II. What are the actors in inflammation in diabetes?

Several pathways that initiate or amplify inflammation can be common to T1D and T2D.
Some of them were focused on during the IGIS symposium and are described below.

1. The role of adipose tissue

Adipose tissue has a main role in the mediation of chronic inflammation and subsequent β-cell dysfunction (Figure 1).5 The primary events in the
sequence leading to chronic inflammation in adipose tissue seem to be obesity-related metabolic changes in adipocytes that induce the production of immunological mediators and recruitment and activation of immune cells, such as macrophages, DCs, and T cells, within adipose tissue. Inflamed adipose tissue also increases its production of proinflammatory adipokines, such as TNF, leptin, retinol-binding protein 4, lipocalin 2, IL-6, IL-18, CC-chemokine ligand 2 (CCL2; also known as monocyte chemoattractant protein-1 [MCP-1]), CXC-chemokine ligand 5, and angiopoietin-like protein 2. Macrophage infiltration is enhanced by increased expression of chemoattractant proteins like MCP-1, and M1-type macrophages that produce TNF, IL-6, and NO are preferentially recruited compared with M2-type that produce anti-inflammatory cytokines. A phenotypic switch of adipose tissue macrophages toward the M1 phenotype is also observed.
Proinflammatory CD4+ T cells in the adipose tissue also stimulate the development of CD8+ T cells, which are capable of lysing both foreign and self-cells. Finally, the amounts of anti-inflammatory cytokines, such as the beneficial fat-cell hormone adiponectin, IL-10, and secreted frizzled-related protein 5, are reduced.6 As they physiologically inhibit TNF-α action on adhesion in endothelial cells, reduce NF-κB activation, and delay macrophage foam-cell development, this leads to a decreased protection against pathological conditions. Ultimately, adipose tissue inflammation causes metabolic stress in β-cells as well as immune cell recruitment leading to islet inflammation and T2D worsening (Anthony Ferrante, Lecture).

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Figure 1. Dysfunctional adipose tissue in obesity drives β-cell inflammation and type 2 diabetes (T2D) (from reference 5: Imai et al. Trends Endocrinol Metab. 2013;24(7):351-360. © 2013, Elsevier Ltd). Excess caloric intake progressively induces weight gain and fat accretion, leading to obesity.
Adipose tissue is responsible for storage of ~90% of the free fatty acid (FFA) load following feeding, and therefore substantial adipocyte remodeling involving primarily hypertrophy and some degree of hyperplasia occurs to accommodate the increasing demand for triglyceride storage. Hypertrophic adipocytes have a significantly reduced response to insulin and become progressively more lipolytic, liberating excessive FFAs. Gene expression of inflammatory proteins and peptides increases, resulting in elevated production of cytokines, chemokines, and other inflammatory mediators, such as 12-lipoxygenase (12-LO). The latter in turn contributes to immune cell recruitment and activation within adipose tissue, including T cells (CD4+ and CD8+), M1-type macrophages (MΦ), natural killer cells (NK), and dendritic cells (DC). Once in adipose tissue, immune cells are an additional source of proinflammatory mediators. The array of adipokines secreted by adipocytes also changes, with increased production of leptin and reduced adiponectin. All of these circulating factors act in an endocrine manner and induce dysfunction in pancreatic β-cells. Elevated FFAs induce lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in β-cells; elevated leptin, coupled with leptin resistance in β-cells, may contribute to reduced insulin secretion. Insulin secretion is further reduced by inflammatory mediators originating from adipose tissue or locally produced by islets and by infiltrating immune cells. Adiponectin has beneficial effects via AdipoR1 and 2 receptors, which reduce oxidative stress and ER stress in β-cells. Reduced adiponectin expression in obesity minimizes its beneficial effects. Higher demand for insulin due to insulin resistance negatively affects β-cells through ER stress and islet expansion. It is also thought that MΦ recruitment amplifies inflammation and islet dysfunction in obesity. It is yet to be determined
whether other immune cells are involved in islet inflammation in T2D. The overall inflammatory responses in β-cells in obesity contribute to reduced functional β-cell mass, leading to T2D when combined with systemic insulin resistance.

