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Cytokines and β-Cell Biology: from Concept to Clinical Translation

The Clinic for Endocrinology and Diabetes (M.Y.D.), University Hospital Zurich, CH-8091 Zurich, Switzerland; Department for Translational Diabetology (J.S., L.A.B., N.B., T.M.-P.), Steno Diabetes Center, DK-2820 Gentofte, Denmark; and Core Unit for Medical Research Methodology (T.M.-P.), Institute of Biomedicine, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark

Correspondence: Address all correspondence and requests for reprints to: Thomas Mandrup-Poulsen, M.D., DMSc, Department for Translational Diabetology, Steno Diabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark. E-mail: tmpo{at}steno.dk

	Abstract

Top Abstract I. Introduction II. Molecular Mechanisms in... III. Regulation and Molecular... IV. Cytokines and β-Cell... V. Inflammatory Cytokines as... VI. Summary and Conclusions References

 
The tale of cytokines and the β-cell is a long story, starting with in vitro discovery in 1984, evolving via descriptive and phenomenological studies to detailed mapping of the signalling pathways, gene- and protein expression patterns, molecular and biochemical effector mechanisms to in vivo studies in spontaneously diabetic and transgenic animal models. Only very recently have steps been taken to translate the accumulating compelling preclinical data into clinical trials. The aim of this chapter is to present an overview of early and recent key observations from our own groups as well as other laboratories that serve to illuminate the road from concept to clinical translation.

I. Introduction

A. Simple question—simple answer?

B. Inflammation: when the heat hits the β-cell

C. Cytokines: not just bad news for the islet endocrine cells

D. Transition in translation: relevance of the preclinical evidence?

II. Molecular Mechanisms in Cytokine-Mediated β-Cell Destruction in the Context of Type 1 Diabetes

A. Mitogen-activated protein kinases

B. Ca²⁺ and MAPKs

C. Sustained MAPK signaling

D. Nuclear factor-B

E. Endoplasmic reticulum stress

F. Summary

III. Regulation and Molecular Mechanisms of Cytokine-Mediated β-Cell Stimulation and Failure in the Context of Type 2 Diabetes

A. Glucose- and leptin-induced β-cell apoptosis

B. The role of IL-1β in type 2 diabetes

C. The Fas-FLIP pathway as a switch between beneficial and deleterious actions of glucose

D. Inflammation and immune cell infiltration in islets of type 2 diabetes

E. Summary and working hypothesis

IV. Cytokines and β-Cell Regeneration in Type 1 and Type 2 Diabetes

A. β-Cell regeneration

B. Mechanisms of β-cell proliferation

C. Cytokines as β-cell growth factors

D. Effects of GLP-1 and GH family members on β-cell growth

E. Summary

V. Inflammatory Cytokines as Targets for Intervention in Type 1 and Type 2 Diabetes

A. Type 1 diabetes

B. Type 2 diabetes

VI. Summary and Conclusions

	I. Introduction

Top Abstract I. Introduction II. Molecular Mechanisms in... III. Regulation and Molecular... IV. Cytokines and β-Cell... V. Inflammatory Cytokines as... VI. Summary and Conclusions References

 
A. Simple question—simple answer?
WHAT CAUSES DIABETES? It's a question commonly asked by patients and their families—so straightforward and yet so complex. The previous perception of type 2 diabetes as being caused by defective insulin action and type 1 diabetes being caused by defective insulin production no longer holds true. Both these mechanisms that lead to reduction or deletion of the biological effects of insulin are elements in the pathogenesis of both common types of diabetes. Thus, increasing experimental and epidemiological evidence links type 1 diabetes to insulin resistance. Indeed recent data suggest that the genetic background of the classical animal model for type 1 diabetes, the nonobese diabetic (NOD) mouse, predisposes to insulin resistance (1). Obesity, which is associated with insulin resistance, shows epidemiological association with the increased incidence of type 1 diabetes (2, 3, 4). This led to the formulation of the so-called "accelerator hypothesis" implying that insulin resistance precipitates type 1 diabetes by decompensating an already smoldering insulin production (5).

Similarly, there is increasing agreement that type 1 and type 2 diabetes are both diseases in which β-cells perish (6, 7, 8). Reduction in β-cell mass is observed in pancreatic specimens from both types of diabetics. Insulin resistance is not a sufficient element and may not even be a necessary element of type 2 diabetes, because many obese insulin-resistant individuals never develop diabetes, and type 2 diabetes can be observed in normal weight subjects with apparent normal insulin sensitivity. So clearly, diabetes will not manifest itself in an even severely insulin-resistant individual as long as that individual has healthy β-cells that are able to compensate for the increased insulin demand. Genetics are important in determining the health of the β-cells as supported by the linkage between several genes involved in β-cell function and type 2 diabetes (9, 10).

What then is the cause of the reduction in β-cell mass? The simplest of answers, i.e., that we do not have a clue, would violate the glimpses of insights that painstaking studies in laboratories and clinics have provided over the last century. To answer that any single factor or mechanism is the cause would be an oversimplification; there is always a simple answer to a complex question, and it is always wrong. To integrate all current knowledge from basic research and animal studies into one cohesive pathogenetic model without any inherent contradiction is difficult, if at all possible. We hypothesize that a genetic predisposition, i.e., in type 1 diabetes mainly controlling innate and adaptive immunity and in type 2 diabetes mainly controlling β-cell function, regeneration, and survival acts in concert with environmental events early in life. Such environmental factors may, for example, determine β-cell development and may be distinct for the two common types of diabetes. They may be permissive for an abnormal reactivity of the β-cell to extracellular stressors, and such stressors may converge on overlapping if not identical intracellular signaling pathways that target the β-cell for impaired secretory function, regulation of apoptosis, and regeneration.

What lessons can we draw to verify or discard this hypothesis from randomized clinical trials, considered to be the highest level of medical evidence? Intriguingly, the only successful interventions directed at the pathogenetic mechanisms of β-cell failure in diabetes seem to involve immunomodulation. Indeed, in type 1 diabetes immunointervention transiently preserves β-cell function if given at disease onset (11, 12, 13, 14). Interpreted in the most naïve way this observation indicates that β-cell destruction has a causal relation to the adaptive/innate immune system. In type 2 diabetes, very few randomized intervention trials targeting directly the etiology of the impairment in β-cell function/survival have been reported. A recent study suggested however that β-cell function in type 2 diabetes may be improved by a targeted antiinflammatory treatment (15). These studies attract attention to immune/inflammatory targets for intervention in both common types of diabetes.

B. Inflammation: when the heat hits the β-cell
Twenty years of basic research have established that the pancreatic β-cell is a target of inflammatory and noninflammatory cytokines that regulate its function, cell cycle, and viability, and have disentangled the complex and interacting signaling pathways that cytokines elicit in this cell (16). IL-1β is the prototype proinflammatory cytokine (17, 18) and is a central cytokine regulating β-cell function, viability, and replication. Indeed, transient activation of receptors for inflammatory cytokines, and in particular the IL-1 receptor (IL-1R), stimulates the β-cell to preproinsulin transcription, proinsulin translation, and insulin secretion, as well as proliferation, allowing the β-cell to adapt to increased insulin requirements during systemic inflammation and stress associated with elevated circulating IL-1 (16, 19, 20, 21). Sustained and more intense IL-R engagement causes progressive functional impairment, ranging from discrete inhibition of insulin granule exocytosis and distinct blockade of substrate metabolism in the Krebs cycle and energy generation to general suppression of protein biosynthesis, and eventually cell death by both necrotic and apoptotic mechanisms (22). These detrimental effects of IL-R activation support pathogenetic implications of inflammation in β-cell failure and destruction in stress-hyperglycemia and diabetes.

