epidermal-growth-factor and Hyperglycemia

Glucose is a key fuel and an important metabolic substrate in mammals. Renal proximal tubular cells (PTCs) not only reabsorb filtered glucose but are also believed to play a role in the glucotoxicity associated with renal pathogenesis, such as in diabetes. The proximal tubule environment is where 90% of the filtered glucose is reabsorbed by the low-affinity/high-capacity Na(+)/glucose cotransporter 2 (SGLT2) and facilitated diffusion glucose transporter 2 (GLUT2). Both active and facilitative glucose transporters have distinct distribution profiles along the proximal tubule related to their particular kinetic characteristics. A number of mechanisms contribute to the changes in the cellular functions, which occur in response to exposure to various endogenous factors. Hyperglycemia was reported to regulate the renal SGLT activities through the reactive oxygen species-nuclear factor-kappaB pathways, which suggests that the transcellular glucose uptake within the PTCs contribute to the development of diabetic-like nephropathy. Angiotensin II (ANG II) plays an important role in its development through epidermal growth factor receptor (EGFR) transactivation. Therefore, a combination of high glucose, ANG II, and EGF are involved in diabetic-like nephropathy by regulating the SGLT activity. In addition, endogenously enhanced SGLTs have a cytoprotective function. The renal proximal tubules play a major role in regulating the plasma glucose levels, and there is increasing interest in the renal glucose transporters on account of their potential implications in the treatment of various conditions including diabetes mellitus.

Topics: Angiotensin II; Animals; Diabetic Nephropathies; Dogs; Epidermal Growth Factor; ErbB Receptors; Glucose; Humans; Hyperglycemia; Kidney Tubules, Proximal; Mice; Rabbits; Rats; Sodium-Glucose Transport Proteins

Diabetes mellitus is associated with typical patterns of long term vascular complications which vary with the organ involved. The microvascular kidney disease (Olgemoller and Schleicher, 1993) is characterized by thickening of the capillary basement membranes and increased deposition of extracellular matrix components (ECM), while loss of microvessels with subsequent neovascularisation is predominant in the eye and peripheral nerves. On the other hand macrovascular disease is characterized by accelerated atherosclerosis. These complications are dependent on long term hyperglycemia. Specific biochemical pathways linking hyperglycaemia to microvascular changes were proposed: the polyol pathway (Greene et al., 1987), non-enzymatic glycation of proteins (Brownlee et al., 1988), glucose autooxidation and oxidative stress (Hunt et al., 1990), hyperglycemic pseudohypoxia (Williamson et al., 1993) enhanced activation of protein kinase C by de novo-synthesis of diacyl glycerol (Lee et al., 1989; DeRubertis and Craven 1994) and others. These pathways are not mutually exclusive (Larkins and Dunlop, 1992; Pfeiffer and Schatz, 1992). They may be linked to alterations in the synthesis of growth factors particularly since atherosclerosis and angioneogenesis are associated with increased proliferation of endothelial and smooth muscle cells. Increased synthesis of ECM components is stimulated by growth factors like transforming growth factor beta (TGF beta) (Derynck et al., 1984) and insulin-like growth factor I (IGF-I) (Moran et al., 1991). This review will summarize some of the recent evidence for an involvement of growth factors in diabetic vascular complications and will attempt to assign their emergence in the sequence of events leading to vascular complications.

