Diabetes Research and Clinical Practice
Lipotoxicity versus adipotoxicity—The deleterious effects of adipose tissue on beta cells in the pathogenesis of type 2 diabetes
Introduction
Type 2 diabetes mellitus (T2D) is a disease thought to result from two seemingly distinct pathologic processes. On the one hand, peripheral insulin resistance necessitating elevated concentrations of insulin to activate the insulin receptor and cause the externalization of the GLUT 4 glucose transporter, allowing glucose to enter the cells in muscle, liver and fat tissue. On the other hand, failure of pancreatic beta cells to continue the increased compensatory insulin secretion. Both of these deleterious processes have been strongly linked to visceral fat accumulation and obesity [1], [2].
It has long been noted that not all patients suffering from insulin resistance develop diabetes. As the pathologic process of insulin resistance worsens, the beta cells adapt by enhancing beta cell mass [3], thus secreting more insulin to supply the growing demand of the periphery. Development of T2D requires a parallel pathologic process in which beta cell mass and function decline [2], [4]. In this review, we aim to focus on the various links between obesity, adipose tissue and beta cell dysfunction, from the direct effect of free fatty acids (FFA), termed lipotoxicity to the remote effects of adipo-cytokines (adipokines) oversecreted by adipose tissue in various pathologic situations.
Section snippets
Beta cell lipotoxicity—direct effects of obesity on beta cell survival and function
FFA have long been considered a link between obesity and the development of diabetes [5]. FFA have been shown to promote a proapoptotic effect on beta cells [6] that may explain, at least partially, the elevated rates of beta cell apoptosis and reduction in beta cell mass seen in diabetes [3]. This effect may be the combined result of endoplasmic reticulum stress [7], increased synthesis of ceramide from serine and palmitoyl CoA condensation leading to induction of the inducible form of NO
Beta cell “adipotoxicity”—effects of obesity-related adipokines on beta cell survival and function
Though thought in the past to function solely as a storage depot of high energy triglycerides, adipose tissue has lately been found to have a much broader role as an endocrine tissue secreting numerous hormones, cytokines and remotely active molecules. These collectively termed as “adipokines” include TNF-alpha, IL-6, leptin, adiponectin, visfatin, resistin, apelin, retinol binding protein (rbp4) and omentin. Adipokines where found to be involved in numerous pathologic processes in remote
Tumor necrosis factor
Increased levels of the inflammatory cytokine, TNF-alpha have been repeatedly linked to obesity in humans and rodents [17], [18], [19]. Apart from its well-described role in inflammation, TNF-alpha has been shown to inhibit insulin signaling and promote insulin resistance by inducing serine phosphorylation of the insulin receptor [20]. In beta cells, TNF-alpha was found to have multiple effects: inhibiting glucose-induced insulin secretion in beta cell lines (INS-1) [21], and promoting beta
IL-6
Up to 30% or IL-6 in the serum is thought to be secreted by adipose tissue, primarily visceral fat [19], [26], [27]. Chronic exposure to IL-6 has been linked to insulin resistance in fat tissue, potentially through the induction of SOCS3 in a rosiglitazone reversible manner [28]. In human polymorphism studies, certain variants of IL-6 have been linked to a tendency for obesity-related insulin resistance [29]. Conversely, beta cells in culture were found to secrete IL-6 in response to
Leptin
Leptin is one of the adipokines that is almost solely secreted by white adipose tissue. It reflects the bulk of body fat stores, increasing proportionally in obese individuals [32], [33]. Leptin is mainly thought to have a role in satiety perception and appetite control in the central nervous system [34]. It has also been successfully used as replacement therapy in lipodystrophy [35], a disease associated with marked insulin resistance. Inconclusive evidence exists regarding the relation of
Adiponectin
Adiponectin is a collagen-like circulating protein that is secreted from adipocytes in subcutaneous fat, and is inversely related to the risk of developing type 2 diabetes [42], [43]. Adiponectin seems to have an active role in inducing insulin sensitivity in muscle and liver tissue through specific AdipoR1 and AdipoR2 receptors. Obesity not only reduces the levels of the circulating hormone, but is also associated with a reduction of the expression of its’ receptors, thus enhancing insulin
Resistin
Resistin was initially found to be expressed and secreted during adipocyte differentiation and induce insulin resistance when injected to rodents [48]. Significant secretion of resistin was found in human omental fat tissue explants when compared with subcutaneous fat [49], but this may be due to non-fat cell contribution in this tissue (e.g. adipose tissue macrophages) [50]. Furthermore, no correlation between obesity and resistin levels was found in humans [51], [52]. Expression of resistin
Visfatin
Visfatin is a recently described [54] protein that is primarily expressed and secreted from adipose tissue in response to obesity or acute infection and sepsis. It is also found in the liver, muscles, bone marrow and lymphocytes, where it was previously referred to as a pre-B cell colony enhancing factor [55]. Visfatin has insulin mimetic effects exerted through direct action on the insulin receptor [54]. Elevated levels of visfatin have been noted in patients with T2D independently of their
Apelin
Apelin was previously idenitified as the endogenous ligand of the orphan G protein-coupled receptor APJ, secreted from the brain, lung, heart, skeletal muscle and kidney [58]. In rodents, it was primarily found to effect central control of body fluid homeostasis, and to lower blood pressure [59], [60]. In humans, the apelin-APJ pathway may have an important role in the physiologic response to heart failure [61]. Apelin was recently found to be secreted from adipocytes during differentiation, in
Retinol binding protein 4
Previously thought to act primarily as a retinol transporter, Rbp4 was recently found by microarray, to be secreted from GLUT 4 depleted adipocytes in a murine model of insulin resistance. These data were strengthened by the observation, that Rbp4 levels where elevated in the serum of various rodent models with IGT or diabetes [41] and humans with obesity and T2D. Furthermore, elevation of serum concentrations of Rbp4 exerted a gluconeogenic effect in the liver through activation of PEPCK and
Adipsin
A serine protease that is primarily synthesized in adipose tissue [65], adipsin is secreted in response to insulin stimulation [66] and is reduced in several murine models of obesity [67]. The role of adipsin (also referred to as complement factor D) in human obesity and diabetes is still unclear [68], and its effect on peripheral insulin resistance and beta cells is unknown.
Omentin
Found in 2004 as a cDNA sequence through an NCBI nucleotide database search for potential adipocyte specific molecules, omentin has since been shown to be expressed and secreted by human omental adipocytes (but not by human subcutaneous adipocytes) and has a role in insulin-stimulated glucose uptake in both depots [69]. Little is known as to a potential peripheral or beta cell specific role.
Conclusion
What is the phathophysiologic process that leads to T2D? Though we are not fully capable of answering this question, some areas are slowly being revealed. T2D is clearly a result of multiple and parallel deleterious processes. It is clear that adipose tissue, and specifically white visceral adipose tissue is a fundamental and basic part of this process with multiple venues of FFA and adipokine mediated insulin resistance and beta cell dysfunction. It is also clear that insulin resistance,
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