Abstract
β-Cell failure coupled with insulin resistance is a key factor in the development of type 2 diabetes. Changes in circulating levels of adipokines, factors released from adipose tissue, form a significant link between excessive adiposity in obesity and both aforementioned factors. In this review, we consider the published evidence for the role of individual adipokines on the function, proliferation, death and failure of β-cells, focusing on those reported to have the most significant effects (leptin, adiponectin, tumour necrosis factor α, resistin, visfatin, dipeptidyl peptidase IV and apelin). It is apparent that some adipokines have beneficial effects whereas others have detrimental properties; the overall contribution to β-cell failure of changed concentrations of adipokines in the blood of obese pre-diabetic subjects will be highly dependent on the balance between these effects and the interactions between the adipokines, which act on the β-cell via a number of intersecting intracellular signalling pathways. We emphasise the importance, and comparative dearth, of studies into the combined effects of adipokines on β-cells.
Introduction
Pancreatic β-cell failure, alongside insulin resistance, can be considered as one of the two key events that leads to the development of type 2 diabetes (Leahy et al. 2010). In the early stages of the disease, insulin resistance is countered by an increase in pancreatic β-cell mass and function (Chang-Chen et al. 2008) that can often delay diagnosis for a period of years. The β-cell eventually succumbs to rising insulin resistance via various mechanisms (including glucotoxicity, lipotoxicity and endoplasmic reticulum stress) and hyperglycaemia ensues (Jonas et al. 2009). What is key in preventing the onset of type 2 diabetes under these conditions is the ability of the body to maintain both pancreatic β-cell mass and function.
The relationship between the pancreas and adipose tissue was for many years believed to be something of a one-way street. It was accepted that insulin secretion from pancreatic islets in response to increased blood glucose caused uptake of glucose into adipocytes via insulin receptor binding and signalling and thus led to increased storage of triacylglycerol. What was also accepted was that insulin resistance in adipose tissue contributed to β-cell failure (Weir et al. 2001), a phenomenon that highlighted the importance of the relationship between these two tissues. Our understanding of adipose tissue has grown immensely over the past few decades so that we now know that adipose tissue is not an inert storage depot for excess energy but an active endocrine organ with a wide, biologically active secretome (Deng & Scherer 2010).
The molecules released from adipose tissue are commonly referred to as adipokines (or adipocytokines). The list of molecules confirmed as adipokines grows every year, as both novel and existing molecules are seen to be secreted by adipose tissue or adipocytes. Most, but not all, adipokines are peptides/proteins with hormone-like properties (some are known cytokines), but in this context, non-esterified fatty acids (NEFAs; free fatty acids) can also be considered to be adipokines. It has been widely demonstrated that the enlargement of adipose tissue depots seen in obesity can lead to dysregulated adipokine secretion, representing a potential pathophysiological link between obesity and type 2 diabetes (and vascular disease; Wellen & Hotamisligil 2005), and so research into their precise role in metabolic disorders is ongoing. It is becoming increasingly clear that adipokines form an important part of an ‘adipo-insular axis’ (see Fig. 1), dysregulation of which may contribute to β-cell failure and hence to type 2 diabetes.
Diagrammatic representation of the interrelationship between adipose tissue and the pancreatic β-cell: the 'adipo-insular axis'. Positive regulation may include stimulation of insulin synthesis and secretion and cell proliferation. Negative regulation can involve inhibition of insulin synthesis and secretion and increased cell apoptosis and/or necrosis.
Citation: Journal of Endocrinology 216, 1; 10.1530/JOE-12-0278
Leptin: the ‘first’ adipokine
With the discovery of the product of the OB gene, leptin, in 1994 by Friedman and colleagues (Zhang et al. 1994), the first insights into adipose-derived hormonal factors that later became known as adipokines, and hence the bidirectional nature of the adipo-insular axis, were established. Leptin can claim to be the first adipokine to be associated with direct pancreatic effects, and certainly the most studied of all the adipokines with respect to its pancreatic effects. After initial clinical work suggested a possible relationship between circulating leptin levels and islet function (Ahren & Larsson 1997), basic laboratory studies confirmed effects of leptin exposure on glucose-stimulated insulin secretion (GSIS) in ex vivo pancreatic islets, although the initial few studies gave mixed results, with inhibitory (Kulkarni et al. 1997, Brown et al. 2002), stimulatory (Tanizawa et al. 1997) and null (Leclercq-Meyer & Malaisse 1998) effects on insulin secretion being reported. It is now generally accepted that leptin has a potent inhibitory effect on insulin secretion from pancreatic β-cells in vitro and in vivo and has the additional effect of reducing pre-proinsulin gene expression (Laubner et al. 2005).
Our own research on this adipokine using human islets showed evidence of a U-shaped response (Brown et al. 2002), with lower concentrations inhibiting insulin release and higher levels having a relatively stimulatory effect, which may provide an explanation for some of the conflicting reports. This type of response is also consistent with the cytokine receptor-like nature of the leptin receptor and signalling cascade. We also demonstrated that leptin decreased uncoupling protein 2 (UCP2) expression in these islets and this may contribute to an effect of the adipokine in ameliorating β-cell apoptosis – further research in a clonal β-cell line from our group also showed an effect of leptin to alter the B-cell lymphoma 2/Bcl2-associated X protein (BCL2/BAX) expression ratio, which may also explain the reduction in apoptosis induced by this factor (Brown & Dunmore 2007). By contrast, a recent study by Chetboun et al. (2012) found no effect of leptin (or adiponectin) on apoptosis, although both adipokines caused a reactive oxygen species (ROS)-mediated increase in cell proliferation and leptin (but not adiponectin)-inhibited GSIS. This potential role of low levels of ROS in promoting β-cell mass may underline the importance of our aforementioned finding that leptin decreases UCP2 as this protein may also have a role in reducing ROS levels – generally thought to be beneficial to β-cells but possibly, in view of Chetboun et al.'s hypothesis, decreasing proliferation. This underlines the need for further research into the role of UCP2 in the β-cell.