The particular propensity to activate the apoptotic program in response to inflammatory cytokines is shared by only a few other cell types, such as certain neuronal cells and theca granulosa cells of the ovary. It seems to be related to inherent properties of the β-cell phenotype acquired during β-cell differentiation and maturation, leading to exacerbated signaling via nuclear factor B (NFB) and MAPK/c-jun N-terminal kinase (JNK) pathways (23). The more we learn about these signaling events in the β-cell, the more we understand that the cellular and molecular events that lead to β-cell apoptosis are aberrantly regulated and uncontrolled versions of normal adaptive responses that serve to armor the β-cell to adapt and defend itself against a stressful and hostile environment.

C. Cytokines: not just bad news for the islet endocrine cells
The cytokine growth factor GH, which shares the Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-1 signaling pathway with the inflammatory cytokines interferon (IFN) and IL-6, has been known since 1989 to stimulate rodent β-cell proliferation (24) and later to protect against cytokine toxicity, in part via differential utilization of the STAT transcription factor subtypes and the induction of suppressor of cytokine signaling molecules. More recently, we observed that the -cell expresses the highest levels of IL-6 receptor compared with other tissues, and that IL-6 enhances proliferation, mass, and secretory activity of the glucagon-producing -cell (25), which may by paracrine action stimulate insulin secretion. As mentioned, IL-1 receptors on the β-cell may contribute to the regulation of compensatory insulin secretion during episodes of inflammation associated with transient and low-grade elevation of circulating IL-1 concentrations, and IL-1β, at low concentrations, leads to β-cell proliferation in human islets (21). Likewise, adenoviral expression of IL-1 receptor antagonist (IL-1Ra) increases β-cell replication in rat islets, probably resulting from a restoration of a beneficial ratio of IL-1 to IL-1Ra (26). These observations emphasize how discrete qualitative or quantitative differences in cytokine signaling pathways in β-cells determine cellular decisions to proliferate, live, or die.

D. Transition in translation: relevance of the preclinical evidence?
A general problem in translational medicine is that although animal models may provide information about the pharmacokinetics and toxicity of novel interventions, they are often of limited utility to judge the clinical potential of a pharmacological target. Both widely used animal models of spontaneous type 1 diabetes have severe limitations: the BioBreeding Worcester (BB) rat has turned out to be a model of virus-induced diabetes (27), and the NOD mouse exhibits features of a rare genetic syndrome including deafness, sialitis, complement and antigen-presentation defects, and ketosis resistance, not found in the human counterpart, and is amenable to more than 125 curative interventions (28).

β-cell susceptibility appears to differ between species (16), although some differences may be related to other factors, e.g., age, presence and composition of non-β-cells, extracellular matrix, and other specific culture conditions (29, 30). Although a hierarchy clearly exists in the cytokine system and some cytokines such as IL-1β and TNF appear to be master regulators for many other cytokines, they do not operate in isolation but in a complex network and in concert with the metabolic, endocrine, and neuronal milieu, with potentiating and inhibiting factors that modulate the cellular outcome to cytokine exposure. Manipulation of the action of single inflammatory mediators by systemic administration of small-molecule inhibitors, receptor agonists, and antagonists or genetic alteration have shown effects on the clinical phenotype of diabetes in rodent models (22). However, these effects are generally modest and do not prove an absolute requirement for these mediators in the disease process. It should be noted that cytokines have redundant biological effects and that there is a striking lack of combinatorial studies of the effect of manipulating the synergistic action of several cytokines. For the same reason, the full clinical potential of preventing inflammatory damage to the β-cell in diabetes may not be disclosed until combinatorial trials have been conducted, based on knowledge of the efficacy and adverse reactions of any single factor of such a combination. Furthermore, the perspective of combining antiinflammatory therapy with interventions targeting T cell reactivity/tolerance such as anti-CD3, β-cell responsiveness/defense, or β-cell regeneration/proliferation is tempting. For safety, ethical, and regulatory reasons, this may require decades of work to reveal, and the challenges are daunting. Recent breakthroughs in the treatment of neoplastic and HIV-associated disease with combinations of drugs ignite a light in the tunnel leading to the cure of diabetes.

In the following sections, we will highlight milestones and recent discoveries in the fields of basic research related to signal transduction and biological effects of cytokines, including cytokine growth factors in β-cells and their relevance for understanding and intervention in the disease processes in diabetic animal models and in patients. The purpose is not to present the medical history of this development or an exhaustive literature survey, which has been published elsewhere (16, 22, 31, 32, 33, 34), but to share a personal view of the context of our own and others' observations, to serve as stimulation for future debate and development toward clinical translation.

	II. Molecular Mechanisms in Cytokine-Mediated β-Cell Destruction in the Context of Type 1 Diabetes

Top Abstract I. Introduction II. Molecular Mechanisms in... III. Regulation and Molecular... IV. Cytokines and β-Cell... V. Inflammatory Cytokines as... VI. Summary and Conclusions References

 
IL-1β-induced β-cell apoptosis is the result of a complex network of signaling events. After receptor binding, IL-1β initiates intracellular signaling within seconds by activating a number of protein complex formations and interactions at the intracellular part of the IL-1 receptor. This in turn activates kinase cascades leading to activation of two major pathways: MAPKs and NFB. Signal transduction by IFN is more linear and involves activation of the Janus kinase (JAK)-signal transducer and activator of transcription-1 (STAT-1) pathway. Distal IL-1β and IFN signaling converges at the level of changes in β-cell gene expression, which eventually leads to activation of the apoptotic program.

In this section, we describe the signal transduction of cytokine-mediated β-cell destruction with emphasis on IL-1β signaling pathways, because this is the most potent β-cell cytotoxic cytokine. It is our purpose not to comprehensively describe every component in the signaling pathways, but instead to provide an overview of key signaling proteins and factors contributing to cytokine-mediated β-cell death (Fig. 1).

View larger version (11K): [in this window] [in a new window]   FIG. 1. IL-1β signal transduction in β-cells. After receptor binding, IL-1β initiates intracellular signaling via recruitment of different adaptor proteins and kinases, including MyD88, IRAK, TRAF6, and TAK1. This, in turn, leads to activation of two main pathways: the MAPKs comprising ERK, p38, and JNK; and the NFB pathway. The activation of MAPKs is to some extent dependent on Ca2+ influx, and there is also cross-talk between ERK MAPK and NFB. The activation of MAPK and NFB signaling converges at the level of changes in gene expression. The gene encoding iNOS is induced and leads to production of NO, which causes ER stress and ultimately cell death. MAPKs are probably also involved in β-cell apoptosis via transcription-independent mechanisms, for example by modulation of the activity and function of Bcl proteins.

Another potential mechanism of JNK-mediated apoptosis in β-cells is via induction of activating transcription factor (ATF)3, a member of the ATF/cAMP responsive element binding protein (CREB) family of transcription factors. Cytokine-stimulated ATF3 induction is reduced in the presence of JNK inhibition, and islets from ATF3 knockout mice are less sensitive to cytokine-induced cell death (44). Interestingly, using an in vitro model system for β-cell differentiation, it was revealed that an acquired attribute of the β-cell phenotype is a more efficient IL-1β-stimulated MAPK-activating machinery (23), which is consistent with the findings that MAPKs play important roles in transducing functional effects of cytokines as described above.

