Beta-Cell Fragility As a Common Underlying Risk Factor in Type 1 and Type 2 Diabetes

doi:10.1016/j.molmed.2016.12.005

Trends in Molecular Medicine

Volume 23, Issue 2, February 2017, Pages 181-194

https://doi.org/10.1016/j.molmed.2016.12.005 Get rights and content

Trends

The beta-cell fragility model proposes that variation in beta-cell susceptibility to apoptosis is common to type 1 diabetes (T1D) and late-stage type 2 diabetes (T2D) patients, with individuals possessing more fragile beta-cells being more likely to develop disease.

At a genetic level, variants in GLIS family zinc finger 3 (GLIS3) are associated with both T1D and T2D. The function of GLIS3 as an antiapoptotic mediator in beta-cells supports the beta-cell fragility model.

The hygiene hypothesis has been proposed to explain the increasing incidence of T1D. However, at an epidemiological level changes in T1D incidence have more in common with obesity and T2D than with other autoimmune disorders.

Elevated dietary fat or lipid exposure increases beta-cell susceptibility to apoptosis in animal models and in vitro, providing a mechanistic link between obesity and beta-cell fragility in T1D and late-stage T2D.

Video Abstract

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Type 1 and type 2 diabetes are distinct clinical entities primarily driven by autoimmunity and metabolic dysfunction, respectively. However, there is a growing appreciation that they may share an etiopathological factor, namely the role of variation in beta-cell sensitivity to stress factors. Increased sensitivity increases the risk of beta-cell death or insulin secretion dysfunction. The beta-cell fragility model proposes that this variation contributes to the risk of developing either type 1 or type 2 diabetes, in the presence of immunological and/or metabolic stress factors. Therapeutics that increase the resistance of beta cells to these factors and decreasing fragility may constitute a new class of anti-diabetogenics, with potential use across both diseases.

Section snippets

Glucose Regulation, Diabetes, and Beta-Cell Fragility

Glucose is the primary energy source for our bodies with blood serving as the distribution system. Blood glucose levels need to be maintained within a relatively tight range to ensure that sufficient glucose is available to tissues while avoiding the pathological glycosylation reactions that occur when blood glucose levels rise too high. Following the digestion of carbohydrate-rich food, the influx of dietary glucose from the intestine results in a spike in blood glucose levels. Under normal

Diabetes: Early and Late Stages

T1D disease is initiated and caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably to insulin itself [3]. Autoreactive T and B lymphocytes, having escaped central tolerance processes, are activated and expanded in secondary lymphoid tissues due to genetic and environmental causes. Autoreactive cells circulate to the pancreatic islets, where autoreactive T cells in particular are thought to drive the destruction of beta-cells

The Causal Model of Beta-Cell Fragility and Diabetes

The concept that primary beta-cell defects may lie at the heart of susceptibility to both T1D and T2D has been proposed by us 17, 18 and others 19, 20, 21 with various iterations and degrees of emphasis on the differences or similarities between T1D and T2D. Here we define the beta-cell fragility model as one where variations in the intrinsic fragility or robustness of beta-cells contribute to the development of diabetes. We define fragility and robustness as extremes on a scale of beta-cell

Distinct and Overlapping Genetic Drivers of T1D and T2D

If beta-cell fragility is a common contributor to both T1D and T2D, it would be predicted that the two diseases would share either common genetic or common environmental causes. At face value, the genetic evidence so far from genome-wide association studies (GWASs) is dominantly aligned against common causality, with very few T2D susceptibility loci showing association with T1D or vice versa 24, 25, 26. However, fewer than 200 regions of the genome have been mapped as risk determinants for the

Parallel Rise in T1D and T2D in Human Populations

Epidemiological data, although equivocal, indicate support for the beta-cell fragility model as a contributor to T1D. T1D in children has been increasing by 2.8% to 4.0% in Western countries over the past decades 48, 49, 50, 51. In American youths, the prevalence of T1D and T2D has increased by 21.1% and 30.5%, respectively, between 2001 and 2009 [52]. In Finland, with the highest reported nationwide annual incidence of T1D in the world, the T1D incidence in children under 15 years of age has