It is apparent that leptin's effects on the β-cell are direct and it is clear that pancreatic β-cells express the leptin receptor, LepR (Ob-R), in both the functional long form (LepRb) and truncated shorter forms (Kieffer et al. 1996). Mechanistically speaking, it appears that leptin can activate multiple signalling pathways in the pancreatic β-cell. The classical pathway associated with leptin binding its receptor is activation of the Jak/STAT pathway where receptor-associated kinase JAK2 phosphorylates tyrosine residues on LepRb, which subsequently recruits and phosphorylates STAT family members that can then translocate to the nucleus and regulate gene transcription (Seufert 2004). Evidence also suggests that various members of the MAPK/ERK pathway are activated in pancreatic β-cells by leptin, possibly through interaction with shorter forms of the leptin receptor (Tanabe et al. 1997). Another pathway affected by leptin is the phosphoinositide 3-kinase (PI3K) pathway (activated by insulin) – Ning et al. (2006) showed that this may involve inhibiting the protein and lipid phosphatase PTEN, which acts downstream of PI3K to dephosphorylate phosphatidylinositol (3,4,5) trisphosphate (PtdIns(3,4,5)P3) and decrease its levels – thus leptin may increase PtdIns(3,4,5)P3, which in turn leads to increased activation of ATP-dependent potassium channels, hyperpolarisation of the β-cell membrane and hence inhibition of GSIS. This potential role of PTEN is supported by the findings of Wang et al. (2010) who showed that deletion of PTEN protected against defects in β-cell function and mass in mouse models of type 2 diabetes including the leptin-deficient ob/ob mouse. The observations described earlier confirmed the presence of a genuine two-way endocrine relationship between the β-cell and adipose tissue and suggested a mechanism for the role of excess fat in pancreatic dysfunction.
In the years following the discovery of leptin and its β-cell-specific effects, many new, and some already identified, molecules came to be designated as adipokines. From this pool, a growing number of these secreted factors were shown to regulate either pancreatic β-cell function or mass, as the clamour for an understanding of an adipokine-based, hormonal link between obesity and diabetes grew.
Adiponectin
Adiponectin was one of the earlier adipokines identified (Scherer et al. 1995, Arita et al. 1999) and, unlike many others, has beneficial effects improving insulin sensitivity and vascular function, thus being both anti-diabetic (Pajvani et al. 2003) and anti-atherogenic (Ouchi et al. 1999). Increased adiposity is associated with decreased adiponectin secretion, apparently because hypertrophic adipocytes release less of the adipokine. Adiponectin has been suggested to circulate primarily as a multimeric (trimeric, hexameric and high molecular weight) association of full-length adiponectin and is locally proteolytically cleaved to a globular (trimeric) form in which the collagen-like amino-terminal domain is released (Pajvani et al. 2003). Adiponectin receptors (AdipoRs) are widely expressed and two forms have been cloned that exhibit 67% homology. Both AdipoR1 and AdipoR2 are seven transmembrane spanning proteins; however, by contrast with other G-protein-coupled receptors, they have external carboxy-terminuses and cytoplasmic amino-terminuses; globular adiponectin has been shown to have a higher affinity for AdipoR1 (Kadowaki & Yamauchi 2005). Many of the effects of the adiponectin–AdipoR interaction have been suggested to be mediated by AMPK, peroxisome proliferator-activated receptor α (PPARα) and p38 MAPK.
There is substantial evidence of adiponectin effects on β-cell function and survival. There is evidence that both AdipoRs are expressed in primary (Kharroubi et al. 2003) and clonal β-cells (Brown et al. 2010a, Wijesekara et al. 2010), with AdipoR1 generally being found to be expressed at much higher levels.
Studies using the NIT-1 mouse clonal β-cell line showed that AdipoR2 was expressed in these cells (Jung et al. 2009); however, although this report mentions measuring AdipoR1, no data are presented. It was found that incubation with the saturated fatty acid palmitate, well established to cause apoptosis in β-cells, for 24 h increased AdipoR2 expression, which then decreased again after 48 h; the PPARα agonist clofibrate delayed palmitate impairment of AdipoR2 expression. Adiponectin increased AMPK phosphorylation compared with both control and palmitate alone – adding clofibrate as well increased AMPK phosphorylation still further and also partly reversed palmitate inhibition of GSIS.
Research employing the INS-1 clonal rat cell, in a novel ‘microfluidic chip’, found that intermittent high glucose (IHG) caused more impairment of β-cells than sustained high glucose (SHG) and that this was partly reversed by adiponectin (Lin et al. 2009a). IHG caused more apoptosis (and necrosis) than SHG, and the apoptosis alone was reversed in both situations by adiponectin; however, these changes were not quantified. IHG impaired GSIS more than SHG, but adiponectin partly reversed the impairment. Adiponectin also partly restored insulin content and insulin and pancreatic and duodenal homeobox 1 (PDX1) gene (mRNA) expression, which had been decreased by IHG more than SHG. The authors found similar effects on AMPK expression.
