Publications by authors named "Alvin C Powers"

151 Publications

Deep learning-based pancreas volume assessment in individuals with type 1 diabetes.

BMC Med Imaging 2022 Jan 5;22(1). Epub 2022 Jan 5.

Department of Diagnostic Medicine, Dell Medical School, University of Texas at Austin, 1701 Trinity St., Stop C0200, Austin, TX, 78712, USA.

Pancreas volume is reduced in individuals with diabetes and in autoantibody positive individuals at high risk for developing type 1 diabetes (T1D). Studies investigating pancreas volume are underway to assess pancreas volume in large clinical databases and studies, but manual pancreas annotation is time-consuming and subjective, preventing extension to large studies and databases. This study develops deep learning for automated pancreas volume measurement in individuals with diabetes. A convolutional neural network was trained using manual pancreas annotation on 160 abdominal magnetic resonance imaging (MRI) scans from individuals with T1D, controls, or a combination thereof. Models trained using each cohort were then tested on scans of 25 individuals with T1D. Deep learning and manual segmentations of the pancreas displayed high overlap (Dice coefficient = 0.81) and excellent correlation of pancreas volume measurements (R = 0.94). Correlation was highest when training data included individuals both with and without T1D. The pancreas of individuals with T1D can be automatically segmented to measure pancreas volume. This algorithm can be applied to large imaging datasets to quantify the spectrum of human pancreas volume.
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http://dx.doi.org/10.1186/s12880-021-00729-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8734282PMC
January 2022

Integrated Analysis of the Pancreas and Islets Reveals Unexpected Findings in Human Male With Type 1 Diabetes.

J Endocr Soc 2021 Dec 29;5(12):bvab162. Epub 2021 Oct 29.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.

Clinical and pathologic heterogeneity in type 1 diabetes is increasingly being recognized. Findings in the islets and pancreas of a 22-year-old male with 8 years of type 1 diabetes were discordant with expected results and clinical history (islet autoantibodies negative, hemoglobin A1c 11.9%) and led to comprehensive investigation to define the functional, molecular, genetic, and architectural features of the islets and pancreas to understand the cause of the donor's diabetes. Examination of the donor's pancreatic tissue found substantial but reduced β-cell mass with some islets devoid of β cells (29.3% of 311 islets) while other islets had many β cells. Surprisingly, isolated islets from the donor pancreas had substantial insulin secretion, which is uncommon for type 1 diabetes of this duration. Targeted and whole-genome sequencing and analysis did not uncover monogenic causes of diabetes but did identify high-risk human leukocyte antigen haplotypes and a genetic risk score suggestive of type 1 diabetes. Further review of pancreatic tissue found islet inflammation and some previously described α-cell molecular features seen in type 1 diabetes. By integrating analysis of isolated islets, histological evaluation of the pancreas, and genetic information, we concluded that the donor's clinical insulin deficiency was most likely the result autoimmune-mediated β-cell loss but that the constellation of findings was not typical for type 1 diabetes. This report highlights the pathologic and functional heterogeneity that can be present in type 1 diabetes.
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http://dx.doi.org/10.1210/jendso/bvab162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633619PMC
December 2021

Microvessels enhance vascularization and function of transplanted insulin-producing cells.

Cell Metab 2021 Nov;33(11):2103-2105

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address:

Transplantation of insulin-producing cells is an emerging treatment for type 1 diabetes. A recent report in Cell Stem Cell (Aghazadeh et al., 2021) outlines a new approach that accelerates the engraftment and improves the survival and function of such cell transplants by mixing adipose tissue-derived ready-made microvessels with human pancreatic progenitor cells or cadaveric islets prior to transplantation.
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http://dx.doi.org/10.1016/j.cmet.2021.10.013DOI Listing
November 2021

Human islet T cells are highly reactive to preproinsulin in type 1 diabetes.

