Summary Replenishing insulin-producing pancreatic β cell mass will benefit both type I and type II diabetics. In adults, pancreatic β cells are generated primarily by self duplication. We report on a novel mouse model of insulin resistance that induces dramatic pancreatic β cell proliferation and β cell mass expansion. Using this model we identify a new hormone, betatrophin, that is primarily expressed in liver and fat. Expression of betatrophin correlates with β cell proliferation in other mouse models of insulin resistance and during gestation. Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic β cell proliferation, expands β cell mass, and improves glucose tolerance. Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.
MicroRNAs (miRNAs) are a growing class of small RNAs (about 22 nt) that play crucial regulatory roles in the genome by targeting mRNAs for cleavage or translational repression. Most of the identified miRNAs are highly conserved among species, indicating strong functional constraint on miRNA evolution. However, nonconserved miRNAs may contribute to functional novelties during evolution. Recently, an X-linked miRNA cluster was reported with multiple copies in primates but not in rodents or dog. Here we sequenced and compared this miRNA cluster in major primate lineages including human, great ape, lesser ape, Old World monkey, and New World monkey. Our data indicate rapid evolution of this cluster in primates including frequent tandem duplications and nucleotide substitutions. In addition, lineage-specific substitutions were observed in human and chimpanzee, leading to the emergence of potential novel mature miRNAs. The expression analysis in rhesus monkeys revealed a strong correlation between miRNA expression changes and male sexual maturation, suggesting regulatory roles of this miRNA cluster in testis development and spermatogenesis. We propose that, like protein-coding genes, miRNA genes involved in male reproduction are subject to rapid adaptive changes that may contribute to functional novelties during evolution.
Summary Investigation of cell cycle kinetics in mammalian pancreatic β-cells has mostly focused on transition from the quiescent (G0) to G1 phase. Here we report that centromere protein A (CENP-A), which is required for chromosome segregation during the M-phase, is necessary for adaptive β-cell proliferation. Receptor-mediated insulin signaling promotes DNA-binding activity of FoxM1 to regulate expression of CENP-A and polo-like kinase-1 (PLK1) by modulating cyclin dependent kinase-1/2. CENP-A deposition at the centromere is augmented by PLK1 to promote mitosis while knocking down CENP-A limits β-cell proliferation and survival. CENP-A deficiency in β-cells leads to impaired adaptive proliferation in response to pregnancy, acute and chronic insulin resistance, and aging in mice. Insulin-stimulated CENP-A/PLK1 protein expression is blunted in islets from patients with type 2 diabetes. These data implicate the insulin-FoxM1/PLK1/CENP-A pathway-regulated mitotic cell cycle progression as an essential component in the β-cell adaptation to delay and/or prevent progression to diabetes.
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