Type 2 diabetes and the aging pancreatic beta cell

Abstract

The incidence of and susceptibility to Type 2 diabetes increases with age, but the underlying mechanism(s) within beta cells that contribute to this increased susceptibility have not been fully elucidated. Here we review how aging affects the proliferative and regenerative capacity of beta cells and how this impacts beta cell mass. In addition we review changes that occur in beta cell function with age. Although we focus on the different rodent models that have provided insight into the characteristics of the aging beta cell, the limited knowledge from non-rodent models is also reviewed. Further studies are needed in order to identify potential beta cell targets for preventing or slowing the progression of diabetes that occurs with age.

Figure 1. Summary of the effects of age on various beta cell parameters.

Multiple factors influence the beta cell as it ages. Each of the factors listed here is discussed in more detail in the text. This graph is a representation of how these parameters change with age. The actual kinetics of each of these changes has not been fully elucidated.

Figure 2. Effects of p16^Ink4a on Cdk4/6.

(A) The p16^Ink4a cell cycle inhibitor sequesters Cdk4 or Cdk6, preventing interactions with cyclin D proteins, and thus phosphorylation of pRB. Hypophosphorylated pRB sequesters the E2F transcription factor, thus thus inihibiting cell cycle progression. (B) In the absence of p16^Ink4a, cyclin D forms a productive complex with either Cdk4 or Cdk6 and phosphorylates RB. This phosphorylation releases the E2F transcription factor, facilitating the G1 to S phase cell cycle transition. Thus, in the presence of elevated p16^Ink4a, such as with aging, there is cell cycle arrest and cellular senescence. Adapted from [32]

Figure 3. Effects of p19^Arf on the cell cycle.

In the absence of p19^Arf, p53 is ubiquitinized and subsequently degraded by the proteosome. p19^Arf inhibits the ubiquitin-modulated effect of p53 by MDM2. p19^Arf inhibits ubiquitin-mediated p53 degradation resulting in induction of p21 and subsequently cell cycle arrest. Adapted from [75] and [76]

Figure 4. BMI-1 and Ezh2: Effects on transcription.

(A) The Ezh2 (Enhancer of zeste homologue 2) component of the PRC2 (Polycomb repressor complex 2) complex methylates lysine (K) 27 of histone H3 (H3K27). This methylation process recruits the PRC1 (Polycomb repressor complex 1) complex. (B) The Ring1A and Ring1B components of this complex ubiquitylate H2AK119. This ubiquitylation causes transcriptional repression, for example at the Ink4a/Arf locus. In addition to Ezh2, the PRC2 complex contains EED (embryonic ectoderm development) and Suz12 (suppressor of zeste homologue 12). The PRC1 complex contains BMI-1, Ring 1A, Ring 1B, PH1 (Polycomb homologue 1), and PH1 (Polyhomeotic homologue 1). Adapted from [77].