B. Ca²⁺ and MAPKs
Because MAPKs, and JNK in particular, play prominent roles in β-cell apoptosis, the molecular mechanisms and factors that regulate β-cell MAPK activation in response to IL-1β have been investigated. The concentration of free cytoplasmic Ca²⁺, which is a crucial determinant of insulin granule exocytosis, also affects the ability of IL-1β to activate MAPKs (40, 45). Interestingly, however, whereas Ca²⁺ plays a permissive and potentiating role for IL-1β-induced MAPK activation, Ca²⁺ alone is an insufficient stimulus for JNK and p38 MAPK activation. Only ERK MAPK activity is directly related to the cytoplasmic free Ca²⁺ concentration, and pronounced ERK activation can be induced by an increase in Ca²⁺ (45, 46, 47). Apparently, the effect of Ca²⁺ on cytokine-induced MAPK activation involves the action of calmodulin, putatively via Ca²⁺/calmodulin-dependent kinases (45), but interestingly, Ca²⁺ may also control protein turnover of the JNK scaffold protein JNK interacting protein/islet-brain 1 (JIP/IB-1) (48), thus regulating the ability of upstream activators to stimulate the JNK pathway.

C. Sustained MAPK signaling
As already mentioned, IL-1β-stimulated β-cell MAPK activation is aberrantly regulated. Hence, IL-1β causes sustained MAPK activity lasting up to several hours in β-cells (35, 45, 49), which is in contrast to most other cells, and the kinetics of MAPK activation may determine whether MAPK signaling is translated into survival or apoptosis. Therefore, increased knowledge about β-cell factors causing prolonged MAPK activation is desirable because the identification of such factors may be exploited therapeutically. There are at least two different mechanisms that are responsible for prolongation of IL-1β-stimulated β-cell MAPK signaling. Firstly, we identified NO produced by iNOS as a possible mediator of prolonged JNK signaling because iNOS inhibition prevented sustained JNK activity in rat islets and because IL-1β-induced persistent JNK activation was reduced in islets from iNOS knockout mice compared with wild-type islets (50). Secondly, IL-1β induction of the natural JNK inhibitor Gadd45β, which otherwise would ensure only transient JNK signaling, is severely impaired in pancreatic β-cells compared with other cells (49).

D. Nuclear factor-B
The role of NFB for cytokine-mediated β-cell death has also been investigated, mainly by expressing a nondegradable, mutant form of the NFB inhibitor IB—the so-called IB super-repressor—in β-cells. Thus, infection of primary rat β-cells with adenovirus encoding the IB super-repressor resulted in decreased apoptotic cell death induced by a combination of IL-1β and IFN (51). Similarly, experiments with human islets have shown that NFB inhibition protects against IL-1β-stimulated, Fas-triggered apoptosis (52). The use of the IB super-repressor and microarray technologies have revealed that cytokine-induced changes in multiple genes are dependent upon NFB in β-cells (53). NFB may well therefore be a master switch determining the fate of the β-cell during an inflammatory attack. Although NFB-dependent alterations in the expression of certain genes are likely to be more important than others, it is reasonable to assume that this effect of NFB is multifactorial and does not rely on changes in a single or few gene products alone. Contradictory to the in vitro findings above pointing toward a proapoptotic function of β-cell NFB, recent data indicated that NFB blockade in mouse islets and insulinoma cells potentiates cell death induced by TNF and IFN (54, 55). In line with these findings, β-cell-specific expression of the IB super-repressor in NOD mice significantly accelerates diabetes development, indicating that NFB in β-cells may play a protective role in type 1 diabetes (54). Hence, the exact role(s) of NFB in controlling β-cell apoptosis seems to be highly dependent upon the exact experimental context and specific combination of cytokines. However, it also indicates that in the NOD mouse, TNF may play a dominant role in β-cell destruction, which may not be the case in humans, and it highlights the need for verifying in vitro findings in vivo. Whether NFB is mainly anti- or proapoptotic in the presence of all three cytokines (IL-1β+IFN+TNF), which might be the most relevant model for human type 1 diabetes, awaits clarification.

E. Endoplasmic reticulum stress
In addition to playing a regulatory role for IL-1β signal transduction to MAPKs, Ca²⁺ is also involved in β-cell stress biology at another level (Fig. 1). Thus, in 2001 it was reported that chemical donors of NO induce β-cell apoptosis by causing Ca²⁺ depletion of the endoplasmic reticulum (ER) leading to ER stress (56). This observation in combination with microarray data showing cytokine-induced up-regulation of CHOP (CCAAT/enhancer binding protein (C/EBP) homologous protein), a classical marker for ER stress, and suppression of the ER Ca²⁺ pump SERCA2b (57) prompted a study exploring whether cytokines cause ER stress in β-cells via NO. We found that IL-1β+IFN in an iNOS-dependent manner led to suppression of the expression of the SERCA2b ER Ca²⁺ pump, depletion of ER Ca²⁺, and induction of several ER stress-induced pathways including CHOP (58). Thus, although the exact contribution of ER stress for β-cell demise and diabetes in animal experimental models and humans is unclear, delineating ER stress-induced signaling pathways leading to apoptosis in β-cells is currently attracting much focus. Future investigations within this area may unravel novel and important information about the signaling mechanisms relevant for β-cell destruction in diabetes.

F. Summary
Since the original observation that cytokines cause β-cell damage published two decades ago (59), much progress has been made toward understanding the "signalosomics" of cytokine-induced β-cell failure. Several of the pathways and elements are potential drug targets. These pathways, however, are not unique for the β-cell, and therapeutic intervention only seems relevant if cell specificity can be achieved, most probably via manipulation of regulatory mechanisms. Of note, virtually every cytokine signaling pathway investigated has been found to be aberrantly regulated in β-cells in terms of kinetics and intensity, in part explained by defect signal inhibition or other defective modulations, most likely inherent properties of the β-cell acquired during β-cell differentiation. Because it is still unknown whether blocking cytokine signaling distally is more effective or safer than blocking signaling proximally, further exploration and mapping of the events that take place inside the β-cell during inflammatory attack will be important for future design of rational intervention strategies to preserve, rescue, and increase residual β-cell mass.

	III. Regulation and Molecular Mechanisms of Cytokine-Mediated β-Cell Stimulation and Failure in the Context of Type 2 Diabetes

Top Abstract I. Introduction II. Molecular Mechanisms in... III. Regulation and Molecular... IV. Cytokines and β-Cell... V. Inflammatory Cytokines as... VI. Summary and Conclusions References

 
As mentioned above, the role of cytokines in the pathogenesis of type 1 diabetes has been discussed for decades. Only recently the concept emerged that cytokines may also mediate nutrient induced β-cell dysfunction during the development of type 2 diabetes. β-Cell failure in type 2 diabetes, first described by Cerasi and Luft (60), was long considered to be purely functional. Accordingly, research on underlying mechanisms focused on regulation of insulin production and secretion, e.g., glucotoxicity (61). The idea that hyperglycemia also induces β-cell apoptosis (62) was first rejected and then considered irrelevant until decreased β-cell mass in type 2 diabetes was eventually generally accepted (8, 63, 64, 65). Identification of an ongoing apoptotic process leading to decreased β-cell mass was also a conceptual move to seek common grounds in the separated worlds of type 1 and type 2 diabetes. A molecular link between the two diabetes types was the observation that glucose-induced β-cell apoptosis is mediated via up-regulation of the Fas-receptor in human islets (66). The Fas receptor, the archetypical death receptor, at that time believed to be confined to the immune system, was the key to the discovery of IL-1β as an inducer of Fas in β-cells and thereby a mediator of glucotoxicity (67). Even more unexpected was the observation that IL-1 is produced by the β-cell itself. This paradigm shift has also been first challenged, but in the meantime, the ability of the β-cell to produce not only IL-1β but also other cytokines was established (68, 69, 70, 71, 72, 73). Finally, the concept was substantiated by a clinical trial (15).