Proc Natl Acad Sci U S A 2021 10;118(41)

Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045;

Cytotoxic CD8 T lymphocytes play a central role in the tissue destruction of many autoimmune disorders. In type 1 diabetes (T1D), insulin and its precursor preproinsulin are major self-antigens targeted by T cells. We comprehensively examined preproinsulin specificity of CD8 T cells obtained from pancreatic islets of organ donors with and without T1D and identified epitopes throughout the entire preproinsulin protein and defective ribosomal products derived from preproinsulin messenger RNA. The frequency of preproinsulin-reactive T cells was significantly higher in T1D donors than nondiabetic donors and also differed by individual T1D donor, ranging from 3 to over 40%, with higher frequencies in T1D organ donors with HLA-A*02:01. Only T cells reactive to preproinsulin-related peptides isolated from T1D donors demonstrated potent autoreactivity. Reactivity to similar regions of preproinsulin was also observed in peripheral blood of a separate cohort of new-onset T1D patients. These findings have important implications for designing antigen-specific immunotherapies and identifying individuals that may benefit from such interventions.
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http://dx.doi.org/10.1073/pnas.2107208118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521679PMC
October 2021

Development of a standardized MRI protocol for pancreas assessment in humans.

PLoS One 2021 24;16(8):e0256029. Epub 2021 Aug 24.

Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristics in type 1 and type 2 diabetes. However, differences in MRI technology and approaches across locations currently limit the incorporation of pancreas imaging into multisite trials. The purpose of this study was to develop a standardized MRI protocol for pancreas imaging and to define the reproducibility of these measurements. Calibrated phantoms with known MRI properties were imaged at five sites with differing MRI hardware and software to develop a harmonized MRI imaging protocol. Subsequently, five healthy volunteers underwent MRI at four sites using the harmonized protocol to assess pancreas size, shape, apparent diffusion coefficient (ADC), longitudinal relaxation time (T1), magnetization transfer ratio (MTR), and pancreas and hepatic fat fraction. Following harmonization, pancreas size, surface area to volume ratio, diffusion, and longitudinal relaxation time were reproducible, with coefficients of variation less than 10%. In contrast, non-standardized image processing led to greater variation in MRI measurements. By using a standardized MRI image acquisition and processing protocol, quantitative MRI of the pancreas performed at multiple locations can be incorporated into clinical trials comparing pancreas imaging measures and metabolic state in individuals with type 1 or type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256029PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384163PMC
December 2021

Combinatorial transcription factor profiles predict mature and functional human islet α and β cells.

JCI Insight 2021 09 22;6(18). Epub 2021 Sep 22.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells, and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled more than 40,000 cells from normal human islets by single-cell RNA-Seq and stratified α and β cells based on combinatorial TF expression. Subpopulations of islet cells coexpressing ARX/MAFB (α cells) and MAFA/MAFB (β cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-Seq, MAFA/MAFB-coexpressing β cells showed enhanced electrophysiological activity. Thus, these results indicate that combinatorial TF expression in islet α and β cells predicts highly functional, mature subpopulations.
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http://dx.doi.org/10.1172/jci.insight.151621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492318PMC
September 2021

Debates in Pancreatic Beta Cell Biology: Proliferation Versus Progenitor Differentiation and Transdifferentiation in Restoring β Cell Mass.

Front Endocrinol (Lausanne) 2021 6;12:722250. Epub 2021 Aug 6.

Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

In all forms of diabetes, β cell mass or function is reduced and therefore the capacity of the pancreatic cells for regeneration or replenishment is a critical need. Diverse lines of research have shown the capacity of endocrine as well as acinar, ductal and centroacinar cells to generate new β cells. Several experimental approaches using injury models, pharmacological or genetic interventions, isolation and expansion of putative progenitors followed by transplantations or a combination thereof have suggested several pathways for β cell neogenesis or regeneration. The experimental results have also generated controversy related to the limitations and interpretation of the experimental approaches and ultimately their physiological relevance, particularly when considering differences between mouse, the primary animal model, and human. As a result, consensus is lacking regarding the relative importance of islet cell proliferation or progenitor differentiation and transdifferentiation of other pancreatic cell types in generating new β cells. In this review we summarize and evaluate recent experimental approaches and findings related to islet regeneration and address their relevance and potential clinical application in the fight against diabetes.
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http://dx.doi.org/10.3389/fendo.2021.722250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378310PMC
August 2021

What is a β cell? - Chapter I in the Human Islet Research Network (HIRN) review series.

