epidermal-growth-factor and Diabetes-Mellitus--Type-1

Topics: Animals; Cell Transplantation; Diabetes Mellitus, Type 1; Diphtheria Toxin; Disease Models, Animal; Epidermal Growth Factor; Heparin-binding EGF-like Growth Factor; Hepatitis; Intercellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Protein Structure, Tertiary; Regenerative Medicine

Transition Therapeutics (through its acquisition of Waratah Pharmaceuticals), in collaboration with Novo Nordisk, is developing E1-INT, an injectable islet neogenesis therapy comprising an epidermal growth factor analog and a gastrin analog, for the treatment of insulin-dependent (type 1) and non-insulin-dependent (type 2) diabetes. The compound is currently undergoing phase II clinical trials.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Industry; Epidermal Growth Factor; Gastrins; Humans; Hypoglycemic Agents; Structure-Activity Relationship

Transgenic expression of gastrin and EGF receptor ligands stimulates islet neogenesis in adult mice, significantly increasing islet mass. The present study aimed to determine whether pharmacological treatment with gastrin and EGF can significantly stimulate beta-cell regeneration in chronic, severe insulin-dependent diabetes. Diabetes was induced by intravenous streptozotocin, resulting in >95% beta cell destruction. Four weeks later, blood glucose levels were restored to normal range by exogenous insulin therapy and rats were treated with EGF/gastrin in combination, gastrin alone, or EGF alone given subcutaneously. After 14 days treatment blood glucose was significantly lower in the EGF/gastrin group compared to the untreated diabetic controls. Along with improved glucose tolerance, EGF/gastrin treatment significantly increased plasma C peptide and pancreatic insulin content compared to diabetic controls. Histological analysis showed that EGF/gastrin treatment significantly increased beta-cell mass as determined by point counting morphometrics. The EGF/gastrin group had a significantly greater number of BrdU labelled beta-cells/section consistent with stimulation of beta-cell replication or neogenesis. An increased number of gastrin receptor positive cells were observed in the EGF/gastrin-treated groups. In contrast to the effectiveness of the EGF/gastrin combination, neither gastrin nor EGF alone improved glucose tolerance in severely streptozotocin-diabetic rats. These studies indicate that physiologically significant improvement in glucose tolerance can be achieved through stimulating beta-cell regeneration with gastrin/EGF administered systemically as conventional pharmacological therapy.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Combinations; Epidermal Growth Factor; Gastrins; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Rats; Receptors, Cholecystokinin

Topics: Adult; Aged; Aging; Alcoholism; Amino Acids; Anesthetics, Local; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Aqueous Humor; Autonomic Nervous System; Biological Transport, Active; Brain Chemistry; Cardiac Glycosides; Catecholamines; Cell Differentiation; Central Nervous System; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Epidermal Growth Factor; Eye; Fibrinolysis; Glaucoma; Granuloma; Graves Disease; Hallucinogens; Humans; Hypertension; Immunity, Cellular; Infant; Infant, Newborn; Leukotriene B4; Metabolism, Inborn Errors; Multiple Sclerosis; Muscle Relaxation; Nutritional Physiological Phenomena; Oxygen; Oxygen Consumption; Pigment Epithelium of Eye; Pineal Gland; Prostaglandin Antagonists; Prostaglandins; Psychotropic Drugs; Retina; Retinal Degeneration; Serotonin; Smoking; SRS-A; Stress, Physiological; Water-Electrolyte Balance

To investigate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) in advanced diabetic foot ulcers (DFU) A double-blind trial was carried out to test two rhEGF dose levels in type 1 or 2 diabetes patients with Wagner's grade 3 or 4 ulcers, with high risk of amputation. Subjects were randomised to receive 75 (group I) or 25 mug (group II) rhEGF through intralesional injections, three times per week for 5-8 weeks together with standardised good wound care. Endpoints were granulation tissue formation, complete healing and need of amputation. Safety was assessed by clinical adverse events (AEs) and laboratory evaluations. Forty-one patients were included. After 5-8 weeks of treatment, 83% patients in the higher dose group and 61% in group II achieved useful granulation tissue covering more than 98% of the wound area. At long-term assessment, 13 (56.5%) patients healed in group I and 9 (50%) in group II. The mean time to complete healing in group I was 20.6 weeks (95% CI: 17.0-24.2) and 19.5 weeks (16.3-22.7) in group II. After 1-year follow-up, only one patient relapsed. Amputation was not necessary in 65% and 66.7% of groups I and II, respectively. The AEs rates were similar. The most frequent were sepsis (33%), burning sensation (29%), tremors, chills and local pain (25% each). rhEGF local injection enhances advanced DFU healing and reduces the risk of major amputation. No dose dependency was observed.