In this section, we describe in more detail the above-mentioned mechanisms regulating β-cell mass and function in the context of type 2 diabetes and propose that these pathways are involved in an islet inflammatory process mainly driven by IL-1β. Although hyperglycemia is certainly not acting alone, other factors contributing to this inflammatory process (e.g., dyslipidemia and adipokines) will not be discussed in this section.

A. Glucose- and leptin-induced β-cell apoptosis
Today, the ability of increased glucose concentrations to induce cell death is widely accepted. Yet, 10 yr ago two publications strongly argued against this concept (65, 74), and conflicting data still exist. The confusion in the field can be explained by the methodological challenge to detect low rates of apoptosis in vivo as well as by differences in species and ages. Detection of apoptosis in tissue sections is demanding and may lead to false-negative results. Indeed, an apoptotic cell is typically cleared by macrophages or neighboring cells within less than 30 min. If for example 1% apoptotic cells are detected in a tissue section, this would reflect 48% cell death per 24 h. In other words, this is a 50% decrease in cell mass within a day. Thus, even taking some regeneration into account, the number of apoptotic cells that can be expected, especially during the slow regression of β-cell mass in the context of metabolic stress, is far below one percent. This explains why an ongoing apoptotic process can easily be overlooked in studies based on snapshots of some tissue sections. This probably explains the conclusions based on electron micrographs that glucose does not induce β-cell structural damage (74). In addition, glucose affects survival of human and rodent islets differently. In fact, graded increases in glucose from 5.5 to 11 mmol/liter and above induce apoptosis of human β-cells in a concentration-dependent fashion (66, 67), whereas studies on rat islets have shown that increasing glucose from a physiological concentration of 5.5 to 11 mmol/liter decreases apoptosis (62, 75). A further increase above 11 mmol/liter has been shown to be either pro- or antiapoptotic depending on the study (62, 65, 75). However, these differences may not be due solely to species differences or genetic background, but may also be related to the age of the individuals. Typically, rat islets are isolated from 2- to 3-month-old animals. At this age rats are often considered to be already adults. However, this is certainly not the case in many aspects, including linear growth. Interestingly, no striking cell cycle differences were apparent anymore when comparing human islets and islets from rats aged 6 months (29).

B. The role of IL-1β in type 2 diabetes
Given that glucose induces β-cell apoptosis, what are the underlying mechanisms? We tested the hypothesis that IL-1β may mediate the deleterious effects of high glucose on human β-cells (67). In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1β, followed by NFB activation, Fas up-regulation, DNA fragmentation, and impaired β-cell function. The IL-1 receptor antagonist IL-1Ra protected cultured human islets from these deleterious effects. β-Cells themselves were identified as the islet cellular source of glucose-induced IL-1β. In vivo, IL-1β-producing β-cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1β was induced in β-cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented β-cell expression of IL-1β. However these data could not be confirmed in a study using islets isolated from patients with type 2 diabetes (76). Unfortunately, several methodological aspects were not taken into account in this study. For example, islets were precultured in medium containing 5.5 mM glucose for 3–4 d before experimentation. The reversibility of glucotoxicity is well documented (77), as well as the reversibility of glucose-induced IL-1β expression (67). An additional limitation of this study is the low number of islet preparations and consequent low statistical power, considering the variability between human islet batches. Furthermore, the high number of non-β-cells is an issue, particularly using islets isolated from diabetic patients with reduced numbers of β-cells compared with the controls. To address this last point, the gene expression profiles of β-cells captured by laser microdissection of pancreas sections from patients with type 2 diabetes were analyzed (78). This study confirmed increased IL-1β mRNA expression in the β-cells from patients with type 2 diabetes.

In the context of type 2 diabetes, other factors may also induce islet production of IL-1β. An interesting candidate is leptin, which is expressed primarily in the adipose tissue and is increased in human obesity before onset of diabetes. In vitro, chronic exposure of human islets to leptin induces IL-1β release from the islet preparation leading to impaired β-cell function and apoptosis (69).

The role of a particular cytokine in disease is best established by demonstrating clinically relevant effects after specific blockade of that cytokine (79). Treatment of patients with type 2 diabetes with IL-1Ra demonstrated an important role of IL-1β in this condition (15). Thus type 2 diabetes shares features with autoinflammatory diseases (79). A key feature of these diseases is a failure to control the processing and secretion of IL-1β. Briefly, pro-IL-1β is processed into active IL-1β via cleavage by the IL-1 converting enzyme, also known as caspase-1. In turn, activation of caspase-1 is tightly controlled by a recently described molecular complex, the inflammasome (80). Whether the inflammasome is genetically defective in patients with type 2 diabetes and/or susceptible to metabolic stress is a tempting hypothesis that remains to be investigated.

C. The Fas-FLIP pathway as a switch between beneficial and deleterious actions of glucose
As discussed above, changes in the concentration of glucose play an essential role in the regulation of β-cell apoptosis. The situation is complicated by the fact that in human islets glucose stimulates β-cell proliferation in the short term but impairs replication after prolonged exposure (66). This can be explained by the IL-1β regulated Fas pathway. In human islets, elevated glucose concentrations impair β-cell proliferation and induce β-cell apoptosis via up-regulation of the Fas receptor. Downstream the caspase-8 inhibitor FADD-like IL-1 converting enzyme inhibitory protein (FLIP) may shift Fas-mediated death signals into signals for cell proliferation (81). Indeed, exposure of islets from nondiabetic organ donors to high glucose levels decreases FLIP expression and increases the percentage of apoptotic β-cells. Up-regulation of FLIP, by incubation with TGFβ or by transfection with an expression vector coding for FLIP, protects β-cells from glucose-induced apoptosis, restores β-cell proliferation, and improves β-cell function (81).

Hitherto, activation of the Fas death receptor was discussed in the context of apoptosis and proliferation in the presence of FLIP. Nevertheless, the Fas-FLIP pathway may also regulate β-cell secretory function. Indeed, in addition to its effect on β-cell turnover, chronic hyperglycemia impairs β-cell secretory function (82). This glucotoxic effect is evident before apoptosis leads to a significant decrease in β-cell mass. This is most striking in vitro, where a 4-d exposure of human islets to elevated glucose concentrations leads to almost complete ablation of β-cell secretory function, although less than 1% of β-cells are apoptotic (67). Because hyperglycemia regulates Fas expression (see Section III.B), we hypothesized that the Fas pathway may not solely mediate glucose-induced changes in cell turnover, but also changes in β-cell secretory function (83). We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of pancreatic duodenal homeobox-1 (Pdx-1), a β-cell specific transcription factor regulating insulin gene expression and mitochondrial metabolism, was decreased in Fas-deficient β-cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by a dramatic increase in β-cell mass. Up-regulation of FLIP enhanced NFB activity via NFB-inducing kinase and RelB. This led to increased Pdx-1 and insulin production independent of changes in cell turnover.

