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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current increase in the incidence of diabetes mellitus complicating pregnancy is of concern since it is associated with an increase in mortality and morbidity of the fetus and neonate. Pregnancy itself is diabetogenic caused by increased insulin resistance due to the production of hormones like estrogen, progesterone, cortisol, human chorionic somatomammotropin (hCS) and human placental lactogen (hPL). The latter increases lypolysis which provides free fatty acids and ketones as fuels for energy for the pregnant mother. This spares maternal blood glucose, amino acids and ketones which cross the placenta to the fetus. The influx of nutrients increases fetal insulin production which together with hPL induce somatogenesis. Maternal hyperglycemia and fetal hypoxemia are shown to be responsible for structural congenital anomalies of the rapidly developing organs of the fetus during the early weeks of gestation while continuing hyperglycemia and hypoxemia in the second and third trimester are factors related to the production of macrosomia, including cardiomyopathy, delay in lung maturation, and polycythemia. Metabolic problems such as hypoglycemia, hypocalcemia, hypomagnesemia and hyperbilirubinemia are common neonatal morbidities. Follow-up of the infants of diabetic mothers indicates that these infants have a 20 fold increase in acquiring diabetes. Early identification of maternal diabetes with strict metabolic control prior to conception as well as throughout pregnancy together with careful fetal monitoring can reduce the incidence of congenital anomalies and morbidities in the fetus and neonate.
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PMID:Infant of diabetic mother: a continuing challenge for perinatal-neonatal medicine. 894 23

Previous studies comparing the expression levels of human placental lactogen (hPL) genes have shown varying results, due to, perhaps, the fact that in all of them only one placenta was being analyzed. Here, the expression of hPL and growth hormone variant (hGH-V) genes in fifteen term placentas was comparatively analyzed at the RNA level, using reverse transcription coupled to polymerase chain reaction (RT-PCR). The abundance of the combined RNA transcripts derived from these genes varied from one placenta to another. The authors found that hPL-4 transcripts were more abundant than those of hPL-3 in most samples (ratios from 1:1 to 6:1), transcripts from the putative hPL-1 pseudogene were more abundant at the unprocessed stage while those of the hGH-V gene were mostly processed. Again, the authors of this study observed wide variation from placenta to placenta in the abundance of both of these types of transcripts. The same was observed when a group of six placentas from abortuses and nine from pregnancies complicated by preclampsia, diabetes and hypertension was studied. The authors conclude that the disagreeing results reported in the literature which are not in agreement concerning the expression levels of hPL genes could be explained by normal variations of their expression levels among the different placentas analyzed.
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PMID:Expression of human placental lactogen and variant growth hormone genes in placentas. 942 74

The recent demonstration of ectopic production of human placental lactogen (PL) in the human testis and ovary prompted us to reassess its role under non-pregnant physiological and pathological conditions. Possible physiological hPL concentrations and potential age-related changes in the sera of healthy young and elderly individuals (n = 75) selected according to the SENIEUR-protocol were investigated by a highly sensitive (detection limit: 2 pg/ml) and specific (cross-reactivity with prolactin and human growth hormone (hGH) of less than 0.001% and 0.0001%, respectively) monoclonal antibody-based time-resolved fluoroimmunoassay (IFMA) established in our laboratory. All individuals, even the aged probands (mean age: 72 +/- 3a), had hPL-levels below 20 pg/ml, in contrast to glycoprotein hormones, such as luteinizing hormone or human chorionic gonadotropin (hCG). To determine the significance of hPL as a tumour marker, serum samples of 12 testicular cancer patients with highly elevated levels of holo-hCG (mean: 42.490 ng/ml) at diagnosis were followed over 6-12 months and analysed with the hPL-IFMA. Elevation of hPL was seen in 10 patients, but the respective levels were 2-3 orders of magnitude smaller than those of holo-hCG and returned earlier to undetectable values. These in vivo data were compared to the hPL secretion pattern of the choriocarcinoma cell lines JAR and BeWo in vitro. In tissue culture supernatants of the two cell lines hPL was detected only in JAR cells, whereas both cell lines secreted holo-hCG. In conclusion, the fact that hPL is not physiologically present in peripheral blood but is produced ectopically in the human testis and ovary suggest auto/paracrine functions of this molecule. The significance of hPL as a tumour marker for patients with testicular cancer is limited as it provides no additional information to holo-hCG.
Exp Clin Endocrinol Diabetes 1998
PMID:Reassessment of the role of human placental lactogen in physiological non-pregnant and pathological conditions. 951 62

