α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes
Marcela Brissova,
Rachana Haliyur,
Diane Saunders,
Shristi Shrestha,
Chunhua Dai,
David M. Blodgett,
Rita Bottino,
Martha Campbell-Thompson,
Radhika Aramandla,
Gregory Poffenberger,
Jill Lindner,
Fong Cheng Pan,
Matthias G. von Herrath,
Dale L. Greiner,
Leonard D. Shultz,
May Sanyoura,
Louis H. Philipson,
Mark Atkinson,
David M. Harlan,
Shawn E. Levy,
Nripesh Prasad,
Roland Stein,
Alvin C. Powers
Affiliations
Marcela Brissova
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA; Corresponding author
Rachana Haliyur
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
Diane Saunders
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
Shristi Shrestha
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
Chunhua Dai
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
David M. Blodgett
Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA; Math and Science Division, Babson College, Wellesley, MA 02457, USA
Rita Bottino
Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, USA
Martha Campbell-Thompson
Department of Pathology, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL, USA
Radhika Aramandla
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
Gregory Poffenberger
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
Jill Lindner
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
Fong Cheng Pan
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
Matthias G. von Herrath
Type 1 Diabetes Center, the La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
Dale L. Greiner
Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
Leonard D. Shultz
The Jackson Laboratory, Bar Harbor, ME, USA
May Sanyoura
Departments of Medicine and Pediatrics, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, IL, USA
Louis H. Philipson
Departments of Medicine and Pediatrics, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, IL, USA
Mark Atkinson
Department of Pathology, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL, USA
David M. Harlan
Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
Shawn E. Levy
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
Nripesh Prasad
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
Roland Stein
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
Alvin C. Powers
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA; Corresponding author
Summary: Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant β cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and β cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-β cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia. : Brissova et al. find that β cells in the type 1 diabetic (T1D) pancreas maintain several functional and molecular features, but α cells have impaired glucagon secretion and an altered gene expression profile. These findings provide insight into the mechanism of α cell dysfunction in T1D. Keywords: type 1 diabetes, glucagon, insulin, pancreatic islet, alpha cells, human