Topics: Animals; Arteriosclerosis; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Epidermal Growth Factor; Fibroblast Growth Factor 2; Growth Hormone; Growth Substances; Humans; Hyperglycemia; Insulin Resistance; Insulin-Like Growth Factor I; Receptors, Somatotropin; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The relationship between diabetes mellitus and pancreatic cancer is complex. Diabetes has been postulated to be both an independent risk factor and a consequence of pancreatic cancer. Our previous study confirmed that curcumin plays a vital role in inhibiting the epithelial-mesenchymal transition of pancreatic cancer cells. However, whether curcumin attenuates hyperglycemia-induced cancer invasive and migratory abilities and the underlying mechanisms are not yet well understood. As high glucose is able to induce the expression of epidermal growth factor (EGF), which is intimately related with tumor progression, the aim of this study was to evaluate whether curcumin could influence the high glucose-induced EGF/EGFR pathway and the biological activity of pancreatic cancer cells. Human pancreatic cancer BxPC-3 cells were exposed to high glucose or EGF, with or without curcumin, LY 294002 (an Akt inhibitor) or PD 98059 (an ERK inhibitor). MTT, Transwell invasion and wound healing assays were used to detect the proliferation, invasion and migration potential of cancer cells. The activation of p-EGFR, p-ERK and p-Akt was determined by western blot analysis. The expression levels of uPA and E-cadherin were examined using qRT-PCR and western blot analysis. The results showed that high glucose could not only promote the proliferation, invasion and migration of pancreatic cancer cells, but also induce the expression of EGF and activation of EGFR, ERK and Akt. These effects of high glucose were counter-balanced by curcumin. EGF-induced proliferative, invasive and migratory abilities of BxPC-3 cells were abrogated by curcumin, LY 294002 and PD 98059. In addition, EGF-modulated activation of EGFR, ERK and Akt, as well as the expression of uPA and E-cadherin were inhibited by curcumin. Taken together, the present study indicates that curcumin suppresses hyperglycemia-driven EGF-induced invasion and migration of pancreatic cancer cells by inhibiting the EGF/EGFR signaling pathway and its downstream signaling molecules including ERK and Akt. Curcumin is a potential anticancer agent for pancreatic cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromones; Curcumin; Epidermal Growth Factor; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Glucose; Humans; Hyperglycemia; Morpholines; Neoplasm Invasiveness; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction

We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments β-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of β-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9(+) (Sox9(+)) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing β cells in an in vitro culture. Whether Sox9(+) ductal cells in the adult pancreas can give rise to β cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin- or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9(+) ductal cell differentiation into insulin-producing β cells, and medium hyperglycemia (300-450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting β-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9(+) ductal cell differentiation into β cells in adult mice.

Topics: Animals; Blood Glucose; Cell Differentiation; Culture Media; Diabetes Mellitus, Experimental; Epidermal Growth Factor; Gastrins; Hyperglycemia; Insulin-Secreting Cells; Kinetics; Mice, Inbred C57BL; Pancreatic Ducts; SOX9 Transcription Factor

When the beta cell mass or function declines beyond a critical point, hyperglycaemia arises. Little is known about the potential pathways involved in beta cell rescue. As two cytokines, epidermal growth factor (EGF) and ciliary neurotrophic factor (CNTF), restored a functional beta cell mass in mice with long-term hyperglycaemia by reprogramming acinar cells that transiently expressed neurogenin 3 (NGN3), the current study assesses the effect of these cytokines on the functional beta cell mass after an acute chemical toxic insult.. Glycaemia and insulin levels, pro-endocrine gene expression and beta cell origin, as well as the role of signal transducer and activator of transcription 3 (STAT3) signalling, were assessed in EGF+CNTF-treated mice following acute hyperglycaemia.. The mice were hyperglycaemic 1 day following i.v. injection of the beta cell toxin alloxan, when the two cytokines were applied. One week later, 68.6 ± 4.6% of the mice had responded to the cytokine treatment and increased their insulin(+) cell number to 30% that of normoglycaemic control mice, resulting in restoration of euglycaemia. Although insulin(-) NGN3(+) cells appeared following acute EGF+CNTF treatment, genetic lineage tracing showed that the majority of the insulin(+) cells originated from pre-existing beta cells. Beta cell rescue by EGF+CNTF depends on glycaemia rather than on STAT3-induced NGN3 expression in acinar cells.. In adult mice, EGF+CNTF allows the rescue of beta cells in distress when treatment is given shortly after the diabetogenic insult. The rescued beta cells restore a functional beta cell mass able to control normal blood glucose levels. These findings may provide new insights into compensatory pathways activated early after beta cell loss.