In our own studies of this adipokine (Brown et al. 2010a), we used the clonal β-cell line BRIN–BD11 and showed AdipoR1 expression to be much higher than that of AdipoR2. We also compared the effects of globular adiponectin (ADN) and the fragment ADN15–36. The protective monounsaturated NEFA oleate, but not the deleterious saturated NEFA palmitate, decreased AdipoR1 mRNA, and a PPARα, but not a PPARγ, agonist decreased AdipoR1 expression. By contrast, palmitate, not oleate, decreased AdipoR2 mRNA but PPARα and not PPARγ agonists decreased AdipoR2 expression. gADN (which has a higher affinity for AdipoR1) but not ADN15–36 greatly increased lipoprotein lipase expression but slightly decreased that of PDX1. Neither fragment affected insulin expression.
Both gADN and ADN15–36 increased β-cell viability, which was reversed by leptin for ADN15–36 only. ERK1/2 inhibition reversed the effect of both ADN fragments. Neither fragment inhibited serum starvation-induced apoptosis. Both fragments increased ERK1/2 phosphorylation; leptin reversed this in case of ADN15–36 but not with gADN.
Wijesekara et al. (2010) also showed that ADN increased ERK phosphorylation in MIN6 cells (and mouse islets) but, in contrast to our studies, found that it protected against serum starvation-induced apoptosis – however, this was measured by cleaved caspase-3 assay. Chai et al. (2011) used gastric bypass surgery to ameliorate type 2 diabetes in an animal model, the Goto-Kakizaki (GK) rat, and showed that the resulting increase in adiponectin levels was associated with decreased islet β-cell apoptosis.
Scherer's et al. have recently produced convincing evidence that many of the actions of adiponectin are mediated through activation, via AdipoR1/R2, of a ceramidase activity leading to generation of sphingosine-1-phosphate and suggest that AMPK is only involved via downstream activation. They have shown, using in vivo adiponectin gene overexpression or ablation in mice, that adiponectin protects against caspase-8-mediated apoptosis in β-cells. In INS-1 clonal β-cells, adiponectin protected against palmitate- or ceramide-induced apoptosis even in cells in which AMPK function was impaired by overexpression of a dominant negative mutant of the enzyme (Holland et al. 2011).
Chetboun et al. (2012), as mentioned earlier, also showed that adiponectin (and leptin) increased proliferation of clonal β-cells (RIN and MIN6) without affecting apoptosis. These effects appeared to involve generation of ROS possibly by inhibiting expression of antioxidant enzymes such as superoxide dismutase. The authors reported a beneficial effect of low levels of ROS including H2O2 contrasting with the deleterious consequences of high levels and suggest that these oxidant molecules can play a physiological role in regulating β-cell mass. They found, however, no effect of adiponectin on insulin secretion (by contrast with the inhibitory effect of leptin mentioned earlier). The authors did not investigate any combined effects of the two adipokines which, as is discussed below, may be an important issue.
Whether by inhibiting apoptosis of β-cells or by increasing proliferation, it is clear that the overall effect of high levels of adiponectin would be to preserve β-cell mass whereas low levels found in obesity and type 2 diabetes would contribute to its reduction. It is also likely that the ratio of adiponectin to leptin (and other adipokines) will be a significant factor in the overall effects of altered levels of adipokines resulting from increased adiposity on β-cell function (see below).
Tumour necrosis factor α
Tumour necrosis factor α (TNFα) is a pro-inflammatory cytokine with a well-established role in the immune system-mediated induction of β-cell death in type 1 diabetes. It is also an adipokine, and high circulating levels in obesity have been implicated in the induction of insulin resistance (Hotamisligil 1999). There is also evidence of TNFα effects on the β-cell, which may further contribute to type 2 diabetes (although one review asserts that the elevation in TNFα in obese humans and animals does not reach levels concomitant with those known to deleteriously affect β-cell function or survival – see Zhao et al. (2006)). As in type 1 diabetes, TNFα can induce β-cell apoptosis via the nuclear factor kappa-light-chain enhancer of activated B cells pathway (Ortis et al. 2008, 2012).
There is a substantial number of reports on direct effects of TNFα inhibiting insulin secretion (for example Kim et al. (2008)), and one study (Cai et al. 2011b) reported that TNFα induces the expression of amylin from the β-cell. This latter study is of particular relevance in diabetes as the authors also report that there was no concurrent induction of proinsulin expression by TNFα. This may therefore lead to an increase in the ratio of amylin to insulin in the β-cell and potentially to a relative excess of amylin over insulin secretion. As amylin accumulating as amyloid is a potential factor in the destruction of β-cells in type 2 diabetes (Westermark et al. 2011) and as it has also been suggested that an increase in circulating amylin/insulin ratio could contribute to insulin resistance, this implies an additional potential role of TNFα in the link between obesity and type 2 diabetes. This would certainly point to a need for further studies of this fascinating hypothesis.
Resistin
In 2001, it seemed that a significant breakthrough in adipokine biology had been made. A new adipocyte-secreted molecule termed resistin was identified, which was shown, as the name would suggest, to potently induce insulin resistance in rodents (Steppan et al. 2001). Resistin was discovered as a result of differential display of adipocyte genes induced and suppressed by treatment with the insulin-sensitising PPARγ-acting thiazolidinedione drugs. Resistin was shown to be strongly down-regulated by rosiglitazone-induced PPARγ activation, and a strong candidate for a ‘diabetes gene’ was suggested. Unfortunately, the observations of a potent effect on insulin resistance in rodents were not successfully reproduced in humans (Nagaev & Smith 2001), which reduced the interest of diabetes researchers in this molecule. Later research did, however, fascinatingly assign several distinct β-cell-specific effects to resistin.
