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

Proliferation of human beta-cells in vitro is desirable for both transplantation and biological studies. In this study, human pancreatic islets obtained from cadavers were kept in tissue culture plates that favored cell attachment. When the cells attached to the matrix produced by the rat-bladder carcinoma cell line 804G, 5'-bromo-2'-deoxyuridine (BrdU) labeling increased from 4.7 +/- 2.5 to 13.2 +/- 2.2%, while cells simultaneously labeled for insulin and BrdU increased from 0 to 32%. Addition of the growth factor hepatocyte growth factor/scatter (HGF/SF) increased BrdU labeling to 17.5 +/- 1.8 and the percentage of double positive (BrdU + insulin) cells to 69%. This is the first in vitro demonstration that human beta-cells grown in monolayer culture are able to replicate when exposed to selected matrices and growth factors. These experiments add further evidence that HGF/SF is an important mitogenic agent for human beta-cells.
Diabetes 1995 Dec
PMID:Growth factor/matrix-induced proliferation of human adult beta-cells. 758 54

Both hepatic and renal regeneration are associated with rapid increases in hepatocyte growth factor (HGF)mRNA levels, not only in the regenerating tissue, but also in the lung. In this study, changes in the levels of HGF mRNA in the terminal ileum and also in distal organs in the rat following massive small bowel resection (MSBR) have been investigated with a sensitive S1 nuclease assay. HGF mRNA levels are low in the ileum and increase only transiently post-MSBR. In contrast to the other models of regeneration, no increase in HGF mRNA levels is observed in the lung nor in kidney and liver post-MSBR. This suggests that the ileum does not release "injurin", the putative humoral mediator of the response of the lung observed after hepatectomy or nephrectomy.
Exp Clin Endocrinol Diabetes 1995
PMID:Hepatocyte growth factor gene expression after massive small bowel resection: lack of stimulation in lung and liver. 762 Nov 6

Fetal mesenchyme-derived factors are likely to play an important role in pancreatic islet development and growth. We have used primary cultures of human fetal pancreatic tissue to identify growth factors that have morphogenic, mitogenic, and insulinotropic activity. The formation of islet-like cell clusters (ICCs) during a 6-day culture was stimulated two- to threefold by hepatocyte growth factor/scatter factor (HGF/SF) basic fibroblast growth factor (FGF)-2, and to a lesser extent by keratinocyte growth factor (FGF-7) and insulin-like growth factor-II (IGF-II). In contrast, transforming growth factor-beta (TGF-beta) had a strong inhibitory effect. The ICCs formed during HGF/SF stimulation consisted mainly of epithelial cells, whereas FGF-2-induced ICCs were predominantly nonepithelial. Furthermore, although both FGF-2 and HGF/SF increased the total insulin content of the cultures, only HGF/SF increased the insulin content per DNA. Quantitatively, HGF/SF stimulated a 2.3-fold increase in the proportion of insulin-positive cells and a 3-fold higher number of replicating beta-cells. Blocking of the IGF-I receptor inhibited ICC formation but did not affect their insulin content. Immunoneutralizing TGF-beta resulted in increased cell growth and insulin content, indicating the presence of an endogenous inhibitory TGF-beta activity in the model system. Our results suggest that HGF/SF may be an important component of the fetal mesenchyme-derived factors responsible for pancreatic islet development. HGF/SF also may prove valuable for supporting the in vitro growth of islet cells.
Diabetes 1994 Jul
PMID:Hepatocyte growth factor/scatter factor has insulinotropic activity in human fetal pancreatic cells. 801 61

Reg is a gene associated with regeneration of pancreatic islets. We have previously shown that nicotinamide induces differentiation of human fetal beta-cells in tissue culture and that hepatocyte growth factor/scatter factor (HGF/SF) is mitogenic for the fetal beta-cells. We now tested whether these conditions, supporting either differentiation or growth, are associated with changes in reg gene expression in human fetal pancreatic cells. Culture for 7 days with 10 mM nicotinamide led to a fourfold decrease in reg mRNA levels (23 +/- 12% of control, n = 5, P < 0.001). In contrast, HGF/SF increased reg expression threefold (302 +/- 68% of control, n = 4, P < 0.05). Nicotinamide, which does not alter the differentiation level of adult beta-cells, did not significantly affect reg expression in adult human islets (84 +/- 4% of control, n = 2, NS). Thus, a higher level of endocrine differentiation is associated with a lower level of reg expression, and a higher rate of beta-cell replication results in increased reg transcription. These results provide the first evidence of a molecular marker, the reg gene, to distinguish between proliferation and differentiation of human beta-cells.
Diabetes 1994 Sep
PMID:Opposite effects of beta-cell differentiation and growth on reg expression in human fetal pancreatic cells. 807 Jun 17