Topics: Adult; Aged; Amputation, Surgical; Analysis of Variance; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Foot; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Epidermal Growth Factor; Female; Follow-Up Studies; Granulation Tissue; Humans; Injections, Intralesional; Male; Middle Aged; Probability; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric; Treatment Outcome; Wound Healing

An increased blood pressure is a known comorbidity of both type 1 diabetes (T1DM) and obesity in children. Increasing evidence suggests a subtle interplay between epidermal growth factor (EGF) and renin along the juxtaglomerular system, regulating the impact of blood pressure on kidney health and the cardiovascular system. In this study, we investigated the relation between urinary EGF, serum renin and blood pressure in children with obesity or T1DM. 147 non-obese children with T1DM and 126 children with obesity, were included. Blood pressure was measured and mean arterial pressure (MAP) and the pulse pressure (PP) were calculated. Serum renin and urinary EGF levels were determined with a commercial ELISA kit. Partial Spearman rank correlation coefficients and multiple linear regression models were used to study the association between renin, the urinary EGF/urinary creatinine ratio and blood pressure parameters. The urinary EGF/urinary creatinine ratio is correlated with the SBP and the MAP in boys with obesity as well as in boys with T1DM. Multiple regression analysis showed that sex and pulse pressure in male subjects were found to be independently associated with renin. Sex, the presence of diabetes, age, the glomerular filtration rate and both pulse pressure and mean arterial pressure in male subjects were independently associated with urinary EGF/urinary creatinine. In conclusion, in boys with either obesity or diabetes, pulse pressure and mean arterial pressure are negatively associated with the functional integrity of the nephron, which is reflected by a decreased expression of urinary EGF.

Topics: Blood Pressure; Child; Creatinine; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Glomerular Filtration Rate; Humans; Male; Pediatric Obesity; Renin

The relationship between urinary endothelial growth factor (uEGF) and cardiovascular autonomic neuropathy (CAN) in adults with type 1 diabetes was evaluated. uEGF levels at baseline and standardized CAN measures were collected at baseline and annually for 3 years for type 1 diabetes adults. Linear regression analysis and linear mixed effects model were used for analysis. In this cohort (n = 44, 59% women, mean ± standard deviation age 34 ± 13 years and diabetes duration 14 ± 6 years), lower baseline uEGF levels correlated with lower baseline expiration : inspiration ratios (P = 0.03) and greater annual declines in Valsalva ratios (P = 0.02) in the unadjusted model, and correlated with lower low-frequency power : high-frequency power ratios (P = 0.01) and greater annual changes in low-frequency power : high-frequency power ratios (P = 0.01) after adjustment for age, sex, body mass index, and hemoglobin A1C. In conclusion, baseline uEGF levels correlate to baseline and longitudinal changes in CAN indices. A large-scale, long-term study is needed to validate uEGF as a reliable CAN biomarker.

Topics: Adult; Autonomic Nervous System; Autonomic Nervous System Diseases; Biomarkers; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Young Adult

Micro-albuminuria is considered an early clinical sign of diabetes nephropathy, however, early decrease of glomerular filtration can be present years before the presence of microalbuminuria. In this study, we explored whether urinary epidermal growth factor (uEGF) might serve as an early marker of diabetes nephropathy compared to microalbuminuria in children and adolescents.. Children with type 1 diabetes mellitus (n = 158) and healthy controls (n = 40) were included in this study. Serum and urine samples were collected three times with an interval of at least one month to determine creatinine (serum and urine), epidermal growth factor and albumin (urine). Demographic data and routine lab values were extracted out of the electronic patient files.. uEGF was significantly lower in children with T1DM compared to healthy controls (p = 0.032). A relatively lower glomerular filtration rate (eGFR) was associated with a decreased uEGF (p < 0.001). uEGF was independently associated with eGFR in a multivariate analysis.. This study provides evidence that uEGF can serve as an early marker of diabetes nephropathy in children and adolescents.