2. Endoplasmic reticulum stress induces islet inflammation

Pancreatic β-cells are physiologically subjected to endoplasmic reticulum (ER) stress to adjust the capacity of the ER to meet the fluctuations in demand for insulin synthesis and secretion. In order to alleviate this stress, the ER triggers an evolutionarily conserved signaling cascade called the unfolded protein response (UPR), which allows adaptation and restoration of ER function. Three different classes of UPR sensors in the ER have been identified: protein kinase RNA (PKR)-like ER kinase (PERK), inositol-requiring enzyme-1α (IRE1α) and activating transcription factor 6 (ATF6).
Briefly, activation of the PERK-ATF4-CHOP (activating transcription factor-4, C/EBP homologous protein) pathway results in reduced global protein synthesis and a subsequent reduction in the workload of the ER. Stimulation of IRE1-XBP1 (X-box binding protein-1) and ATF6 pathways launches a transcriptional program to produce chaperones and proteins involved in ER biogenesis, and in the degradation of the misfolded proteins via the ER-associated degradation complex (ERAD). If this fails, apoptosis is eventually triggered.7

As mentioned above, the elevated glucose and free fatty acid (FFA) levels commonly seen in T2D, as well as the increased demand in insulin synthesis, cause oxidative and ER stresses in the β-cell and the adipocyte that in turn induce pancreatic islet inflammation and insulin resistance (Figure 2) (Raghavendra Mirmira, Decio Eizirik, Lectures). A prolonged or excessive β-cell UPR contributes to β-cell dysfunction and
death in T2D.7 ER stress may also play a critical role in the pathogenesis of T1D.5,7 Thus, targeting ER stress is a tempting approach, but it needs to take into account the “cost-benefit” ratio of modulating it in diabetes, since the UPR pathways are essential for β-cell function and survival.7

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Figure 2. Major inflammatory mediators and signaling pathways involved in β-cell demise (from reference 5: Imai et al. Trends Endocrinol Metab.
2013;24(7):351-360. © 2013, Elsevier Ltd). The major triggers of inflammation in islets are shared with those that induce inflammation in adipose tissue, liver, and muscle: excess saturated free fatty acids (FFAs), lipid mediators such as lipoxygenase products 12(S)-hydroxyeicosatetraenoic acid (12[S]-HETE), increased glucose, and proinflammatory cytokines and chemokines. Islet amyloid polypeptide (IAPP) is so far acknowledged as an islet-specific inflammatory mediator, and is produced and secreted solely by β-cells. Inflammatory mediators activate cellular stress: saturated FFAs and glucose increase endoplasmic reticulum (ER) stress (via CCAAT/enhancer-binding protein homologous protein [CHOP]/inositol-requiring enzyme-1α [IREα1]). Interleukin 1β (IL-1β) increases the expression of NADPH oxidase 1/4 (NOX1/4), activating NADPH oxidase and divalent metal transporter 1 (DMT1), which increases iron transport; both lead to an increase in reactive oxygen species (ROS) and, together with IAPP, contribute to increased oxidative stress. 12(S)-HETE, produced by 12-lipoxygenase (12-LO), activates the G-protein-coupled receptor GPR31, and induces downstream inflammatory signals. Cytokines produced locally or from circulation also activate inflammatory pathways via specific cytokine receptors in β-cells. In response to cytokine receptors, Janus kinase (JAK)/tyrosine kinase (TYK), p38 mitogen-activated protein kinase (p38MAPK) and jun N-terminal kinase (JNK) are activated; JNK is also phosphorylated in response to Toll-like receptor 4 (TLR4) activation or IAPP intracellular aggregation; p38MAPK is activated downstream of GPR31; ROS activate JNK, p38MAPK, or nuclear factor-κB (NF-κB); activation of myeloid differentiation primary response 88 (Myd88/TRIF downstream of TLR4 also leads to NF-κB activation; other transcription factors activated downstream of kinases are c-Jun, activating protein 2 (AP2) (downstream of JNK) and signal transducer and activator of transcription (STAT)3/4/5 (downstream of p38MAPK and JAK/TYK). A positive feedback loop is operational in β-cells in
which inflammatory mediators extrinsic to β-cells converge in activating transcription of various cytokines, chemokines, and other inflammatory mediators that in turn act in an autocrine manner to exacerbate the inflammatory response. In addition, there is extensive intracellular cross-talk between signaling molecules involved in oxidative stress, ER stress, mitochondrial dysfunction, and inflammatory responses. CCL, CC-chemokine ligand; CXCL, CXC-chemokine ligand; TNF, tumor necrosis factor.

