Insulin is the primary hormone involved in glucose homeostasis, and impairment of insulin action and/or secretion has a critical role in the pathogenesis of diabetes mellitus. Type-II SH2-domain-containing inositol 5-phosphatase, or 'SHIP2', is a member of the inositol polyphosphate 5-phosphatase family. In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling events mediated by both phosphoinositide-3-OH kinase and Ras/mitogen-activated protein kinase. Here we report the generation of mice lacking the SHIP2 gene. Loss of SHIP2 leads to increased sensitivity to insulin, which is characterized by severe neonatal hypoglycaemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. Adult mice that are heterozygous for the SHIP2 mutation have increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter and increased glycogen synthesis in skeletal muscles. Our results show that SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo.
Cyclic AMP has been shown to inhibit cell proliferation in many cell types and to activate it in some. The latter has been recognized only lately, thanks in large part to studies on the regulation of thyroid cell proliferation in dog thyroid cells. The steps that led to this conclusion are outlined. Thyrotropin activates cyclic accumulation in thyroid cells of all the studied species and also phospholipase C in human cells. It activates directly cell proliferation in rat cell lines, dog, and human thyroid cells but not in bovine or pig cells. The action of cyclic AMP is responsible for the proliferative effect of TSH. It accounts for several human diseases: congenital hyperthyroidism, autonomous adenomas, and Graves' disease; and, by default, for hypothyroidism by TSH receptor defect. Cyclic AMP proliferative action requires the activation of protein kinase A, but this effect is not sufficient to explain it. Cyclic AMP action also requires the permissive effect of IGF-1 or insulin through their receptors, mostly as a consequence of PI3 kinase activation. The mechanism of these effects at the level of cyclin and cyclin-dependent protein kinases involves an induction of cyclin D3 by IGF-1 and the cyclic AMP-elicited generation and activation of the cyclin D3-CDK4 complex.
Through the cAMP signaling pathway, TSH stimulates thyroid follicular cell proliferation, differentiation, and function. Although the autocrine production of IGF-I in the thyroid gland suggests an important physiological function for this factor in these processes, the exact role of the IGF-I/IGF-I receptor system in vivo remains unclear. Although the mitogenic action of TSH requires the presence of IGF-I or insulin in primary culture of dog and human thyroid cells, IGF-I has an effect equal to and independent of the effect of TSH on cell proliferation in rat thyroid cell lines and may even be the main growth regulator in this case. To investigate the in vivo function of the IGF-I/IGF-I receptor system, transgenic mice overexpressing human IGF-I, IGF-I receptor, or both in the thyroid were generated. Adult transgenic mice did not present external signs of thyroid dysfunction, but mice overexpressing both transgenes had significantly increased gland weight and follicular lumen area. A decreased TSH level together with a slightly increased serum T(4) concentration and increased thyroidal iodine uptake were also observed, suggesting that IGF-I and IGF-I receptor stimulate thyroid function to some extent in vivo.
Background: Meditation refers to a group of practices commonly proposed to treat stress-related conditions and improve overall wellness. In particular, meditation might exert beneficial actions on heart rate variability (HRV) by acting on autonomic tone with an increase in the vagal activity. The effects of heartfulness meditation (HM) on HRV remain poorly defined. Methods: We investigated the effects of HM on HRV in a group of 26 healthy subjects. Subjects were regularly practicing this form of meditation on a daily basis. We assessed the HRV and residual HRV (rHRV) at rest and during meditation. We also used as control a period of respiratory rhythm imposed by an auditory signal, with the imposed breathing rhythm being identical to the spontaneous rhythm recorded during meditation. Results: During deep meditation period, the standard deviation of RR intervals (SD RR ), coefficient of variation of RR intervals (CV RR ), and total power (TP) were decreased while the low-frequency power (LFP), normalized LFP (nLFP), and normalized residual LFP (nrLFP) were increased as compared with those at rest, suggesting that the global vagal modulation was suppressed while the baroreflex was increased during deep medication. At the end of meditation, the LFP, residual LFP (rLFP), nLFP, nrLFP, low-/high-frequency power ratio (LHR), and residual LHR (rLHR) were increased while the residual very low-frequency power (rVLFP), normalized high-frequency power (nHFP), and normalized residual HFP (nrHFP) were decreased, as compared with those during paced breathing, suggesting that the vagal modulation was decreased while the sympathetic modulation was increased by deep meditation. During paced breathing period, the SD RR , CV RR , TP, LFP, rLFP, nLFP, nrLFP, LHR, and rLHR were decreased while nHFP and nrHFP were increased as compared with at rest, suggesting that paced breathing could suppress the sympathetic modulation and enhance the vagal modulation. Conclusion: HM can induce a suppression of global vagal modulation and increased the sympathetic modulation and baroreflex. In addition, paced breathing can suppress the sympathetic modulation and enhance the vagal modulation. Unlike studies using other types of meditation, we did not identify evidence of increased vagal tone during HM.
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