A significant amount of information regarding the pathogenesis of gestational diabetes mellitus (GDM) has been gathered since the Third Workshop-Conference on GDM. In spite of this, it is still not known why GDM develops in 2-3% of all pregnant women. Similar frequencies of HLA-DR2, DR3, and DR4 antigens in healthy pregnant women and women with GDM and low prevalences of markers for autoimmune destruction of the beta-cells in GDM pregnancy rule out the possibility that GDM is a disease of autoimmune origin. Insulin secretion during an oral glucose tolerance test (OGTT) or a meal is substantially increased in women with GDM compared with the same women postpartum. However, insulin secretion increases less in women with GDM than in pregnant women who retain normal glucose tolerance (NGT). Peak insulin concentrations during an OGTT occur later in women with GDM, and following intravenous glucose, a reduced first-phase insulin response is also seen in these women. Second-phase insulin responses are similar in pregnant women with NGT and GDM. Excessive secretion of proinsulin, which does not always return to normal postpartum, is often observed in women with GDM. It is conceivable that this might reflect a stress on the beta-cells and that the beta-cells are stressed because they try to counter the decreased insulin sensitivity that develops during pregnancy. Thus, insulin sensitivity decreases by 50-70% in both normal and GDM pregnancy, but whereas insulin sensitivity returns to normal postpartum in pregnant women with NGT, this is not always the case in GDM. Insulin receptor binding to target tissues is largely unaffected by normal and GDM pregnancy; the same is true for basal and insulin-stimulated insulin receptor-bound tyrosine kinase activity. There is indication that certain post-insulin-insulin receptor binding events are altered in tissues from women with GDM. However, data are still scarce, and more studies are needed before the intracellular events leading to a decreased insulin sensitivity have been resolved. Hormones that circulate in high concentrations in pregnancy (e.g., progesterone, cortisol, prolactin, human placental lactogen, and estrogen) have all been shown, in animal models, to be able to influence beta-cell function and/or the peripheral tissue sensitivity to insulin, but whether they play similar roles in human pregnancy remains to be investigated.
Diabetes Care 1998 Aug
PMID:Etiology and pathogenesis of gestational diabetes. 970 23

Formation of new beta cells can take place by two pathways: replication of already differentiated beta cells or neogenesis from putative islet stem cells. Under physiological conditions both processes are most pronounced during the fetal and neonatal development of the pancreas. In adulthood little increase in the beta cell number seems to occur. In pregnancy, however, a marked hyperplasia of the beta cells is observed both in rodents and man. Increased mitotic activity has been seen both in vivo and in vitro in islets exposed to placental lactogen (PL), prolactin (PRL) and growth hormone (GH). Receptors for both GH and PRL are expressed in islet cells and are upregulated during pregnancy. By mutational analysis we have identified different functional domains of the cytoplasmic part of the GH receptor. Thus the mitotic signaling only requires the membrane proximal part of the receptor and activation of the tyrosine kinase JAK2 and the transcription factors STAT1 and 3. The activation of the insulin gene however also requires the distal part of the receptor and activation of calcium uptake and STAT5. In order to identify putative autocrine growth factors or targets for growth factors we have cloned a novel GH/PRL stimulated rat islet gene product, Pref-1 (preadipocyte factor-1). This protein contains six EGF-like motifs and may play a role both in embryonic pancreas differentiation and in beta cell growth and function. In summary, the increasing knowledge about the mechanisms involved in beta cell differentiation and proliferation may lead to new ways of forming beta cells for treatment of diabetes in man.
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PMID:Beta cell proliferation and growth factors. 993 Sep 29