Mol Metab 2021 11 17;53:101323. Epub 2021 Aug 17.

Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, and VA Tennessee Valley Healthcare System, Nashville, TN, USA. Electronic address:

Background: The pancreatic β cell, as the sole source of the vital hormone insulin, has been under intensive study for more than a century. Given the potential of newly created insulin-producing cells as a treatment or even cure of type 1 diabetes (T1D) and possibly in severe cases of type 2 diabetes (T2D), multiple academic and commercial laboratories are working to derive surrogate glucose-responsive, insulin-producing cells.

Scope Of Review: The recent development of advanced phenotyping technologies, including molecular, epigenomic, histological, or functional, have greatly improved our understanding of the critical properties of human β cells. Using this information, here we summarize the salient features of normal, fully functional adult human β cells, and propose minimal criteria for what should rightfully be termed 'β cells' as opposed to insulin-producing but not fully-functional surrogates that we propose should be referred to as 'β-like' cells or insulin-producing cells.

Major Conclusions: Clear criteria can be established to differentiate fully functional, mature β cells from 'β-like' surrogates. In addition, we outline important knowledge gaps that must be addressed to enable a greater understanding of the β cell.
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http://dx.doi.org/10.1016/j.molmet.2021.101323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452767PMC
November 2021

There is more than one way to reach type 2 diabetes.

Nat Metab 2021 07;3(7):894-895

The Human Pancreas Atlas Program (HPAP).

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http://dx.doi.org/10.1038/s42255-021-00415-6DOI Listing
July 2021

Endocrine toxicities of immune checkpoint inhibitors.

Nat Rev Endocrinol 2021 07 19;17(7):389-399. Epub 2021 Apr 19.

Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, USA.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target two key signalling pathways related to T cell activation and exhaustion, by binding to and inhibiting cytotoxic T lymphocyte antigen 4 (CTLA4) or PD1 and its ligand PDL1. ICIs, such as nivolumab, pembrolizumab and ipilimumab, are approved for the treatment of numerous and diverse cancer types, in various combination regimens, and are now an established cornerstone of cancer therapeutics. Toxicities induced by ICIs are autoimmune in nature and are referred to as immune-related adverse events (irAEs); these events can affect any organ system in an unpredictable fashion. Importantly, irAEs can manifest as endocrinopathies involving the thyroid (hypothyroidism or thyrotoxicosis), pituitary (hypophysitis), adrenal glands (adrenal insufficiency) and pancreas (diabetes mellitus). These events are a frequent source of acute and persistent morbidity in patients treated with ICIs and can even be fatal. Over the past few years, there has been a growing understanding of the underlying pathogenesis of irAEs that has led to the development of more effective management strategies. Herein, we review the current understanding of the pathobiology, clinical manifestations and treatment approaches to endocrine toxicities arising from ICIs.
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http://dx.doi.org/10.1038/s41574-021-00484-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769055PMC
July 2021

The Human Islet: Mini-Organ With Mega-Impact.

Endocr Rev 2021 Sep;42(5):605-657

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

This review focuses on the human pancreatic islet-including its structure, cell composition, development, function, and dysfunction. After providing a historical timeline of key discoveries about human islets over the past century, we describe new research approaches and technologies that are being used to study human islets and how these are providing insight into human islet physiology and pathophysiology. We also describe changes or adaptations in human islets in response to physiologic challenges such as pregnancy, aging, and insulin resistance and discuss islet changes in human diabetes of many forms. We outline current and future interventions being developed to protect, restore, or replace human islets. The review also highlights unresolved questions about human islets and proposes areas where additional research on human islets is needed.
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http://dx.doi.org/10.1210/endrev/bnab010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476939PMC
September 2021

Distinguishing the real from the hyperglycaemia: does COVID-19 induce diabetes?

