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- Author: Michaël Thomas x
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Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
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Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
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Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
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Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
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Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique, Université Joseph Fourier, Unité 878, Grenoble, France
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Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its homolog Bombina variegata (Bv8), also termed prokineticin-1 and -2 (PK1 and PK2) respectively, are newly identified peptides with specific mitogenic activity on endocrine gland-derived endothelial cells. In the present study, we analyzed the sites of expression of EG-VEGF/PK1, Bv8/PK2, and their receptors (PKR1 and PKR2) in the adrenal cortex and checked for new biological functions of these factors on the endocrine cell compartment. RT-PCR and immunostaining analyses revealed that glomerulosa and fasciculata cells express both factors and both receptors. EG-VEGF/PK1 had no effect on the steroidogenic activity of both bovine glomerulosa and fasciculata cells but appeared to be mitogenic for both cell types. Binding of EG-VEGF/PK1 to fasciculata cells stimulated the phosphorylation of ERK1/2. Pretreatment with pertussis toxin suppressed this effect, indicating that it was Gi mediated. EG-VEGF/PK1 also increased the phosphorylation of Akt in endocrine cells of the adrenal cortex. EG-VEGF/PK1 and Bv8/PK2 thus represent new regulatory peptides acting as autocrine mitogens for endocrine cells.
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Recent data indicate that dipeptidyl peptidase 4 (DPP4) inhibitors have anti-inflammatory and β-cell-sparing effects in animal models of type 1 diabetes. To evaluate the effects of the DPP4 inhibitor linagliptin on β-cell mass and insulinitis, we examined the progression of diabetes (blood glucose >11 mmol/l) in non-obese diabetic (NOD) mice with terminal stereological assessment of cellular pancreatic changes. Female NOD mice were fed a normal chow diet or a diet containing linagliptin 0.083 g/kg chow for 60 days. At study end, the incidence of diabetes in linagliptin-treated mice was reduced by almost 50% compared with vehicle (10 of 31 mice vs 18 of 30 mice, P=0.021). The total islet mass and total β-cell mass, identified by insulin immunoreactivity, were greater in non-diabetic linagliptin-treated mice compared with non-diabetic vehicle-treated mice (P<0.01 for both) but were greatly reduced in diabetic mice irrespective of treatment. No changes were seen in the α, δ and γ endocrine cell pool. Moreover, the total mass of lymphocyte insulinitis was significantly reduced in linagliptin-treated mice compared with vehicle. The data indicate that linagliptin treatment delays the onset of diabetes in NOD mice by protecting β-cell mass.
Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Rather than a traditional growth factor, fibroblast growth factor-21 (FGF21) is considered to be a metabolic hormone. In the current study, we investigated serum FGF21 levels in the self-contained population of Sorbs. Serum FGF21 concentrations were quantified by ELISA and correlated with IGF1 as well as metabolic, renal, hepatic, inflammatory, and cardiovascular parameters in 913 Sorbs from Germany. Moreover, human IGF1 protein secretion was investigated in FGF21-stimulated HepG2 cells. Median FGF21 serum concentrations were 2.1-fold higher in subjects with type 2 diabetes mellitus (141.8 ng/l) compared with controls (66.7 ng/l). Furthermore, nondiabetic subjects with FGF21 levels below the detection limit of the ELISA showed a more beneficial metabolic profile compared with subjects with measurable FGF21. Moreover, FGF21 was significantly lower in female compared with male subjects after adjustment for age and BMI. In multiple regression analyses, circulating FGF21 concentrations remained independently and positively associated with gender, systolic blood pressure, triglycerides, and γ glutamyl transferase whereas a negative association was observed with IGF1 in nondiabetic subjects. Notably, FGF21 significantly inhibited IGF1 secretion into HepG2 cell culture supernatants in preliminary in vitro experiments. FGF21 serum concentrations are associated with facets of the metabolic syndrome, hepatocellular function, as well as GH status.
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Influence of human parathyroid hormone (hPTH 1–34) on muscle and bone healing was studied in either orchiectomized (Orx at 8 months of age) or sham-operated male rats. Eleven-month-old Sprague–Dawley rats underwent bilateral transverse metaphyseal osteotomy of tibia and were divided into four groups (n=12): 1) sham-vehicle, 2) sham group-PTH everyday, 3) Orx-vehicle, 4) Orx-PTH everyday, and 5) Orx-PTH every other day. PTH dosage was 40 μg/kg body weight. After 5 weeks, fiber cross-sectional area, capillary density, and enzyme activity (lactate dehydrogenase, citrate synthase, and complex I) were measured in soleus (MS), gastrocnemius (MG), and longissimus (ML) muscles; tibiae were analyzed by computed tomographical, histological, and gene expression analyses. The effect of PTH in all rats was increased serum osteocalcin, cortical and callus densities and callus area. In sham rats capillary density was increased in limb muscles (MS: 1.3–1.7, MG: 1.2–1.4 capillaries/fiber), and rate of osseous bridging of osteotomy was enhanced (67–100%). In Orx rats serum creatine kinase was decreased (6670–2847 U/l), and bone genes (Igf-1, osteoprotegerin, and receptor activator of nuclear factor kB ligand) were up-regulated. Cross-sectional area, enzyme activity, food intake, weight of body, visceral organs, adipose tissue, MG, and MS were not affected by PTH. PTH had a favorable effect on muscle capillary density and improved bone healing being more effective in sham rats and having no adverse systemic effect. The effect was less if PTH was applied every other day. The findings may show up trends for therapeutic treatment of male patients.
Chemical Biology and Therapeutics Program, Broad Institute of Harvard and MIT, Boston, Massachusetts, USA
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Department of Food Science, University of Copenhagen, Copenhagen, Denmark
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In addition to degrading misfolded and damaged proteins, the proteasome regulates the fate of cells in response to stress. The role of the proteasome in pro-inflammatory cytokine-induced human beta-cell apoptosis is unknown. Using INS-1, INS-1E and human islets exposed to combinations of IFNγ, IL-1β and TNFα with or without addition of small molecules, we assessed the role of the immunoproteasome in pancreatic beta-cell demise. Here, we show that cytokines induce the expression and activity of the immuno-proteasome in INS-1E cells and human islets. Cytokine-induced expression of immuno-proteasome subunits, but not activity, depended upon histone deacetylase 3 activation. Inhibition of JAK1/STAT1 signaling did not affect proteasomal activity. Inhibition of the immuno-proteasome subunit PSMB8 aggravated cytokine-induced human beta-cell apoptosis while reducing intracellular levels of oxidized proteins in INS-1 cells. While cytokines increased total cellular NFκB subunit P50 and P52 levels and reduced the cytosolic NFκB subunit P65 and IκB levels, these effects were unaffected by PSMB8 inhibition. We conclude that beta cells upregulate immuno-proteasome expression and activity in response to IFNγ, likely as a protective response to confine inflammatory signaling.
Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA
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Skeletal Biology Laboratory, Center for Healthy Aging Research, Department of Neuroscience, Biostatistics, Department of Physiological Sciences, Department of Large Animal Clinical Sciences, Maine Medical Center Research Institute, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331, USA
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Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9 months old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin, n=7) or a control vector encoding green fluorescent protein (rAAV-GFP, n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (−4±2%) while rAAV-GFP-treated rats gained weight (14±2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight (−80%), serum leptin (−77%), and serum IGF1 (−34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (P<0.1) in rAAV-GFP-treated rats (13.5 months old) compared to baseline control rats (9 months old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover.
Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9–39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.
