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Inflammatory Pathways Linked to β Cell Demise in Diabetes

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Islets of Langerhans

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Abstract

Inflammation is proposed to play a key role in the development of both type 1 diabetes (T1D) and type 2 diabetes (T2D). It is well established that autoimmunity against β cells is responsible for massive loss of β cells in T1D. Recently, it has been recognized that chronic low-grade inflammation is not limited to insulin target organs but is also seen in islets in T2D. In T1D, T lymphocytes are primed to destroy the β cells. However, the process that leads to the development of self-reactive T lymphocytes remains elusive and is an area of intense research. A complex interplay between genetic and environmental factors, β cells, and immune cells is likely involved in the process. Immunomodulatory therapies have been attempted with some promises in animal models of T1D but have not yielded satisfactory effects on humans. Recent initiatives to evaluate T1D pathology in human donor pancreata hold promise to increase our knowledge in the coming years. In T2D, overnutrition results in metabolic stress including glucolipotoxicity, endoplasmic reticulum stress, and oxidative stress that potentially trigger an inflammatory response in the islets. Substantial evidence exists for an increase in humoral inflammatory mediators and an accumulation of macrophages in the islets of T2D subjects. Anti-inflammatory therapies targeting IL-1β and NFkB have shown improvement in β cell functions in small short term studies of T2D humans, providing a proof of principle for targeting islet inflammation in T2D. However, the nature of islet inflammation in T2D needs better characterization to tailor anti-inflammatory therapies that are effective and durable for T2D.

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Abbreviations

12/15LO:

12/15-Lipoxygenase

12-HETE:

12-Hyrdroxyeicosatetraenoic acid

12LO:

12-Lipoxygenase

A1c:

Hemoglobin A1c

AAb:

Autoantibody

ACE:

Angiotensin-converting enzyme

AdipoR1:

Adiponectin receptor 1

AMPK:

AMP-activated kinase

ANGPTL8:

Angiopoietin-like 8

AP-1:

Activator protein-1

ARb:

Angiotensin receptor blockers

AT:

Adipose tissue

ATF6:

Activating transcription factor-6

CANTOS:

Canakinumab Anti-inflammatory Thrombosis Outcomes Study

CB1:

Cannabinoid receptor type 1

CCL:

Chemokine (C-C motif) ligand

CDKAL1:

CDK5 regulatory subunit-associated protein-1-like

CHOP:

C/EBP homology protein

CLECL1:

C-type leptin-like 1

CVD:

Cardiovascular disease

CXCL:

Chemokine(C-X-C motif) ligand

DAISY:

Diabetes Association in Support of Youth

DC:

Dendritic cells

DEXI:

Dexamethasone induced

DHA:

Docosahexaenoic acid

DMT1:

Divalent metal transporter 1

DPPIV:

Dipeptidyl peptidase-IV

EIF2AK3:

Eukaryotic translation initiation factor 2α kinase-3

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinases

FasL:

Fas ligand

GAD:

Glutamic acid decarboxylase

GIP:

Gastric inhibitory polypeptide

GK rat:

Goto-Kakizaki rat

GLIS3:

Gli-similar 3

GLP:

Glucagon-like peptide

GWAS:

Genome-wide association study

HLA:

Human leukocyte antigen

HOMA:

Homeostasis Model Assessment

hsCRP:

High sensitivity C-reactive protein

IA2:

Islet antigen 2

IAA:

Insulin autoantibody

IAPP:

Islet amyloid polypeptide

ICA:

Islet cell antibody

IFN:

Interferon

IL:

Interleukin

IL-18RAP:

IL-18R accessory protein

IL-1Ra:

IL-1 receptor antagonist

iNKT:

Invariant natural killer T cells

IRE1:

Inositol requiring enzyme-1

IRS:

Insulin receptor substrate

JDRF:

Juvenile Diabetes Research Foundation

JNK:

c-Jun N-terminal kinase

KIR:

Killer immunoglobulin-like receptor

LADA:

Latent autoimmune diabetes of adults

Lp:

