RESUMO
Adult human ß-cells replicate slowly. Also, despite the abundance of rodent ß-cell lines, there are no human ß-cell lines for diabetes research or therapy. Prior studies in four commonly studied rodent ß-cell lines revealed that all four lines displayed an unusual, but strongly reproducible, cell cycle signature: an increase in seven G(1)/S molecules, i.e. cyclins A, D3, and E, and cdk1, -2, -4, and -6. Here, we explore the upstream mechanism(s) that drive these cell cycle changes. Using biochemical, pharmacological and molecular approaches, we surveyed potential upstream mitogenic signaling pathways in Ins 1 and RIN cells. We used both underexpression and overexpression to assess effects on rat and human ß-cell proliferation, survival and cell cycle control. Our results indicate that cMyc is: 1) uniquely up-regulated among other candidates; 2) principally responsible for the increase in the seven G(1)/S molecules; and, 3) largely responsible for proliferation in rat ß-cell lines. Importantly, cMyc expression in ß-cell lines, although some 5- to 7-fold higher than normal rat ß-cells, is far below the levels (75- to 150-fold) previously associated with ß-cell death and dedifferentiation. Notably, modest overexpression of cMyc is able to drive proliferation without cell death in normal rat and human ß-cells. We conclude that cMyc is an important driver of replication in the two most commonly employed rat ß-cell lines. These studies reverse the current paradigm in which cMyc overexpression is inevitably associated with ß-cell death and dedifferentiation. The cMyc pathway provides potential approaches, targets, and tools for driving and sustaining human ß-cell replication.
Assuntos
Células Secretoras de Insulina/patologia , Insulinoma/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células , Fase G1 , Regulação Neoplásica da Expressão Gênica , Humanos , Células Secretoras de Insulina/metabolismo , Insulinoma/genética , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fase S , Transdução de Sinais , Regulação para CimaRESUMO
OBJECTIVE: To compare two subcutaneous insulin strategies for glycemic management of hyperglycemia in non-critically ill hospitalized patients with diabetes during enteral nutrition therapy (ENT). RESEARCH DESIGN AND METHODS: Fifty inpatients were prospectively randomized to receive sliding-scale regular insulin (SSRI) alone (n = 25) or in combination with insulin glargine (n = 25). NPH insulin was added for persistent hyperglycemia in the SSRI group (glucose >10 mmol/l). RESULTS: Glycemic control was similar in the SSRI and glargine groups (mean +/- SD study glucose 8.9 +/- 1.6 vs. 9.2 +/- 1.6 mmol/l, respectively; P = 0.71). NPH insulin was added in 48% of the SSRI group subjects. There were no group differences in frequency of hypoglycemia (1.3 +/- 4.1 vs. 1.1 +/- 1.8%; P = 0.35), total adverse events, or length of stay. CONCLUSIONS: Both insulin strategies (SSRI with the addition of NPH for persistent hyperglycemia and glargine) demonstrated similar efficacy and safety in non-critically ill hospitalized patients with type 2 diabetes during ENT.