D. Inflammation and immune cell infiltration in islets of type 2 diabetes
Pancreatic islets from type 2 diabetes patients are known to present with amyloid deposits, fibrosis, and increased cell death. Furthermore, as mentioned above, the human pancreatic β-cell produces increased IL-1β in response to glucotoxicity. However, by definition, an inflammatory process also includes immune cell infiltration. Therefore, we investigated this notion in several animal models of type 2 diabetes and in the islets of type 2 diabetic patients (84). Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat-fed mice, the Goto-Kakisaki rat, and the db/db mouse. When cultured islets were exposed to a diabetic milieu (high glucose and high fat), increased amounts of islet-derived inflammatory factors were produced and released, including the chemokine IL-8, which may contribute to the attraction of macrophages. Interestingly, IL-8 is highly dependent upon IL-1β, and therefore immune cell infiltration may also improve by IL-1 antagonism.

E. Summary and working hypothesis
We propose a hypothesis for the role of IL-1β in mediating the underlying mechanisms by which glucose and leptin increase both β-cell functional mass and its failure (Fig. 2). According to this hypothesis, long-term adaptation of the β-cells to conditions of increased demand may be triggered by hyperglycemic excursions or increased circulating leptin levels. This may occur very early in the progression from obesity/insulin resistance to diabetes (85). These excursions of glucose and leptin elicit β-cell production of IL-1β followed by Fas up-regulation. In the presence of the caspase-8 inhibitor FLIP, Fas engagement signals proliferation and enhanced function. However, excessive glucose or leptin stimulation will decrease FLIP, switching this adaptive pathway toward deleterious signals and eventually to β-cell failure and diabetes (81). In parallel, glucose and leptin-induced IL-1β will induce production and release of chemokines (e.g., IL-8), which will attract immune cells, typically macrophages. These cells may contribute to β-cell regeneration at early stages of the disease and to β-cell failure at later stages. However, the precise role of macrophages in type 2 diabetic islets remains to be clarified.

View larger version (14K): [in this window] [in a new window]   FIG. 2. IL-1β as a common mediator of metabolic regulation of β-cell function, proliferation, and apoptosis. Long-term adaptation of the β-cells to conditions of increased demand may be triggered by hyperglycemic excursions or increased circulating leptin levels that elicit β-cell production of IL-1β followed by Fas up-regulation. In the presence of the caspase-8 inhibitor FLIP, Fas engagement signals proliferation and enhanced function (right panel). Excessive glucose or leptin stimulation will decrease FLIP, switching this adaptive pathway toward deleterious signals and eventually to β-cell failure and diabetes (left panel). In parallel, glucose- and leptin-induced IL-1β will induce production and release of chemokines (e.g., IL-8), which will attract immune cells, typically macrophages. These cells may contribute to β-cell regeneration at early stages of the disease and to β-cell failure at later stages.

	IV. Cytokines and β-Cell Regeneration in Type 1 and Type 2 Diabetes

Top Abstract I. Introduction II. Molecular Mechanisms in... III. Regulation and Molecular... IV. Cytokines and β-Cell... V. Inflammatory Cytokines as... VI. Summary and Conclusions References

B. Mechanisms of β-cell proliferation
Several factors have been implicated in the regulation of compensatory β-cell proliferation under conditions of increased demand for insulin. Glucose is known to be an important regulator of β-cell mass and proliferation both in vivo and in vitro. Continuous glucose infusion resulting in hyperglycemia in mice and rats results in increased β-cell proliferation (87, 96) without affecting β-cell size or apoptosis. Also, in cultured β-cells glucose has potent growth regulatory effects affecting cell cycle parameters and responsiveness to other β-cell growth factors (97). The effects of glucose are dose dependent within the physiologically relevant range and affect the ability of other β-cell growth factors such as IGF-I (98), GH (99), and hepatocyte growth factor (HGF) (100) to stimulate β-cell proliferation with little or no stimulation of proliferation at glucose concentrations below 5 mM. The underlying molecular mechanism responsible for the growth stimulatory activity of hyperglycemia has not been elucidated. It might be possible that the effects of glucose are mediated through the increased secretion of insulin and an autocrine or paracrine effect of insulin on the β-cell is responsible for mitogenic effects of glucose. Indeed, insulin has been shown to act as a β-cell mitogen, and β-cell-specific insulin receptor deficient mice are characterized by a decrease in β-cell number and reduced β-cell proliferation (101). Alternatively, glucose-induced IL-1 may drive β-cell proliferation via Fas in the presence of FLIP, as mentioned above.

The molecular mechanism responsible for regulation of β-cell mitosis seems to be similar to those found in other cell types. The main point of regulation is the transition from G₀ to G₁ and the initiation of the S-phase. Typical G₁/S-phase checkpoint molecules such as Rb, E2F's cyclin A, D, and E, as well as inhibitory kinases) and cyclin inhibitory proteins (CIPs) are expressed in β-cells and seem to be involved in the regulation of cell cycle progression (102). Of these, p21^CIP expression was specifically found to be up-regulated by both HGF and placental lactogen (PL) in murine islets, and in islets from p21^CIP-deficient mice increased proliferative response to HGF and PL was observed, indicating that this cell cycle inhibitor plays an important role in growth factor-induced β-cell growth. Also, p27 is involved in β-cell proliferation because mice deficient in this cell cycle regulator exhibit increased β-cell mass and enhanced proliferation of β-cells (103). Interestingly p27-deficient mice are also less sensitive to single high-dose streptozotocin-induced diabetes compared with wild-type mice and show increased β-cell proliferation after streptozotocin treatment. Very little is known about how proinflammatory cytokines affect cell cycle regulators.

C. Cytokines as β-cell growth factors
In addition to glucose, as described in Section IV.B, many other factors including classical growth factors have been shown to stimulate the proliferation of β-cells (104). These factors include HGF (105), IGF-I (106), glucagon-like peptide-1 (GLP-1) (107), gastrin (108), and members of the GH-prolactin (PRL) family of hormones (109, 110). Interestingly, we have recently found that IL-1β, which is known to induce apoptosis of β-cells, has growth stimulatory activity at low concentrations (10–20 pg/ml), whereas higher concentrations (>2 ng/ml) induce apoptosis in human β-cells (21). The growth stimulatory action of low concentrations of IL-1β was mediated by induction of the caspase 8 inhibitor FADD-like IL-1β-converting enzyme (FLICE)-inhibitory protein FLIP. The possible clinical application of using growth factors to induce β-cell regeneration is questionable because most of these growth factors induce proliferation of not only β-cells, but also many other cell types, raising the concern for induction of neoplasia.

D. Effects of GLP-1 and GH family members on β-cell growth
Special attention has to be made to β-cell growth factors for which clinical experience already exists and possible side effects can be addressed. Two such factors, GLP-1 agonists (including Exendin-4) and GH, are already approved for clinical use, and considering their documented effects on β-cell growth, their potential as factors to increase β-cell mass in diabetes will be discussed in detail.

GLP-1 secreted from the intestinal L cells in response to food intake has been shown in numerous studies to stimulate proliferation of β-cells both in vivo and in vitro (111). The mitogenic effects of GLP-1 are mediated by cAMP and involve activation of protein kinase A (PKA), protein kinase B (PKB), and protein kinase C (PKC) as well as phosphatidylinositol-3 kinase (PI3K) (112, 113, 114, 115). In vivo, administration of GLP-1 or Exendin-4 results in increased β-cell mass by increasing proliferation in both prediabetic and diabetic animal models (116, 117). In addition to its stimulatory effects on β-cell mitosis, GLP-1 also promotes differentiation and functional maturation of human β-cell precursors by increasing the expression of the β-cell transcription factor Pdx-1 (118). Finally GLP-1 also protects β-cells from cytokine and free fatty acid-induced apoptosis (119), suggesting that GLP-1 can increase β-cell mass by inhibiting mechanisms responsible for β-cell loss in both type 1 and type 2 diabetes.