Support for the Beta-Cell Fragility Model in Disease Models

The strongest support for the beta-cell fragility postulates comes from disease models that allow the dissection of beta-cell-intrinsic function. The primary animal model of T1D is the non-obese diabetic (NOD) mouse, which hosts a large set of genetic polymorphisms rendering these animals prone to anti-islet autoimmunity [79]. Intriguingly, NOD diabetes-associated loci overlap with diabetes-associated loci from the related T2D mouse strain Nagoya–Shibata–Yasuda (NSY) [19], raising the

Concluding Remarks

The beta-cell fragility model postulates that intrinsic individual-to-individual variation in beta-cell vulnerability to stress contributes to susceptibility for both T1D and T2D. ‘Contribution’ is a key word in this description. Phenotypic and expression changes in islets are well documented in both T1D and T2D patients 1, 12, 22, 96, 97. However, not all of these changes will necessarily contribute to disease as many will be secondary to the disease process itself. At the opposite end of the

Acknowledgments

The authors thank Dr Carl GmbH (Stuttgart) for generating the online videos. Research leading to this review was supported by the JDRF, the Wellcome Trust, and the ERC. V.L. is an FWO Fellow.

Glossary

Adiposity: the contribution of adipocytes to a tissue.
Alpha-cells: glucagon-producing cells of the pancreatic islets.
Beta-cells: insulin-producing cells of the pancreatic islets.
Central tolerance: series of processes driving immunological tolerance during T cell differentiation in the thymus.
Chromosome conformational capture techniques: molecular techniques that act to fix long-range DNA interactions in place and then measure the relative proximity of regions.
Compensatory capacity: the ability of

References (102)

S.E. Gitelman et al.
Regulatory T cell therapy for type 1 diabetes: may the force be with you
J. Autoimmun.
(2016)
P.M. Ridker
Loci related to metabolic-syndrome pathways including LEPRHNF1AIL6R, and GCKR associate with plasma C-reactive protein: the Women’s Genome Health Study
Am. J. Hum. Genet.
(2008)
C.C. Patterson
Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study
Lancet
(2009)
V. Harjutsalo
Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study
Lancet
(2008)
O. Pinhas-Hamiel et al.
Who is the wise man? The one who foresees consequences: childhood obesity, new associated comorbidity and prevention
Prev. Med.
(2000)
C. Selmi
The X chromosome and the sex ratio of autoimmunity
Autoimmun. Rev.
(2012)
P.E. Wandell et al.
Gender differences and time trends in incidence and prevalence of type 2 diabetes in Sweden—a model explaining the diabetes epidemic worldwide today?
Diabetes Res. Clin. Pract.
(2014)
L.S. Wicker
Type 1 diabetes genes and pathways shared by humans and NOD mice
J. Autoimmun.
(2005)
M. Lindahl
MANF is indispensable for the proliferation and survival of pancreatic beta cells
Cell Rep.
(2014)
S.A. Soleimanpour
The diabetes susceptibility gene Clec16a regulates mitophagy
Cell
(2014)

R. Planas

Global gene expression changes in type 1 diabetes: insights into autoimmune response in the target organ and in the periphery

Immunol. Lett.

(2010)

M. Cnop

Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities

Diabetes

(2005)

A. Anik

Maturity-onset diabetes of the young (MODY): an update

J. Pediatr. Endocrinol. Metab.

(2015)

J.D. Roizen

Progress in understanding type 1 diabetes through its genetic overlap with other autoimmune diseases

Curr. Diabetes Rep.

(2015)

G. Christoffersson et al.

A deeper look into type 1 diabetes – imaging immune responses during onset of disease

Front. Immunol.

