The mechanisms linking adiposopathy to type 2 diabetes

Abstract

Obesity is defined as excessive accumulation of body fat in proportion to body size. When obesity occurs, the functions of adipose tissue may be deregulated, which is termed as adiposopathy. Adiposopathy is an independent risk factor for many diseases, including diabetes and cardiovascular diseases. In overweight or obese subjects with adiposopathy, hyperlipidemia exerts lipotoxicity in pancreatic islet and liver and induces pancreatic β cell dysfunction and liver insulin resistance, which are the decisive factors causing type 2 diabetes. Moreover, adipokines have been shown to play important roles in the regulation of glucose homeostasis. When adiposopathy occurs, abnormal changes in the serum adipokine profile correlate with the development and progression of pancreatic β cell dysfunction and insulin resistance in peripheral tissue. The current paper briefly discusses the latest findings regarding the effects of adiposopathy-related lipotoxicity and cytokine toxicity on the development of type 2 diabetes.

Keywords

obesity / adiposopathy / lipotoxicity / adipokines / diabetes

Introduction

Type 2 diabetes is a chronic disease characterized by impaired insulin secretion from pancreatic islet β cells and insulin resistance in glucose-metabolizing tissue. Increased fasting blood glucose concentration is one of the main characteristics of diabetes. When fasted, the liver plays a vital role in maintaining blood glucose because it is the main tissue capable of producing and releasing glucose into circulation. Thus, liver insulin resistance plays a key role in the development of type 2 diabetes. According to the latest epidemiological research in 2010, type 2 diabetes has become prevalent in China, and the number of individuals with diabetes in China is over 90 million [1]. Persistent hyperglycemia may lead to serious damages to many organs, particularly the brain, blood vessels and kidneys.

The development and progression of type 2 diabetes represent the combined effects of genetics, nutrition and lifestyle and involve both gene-gene and gene-environment interactions. Over the past few decades, the correlation between the prevalence of type 2 diabetes and obesity has become well noted, as more than 80% of type 2 diabetic patients are overweight or obese [2]. Obesity is characterized by both elevated number and volume of adipose cells, which leads to the excessive deposition of triglycerides (TG).

With the excessive deposition of TG in adipose tissue, its functions may be deregulated, which has been termed as adiposopathy (adipose-opathy) or “sick fat.” [3,4]. Generally, lipolysis in “sick fat” is higher than in “healthy fat,” leading to elevated levels of circulating free fatty acids (FFAs) in obese subjects with adiposopathy. It has been believed that rosiglitazone and pioglitazone, the agonists of PPARγ, exert their antidiabetic effects mainly via correction of the abnormal functions of adipose tissue, although they often lead to increased body weight and obesity [4]. Moreover, obese patients with “healthy fat” will not develop type 2 diabetes. Clearly, it should be noted that it is adiposopathy but not simple obesity that plays an important role in the progression of type 2 diabetes [3,5,6]. The excess FFAs in the serum will be redistributed to other glucose-metabolizing tissue such as pancreatic islet, liver and muscle. Moreover, excess FFA may also be deposited in other fat depots, such as perivascular fat, pericardial fat, and visceral fat. In particular, visceral adiposity is reflective of a pathological state associated with metabolic diseases.

Eventually, excessive deposition of FFAs or TG will inhibit insulin secretion in islets and induce insulin resistance in the liver and muscle [7-9]. The underlying mechanism(s) for lipid-induced islet dysfunction and insulin resistance includes ER stress, mitochondrial dysfunction and excessive reactive oxygen species (ROS) production [7]. These deleterious effects of FFAs and other lipids on tissue are called lipotoxicity. Since the discovery of leptin and other adipose-derived hormones [10], scientists have recognized that adipose tissue not only serves as an energy reserve but is also an endocrine organ. To date, increasing evidence has shown that adipose tissue plays important roles in the regulation of many physiological processes such as reproduction, energy metabolism, immune response and glucose and lipid metabolism by secreting adipokines. Adipokine is a general term for adipose-specific cytokines such as leptin, adiponectin, visfatin and omentin as well as nonadipose-specific cytokines such as IL-6, IL-1β and TNF-α. Abnormal expression and secretion of some adipokines including leptin, resistin and adiponectin in “sick fat” are strongly associated with the development and progression of islet dysfunction, insulin resistance and type 2 diabetes [11-13].