Topics: Alloxan; Animals; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Ciliary Neurotrophic Factor; Epidermal Growth Factor; Hyperglycemia; Insulin; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Signal Transduction

Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose responsive, and they reinstate normal glycemic control for up to 248 d. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3)-expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta-cell reprogramming through transient cytokine exposure rather than genetic modification.

Topics: Acinar Cells; Animals; Cell Differentiation; Cell Proliferation; Ciliary Neurotrophic Factor; Diabetes Mellitus; Epidermal Growth Factor; Hyperglycemia; Insulin-Secreting Cells; Mice; Mice, Inbred NOD; Signal Transduction

Surrogate β-cells derived from stem cells are needed to cure type 1 diabetes, and neonatal liver cells may be an attractive alternative to stem cells for the generation of β-cells. In this study, we attempted to generate insulin-producing cells from neonatal porcine liver-derived cells using adenoviruses carrying three genes: pancreatic and duodenal homeobox factor1 (PDX1)/VP16, BETA2/NeuroD and v-maf musculo aponeurotic fibrosarcoma oncogene homolog A (MafA), which are all known to play critical roles in pancreatic development. Isolated neonatal porcine liver-derived cells were sequentially transduced with triple adenoviruses and grown in induction medium containing a high concentration of glucose, epidermal growth factors, nicotinamide and a low concentration of serum following the induction of aggregation for further maturation. We noted that the cells displayed a number of molecular characteristics of pancreatic β-cells, including expressing several transcription factors necessary for β-cell development and function. In addition, these cells synthesized and physiologically secreted insulin. Transplanting these differentiated cells into streptozotocin-induced immunodeficient diabetic mice led to the reversal of hyperglycemia, and more than 18% of the cells in the grafts expressed insulin at 6 weeks after transplantation. These data suggested that neonatal porcine liver-derived cells can be differentiated into functional insulin-producing cells under the culture conditions presented in this report and indicated that neonatal porcine liver-derived cells (NPLCs) might be useful as a potential source of cells for β-cell replacement therapy in efforts to cure type I diabetes.

Topics: Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Glucose; Heterografts; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Liver; Maf Transcription Factors, Large; Mice; Swine; Trans-Activators

The aim of this study was to investigate whether combined epidermal growth factor (EGF) and gastrin can correct the hyperglycemia induced by streptozotocin (STZ) in rats and to determine the involvement of the transcription factor pancreatic and duodenal homeobox 1 (PDX1) in this process.. Rat diabetes was induced by intraperitoneal injection of STZ. The mRNA and protein levels of insulin and PDX1 were determined by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. Serum levels of C-peptide and insulin were analyzed using radioimmunoassay kits.. The combined administration of EGF and gastrin efficiently reversed the hyperglycemia induced by STZ. Elevated insulin concentration was detected in diabetic rats treated with EGF plus gastrin. The authors also found that both insulin and PDX1 expression were reduced in STZ-treated rats. Interestingly, the combination treatment also significantly enhanced the mRNA levels of insulin and PDX1, and that of their protein products.. Therapy with EGF plus gastrin corrected hyperglycemia and maintained insulin content in STZ-induced diabetic rats via up-regulation of PDX1 expression, suggesting that this combination treatment may provide a valuable approach for pancreatic islet neogenesis in vivo.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Combinations; Epidermal Growth Factor; Gastrins; Homeodomain Proteins; Humans; Hyperglycemia; Injections, Subcutaneous; Insulin; Islets of Langerhans; Male; Radioimmunoassay; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trans-Activators