Topics: Adolescent; Albuminuria; Biomarkers; Child; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Epidermal Growth Factor; Glomerular Filtration Rate; Humans; Kidney

Here we present a plasmonic nanoledge device with high sensitivity and selectivity used to detect protein biomarkers simply by functionalizing the device, which specifically binds to particular biomolecule or biomarkers. We employ this plasmonic nanoledge device for the detection of anti-insulin antibodies of type 1 diabetes (T1D) in buffer and human serum at the range of pg ml

Topics: Antibodies; Biomarkers; Biosensing Techniques; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Humans; Insulin; Limit of Detection; Serum Albumin, Bovine; Surface Plasmon Resonance

Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9

Topics: Animals; Autoimmunity; Blood Glucose; Cell Transdifferentiation; Chimerism; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Female; Gastrins; Gene Expression Regulation; Glucagon; Glucagon-Secreting Cells; Insulin; Insulin-Secreting Cells; Mesenchymal Stem Cells; Mice; Mice, Inbred NOD; Precursor Cells, B-Lymphoid; Regeneration

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

Type 1 diabetes (T1D) results from an autoimmune destruction of insulin-producing β cells. Currently, islet transplantation is the only curative therapy for late-stage T1D, but the beneficial effect is limited in its duration, even under chronic immunosuppression, because of the chronic graft rejection mediated by both auto- and alloimmunity. Clinical islet transplantation is also restricted by a severe shortage of donor islets. Induction of mixed chimerism reverses autoimmunity, eliminates insulitis, and reverses new-onset but not late-stage disease in the nonobese diabetic (NOD) mouse model of T1D. Administration of gastrin and epidermal growth factor (EGF) also reverses new-onset but not late-stage T1D in this animal model. Here, we showed that combination therapy of induced mixed chimerism under a radiation-free nontoxic anti-CD3/CD8 conditioning regimen and administration of gastrin/EGF augments both β cell neogenesis and replication, resulting in reversal of late-stage T1D in NOD mice. If successfully translated into humans, this combination therapy could replace islet transplantation as a long-term curative therapy for T1D.

Topics: Animals; Combined Modality Therapy; Diabetes Mellitus, Type 1; Disease Models, Animal; Epidermal Growth Factor; Female; Gastrins; Humans; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Regeneration; Translational Research, Biomedical; Transplantation Chimera; Transplantation Conditioning

The effects of embryonic stem cells (ESCs) on diabetic wound healing were investigated using an excisional skin wound model in 110 diabetes-induced rats. We transplanted a clonal population of ESCs (5 × 10(6)) by topical injection into full thickness skin wounds. Four study groups were used; nondiabetic rats as a control, non-insulin controlled diabetic rats not treated with ESCs, insulin controlled diabetic rats not treated with ESCs, and insulin controlled diabetic rats treated with ESCs. Five rats in each experimental group were sacrificed on days 1, 5, 10, 15, and 20 after wounding. Wounds images were acquired daily and wound sizes were calculated. We measured the mRNA levels of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), and fibronectin levels in extracellular matrix, and assessed wound healing by assessing histological parameters of epidermal regeneration, granulation tissue thickness, and angiogenesis. In the ESC-treated group, wound sizes were significantly smaller than in the insulin controlled diabetic group not treated with ESCs on days 5 and 10 (p < 0.05), and EGF and VEGF levels were markedly higher on days 5 and 10, fibronectin levels on day 5 after injection. All histological scores in the ESC-treated group were significantly higher than those of the insulin controlled diabetic group on day 5 (p < 0.05). Our results shows that topical ESCs enhance diabetic wound healing during the early stage, and suggest that ESCs transplantation offers a novel therapeutic modality for the treatment of diabetic wounds.

