Query: ivan achel valdez

title: Insulin Resistance is Mechanistically Linked to Hepatic Mitochondrial Remodeling in Nonalcoholic Fatty Liver Disease.
abstract: Insulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non alcoholic fatty liver disease (NAFLD) but the etiological role of these processes in disease progression remains unclear.  We investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation in a rodent model of T2D/NAFLD.  Livers from obese, insulin resistant mice displayed augmented mitochondrial content and increased TCA cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with the thiazolidinedione pioglitazone mitigated pyruvate driven TCA cycle activity and PDH activation via both allosteric (intracellular pyruvate availability) and covalent (PDK4 and PDP2) mechanisms that were dependent on PPARg activity in isolated primary hepatocytes. Improved mitochondrial function following pioglitazone treatment was entirely dissociated from changes in hepatic triglycerides, diacylglycerides or fatty acids. Instead, we highlight a role for the mitochondrial phospholipid cardiolipin, which underwent pathological remodeling in livers from obese mice that was reversed by insulin sensitization.  Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity associated disease.

title: Effect of Mild Physiologic Hyperglycemia on Insulin Secretion, Insulin Clearance and Insulin Sensitivity in Healthy Glucose Tolerant Subjects.
abstract: The aim of the present study was to evaluate the effect of sustained physiologic increase ~50 mg/dl in plasma glucose concentration on insulin secretion in normal glucose tolerant (NGT) subjects. Twelve NGT subjects without family history of T2DM (FH and 8 NGT with family history of T2DM (FH+ received OGTT and 2 step hyperglycemic clamp +100 and +300 mg/dl) followed by IV arginine bolus before and after 72 hour glucose infusion. Fasting plasma glucose (FPG) increased from 94+ 2 to 142+ 4 mg/dl for 72 hours. First phase insulin secretion (0 10 min) increased by 70% while second phase insulin secretion during the 1st (10 80 min) and 2nd (90 160 min) hyperglycemic clamp steps increased by 3.8 fold and 1.9 fold, respectively, following 72 hours of physiologic hyperglycemia. Insulin sensitivity (M/I during hyperglycemic clamp) declined by ~30% and ~55% (both p<0.05) respectively, during the first and second hyperglycemic clamp steps. Insulin secretion/insulin resistance (disposition) index declined by 60% (2nd clamp step) and by 62% following arginine (both p<0.005) following 72 hour glucose infusion. The effect of 72 hour glucose infusion on insulin secretion and insulin sensitivity was similar in subjects with and without FH of T2DM. Following 72 hours of physiologic hyperglycemia, metabolic clearance rate of insulin was markedly reduced (p<0.01) These results demonstrate that sustained physiologic hyperglycemia for 72 hours: (i) increases absolute insulin secretion but impairs beta cell function; (ii) causes insulin resistance; (iii) reduces MCR of insulin.

title: Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3 Dependent NGN3 Activation.
abstract: A major goal of diabetes research is to develop strategies that replenish pancreatic insulin producing beta cells. One emerging strategy is to harness pancreatic plasticity the ability of pancreatic cells to undergo cellular interconversions a phenomenon implicated in physiological stress and pancreatic injury. Here, we investigate the effects of inflammatory cytokine stress on the differentiation potential of ductal cells in a human cell line, in mouse ductal cells by pancreatic intraductal injection, and during the progression of autoimmune diabetes in the non obese diabetic (NOD) mouse model. We find that inflammatory cytokine insults stimulate epithelial to mesenchymal transition (EMT) as well as the endocrine program in human pancreatic ductal cells via STAT3 dependent NGN3 activation. Furthermore, we show that inflammatory cytokines activate ductal to endocrine cell reprogramming in vivo independent of hyperglycemic stress. Together, our findings provide evidence that inflammatory cytokines direct ductal to endocrine cell differentiation, with implications for beta cell regeneration.

title: Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia
abstract: Patients with an HNF1BS148L/ mutation (MODY5) typically exhibit pancreatic hypoplasia. However, the molecular mechanisms are unknown due to inaccessibility of patient material and because mouse models do not fully recapitulate MODY5. Here, we differentiated MODY5 human induced pluripotent stem cells (hiPSCs) into pancreatic progenitors, and show that the HNF1BS148L/ mutation causes a compensatory increase in several pancreatic transcription factors, and surprisingly, a decrease in PAX6 pancreatic gene expression. The lack of suppression of PDX1, PTF1A, GATA4, and GATA6 indicates that MODY5 mediated pancreatic hypoplasia is mechanistically independent. Overexpression studies demonstrate that a compensatory increase in PDX1 gene expression is due to mutant HNF1BS148L/ but not wild type HNF1B or HNF1A. Furthermore, HNF1B does not appear to directly regulate PAX6 gene expression necessary for glucose tolerance. Our results demonstrate compensatory mechanisms in the pancreatic transcription factor network due to mutant HNF1BS148L/ protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia.

title: Dynamic proteome profiling of human pluripotent stem cell derived pancreatic progenitors
abstract: A comprehensive characterization of the molecular processes controlling cell fate decisions is essential to derive stable progenitors and terminally differentiated cells that are functional from human pluripotent stem cells (hPSCs) Here, we report the use of quantitative proteomics to describe early proteome adaptations during hPSC differentiation toward pancreatic progenitors. We report that the use of unbiased quantitative proteomics allows the simultaneous profiling of numerous proteins at multiple time points, and is a valuable tool to guide the discovery of signaling events and molecular signatures underlying cellular differentiation. We also monitored the activity level of pathways whose roles are pivotal in the early pancreas differentiation, including the Hippo signaling pathway. The quantitative proteomics data set provides insights into the dynamics of the global proteome during the transition of hPSCs from a pluripotent state toward pancreatic differentiation.