Lancet Diabetes Endocrinol 2021 06 7;9(6):328-329. Epub 2021 Apr 7.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA; VA Tennessee Valley Healthcare System, Nashville, TN, USA.

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http://dx.doi.org/10.1016/S2213-8587(21)00087-5DOI Listing
June 2021

Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote β cell regeneration.

NPJ Regen Med 2021 Apr 6;6(1):22. Epub 2021 Apr 6.

Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA.

Endogenous β cell regeneration could alleviate diabetes, but proliferative stimuli within the islet microenvironment are incompletely understood. We previously found that β cell recovery following hypervascularization-induced β cell loss involves interactions with endothelial cells (ECs) and macrophages (MΦs). Here we show that proliferative ECs modulate MΦ infiltration and phenotype during β cell loss, and recruited MΦs are essential for β cell recovery. Furthermore, VEGFR2 inactivation in quiescent ECs accelerates islet vascular regression during β cell recovery and leads to increased β cell proliferation without changes in MΦ phenotype or number. Transcriptome analysis of β cells, ECs, and MΦs reveals that β cell proliferation coincides with elevated expression of extracellular matrix remodeling molecules and growth factors likely driving activation of proliferative signaling pathways in β cells. Collectively, these findings suggest a new β cell regeneration paradigm whereby coordinated interactions between intra-islet MΦs, ECs, and extracellular matrix mediate β cell self-renewal.
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http://dx.doi.org/10.1038/s41536-021-00129-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024255PMC
April 2021

Type 1 diabetes mellitus: much progress, many opportunities.

Authors:
Alvin C Powers

J Clin Invest 2021 04;131(8)

As part of the centennial celebration of insulin's discovery, this review summarizes the current understanding of the genetics, pathogenesis, treatment, and outcomes in type 1 diabetes (T1D). T1D results from an autoimmune response that leads to destruction of the β cells in the pancreatic islet and requires lifelong insulin therapy. While much has been learned about T1D, it is now clear that there is considerable heterogeneity in T1D with regard to genetics, pathology, response to immune-based therapies, clinical course, and susceptibility to diabetes-related complications. This Review highlights knowledge gaps and opportunities to improve the understanding of T1D pathogenesis and outlines emerging therapies to treat or prevent T1D and reduce the burden of T1D.
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http://dx.doi.org/10.1172/JCI142242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262558PMC
April 2021

Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets.

Proc Natl Acad Sci U S A 2021 03;118(9)

Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549;

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-β-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.
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http://dx.doi.org/10.1073/pnas.2022142118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936318PMC
March 2021

COVID-19 vaccine prioritisation for type 1 and type 2 diabetes.

Lancet Diabetes Endocrinol 2021 03 18;9(3):140-141. Epub 2021 Jan 18.

Division of Endocrinology, Metabolism and Diabetes and Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

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http://dx.doi.org/10.1016/S2213-8587(21)00017-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831734PMC
March 2021

RIPK3-mediated inflammation is a conserved β cell response to ER stress.

Sci Adv 2020 Dec 18;6(51). Epub 2020 Dec 18.

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA.

Islet inflammation is an important etiopathology of type 2 diabetes; however, the underlying mechanisms are not well defined. Using complementary experimental models, we discovered RIPK3-dependent IL1B induction in β cells as an instigator of islet inflammation. In cultured β cells, ER stress activated RIPK3, leading to NF-kB-mediated proinflammatory gene expression. In a zebrafish muscle insulin resistance model, overnutrition caused islet inflammation, β cell dysfunction, and loss in an ER stress-, -, and -dependent manner. In mouse islets, high-fat diet triggered the IL1B expression in β cells before macrophage recruitment in vivo, and RIPK3 inhibition suppressed palmitate-induced β cell dysfunction and expression in vitro. Furthermore, in human islets grafted in hyperglycemic mice, a marked increase in ER stress, RIPK3, and NF-kB activation in β cells were accompanied with murine macrophage infiltration. Thus, RIPK3-mediated induction of proinflammatory mediators is a conserved, previously unrecognized β cell response to metabolic stress and a mediator of the ensuing islet inflammation.
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http://dx.doi.org/10.1126/sciadv.abd7272DOI Listing
December 2020