The present paper aims to briefly discuss the underlying mechanism(s) that links adiposopathy to type 2 diabetes. The latest findings regarding lipotoxicity in islet β cell and liver are summarized and discussed. Moreover, the roles of some important adipokines, including IL-1β, leptin, resistin, adiponectin, visfatin and chemerin, in the development and progression of pancreatic β cell dysfunction and liver insulin resistance are also discussed.

Free fatty acid (FFA) is a major link between adiposopathy and type 2 diabetes

Type 2 diabetes (T2DM) is closely linked to adiposopathy and increased circulating FFA levels [14]. Elevated circulating FFA levels promote lipid accumulation and contribute to the pathogenesis of T2DM. FFAs are thus an important link between adiposopathy and T2DM. As an important energy source, FFAs are normally stored as triglycerides in adipocytes. In obesity, fat mass expands in order to store excess energy. When adiposopathy occurs, plasma FFA levels are increased due to the elevated release of FFAs from enlarged and stressed adipose tissue with the abnormal functions. Initially, FFAs are insulin secretagogues in islet β cells. The role of FFAs in insulin secretion has been exemplified by the use of genetically engineered mice that have their G-protein-coupled receptor 40 (GPR40), an FFA receptor, deleted. Mice without GPR40 display approximately 50% reduction in insulin secretion [15]. However, long-term exposure to high levels of FFAs impairs glucose-stimulated insulin secretion and decreases insulin biosynthesis, resulting in insulin resistance and β-cell apoptosis.

FFAs and insulin resistance

In the presence of overnutrition, adiposopathy will result in ectopic fat deposition. The excessive FFAs are ultimately stored in nonadipose tissue, such as liver, muscle, heart and pancreatic tissue. The idea that fat accumulation in tissue other than adipose tissue results in insulin resistance is supported by transgenic animal models [16]. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase exhibited defects in insulin action and signaling. The defects are associated with an increase in intracellular fatty acid-derived metabolites. In humans, most obese patients with T2DM have higher plasma FFA levels, which cause insulin resistance in many types of tissue, including skeletal muscle, liver, and adipose tissue. The skeletal muscle and the liver are the two most important insulin targets. Insulin resistance in skeletal muscle and the liver plays a primary role in the development of T2DM. Acute increases in plasma FFA levels stimulate insulin secretion by a direct stimulatory effect on insulin secretion or by a decline in insulin clearance. Insulin resistance develops within hours after an acute increase in plasma FFAs in humans [17]. In obese but non-diabetic individuals, FFA induced insulin resistance is compensated by FFA mediated over-secretion of insulin. In pre-diabetic subjects, however, this compensation fails and the consequence of FFA induced insulin resistance is the development of T2DM [14,18]. Conversely, lowering FFAs reduces insulin resistance. Thiazolidinediones (TZDs), a class of insulin-sensitizing drugs, improve insulin action by stimulating fat oxidation in adipose tissue related to FFA uptake, binding and oxidative phosphorylation and thus decreases plasma free fatty acid levels in diabetic patients [19]. Consistent with human studies, the administration of thiazolidinediones (TZDs) in rodents also reduces insulin resistance through a sustained reduction in circulating FFA levels [20], which is mainly achieved via the correction of adiposopathy.

Although it has been shown that an increased level of FFAs can cause a defect in insulin signaling, the mechanisms by which FFAs cause insulin resistance are still not completely understood. Recently, several mechanisms have been proposed to explain how FFAs can interfere with insulin action, which include the lipid metabolite hypothesis, the inflammation hypothesis and the oxidative and endoplasmic reticulum stress hypothesis.

