Secrets of insulin and IGF-1 regulation of insulin secretion revealed.
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ABSTRACT:
SUBMITTER: Shepherd PR
PROVIDER: S-EPMC1223857 | biostudies-other | 2004 Jan
REPOSITORIES: biostudies-other
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Project description:Pancreatic ?-cell insulin production is orchestrated by a complex circuitry involving intracellular elements including cyclic AMP (cAMP). Tackling aberrations in glucose-stimulated insulin release such as in diabetes with pharmacological agents, which boost the secretory capacity of ?-cells, is linked to adverse side effects. We hypothesized that a photoactivatable adenylyl cyclase (PAC) can be employed to modulate cAMP in ?-cells with light thereby enhancing insulin secretion. To that end, the PAC gene from Beggiatoa (bPAC) was delivered to ?-cells. A cAMP increase was noted within 5?minutes of photostimulation and a significant drop at 12?minutes post-illumination. The concomitant augmented insulin secretion was comparable to that from ?-cells treated with secretagogues. Greater insulin release was also observed over repeated cycles of photoinduction without adverse effects on viability and proliferation. Furthermore, the expression and activation of bPAC increased cAMP and insulin secretion in murine islets and in ?-cell pseudoislets, which displayed a more pronounced light-triggered hormone secretion compared to that of ?-cell monolayers. Calcium channel blocking curtailed the enhanced insulin response due to bPAC activity. This optogenetic system with modulation of cAMP and insulin release can be employed for the study of ?-cell function and for enabling new therapeutic modalities for diabetes.
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Project description:The multilayered epidermis is established through a stratification program, which is accompanied by a shift from symmetric toward asymmetric divisions (ACD), a process under tight control of the transcription factor p63. However, the physiological signals regulating p63 activity in epidermal morphogenesis remain ill defined. Here, we reveal a role for insulin/IGF-1 signaling (IIS) in the regulation of p63 activity. Loss of epidermal IIS leads to a biased loss of ACD, resulting in impaired stratification. Upon loss of IIS, FoxO transcription factors are retained in the nucleus, where they bind and inhibit p63-regulated transcription. This is reversed by small interfering RNA-mediated knockdown of FoxOs. Accordingly, transgenic expression of a constitutive nuclear FoxO variant in the epidermis abrogates ACD and inhibits p63-regulated transcription and stratification. Collectively, the present study reveals a critical role for IIS-dependent control of p63 activity in coordination of ACD and stratification during epithelial morphogenesis.
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Project description:In the brain, glutamate is an extracellular transmitter that mediates cell-to-cell communication. Prior to synaptic release it is pumped into vesicles by vesicular glutamate transporters (VGLUTs). To inactivate glutamate receptor responses after release, glutamate is taken up into glial cells or neurons by excitatory amino acid transporters (EAATs). In the pancreatic islets of Langerhans, glutamate is proposed to act as an intracellular messenger, regulating insulin secretion from ?-cells, but the mechanisms involved are unknown. By immunogold cytochemistry we show that insulin containing secretory granules express VGLUT3. Despite the fact that they have a VGLUT, the levels of glutamate in these granules are low, indicating the presence of a protein that can transport glutamate out of the granules. Surprisingly, in ?-cells the glutamate transporter EAAT2 is located, not in the plasma membrane as it is in brain cells, but exclusively in insulin-containing secretory granules, together with VGLUT3. In EAAT2 knock out mice, the content of glutamate in secretory granules is higher than in wild type mice. These data imply a glutamate cycle in which glutamate is carried into the granules by VGLUT3 and carried out by EAAT2. Perturbing this cycle by knocking down EAAT2 expression with a small interfering RNA, or by over-expressing EAAT2 or a VGLUT in insulin granules, significantly reduced the rate of granule exocytosis. Simulations of granule energetics suggest that VGLUT3 and EAAT2 may regulate the pH and membrane potential of the granules and thereby regulate insulin secretion. These data suggest that insulin secretion from ?-cells is modulated by the flux of glutamate through the secretory granules.
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Project description:AimsThe inability of pancreatic ?-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in ?-cells on ?-cell function and glucose homeostasis.ResultsSilencing of Nrf1 in ?-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 ?-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from ?-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and aerobic glycolysis, which is associated with the elevated basal insulin release and reduced glucose responsiveness. The elevated glycolysis and reduced glucose responsiveness due to Nrf1 silencing likely result from altered expression of glucose metabolic enzymes, with induction of high-affinity hexokinase 1 and suppression of low-affinity glucokinase.InnovationOur study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in ?-cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS.ConclusionNrf1 plays critical roles in regulating glucose metabolism, mitochondrial function, and insulin secretion, suggesting that Nrf1 may be a novel target to improve the function of insulin-secreting ?-cells.
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Project description:The insulin-like growth factor 1 (IGF-1) stimulates expression and secretion of vascular endothelial growth factor-A (VEGF-A), the main actor in ocular neovascularization, by RPE cells. Activity of IGF-1 is regulated by interaction between its receptor and Caveolin-1 (Cav-1), the main component of caveolae. The aim of this study was to investigate whether modulation of Cav-1 expression affects synthesis and secretion of VEGF-A. ARPE-19 cells were transfected with small interfering RNA for Cav-1 (si-Cav-1) and with control siRNA (si-CTR) and stimulated with IGF-1. We found that down-regulation of Cav-1 did not affect activation of IGF-1R but regulated in an opposite manner the phosphorylation of Akt and Erk1/2. Moreover, we found that IGF-1 increased mRNA levels of VEGF-A in both si-CTR and in si-Cav-1 ARPE-19 cells and that Cav-1 silencing significantly reduced basal and IGF-1-stimulated VEGF-A release. Then we investigated the response of the microvascular endothelial cell line HMEC-1 to secretory products of ARPE-19 cells by evaluating wound healing closure, finding that conditioned media from si-Cav-1-ARPE-19 cells reduced endothelial cell migration rate. These data demonstrate that Cav-1 regulates secretion of VEGF-A, and that the depletion of Cav-1 reduces IGF-1 induced VEGF-A secretion in ARPE-19 cells and the migratory potential of their secretory products.
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Project description:A hallmark of aging is immunosenescence, a decline in immune function that appeared to be inevitable. Surprisingly, here we show that genetic inhibition of DAF-2/insulin/IGF-1 receptor drastically delays immunosenescence and even rejuvenates immunity in C. elegans. We find that p38 mitogen activated protein kinase (PMK-1), a key determinant of immunosenescence in wild-type, is dispensable for this rejuvenated immunity. Instead, we demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(-) animals. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of zip-10/bZip transcription factor, which in turn down-regulates ins-7, an agonistic insulin-like peptide, for further reduction in insulin/IGF-1 signaling (IIS). Thus, reduced IIS bypasses immunosenescence and rejuvenates immunity via up-regulating anti-aging transcription factors that regulate an endocrine insulin-like peptide through a positive feedback mechanism. Because many functions of IIS are conserved across phyla, our study may lead to developing strategies for immune rejuvenation in humans.
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