Pancreatlas: Applying an Adaptable Framework to Map the Human Pancreas in Health and Disease.

Patterns (N Y) 2020 Nov 5;1(8):100120. Epub 2020 Oct 5.

Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Human tissue phenotyping generates complex spatial information from numerous imaging modalities, yet images typically become static figures for publication, and original data and metadata are rarely available. While comprehensive image maps exist for some organs, most resources have limited support for multiplexed imaging or have non-intuitive user interfaces. Therefore, we built a Pancreatlas resource that integrates several technologies into a unique interface, allowing users to access richly annotated web pages, drill down to individual images, and deeply explore data online. The current version of Pancreatlas contains over 800 unique images acquired by whole-slide scanning, confocal microscopy, and imaging mass cytometry, and is available at https://www.pancreatlas.org. To create this human pancreas-specific biological imaging resource, we developed a React-based web application and Python-based application programming interface, collectively called Flexible Framework for Integrating and Navigating Data (FFIND), which can be adapted beyond Pancreatlas to meet countless imaging or other structured data-management needs.
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http://dx.doi.org/10.1016/j.patter.2020.100120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691395PMC
November 2020

SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 Are Expressed in the Microvasculature and Ducts of Human Pancreas but Are Not Enriched in β Cells.

Cell Metab 2020 12 13;32(6):1028-1040.e4. Epub 2020 Nov 13.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address:

Isolated reports of new-onset diabetes in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into β cells via co-expression of its canonical cell entry factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2); however, their expression in human pancreas has not been clearly defined. We analyzed six transcriptional datasets of primary human islet cells and found that ACE2 and TMPRSS2 were not co-expressed in single β cells. In pancreatic sections, ACE2 and TMPRSS2 protein was not detected in β cells from donors with and without diabetes. Instead, ACE2 protein was expressed in islet and exocrine tissue microvasculature and in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. These findings reduce the likelihood that SARS-CoV-2 directly infects β cells in vivo through ACE2 and TMPRSS2.
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http://dx.doi.org/10.1016/j.cmet.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664344PMC
December 2020

SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells.

bioRxiv 2020 Oct 20. Epub 2020 Oct 20.

Reports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into host β cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. and transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet β cells through these cell entry proteins.
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http://dx.doi.org/10.1101/2020.08.31.275719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587777PMC
October 2020

Dapagliflozin Does Not Directly Affect Human α or β Cells.

Endocrinology 2020 08;161(8)

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Selective inhibitors of sodium glucose cotransporter-2 (SGLT2) are widely used for the treatment of type 2 diabetes and act primarily to lower blood glucose by preventing glucose reabsorption in the kidney. However, it is controversial whether these agents also act on the pancreatic islet, specifically the α cell, to increase glucagon secretion. To determine the effects of SGLT2 on human islets, we analyzed SGLT2 expression and hormone secretion by human islets treated with the SGLT2 inhibitor dapagliflozin (DAPA) in vitro and in vivo. Compared to the human kidney, SLC5A2 transcript expression was 1600-fold lower in human islets and SGLT2 protein was not detected. In vitro, DAPA treatment had no effect on glucagon or insulin secretion by human islets at either high or low glucose concentrations. In mice bearing transplanted human islets, 1 and 4 weeks of DAPA treatment did not alter fasting blood glucose, human insulin, and total glucagon levels. Upon glucose stimulation, DAPA treatment led to lower blood glucose levels and proportionally lower human insulin levels, irrespective of treatment duration. In contrast, after glucose stimulation, total glucagon was increased after 1 week of DAPA treatment but normalized after 4 weeks of treatment. Furthermore, the human islet grafts showed no effects of DAPA treatment on hormone content, endocrine cell proliferation or apoptosis, or amyloid deposition. These data indicate that DAPA does not directly affect the human pancreatic islet, but rather suggest an indirect effect where lower blood glucose leads to reduced insulin secretion and a transient increase in glucagon secretion.
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http://dx.doi.org/10.1210/endocr/bqaa080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375801PMC
August 2020

