Inosine monophosphate dehydrogenase: A molecular switch integrating pleiotropic GTP-dependent beta-cell functions

Studies of pancreatic islet function in the pathogenesis of type 2 diabetes mellitus have tended to focus on the short-term control of insulin secreti on. However, the long-term control of beta-cell mass is also relevant to di abetes, since this parameter is reduced substantially even in non-insulin-d ependent diabetes in humans. In animal models of type 2 diabetes, the norma l balance between beta-cell proliferation and programmed cell death is pert urbed. We take the perspective in this overview that inosine monophosphate dehydrogenase (IMPDH; EC 1.1.1. 205) may represent a previously neglected m olecular integrator or sensor that exerts both functional (secretory) and a natomical (proliferative) effects within beta-cells. These properties refle ct the fact that IMPDH is a rate-limiting enzyme in the new synthesis of th e purine guanosine triphosphate (GTP), which modulates both exocytotic insu lin secretion and DNA synthesis, as well as a number of other critical cell ular functions within the beta-cell. Alterations in the expression or activ ity of IMPDH may be central to beta-cell replication, cell cycle progressio n, differentiation, and maintenance of adequate islet mass, effects that ar e probably mediated both by GTP directly, and indirectly via low molecular mass GTPases. If GTP becomes depleted, a hierarchy of beta-cell functions b ecomes progressively paralyzed, until eventually the effete cell is removed via apoptosis.