title: Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long Standing Type 1 Diabetes.
abstract: The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration 50 years) with severe (Medalist +C) or absent to mild complications (Medalist C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. We propose miR200 regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.

title: Comparable Generation of Activin Induced Definitive Endoderm via Additive Wnt or BMP Signaling in Absence of Serum
abstract: There is considerable interest in differentiating human pluripotent stem cells (hPSCs) into definitive endoderm (DE) and pancreatic cells for in vitro disease modeling and cell replacement therapy. Numerous protocols use fetal bovine serum, which contains poorly defined factors to induce DE formation. Here, we compared Wnt and BMP in their ability to cooperate with Activin signaling to promote DE formation in a chemically defined medium. Varying concentrations of WNT3A, glycogen synthase kinase (GSK) 3 inhibitors CHIR99021 and 6 bromoindirubin 3' oxime (BIO) and BMP4 could independently co operate with Activin to effectively induce DE formation even in the absence of serum. Overall, CHIR99021 is favored due to its cost effectiveness. Surprisingly, WNT3A was ineffective in suppressing E CADHERIN/CDH1 and pluripotency factor gene expression unlike GSK 3 inhibitors or BMP4. Our findings indicate that both Wnt and BMP effectively synergize with Activin signaling to generate DE from hPSCs, although WNT3A requires additional factors to suppress the pluripotency program inherent in hPSCs.

title: Insulin receptor mediated signaling regulates pluripotency markers and lineage differentiation
abstract: Insulin receptor (IR) mediated signaling is involved in the regulation of pluripotent stem cells; however, its direct effects on regulating the maintenance of pluripotency and lineage development are not fully understood. The main objective of this study is to understand the role of IR signaling in pluripotency and lineage development.  To explore the role of IR signaling, we generated IR knock out (IRKO) mouse induced pluripotent stem cells (miPSCs) from E14.5 mouse embryonic fibroblasts (MEFs) of global IRKO mice using a cocktail of four reprogramming factors: Oct4, Sox2, Klf4, cMyc. We performed pluripotency characterization and directed the differentiation of control and IRKO iPSCs into neural progenitors (ectoderm) adipocyte progenitors (mesoderm) and pancreatic beta like cells (endoderm) We mechanistically confirmed these findings via phosphoproteomics analyses of control and IRKO iPSCs.  Interestingly, expression of pluripotency markers including Klf4, Lin28a, Tbx3, and cMyc were upregulated, while abundance of Oct4 and Nanog were enhanced by 4 fold and 3 fold, respectively, in IRKO iPSCs. Analyses of signaling pathways demonstrated downregulation of phospho STAT3, p mTor and p Erk and an increase in the total mTor and Erk proteins in IRKO iPSCs in the basal unstimulated state. Stimulation with leukemia inhibitory factor (LIF) showed a ~33% decrease of phospho ERK in IRKO iPSCs. On the contrary, Erk phosphorylation was increased during in vitro spontaneous differentiation of iPSCs lacking IRs. Lineage specific directed differentiation of the iPSCs revealed that cells lacking IR showed enhanced expression of neuronal lineage markers (Pax6, Tubb3, Ascl1 and Oligo2) while exhibiting a decrease in adipocyte (Fas, Acc, Pparg, Fabp4, C/ebpa, and Fsp27) and pancreatic beta cell markers (Ngn3, Isl1, and Sox9) Further molecular characterization by phosphoproteomics confirmed the novel IR mediated regulation of the global pluripotency network including several key proteins involved in diverse aspects of growth and embryonic development.  We report, for the first time to our knowledge, the phosphoproteome of insulin, IGF1, and LIF stimulation in mouse iPSCs to reveal the importance of insulin receptor signaling for the maintenance of pluripotency and lineage determination.

title: Cellular stress drives pancreatic plasticity
abstract: Physiological and nonphysiological stress induces intrapancreatic cell to cell conversion. Controversy has long surrounded research on pancreatic beta cell regeneration. Some groups have used nonphysiological experimental methodologies to build support for the existence of pancreatic progenitor cells within the adult pancreas that constantly replenish the beta cell pool; others argue strongly against this mode of regeneration. Recent research has reinvigorated enthusiasm for the harnessing of pancreatic plasticity for therapeutic application for example, the transdifferentiation of human pancreatic exocrine cells into insulin secreting beta like cells in vitro; the conversion of mouse pancreatic acinar cells to beta like cells in vivo via cytokine treatment; and the potential redifferentiation of dedifferentiated mouse beta cells in vivo. Here, we highlight key findings in this provocative field and provide a perspective on possible exploitation of human pancreatic plasticity for therapeutic beta cell regeneration.

title: Ivan Valdez Bubnov, Poder naval y modernizacion del Estado politica de construccion naval espanola
abstract: Resulta paradojico que disponiendo la Espana de la edad moderna de un sistema naval poderoso (si exceptuamos la segunda mitad del siglo xvii) y disfrutando de una innegable tradicion naval, sean tan pocos los estudios de conjunto contemporaneos sobre uno de los mas decisivos aspectos de la politica imperial hispana. No hay que olvidar que la esencia del poderio espanol entre los siglos xvi y xviii se baso en el control oceanico del Atlantico, y que sus buques y marinos supieron hacer frente con exito tangible a los ataques coordinados de las principales potencias europeas. El libro del profesor Valdez Bobnov, destacado especialista en historia naval adscrito a la Universidad Nacional Autonoma de Mexico, trata, en una notable investigacion, de soslayar tan inexplicable vacio.