Decreased pancreatic acinar cell number in type 1 diabetes.

Diabetologia 2020 07 9;63(7):1418-1423. Epub 2020 May 9.

Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, 7465 Medical Research Bldg IV, 2215 Garland Avenue, Nashville, TN, 37232-0475, USA.

Aims/hypothesis: Individuals with longstanding and recent-onset type 1 diabetes have a smaller pancreas. Since beta cells represent a very small portion of the pancreas, the loss of pancreas volume in diabetes is primarily due to the loss of pancreatic exocrine mass. However, the structural changes in the exocrine pancreas in diabetes are not well understood.

Methods: To characterise the pancreatic endocrine and exocrine compartments in diabetes, we studied pancreases from adult donors with type 1 diabetes compared with similarly aged donors without diabetes. Islet cell mass, islet morphometry, exocrine mass, acinar cell size and number and pancreas fibrosis were assessed by immunohistochemical staining. To better understand possible mechanisms of altered pancreas size, we measured pancreas size in three mouse models of insulin deficiency.

Results: Pancreases from donors with type 1 diabetes were approximately 45% smaller than those from donors without diabetes (47.4 ± 2.6 vs 85.7 ± 3.7 g), independent of diabetes duration or age of onset. Diabetic donor pancreases had decreased beta cell mass (0.061 ± 0.025 vs 0.94 ± 0.21 g) and reduced total exocrine mass (42.0 ± 4.9 vs 96.1 ± 6.5 g). Diabetic acinar cells were similar in size but fewer in number compared with those in pancreases from non-diabetic donors (63.7 ± 8.1 × 10 vs 121.6 ± 12.2 × 10 cells/pancreas), likely accounting for the difference in pancreas size. Within the type 1 diabetes exocrine tissue, there was a greater degree of fibrosis. The pancreases in three mouse models of insulin deficiency were similar in size to those in control mice.

Conclusions/interpretation: Pancreases from donors with type 1 diabetes are smaller than normal donor pancreases because exocrine cells are fewer in number rather than smaller in size; these changes occur early in the disease process. Our mouse data suggest that decreased pancreas size in type 1 diabetes is not directly caused by insulin deficiency, but the precise mechanism responsible remains unclear.
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http://dx.doi.org/10.1007/s00125-020-05155-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403487PMC
July 2020

Integrated human pseudoislet system and microfluidic platform demonstrate differences in GPCR signaling in islet cells.

JCI Insight 2020 05 21;5(10). Epub 2020 May 21.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Pancreatic islets secrete insulin from β cells and glucagon from α cells, and dysregulated secretion of these hormones is a central component of diabetes. Thus, an improved understanding of the pathways governing coordinated β and α cell hormone secretion will provide insight into islet dysfunction in diabetes. However, the 3D multicellular islet architecture, essential for coordinated islet function, presents experimental challenges for mechanistic studies of intracellular signaling pathways in primary islet cells. Here, we developed an integrated approach to study the function of primary human islet cells using genetically modified pseudoislets that resemble native islets across multiple parameters. Further, we developed a microperifusion system that allowed synchronous acquisition of GCaMP6f biosensor signal and hormone secretory profiles. We demonstrate the utility of this experimental approach by studying the effects of Gi and Gq GPCR pathways on insulin and glucagon secretion by expressing the designer receptors exclusively activated by designer drugs (DREADDs) hM4Di or hM3Dq. Activation of Gi signaling reduced insulin and glucagon secretion, while activation of Gq signaling stimulated glucagon secretion but had both stimulatory and inhibitory effects on insulin secretion, which occur through changes in intracellular Ca2+. The experimental approach of combining pseudoislets with a microfluidic system allowed the coregistration of intracellular signaling dynamics and hormone secretion and demonstrated differences in GPCR signaling pathways between human β and α cells.
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http://dx.doi.org/10.1172/jci.insight.137017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259531PMC
May 2020

