transforming-growth-factor-beta and Glucose-Intolerance

M-LP/Mpv17L is a protein that was initially identified during screening of age-dependently expressed genes in mice. We have recently demonstrated that M-LP/Mpv17L-knockout (M-LP/Mpv17L-KO) in human hepatoma cells leads to a reduction of cellular cyclic nucleotide phosphodiesterase (PDE) activity, and that in vitro-synthesized M-LP/Mpv17L possesses PDE activity. These findings suggest that M-LP/Mpv17L functions as an atypical PDE, even though it has none of the well-conserved catalytic region or other structural motifs characteristic of the PDE family. In this study, we found that M-LP/Mpv17L-KO mice developed β-cell hyperplasia and improved glucose tolerance. Deficiency of M-LP/Mpv17L in islets from KO mice at early postnatal stages or siRNA-mediated suppression of M-LP/Mpv17L in rat insulinoma cells led to marked upregulation of lymphoid enhancer binding factor 1 (Lef1) and transcription factor 7 (Tcf7), key nuclear effectors in the Wnt signaling pathway, and some of the factors essential for the development and maintenance of β-cells. Moreover, at the protein level, increases in the levels of phosphorylated β-catenin and glycogen synthase kinase-3β (GSK-3β) were observed, indicating activation of the Wnt and TGF-β signaling pathways. Taken together, these findings suggest that protein kinase A (PKA)-dependent phosphorylations of β-catenin and GSK-3β, the key mediators of the Wnt and/or TGF-β signaling pathways, are the most upstream events triggering β-cell hyperplasia and improved glucose tolerance caused by M-LP/Mpv17L deficiency.

Topics: Animals; Cell Proliferation; Glucose Intolerance; Hyperplasia; Insulin-Secreting Cells; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Transforming Growth Factor beta; Wnt Signaling Pathway

Anti-inflammatory cytokines act as double edged swords- they can dampen inflammation but can also suppress immunity. The role played by these cytokines in latent TB infected (LTBI) subjects, with various grades of glucose intolerance was studied. Both serum levels and recall-secretion of IL-27, IL-10, IL-1Ra and TGF-β in Normal Glucose Tolerance (NGT), Pre-Diabetes (PDM), Newly diagnosed Diabetes (NDM) and Known Diabetes (KDM) subjects, both with and without LTBI (n = 382), were quantified by ELISA. All the subjects were screened for LTBI by QuantiFERON-TB Gold test. Serum levels of IL-27, IL-10 and IL-1Ra were significantly elevated in the LTB

Topics: Adult; Cholesterol; Cytokines; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Glucose Intolerance; Humans; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-27; Latent Tuberculosis; Middle Aged; Reproducibility of Results; Sensitivity and Specificity; Transforming Growth Factor beta

Accumulating evidence suggests that both an adverse prenatal and early postnatal environment increase susceptibility to renal and metabolic dysfunction later in life; however, whether exposure to adverse conditions during both prenatal and postnatal development act synergistically to potentiate the severity of renal and metabolic injury remains unknown. Sprague-Dawley rats were fed either a standard diet or a diet high in fat/fructose throughout pregnancy and lactation. After being weaned, female offspring were randomized to either standard diet or the high-fat/high-fructose diet, resulting in the following treatment groups: NF-NF, offspring of mothers fed a standard diet and fed a standard diet postnatally; NF-HF, offspring of mothers fed a standard diet and fed a high-fat/fructose diet postnatally; HF-NF, offspring of mothers fed a high-fat/fructose diet and fed a standard diet postnatally; HF-HF, offspring of mothers fed a high-fat/fructose diet and fed a high-fat/fructose diet postnatally. At the time of euthanasia (17 wk of age), HF-HF offspring weighed 30% more and had 110% more visceral fat than NF-NF offspring. The HF-HF offspring also had elevated blood glucose levels, glucose intolerance, 286% increase in urine albumin excretion, and 60% increase in glomerulosclerosis compared with NF-NF. In addition, HF-HF offspring exhibited a 100% increase in transforming growth factor-β protein expression and 116% increase in the abundance of infiltrated macrophages compared with the NF-NF offspring. These observations suggest that high-fat/fructose feeding during prenatal and throughout postnatal life increases the susceptibility to renal and metabolic injury later in life.

Topics: Albuminuria; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Disease Susceptibility; Female; Fructose; Glomerulonephritis; Glucose Intolerance; Intra-Abdominal Fat; Macrophages; Metabolic Diseases; Obesity; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

Loss of thrombospondin (TSP)-1 in pancreatic islets has been shown to cause islet hyperplasia. This study tested the hypothesis that endothelial-derived TSP-1 is important for β-cell function.. Islet function was evaluated both in vivo and in vitro. Messenger RNA and protein expression were measured by real-time PCR and Western blot, respectively. The role of endothelial-derived TSP-1 for β-cell function was determined using a transplantation design in which recipient blood vessels either were allowed to grow or not into the transplanted islets.. TSP-1-deficient mice were glucose intolerant, despite having an increased β-cell mass. Moreover, their islets had decreased glucose-stimulated insulin release, (pro)insulin biosynthesis, and glucose oxidation rate, as well as increased expression of uncoupling protein-2 and lactate dehydrogenase-A when compared with control islets. Almost all TSP-1 in normal islets were found to be derived from the endothelium. Transplantation of free and encapsulated neonatal wild-type and TSP-1-deficient islets was performed in order to selectively reconstitute with TSP-1-positive or -negative blood vessels in the islets and supported that the β-cell defects occurring in TSP-1-deficient islets reflected postnatal loss of the glycoprotein in the islet endothelial cells. Treatment of neonatal TSP-1-deficient mice with the transforming growth factor (TGF)β-1-activating sequence of TSP-1 showed that reconstitution of TGFβ-1 activation prevented the development of decreased glucose tolerance in these mice. Thus, endothelial-derived TSP-1 activates islet TGFβ-1 of importance for β-cells.. Our study indicates a novel role for endothelial cells as functional paracrine support for pancreatic β-cells.

Topics: Animals; Endothelial Cells; Extracellular Matrix Proteins; Glucose Intolerance; Insulin-Secreting Cells; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Thrombospondin 1; Transforming Growth Factor beta