The GH family of hormones includes (in addition to GH itself) PRL and PL. These hormones share several structural and biological properties and are considered members of the cytokine family of proteins and bind to specific receptors that are members of the class 1 cytokine receptor family (120). Both GH and PRL have been shown in several studies to stimulate proliferation of β-cells in vitro (109, 110), an effect independent of local production of IGF-I. GH plays a role in the normal postnatal development of the β-cell because mice deficient for the GH receptor exhibit a 4.5-fold reduction in β-cell mass and significantly decreased proliferation of β-cells without affecting -cell mass (121). PRL and PL are also important regulators of β-cell mass, in particular during pregnancy where induction of β-cell proliferation and increased β-cell mass is part of an important adaptation to the increased demand for insulin (88). In mice lacking functional PRL receptors (which also mediate the action of PL) a reduction in β-cell mass was observed as early as 3 wk of age, and the effect was present in 8-month-old animals (122). In addition to the effect on β-cell mass, PRL receptor deficiency was also associated with blunted glucose-induced insulin release in isolated islets and mild glucose tolerance after ip glucose tolerance. Together, the data from GH and PRL receptor-deficient mice indicate an important physiological role of these hormones in the regulation of β-cell mass and proliferation. However, very little is known about the effect of GH and PRL on human β-cells. In transgenic mice with specific overexpression of PL in the β-cells, a dramatic up-regulation of β-cell mass and proliferation was observed (123). This was accompanied by fasting hypoglycemia and inappropriately high plasma insulin concentrations. In addition to its mitogenic effect, PL also protected β-cells against single high-dose streptozotocin-induced β-cell death in transgenic mice (124). Similarly, GH was recently shown to inhibit cytokine-induced apoptosis in vitro by an STAT5-dependent mechanism (125). This antiapoptotic effect of GH was associated with an up-regulation of the antiapoptotic Bcl-X_L gene, suggesting that this gene might be an important mediator of the antiapoptotic activity of GH on β-cells.

The mechanism by which GH and PRL stimulate β-cell replication has been studied in some detail. Tyrosine phosphorylation and nuclear translocation of the transcription factor STAT5 has been shown in response to GH and PRL in β-cells (126, 127). However GH and PRL also induce several other signaling pathways including MAPKs, PI3K, and PKC, but the activation of STAT5 is both sufficient and necessary for GH induction of β-cell proliferation because a dominant negative mutant of STAT5 is able to completely suppress GH-induced β-cell proliferation (128), and a constitutively active mutant of STAT5 can drive β-cell proliferation in a GH-independent manner (129). GH induces directly the transcription of the cyclin D2 gene in β-cells by activation of STAT5 and subsequent binding of activated STAT5 to the cyclin D2 promoter, whereas no activation of cyclin D1 or D3 transcription by GH was observed (129). Interestingly, GLP-1 was found to stimulate cyclin D1 transcription in β-cells in a cAMP-dependent manner, without affecting cyclin D2 and D3 expression (112). The ability of GH and GLP-1 to induce transcription of two different cyclin Ds might explain the additive effects of these to β-cell growth factors on induction of rat β-cell proliferation (112).

The ability of both GLP-1 and GH to stimulate β-cell proliferation and inhibit apoptosis raises the interesting possibility of increasing β-cell mass in diabetics using these drugs. As the experience using GLP-1 and its agonists in the treatment of diabetes will accumulate in the coming years it will be possible to assess the possible effects on β-cell mass in treated individuals. The potent effects of GH and PRL on β-cell proliferation and apoptosis might also support initiation of trials in which these factors are evaluated for their beneficial effects on β-cell mass and glucose homeostasis either alone or in combination with GLP-1 and its agonists (Fig. 3).

View larger version (10K): [in this window] [in a new window]   FIG. 3. Regulation of β-cell proliferation and apoptosis by GH/PRL and GLP-1. GH/PRL binds to specific receptors present in β-cells and activates the cytoplasmic tyrosine kinase JAK2. STAT5 is subsequently activated by phosphorylation by JAK2 and translocates to the nucleus where it directly regulates cell proliferation through transcription of cyclin D2. STAT5 also induces transcription of Bcl-XL resulting in protection of apoptosis induced by proinflammatory cytokines and free fatty acids. GLP-1 binds to receptors on β-cells and stimulates the generation of cAMP and activation of PKA. The transcription factor CREB mediates the effects of GLP-1 by inducing transcription of cyclin D1, which is involved in cell proliferation, and of bcl-2, which induces protection from cytokine and free fatty acid-induced apoptosis.

	V. Inflammatory Cytokines as Targets for Intervention in Type 1 and Type 2 Diabetes

Top Abstract I. Introduction II. Molecular Mechanisms in... III. Regulation and Molecular... IV. Cytokines and β-Cell... V. Inflammatory Cytokines as... VI. Summary and Conclusions References

 
This section will focus on intervention studies in animal models and patients with diabetes to provide evidence of causality between cytokine action and disease. Therefore, descriptive or associative studies of tissue cytokine expression or circulating cytokine levels and clinical phenotype will not be included.

Manipulation of cytokine action involves methodological challenges. Systemic exogenous administration or transgenic expression under a general promoter is difficult to interpret because of secondary effects, age- and development-dependent differences in therapeutic window, and limited local tissue concentrations obtained. On the other hand, systemic administration of inhibitors or global knockout of cytokine action pose similar problems in particular in deciding at which cellular compartment the effects are exerted. Tissue specific overexpression of agonists or of antagonists is confounded by the derived cellular functional effects by forced protein synthesis and by the difficulty in obtaining the appropriate protein concentration in the intercellular surroundings. The following paragraphs are attempts to synthesize and interpret the available information from interventional studies in animal models and humans when considering these possible confounders. Due to the complexity of the cytokine network and incomplete information for many cytokines, we will focus on the three prototypic inflammatory cytokines: IL-1β, TNF, and IFN. IL-6 is often erroneously referred to as an inflammatory cytokine. In fact, IL-6 should rather be regarded as a chameleon that takes color from its surroundings. Diverging and contradictory studies of the actions of IL-6 in vitro, animal models, and humans can be explained from the difference in inflammatory context in which the effect of this cytokine is studied (for review, see Refs. 130, 131, 132). Thus, IL-6 will not be considered further here.

A. Type 1 diabetes
As reviewed above, there are extensive and detailed studies to suggest that combinations of inflammatory cytokines in vitro cause profound defects in the function of β-cells from all species studied and lead to β-cell demise by necrosis and/or apoptosis. The following section will briefly review our current insight into the role of these cytokines in vivo based on pharmacological or genetic manipulation with their action.

1. IL-1β.
Intraperitoneal injections of human recombinant IL-1β cause transient hyperglycemia and insulinopenia in normal rats (133), the experiment being limited by the development of neutralizing antibodies. As reviewed elsewhere (16, 22), systemic species homologous IL-1 administration to low-dose streptozotocin (LD-STZ)-treated mice or to NOD mice or BB rats aggravates, protects, or is inert depending upon dose, timing, duration, and model. Transgenic models with local islet overexpression of IL-1 have not been reported.