Recent advances in human islet transplantation have highlighted the need for expanding the pool of beta-cells available for transplantation. We have developed three transgenic models in which growth factors (hepatocyte growth factor [HGF], placental lactogen, or parathyroid hormone-related protein) have been targeted to the beta-cell using rat insulin promoter (RIP). Each displays an increase in islet size and islet number, and each displays insulin-mediated hypoglycemia. Of these three models, the RIP-HGF mouse displays the least impressive phenotype under basal conditions. In this study, we show that this mild basal phenotype is misleading and that RIP-HGF mice have a unique and salutary phenotype. Compared with normal islets, RIP-HGF islets contain more insulin per beta-cell (50 +/- 5 vs. 78 +/- 9 ng/islet equivalent [IE] in normal vs. RIP-HGF islets, P < 0.025), secrete more insulin in response to glucose in vivo (0.66 +/- 0.06 vs. 0.91 +/- 0.10 ng/ml in normal vs. RIP-HGF mice, P < 0.05) and in vitro (at 22.2 mmol/l glucose: 640 +/- 120.1 vs. 1,615 +/- 196.9 pg. microg protein(-1). 30 min(-1) in normal vs. RIP-HGF islets, P < 0.01), have two- to threefold higher GLUT2 and glucokinase steady-state mRNA levels, take up and metabolize glucose more effectively, and most importantly, function at least twice as effectively after transplantation. These findings indicate that HGF has surprisingly positive effects on beta-cell mitogenesis, glucose sensing, beta-cell markers of differentiation, and transplant survival. It appears to have a unique and unanticipated effective profile as an islet mass- and function-enhancing agent in vivo.
Diabetes 2001 Dec
PMID:Transgenic overexpression of hepatocyte growth factor in the beta-cell markedly improves islet function and islet transplant outcomes in mice. 1172 58

Historically, insulin resistance during pregnancy has been ascribed to increased production of placental hormones and cortisol. The purpose of this study was to test this hypothesis by correlating the longitudinal changes in insulin sensitivity during pregnancy with changes in placental hormones, cortisol, leptin, and tumor necrosis factor (TNF)-alpha. Insulin resistance was assessed in 15 women (5 with gestational diabetes mellitus [GDM] and 10 with normal glucose tolerance) using the euglycemic-hyperinsulinemic clamp procedure, before pregnancy (pregravid) and during early (12-14 weeks) and late (34-36 weeks) gestation. Body composition, plasma TNF-alpha, leptin, cortisol, and reproductive hormones (human chorionic gonadotropin, estradiol, progesterone, human placental lactogen, and prolactin) were measured in conjunction with the clamps. Placental TNF-alpha was measured in vitro using dually perfused human placental cotyledon from five additional subjects. Compared with pregravid, insulin resistance was evident during late pregnancy in all women (12.4 +/- 1.2 vs. 8.1 +/- 0.8 10(-2) mg. kg(-1) fat-free mass. min(-1). microU(-1). ml(-1)). TNF-alpha, leptin, cortisol, all reproductive hormones, and fat mass were increased in late pregnancy (P < 0.001). In vitro, most of the placental TNF-alpha (94%) was released into the maternal circulation; 6% was released to the fetal side. During late pregnancy, TNF-alpha was inversely correlated with insulin sensitivity (r = -0.69, P < 0.006). Furthermore, among all of the hormonal changes measured in this study, the change in TNF-alpha from pregravid to late pregnancy was the only significant predictor of the change in insulin sensitivity (r = -0.60, P < 0.02). The placental reproductive hormones and cortisol did not correlate with insulin sensitivity in late pregnancy. Multivariate stepwise regression analysis revealed that TNF-alpha was the most significant independent predictor of insulin sensitivity (r = -0.67, P < 0.0001), even after adjustment for fat mass by covariance (r = 0.46, P < 0.01). These observations challenge the view that the classical reproductive hormones are the primary mediators of change in insulin sensitivity during gestation and provide the basis for including TNF-alpha in a new paradigm to explain insulin resistance in pregnancy.
Diabetes 2002 Jul
PMID:TNF-alpha is a predictor of insulin resistance in human pregnancy. 1208 51