Topics: Animals; Blood Glucose; Blood Urea Nitrogen; Creatinine; Diabetes Mellitus, Type 1; Embryonic Stem Cells; Epidermal Growth Factor; Extracellular Matrix; Fibronectins; Glycated Hemoglobin; Granulation Tissue; Leukocyte Count; Male; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vascular Endothelial Growth Factor A; Wound Healing

The aim of this study was to examine the effect of protein kinase Cbeta inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects.. Albuminuric subjects were randomized (2:1) to ruboxistaurin (32 mg daily; n = 13) or placebo (n = 7) for 8 weeks. Renal hemodynamic function was measured during clamped euglycemia or hyperglycemia and before and after ruboxistaurin or placebo.. Ruboxistaurin was not associated with between-group differences during clamped euglycemia or hyperglycemia. In a post hoc analysis comparing hyperfilterers with normofilterers during euglycemia, glomerular filtration rate and MCP-1 decreased, whereas the epidermal growth factor-to-MCP-1 ratio increased in hyperfilterers versus normofilterers (all P < 0.05).. The effect of ruboxistaurin is modest and dependent, at least in part, on the level of ambient glycemia and baseline glomerular filtration rate.

Topics: Albuminuria; Blood Pressure; Chemokine CCL2; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enzyme Inhibitors; Epidermal Growth Factor; Glomerular Filtration Rate; Hemodynamics; Humans; Indoles; Kidney; Maleimides; Protein Kinase C; Protein Kinase C beta

Topics: Activins; Androstadienes; Cell Differentiation; Diabetes Mellitus, Type 1; Embryonic Stem Cells; Epidermal Growth Factor; Humans; Insulin-Secreting Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pluripotent Stem Cells; Transforming Growth Factor beta; Wortmannin

The precise fate of beta cells and the presence of islet infiltrates after onset of type 1 diabetes have not yet been fully characterized. Recently we showed that in newly diabetic NOD mice an appreciable number of beta cells remain. This was also observed during the first 2 weeks of diabetes in NOD mice without treatment with insulin. However, the mean number of beta cells per unit islet cross-sectional area decreased with increasing duration of disease. In contrast, glucagon and somatostatin cell numbers showed an increase. The persistence of insulitis in several islets until 4 weeks of diabetes suggests ongoing beta cell autoimmunity over a protracted phase. Combined daily treatment of newly diabetic NOD mice with epidermal growth factor (EGF) and gastrin for the first 14 days of diabetes resulted in temporary restoration of normoglycemia in 7 of 15 mice. We speculate that the residual beta cells present soon after onset of diabetes may respond to experimental regeneration. Treatment of newly diabetic NOD mice with the bioactive peptides EGF and gastrin resulted in partial and temporary reversal of diabetes. We propose that peptide therapies combined with other benign immunomodulatory approaches to rescue and preserve beta cells in the long term and to prevent recurring autoimmunity may be more effective than peptide therapy alone in reversing diabetes in NOD mice.

Topics: Age Factors; Age of Onset; Animals; Autoimmunity; Diabetes Mellitus, Type 1; Disease Progression; Drug Evaluation, Preclinical; Epidermal Growth Factor; Female; Gastrins; Hypoglycemic Agents; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Inbred NOD; Peptides; Remission Induction; Time Factors

In a previous study, we observed that combination therapy of nonobese diabetic (NOD) mice with epidermal growth factor (EGF) and gastrin partially restored pancreatic islet beta-cell mass and reversed hyperglycemia without the use of immunotherapy. Herein we have studied the effects of EGF plus gastrin on recurrent autoimmune responses in diabetic NOD mice transplanted with syngeneic islets. EGF (10 microg/kg) plus gastrin (30 microg/kg) given intraperitoneally (i.p.) once daily to diabetic NOD mice (blood glucose, 23 +/- 2 mmol/L) significantly prolonged the median survival time of NOD islet grafts to 60 days (n = 10 mice) measured as the days until hyperglycemia recurrence (blood glucose > or =12 mmol/L; versus EGF alone to 36 days (n = 10), or gastrin alone, 19 days (n = 10), or vehicle, 11 days (n = 9). At 7-14 days after transplantation insulin-stained beta-cells were much more numerous in islet grafts of EGF plus gastrin-treated mice (13.0 +/- 0.9 x 10(5) cells) versus grafts in vehicle-treated mice (1.0 +/- 0.3 x 10(5) cells). CD45+ leukocytes were significantly reduced in number and surrounded but did not destroy the beta cells in the islets of EGF plus gastrin-treated mice (29 +/- 2 x 10(5) cells) versus those in vehicle-treated mice (57 +/- 3 x 10(5) cells). We concluded that the EGF plus gastrin combination therapy inhibited the recurrent autoimmune response and delayed rejection of syngeneic islet grafts, suggesting a therapeutic role for these peptides in islet transplantation.

