epidermal-growth-factor and Diabetes-Mellitus--Type-2

Type 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate beta-cell compensation. Currently available therapeutic agents lower blood glucose through multiple mechanisms but do not directly reverse the decline in beta-cell mass. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by Exenatide (exendin-4), not only acutely lower blood glucose but also engage signaling pathways in the islet beta-cell that lead to stimulation of beta-cell replication and inhibition of beta-cell apoptosis. Similarly, glucose-dependent insulinotropic polypeptide (GIP) receptor activation stimulates insulin secretion, enhances beta-cell proliferation, and reduces apoptosis. Moreover, potentiation of the endogenous postprandial levels of GLP-1 and GIP via inhibition of dipeptidyl peptidase-IV (DPP-IV) also expands beta-cell mass via related mechanisms. The thiazolidinediones (TZDs) enhance insulin sensitivity, reduce blood glucose levels, and also preserve beta-cell mass, although it remains unclear whether TZDs affect beta-cell mass via direct mechanisms. Complementary approaches to regeneration of beta-cell mass involve combinations of factors, exemplified by epidermal growth factor and gastrin, which promote islet neogenesis and ameliorate diabetes in rodent studies. Considerable preclinical data support the concept that one or more of these therapeutic approaches, alone or in combination, may potentially reverse the decline in beta-cell mass that is characteristic of the natural history of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Epidermal Growth Factor; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Agents; Glucagon-Like Peptide-1 Receptor; Humans; Insulin-Secreting Cells; Receptors, Glucagon; Thiazolidinediones

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

To investigate whether the addition of human recombinant epidermal growth factor (h-EGF) to 2% carboxymethyl cellulose gel is more effective in diabetic wound healing than standard treatment, a pilot, double-blind, randomized and controlled clinical trial with therapeutic intervention was performed at a university hospital. The sample consisted of 25 patients (14 in the intervention group that used rh-EGF and 11 in the control group that used 2% carboxymethyl cellulose gel). Data were tabulated in SPSS and analysed by intention to treat, without loss or exclusion of participants. Twenty-five subjects participated with a mean age of 60.6 years, a predominance of males in both groups and 100% prevalence of type-2 diabetes. Within 12 weeks, complete wound healing occurred in three ulcers in the intervention group versus one ulcer in the control group. The percent reduction in the wound area was significantly higher in the intervention group than in the control group (p = 0.049). Concerning the types of tissue, an increase in granulation and epithelial tissue and a reduction in exudate levels were observed in both groups. Decreased slough occurred only in the intervention group. No participant experienced serious or local adverse events during the study period. This study shows that h-EGF is effective, with a statistically significant reduction in wound area, improvement of tissue quality, and safe treatment of chronic wounds. In addition, this study demonstrated that blinding of participants during research using h-EGF is feasible.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Epidermal Growth Factor; Humans; Leg Ulcer; Male; Middle Aged; Wound Healing

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

As oxidative stress contributes to both progression and pathologic complications of diabetes and effective therapeutic strategies to prevent or delay the damage remain limited, the aim of the present study was to assess the efficacy of pentoxifylline in reducing of oxidative stress. Since there is a relationship between nitric oxide (NO), epidermal growth factor (EGF) and oxidative stress, we measured the effect of this drug on these parameters in comparison to placebo.. Thirty-nine patients with type-2 diabetes mellitus were randomized in a double blind, placebo-controlled clinical trial to receive either pentoxifylline 400 mg four times a day or placebo for 14 days. Blood samples were obtained at baseline and at the end of the study. Samples were analyzed for thiobarbituric reactive substances (TBARS) as a marker of lipid peroxidation, ferric reducing ability (total antioxidant power, TAP), EGF and NO levels.. Pentoxifylline in comparison to placebo was effective (P < 0.05) in reduction of lipid peroxidation in plasma of the patients without significant effects on TAP, levels of EGF and NO in plasma.. Adding of pentoxifylline to drug regimen of diabetic type-2 patients can be helpful. Exact mechanism of action of pentoxifylline in reduction of blood lipid peroxidation remains to be elucidated.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Epidermal Growth Factor; Female; Free Radical Scavengers; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipid Peroxidation; Male; Metformin; Middle Aged; Nitric Oxide; Oxidative Stress; Pentoxifylline; Sulfonylurea Compounds; Thiobarbituric Acid Reactive Substances; Time Factors; Treatment Outcome

