Christopher J. Rhodes, Ph.D.

Signaling Transduction Mechanisms in the Pancreatic ß-Cell for Control of Insulin Production & Secretion; ß-Cell Growth and Death

Research Summary

The general theme of Rhodes’ laboratory is to examine molecular mechanisms that control key functions of the pancreatic islet ß-cell, and investigating how these go awry in the pathogenesis of diabetes. The following projects are ongoing:

A) Translational Control of Proinsulin Biosynthesis – is the principle means by which insulin secreted from the ß-cell is rapidly replenished to keep insulin stores at optimal levels. However, the molecular mechanism behind glucose-regulated translation control of proinsulin biosynthesis has yet to be unveiled. We are currently investigating the metabolic signaling pathway that controls the process. Also, a conserved cis-element in 5’-untranslated region of preproinsulin mRNA has been discovered that is required for specific translation control of proinsulin biosynthesis. A trans-acting protein associates with this cis-element in a glucose-dependent fashion is currently undergoing identification. A link between the metabolic signaling pathway and post-translational modification of this mRNA-binding protein will be a major breakthrough for better understanding the mechanism behind translation control of proinsulin biosynthesis under normal and diabetic conditions.

C) Signal Transduction Pathways for Control of ß-Cell Growth and Death – It has only been recently acknowledged that the onset of type-2 diabetes (like type-1 diabetes) is marked by significant loss of ß-cells. As such, either increasing ß-cell growth and/or promoting ß-cell survival could be an effective therapy to delay (or even prevent) the onset of type-2 diabetes. However, little is known about the molecular mechanisms that instigate ß-cell growth and death relative to temporal metabolic homeostasis. The Rhodes laboratory has been investigating growth factor and nutrient signal transduction pathways in ß-cells (e.g. IRS/PI3K/PKB; IRS/Ras/Raf/Erk; JAK2/STAT etc.) to see if they play a role in increasing ß-cell growth (by ß-cell replication, size and neogenesis) and/or promoting ß-cell survival (i.e. anti-apoptotic). An important role for IRS-2 has arisen from these studies. Without IRS-2 expression ß-cells undergo spontaneous apoptosis, but increasing IRS-2 levels promotes ß-cell growth and survival. IRS-2 turnover is especially rapid in ß-cells and its expression is dynamically regulated at the transcriptional level. As such, control of IRS-2 expression may be an attractive therapeutic target. Investigations to better define the regulation of IRS-2 gene expression in ß-cells are underway. Molecular mechanisms that trigger ß-cell apoptosis relative to the pathogenesis of type-2 diabetes are also being examined, with a focus on fatty acid induced inhibition of IRS/PI3K/PKB signaling pathways.

Selected Papers

Yaekura K, Julyan R, Wicksteed B, Hays L, Alarcon C, Sommers S, Poitout V, Baskin D, Wang Y, Philipson L, Rhodes CJ. (2003). Insulin secretory deficiency and glucose intolerance in Rab3A null mice. J. Biol. Chem. 278:9715-9821.

Wicksteed BL, Alarcón C, Briaud I, Lingohr MK, Rhodes CJ. (2003). Glucose-induced translational control of proinsulin biosynthesis is proportional to preproinsulin mRNA levels, but not regulated via a positive feedback of secreted insulin on  in islet ß-cells. J. Biol. Chem. 278: 42080-42090. 

Briaud I, Dickson LM, Lingohr MK, McCuaig J, Lawrence JC, Rhodes CJ. (2005). IRS-2 proteosomal degradation mediated by mTOR Ser/Thr phosphorylation decreases pancreatic ß-cell survival. J. Biol. Chem. 280:2282-93

Rhodes CJ. (2005). Type-2 diabetes – A matter of ß-cell life and death? Science 307:380-4.