) was immunostained for insulin, VMAT2 and other pancreatic hormones. Most beta cells expressed VMAT2. VMAT2 expression was not changed by the presence of diabetes. In tail of pancreas VMAT2 immunostaining closely correlated with insulin staining. However, VMAT2 was also expressed in some pancreatic polypeptide (PP) cells. Although VMAT2 was not excluded as a target for beta cell mass measurement, expression of VMAT2 in PP cells predicts residual VMAT2 expression in human pancreas even in the absence of beta cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s10735-008-9195-9) contains supplementary material, which is available to authorized users.

Visualizing pancreatic β-cell mass with [11C]DTBZ

Beta-cell mass (BCM) influences the total amount of insulin secreted, varies by individual and by the degree of insulin resistance, and is affected by physiologic and pathologic conditions. The islets of Langerhans, however, appear to have a reserve capacity of insulin secretion and, overall, assessments of insulin and blood glucose levels remain poor measures of BCM, beta-cell function and progression of diabetes. Thus, novel noninvasive determinations of BCM are needed to provide a quantitative endpoint for novel therapies of diabetes, islet regeneration and transplantation. Built on previous gene expression studies, we tested the hypothesis that the targeting of vesicular monoamine transporter 2 (VMAT2), which is expressed by beta cells, with [11C]dihydrotetrabenazine ([11C]DTBZ), a radioligand specific for VMAT2, and the use of positron emission tomography (PET) can provide a measure of BCM. In this report, we demonstrate decreased radioligand uptake within the pancreas of Lewis rats with streptozotocin-induced diabetes relative to their euglycemic historical controls. These studies suggest that quantitation of VMAT2 expression in beta cells with the use of [11C]DTBZ and PET represents a method for noninvasive longitudinal estimates of changes in BCM that may be useful in the study and treatment of diabetes.

Longitudinal noninvasive PET-based cell mass estimates in a spontaneous diabetes rat model

Diabetes results from an absolute or relative reduction in pancreatic beta cell mass (BCM) leading to insufficient insulin secretion and hyperglycemia. Measurement of insulin secretory capacity is currently used as a surrogate measure of BCM. However, serum insulin concentrations provide an imprecise index of BCM, and no reliable noninvasive measure of BCM is currently available. Type 2 vesicular monoamine transporters (VMAT2) are expressed in human islet beta cells, as well as in tissues of the CNS. [11C]Dihydrotetrabenazine ([11C]DTBZ) binds specifically to VMAT2 and is a radioligand currently used in clinical imaging of the brain. Here we report the use of [11C]DTBZ to estimate BCM in a rodent model of spontaneous type 1 diabetes (the BB-DP rat). In longitudinal PET studies of the BB-DP rat, we found a significant decline in pancreatic uptake of [11C]DTBZ that anticipated the loss of glycemic control. Based on comparison of standardized uptake values (SUVs) of [11C]DTBZ and blood glucose concentrations, loss of more than 65% of the original SUV correlated significantly with the development of persistent hyperglycemia. These studies suggest that PET-based quantitation of VMAT2 receptors provides a noninvasive measurement of BCM that could be used to study the pathogenesis of diabetes and to monitor therapeutic interventions.