To compare the effect of the antihypertensive drugs nitrendipine and enalapril on the excretion of epidermal growth factor (EGF) and albumin in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) subjects.. After a 4-week washout period, mildly hypertensive (systolic blood pressure [sBP] > or = 140 mmHg and/or diastolic blood pressure [dBP] > or = 90 mmHg) NIDDM patients with albuminuria (15-200 micrograms/min) were randomized into an 8-month-long therapy with either nitrendipine (n = 11) or enalapril (n = 10). Blood pressure, EGF, and microalbumin excretion were measured at baseline and throughout the treatment period.. A significant fall in sBP was noticed in the enalapril group and in dBP in the nitrendipine group. In the enalapril group, EGF excretion progressively increased from 188 to 214 nmol/mmol creatinine after 6 weeks and to 274 after 8 months of therapy (P = 0.03). There was a significant fall in albumin excretion while patients were on enalapril, but in the nitrendipine group, neither albuminuria nor EGF excretion changed significantly. There was no correlation of improved EGF excretion with a decrease in albuminuria or BP.. The angiotensin-converting enzyme inhibitor enalapril has been effective in decreasing albumin and increasing EGF excretion. Measurement of urinary EGF may provide a new valuable index of renal function.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Epidermal Growth Factor; Humans; Hypertension; Middle Aged; Nitrendipine

We evaluated the effect of topical epidermal growth factor treatment on healing of chronic wounds in a prospective, open-label, crossover trial. Five males and four females who ranged in age from 40 to 72 years (average 57 +/- 9 years) were enrolled. Four patients had adult-onset diabetes mellitus, two had rheumatoid arthritis, two had old burn scars, and one had a failed abdominal incision. The average duration of the ulcers prior to treatment with epidermal growth factor was 12 +/- 5 months (range 1 to 48 months). Following failure of the wounds to heal with conventional therapies, including debridement, skin graphs, and vascular reconstruction, wounds were treated twice daily with Silvadene alone for periods ranging from 3 weeks to 6 months. No evidence of healing was observed in any of the patients' wounds during Silvadene treatment, and patients were crossed over to twice a day treatment with Silvadene containing 10 micrograms epidermal growth factor per gram. Wounds of eight patients healed completely with epidermal growth factor-Silvadene treatment in an average of 34 +/- 26 days (mean +/- SD, range 12 to 92 days) and did not reoccur for periods ranging from 1 to 4 years. One patient failed therapy. These results suggest that topical treatment of chronic wounds with epidermal growth factor may stimulate healing.

Topics: Administration, Cutaneous; Adult; Aged; Arthritis, Rheumatoid; Burns; Chronic Disease; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prospective Studies; Silver Sulfadiazine; Skin Ulcer; Wound Healing

Recent years have witnessed a growing research interest in traditional Chinese medicine as a neuroprotective nutrient in the management of diabetic cognitive dysfunction. However, the underlying molecular mechanisms of sinomenine in mediating ferroptosis of hippocampal neurons have been poorly understood. This study sought to decipher the potential effect and molecular mechanism of sinomenine in the cognitive dysfunction following type 2 diabetes mellitus (T2DM). Multi-omics analysis was conducted to identify the microbiota-gut-brain axis in T2DM patient samples obtained from the publicly available database. In HT-22 cells, erastin was utilized to create a ferroptosis model, and streptozotocin was injected intraperitoneally to create a rat model of DM. It was noted that intestinal flora imbalance occurred in patients with T2DM-associated cognitive dysfunction. Sinomenine could reduce Erastin-induced hippocampus neuronal ferroptosis by increasing EGF expression. EGF protected hippocampal neurons against ferroptosis by activating the Nrf2/HO-1 signaling pathway. Furthermore, in vivo results confirmed that sinomenine blocked ferroptosis of hippocampal neurons and alleviated cognitive dysfunction in T2DM rats. Collectively, these results suggest that sinomenine confers neuroprotective effects by curtailing hippocampal neuron ferroptosis via the EGF/Nrf2/HO-1 signaling and microbiota-gut-brain axis. It may be a candidate for the treatment of diabetic cognitive dysfunction.

