PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients.

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced β cell stress, and promoted β cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin.

MFng is dispensable for mouse pancreas development and function.

Notch signaling regulates pancreatic cell differentiation, and mutations of various Notch signaling components result in perturbed pancreas development. Members of the Fringe family of beta1,3-N-acetylglucosaminyltransferases, Manic Fringe (MFng), Lunatic Fringe (LFng), and Radical Fringe (RFng), modulate Notch signaling, and MFng has been suggested to regulate pancreatic endocrine cell differentiation. We have characterized the expression of the three mouse Fringe genes in the developing mouse pancreas between embryonic days 9 and 14 and show that the expression of MFng colocalized with the proendocrine transcription factor Ngn3.

A role for E2-2 at the DN3 stage of early thymopoiesis.

Roles for the E-proteins E2A and HEB during T lymphocyte development have been well established. Based on our previous observations of counter selection against T cells lacking E2-2, it seemed reasonable to assume that there would be a function also for E2-2 in thymocyte development. Aiming at assigning such a role for E2-2, we analyzed the expression of E2-2, E2A, HEB as well as Id mRNA during T cell development.

Gene array identification of Ipf1/Pdx1-/- regulated genes in pancreatic progenitor cells.

Background: The homeodomain transcription factor IPF1/PDX1 exerts a dual role in the pancreas; Ipf1/Pdx1 global null mutants fail to develop a pancreas whereas conditional inactivation of Ipf1/Pdx1 in beta-cells leads to impaired beta-cell function and diabetes. Although several putative target genes have been linked to the beta-cell function of Ipf1/Pdx1, relatively little is known with respect to genes regulated by IPF1/PDX1 in early pancreatic progenitor cells.

Results: Microarray analyses identified a total of 111 genes that were differentially expressed in e10.

Dmu expression causes enrichment of MZ B cells, but is non permissive for B cell maturation in Rag2-/- mice even if combined with Bcl-2.

Rearrangements in reading frame 2 promote the expression of a truncated heavy chain, the Dmu protein. Dmu can assemble into a pre-B cell receptor like complex that appears to induce a subset of signals elicited by full length mu, but cannot promote the pro-B to pre-B cell transition of Rag-/- B cells. In order to determine if this could stem from an impaired survival signal not properly induced by the Dmu protein, we introduced Bcl-2 into Dmu-transgenic, Rag2-/- mice.

The basic helix-loop-helix transcription factor E2-2 is involved in T lymphocyte development.

E2A, HEB and E2-2 genes encode a group of basic helix-loop-helix (bHLH) transcription factors that are structurally and functionally similar. Deletion of the genes encoding either of these proteins leads to early lethality and a block in B lymphocyte development. Evidence for a function in T lymphocyte development has, however, only been reported for E2A and HEB.

Functional expression of Cre recombinase in sub-regions of mouse CNS and retina.

We describe a strategy for generating CNS and retina sub-region-specific mutations using the Cre/loxP system. Transgenic mice expressing Cre recombinase under the control of the c-kit promoter were established. Functional Cre expression was predominantly found to be restricted to the CA1, CA2 and CA3 regions of the hippocampus, the anterior region of the dentate gyrus, and to the ganglion cell layer of the retina.

Transgenic Cre recombinase expression in germ cells and early embryogenesis directs homogeneous and ubiquitous deletion of loxP-flanked gene segments.

We report on the establishment of a transgenic mouse line expressing Cre recombinase under control of the c-kit promoter. Expression of Cre recombinase was only observed in late spermatogenesis and oogenesis, however, Cre-mediated deletion of floxed gene segments occurred at this stage as well as in early embryogenesis. As a consequence of this, a chimeric distribution of loxed alleles was found in a large fraction of these mice.

Regulation of B lymphocyte development by the truncated immunoglobulin heavy chain protein Dmu.

The development of B lymphocytes from progenitor cells is dependent on the expression of a pre-B cell-specific receptor made up by a mu heavy chain associated with the surrogate light chains, immunoglobulin (Ig)alpha, and Igbeta. A variant pre-B cell receptor can be formed in which the mu heavy chain is exchanged for a truncated mu chain denoted Dmu. To investigate the role of this receptor in the development of B cells, we have generated transgenic mice that express the Dmu protein in cells of the B lineage.

Induction of diabetes in NOD<-->C57BL/6 embryo aggregation chimeras by cyclophosphamide through preferential depletion of C57BL/6 lymphocytes.

The majority of embryo aggregation (EA) mouse chimeras between non-obese diabetic (NOD) mice and C57BL/6 (B6) mice show clear signs of insulitis frequently accompanied by beta-cell destruction. Less than 5% of these chimeras, however, spontaneously progress to autoimmune diabetes, an incidence far lower than observed in NOD mice. The resistance in chimeras can be accounted for by the target organ chimerism and/or the immune system chimerism.

Establishment and characterization of RAG-2 deficient non-obese diabetic mice.

The authors have established a new immunodeficient mouse strain on the genetic background of the diabetes prone non-obese diabetic (NOD) mouse. A deletion mutant of the RAG-2 gene was back crossed 10 generations onto the NOD/Bom strain background. The homozygous NODrag-2-/- mice lack functionally mature B and T lymphocytes and do not develop insulitis or diabetes throughout life.

Specific destruction of islet transplants in NOD<-->C57BL/6 and NOD<-->C3H/Tif embryo aggregation chimeras irrespective of allelic differences in beta-cell antigens.

We have tested the hypothesis that allelic differences in the antigens expressed by the beta-cells of the islets of Langerhans influence the development of insulitis in the non-obese diabetic (NOD) mouse. Islets of Langerhans from NOD, C57BL/6 and C3H/Tif mice were transplanted under the kidney capsule of NOD<-->C57BL/6 and NOD<-->C3H/Tif embryo aggregation (EA) chimeras and the infiltration was scored 5-7 weeks later. Mononuclear cell infiltration of pancreatic islets was observed in 60% of the NOD<-->C57BL/6 and in 55% of the NOD<-->C3H/Tif EA chimeras.

Hormonal regulation of endometriosis and the rationales and effects of gonadotrophin-releasing hormone agonist treatment: a review.

The knowledge about the role of oestrogen in the regulation of endometriosis growth and symptoms has been reviewed. Studies on oestrogen and progesterone metabolism and receptivity in endometriotic tissue and the impact on growth regulation and clinical symptoms of steroidal hormones are discussed. These include tissue sample assays, ex-vivo tissue culturing as well as clinical studies concerning the effect of different hormonal treatment.