Pancreatic islet beta cell-specific deletion of G6pc2 reduces fasting blood glucose.

J Mol Endocrinol 2020 05;64(4):235-248

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

The G6PC1, G6PC2 and G6PC3 genes encode distinct glucose-6-phosphatase catalytic subunit (G6PC) isoforms. In mice, germline deletion of G6pc2 lowers fasting blood glucose (FBG) without affecting fasting plasma insulin (FPI) while, in isolated islets, glucose-6-phosphatase activity and glucose cycling are abolished and glucose-stimulated insulin secretion (GSIS) is enhanced at submaximal but not high glucose. These observations are all consistent with a model in which G6PC2 regulates the sensitivity of GSIS to glucose by opposing the action of glucokinase. G6PC2 is highly expressed in human and mouse islet beta cells however, various studies have shown trace G6PC2 expression in multiple tissues raising the possibility that G6PC2 also affects FBG through non-islet cell actions. Using real-time PCR we show here that expression of G6pc1 and/or G6pc3 are much greater than G6pc2 in peripheral tissues, whereas G6pc2 expression is much higher than G6pc3 in both pancreas and islets with G6pc1 expression not detected. In adult mice, beta cell-specific deletion of G6pc2 was sufficient to reduce FBG without changing FPI. In addition, electronic health record-derived phenotype analyses showed no association between G6PC2 expression and phenotypes clearly unrelated to islet function in humans. Finally, we show that germline G6pc2 deletion enhances glycolysis in mouse islets and that glucose cycling can also be detected in human islets. These observations are all consistent with a mechanism by which G6PC2 action in islets is sufficient to regulate the sensitivity of GSIS to glucose and hence influence FBG without affecting FPI.
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http://dx.doi.org/10.1530/JME-20-0031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331801PMC
May 2020

Repeatability and Reproducibility of Pancreas Volume Measurements Using MRI.

Sci Rep 2020 03 16;10(1):4767. Epub 2020 Mar 16.

Department of Diagnostic Medicine, Dell Medical School, University of Texas at Austin, Austin, Texas, USA.

Reduced pancreas volume, as measured by non-contrast magnetic resonance imaging (MRI), is observed in individuals with newly-diagnosed type 1 diabetes (T1D) and declines over the first year after diagnosis. In this study, we determined the repeatability and inter-reader reproducibility of pancreas volume measurements by MRI. Test-retest scans in individuals with or without T1D (n = 16) had an intraclass correlation coefficient (ICC) of 0.985 (95% CI 0.961 to 0.995) for pancreas volume. Independent pancreas outlines by two board-certified radiologists (n = 30) yielded an ICC of 0.945 (95% CI 0.889 to 0.973). The mean Dice coefficient, a measurement of the degree of overlap between pancreas regions of interest between the two readers, was 0.77. Prandial state did not influence pancreatic measurements, as stomach volume did not correlate with pancreas volume. These data demonstrate that MRI measurements of pancreas volume between two readers are repeatable and reproducible with ICCs that correspond to excellent clinical significance (ICC > 0.9), are not related to changes in stomach volume, and could be a useful tool for clinical investigation of diabetes and other pancreas pathologies.
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http://dx.doi.org/10.1038/s41598-020-61759-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076034PMC
March 2020

Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable.

JCI Insight 2020 01 16;5(1). Epub 2020 Jan 16.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and.

