Файл: Extracellular and Intracellular Signaling (книга).pdf

inhibits insulin gene expression and insulin secretion. The consensus view is that leptin directly suppresses insulin secretion. Acute physiological increases in serum leptin levels in vivo significantly reduces glucose-mediated insulin secretion in rats in a dose-dependent fashion.216 Demonstration of acute glucose intolerance by intracerebroventricular administration of pharmacological doses of leptin in mice suggests that these e ects could be via central actions,217 possibly by increasing SNS activity.218

Partially pancreatectomized (Px) rats are a model of mild T2DM, in which insulin secretion is approximately halved but insulin resistance is increased.219 A recent study showed that hypothalamic leptin modulates b-cell function and mass via the SNS in Px diabetic rats.220 Acute ICV infusion of leptin suppressed firstand second-phase insulin secretion through the SNS, while long-term leptin infusion reduced second-phase insulin secretion only, and did not decrease b-cell mass.

Leptin signaling occurs typically through the JAK-STAT pathway resulting in induction of specific genes. Leptin can also induce b-cell apoptosis and impairs GSIS though JNK activation.221 JAK2 has been identified in rat islets and INS-1 b cells and STAT5 translocates to the nucleus on activation.222 In b cells, leptin activates STAT5,223 which also mediates e ects of prolactin and growth hormone to increase b-cell mass.224 When subjected to a high-fat diet, transgenic mice expressing a dominant-negative mutant of STAT5a (RIP-DNSTAT5 mice) showed greater impairment of glucose tolerance than those expressing a constitutive active mutant of STAT5b and reduced b-cell proliferation.225 STAT translocation is maximal within 30 min.222 Interestingly, leptin modulates b-cell expression of IL-1 receptor antagonist and release of IL-1b in human islets,226 thus at least two bioactive molecules released from adipose tissue could induce islet inflammation.

Both adiponectin receptors are expressed in the b cell. Two distinct regions of the adiponectin molecule, the globular domain and a small N-terminal region, have agonist properties. A recent study investigated the e ects of two agonist regions of adiponectin on insulin secretion, gene expression, cell viability and cell signaling in the rat b-cell line BRIN-BD11. Both globular adiponectin and adiponectin (15-36) increased cell viability.227 Adiponectin also reduces glucotoxi- city-induced apoptosis of INS-1 rat insulin-secreting cells.228 Leptin coincubation attenuated adiponectin (15-36) but not globular adiponectin induced cell viability. Globular adiponectin, but not adiponectin (15-36), caused a significant 450% increase in PDX-1 expression. AdipoR1 was expressed at a higher level than AdipoR2 and AdipoR mRNA levels were di erentially regulated by NEFA and PPAR agonists. Treatment with the FAs oleate and palmitate and PPAR agonists WY14643 (PPARa agonist) and rosiglitazone (PPARg agonist) were compared for e ects on AdipoR1 and AdipoR2 expression. Twenty-four- hour exposure to oleate (a mono-unsaturated FA) significantly decreased AdR-1 mRNA expression, but AdR-2 mRNA levels were not significantly altered. A similar decrease in AdipoR1 mRNA expression was observed after treatment with WY14643, but this latter treatment also decreased AdR-2 mRNA expression. Palmitate (a saturated FA) decreased AdipoR2 mRNA expression, but not

or intermittent but, as discussed above, could set the stage for obesity in nutritional surplus. The selection of strong immune or inflammatory response is advantageous during periods of infection, but also requires prioritization of available nutrients should they be in short supply. The histology of islets from patients with T2DM displays an inflammatory process, characterized by the presence of cytokines, apoptotic cells and immune cell infiltration;246 similarly, exposure to high glucose enhances IL-1b expression associated with severe

impairment of insulin-mediated signal transduction in cultured, proliferating bTC-6 cells.167

Overfeeding postnatally causes increased adiposity and insulin resistance and, importantly, genes involved in inflammation (e.g. TNFa) are overexpressed in adipose tissue when the animals are placed on a high-fat diet.247 We propose that a state of low-grade inflammation in the islet, induced by increased chronic exposure to adipocyte-derived cytokines such as TNFa, could predispose the b cell to react to nutrient stressors in an exaggerated fashion, so predisposing to gluco-lipotoxicity. This could arise because intracellular signaling pathways utilized by proinflammatory cytokines overlap with, or are identical to, those activated by lipids and high glucose. It is tempting to speculate that programming of obesity by early life events such as maternal protein restriction during gestation and lactation induces a propensity for adipocytes to respond to proinflammatory cytokines released by macrophages with augmented adipocytokine expression and secretion which, in turn, impacts b-cell function and compensation for insulin resistance.

2.15Other Adipose-derived Factors that Could Contribute to the Adipoinsular Axis

Wnt proteins are a large family of secreted lipidated glycoproteins that regulate crucial aspects of development, including cell-fate specification, proliferation and survival. On presentation to its target cell, canonical Wnt signaling begins with Wnt proteins binding to a co-receptor complex that consists of frizzled (Fzd) family receptors with the lipoprotein receptor related 5/6 (Lrp5/6) proteins. In the presence of Wnt, the intracellular sca olding protein Dishevelled (Dvl) associates with the transmembrane Wnt–Frizzled–LRP complex. Wnt receptor binding causes coordinate phosphorylation of Dvl and the intracellular domain of LRP. Activated Dvl inactivates a protein complex that includes the constitutively active serine-threonine kinase glycogen synthase kinase 3b (GSK3b) and the sca olding proteins axin and adenomatosis polyposis coli (APC). A pool of b-catenin that is phosphorylated by GSK3 seems to be specifically involved in regulating gene expression. In the absence of ligand binding to both receptors, previously ‘‘primed’’ b-catenin (i.e. b-catenin phosphorylated by casein kinase 1 on Ser45) is phosphorylated by GSK3b at three further sites: Thr41, Ser37 and Ser33. This results in its ubiquination, which targets it for proteosomal degradation. GSK3 b inactivation by the