Our research showed that resistin down-regulated insulin receptor expression levels (necessary for maintenance of β-cell mass) in clonal β-cells and hence decreased cell viability (Brown et al. 2007). This was then followed by a study that showed that resistin actually induced insulin resistance in pancreatic islets, causing a subsequent reduction in GSIS (Nakata et al. 2007). It should be noted that the islets and β-cells used in these studies were of mouse origin, and the findings have not as yet been repeated in human islets. What has been shown in human islets is that resistin is actually expressed within them and that its expression is up-regulated in type 2 diabetes (Minn et al. 2003, Al-Salam et al. 2011), so although the role of resistin in regulating human pancreatic β-cell mass/function as an adipokine may be yet to be demonstrated, it seems that it may nevertheless have an important role as an intracellular protein.
Visfatin/nicotinamide phosphoribosyltransferase
One of the more interesting recently described adipokines is visfatin. Visfatin, previously described as pre-B-cell colony-enhancing factor 1 (PBEF1), is actually a phosphoribosyltransferase enzyme (nicotinamide phosphoribosyltransferase (NAMPT)) that is secreted from adipose tissue via a non-classical pathway. Originally reported as an insulin mimetic in a study (Fukuhara et al. 2005) subsequently partially retracted, research has actually shown that visfatin can act in a adipokine-like way to increase insulin secretion (Revollo et al. 2007, Brown et al. 2010b). Our studies showed that visfatin not only increased insulin secretion from βTC6 cells but it also had a direct effect activating β-cell insulin receptors, increasing their phosphorylation (Brown et al. 2010b). A recent study using the MIN6 cell line showed that visfatin stimulated β-cell proliferation and inhibited β-cell apoptosis induced by palmitate, via ERK1/2- and PI3K/Akt-mediated pathways (Cheng et al. 2011), findings that suggest the potential for visfatin to have positive effects on β-cell mass. The mechanisms behind the actions of visfatin in the β-cell are not yet fully understood but also appear to involve the enzymatic production of nicotinamide mononucleotide (Sheng et al. 2011), which can then regulate PDX1 expression and therefore insulin transcription. It is yet to be determined whether the overall effects of visfatin are beneficial or deleterious to β-cells – there is some evidence that the beneficial effects occur at lower physiological levels whereas higher pathological concentrations may have harmful effects (Brown et al. 2010b).
Dipeptidyl peptidase IV
In an exciting and potentially very important recent finding, dipeptidyl peptidase IV (DPP-IV) has been shown to be released from mature primary human adipocytes (Lamers et al. 2011). DPP-IV is a peptidase known to cleave the incretin glucagon-like peptide 1 (GLP1) at the NH2 terminus, thus reducing its half-life to several minutes (Drucker 1998). Although this interaction is not β-cell specific, it has clear implications for the β-cell. GLP1 is thought to stimulate as much as two-thirds of the insulin secreted postprandially (Kazafeos 2011) and therefore is a major player in β-cell function. Evidence also suggests that GLP1 can also stimulate proliferation of pancreatic β-cells and therefore positively regulates β-cell mass (Buteau 2008). It is therefore clear that the actions of this novel adipokine can have a potent effect on the pancreatic β-cell, and the ability of the pancreas to counteract rising insulin resistance.
Apelin
Apelin is a recently identified peptide with widespread expression including in adipose tissue and which therefore functions as an adipokine with effects on feeding behaviour and glucose utilisation. The apelin receptor, the APJ receptor, is expressed in islets and apelin activation of its receptor inhibits insulin secretion (Sörhede Winzell et al. 2005), and it has been shown in clonal INS-1 β-cells that this is by activation of PI3K–phosphodiesterase 3B (Guo et al. 2009). Recent evidence suggests that apelin is itself expressed in pancreatic islets, particularly in β- and α-cells, raising the possibility of autocrine/paracrine effects (Ringström et al. 2010).
Interaction between adipokines in their effects on the β-cell
It is clear, as we have discussed earlier, that many adipokines have substantial effects on both the function and survival of β-cells; however, most of the reported studies have been done with individual adipokines in isolation (although there are a few studies such as that of Brown et al. (2010a) in which the interaction of the beneficial adipokine adiponectin with the mainly deleterious adipokine leptin was investigated). A summary of the main adipokines that have demonstrable effects in the β-cell, and of the nature of these effects, is given in Table 1.