(2016)

E. Bonifacio

Rebranding asymptomatic type 1 diabetes: the case for autoimmune beta cell disorder as a pathological and diagnostic entity

Diabetologia

(2016)

R.A. Oram

The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells

Diabetologia

(2014)

H. Kolb et al.

Immunotherapy for type 1 diabetes: why do current protocols not halt the underlying disease process?

Cell Metab.

(2016)

Y.H. Lee

Glucagon is the key factor in the development of diabetes

Diabetologia

(2016)

R.H. Unger et al.

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

J. Clin. Invest.

(2012)

Y. Heianza

Screening for pre-diabetes to predict future diabetes using various cut-off points for HbA_1c and impaired fasting glucose: the Toranomon Hospital Health Management Center Study 4 (TOPICS 4)

Diabet. Med.

(2012)

A.E. Butler

Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes

Diabetes

(2003)

K. Munnee

Comparing the clinical outcomes between insulin-treated and non-insulin-treated patients with type 2 diabetes mellitus after coronary artery bypass surgery: a systematic review and meta-analysis

Medicine

(2016)

K. Maedler

Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets

Diabetes

(2001)

S.H. Back et al.

Endoplasmic reticulum stress and type 2 diabetes

Annu. Rev. Biochem.

(2012)

R. Zhou

Thioredoxin-interacting protein links oxidative stress to inflammasome activation

Nat. Immunol.

(2010)

J. Dooley

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

Nat. Genet.

(2016)

J.A. Todd

Intolerable secretion and diabetes in tolerant transgenic mice, revisited

Nat. Genet.

(2016)

H. Ikegami

Mouse models of type 1 and type 2 diabetes derived from the same closed colony: genetic susceptibility shared between two types of diabetes

ILAR J.

(2004)

T. Wilkin

Testing the accelerator hypothesis: a new approach to type 1 diabetes prevention (adAPT 1)

Diabetes Obes. Metab.

(2016)

T.C. Nogueira

GLIS3, a susceptibility gene for type 1 and type 2 diabetes, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim

PLoS Genet.

(2013)

K.C. Herold

Beta cell death and dysfunction during type 1 diabetes development in at-risk individuals

J. Clin. Invest.

(2015)

K.J. Basile

Overlap of genetic susceptibility to type 1 diabetes, type 2 diabetes, and latent autoimmune diabetes in adults

Curr. Diabetes Rep.

(2014)

R.B. Prasad et al.

Genetics of type 2 diabetes—pitfalls and possibilities

Genes

(2015)

H.Q. Qu

Association analysis of type 2 diabetes loci in type 1 diabetes

Diabetes

(2008)

S.M. Raj

No association of multiple type 2 diabetes loci with type 1 diabetes

Diabetologia

(2009)

J.C. Barrett

Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes

Nat. Genet.

(2009)

J. Dupuis

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Nat. Genet.

(2010)

H. Li

A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans

Diabetes

(2013)

Y.S. Cho

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in East Asians

Nat. Genet.

(2011)

E.C. Somers

Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder?

Am. J. Epidemiol.

(2009)

T. Karaderi

Insights into the genetic susceptibility to type 2 diabetes from genome-wide association studies of obesity-related traits

Curr. Diabetes Rep.

(2015)

M. Dauriz et al.

Current insights into the joint genetic basis of type 2 diabetes and coronary heart disease

Curr. Cardiovasc. Risk Rep.

(2014)

S. Ligthart

Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein

PLoS One

(2015)

T.M. Teslovich

Biological, clinical and population relevance of 95 loci for blood lipids

Nature

(2010)

D.I.G. Replication

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Nat. Genet.

(2014)

A.E. Locke

Genetic studies of body mass index yield new insights for obesity biology

Nature

(2015)

T.M. Frayling

A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity

Science

(2007)

A.P. Morris

Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Nat. Genet.

(2012)

R.A. Scott

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Nat. Genet.