Topics: Animals; Combined Modality Therapy; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Epidermal Growth Factor; Female; Gastrins; Immunohistochemistry; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Leukocyte Count; Mice; Mice, Inbred NOD; Subrenal Capsule Assay; Transplantation, Isogeneic

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

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Gastrins; Growth Substances; Humans; Islets of Langerhans; Mice; Regeneration

Epidermal growth factor is a ubiquitous mitogen that also possesses insulin-like properties. Fetal mal-growth is associated with altered epidermal growth factor levels. Maternal diabetes is frequently complicated by macrosomia, but the effect of maternal diabetes on fetal epidermal growth factor levels is not known. We studied cord serum epidermal growth factor concentrations in pregnancies complicated by diabetes and in normal pregnancies.. Cord serum epidermal growth factor concentrations were measured at birth by a sandwich-type time-resolved immunofluorometric assay in 63 pregnancies complicated by insulin-dependent diabetes mellitus, in 25 pregnancies complicated by insulin-treated gestational diabetes, and in 56 normal pregnancies.. Cord serum epidermal growth factor correlated positively with the duration of pregnancy in diabetic and normal pregnancies. In a subgroup of women at similar gestational ages (38-39 weeks), cord serum epidermal growth factor concentrations were higher in pregnancies complicated by insulin-dependent diabetes mellitus (962 +/- 211 ng/L, P =.047; n = 9) and in pregnancies complicated by gestational diabetes (1133 +/- 115 ng/L, P =.001; n = 9) than in controls (564 +/- 75 ng/L; n = 22). In multiple regression analysis, only umbilical artery hemoglobin in diabetic pregnancies and vaginal delivery in normal pregnancies were associated with cord serum epidermal growth factor.. Epidermal growth factor concentrations are higher than normal in fetuses of diabetic mothers at term. Pregnancy complications, such as hypertensive disorders, fetal hypoxia and fetal malgrowth, may not explain the rise in epidermal growth factor levels. We hypothesize that the rise in epidermal growth factor levels is a metabolic response of the fetoplacental unit to diabetes-related hyperglycemia.. III

Topics: Adult; Analysis of Variance; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes, Gestational; Epidermal Growth Factor; Female; Fetal Blood; Fetal Macrosomia; Gestational Age; Humans; Maternal Age; Pregnancy; Pregnancy in Diabetics; Pregnancy Outcome; Pregnancy, High-Risk; Probability; Reference Values; Regression Analysis; Risk Assessment

Using the NOD mouse, a model for type 1 diabetes, we examined how reduced concentrations of epidermal growth factor (EGF) in the saliva, after onset of type 1 diabetes, affect oral wound healing. Diabetic NOD/LtJ mice on insulin therapy, prediabetic NOD/LtJ, and age- and sex-matched BALB/cJ mice were given a cutaneous tongue punch and allowed to undergo normal healing. With diabetes onset and a reduction in saliva-derived growth factor levels, the rate of tongue wound healing was reduced compared with nondiabetic NOD/LtJ and healthy BALB/cJ mice. Addition of exogenous EGF to the drinking water did not accelerate the rate of healing in BALB/cJ or prediabetic NOD/LtJ; however, diabetic NOD/LtJ mice exhibited accelerated wound healing similar to healthy mice. These results demonstrate that loss of growth factors from saliva is associated with profoundly reduced oral wound healing, suggesting that therapeutic treatment with topical delivery may be beneficial to patients with type 1 diabetes and oral wound complications.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Female; Homeostasis; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Organ Size; RNA, Messenger; Tongue; Wound Healing; Wounds and Injuries