Systemic IL-1 blockade using either administration of IL-1Ra or soluble IL-1 type 1 receptor (sIL-1T1R) reduces diabetes incidence in all the aforementioned models and reduces xenograft and allograft rejection, as well as disease recurrence in syngeneic grafts transplanted in animal models of spontaneous autoimmune diabetes (26, 134, 135, 136, 137, 138). Systemic knockout of the IL-1RT1 reduced diabetes incidence by 30% (139). No effect on diabetes incidence was observed in NOD mice lacking the IL-1 converting enzyme (or caspase-1) (140), probably due to unaltered activity of IL-1β processed by membrane calpains and extracellular proteases or in its membrane-bound form, or due to alternative proIL-1β to IL-1β cleavage by, e.g., proteinase-3. There is no reported study of the effect of β-cell-specific knockout of single or combinations of cytokine receptors, which would be required to appreciate the full effect of inhibiting the synergistic effects of cytokine signaling only at the level of the β-cell in spontaneous animal models. No human intervention studies of the effect of IL-1 blockade in individuals at risk for or patients with type 1 diabetes have been carried out. We are currently planning an investigator-initiated trial of IL-1Ra treatment in recent-onset type 1 diabetic subjects.

In summary, blocking IL-1β action is effective in preventing islet graft destruction due to rejection and autoimmune disease recurrence, and in reducing diabetes incidence in animal models, although IL-1β does not seem indispensable for diabetes development. Most studies have not been designed to identify whether protection is caused by blocking costimulatory effects of IL-1β on the adaptive immune system, reducing systemic inflammation, or shielding the β-cells from inflammatory damage. One report showing protective effect of soluble IL-1T1 receptor in the NOD mouse also demonstrated that T cell activity was not affected, indicating a protective effect of IL-1 blockade directly at the level of the β-cells (141).

2. TNF.
Systemic administration of TNF has been shown to aggravate LD-STZ-induced diabetes but to protect against diabetes development in the adult NOD mouse and BB rat (16). Expression of TNF under the rat insulin promoter (RIP) in non-diabetes prone animals causes insulitis but not diabetes. β-Cell-specific TNF expression in NOD mice aggravates insulitis and reduces diabetes incidence in adult NOD mice, but increases diabetes incidence in neonates without accompanying insulitis (22). Anti-TNF treatment was ineffective in BB rats, increased diabetes incidence in adult NOD mice, and reduced the incidence in neonates, consistent with the results of β-cell-specific TNF expression. A very similar dual role was seen in the RIP-lymphocytic choriomeningitis virus (LCMV) model, which develops diabetes when infected with LCMV due to T cell-dependent destruction of LCMV-expressing β-cell (142). If TNF is expressed in β-cells together with the T cell costimulus B7–1, diabetes is provoked in both non-diabetes-prone and diabetes-prone animals.

Taken together, these data indicate that TNF has little diabetogenic action in itself but, if expressed locally in the context of an inflammatory environment, modulates the pathogenetic process dependent upon the timing of administration and the model studied. Recent studies have elucidated the mechanisms responsible for the temporal differences in TNF action in the NOD mouse and the RIP-LCMV model. In the neonate, islet expression of TNF enhances islet antigen presentation to T cells by recruiting dendritic cells and macrophages (142), and TNF also increases dendritic cell maturation (143) as well as down-regulates CD4+CD25+ regulatory T-cell levels and function (144). In the adult, animal TNF reduces CD8+ T cell number and activity (142) and increases the number of regulatory T cells (144).

In summary, these studies illustrate the complexity of the action of inflammatory cytokines. Studies are needed to test the importance of TNF action on the β-cell in vivo with the necessary scrutiny, e.g., by investigating diabetes incidence in models of spontaneous type 1 diabetes with transgenic deletion of β-cell TNF receptors.

3. IFN.
Systemic IFN administration has no effect in adult NOD mice, but anti-IFN treatment does reduce diabetes incidence in both this model and BB rats (16). RIP-IFN transgenic mice on non-diabetes-prone background develop pronounced pancreatitis, insulitis, and diabetes, which are prevented by postnatal administration of anti-IFN (145). Surprisingly, this was not reproduced by expressing IFN under the glucagon promoter (146). There are no reports of RIP-IFN transgenic NOD mice. There is consensus that systemic or β-cell-specific disruption of IFN action does not affect diabetes incidence in the NOD mouse or LD-STZ diabetes (22). Interestingly, deletion of a transcription factor of IFN signaling IFN regulatory factor 1 increases susceptibility to LD-STZ diabetes (147).

Taken together, these studies indicate that IFN action is dispensable for development of animal type 1 diabetes. To what extent this is due to redundant JAK-STAT signaling via other cytokines such as IL-6 known to potentiate β-cell IL-1β signaling has not been investigated.

There are case reports showing development of type 1 diabetes in patients treated with IFN for chronic hepatitis (148, 149), but no clinical studies of the effect of manipulating IFN action in this disease.

In summary, there is little evidence to support a critical role for IFN in the pathogenesis of type 1 diabetes in animal models, but on the other hand there are no studies to exclude that IFN may synergize with other inflammatory factors to cause β-cell destruction in human type 1 diabetes.

B. Type 2 diabetes
Type 2 diabetes is associated with low-level inflammation, and inflammatory mediators have been implicated in both insulin resistance and β-cell dysfunction in this disorder (7, 31, 32, 150). As reviewed in Section III, above, cytokines and in particular IL-1β are mediators of β-cell glucotoxicity in vitro. The aim of the following paragraph is to provide a short overview of the understanding of the role of these mechanisms in obesity, insulin resistance, and type 2 diabetes in vivo provided from interventional procedures in animal models and humans.

1. IL-1β.
Interesting information about the metabolic effects of IL-1β has come from studies of systemic IL-1Ra knockout animals. These animals have no increase in circulating IL-1β or other proinflammatory cytokines, but a dramatically altered IL-1β/IL-1Ra balance resulting in increased IL-1β action. A consistent and central role for IL-1 in obesity and lipid metabolism has been reported (151, 152, 153, 154, 155). IL-1Ra–/– mice are lean, with impaired adipogenesis, reduced adipocyte size, fat storage, lipase activity, and cholesterol homeostasis and serum leptin levels. They have increased food intake, which is compensated by increased energy expenditure. The animals are resistant to monosodium glutamate-induced obesity. Interestingly, these animals are normoglycemic with reduced insulin secretion and increased insulin sensitivity. The role of IL-1 in body weight composition and metabolism was supported by the observation of obesity and secondary insulin resistance in systemic IL-1T1 receptor knockout mice (156).

Administration of IL-1Ra to animal models of type 2 diabetes (ob/ob mice, high-fat-feeding models, Goto-Kakisaki rats, and P. obesus) have shown prevention of diabetes and improvement in β-cell function (157) without affecting insulin sensitivity. Interestingly, IL-1Ra increased basal and stimulated insulin levels with no change in insulin sensitivity in normal mice (158), indicating that IL-1β suppresses β-cell function independently of insulin sensitivity.

Taken together these studies indicate that IL-1β is involved in negatively regulating adipogenesis and β-cell function and that the latter effect is independent of its action on body composition and insulin sensitivity. These observations are supported by a recent randomized, placebo-controlled trial of 13 wk of IL-1Ra administration to patients with uncontrolled type 2 diabetes (15). In this study, glycemic control and β-cell function, but not body weight or insulin sensitivity, were significantly improved, and the intervention was well tolerated without any increase in hypoglycemic events.

In summary, there is increasing evidence from in vivo studies in animals and patients that IL-1 negatively affects β-cell function and plays a role in the pathogenesis of progressive β-cell failure in type 2 diabetes. More studies are needed to investigate the effects of higher doses of IL-1 blockers and the durability of these effects and safety profile when given for longer periods of time.