a. IL-1: a master cytokine that triggers and amplifies inflammatory responses

IL-1β is a powerful mediator of inflammatory responses that mainly acts on neutrophils and other leukocyte populations to regulate their activation and production of other mediators of inflammation (such as TNF-α and IL-6), and promote their recruitment to inflamed tissues. Mice deficient in IL-1β are more susceptible than wild-type to infection with bacteria, viruses, or fungi. However, the production of IL-1β must be tightly controlled.
In the pancreatic islets, IL-1β improves insulin secretion, increases β-cell replication, and decreases β-cell apoptosis when expressed at low doses, but it is related to impaired β-cell proliferation and β-cell dysfunction when induced at high levels by metabolic stresses, such as chronic hyperglycemia and FFA. For example, exposure of human pancreatic cells to the saturated fatty acid palmitate induces ER stress, NF-κB activation, and upregulation of IL-1β, TNF, and IL-6 expression, among other cytokines. In monocytes, macrophages, and DCs, pro-IL-1β is expressed only at very low levels. Many stimuli from the innate immune system, such as cytokines (eg, TNF-α, IL1-α, IL-1β), or the stimulation of phagocytic cells with TLR ligands induce activation of NF-κB and the upregulation of pro-IL-1β. Then, maturation of pro-IL-1β into the biologically active cytokine IL-1β is carried out by the cysteine-protease caspase-1, which is itself activated by proteolytic cleavage induced by a molecular platform, generically called the inflammasome (Figures 2 and 3).3,5 The inflammasome is a complex of several proteins and plays a
key role in mediating activation of innate immunity; it can be activated by a variety of metabolic disturbances, including those pertaining to glucose and human islet amyloid polypeptide (hIAPP) in pancreatic islets, as well as lipopolysaccharide, FFA, and ceramides in adipose tissue
in diabetic patients.
Recent data have shown that thioredoxin-interacting protein (TXNIP) is a critical link between ER stress and inflammation in β-cells, since it is
activated by ER stressors via the PERK and IRE1 pathways and triggers IL-1β production via the NLRP3 (NLR family, pyrin domain containing 3) inflammasome, contributing to local inflammation (Figure 3).3 Once it is secreted, IL-1β binds to the IL-1 receptor I (IL-1R1) on target T cells, a process that is inhibited by its natural antagonist IL-1Ra (IL-1F3). IL-1Ra expression and release are induced by IL-1β and in response to many proinflammatory stimuli.8 Recent data from the Whitehall II cohort showed that individuals who will develop T2D are characterized by a complex immune activation that includes upregulation of both proinflammatory and anti-inflammatory cytokines (such as IL-1Ra), the latter, however, being insufficient to prevent the disease9 (Shizuo Akira, Christian Herder, Lectures).

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Figure 3. High concentrations of glucose promote β-cell production of interleukin-1β (IL-1β) through the dissociation of thioredoxin-interacting
protein (TXNIP) from its inhibitor thioredoxin (TXR), resulting in activation of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, activation of caspase 1 and processing of pro-IL-1β into its mature form (from reference 3: Donath and Shoelson. Nat Rev Immunol.
2011;11:98-107. © 2011, Nature Publishing Group). IL-1β induces the production of a wide range of cytokines and chemokines such as CC-chemokine
ligand 2 (CCL2), CCL3, and CXC-chemokine ligand 8 (CXCL8) through nuclear factor-κB (NF-κB) activation. This is enhanced by free fatty acid (FFA)-induced activation of Toll-like receptor 2 (TLR2) or TLR4 and leads to the recruitment of macrophages. FFAs may also directly activate the NLRP3 inflammasome.
Islet-derived amyloid can activate the recruited macrophages through the NLRP3 inflammasome, increasing IL-1β production and the vicious cycle of IL-1β autostimulation through IL-1 receptor type 1 (IL-1R1). ASC, apoptosis-associated speck-like protein containing a CARD; MYD88, myeloid
differentiation primary-response protein 88.