Topics: Animals; Brain-Gut Axis; Cognition; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Ferroptosis; Hippocampus; Neurons; NF-E2-Related Factor 2; Rats; Signal Transduction

Diabetic foot ulcers (DFU) are a common complication of Type 2 Diabetes Mellitus (T2DM). Development of bioactive wound healing covers is an important task in medicine. The use of autologous platelet-rich plasma (PRP) consisting of growth factors, cytokines and components of extracellular matrix is a perspective approach for DFU treatment, but we previously found that some T2DM PRP samples have a toxic effect on mesenchymal stem cells (MSCs) in vitro. Here, we covalently immobilized T2DM PRP proteins on polycaprolactone (PCL) nanofibers, and the growth of endothelial cells on the PCL-COOH-PRP was investigated. Additionally, the level of NO reflecting the cytotoxic effects of PRP, angiogenin, and VEGF levels were measured in T2DM PRP samples. The results showed that the application of PCL-COOH-PRP nanofibers allows to remove the cytotoxicity of T2DM PRP and to improve endothelial cell adhesion and proliferative activity. We showed that the origin of T2DM PRP (the level of PRP toxicity or presence/absence of DFU) does not influence the efficiency of cell growth on PCL-COOH-PRP, and on the level of angiogenin, vascular epidermal growth factor (VEGF) in PRP itself.

Topics: Cell Proliferation; Diabetes Mellitus, Type 2; Diabetic Foot; Endothelial Cells; Epidermal Growth Factor; Humans; Nanofibers; Platelet-Rich Plasma; Vascular Endothelial Growth Factor A

Cell-cell interactions are necessary for optimal endocrine functions in the pancreas. β-cells, characterized by the expression and secretion of the hormone insulin, are a major constituent of functional micro-organs in the pancreas known as islets of Langerhans. Cell-cell contacts between β-cells are required to regulate insulin production and glucose-stimulated insulin secretion, which are key determinants of blood glucose homeostasis. Contact-dependent interactions between β-cells are mediated by gap junctions and cell adhesion molecules such as E-cadherin and N-CAM. Recent genome-wide studies have implicated Delta/Notch-like EGF-related receptor

Topics: Adult; Animals; Blood Glucose; Cadherins; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Homeostasis; Humans; Insulin; Mice

Underlying molecular mechanisms of the kidney protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with type 2 diabetes (T2D). The underlying molecular mechanisms of the SGLT2 inhibitor canagliflozin on EGF using single-cell RNA sequencing from kidney tissue were examined. Urinary EGF-to-creatinine ratio (uEGF/Cr) was measured in 3521 CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52. Associations of uEGF/Cr with kidney outcome were assessed using multivariable-adjusted Cox regression models. Single-cell RNA sequencing was performed using protocol kidney biopsy tissue from ten young patients with T2D on SGLT2i, six patients with T2D on standard care only, and six healthy controls (HCs). In CANVAS, each doubling in baseline uEGF/Cr was associated with a 12% (95% confidence interval 1-22) decreased risk of kidney outcome. uEGF/Cr decreased after 52 weeks with placebo and remained stable with canagliflozin (between-group difference +7.3% (2.0-12.8). In young persons with T2D, EGF mRNA was primarily expressed in the thick ascending loop of Henle. Expression in biopsies from T2D without SGLT2i was significantly lower compared to HCs, whereas treatment with SGLT2i increased EGF levels closer to the healthy state. In young persons with T2D without SGLT2i, endothelin-1 emerged as a key regulator of the EGF co-expression network. SGLT2i treatment was associated with a shift towards normal EGF expression. Thus, decreased uEGF represents increased risk of kidney disease progression in patients with T2D. Canagliflozin increased kidney tissue expression of EGF and was associated with a downstream signaling cascade linked to tubular repair and reversal of tubular injury.

Topics: Canagliflozin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Glucose; Humans; Sodium; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Epidermal downgrowth around percutaneous devices produce sinus tracts, which then accumulate bacteria becoming foci of infection. This mode to failure is epidermal-centric, and is accelerated by changes in the chemokines and cytokines of the underlying periprosthetic granulation tissue (GT). In order to more fully comprehend the mechanism of downgrowth, in this 28-day study, percutaneous devices were placed in 10 Zucker diabetic fatty rats; 5 animals were induced with diabetes mellitus II (DM II) prior to the surgery and 5 animals served as a healthy, nondiabetic cohort. At necropsy, periprosthetic tissues were harvested, and underwent histological and polymerase chain reaction (PCR) studies. After isolating GTs from the surrounding tissue and extracting ribonucleic acids, PCR array and quantitative-PCR (qPCR) analyses were carried-out. The PCR array for 84 key wound-healing associated genes showed a five-fold or greater change in 31 genes in the GTs of healthy animals compared to uninjured healthy typical skin tissues. Eighteen genes were overexpressed and these included epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR). Thirteen genes were underexpressed. When GTs of DM II animals were compared to healthy animals, there were 8 genes overexpressed and 25 genes underexpressed; under expressed genes included EGF and EGFR. The qPCR and immunohistochemistry data further validated these observations. Pathway analysis of genes up-regulated 15-fold or more indicated two, EGFR and interleukin-10, centric clustering effects. It was concluded that EGFR could be a key player in exacerbating the epidermal downgrowth, and might be an effective target for preventing downgrowth.