2. TNF.
In vitro, TNF has pronounced inhibitory effects on insulin signaling via the activation of stress kinases such as JNK that directly inhibit insulin receptor substrate tyrosine phosphorylation and downstream insulin signaling. JNK also elicits ER stress and mitochondrial generation of reactive oxygen species that potentiate NFB-dependent transcription of inflammatory genes, lipolysis, and inhibition of peroxisome proliferator-activated receptor- that further contributes to insulin resistance (159). Consistent with these cellular effects, TNF administration or neutralization reduces or increases insulin sensitivity, respectively (for review, see Refs. 158 and 160). Obese mice with targeted null mutations in genes encoding TNF or TNF receptors improved insulin sensitivity, predominantly due to disrupted signaling via the p55 TNF receptor (161, 162), although this has not been a consistent finding for unclear reasons (158, 163). Preventing the activation of this receptor also reduced brown adipocyte apoptosis and enhanced thermogenesis via increased uncoupling protein expression (164).

Case reports and small or uncontrolled studies of insulin sensitivity in patients with rheumatic disease treated with anti-TNF therapy claimed to show improved insulin sensitivity (165, 166, 167), whereas this could not be confirmed in a controlled open study (168). Two uncontrolled and one open parallel group study failed to show any effect on insulin sensitivity of anti-TNF therapy after a single dose of p55 soluble receptor:Fc fusion protein or the anti-TNF antibody infliximab (169, 170) or a 4-wk treatment with etanercept (171), although doses were comparable to those effective in rheumatoid disease and the latter study demonstrated significant reduction in systemic inflammatory markers. Also there was no indication of improved β-cell function in these studies. Similar negative findings were reported in a 4-wk randomized, double-blind study of anti-TNF antibody therapy in obese type 2 diabetic patients.

In summary, in stark contrast to in vitro and animal models studies, there is no evidence from clinical studies to date to support a role of TNF in human insulin resistance or type 2 diabetes. Limitations to these studies include small sample sizes, lack of dose-finding studies, and short duration. More studies are required to clarify the role of TNF in human insulin resistance and type 2 diabetes.

3. IFN.
There is limited, if any, information available in the literature regarding the effect of IFN on insulin action in vitro or in animal models of obesity or type 2 diabetes. In hepatitis patients treated with IFN, responders to treatment showed reduced insulin resistance, but this was most likely related to the successful treatment of their chronic infection and not to IFN per se because nonresponders showed no change in insulin resistance (172). Case reports have shown deterioration of insulin sensitivity in IFN and IFN-treated subjects (173, 174). In summary, there is no current evidence for IFN in insulin resistance or type 2 diabetes.

	VI. Summary and Conclusions

Top Abstract I. Introduction II. Molecular Mechanisms in... III. Regulation and Molecular... IV. Cytokines and β-Cell... V. Inflammatory Cytokines as... VI. Summary and Conclusions References

 
Twenty-five years ago cytokines were considered to be signal mediators confined to the regulation of the immune response. Today the fact is that virtually every cell in the organism is capable of responding to and even producing cytokines. The β-cell has turned out to be no exception. As in most other cellular examples, cytokine production and action have been evolutionary advantages as part of the adaptation to tissue damage, stress, and inflammation. In the case of the β-cell, the positive selection pressure has been exerted on the stimulatory action of inflammatory cytokines on insulin secretion to adapt to increased demands for insulin during inflammation and stress, and growth factors belonging to the cytokine family assist in stimulating replication and regeneration of the stressed β-cell. However, there is no rose without a thorn. Uncontrolled inflammation may cause cellular dysfunction and aggravate tissue damage. Interestingly, due to inherent properties of the β-cell acquired during cell maturation, the β-cell is extremely sensitive to the activation of the apoptotic program by cytokines, mediated by an aberrant regulation of intracellular signaling.

We have also learned to understand that activation of the inflammatory response can be caused by factors other than antigens and physiochemical substances. Lipid loading of the adipocyte is a potent stimulus for adipokine, cytokine, and chemokine production, causing recruitment of inflammatory cells to the adipose tissue. Again this is believed to be an adaptive response, helping the organism to maintain stable weight via the anorectic action of several cytokines. However, metabolic factors also affect β-cell cytokine production, with the adaptive purpose of stimulating β-cell function and replication. When exaggerated, β-cell apoptosis ensues.

Thus we propose that β-cell failure and destruction in type 1 and type 2 diabetes are caused by different stimuli converging on a common intracellular pathway (Fig. 4).

View larger version (14K): [in this window] [in a new window]   FIG. 4. β-Cell failure in type 1 and type 2 diabetes: convergence on a common pathway? Type 1 diabetes: Cytokines, in particular IL-1β, induce Fas expression on β-cells. This will sensitize β-cells to T cell-mediated killing via the Fas ligand (FasL), suicidal engagement of the constitutively expressed FasL on the same β-cell, or fratricidal engagement with FasL on neighboring β-cells. Inflammatory cytokines (IL-1β, IFN) may also induce apoptosis by activation of the NFB and MAPK/JNK pathways. Fas signaling promotes NFB activation. Type 2 diabetes: Elevated glucose and possibly leptin induce β-cell IL-1β production, which will activate the same pathways as described above.

For the translation of these basic findings, much more preclinical and clinical research is needed. Can diabetes be prevented by deleting combinations of receptors for proinflammatory cytokines specifically on β-cells? Will stable expression of regulatory factors of cytokine signaling in β-cells rescue them from disease recurrence and rejection after transplantation? Will such regulatory nodes constitute drugable targets? Can the promising results of IL-1Ra treatment in type 2 diabetes be reproduced and extended to type 1 diabetes? Is there a place for antiinflammatory treatment of islet donor, graft, and/or recipient to prolong islet graft survival in clinical transplantation?

With the current and planned international research effort in this area, we should know before too long, lending promise to the development of new clinical practices that can secure the health and life quality of our patients in the future.

	Acknowledgments

 
We thank Annette Thyde for help with the preparation of this manuscript. We are grateful to all the foundations that have provided us with funding over the years making the research behind this review possible. In particular, we are thankful to Novo Nordisk A/S, Juvenile Diabetes Research Foundation, The Danish Diabetes Association, European Foundation for the Study of Diabetes, Swiss National Science Foundation, and the University Research Priority Program "Integrative Human Physiology" at the University of Zurich.

	Footnotes

 
Disclosure Statement: The authors have nothing to disclose.

First Published Online November 29, 2007

Abbreviations: ATF, Activating transcription factor; BB, BioBreeding Worcester; CIP, cyclin inhibitory protein; CREB, cAMP responsive element binding protein; ER, endoplasmic reticulum; FLIP, FADD-like IL-1 converting enzyme inhibitory protein; GLP-1, glucagon-like peptide-1; HGF, hepatocyte growth factor; IFN, interferon; IL-1Ra, IL-1 receptor antagonist; iNOS, inducible NO synthase; JAK, Janus kinase; JNK, c-jun N-terminal kinase; LCMV, lymphocytic choriomeningitis virus; LD-STZ, low-dose streptozotocin; NFB, nuclear factor B; NO, nitric oxide; NOD, nonobese diabetic; Pdx-1, pancreatic duodenal homeobox-1; PI3K, phosphatidylinositol-3 kinase; PKA, protein kinase A; PL, placental lactogen; PRL, prolactin; RIP, rat insulin promoter; STAT, signal transducer and activator of transcription.

Received for publication September 19, 2007. Accepted for publication November 13, 2007.

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