A novel member of the low density lipoprotein receptor (LDLR) gene family has been identified and characterized. This gene, termed LDL receptor-related protein 6 (LRP6), encodes a transmembrane protein which has 71% identity and is structurally similar to the protein encoded by LRP5, a proposed candidate gene for type 1 diabetes located on human chromosome 11q13. LRP6 maps to human chromosome 12p11-p13. Mouse Lrp6 encodes a protein that has 98% identity to human LRP6 and maps to chromosome 6. Unlike other members of the LDLR family, LRP6 and LRP5 display a unique pattern of four epidermal growth factor (EGF) and three LDLR repeats in the extracellular domain. The cytoplasmic domain of LRP6 is not similar to other members of the LDLR family, while comparison with LRP5 reveals proline-rich motifs that may mediate protein-protein interactions. Thus, it is likely that LRP6 and LRP5 comprise a new class of the LDLR family.

Topics: Amino Acid Sequence; Animals; Chromosome Mapping; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 12; Cloning, Molecular; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Gene Library; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Mice; Molecular Sequence Data; Multigene Family; Polymerase Chain Reaction; Receptors, Immunologic; Recombinant Proteins; Sequence Alignment; Sequence Homology, Amino Acid

Urinary epidermal growth factor (EGF) excretion is seen as a marker of tubular function, and some studies conclude that EGF excretion can already be reduced early in the development of diabetic renal disease. It is even suggested that EGF could play a role in kidney and glomerular enlargement and hypertrophy in diabetic subjects. We have investigated various groups of subjects, namely healthy controls (n = 5), patients with non-diabetic chronic renal insufficiency (n = 10), and normoalbuminuric (n = 9), microalbuminuric (n = 13) and nephropathic (n = 9) insulin-dependent diabetic subjects. In all subjects glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured using a continuous infusion of 125I-iothalamate and 131I-hippuran, respectively. Diabetic subjects were tested during (near) normoglycaemic conditions. During the renal function test urine was collected for EGF measurement (in ng). With lower GFR values, EGF excretion/min was also lower. GFR correlated well with EGF/min (r = 0.63, p < 0.001). Fractional EGF clearance (EGF/GFR) was comparable in all groups. There was no correlation between urinary albumin excretion rate and EGF excretion in the diabetic subjects (r = -0.18, n.s.) and in all subjects (r = -0.12, n.s.). There was a significant correlation between UAER and GFR (r = -0.51, p < 0.005). No significant correlation could be found between urinary albumin excretion rate (UAER) and EGF/GFR (r = -0.07, n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Albuminuria; Biomarkers; Blood Flow Velocity; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Epidermal Growth Factor; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Circulation

Based on previous findings that epidermal growth factor (EGF), which plays an important role in maintenance of spermatogenesis, is deficient in diabetic mice, the significance of EGF deficiency in the pathogenesis of oligozoospermia in streptozotocin-induced diabetic mice was studied. EGF levels in the submandibular glands and plasma of diabetic mice were 0.61 +/- 0.07 micrograms/mg tissue and 0.25 +/- 0.02 ng/ml (mean +/- SE), respectively, whereas those of normal mice were 1.63 +/- 0.08 micrograms/mg tissue and 0.54 +/- 0.04 ng/ml, respectively. The epididymal sperm counts of diabetic mice, 4.7 +/- 0.14 x 10(5)/mg tissue, were significantly lower (P less than 0.01) than those of normal mice, 6.0 +/- 0.10 x 10(5)/mg tissue. Administration of EGF (5 micrograms/mouse/day) to diabetic mice significantly (P less than 0.01) increased their sperm counts to 5.5 +/- 0.16 x 10(5)/mg tissue without affecting plasma levels of testosterone and glucose. Furthermore, insulin treatment (1 U/mouse/day) of diabetic mice restored the submandibular gland, plasma EGF concentrations, and sperm counts to normal levels. The restorative effects of insulin on sperm production appeared to be mediated, at least in part, by EGF, because its effect was significantly (P less than 0.01) reduced by the concomitant administration of EGF antiserum. In addition, the plasma testosterone levels of diabetic mice, 67 +/- 14.3 ng/ml, were lower that those of normal mice, 122 +/- 19.1 ng/ml. Administration of testosterone (1 mg/mouse/day) normalized the submandibular gland and plasma EGF levels and significantly increased sperm counts in the epididymis. These results suggest that EGF deficiency is a possible cause for the pathogenesis of oligozoospermia in diabetic mice.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Epididymis; Immune Sera; Insulin; Male; Mice; Mice, Inbred Strains; Oligospermia; Sperm Count; Streptozocin; Submandibular Gland; Testosterone