Posttransplantation diabetes mellitus (PTDM) is a common and significant complication related to immunosuppressive agents required to prevent organ or cell transplant rejection. To elucidate the effects of 2 commonly used agents, the calcineurin inhibitor tacrolimus (TAC) and the mTOR inhibitor sirolimus (SIR), on islet function and test whether these effects could be reversed or prevented, we investigated human islets transplanted into immunodeficient mice treated with TAC or SIR at clinically relevant levels. Both TAC and SIR impaired insulin secretion in fasted and/or stimulated conditions. Treatment with TAC or SIR increased amyloid deposition and islet macrophages, disrupted insulin granule formation, and induced broad transcriptional dysregulation related to peptide processing, ion/calcium flux, and the extracellular matrix; however, it did not affect regulation of β cell mass. Interestingly, these β cell abnormalities reversed after withdrawal of drug treatment. Furthermore, cotreatment with a GLP-1 receptor agonist completely prevented TAC-induced β cell dysfunction and partially prevented SIR-induced β cell dysfunction. These results highlight the importance of both calcineurin and mTOR signaling in normal human β cell function in vivo and suggest that modulation of these pathways may prevent or ameliorate PTDM.
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http://dx.doi.org/10.1172/jci.insight.130770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030815PMC
January 2020

Lipid Droplet Accumulation in Human Pancreatic Islets Is Dependent On Both Donor Age and Health.

Diabetes 2020 03 13;69(3):342-354. Epub 2019 Dec 13.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN

Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell-derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function.
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http://dx.doi.org/10.2337/db19-0281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034188PMC
March 2020

Serotonin Regulates Adult β-Cell Mass by Stimulating Perinatal β-Cell Proliferation.

Diabetes 2020 02 5;69(2):205-214. Epub 2019 Dec 5.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea

A sufficient β-cell mass is crucial for preventing diabetes, and perinatal β-cell proliferation is important in determining the adult β-cell mass. However, it is not yet known how perinatal β-cell proliferation is regulated. Here, we report that serotonin regulates β-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In β-cell-specific knockout ( βKO) mice, perinatal β-cell proliferation was reduced along with the loss of serotonin production in β-cells. Adult βKO mice exhibited glucose intolerance with decreased β-cell mass. Disruption of in β-cells also resulted in decreased perinatal β-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in β-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the β-cell mass by regulating perinatal β-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.
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http://dx.doi.org/10.2337/db19-0546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971487PMC
February 2020

Research digest: pioneering an oral GLP-1 receptor agonist.

Lancet Diabetes Endocrinol 2019 12 6;7(12):897. Epub 2019 Nov 6.

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http://dx.doi.org/10.1016/S2213-8587(19)30360-2DOI Listing
December 2019

Gut-Proglucagon-Derived Peptides Are Essential for Regulating Glucose Homeostasis in Mice.

Cell Metab 2019 11 5;30(5):976-986.e3. Epub 2019 Sep 5.

Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON M5G1X5, Canada. Electronic address:

The importance of pancreatic versus intestinal-derived GLP-1 for glucose homeostasis is controversial. We detected active GLP-1 in the mouse and human pancreas, albeit at extremely low levels relative to glucagon. Accordingly, to elucidate the metabolic importance of intestinal proglucagon-derived peptides (PGDPs), we generated mice with reduction of Gcg expression within the distal (Gcg) or entire (Gcg) gut. Substantial reduction of gut Gcg expression markedly reduced circulating levels of GLP-1, and impaired glucose homeostasis, associated with increased levels of GIP, and accelerated gastric emptying. Gcg mice similarly exhibited lower circulating GLP-1 and impaired oral glucose tolerance. Nevertheless, plasma levels of insulin remained normal following glucose administration in the absence of gut-derived GLP-1. Collectively, our findings identify the essential importance of gut-derived PGDPs for maintaining levels of circulating GLP-1, control of gastric emptying, and glucose homeostasis.
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http://dx.doi.org/10.1016/j.cmet.2019.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140521PMC
November 2019
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