Hypothesis: Causes of Type 2 Diabetes in Progeroid Werner Syndrome
نویسنده
چکیده
The premature ageing Werner syndrome (WS) is characterized by the early onset of many age related phenotypes, including graying of hair, cataracts, atherosclerosis, cancer and type 2 diabetes. Type 2 diabetes (DM2) is the loss of blood glucose homeostastis, due to insulin resistance and a failure of acute glucose-stimulated insulin secretion (GSIS) by pancreatic cells. Early compensation for insulin resistance usually occurs through increased insulin secretion consequent on increased cell mass, requiring proliferation of cells; DM2 progresses if there is failure of compensation. How loss of the WRN DNA helicase/exonuclease in WS contributes to DM2 has long been a puzzle. Loss of function mutations in WRN result in problems with DNA replication, repair and recombination, consequential genomic instability and premature onset of cellular senescence. Here, I suggest that the high prevalence of DM2 in WS is a consequence of senescence of WS cells, with islet cells undergoing highly premature failure of the hyperproliferative compensatory stage, rapidly leading to late stage diabetes. The additional contribution to DM2 progression by pro-inflammatory cytokines is
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