Summary of adipokines with demonstrated effects on pancreatic β-cells
| Adipokine | Effect | References |
|---|---|---|
| Adiponectin | Increases GSIS | Gu et al. (2006) |
| Increases proliferation | Brown et al. (2010a) | |
| Apelin | Inhibits insulin secretion | Guo et al. (2009) |
| DPP-IV | Inhibits GLP1 | Lamers et al. (2011) |
| FGF | Increases β-cell proliferation | Kilkenny & Rocheleau (2008) |
| Increases insulin transcription | Wente et al. (2006) | |
| IGF1 | Increases β-cell mass | Dickson et al. (2001) |
| Interleukin-1β | Increases nitric oxide | Corbett et al. (1992) |
| Cytotoxic | Mandrup-Poulsen et al. (1986) | |
| Interleukin-6 | Increases GSIS | Shimizu et al. (2000) and Suzuki et al. (2011) |
| Leptin | Inhibits GSIS | Brown et al. (2002) |
| Decreases pre-proinsulin levels | Pallett et al. (1997) | |
| Protects from apoptosis | Brown & Dunmore (2007) | |
| MCP1 | Increased amylin expression | Cai et al. (2011a) |
| Non-esterified fatty acids | Increases GSIS (acute) | Thams & Capito (2001) |
| Inhibits GSIS (chronic) | Newsholme et al. (2007) | |
| Decreases insulin transcription | Jacqueminet et al. (2000) | |
| Induces apoptosis | Kharroubi et al. (2004) | |
| Resistin | Decreases insulin receptor and increases cell viability | Brown et al. (2007) |
| TGFβ | Regulates insulin transcription | Lin et al. (2009b) |
| TNFα | Inhibits GSIS | Zhang & Kim (1995) |
| Decreases insulin transcription | Tsiotra et al. (2001) | |
| Induces apoptosis | Ortis et al. (2008) | |
| Increases amylin but not pro-insulin gene expression | Cai et al. (2011b) | |
| Visfatin | Increases insulin secretion | Brown et al. (2010b) |
It is obviously the case that in vivo, the β-cell is exposed to altered levels of the full range of adipokines in obese individuals and, as shown in Fig. 2, many adipokines act via pathways that intersect – for example signalling pathways involving PI3K, AMPK, MAPK/ERK1/2 and the insulin receptor itself are affected by many of the adipokines described earlier. The reported changes in circulating adipokine concentrations observed in metabolic diseases are complex and will require further elucidation; nevertheless, future studies are needed that focus on comparisons of the effects of combinations of adipokines at levels, which may be found in physiological (i.e. in lean individuals) and pathological (obese, diabetic and/or vascular disease) states.
Complex interaction between adipokines in β-cell specific effects. Many adipokines act via post-receptor pathways in the β-cell which intersect in a number of places. In addition insulin itself, the release of which is affected by these adipokines, has autocrine effects on the β-cell. Signalling pathways which are negatively or positively affected by adipokines include one of the main pathways activated in insulin signalling the PI3K pathway as well as pathways such as MAPK/ERK1/2 and AMPK. AC, Adenylyl cyclase; AdipoR, Adiponectin receptor; Akt/PKB, Protein Kinase B; AMPK, AMP-activated protein kinase; ApelinR, Apelin receptor (APJ receptor); DPP-IV, Dipeptidyl peptidase IV; ERK, Extracellular signal-regulated kinases; GLP1, Glucagon-like peptide 1; GLP1-R, GLP1 receptor; InsR, Insulin Receptor; JAK/STAT, Janus Kinase/ Signal Transducer and Activator of Transcription; KATP, ATP-sensitive potassium channel/sulphonylurea receptor; LepR, Leptin receptor; MAPK, Mitogen-activated protein kinases (eg ERK, JNK, p38); NFκB, nuclear factor kappa B; NMN, nicotinamide mononucleotide; PDE-3B, phosphodiesterase-3B; PDX-1, Pancreatic and duodenal homeobox 1; PI3K, phosphatidyl inositol 3 kinase; PKA, protein kinase A (cAMP-dependent protein kinase; PTEN, Phosphatase and tensin homolog; TNFR-1, TNFα-receptor 1
Citation: Journal of Endocrinology 216, 1; 10.1530/JOE-12-0278
Conclusion
In conclusion, a growing number of hormones and other active circulating factors have been found to be secreted by adipose tissue that have established roles in the maintenance or loss of β-cell mass or function. It remains to be seen whether these factors play a causative role in the development of diabetes, or if they contribute to progression of diabetes by affecting the speed at which the β-cell loses its ability to compensate for increases in insulin resistance seen in pre- and early type 2 diabetes. It can be stated with some confidence, nevertheless, based on the evidence so far available that adipokines are likely to be a significant factor in β-cell failure and there is therefore a need for further research in the field, which may in the longer term suggest therapeutic approaches to ameliorating this growing disease.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review reported.
Funding
This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
References
Ahren B & Larsson H 1997 Leptin – a regulator of islet function?: its plasma levels correlate with glucagon and insulin secretion in healthy women. Metabolism: Clinical and Experimental 46 1477–1481. (doi:10.1016/S0026-0495(97)90152-9)
Al-Salam S, Rashed H & Adeghate E 2011 Diabetes mellitus is associated with an increased expression of resistin in human pancreatic islet cells. Islets 3 246–249. (doi:10.4161/isl.3.5.16427)
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T & Miyaoka K et al. 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochemical and Biophysical Research Communications 257 79–83. (doi:10.1006/bbrc.1999.0255)