b. The central role of NF-κB

NF-κB is a transcription regulator that is activated by various intra- and extracellular stimuli such as oxidant free radicals, bacterial or viral products, proinflammatory cytokines (IL-1β, TNF), TLRs, and the UPR. NF-κB is bound to the NF-κB inhibitor IkB and sequestered in the cytoplasm at baseline. Activated NF-κB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions.
Its inappropriate activation has been associated with a number of inflammatory diseases, whereas its persistent inhibition leads to inappropriate immune cell development or delayed cell growth. The UPR sensor PERK-ATF4-CHOP suppresses translation of IkB through eIF2a (eukaryotic translation initiation factor 2A) and IRE1a-XBP1 promotes its degradation through activation of its kinase, IKK. This results in increased activation of NF-κB and subsequent upregulated production of proinflammatory cytokines and chemokines, which amplify ER and oxidative stresses, mitochondrial dysfunction, apoptosis, and other adverse reactions that intensify the downward spiral of cellular dysfunction in the inflamed islet (Figures 2 and 4).5,7 Pretreatment of β-cells with the ER stressor cyclopiazonic acid (CPA) or with the fatty acids oleate and palmitate sensitizes them to the proinflammatory effects of a low dose of IL-1β, leading to increased NF-κB activation and exacerbation of islet inflammation (Figure 4)7 (Decio Eizirik, Lecture).

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Figure 4. The cross-talk between the unfolded protein response (UPR) and inflammation in pancreatic β-cells (from reference 7: Eizirik et al. Diabetologia.
2013;56(2):234-241. © 2013, Springer-Verlag Berlin Heidelberg). Pancreatic β-cell endoplasmic reticulum (ER) stress can be induced by environmental factors such as obesity and obesity-induced insulin resistance and increased nonesterified fatty acid (NEFA) levels. The ongoing UPR sensitizes β-cells to a second hit by proinflammatory cytokines via activation of the IRE1-XBP1s (inositol-requiring enzyme-1/X-box binding protein 1 spliced) and PERK-ATF4-CHOP pathways. The effect of XBP1s is mediated at least partly by degradation of forkhead box protein O1 (FOXO1). Cytokine exposure induces the activation of nuclear factor-κB (NF-κB), which has predominantly proinflammatory and proapoptotic roles in β-cells. Cytokines trigger ER stress via inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) pump and consequent ER Ca2+ depletion. This may either be a direct effect of cytokines, by mechanisms that remain to be clarified, or mediated via NF-κB-induced inducible nitric oxide synthase (iNOS) expression and NO production. The outcome of this cross-talk between the UPR and inflammation is an upregulation in the production and secretion of proinflammatory cytokines and chemokines. This leads to further recruitment of immune cells and exacerbation of local inflammation. The ultimate result is increased insulitis and β-cell apoptosis and, in genetically susceptible individuals progression to clinical type 1 diabetes. AT4, activating transcription factor 4; CHOP, C/EBP homologous protein; PERK, protein kinase RNA (PRK)-like ER kinase.

c. 12-lipoxygenase is a potential mediator of stress on cytokine exposure

12/15-lipoxygenases (12/15-LO, murine Alox15 gene) are oxidoreductases for arachidonic acid (AA) and other fatty acids. Oxygenation of AA results in the inflammatory 12(S)-hydroperoxyeicosatetraenoic acid and 13(S)-hydroxy-9Z,11E-octadecadienoic acid. The first compound, being unstable and highly toxic, is almost immediately converted to the more stable 12-hydroxyeicosatetraenoic acid (12-HETE) by glutathione peroxidase. 12-HETE has been implicated in the pathogenesis of several diseases, including diabetes, where it has proatherogenic effects and mediates the actions of growth factors and proinflammatory cytokines (including IL-1β, TNF-α, and IFN-γ) (Figure 2).5,10 This is the case for T2D, as 12/15-LO expression is highly increased in islets of T2D animal models, such as Sprague-Dawley rats after 90% partial pancreatectomy, prediabetic Zucker diabetic fatty (ZDF) rats, or C57BL/6J mice fed a Western diet. In vivo data also showed a role for the enzyme in T1D, as deletion of 12/15-LO protected C57BL/6J mice from developing T1D induced by multiple low-dose streptozotocin and also protected nonobese diabetic
(NOD) mice from T1D with significant reduction in pancreatic inflammation compared with age-matched NOD mice.10Macrophage-specific deletion of 12/15-LO decreased proinflammatory cytokines and preserved healthy islets, while adipose tissue–specific deletion reduced local and islet inflammation, decreased macrophage infiltration, and improved insulin secretion and sensitivity with increased islet mass.11 In addition to its proinflammatory effects, 12/15-LO mediates ER stress in the adipocyte and the pancreatic islets, as 12/15-LO deficient mice placed on a high-fat
diet exhibit attenuated signs of ER stress. Since ER stress itself increases 12/15-LO expression, 12/15-LO activity and ER stress can create a feed-forward loop that results in a downward spiral of cellular dysfunction11 (Jerry Nadler, Lecture).