The lipid metabolite hypothesis: It has been proposed that increased plasma FFA levels result in the elevation of intracellular accumulation of fatty acid metabolites such as diacylglycerol (DAG), long-chain acyl-coenzyme A (acyl-CoA) and ceramide. These metabolites, in turn, activate several serine/threonine kinases such as protein kinase C (PKC) and c-Jun N-terminal kinase (JNK). The activation of one or several of these serine/threonine kinases can phosphorylate insulin receptor substrate-1 (IRS-1) on serine or threonine residues. Consequently, IRS-1 activation through tyrosine phosphorylation is impaired. The activity of IRS/PI3 kinase/Akt is subsequently decreased, and this will finally result in attenuated insulin action [21]. In the liver and muscle of insulin resistant humans and rodents, DAG accumulation is increased with abnormally activated PKC [22]. Furthermore, oral fat ingestion rapidly induces insulin resistance by reducing nonoxidative glucose disposal, which associates with PKCα activation and a rise in distinct myocellular membrane DAG [23].

The inflammation hypothesis: It is now recognized that obesity, in particular adiposopathy, is an inflammatory state. The ability of FFAs to cause inflammation in adipocytes and the liver has been well documented. FFA-mediated activation of IκB kinase β (IKKβ) results in the translocation of nuclear transcription factor-κB (NF-κB) to the nucleus where NF-κB regulates the transcription of its target genes. As a consequence, the production of proinflammatory cytokines is increased, and finally insulin resistance takes place [24-26]. The possible mechanisms by which FFA-induced NF-κB activation can result in insulin resistance include activation of JNK [27] and induction of suppressor of cytokine signaling (SOCS) that can interfere with the binding of IRS1/2 to the insulin receptor [28]. In the liver and muscle of insulin resistant humans and rodents, NF-κB signaling pathway was activated with elevated expression of the NF-κB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2 [24,29].

The oxidative and endoplasmic reticulum stress hypotheses: It has been shown that FFAs activate NADPH oxidase and induce reactive oxygen species (ROS) in cultured adipocytes [30]. The ROS-induced oxidative stress results in dysregulated proinflammatory cytokine production. FFAs have also been shown to produce endoplasmic reticulum (ER) stress in adipocytes, liver cells and pancreatic β cells [31]. ER stress can induce insulin resistance via activation of JNK. For example, exposure to saturated palmitate results in excessive production of ROS, which induces insulin resistance in the liver and muscle cells via activation JNK [32-34]. Inhibition of ROS production attenuated palmitate-induced insulin resistance in liver cells [32,33]. Thus, FFA-induced oxidative and/or endoplasmic reticulum stress is believed to contribute to FFA-mediated insulin resistance as well.

FFAs and pancreatic β-cell dysfunction

FFAs are important for normal β-cell function. They are recognized for their ability to influence insulin secretion from pancreatic β cells in response to glucose and non-glucose secretagogues. An acute increase in FFAs enhances glucose-stimulated insulin secretion (GSIS). In contrast, chronic exposure of β cells to high concentrations of FFAs impairs several aspects of β cell function including GSIS. The mechanisms underlying the dual and opposing effects of FFAs on insulin secretion have been extensively investigated. Several mechanisms have been proposed to be involved in the regulation of insulin secretion by FFAs. The first mechanism relates to GPR40, an FFA receptor. The PPAR class of nuclear receptors and members of the G protein-coupled receptors have been shown to be activated by FFAs. Among these, GPR40 is selectively and abundantly expressed in both rodent and human pancreatic β cells. Itoh et al. established the role of GPR40 in FFA-mediated insulin secretion. They demonstrated that FFAs regulated insulin secretion from pancreatic β cells through GPR40 [35]. The binding of FFAs to GPR40 results in the activation of intracellular signaling and a subsequent increase in intracellular calcium and secretory granule exocytosis. In another study by Steneberg and colleagues [36], the authors showed that GPR40-deficient β cells secrete less insulin in response to FFAs. Conversely, overexpression of GPR40 in β cells of mice leads to impaired β cell function and diabetes. Thus, they concluded that GPR40 plays an important role in the chain of events linking obesity and T2DM. The second mechanism involves increased FFA-induced β cell apoptosis via de novo ceramide formation and increased nitric oxide (NO) production [37]. Ceramide is a key component of the signal transduction pathway for apoptosis [38]. Intracellular NO is also an important mediator of programmed cell death. The contribution of oxidative and ER stress to β cell apoptosis is likely a third possible mechanism. It has been shown that ER stress markers were increased in the islets of a mouse model for diabetes and in patients with T2DM [39,40]. Chronic exposure of islet β cells to FFAs induces ER stress and leads to β cell dysfunction by reducing protein translation and activating apoptotic pathways that reduce β cell mass. It is believed that FFAs activate ER stress response via an NF-κB- and NO-independent mechanisms [41]. A recent study by Yuan et al. suggested that NADPH oxidase 2-derived ROS mediates FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways [42]. Martinez et al. also highlighted the important role of FoxO1 in FFAs and ER stress-induced β cell apoptosis. Foxo1 activity was increased with the administration of fatty acids. Inhibition of Foxo1 could protect pancreatic β cells from fatty acid and ER stress-induced apoptosis [43].

