Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in beta(INS-1)-cells.

Glucose-dependent insulinotropic polypeptide (GIP) acts as a glucose-dependent growth factor for beta-cells. Here we show that GIP and glucose also act synergistically as anti-apoptotic factors for beta-cells, using the well-differentiated beta-cell line, INS-1. Mitogenic and anti-apoptotic signaling of GIP were dependent upon pleiotropic activation of protein kinase A (PKA)/cAMP regulatory element binder (CREB), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-kinase)/PKB signaling modules. The signaling modules activated by GIP were dependent on glucose metabolism and calcium influx and were tightly linked by multiple activating and inhibiting cross-talk. These interactions included: (i) a central role of tyrosine phosphorylation for stimulation of PKA/CREB, MAPK and PI3-kinase/PKB, (ii) inhibition of PKA/CREB by the MAPK pathway at the level of MAPK kinase-1 or downstream, (iii) activation of MAPK signaling by PI3-kinase and PKA at the level of extracellular-signal regulated kinase 1/2 or upstream, and (iv) activation of PKB by MAPK and PKA signaling at the level of PKB or upstream. Furthermore, we demonstrated inhibition of CREB signaling by Ca(2+)/calmodulin kinase I/IV. These results indicated that GIP acts as a mitogenic and anti-apoptotic factor for beta-cells by pleiotropic activation of tightly linked signaling pathways in beta-cells.

Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling.

Activation of the G-protein-coupled receptor for glucose-dependent insulinotropic polypeptide facilitates insulin-release from pancreatic beta-cells. In the present study, we examined whether glucose-dependent insulinotropic polypeptide also acts as a growth factor for the beta-cell line INS-1. Here, we show that glucose-dependent insulinotropic polypeptide induced cellular proliferation synergistically with glucose between 2.5 mM and 15 mM by pleiotropic activation of signaling pathways. Glucose-dependent insulinotropic polypeptide stimulated the signaling modules of PKA/cAMP regulatory element binder, MAPK, and PI3K/protein kinase B in a glucose- and dose-dependent manner. Janus kinase 2 and signal transducer and activators of transcription 5/6 pathways were not stimulated by glucose-dependent insulinotropic polypeptide. Activation of PI3K by glucose-dependent insulinotropic polypeptide and glucose was associated with insulin receptor substrate isoforms insulin receptor substrate-2 and growth factor bound-2 associated binder-1 and PI3K isoforms p85alpha, p110alpha, p110beta, and p110gamma. Downstream of PI3K, glucose-dependent insulinotropic polypeptide-stimulated protein kinase Balpha and protein kinase Bbeta isoforms and phosphorylated glycogen synthase kinase-3, forkhead transcription factor FKHR, and p70S6K. These data indicate that glucose-dependent insulinotropic polypeptide functions synergistically with glucose as a pleiotropic growth factor for insulin-producing beta-cells, which may play a role for metabolic adaptations of insulin-producing cells during type II diabetes.

Integrative mitogenic role of protein kinase B/Akt in beta-cells.

Protein kinase B/Akt (PKB/Akt) is activated by phosphatidylinositol 3-kinase (PI 3-K) and is a central mediator of cellular proliferation and protection against apoptosis. Insulin, insulin-like growth factor (IGF-1), and glucagon-like peptide-1 (GLP-1) act as glucose-dependent growth factors for pancreatic beta-cells. We assessed signaling pathways and stimulation patterns of PKB/Akt activation by these ligands in the beta-cell line INS-1. Insulin, IGF-1, and GLP-1 induced distinctive time dependent, dose dependent, and glucose dependent phosphorylation of PKB/Akt. Insulin and IGF-1 stimulated PI 3-K activity was mainly associated with insulin receptor substrate (IRS) isoforms IRS-1 and IRS-2 and less so with the IRS-isoform Grb-2 associated binder-1 (Gab-1). In contrast, GLP-1 induced PI 3-K activity mainly in Gab-1 and also in IRS-2 immunoprecipitates, although in an attenuated kinetic. Thus, activation pathways of PKB/Akt by insulin, IGF-1, and GLP-1 converge at the level of IRS-isoforms and PI 3-K inducing differential activation of PKB/Akt. These data indicate an essential role of PKB/Akt in regulation of beta-cell proliferation.

[Modification of the aerobic metabolism of human full skin complexes. An in vitro study]. / Zur Beeinflussbarkeit des aeroben Metabolismus humaner Vollhautkomplexe. Eine In-vitro-Studie.

The effect of increased oxygen supply on oxygen uptake of isolated human full-thickness skin grafts was investigated. Acute hyperoxic conditions led to temporary slight reductions of the cellular oxygen consumption rate, whereas pronounced longer-lasting effects could not be demonstrated. It was concluded that hyperoxic intervention is not suitable to compensate for the complex metabolic disorders arising in transplanted tissue.

[Clinico-anatomic study for constructing pedicled myocutaneous trapezius flaps]. / Klinische-anatomische Studie zur Bildung gestielter myokutaner Trapeziuslappen.

The authors investigated musculocutaneous flaps, paying particular attention to vascular anatomy, the development and length of their main vessels, their potential arc of transposition. Beyond that, their applications for soft tissue coverage in the head and neck region and procedures for coverage of the donor site were studied. When compared with the literature, the results show that pedicled musculocutaneous and osteomusculocutaneous trapezius flaps are especially suited for reconstructive surgery of the head and neck.

[Studies on the vitality of periodontal cells correlated with the duration and medium of extracorporeal storage]. / Untersuchungen zur Vitalität von Periodontalzellen in Abhängigkeit von extrakorporaler Verweildauer und Lagermedium.

Some decisive factors for the success of tooth replantation such as perfusion conditions or duration of storage were the subject of this biological/functional study. Evidence for a remaining vitality of the periodontal cells was derived from the pattern of cellular oxygen uptake. The use of pure water, dry storage, or even isotonic saline failed to prevent a decrease in aerobic metabolism within one hour. Storage of the teeth in the patient's blood or serum optimally fulfills the requirements for survival of the periodontium over up to 10 hours. Recommendations for the handling of isolated teeth before replantation are given.

[Transcutaneous pO2-measuring for the estimation of the vascularization behavior in omental vascularized and peduncled abdominal flaps. An experimental study in swine]. / Transkutane pO2-Messung zur Beurteilung des Vaskularisationsverhaltens am omental vaskularisierten und gestielten Abdominallappen. Eine experimentelle Studie am Schwein.

To evaluate the tissue vascularizing potency of omentum majus different types of pig skin flaps supplied by omentum were risen within an experimental surgical study. The reorientation process of blood flow from autochthonal epigastric to omental vessels was followed up by means of flap transcutaneous pO2 measurements. The fitness of tissue tpO2 method which results were found to be in good accordance with clinical experiences of flap surviving and healing will be discussed.

[Vascular supply of the free fasciocutaneous forearm flap--an anatomical study]. / Die Gefässversorgung des freien fasziokutanen Unterarmlappens--eine anatomische Studie.

The vascular supply of the forearm skin--especially of the ventral antebrachial region--was investigated by means of selective angiographies and intravascular dye injections in 43 upper extremities of corpses. Besides the definition of the interesting supply regions assertions were made about the kind and the character of the angioarchitecture as well as recommendations for the flap planning and other clinical references.