Lactobacillus plantarum

LPS:

Lipopolysaccharide

MΦ:

Macrophages

MAPK:

Mitogen-activated protein kinase

MHC:

Major histocompatibility complex

MIP:

Macrophage Inflammatory Proteins

NADPH:

Nicotinamide adenine dinucleotide phosphate

NEFA:

Non-esterified fatty acids

NFκB:

Nuclear factor kappa light chain enhancer of activated B cells

NK:

Natural killer

NLRP3:

NLR family, pyrin domain containing 3

NOD:

Nonobese diabetic

Non-DM:

Nondiabetic

nPOD:

Network for the Pancreatic Organ Donor with Diabetes

OM:

Omental

PA:

Palmitic acids

PERK:

PKR-like eukaryotic initiation factor 2α kinase

PEVNET:

Persistent Virus Infection in Diabetes Network

PI3K:

Phosphoinositide 3-kinase

PKB:

Protein kinase B

PPAR:

Peroxisome proliferator-activated receptor

PTB1B:

Protein tyrosine phosphatase 1B

PTEN:

Phosphatase and tensin homolog

qRT-PCR:

Real-time reverse transcription polymerase chain reaction

ROS:

Reactive oxygen species

SC:

Subcutaneous

SLE:

Systemic lupus erythematosus

SOCS3:

Suppressor of cytokine signaling 3

STAT:

Signal transducer and activator of signal transduction

STZ:

Streptozotocin

SUOX:

Sulfite oxidase

SVF:

Seminal vesicle fluid

T1D:

Type 1 diabetes

T2D:

Type 2 diabetes

Th:

T helper

TINSAL-T2D:

Targeting-Inflammation Using Salsalate in Type 2 Diabetes

TLR4:

Toll receptor 4

TNF:

Tumor necrosis factor

TXNIP:

Thioredoxin-interacting protein

UKPDS:

United Kingdom Prospective Diabetes Study

UPR:

Unfolded protein response

WFS1:

Wolfram syndrome 1

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Acknowledgement

Human studies in unpublished data were approved by the Institutional Review Board at EVMS. Human islets in unpublished data were provided by Integrated Islet Distribution Program (IIDP). Funding support for the authors includes Juvenile Research Foundation grant (Nadler, Taylor-Fishwick), American Diabetes Association (Morris), National Institutes of Health (R01-DK090490 to Imai, R15-HL114062 to Dobrian, R01-HL112605 to Nadler), Astra Zeneca (Dobrian, Nadler), and Congressionally Directed Medical Research Program, Department of Defense (PR093521 to Taylor-Fishwick).

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Authors and Affiliations

  1. Department of Internal Medicine, Eastern Virginia Medical School, Strelitz Diabetes Center, 700 West Olney Road, Norfolk, VA, 23507, USA

    Yumi Imai & Jerry L. Nadler

  2. Departments of Internal Medicine and Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Strelitz Diabetes Center, 700 W. Olney Road, Lewis Hall, 2126, Norfolk, VA, 23507, USA

    Margaret A. Morris

  3. Department of Physiological Sciences, Eastern Virginia Medical School, 700 West Olney Road, Norfolk, VA, 23507, USA

    Anca D. Dobrian

  4. Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, W. Olney Road, Norfolk, VA, USA

    David A. Taylor-Fishwick

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  1. Yumi Imai
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  2. Margaret A. Morris
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  3. Anca D. Dobrian
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  4. David A. Taylor-Fishwick
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  5. Jerry L. Nadler
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Correspondence to Yumi Imai .

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Editors and Affiliations

  1. Department of Clinical Sciences and Education, Sodersjukhuset, Karolinska Institutet, Stockholm, Sweden

    Md. Shahidul Islam

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Imai, Y., Morris, M.A., Dobrian, A.D., Taylor-Fishwick, D.A., Nadler, J.L. (2015). Inflammatory Pathways Linked to β Cell Demise in Diabetes. In: Islam, M. (eds) Islets of Langerhans. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6686-0_30

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