activated Wnt–Fzd–LRP complex prevents degradation of b-catenin, promoting its cytoplasmic accumulation. In a pancreatic b-cell line (INS-1 cells), which express a range of components of the Wnt pathway including b-catenin and GSK, the non-receptor protein tyrosine phosphatase-BL (ptpn13) PTP-BL opposes Wnt signaling as the increase in b-catenin seen in response to exogenous Wnt3a is prevented following induction of PTP-BL.248

Following its cytoplasmic accumulation, b-catenin translocates to the nucleus, where T-cell-specific transcription factor/lymphoid enhancer binding factor 1 (TCF/LEF1) family binding proteins, such as TCF7L2 (previously known as TCF4), are normally maintained in a repressed state by association with Groucho. b-catenin acts as a transcriptional co-activator by displacing Groucho and, with TCF/LEF1, forming a complex that activates transcription of canonical TCF/LEF1-regulated genes. A close association exists between poly-morphisms in the TCF7L2 gene and susceptibility toward type 2 diabetes in human populations. In Europeans, TCF7L2 is the most important locus

predisposing to T2DM. Although originally reported to be non-detectable,249 TCF7L2 is now known to be expressed in both islets and INS-1 cells.250–252

Alterations in TCF7L2 expression confer risk for genotypes associated with impaired b-cell function.253,254 TCF7L2 expression is increased 5-fold in

type 2-diabetic pancreatic islets.255 Thus understanding of how islet Wnt signaling is regulated and how it influences islet function is of immense potential importance for identifying means to decrease the risk of developing type 2 diabetes.

TCF7L2 expression is increased 5-fold in T2DM pancreatic islets and overexpressing TCF7L2 in human islets using an adenovirus system reduces insulin secretion but, paradoxically, insulin gene expression positively correlates with TCF7L2 gene expression.255 These findings suggest that TCFL2 could be involved in regulating islet compensation for the insulin resistance that precedes and accompanies the development of T2DM. Consistent with this idea, older mice lacking LRP5, the Wnt coreceptor, have impaired b-cell function and impaired glucose tolerance when challenged with a high-fat diet.256 Rat pancreatic islets express TCF7L2 and TCF7L2 gene expression is significantly elevated in islets from prediabetic Zucker fa/fa rats.257 This indicates that islet TCF7L2 expression may be a patho/physiological variable. Taken together, these data strongly support the concept that altered Wnt signaling may be required to maintain islet functions in conditions demanding adaptive b-cell responses to insulin resistance.

Exposure of islets to exogenous Wnt-3a stimulates glucose-simulated insulin secretion (GSIS).256 This is blocked by a soluble form of Wnt receptor, secreted Fzd-related (sFRP) protein-1.256 Importantly, adipocyte-derived Wnt signaling molecules present in fat cell-conditioned media stimulate insulin secretion by primary islets, an action blocked by sFRP-1258 indicating a specific e ect of Wnt ligands. Treatment with human adipose-conditioned media increases the transcription of a TCF reporter gene in INS-1 cells and induces their proliferation.258 Thus, as these authors suggest, the increased adipocyte mass in obesity (an insulin-resistant state) might be important to increase b-cell mass.

2.16 Concluding Remarks

It is increasingly apparent that the ability of white adipose tissue to secrete bioactive signaling molecules, adipokines, can underlie many of the pathophysiological adaptations of metabolism associated with endocrine disorders, including T2DM. In this chapter, we have attempted to discuss and develop a number of recent avenues of research that highlight the potential roles of adipokines in the development of T2DM. These include the potential for autocrine e ects of adipokines, notably leptin and adiponectin, to influence the function of the adipocyte. We have also highlighted the potential role of the lipo-oxidative transcription factor PPARa in influencing the potential autocrine actions of leptin. Strong evidence exists to support the concept that an inappropriate early life environment can increase the risk of type 2 diabetes in adulthood. We have developed this concept to include a role for an inappropriate early life environment in orchestrating metabolic maladaptations leading to T2DM via augmented FA release in combination with altered secretion or action of adipo/cytokines. Circadian rhythms within the adipocyte influence adipocyte fat storage and consequently the risk of obesity. We have examined the evidence that circadian disturbances precede the onset of obesity. Adipose-tissue-generated products, namely FA and adipokines, as well as cytokines have a significant role in the regulation of pancreatic b-cell function, in particular insulin secretion, and are now recognized to play a crucial role in determining the ability of the b cell to secrete adequate insulin to compensate for a deterioration in insulin sensitivity. We have developed this to encompass a novel mechanism whereby a state of low-grade inflammation in the islet, induced by increased chronic exposure to adipocyte-derived cytokines such as TNFa, could predispose the b cell to react to nutrient stressors in an exaggerated fashion, so predisposing to gluco-lipotoxicity and T2DM. Finally, we have discussed the potential that Wnt signaling may influence islet function and may be involved in linking the increased adipocyte mass in obesity to increase b cell mass.

Acknowledgements

Our research in this area has been supported in part by project grants from Diabetes UK (RD06/0003424 and RD03/0002725) to MCS and MJH and a Diabetes UK equipment grant (RD06/0003424) to MCS, for which we are grateful.

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