Adipokines in the regulation of pancreatic β cell function

IL-1β

IL-1β is a nonadipose-specific cytokine, and increased plasma IL-1β levels have been reported to be associated with hyperglycemia in overweight subjects with adiposopathy [44]. In vitro chronic exposure of pancreatic β cell to IL-1β activates the expression of inducible nitric oxide synthase (iNOS), inhibits insulin secretion and promotes cell apoptosis [45]. These deleterious effects of IL-1β on pancreatic β cells can be blocked by overexpression of IL-1 receptor antagonist (IL-1Ra) [46]. It has been further revealed that IL-1β stimulates iNOS expression in pancreatic β cells predominantly via activation of NF-κB [47]. In vivo IL-1β-neutralizing antibody treatment for 13 weeks significantly ameliorates hyperglycemia and improves islet functions in high-fat diet induced diabetic mice [48]. A 13-week treatment of type 2 diabetic patients with anakinra, a recombinant human interleukin-1 receptor antagonist, also attenuates hyperglycemia and improves islet insulin secretion dysfunction [49]. All these results indicate that IL-1β is a deleterious cytokine that has detrimental effects on pancreatic β cell function.

Leptin

Serum leptin level is significantly elevated in obese rodents and humans with adiposopathy. Recently, leptin receptors have been shown to be expressed in pancreatic β cells of mouse, rat and human islets [50]. Leptin inhibits proinsulin synthesis and insulin secretion in β cell lines by activating ATP-regulated potassium (K_ATP) channels and stimulating the expression of SOCS-3 [51-53]. Controversially, mice with specific disruption of their leptin receptors in pancreatic β cells develop severe glucose intolerance when fed a high-fat-diet due to impaired insulin secretion by pancreatic β cells [54]. Leptin can suppress PTEN activity and elevate cellular PIP3 levels, which activates the PI3K/Akt signaling pathway in pancreatic β cells. This suggests that leptin may be involved in the proliferation of β cells in overweight individuals [55] since IRS2-PI3K-Akt signaling axis has been reported to play a crucial role in β cell proliferation [56]. Overall, leptin is involved in the regulation of pancreatic β cell function, and elevated serum leptin levels may contribute to the development of insulin secretion dysfunction in obese individuals with adiposopathy.

Resistin

Resistin is another adipokine identified in 2001 [57]. Increased serum resistin levels are associated with insulin resistance in rodents and humans with adiposopathy. To date, the resistin receptor has not yet been identified. Resistin is also functionally expressed in human and rodent islets, and its expression is upregulated in insulin resistant mouse islets [58]. In vitro, resistin significantly inhibits the expression of the insulin receptor in murine β cell line βTC-6 cells or rattus β cell line BRIN-BD11 cells [59]. Resistin induces apoptosis of rattus β cell line RINm5F cells via activation of caspase-3 and NF-κB [60]. In vivo neutralization of circulating resistin attenuates hyperglycemia and improves insulin sensitivity in mice [57]. Elevating serum resistin levels by tail-vein injection of adenovirus expressing resistin impairs glucose-induced insulin secretion in pancreatic islets. It was further showed that resistin impairs insulin secretion in islets by inducing SOCS-3 expression and inhibiting the PI3K-Akt signaling pathway [61]. Overall, resistin is a deleterious cytokine that is detrimental to islet β cell function, and elevated circulating resistin levels in obese or insulin resistant people will impair insulin secretion from islets and exaggerate glucose homeostasis.