Parotid saliva was collected over a 12-min period from 24 insulin dependent diabetic patients with varying degrees of autonomic neuropathy and 12 age and sex matched non-diabetic controls. Epidermal growth factor (EGF) concentrations in saliva were measured by radio-immunoassay. The EGF concentrations in diabetics with no autonomic neuropathy or with combined autonomic neuropathy were equivalent but secretion of EGF was significantly elevated at the 6- and 12-min periods of collection in diabetic patients with early or established autonomic neuropathy. It is postulated that when parasympathetic autonomic neuropathy is present a relative "over-activity" of the sympathetic innervation promotes release of salivary EGF. This sympathetic predominance may maintain salivary EGF concentration despite the elevated salivary flow and volume which is associated with parasympathetic autonomic neuropathy.

Topics: Autoimmune Diseases; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Female; Humans; Male; Parotid Gland; Saliva; Sympathetic Nervous System

Excretion of epidermal growth factor (EGF) is decreased in renal failure. We assayed it in diabetes mellitus in an attempt to relate it to clinical parameters, esp. those of diabetic nephropathy. EGF excretion declined with age but in all age groups of diabetic patients was below the first percentile for controls. In 26 control and 34 prepubertal diabetic children excretion was correspondingly 1126 +/- 442 and 932 +/- 489 pmol/mmol creatinine (P = 0.087); in 26 control and 42 diabetic adolescents below age 18, 778 +/- 222 and 676 +/- 335 (P = 0.023) and in 81 control and 83 diabetic adults, 371 +/- 153 and 235 +/- 140 (P less than 0.0001). Decreased excretion of EGF was seen in some patients without any diabetic complications. Excretion of EGF was independently and inversely correlated with age and duration of diabetes but not with type of diabetes, treatment, body built, C-peptide, plasma glucose, glycohemoglobin or retinopathy. A positive correlation was seen with creatinine clearance and a negative correlation, with albuminuria, but the strongest and the only independent correlation found by stepwise multiple variable selection was with serum creatinine (r -0.711, P less than 0.0001). EGF excretion was not elevated in patients with hyperfiltration. We conclude that EGF excretion is abnormal in many patients with diabetes and that this abnormality reflects a kidney function different from glomerular filtration or glomerular permeability.

Topics: Adolescent; Adult; Aged; Aging; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epidermal Growth Factor; Female; Humans; Male; Puberty

To study the relationship between glomerular and tubular function we investigated glomerular filtration rate (GFR), urinary albumin excretion, and urinary excretion of epidermal growth factor (EGF, a mitogenic peptide synthesized in the renal tubular cells) in normal subjects (group I, n = 7) and in Type 1 (insulin-dependent) diabetic patients with normoalbuminuria (group II, n = 11); with incipient nephropathy (microalbuminuria) (group III, n = 9); with nephropathy and normal GFR (group IV, n = 12); and with reduced GFR (group V, n = 8). EGF (nmol 24 h-1) decreased with progressive glomerular involvement, from 7.9 (4.1-10.5) (median and range) in group I, to 6.7 (1.3-9.2) in group II, 5.0 (3.6-7.4) in group III, 4.1 (2.5-9.5) in group IV, and 1.1 (0.1-2.5) in group V. The urinary excretion of EGF was significantly reduced in patients with elevated UAE (group III, IV, and V) compared with normal control subjects (p less than 0.05). A significant correlation between urinary excretion of EGF and GFR (r = 0.71, p less than 0.001) and an inverse correlation between the urinary excretion of EGF and albumin (r = -0.35, p less than 0.05) was demonstrated in the Type 1 diabetic patients with GFR greater than 90 ml min-1. Our study demonstrates that urinary excretion of epidermal growth factor diminishes with increasing nephron impairment, and that renal tubular function as judged by the excretion of EGF is reduced early in the development of diabetic kidney disease.

Topics: Adult; Albuminuria; Biomarkers; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Epidermal Growth Factor; Female; Glomerular Filtration Rate; Humans; Male; Reference Values