Brown JEP & Dunmore SJ 2007 Leptin decreases apoptosis and alters BCL-2:Bax ratio in clonal rodent pancreatic β-cells. Diabetes/Metabolism Research and Reviews 23 497–502. (doi:10.1002/dmrr.726)
Brown JE, Thomas S, Digby JE & Dunmore SJ 2002 Glucose induces and leptin decreases expression of uncoupling protein-2 mRNA in human islets. FEBS Letters 513 189–192. (doi:10.1016/S0014-5793(02)02296-2)
Brown JE, Onyango DJ & Dunmore SJ 2007 Resistin down-regulates insulin receptor expression, and modulates cell viability in rodent pancreatic β-cells. FEBS Letters 581 3273–3276. (doi:10.1016/j.febslet.2007.06.031)
Brown JE, Conner AC, Digby JE, Ward KL, Ramanjaneya M, Randeva HS & Dunmore SJ 2010a Regulation of β-cell viability and gene expression by distinct agonist fragments of adiponectin. Peptides 31 944–949. (doi:10.1016/j.peptides.2010.02.004)
Brown JE, Onyango DJ, Ramanjaneya M, Conner AC, Patel ST, Dunmore SJ & Randeva HS 2010b Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells. Journal of Molecular Endocrinology 44 171–178. (doi:10.1677/JME-09-0071)
Buteau J 2008 GLP-1 receptor signaling: effects on pancreatic β-cell proliferation and survival. Diabetes & Metabolism 34 S73–S77. (doi:10.1016/S1262-3636(08)73398-6)
Cai K, Qi D, Hou X, Wang O, Chen J, Deng B, Qian L, Liu X & Le Y 2011a MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. PLoS ONE 6 e19559. (doi:10.1371/journal.pone.0019559)
Cai K, Qi D, Wang O, Chen J, Liu X, Deng B, Qian L, Liu X & Le Y 2011b TNF-α acutely upregulates amylin expression in murine pancreatic β cells. Diabetologia 54 617–626. (doi:10.1007/s00125-010-1972-9)
Chai F, Wang Y, Zhou Y, Liu Y, Geng D & Liu J 2011 Adiponectin downregulates hyperglycemia and reduces pancreatic islet apoptosis after roux-en-y gastric bypass surgery. Obesity Surgery 21 768–773. (doi:10.1007/s11695-011-0357-6)
Chang-Chen KJ, Mullur R & Bernal-Mizrachi E 2008 β-Cell failure as a complication of diabetes. Reviews in Endocrine & Metabolic Disorders 9 329–343. (doi:10.1007/s11154-008-9101-5)
Cheng Q, Dong W, Qian L, Wu J & Peng Y 2011 Visfatin inhibits apoptosis of pancreatic β-cell line, MIN6, via the mitogen-activated protein kinase/phosphoinositide 3-kinase pathway. Journal of Molecular Endocrinology 47 13–21. (doi:10.1530/JME-10-0106)
Chetboun M, Abitbol G, Rozenberg K, Rozenfeld H, Deutsch A, Sampson SR & Rosenzweig T 2012 Maintenance of redox state and pancreatic β-cell function: role of leptin and adiponectin. Journal of Cellular Biochemistry 113 1966–1976. (doi:10.1002/jcb.24065)
Corbett JA, Wang JL, Sweetland MA, Lancaster JR Jr & McDaniel ML 1992 Interleukin 1β induces the formation of nitric oxide by β-cells purified from rodent islets of Langerhans. Evidence for the β-cell as a source and site of action of nitric oxide. Journal of Clinical Investigation 90 2384–2391. (doi:10.1172/JCI116129)
Deng Y & Scherer PE 2010 Adipokines as novel biomarkers and regulators of the metabolic syndrome. Annals of the New York Academy of Sciences 1212 E1–E19. (doi:10.1111/j.1749-6632.2010.05875.x)
Dickson LM, Lingohr MK, McCuaig J, Hugl SR, Snow L, Kahn BB, Myers MG Jr & Rhodes CJ 2001 Differential activation of protein kinase B and p70(S6)K by glucose and insulin-like growth factor 1 in pancreatic β-cells (INS-1). Journal of Biological Chemistry 276 21110–21120. (doi:10.1074/jbc.M101257200)
Drucker DJ 1998 Glucagon-like peptides. Diabetes 47 159–169. (doi:10.2337/diabetes.47.2.159)
Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T & Murakami H et al. 2005 Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307 426–430. (doi:10.1126/science.1097243)
Gu W, Li X, Liu C, Yang J, Ye L, Tang J, Gu Y, Yang Y, Hong J & Zhang Y et al. 2006 Globular adiponectin augments insulin secretion from pancreatic islet β cells at high glucose concentrations. Endocrine 30 217–221. (doi:10.1385/ENDO:30:2:217)
Guo L, Li Q, Wang W, Yu P, Pan H, Li P, Sun Y & Zhang J 2009 Apelin inhibits insulin secretion in pancreatic β-cells by activation of PI3-kinase–phosphodiesterase 3B. Endocrine Research 34 142–154. (doi:10.3109/07435800903287079)
Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N & Rutkowski JM et al. 2011 Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nature Medicine 17 55–63. (doi:10.1038/nm.2277)
Hotamisligil GS 1999 Mechanisms of TNF-α-induced insulin resistance. Experimental and Clinical Endocrinology & Diabetes 107 119–125. (doi:10.1055/s-0029-1212086)
Jacqueminet S, Briaud I, Rouault C, Reach G & Poitout V 2000 Inhibition of insulin gene expression by long-term exposure of pancreatic β cells to palmitate is dependent on the presence of a stimulatory glucose concentration. Metabolism 49 532–536. (doi:10.1016/S0026-0495(00)80021-9)
Jonas JC, Bensellam M, Duprez J, Elouil H, Guiot Y & Pascal SM 2009 Glucose regulation of islet stress responses and β-cell failure in type 2 diabetes. Diabetes, Obesity & Metabolism 11 (Suppl 4) 65–81. (doi:10.1111/j.1463-1326.2009.01112.x)
Jung TW, Lee MW, Lee YJ, Kim SM, Lee KT, Whang WK, Cheon HJ, Jeong YT, Chung KW & Cho JM et al. 2009 Regulation of adiponectin receptor 2 expression via PPAR-α in NIT-1 cells. Endocrine Journal 56 377–382. (doi:10.1507/endocrj.K08E-354)
Kadowaki T & Yamauchi T 2005 Adiponectin and adiponectin receptors. Endocrine Reviews 26 439–451. (doi:10.1210/er.2005-0005)
Kazafeos K 2011 Incretin effect: GLP-1, GIP, DPP4. Diabetes Research and Clinical Practice 93 (Suppl 1) S32–S36.