Transgenic overexpression of either parathyroid hormone-related peptide (PTHrP) or mouse placental lactogen type 1 (mPL1) in pancreatic beta-cells, using the rat insulin II promoter (RIP), results in islet hyperplasia either through prolonged beta-cell survival or through increased beta-cell proliferation and hypertrophy, respectively. For determining whether the two proteins might exert complementary, additive, or synergistic effects on islet mass and function when simultaneously overexpressed in beta-cells in vivo, RIP-PTHrP and RIP-mPL1 mice were crossed to generate mice doubly transgenic for PTHrP and mPL1. These double-transgenic mice displayed marked islet hyperplasia (threefold), hypoglycemia, increased beta-cell proliferation (threefold), and resistance to the diabetogenic and cytotoxic effects of streptozotocin compared with their normal siblings. Although the phenotype of the double-transgenic mice was neither additive nor synergistic relative to their single-transgenic counterparts, it was indeed complementary, yielding the maximal salutary phenotypic features of both individual transgenes. Finally, mPL1, for the first time, was shown to exert a protective effect on the survival of beta-cells, placing it among the few proteins that can improve function and proliferation and prolong the survival of beta-cells. Placental lactogen 1 is an attractive target for future therapeutic strategies in diabetes.
Diabetes 2004 Dec
PMID:Characterization of mice doubly transgenic for parathyroid hormone-related protein and murine placental lactogen: a novel role for placental lactogen in pancreatic beta-cell survival. 1556 42

We hypothesized that combined transgenic overexpression of hepatocyte growth factor (HGF) and placental lactogen in islets would lead to even greater increases in beta-cell mass and replication than either growth factor alone. This did not occur, suggesting that beta-cell replication is saturable or subject to molecular restraint. We therefore performed the first comprehensive G(1)/S cell cycle survey in islets, cataloguing the broad range of kinases, cyclins, and kinase inhibitors that control the G(1)/S transition in islets from normal, HGF, placental lactogen, and doubly transgenic mice. Many of the G(1)/S checkpoint regulators (E2Fs; pRb; p107; p130; cyclins D(1),(2),(3), A, and E; cdk-2; cdk-4; p15; p16; p18; p19; p21; p27; MDM2; p53; c-Myc; and Egr-1) are present in the murine islet. Most of these proteins were unaltered by overexpression of HGF or placental lactogen, either alone or in combination. In contrast, p21(cip) was uniquely, dramatically, and reproducibly upregulated in placental lactogen and HGF islets. p21(cip) was also present in, and upregulated in, proliferating human islets, localizing specifically in beta-cells and translocating to the nucleus on mitogenic stimulation. Homozygous p21(cip) loss releases islets from growth inhibition, markedly enhancing proliferation in response to HGF and placental lactogen.
Diabetes 2006 Jan
PMID:Evaluation of beta-cell replication in mice transgenic for hepatocyte growth factor and placental lactogen: comprehensive characterization of the G1/S regulatory proteins reveals unique involvement of p21cip. 1638 Apr 78

p21(cip1), a regulatory molecule upstream of the G(1/0) checkpoint, is increased in beta-cells in response to mitogenic stimulation. Whereas p21(cip1) can variably stimulate or inhibit cell cycle progression, in vitro studies suggest that p21(cip1) acts as an inhibitor in the pancreatic beta-cell. To determine the functional role of p21(cip1) in vivo, we studied p21-null mice. Surprisingly, islet mass, beta-cell replication rates, and function were normal in p21-null mice. We next attempted to drive beta-cell replication in p21-null mice by crossing them with rat insulin II promoter-murine PL-1 (islet-targeted placental lactogen transgenic) mice. Even with this added replicative stimulus of PL, p21-null islets showed no additional stimulation. A G(1/S) proteome scan demonstrated that p21(cip1) loss was not associated with compensatory increases in other cell cycle inhibitors (pRb, p107, p130, p16, p19, and p27), although mild increases in p57 were apparent. Surprisingly, p18, which had been anticipated to increase, was markedly decreased. In summary, isolated p21(cip1) loss, as for pRb, p53, p18, and p27 and other inhibitors, results in normal beta-cell development and function, either because it is not essential or because its function is subserved or complimented by another protein. These studies underscore marked inhibitory pressure and the complexity and plasticity of inhibitory pathways that restrain beta-cell replication.
Diabetes 2006 Dec
PMID:The cell cycle inhibitory protein p21cip is not essential for maintaining beta-cell cycle arrest or beta-cell function in vivo. 1713 Apr 70


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