Ex vivo expansion of human fetal pancreatic endocrine cells is important for biological studies and as a potential tissue source for transplantation in insulin-deficient states. In tissue culture experiments involving the use of hepatocyte growth factor/scatter factor and selected extracellular matrices, we obtained a 30-fold increase in cell number of human fetal pancreatic epithelial cells. This proliferation in monolayer culture was associated with marked downregulation of insulin and glucagon gene expression. However, gene expression increased when the cells were combined into three-dimensional aggregates, suggesting that cell-cell contact mediated mechanisms regulate the transcription of islet-specific genes, a process enhanced by nicotinamide (NIC). After transplantation into nude mice, either as cell suspensions or aggregates, only the cell aggregates treated with NIC developed into mature functional islet-like structures. These are the first experiments to describe the interactions of specific matrices and growth factors in the ex vivo expansion of human fetal pancreatic cells, and they also show the importance of cell aggregates in the context of cellular and molecular events that might positively influence islet cell transplantation.
Diabetes 1996 Sep
PMID:Regulation of proliferation and differentiation of human fetal pancreatic islet cells by extracellular matrix, hepatocyte growth factor, and cell-cell contact. 877 26

Hepatocyte growth factor (HGF) is expressed in placental syncitium and fetal organs and acts as a mitogen, motogen, and morphogen in vitro, suggesting a role in fetal growth and development. We aimed to examine the correlates of serum HGF in human cord blood. HGF was measured by ELISA using recombinant human HGF and mouse MAb to recombinant human HGF (Immunology Institute, Tokyo). Umbilical vein blood was collected prospectively at 148 deliveries including 94 normal pregnancies and 54 pregnancies complicated by medical conditions, primarily diabetes mellitus and pregnancy-induced hypertension. Growth parameters, gestation, pregnancy history, and perinatal events were recorded. Sera from 54 adolescents and 32 adult controls were also analyzed. Cord HGF [0.97 (0.66-1.33) ng/mL] [median (25-75 percentile)] was higher than HGF levels in adolescent sera [0.28 (0.21-0.35) ng/mL, p < 0.0001] and adult control sera [0.23 (0.14-0.31) ng/mL, p < 0.0001]. Cord HGF correlated with gestational age (r = 0.42, p = 0.0001) in normal pregnancies, with term babies (n = 69) having higher cord HGF than babies less than 37 wk of gestation (n = 25) [1.11 (0.78-1.45), 0.78 (0.46-1.03) ng/mL, p = 0.0007]. However, there was no relationship between gestation and cord HGF in complicated pregnancies. Cord HGF did not differ at term between appropriate for gestational age babies and small for gestational age babies. There were no independent correlations between cord HGF and birth weight, birth length and placental weight. We provide evidence for the first time that cord HGF levels are high and relate to gestation in normal pregnancies. HGF may have a significant role in fetal development during pregnancy.
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PMID:Relationship of hepatocyte growth factor in human umbilical vein serum to gestational age in normal pregnancies. 892 55

Endothelial cells are known to secrete various antiproliferative and vasodilating factors. Although injury of endothelial cells has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes, the mechanisms of endothelial injury in diabetes are not yet clarified. Therefore, it is important to know the effects of high glucose on the factors that may influence endothelial cell growth. A novel member of endothelium-specific growth factors, hepatocyte growth factor (HGF), is produced in vascular cells. To investigate the effects of high glucose on vascular cells, we examined 1) the effects of high glucose on endothelial cell and vascular smooth muscle cell (VSMC) growth and 2) the effects of high glucose on local HGF production in endothelial cell and VSMC. Treatment of human aortic endothelial cell with a high concentration of D-glucose, but not mannitol and L-glucose, resulted in a significant decrease in cell number. Interestingly, addition of recombinant HGF attenuated high D-glucose-induced endothelial cell death. Therefore, we measured local HGF secretion of endothelial cell. Importantly, local HGF production was significantly decreased by high D-glucose treatment. In contrast, high D-glucose treatment resulted in a significant increase in the number of human aortic VSMCs, whereas local HGF production was significantly decreased in accordance with increase in D-glucose concentration. No significant changes in numbers were observed in VSMC treated with high mannitol and L-glucose. We also studied the mechanisms of local HGF suppression by high D-glucose. High D-glucose treatment stimulated transforming growth factor-beta (TGF-beta) concentration in endothelial cell and VSMC. Decreased local vascular HGF production was abolished by addition of anti-TGF-beta antibody. As TGF-beta inhibited local HGF production in endothelial cell and VSMC, increased TGF-beta induced by high D-glucose may suppress local HGF production. This study demonstrated that high D-glucose induced endothelial cell death, stimulated VSMC growth, and decreased local HGF production through the stimulation of TGF-beta production both in endothelial cell and VSMC. Overall, decrease in a local endothelial stimulant, HGF, by high D-glucose may be a trigger of endothelial injury in diabetes, potentially resulting in the progression of atherosclerosis.
Diabetes 1997 Jan
PMID:Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes. 897 Oct 94