Nerve growth factor (NGF) is a well-known mediator for maintaining the survival of neurons, while recent studies report that its absence induces apoptosis in cultured β cells of humans and rats. However, its relationship with other growth factors that have important roles in the survival and function of β cells such as epidermal growth factor (EGF) has not yet been elucidated. The aim of this study was to investigate the effects of NGF withdrawal on the synthesis and secretion of EGF, insulin with respect to β cell apoptosis in hyperglycemic rats.. β cells were isolated from euglycemic and streptozotocin-induced hyperglycemic rats and treated with NGF neutralizing antibody for withdrawal of NGF in culture medium. NGF, EGF and insulin levels in cell lysates and secretion samples were measured by enzyme-linked immunosorbent assay, and their gene expressions were determined by real-time reverse transcription polymerase chain reaction assay. Apoptosis was quantitatively determined by cytoplasmic histone-associated DNA fragments.. Nerve growth factor neutralization triggered β cell apoptosis. In addition decreased insulin, increased NGF and EGF were observed at gene expression and protein levels by NGF neutralization. Moreover, NGF withdrawal decreased secretion of these peptides from β cells. Although the alterations seemed to be similar under euglycemic and hyperglycemic conditions, NGF withdrawal more strongly affected β cells of hyperglycemic rats.. These important findings indicate that NGF is an important regulator for the synthesis and secretion of EGF and insulin from the β cells. Moreover, results suggested that NGF withdrawal causes apoptosis by decreasing EGF, NGF and insulin secretion from β cells of hyperglycemic rats.

Topics: Animals; Antibodies, Neutralizing; Apoptosis; Blood Glucose; Epidermal Growth Factor; Hyperglycemia; Insulin; Insulin-Secreting Cells; Male; Nerve Growth Factor; Rats; Rats, Wistar; Streptozocin

Multiple lines of evidence suggest that a large portion of pancreatic cancer patients suffer from either hyperglycemia or diabetes, both of which are characterized by high blood glucose level. However, the underlying biological mechanism of this phenomenon is largely unknown. In the present study, we demonstrated that the proliferative ability of two human pancreatic cancer cell lines, BxPC-3 and Panc-1, was upregulated by high glucose in a concentration-dependent manner. Furthermore, the promoting effect of high glucose levels on EGF transcription and secretion but not its receptors in these PC cell lines was detected by using an EGF-neutralizing antibody and RT-PCR. In addition, the EGFR transactivation is induced by high glucose levels in concentration- and time-dependent manners in PC cells in the presence of the EGF-neutralizing antibody. These results suggest that high glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. Our findings may provide new insight on the links between high glucose level and PC in terms of the molecular mechanism and reveal a novel therapeutic strategy for PC patients who simultaneously suffer from either diabetes or hyperglycemia.

Topics: Cell Line, Tumor; Cell Proliferation; Diabetes Mellitus; Epidermal Growth Factor; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glucose; Humans; Hyperglycemia; Pancreatic Neoplasms; Transcriptional Activation

microvascular complications in diabetes identify those at risk of cardiovascular disease (CVD), suggesting a link between abnormal neovascularisation and CVD. This may be related to high plasma vascular endothelial growth factor (VEGF). We hypothesised increased angiopoietins (Ang)-1 and -2 in patients with diabetes that are related to VEGF, medium-term glycaemic control, endothelial damage/dysfunction and atherosclerosis.. we measured plasma Ang-1 and Ang-2 alongside VEGF (all by ELISA) in 96 patients with type-2 diabetes mellitus (41 with and 56 without overt CVD) who were compared to 35 age- and sex-comparable healthy controls. Common carotid intima-media thickness (CC-IMT) was used to assess carotid atherosclerosis, plasma von Willebrand factor (vWf) and urine albumin:creatinine ratio (UACr) to quantify and endothelial damage/dysfunction, and HbA1c to mark medium-term hypergylcaemia.. Ang-2 (but not Ang-1) was higher in patients with diabetes compared to controls (p<0.01), with no significant difference between patients with and without CVD. As expected, CC-IMT, UACr, HbA1c, vWf, and VEGF were also abnormal in the patients. Within the patient group alone, and in the entire cohort, VEGF and Ang-2 correlated strongly (both p<0.001) and with several other markers. However, in multivariate analysis, the only significant relationship that remained after adjustments was between VEGF and HbA1c (p<0.001).. Angiogenic growth factor Ang-2, like VEGF, is raised in diabetes regardless of vascular disease. Both growth factors correlated with HbA1c and with each other, not with endothelial injury or atherosclerosis, but after multiple adjustment, only that between HbA1c and VEGF significant remained. VEGF is likely to have a more prominent role in diabetes than Ang-2.