Adiponectin

Adiponectin is another adipose-derived cytokine with a circulating concentration greater than 5 mg/ml [62]. In obese and type 2 diabetic patients, serum adiponectin levels were significantly decreased. Low serum adiponectin level is an independent risk factor of type 2 diabetes [63,64]. There are two subtypes of adiponectin receptors, which are designated as AdipoR1 and AdipoR2, respectively. Both AdipoR1 and AdipoR2 are functionally expressed in human and rat pancreatic β cells, and their expression can be upregulated by oleate (unsaturated fatty acid) but not palmitate (saturated fatty acid) [65]. AdipoR2-deficient mice show increased failure of pancreatic β cell function when fed a high-fat-diet compared to control mice [66]. FFAs significantly reduced the expression of AdipoR2 in murine pancreatic cell line NIT-1 cells [67]. In support, adiponectin pretreatment prevents insulin secretion dysfunction and apoptosis induced by inflammatory cytokines, free fatty acids and high glucose in rattus pancreatic β cell line INS-1 cells [68,69]. Brown and colleagues further reported that adiponectin stimulates PDX-1 expression and inhibits LPL expression in BRIN-BD11 cells [70]. In human islets, pretreatment with full-length adiponectin induces phosphorylation of acetyl coenzyme A carboxylase (ACC), suggesting that adiponectin may repress lipid synthesis in islets [71]. All these results suggest that inhibition of adiponectin signaling may be involved in lipid- and cytokine-induced pancreatic β dysfunction. Overall, adiponectin is a cytokine that protects pancreatic β cell function, and decreased circulating adiponectin levels are associated with islet dysfunction in obese individuals.

Visfatin/chemerin

Revollo and colleagues further reported that visfatin^+/- mice showed impaired glucose tolerance and reduced glucose-stimulated insulin secretion, suggesting that visfatin may directly regulate insulin secretion in β cells [72]. In vitro visfatin upregulates the mRNA expression of pro-insulin and enhances insulin secretion by 46% in β-TC6 cells in the presence of low glucose. The effects of visfatin can be blocked by FK866, a specific inhibitor of nicotinamide phosphoribosyltransferase (NAMPT) [73]. Recently, visfatin has been shown to potentiate glucose stimulated insulin secretion in human islets without significant effect on β-cell survival [74]. Visfatin also stimulates β-cell proliferation and prevents apoptosis via activation of PI3K-Akt and ERK1/2 signaling pathways [75]. Chemerin and its receptor ChemR23 are constitutively expressed in β-cell. Chemerin-deficient mice exhibit impaired insulin secretion from pancreatic β-cell, while chemerin transgenic mice exhibit enhanced glucose-stimulated insulin secretion [76].

Overall, visfatin may have protective effects on pancreatic β cell function, but further research is still needed to clarify the underlying mechanism.

Adipokines in the regulation of insulin sensitivity

IL-1β

Liver insulin resistance is always associated with inflammation with regards to adiposopathy. Circulating IL-1β levels are elevated in adiposopathic individuals [77,78]. IL-1Ra treatment significantly attenuates hyperglycemia, improves insulin sensitivity, and reduces inflammation in the liver of type 2 diabetic GK rats [79]. In vitro, IL-1β directly induces insulin resistance in hepatoma cells (Fao) and HepG2 cells and in primary cultured rat hepatocytes [80]. IL-1β is further shown to induce insulin resistance in liver cells by stimulating the expression of SOCS-3, which binds to IR and IRS-1/2, and blocks the activation of the insulin signaling pathway [81]. IL-1β is an insulin-desensitizing cytokine, and increased serum IL-1β levels may contribute to the development of insulin resistance in the livers of obese individuals with adiposopathy. Similarly, IL-1 has also been reported to induce insulin resistance in muscle cells [82].

