Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis

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Abstract

The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, “The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis” on 10–12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment.

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Epidemiology of type 1 diabetes.

David Maahs, Nancy West, Jean M Lawrence … (2010)

This article describes the epidemiology of type 1 diabetes mellitus (T1D) around the world and across the lifespan. Epidemiologic patterns of T1D by demographic, geographic, biologic, cultural, and other factors in populations are presented to gain insight about the causes, natural history, risks, and complications of T1D. Data from large epidemiologic studies worldwide indicate that the incidence of T1D has been increasing by 2% to 5% worldwide and that the prevalence of T1D is approximately 1 in 300 in the United States by 18 years of age. Research on risk factors for T1D is an active area of research to identify genetic and environmental triggers that could potentially be targeted for intervention. Although significant advances have been made in the clinical care of T1D with resultant improvements in quality of life and clinical outcomes, much more needs to be done to improve care of, and ultimately find a cure for, T1D. Epidemiologic studies have an important ongoing role to investigate the complex causes, clinical care, prevention, and cure of T1D. Copyright 2010 Elsevier Inc. All rights reserved.

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Five stages of evolving beta-cell dysfunction during progression to diabetes.

Gordon Weir, Susan Bonner-Weir (2004)

This article proposes five stages in the progression of diabetes, each of which is characterized by different changes in beta-cell mass, phenotype, and function. Stage 1 is compensation: insulin secretion increases to maintain normoglycemia in the face of insulin resistance and/or decreasing beta-cell mass. This stage is characterized by maintenance of differentiated function with intact acute glucose-stimulated insulin secretion (GSIS). Stage 2 occurs when glucose levels start to rise, reaching approximately 5.0-6.5 mmol/l; this is a stable state of beta-cell adaptation with loss of beta-cell mass and disruption of function as evidenced by diminished GSIS and beta-cell dedifferentiation. Stage 3 is a transient unstable period of early decompensation in which glucose levels rise relatively rapidly to the frank diabetes of stage 4, which is characterized as stable decompensation with more severe beta-cell dedifferentiation. Finally, stage 5 is characterized by severe decompensation representing a profound reduction in beta-cell mass with progression to ketosis. Movement across stages 1-4 can be in either direction. For example, individuals with treated type 2 diabetes can move from stage 4 to stage 1 or stage 2. For type 1 diabetes, as remission develops, progression from stage 4 to stage 2 is typically found. Delineation of these stages provides insight into the pathophysiology of both progression and remission of diabetes.

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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Jason Flannick, Gudmar Thorleifsson, Nicola Beer … (2014)

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.

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Author and article information

Journal

Journal ID (nlm-ta): Diabetes

Journal ID (iso-abbrev): Diabetes

Journal ID (hwp): diabetes

Journal ID (pmc): diabetes

Journal ID (publisher-id): Diabetes

Title: Diabetes

Publisher: American Diabetes Association

ISSN (Print): 0012-1797

ISSN (Electronic): 1939-327X

Publication date (Print): February 2017

Publication date (Electronic): 15 December 2016

Volume: 66

Issue: 2

Pages: 241-255

Affiliations

[1] ¹Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL

[2] ²The University of Chicago Medicine, Chicago, IL

[3] ³Technische Universität Dresden, Dresden, Germany

[4] ⁴American Diabetes Association, Arlington, VA

[5] ⁵University of Colorado Anschutz Medical Campus, Aurora, CO

[6] ⁶Lund University, Skåne University Hospital, Malmö, Sweden

[7] ⁷Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

[8] ⁸Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

[9] ⁹Baker IDI Heart and Diabetes Institute, Melbourne, Australia

[10] ¹⁰Metabolic Institute of America, Tarzana, CA

[11] ¹¹JDRF, New York, NY

[12] ¹²Katholieke Universiteit Leuven, Leuven, Belgium

[13] ¹³University of Washington and VA Puget Sound Health Care System, Seattle, WA

[14] ¹⁴University of Florida College of Medicine, Gainesville, FL

[15] ¹⁵University of Miami Miller School of Medicine, Miami, FL

[16] ¹⁶University Hospital Aintree, Liverpool, U.K.

Author notes

Corresponding author: Allison T. McElvaine, amcelvaine@ 123456diabetes.org .

Author information

Jay S. Skyler http://orcid.org/0000-0003-1136-8110

Ezio Bonifacio http://orcid.org/0000-0002-8704-4713

Tamara Darsow http://orcid.org/0000-0002-6650-6368

Robert H. Eckel http://orcid.org/0000-0002-4870-4600

Leif Groop http://orcid.org/0000-0002-0187-3263

Allison T. McElvaine http://orcid.org/0000-0002-0654-4047

Desmond A. Schatz http://orcid.org/0000-0002-1044-5762

John P.H. Wilding http://orcid.org/0000-0003-2839-8404

Article

Publisher ID: 0806

DOI: 10.2337/db16-0806

PMC ID: 5384660

PubMed ID: 27980006

SO-VID: cd566d73-7d67-4709-a9da-35f0995730bc

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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

History

Date received : 01 July 2016

Date accepted : 23 November 2016

Page count

Figures: 1, Tables: 1, Equations: 0, References: 176, Pages: 15

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Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 133

Epidemiology of type 1 diabetes.

Five stages of evolving beta-cell dysfunction during progression to diabetes.

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

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