Topics: Aged; Angiopoietin-1; Angiopoietin-2; Carotid Artery Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Epidermal Growth Factor; Female; Humans; Hyperglycemia; Male; Middle Aged; Multivariate Analysis; Vascular Endothelial Growth Factor A; von Willebrand Factor

Combination therapy with epidermal growth factor (EGF) and gastrin induces beta-cell regeneration in rodents with chemically induced diabetes. We investigated whether EGF plus gastrin could correct hyperglycemia in NOD mice with autoimmune diabetes. Combined treatment with EGF (1 mug/kg) and gastrin (3 mug/kg) for 2 weeks restored normoglycemia after diabetes onset in NOD mice, whereas EGF or gastrin alone did not. Fasting blood glucose remained normal (3.5-6.5 mmol/l) or mildly elevated (<11 mmol/l) in five of six mice (83%) for 10 weeks after EGF plus gastrin treatment was stopped, whereas all mice treated with vehicle or EGF or gastrin alone became severely hyperglycemic (12-35 mmol/l). Pancreatic beta-cell mass was increased threefold and insulin content was increased eightfold in mice treated with EGF plus gastrin compared with pretreatment values. The correction of hyperglycemia correlated significantly with increases in pancreatic beta-cell mass and insulin content. In addition, splenic cells from mice treated with EGF plus gastrin delayed diabetes induction by adoptive transfer of diabetogenic cells into immunodeficient NOD-scid mice, suggesting the induction of immunoregulatory cells in NOD mice treated with EGF plus gastrin. We conclude that a short course of combined EGF and gastrin therapy increases pancreatic beta-cell mass and reverses hyperglycemia in acutely diabetic NOD mice; the impact of this combined therapy may result from the effects of EGF and gastrin on beta-cells, immune cells, or both.

Topics: Animals; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Epidermal Growth Factor; Female; Gastrins; Hyperglycemia; Islets of Langerhans; Mice; Mice, Inbred NOD

Several laboratories report different effects of epidermal growth factor (EGF) on glycogen metabolism in hepatocytes. The discrepancies may be attributed to differences in the experimental conditions. It is therefore important to establish the actual effect of EGF in vivo. Because large physiological variations of EGF concentration in plasma occur in mice, we used this species to address this question. In freshly isolated mouse hepatocytes, EGF increased glycogen degradation in a dose-dependent manner. The maximal effect (36% increase over basal glycogenolysis) was smaller than maximal effects of classical glycogenolytic hormones like adrenaline or glucagon (more than 150% increase over basal). This is in keeping with the smaller effect of EGF on phosphorylase a activity. In contrast with these hormones, EGF did not inhibit glycolysis. Thus these effects of EGF in mouse hepatocytes are similar to those recently described by us in rat hepatocytes [Quintana, Grau, Moreno, Soler, Ramirez and Soley (1995) Biochem J 308, 889-894]. When administered to whole animals, EGF increased phosphorylase a activity, decreased the glycogen content in the liver and caused mild hyperglycaemia. Taking together the results obtained for isolated cells and for whole animals, we suggest that the glucosyl residues released from glycogen are used mostly by the liver rather than released to the circulation. This would be different from the action of the classical glycogenolytic hormones, adrenaline and glucagon.

Topics: Animals; Blood Glucose; Dose-Response Relationship, Drug; Epidermal Growth Factor; Epinephrine; Glucagon; Hyperglycemia; Liver Glycogen; Male; Mice