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 secretion. However, the long-term control of beta-cell mass is also relevant to diabetes, since this parameter is reduced substantially even in non-insulin-dependent diabetes in humans. In animal models of type 2 diabetes, the normal balance between beta-cell proliferation and programmed cell death is perturbed. We take the perspective in this overview that inosine monophosphate dehydrogenase (IMPDH; EC 1.1.1. 205) may represent a previously neglected molecular integrator or sensor that exerts both functional (secretory) and anatomical (proliferative) effects within beta-cells. These properties reflect the fact that IMPDH is a rate-limiting enzyme in the new synthesis of the purine guanosine triphosphate (GTP), which modulates both exocytotic insulin secretion and DNA synthesis, as well as a number of other critical cellular functions within the beta-cell. Alterations in the expression or activity of IMPDH may be central to beta-cell replication, cell cycle progression, differentiation, and maintenance of adequate islet mass, effects that are probably mediated both by GTP directly, and indirectly via low molecular mass GTPases. If GTP becomes depleted, a hierarchy of beta-cell functions becomes progressively paralyzed, until eventually the effete cell is removed via apoptosis.
Pacific Northwest Research Institute, Seattle, WA 98122, USA.
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Metz
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Kowluru
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000502:physiology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009173:Mycophenolic Acid / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007328:Insulin; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D020558:GTP Phosphohydrolases; D009173:Mycophenolic Acid; D005947:Glucose