Kharroubi I, Rasschaert J, Eizirik DL & Cnop M 2003 Expression of adiponectin receptors in pancreatic β cells. Biochemical and Biophysical Research Communications 312 1118–1122. (doi:10.1016/j.bbrc.2003.11.042)
Kharroubi I, Ladrière L, Cardozo AK, Dogusan Z, Cnop M & Eizirik DL 2004 Free fatty acids and cytokines induce pancreatic β-cell apoptosis by different mechanisms: role of nuclear factor-κB and endoplasmic reticulum stress. Endocrinology 145 5087–5096. (doi:10.1210/en.2004-0478)
Kieffer TJ, Heller RS & Habener JF 1996 Leptin receptors expressed on pancreatic β-cells. Biochemical and Biophysical Research Communications 224 522–527. (doi:10.1006/bbrc.1996.1059)
Kilkenny DM & Rocheleau JV 2008 Fibroblast growth factor receptor-1 signaling in pancreatic islet β-cells is modulated by the extracellular matrix. Molecular Endocrinology 22 196–205. (doi:10.1210/me.2007-0241)
Kim HE, Choi SE, Lee SJ, Lee JH, Lee YJ, Kang SS, Chun J & Kang Y 2008 Tumour necrosis factor-α-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx. Journal of Endocrinology 198 549–560. (doi:10.1677/JOE-08-0131)
Kulkarni RN, Wang ZL, Wang RM, Hurley JD, Smith DM, Ghatei MA, Withers DJ, Gardiner JV, Bailey CJ & Bloom SR 1997 Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. Journal of Clinical Investigation 100 2729–2736. (doi:10.1172/JCI119818)
Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, Eckardt K, Kaufman JM, Ryden M & Müller S et al. 2011 Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 60 1917–1925. (doi:10.2337/db10-1707)
Laubner K, Kieffer TJ, Lam NT, Niu X, Jakob F & Seufert J 2005 Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic β-cells. Diabetes 54 3410–3417. (doi:10.2337/diabetes.54.12.3410)
Leahy JL, Hirsch IB, Peterson KA & Schneider D 2010 Targeting β-cell function early in the course of therapy for type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 95 4206–4216. (doi:10.1210/jc.2010-0668)
Leclercq-Meyer V & Malaisse WJ 1998 Failure of human and mouse leptin to affect insulin, glucagon and somatostatin secretion by the perfused rat pancreas at physiological glucose concentration. Molecular and Cellular Endocrinology 141 111–118. (doi:10.1016/S0303-7207(98)00087-2)
Lin P, Chen L, Li D, Liu J, Yang N, Sun Y, Xu Y, Fu Y & Hou X 2009a Adiponectin reduces glucotoxicity-induced apoptosis of INS-1 rat insulin-secreting cells on a microfluidic chip. Tohoku Journal of Experimental Medicine 217 59–65. (doi:10.1620/tjem.217.59)
Lin HM, Lee JH, Yadav H, Kamaraju AK, Liu E, Zhigang D, Vieira A, Kim SJ, Collins H & Matschinsky F et al. 2009b Transforming growth factor-β/Smad3 signaling regulates insulin gene transcription and pancreatic islet β-cell function. Journal of Biological Chemistry 284 12246–12257. (doi:10.1074/jbc.M805379200)
Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello CA, Svenson M & Nielsen JH 1986 Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia 29 63–67. (doi:10.1007/BF02427283)
Minn AH, Patterson NB, Pack S, Hoffmann SC, Gavrilova O, Vinson C, Harlan DM & Shalev A 2003 Resistin is expressed in pancreatic islets. Biochemical and Biophysical Research Communications 310 641–645. (doi:10.1016/j.bbrc.2003.09.061)
Nagaev I & Smith U 2001 Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochemical and Biophysical Research Communications 285 561–564. (doi:10.1006/bbrc.2001.5173)
Nakata M, Okada T, Ozawa K & Yada T 2007 Resistin induces insulin resistance in pancreatic islets to impair glucose-induced insulin release. Biochemical and Biophysical Research Communications 353 1046–1051. (doi:10.1016/j.bbrc.2006.12.134)
Newsholme P, Keane D, Welters HJ & Morgan NG 2007 Life and death decisions of the pancreatic β-cell: the role of fatty acids. Clinical Science 112 27–42. (doi:10.1042/CS20060115)
Ning K, Miller LC, Laidlaw HA, Burgess LA, Perera NM, Downes CP, Leslie NR & Ashford ML 2006 A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic β-cells. EMBO Journal 25 2377–2387. (doi:10.1038/sj.emboj.7601118)
Ortis F, Pirot P, Naamane N, Kreins AY, Rasschaert J, Moore F, Théâtre E, Verhaeghe C, Magnusson NE & Chariot A et al. 2008 Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic β cells. Diabetologia 51 1213–1225. (doi:10.1007/s00125-008-0999-7)
Ortis F, Miani M, Colli ML, Cunha DA, Gurzov EN, Allagnat F, Chariot A & Eizirik DL 2012 Differential usage of NF-κB activating signals by IL-1β and TNF-α in pancreatic β cells. FEBS Letters 586 984–989. (doi:10.1016/j.febslet.2012.02.021)
Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M & Nakamura T et al. 1999 Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100 2473–2476. (doi:10.1161/01.CIR.100.25.2473)
Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M & Scherer PE 2003 Structure–function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. Journal of Biological Chemistry 278 9073–9085. (doi:10.1074/jbc.M207198200)
Pallett AL, Morton NM, Cawthorne MA & Emilsson V 1997 Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic islets. Biochemical and Biophysical Research Communications 238 267–270. (doi:10.1006/bbrc.1997.7274)
Revollo JR, Körner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C & Townsend RR et al. 2007 Nampt/PBEF/visfatin regulates insulin secretion in β cells as a systemic NAD biosynthetic enzyme. Cell Metabolism 6 363–375. (doi:10.1016/j.cmet.2007.09.003)
Ringström C, Nitert MD, Bennet H, Fex M, Valet P, Rehfeld JF, Friis-Hansen L & Wierup N 2010 Apelin is a novel islet peptide. Regulatory Peptides 162 44–51. (doi:10.1016/j.regpep.2010.03.005)
Scherer PE, Williams S, Fogliano M, Baldini G & Lodish HF 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. Journal of Biological Chemistry 270 26746–26749. (doi:10.1074/jbc.270.45.26746)
Seufert J 2004 Leptin effects on pancreatic β-cell gene expression and function. Diabetes 53 (Suppl 1) S152–S158. (doi:10.2337/diabetes.53.2007.S152)
Sheng F, Ren X, Dai X, Xu X, Dong M, Pei Q, Qu J, Zhou Z, Zhou H & Liu Z 2011 Effect of nicotinamide mononucleotide on insulin secretion and gene expressions of PDX-1 and FoxO1 in RIN-m5f cells. Zhong Nan Da Xue Xue Bao. Yi Xue Ban=Journal of Central South University. Medical sciences 36 958–963.
