title: Islet autoimmunity identifies a unique pattern of impaired pancreatic beta-cell function, markedly reduced pancreatic beta cell mass and insulin resistance in clinically diagnosed type 2 diabetes.
abstract: There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired β-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic β-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage.
authors.affiliation: The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Division of Endocrinology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Subauste
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America; The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gianani
authors.affiliation: The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Chang
authors.affiliation: The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Plunkett
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America; The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Pietropaolo
authors.affiliation: The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Ying-Jian
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Emma
authors.initials: E
authors.lastname: Barinas-Mitchell
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Lewis H
authors.initials: LH
authors.lastname: Kuller
authors.affiliation: Geriatrics Center and Institute of Gerontology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Galecki
authors.affiliation: Geriatrics Center and Institute of Gerontology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Halter
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America; The Brehm Center for Diabetes Research, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pietropaolo
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D015415:Biomarkers; D001786:Blood Glucose; D001823:Body Composition; D002096:C-Peptide / Q000378:metabolism; D048429:Cell Size; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014019:Tissue Donors
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D001786:Blood Glucose; D002096:C-Peptide; D006684:HLA-DR Antigens; D007328:Insulin