Leptin

Leptin is one of the most important cytokines secreted by adipose, and it has direct effects on the liver. In Fao cells, leptin can induce the phosphorylation of Akt and glycogen synthase kinase 3 (GSK3), suggesting the enhancement of glycogen synthesis [83]. Zucker+ /fat rats with partially insufficient leptin receptors exhibit higher hepatic triglyceride content, serum insulin, TG and leptin levels without hyperphagia or body weight change when compared with control rats. This indicates that leptin may play a role in the prevention of triglyceride accumulation in the liver [84]. In perfused rat liver, leptin at physiological concentrations directly inhibits 8-Br-cAMP-stimulated glucose production and glycogenolysis [85].

It has been reported that insulin resistance may have crosstalk with leptin resistance. Huang and colleagues have reported that a 90-min perfusion of isolated livers from lean rats in the presence of 10 ng/ml leptin significantly decreased TG content and increased PI3k activity in the liver, but these effects of leptin were not observed in the liver of high-fat-diet induced insulin-resistant rats [86]. Chronic leptin infusion in the intra peritoneal cavity induces both leptin resistance and insulin resistance in rats [87]. Fructose-fed rats were found to be leptin resistant and insulin resistant with increased expression of SOCS-3 in the liver [88,89]. Similarly, chronic exposure to leptin also induces SOCS-3 expression and its association with insulin receptor in skeletal muscle cells, leading to repression of insulin signaling [90,91]. These results suggest that leptin at physiological levels may enhance insulin signaling, whereas chronic exposure to high level of leptin induces insulin resistance in the liver and muscle.

Resistin

Resistin has been reported to inhibit insulin-stimulated glycogen synthesis and phosphorylation of IRS-1, Akt and GSK-3 in rat hepatoma cell line H4IIE cells [92]. Resistin treatment also decreases glycogen content in the presence of insulin in primary cultured rat hepatocytes [92]. Resistin is further shown to induce insulin resistance in liver cells via AMPK- or SOCS-3-dependent pathways [92,94,95]. Recently, resistin has also been shown to be expressed in the liver [96,97]. Viral-mediated overexpression of resistin in HepG2 cells significantly represses the expression of insulin receptor substrate 2 (IRS-2) and c-cbl associated protein (CAP), stimulates the expression of GSK-3β concomitant and inhibits insulin-stimulated glucose uptake and glycogen synthesis [96]. Moreover, resistin has also been shown to induce insulin resistance, inhibit insulin-stimulated glucose uptake and repress the expression of GLUT4 mRNA in skeletal muscle cells [98,99]. Overall, resistin is an insulin-desensitizing cytokine, and elevated circulating resistin levels will induce insulin resistance in the liver and muscle and exaggerate global glucose homeostasis in obese individuals with adiposopathy.

Adiponectin

The liver is one type of main target tissue of adiponectin, and both of the two adiponectin receptor subtypes are functionally expressed in the liver [100]. Nawrocki and colleagues have found that adiponectin-deficient mice exhibit severe hepatic but not global insulin resistance, and these mice are more susceptible to high-fat-diet induced insulin resistance when compared to wild type mice [101]. Delivery of adiponectin-expressing plasmid into non-obese type 2 diabetic mice via the tail vein significantly attenuates hyperglycemia [102]. Adiponectin attenuates alcoholic- and non-alcoholic fatty liver in mice [103,104]. It has been further shown that adiponectin may exert its glucose-lowering effects via activation of AMPK in the liver [105]. In obese women, increased serum adiponectin levels correlate with improved liver insulin sensitivity but not global insulin sensitivity during weight loss [106]. The anti-diabetic drug rosiglitazone, the agonist of PPARγ, can stimulate the expression of AdpR2 in HepG2 cells [107]. Furthermore, the anti-diabetic and AMPK-activating effects of PPARγ agonists have been shown to be blunted in ob/ob-adiponectin null mice than in ob/ob mice [101]. These results have suggested that the anti-diabetic effects of PPARγ agonists may partially be achieved through an adiponectin-dependent pathway. Both subtypes of adiponectin receptors are also constitutively expressed in skeletal muscle cells [108], and adiponectin has been shown to ameliorate insulin resistance in these cells via blockade of NF-κB activity [109] and activation of LKB1/AMPK pathway [110]. Overall, adiponectin is an insulin-sensitizing cytokine, and a decrease in circulating adiponectin levels in obese individuals may contribute to the development and progression of insulin resistance in liver and skeletal muscle.