(2012)

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Part 1 of this 2-part review outlined the importance of disease classification in diabetes genetic studies, as well as the ways in which genetic variants may contribute to risk of a complex disease within an individual, or within a particular group of individuals. Part 2, presented here, describes in more detail our current understanding of the genetics of canine diabetes mellitus compared to our knowledge of the human disease. Ongoing work to improve our knowledge, using new technologies, is also introduced.

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Trends in Molecular Medicine

ReviewBeta-Cell Fragility As a Common Underlying Risk Factor in Type 1 and Type 2 Diabetes

Trends

Video Abstract

Section snippets

Glucose Regulation, Diabetes, and Beta-Cell Fragility

Diabetes: Early and Late Stages

The Causal Model of Beta-Cell Fragility and Diabetes

Distinct and Overlapping Genetic Drivers of T1D and T2D

Parallel Rise in T1D and T2D in Human Populations

Support for the Beta-Cell Fragility Model in Disease Models

Concluding Remarks

Acknowledgments

Glossary

J. Autoimmun.

Am. J. Hum. Genet.

Lancet

Lancet

Prev. Med.

Autoimmun. Rev.

Diabetes Res. Clin. Pract.

J. Autoimmun.

Cell Rep.

Cell

Immunol. Lett.

Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities

Diabetes

Maturity-onset diabetes of the young (MODY): an update

J. Pediatr. Endocrinol. Metab.

Progress in understanding type 1 diabetes through its genetic overlap with other autoimmune diseases

Curr. Diabetes Rep.

A deeper look into type 1 diabetes – imaging immune responses during onset of disease

Front. Immunol.

Rebranding asymptomatic type 1 diabetes: the case for autoimmune beta cell disorder as a pathological and diagnostic entity

Diabetologia

The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells

Diabetologia

Immunotherapy for type 1 diabetes: why do current protocols not halt the underlying disease process?

Cell Metab.

Glucagon is the key factor in the development of diabetes

Diabetologia

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

J. Clin. Invest.

Screening for pre-diabetes to predict future diabetes using various cut-off points for HbA1c and impaired fasting glucose: the Toranomon Hospital Health Management Center Study 4 (TOPICS 4)

Diabet. Med.

Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes

Diabetes

Comparing the clinical outcomes between insulin-treated and non-insulin-treated patients with type 2 diabetes mellitus after coronary artery bypass surgery: a systematic review and meta-analysis

Medicine

Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets

Diabetes

Endoplasmic reticulum stress and type 2 diabetes

Annu. Rev. Biochem.

Thioredoxin-interacting protein links oxidative stress to inflammasome activation

Nat. Immunol.

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

Nat. Genet.

Intolerable secretion and diabetes in tolerant transgenic mice, revisited

Nat. Genet.

Mouse models of type 1 and type 2 diabetes derived from the same closed colony: genetic susceptibility shared between two types of diabetes

ILAR J.

Testing the accelerator hypothesis: a new approach to type 1 diabetes prevention (adAPT 1)

Diabetes Obes. Metab.

GLIS3, a susceptibility gene for type 1 and type 2 diabetes, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim

PLoS Genet.

Beta cell death and dysfunction during type 1 diabetes development in at-risk individuals

J. Clin. Invest.

Overlap of genetic susceptibility to type 1 diabetes, type 2 diabetes, and latent autoimmune diabetes in adults

Curr. Diabetes Rep.

Genetics of type 2 diabetes—pitfalls and possibilities

Genes

Association analysis of type 2 diabetes loci in type 1 diabetes

Diabetes

No association of multiple type 2 diabetes loci with type 1 diabetes

Diabetologia

Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes

Nat. Genet.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Nat. Genet.

A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans

Review
Beta-Cell Fragility As a Common Underlying Risk Factor in Type 1 and Type 2 Diabetes

Screening for pre-diabetes to predict future diabetes using various cut-off points for HbA_1c and impaired fasting glucose: the Toranomon Hospital Health Management Center Study 4 (TOPICS 4)