Christopher J. Rhodes Ph.D.

The onset of type-2 diabetes is marked insulin secretory dysfunction and loss of ß-cell mass, so that the inherent insulin resistance is no longer compensated for [1]. The Rhodes laboratory has an interest in molecular mechanisms that control pancreatic ß-cell growth and survival, with a particular interest in IRS-2 signal transduction pathways (Figure 1a). Increased IRS-2 expression in ß-cells can promote controlled growth and particularly survival, but without IRS-2 expression ß-cell spontaneously go into apoptosis. We are examining mechanisms whereby IRS-2 signaling links to elements of the cell cycle that controls ß-cell replication and as well as transcription factors that influence ß-cell differentiation and neogenesis. Downstream of IRS-2 in the signaling pathway is an protein kinase known as PKB (also known as Akt; Figure 1). Activation of PKB is key for promoting ß-cell survival, and we are examining which of the many PKB protein-substrates are dominantly anti-apoptotic [2]. Conversely, mechanisms whereby fatty acid moieties inhibit PKB activation are also being examined in ß-cells, which may also give insight into the pathogenesis of type-2 diabetes as well as reveal possible new therapeutic strategies to treat or even prevent the disease. Recently, we have found that IRS-2 has a very high turnover in ß-cells, yet its expression is quite highly regulated (especially by glucose) predominately at the transcriptional level [3]. Investigations are currently underway to find the key regulatory cis-elements in the IRS-2 promoter, and interacting transcription factors, that tightly control IRS-2 expression. In addition, the Rhodes laboratory is embarking on a translational approach via small molecule screen to find potential reagents that might be used to treat and/or prevent type-2 diabetes.

[1] Rhodes CJ. Type-2 diabetes – A matter of ß-cell life and death? Science. 2005; 307: 380-384
[2] Dickson L, Rhodes CJ. Pancreatic ß-cell growth and survival in the onset of type-2 diabetes: A role for protein kinase-B in the Akt? Am J Physiol. 2004; 287: E192-E198
[3] Lingohr MK, Briaud I, Dickson LM, et al. Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet beta-cells. J Biol Chem. 2006; 281: 15884-15892