3. IL-6 and exercise: role of a myokine with both pro- and antiinflammatory properties

Physical inactivity contributes directly to the development of low-grade inflammation in overweight and obese persons.6,13 Indeed, modern sedentary lifestyle leads to the accumulation of visceral fat, adipose tissue infiltration by proinflammatory immune cells and increased levels of circulating inflammation markers such as IL-6, TNF, and CRP. On the contrary, regular physical activity is recognized to have antiinflammatory
properties and to reduce the risk for metabolic diseases in the long term. The beneficial effects of exercise are numerous: weight loss, reduction of the visceral fat mass with a subsequent lesser production of proinflammatory adipokines and increased synthesis of adiponectin, decreased TLR expression on monocytes and macrophages with consequent inhibition of proinflammatory downstream responses, or induction of anti-inflammatory cytokines from contracting skeletal muscle.6 In this last case, the active muscle is able to produce and secrete transient high levels of IL-6, whose resting concentrations are typically very low in young, healthy individuals, whereas they are two- to threefold higher in older adults or those with metabolic disease, such as obesity and T2D. Prolonged moderate-intensity exercise is thus capable of elevating levels of circulating IL-6 and of its receptor IL-6R to form a binary complex (IL-6/IL-6R) that induces a strong rise in circulating levels of the anti-inflammatory cytokine IL-10 (whose principal function appears to be the downregulation of adaptive immune response and minimization of inflammation-induced tissue damage), and also stimulates the antagonistic receptors of proinflammatory cytokines TNF-α and IL-1β to blunt their activity.6
In tissues lacking membrane-bound IL-6R, the soluble form of the receptor, sIL-6R, allows IL-6 signaling to occur, a process termed trans-signaling. sIL-6R expression is also increased by exercise. Muscle-derived IL-6 seems also to play an important role in the maintenance of energy supply. Indeed, IL-6 can enhance lipolysis in humans and might play a role in glucose metabolism as it stimulates glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells and pancreatic α-cells, improving insulin secretion and blood glucose in response to exercise6,13,14
(Figures 5 and 6) (Myra Nimmo, Mark Febbraio, Lectures).

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Figure 5. The effect of diet and physical activity on inflammation and disease (from reference 6: Gleeson et al. Nat Rev Immunol. 2011;11(9):607-
615. © 2011, Nature Publishing Group). A healthy diet and physical activity maintain the anti-inflammatory phenotype of adipose tissue, which is
marked by small adipocyte size and the presence of anti-inflammatory immune cells, such as M2-type macrophages and CD4+ regulatory T cells (Treg).
A positive energy balance and physical inactivity lead to an accumulation of visceral fat and adipose tissue infiltration by proinflammatory macrophages and T cells. The proinflammatory M1 macrophage phenotype predominates and inflamed adipose tissue releases proinflammatory adipokines, such as tumor necrosis factor (TNF), which causes a state of persistent low-grade systemic inflammation. This may promote the development of insulin resistance, tumor growth, neurodegeneration and atherosclerosis. Atherosclerosis is exacerbated by the deleterious changes in the blood lipid profile that are associated with a lack of physical activity. LDL, low-density lipoprotein; IL-6, interleukin 6; TLR, Toll-like receptor.

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Figure 6. The cytokine cascade in response to sepsis and exercise (from reference 13: Petersen and Pedersen. J Appl Physiol. 2005;98(4):1154-1162. © 2005, American Physiological Society). In sepsis (A), the cytokine cascade within the first few hours consists of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-1 receptor antagonist (IL-1ra), TNF receptor (TNF-R), and IL-10. The cytokine response to exercise (B) does not include TNF-α and IL-1, but does show a marked increase in IL-6, which is followed by IL-1ra, TNF-R, and IL-10. Increased C-reactive protein (CRP) levels do not appear until 8-12 hours later.