Renal hypertrophy develops early in the course of diabetes and has been linked to progressive renal disease. Although the mechanism of renal hypertrophy is unknown, evidence suggests that local alterations in the production of one or more growth factors and/or their receptors are crucial to this process. In this study, we demonstrate that the c-met protooncogene product, a tyrosine kinase receptor for hepatocyte growth factor (HGF), is increased in the kidney of the diabetic rat. Northern blot analysis showed that renal expression of the c-met gene was substantially increased in rats made diabetic by administration of streptozotocin. Immunohistochemical studies revealed that the protein for c-met was concordantly elevated in cortical and medullar tubular epithelium following the onset of diabetes. Moreover, in vitro studies demonstrated that short-term exposure to high glucose concentration markedly stimulated c-met expression in cultured proximal tubular (opossum kidney) and inner medulla collecting duct cells (mIMCD-3). The results of enhanced renal expression of c-met together with elevated HGF indicate that the HGF/c-met system is markedly activated in the diabetic rat. These findings suggest that the HGF/c-met system may play a role in the diabetic renal hypertrophy.
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PMID:In vivo and in vitro evidence for increased expression of HGF receptor in kidney of diabetic rat. 899 94

Injury of endothelial cells (EC) has been postulated as the initial trigger of the progression of atherosclerosis in patients with diabetes mellitus. We previously reported that decrease in a novel endothelium-specific growth factor, hepatocyte growth factor (HGF), by high D-glucose might be a trigger of endothelial injury. However, the physiological role of the local vascular HGF system has not yet been clarified. To investigate the role of HGF in endothelial injury, we initially examined the effects of HGF on endothelial injury induced by serum deprivation. Decrease in EC number by serum deprivation was significantly attenuated by addition of HGF as well as recombinant basic fibroblast growth factor, whereas vascular endothelial growth factor showed no effect. Apoptotic changes in EC induced by serum deprivation were also significantly attenuated by addition of HGF (p < 0.01). Given the protective action of HGF, we next studied the physiological role of local HGF production in endothelial regulation. We focused on the protective actions of prostaglandin (PG) I2, PGE and a phosphodiesterase type 3 inhibitor (cilostazol) on endothelial injury by high glucose, since these agents are widely used in the treatment of peripheral arterial disease which is frequently observed in diabetic patients. Treatment of human aortic EC with PGE1, PGE2, and a PGI2 analogue (beraprost sodium) as well as cilostazol stimulated EC growth. HGF concentration in conditioned medium from EC treated with PGE1, PGE2 or PGI2 analogue as well as cilostazol was significantly higher than that with vehicle (p < 0.01). Interestingly, treatment with PGI2 analogue or cilostazol attenuated high D-glucose-induced EC death, which was abolished by neutralizing anti-HGF antibody. Moreover, decreased local HGF production by high D-glucose was also significantly attenuated by PGI2 analogue or cilostazol. Finally, we tested the effects of PGE, PGI2 analogue and cilostazol on local HGF production in human aortic vascular smooth muscle cells (VSMC). Although high D-glucose treatment resulted in a significant increase in VSMC number, PGI2 analogue and/or cilostazol treatment had no effects on VSMC growth. However, the decrease in local HGF production by high D-glucose was significantly attenuated by addition of PGI2 analogue or cilostazol. Overall, this study demonstrated that treatment with PGE, PGI2 analogue or cilostazol prevented aortic EC death induced by high D-glucose, probably through the activation of local HGF production. Increased local vascular HGF production by prostaglandins and cilostazol may prevent endothelial injury, potentially resulting in the improvement of peripheral arterial disease.
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PMID:Role of hepatocyte growth factor in endothelial regulation: prevention of high D-glucose-induced endothelial cell death by prostaglandins and phosphodiesterase type 3 inhibitor. 930 Feb 42

It has recently been reported that human adult beta-cells proliferate during culture on an extracellular matrix prepared from rat 804G cells and in the presence of hepatocyte growth factor (HGF). The present study compares the mitogenic effect of this condition on human beta-cells and on neighboring non-endocrine duct cells. Islet cell-enriched fractions were prepared from adult human organ donors and cultured in suspension or on 804G matrix, with or without HGF. The combination of 804G matrix and HGF increased the number of 5-bromo-2'-deoxyuridine-positive (BrdU+) cells within 48 h reaching a maximum after 4 days. In sections, virtually all BrdU+ cells were negative for insulin or glucagon and for preproinsulin mRNA but expressed the ductal cell markers cytokeratin 19 and 7, carbonic anhydrase-II, and carbohydrate antigen 19-9. After 4 days of culture, the cytokeratin 19+ ductal cells exhibited a BrdU-labeling index of 30% (P < 0.01 vs. 2% without HGF and matrix), whereas <0.1% of insulin-positive and <1% of glucagon-positive cells were labeled. Formation of bilayers with ductal cells covering the endocrine cells may cause erroneous interpretation on double positivity in unsectioned tissue. It is concluded that culture of human islet cell preparations with HGF and 804G matrix stimulates the proliferation of the duct cells but not of the underlying beta-cells.
Diabetes 1998 Jan
PMID:Culture of adult human islet preparations with hepatocyte growth factor and 804G matrix is mitogenic for duct cells but not for beta-cells. 942 88


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