Visfatin/chemerin

Visceral visfatin levels significantly declined in patients with nonalcoholic fatty liver disease (NAFLD) [111]. Although the insulin mimetic effects of visfatin are controversial, visfatin is believed to play important roles in the regulation of hepatic insulin signaling [112]. Elevation of plasma visfatin levels via injection of visfatin-expressing plasmid increases global insulin sensitivity and enhances tyrosine phosphorylated IRS-1 level in the liver [113]. However, it has also been reported that increased serum visfatin correlates with nonalcoholic fatty liver in children [114]. Activation of visfatin is associated with increased mitochondrial ATP synthesis and glucose uptake in human skeletal muscle after exercise [115]. These results have suggested that visfatin may be an insulin-sensitizing factor, but further study is still needed to clarify its underlying mechanism.

Chemerin is a new adipokine. Serum chemerin levels correlate with fatty liver in obese patients and decrease after bariatric surgery-mediated weight loss [116]. Serum chemerin levels are also elevated in diabetic mice, and administration of exogenous chemerin exacerbates glucose intolerance, lowers serum insulin levels and decreases tissue glucose uptake in obese/diabetic but not normoglycemic mice [117]. In males without typical characteristics of metabolic syndrome, global insulin sensitivity was negatively correlated with serum chemerin level [118]. Chemerin treatment induces insulin resistance in the skeletal muscle [119]. However, chemerin-deficient mice exhibit increased hepatic glucose production, while chemerin transgenic mice exhibit enhanced glucose-stimulated insulin secretion and improved glucose tolerance [76]. Overall, chemerin might be a new insulin-desensitizing adipokine, and increased serum chemerin levels may be involved in the development of insulin resistance.

Overall, an increase in circulating insulin-desensitizing adipokines is always concomitant with a decrease in insulin-sensitizing adipokines in obese individuals with adiposopathy, suggesting that the ratios of insulin-desensitizing adipokines to insulin-sensitizing adipokines may be very good predictors of type 2 diabetes. Actually, an adiponectin-resistin (AR) index (AR= 1+ lg(R0/A0); R0: fasting serum resistin level; A0: fasting serum adiponectin level) has been shown to be a better predictor of type 2 diabetes than adiponectin or resistin alone [120].

Crossregulation among insulin, FFAs and adipokines

It should be noted that crossregulation among insulin, FFAs and adipokines in adipose tissue and the liver may play a vital role in exaggerating glucose homeostasis in overweight or obese individuals (Fig. 1). Insulin and FFAs can stimulate the expression and secretion of leptin from adipose [121]. FFAs can regulate the expression of adipokines such as resistin, TNF-α and IL-1β in adipose tissue and the liver [24,122]. Adiponectin and resistin have also been shown to regulate the synthesis of FFAs and TG in adipocytes and the liver [12,123]. Other potential crossregulations among adipokines, FFAs, glucose and insulin are summarized in Table 1.

Summary and perspective

Over the past two decades, it has been widely accepted that the increased prevalence of type 2 diabetes is strongly associated with adiposopathy. In obese individuals with adiposopathy, ectopic fat in islet and the liver leads to lipotoxicity in the tissue. Lipotoxicity ultimately impairs the insulin secretion function of β cells and induces insulin resistance in the liver and muscle. Moreover, circulating insulin-sensitizing and β-cell-protective adipokines decreased, whereas insulin-desensitizing and β-cell-deleterious adipokines increased, resulting in the disturbance of the normal serum adipokine profile in obese individuals with adiposopathy. An abnormal serum adipokine profile also plays important roles in the development and progression of pancreatic β cell dysfunction and type 2 diabetes (Fig. 1). Body weight control, lifestyle intervention and drugs that correct adiposopathy are the effective strategies for the prevention and treatment of type 2 diabetes.

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