4. Importance of vitamin D for β-cell and immune function

Vitamin D is well known for its central effects in bone tissue and in calcium/phosphate homeostasis. It also has fundamental roles in immunomodulation and in the regulation of proliferation and/or differentiation of numerous cell types. Vitamin D deficiency has been characterized as one of the numerous risk factors associated with both T1D and T2D in humans as well as in animal models. For example, many studies have revealed a worldwide association between vitamin D deficiency and the prevalence of T1D and certain polymorphisms in key vitamin D–related genes have been associated with T1D. An inverse relationship between serum vitamin D and decreased β-cell function, impaired glucose tolerance, or T2D has been observed in several ethnic groups. Moreover, certain allelic variations of genes involved in vitamin D signaling may influence insulin secretion and sensitivity and glucose tolerance.
Vitamin D is a fat-soluble vitamin group including ergocalciferol, or vitamin D2, and cholecalciferol, or vitamin D3. Vitamin D2 is found in vegetal diets, eg, in cereals, mushrooms, and yeasts; vitamin D3 is also obtained from diets that include fish or enrichedmilk foods, but the major part is synthesized from the conversion of 7-dehydrocholesterol in the skin by sunlight’s ultraviolet B (UVB) rays. Interestingly, worldwide studies have reported that the degree of latitude and UVB irradiance influence the incidence of T1D and to a lower extent T2D. The previtamin D3 is isomerized to cholecalciferol, which is hydroxylated by 25-hydroxylases to form 25-OHD3 in the liver. Next, a second hydroxyl group is added by 1α-hydroxylase (1α-OHase) primarily, but not exclusively, in the kidney to form the biologically active vitamin D3, 1,25-(OH)2D3. Vitamin D signaling is mediated by binding of 1,25-(OH)2D3 to the intracellular vitamin D receptor (VDR), which forms homodimers or heterodimers with the retinoid X receptor (RXR). After translocation to the nucleus, the complex binds to vitamin D response elements (VDREs) in target genes. VDR is expressed in a wide variety of tissues, such as pancreatic islets and in all cells of the immune system, including APCs and lymphocytes, suggesting both direct and indirect effects of 1,25-(OH)2D3.2
Whereas few data support that 1,25-(OH)2D3 activates the differentiation and activation of macrophages from monocytes, many indicate that 1,25-(OH)2D3 has anti-inflammatory effects, mainly through reducing the expression of MHC class II on APCs and subsequent T-lymphocyte stimulation.
There is also evidence that 1,25-(OH)2D3 directs DCs toward a more tolerogenic state with the ability to induce Treg cells, suggesting that vitamin D deficiency in T1D leads to a failure of tolerance and autoimmunity.
Vitamin D also directly influences β-cell function. Experiments in vitamin D–deficient animals showed impaired glucose-induced insulin secretion that could be improved by vitamin D supplementation. However, data are controversial, some concluding that 1,25-(OH)2D3 has either no effect on insulin secretion or an inhibitory effect. In all cases, caution in interpreting the results is needed as an important feature of vitamin D deficiency in vivo is hypocalcemia, which by itself can dramatically decrease insulin secretion and impair β-cell function. Note that calcium homeostasis is also involved in the proliferation and/or differentiation of immune cells, such as DCs and T cells.
During T1D, β-cells are able to produce and secrete chemokines to recruit immune cells, thereby mediating their own destruction. In different in vitro models (INS-1E cells, NOD, NOD/SCID [severe combined immunodeficiency], and human islets) and in in vivo models (NOD and NOD.SCID mice), treatment with 1,25-(OH)2D3 or an analog has been shown to be capable of reducing gene expression and/or protein secretion levels of several chemokines and cytokines.15 Moreover, such a treatment of NOD.SCID islets was shown to lead to to upregulation of the NF-κB inhibitor IkB, thereby inhibiting transcriptional regulation of a proinflammatory pathway by NF-κB.15 However, there is still controversy over the ability of 1,25-(OH)2D3 to protect β-cells from cytokine-induced (such as by IL-1β, IFN-γ, and TNF-α) impaired insulin production and secretion or cell death (Chantal Mathieu, Lecture).

“Islet Inflammation”
I. General points on islet inflammation in diabetes
II. What are the actors in inflammation in diabetes?
III. Conclusion
References
Lectures during IGIS meeting