Shimizu H, Ohtani K, Kato Y & Mori M 2000 Interleukin-6 increases insulin secretion and preproinsulin mRNA expression via Ca2+-dependent mechanism. Journal of Endocrinology 166 121–126. (doi:10.1677/joe.0.1660121)
Sörhede Winzell M, Magnusson C & Ahrén B 2005 The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice. Regulatory Peptides 131 12–17. (doi:10.1016/j.regpep.2005.05.004)
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS & Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409 307–312. (doi:10.1038/35053000)
Suzuki T, Imai J, Yamada T, Ishigaki Y, Kaneko K, Uno K, Hasegawa Y, Ishihara H, Oka Y & Katagiri H 2011 Interleukin-6 enhances glucose-stimulated insulin secretion from pancreatic β-cells: potential involvement of the PLC–IP3-dependent pathway. Diabetes 60 537–547. (doi:10.2337/db10-0796)
Tanabe K, Okuya S, Tanizawa Y, Matsutani A & Oka Y 1997 Leptin induces proliferation of pancreatic β cell line MIN6 through activation of mitogen-activated protein kinase. Biochemical and Biophysical Research Communications 241 765–768. (doi:10.1006/bbrc.1997.7894)
Tanizawa Y, Okuya S, Ishihara H, Asano T, Yada T & Oka Y 1997 Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic β cells. Endocrinology 138 4513–4516. (doi:10.1210/en.138.10.4513)
Thams P & Capito K 2001 Differential mechanisms of glucose and palmitate in augmentation of insulin secretion in mouse pancreatic islets. Diabetologia 44 738–746. (doi:10.1007/s001250051683)
Tsiotra PC, Tsigos C & Raptis SA 2001 TNFα and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells. International Journal of Obesity and Related Metabolic Disorders 25 1018–1026. (doi:10.1038/sj.ijo.0801657)
Wang L, Liu Y, Yan Lu S, Nguyen KT, Schroer SA, Suzuki A, Mak TW, Gaisano H & Woo M 2010 Deletion of Pten in pancreatic β-cells protects against deficient β-cell mass and function in mouse models of type 2 diabetes. Diabetes 59 3117–3126. (doi:10.2337/db09-1805)
Weir GC, Laybutt DR, Kaneto H, Bonner-Weir S & Sharma A 2001 β-Cell adaptation and decompensation during the progression of diabetes. Diabetes 50 S154–S159. (doi:10.2337/diabetes.50.2007.S154)
Wellen KE & Hotamisligil GS 2005 Inflammation, stress, and diabetes. Journal of Clinical Investigation 115 1111–1119. (doi:10.1172/JCI25102)
Wente W, Efanov AM, Brenner M, Kharitonenkov A, Köster A, Sandusky GE, Sewing S, Treinies I, Zitzer H & Gromada J 2006 Fibroblast growth factor-21 improves pancreatic β-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55 2470–2478. (doi:10.2337/db05-1435)
Westermark P, Andersson A & Westermark GT 2011 Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiological Reviews 91 795–826. (doi:10.1152/physrev.00042.2009)
Wijesekara N, Krishnamurthy M, Bhattacharjee A, Suhail A, Sweeney G & Wheeler MB 2010 Adiponectin-induced ERK and Akt phosphorylation protects against pancreatic β cell apoptosis and increases insulin gene expression and secretion. Journal of Biological Chemistry 285 33623–33631. (doi:10.1074/jbc.M109.085084)
Zhang S & Kim KH 1995 TNF-α inhibits glucose-induced insulin secretion in a pancreatic β-cell line (INS-1). FEBS Letters 18 237–239. (doi:10.1016/0014-5793(95)01272-9)
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L & Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372 425–432. (doi:10.1038/372425a0)
Zhao Y-F, Feng DD & Chen C 2006 Contribution of adipocyte-derived factors to β-cell dysfunction in diabetes. International Journal of Biochemistry & Cell Biology 38 804–819. (doi:10.1016/j.biocel.2005.11.008)
