Cell signalling networks of relevance for obesity and diabetes
The overall aim is to identify disease mechanisms and targets for treatment of diabetes with focus on phosphodiesterases, incretins and inflammation in human tissues of relevance for the regulation of lipid metabolism and insulin secretion.
Although type 2 diabetes (T2D) is a heterogenous disorder, the pathogenesis involves two fundamental abnormalities: resistance to the biological activities of insulin and inadequate insulin secretion from the pancreatic beta-cell. In individuals who are genetically predisposed, T2D commonly arises with progressive obesity, in particular visceral obesity. Exactly what causes this strong and consistent association between obesity, insulin resistance and development of T2D is not known. Spillover of fatty acids from adipose tissue with consequent deposition in non-adipocytes is one likely cause. In addition, obesity is associated with chronic low grade inflammation and imbalance in the circulating levels of adipokines, which could also contribute to the development of insulin resistance. The mechanisms acting at the interface between insulin signalling, on one hand, and inflammation, dyslipidemia, cell stress and altered levels of adipokines on the other, are not fully known.
However, activation of kinase cascades leading to increased serine phosphorylation and thereby reduced tyrosine phophorylation of insulin receptor substrates, key up-stream components in insulin signalling, is believed to have a role. In addition, increased production of SOCS (suppressors of cytokine signalling) and activation of tyrosine and lipid phosphatases are other important actors in the development of insulin resistance. We have over the years elucidated mechanisms involved in the interplay between insulin and cAMP signalling networks and how dysregulation of this interplay may cause insulin resistance and diabetes. At the mechanistic level, we have identified a number of new regulatory mechanisms, especially in adipocytes involving phosphodiesterases (PDEs), exchange protein activated by cAMP (Epac), protein kinase B (PKB) and AMP-activated kinase (AMPK). For example, we have shown that specific pools of cAMP, degraded by distinct PDEs, are involved in the regulation of the activity both of PKB, a key mediator of insulin action, and AMPK, a key energy sensor. Furthermore, by altering the expression of PDE3B (a cAMP-degrading enzyme activated by insulin), we have generated mouse models for dysregulated glucose and lipid metabolism in target tissues for insulin as well as for dysregulated insulin secretion. These mice show a number of defects related to energy metabolism, such as insulin resistance, inflamed adipose tissue, altered mitochondrial function, increased glucose production, altered adipokine secretion and altered insulin secretion.
Although PDEs were described soon after the discovery of cAMP in the 1960s, their complexity and functions in signalling is only recently beginning to be fully realized. We now know that at least 100 different PDE proteins, unique in their ability to degrade cAMP and cGMP, importantly contribute to the regulation of cAMP levels in cells. All known PDEs are collected in 11 families (PDEs 1-11), each having its typical isoforms and splice variants. Current data suggest that individual isozymes modulate distinct regulatory pathways in the cell. These properties therefore offer the opportunity for selectively targeting specific PDEs for treatment of specific disease states. Inhibitors of PDE3 and 5 are already used in the clinic for the treatment of cardiac dysfunction/claudiocatio intermittens and impotence, respectively. In addition to PDE3B, which has been extensively studied by us, several other PDEs appear to be of importance for the regulation of metabolism.
Last updated: July 30, 2009
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