Topics: Alloys; Animals; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Epidermal Growth Factor; ErbB Receptors; Gene Expression Regulation; Granulation Tissue; Humans; Male; Pilot Projects; Prosthesis Implantation; Rats, Zucker; Skin; Titanium; Wound Healing

To enhance the understanding of dry eye (DE) in diabetes by evaluating the ocular surface characteristics and the levels of tear inflammatory cytokines.. Cross-sectional study.. Subjects were divided into 4 groups: 32 patients in the diabetes with DE group; 24 patients in the diabetes without DE group; 28 patients in the nondiabetes with DE group; and 29 volunteers in the normal group. Ocular surface disease index (OSDI) was self-answered and ocular surface characteristics including tear film break-up time (BUT), Schirmer I test, corneal fluorescein staining (CFS), and corneal sensitivity were evaluated. Concentrations of epidermal growth factor (EGF), IL-17A, IL-1β, and tumor necrosis factor alpha (TNF-α) were measured by mutiplex bead analysis. Spearman correlations between cytokines and ocular surface parameters were calculated.. The level of EGF in tears significantly increased in the diabetes with DE group and positively correlated with the CFS and negatively correlated with the Schirmer I test in this group (P < .05). No differences were found in the levels of IL-17A, IL-1β, and TNF-α in the diabetes with DE and diabetes without DE groups compared to the normal group (P > .05). The nondiabetes with DE group showed increased levels of IL-17A, IL-1β, and TNF-α in tears compared to the normal group and the levels of IL-1β and TNF-α in tears positively correlated with CFS (P < .05).. Our study showed that levels of EGF in tears have potential to be the diagnostic biomarker of DE in diabetes. No differences of IL-17A, IL-1β, and TNF-α in tears were found between the diabetes with DE and normal group, suggesting different pathogenesis of diabetes DE vs nondiabetes DE.

Topics: Aged; Biomarkers; Cross-Sectional Studies; Cytokines; Diabetes Mellitus, Type 2; Dry Eye Syndromes; Epidermal Growth Factor; Eye Proteins; Female; Humans; Interleukin-17; Interleukin-1beta; Male; Middle Aged; Tears

To identify determinants of early progressive renal decline in type 2 diabetes a range of markers was studied in 1032 patients enrolled into the 2nd Joslin Kidney Study. eGFR slopes estimated from serial measurements of serum creatinine during 5-12 years of follow-up were used to define early renal decline. At enrollment, all patients had normal eGFR, 58% had normoalbuminuria and 42% had albuminuria. Early renal decline developed in 6% and in 18% patients, respectively. As determinants, we examined baseline values of clinical characteristics, circulating markers: TNFR1, KIM-1, and FGF23, and urinary markers: albumin, KIM-1, NGAL, MCP-1, EGF (all normalized to urinary creatinine) and the ratio of EGF to MCP-1. In univariate analysis, all plasma and urinary markers were significantly associated with risk of early renal decline. When analyzed together, systolic blood pressure, TNFR1, KIM-1, the albumin to creatinine ratio, and the EGF/MCP-1 ratio remained significant with the latter having the strongest effect. Integration of these markers into a multi-marker prognostic test resulted in a significant improvement of discriminatory performance of risk prediction of early renal decline, compared with the albumin to creatinine ratio and systolic blood pressure alone. However, the positive predictive value was only 50% in albuminuric patients. Thus, markers in plasma and urine indicate that the early progressive renal decline in Type 2 diabetes has multiple determinants with strong evidence for involvement of tubular damage. However, new, more informative markers are needed to develop a better prognostic test for such decline that can be used in a clinical setting.

Topics: Adult; Albuminuria; Biomarkers; Blood Pressure; Chemokine CCL2; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Early Diagnosis; Epidermal Growth Factor; Female; Fibroblast Growth Factor-23; Glomerular Filtration Rate; Hepatitis A Virus Cellular Receptor 1; Humans; Kidney; Male; Middle Aged; Predictive Value of Tests; Prognosis; Receptors, Tumor Necrosis Factor, Type I; Risk Assessment; Risk Factors; Time Factors

To assess changes in metabolic risk factors and cancer-related growth factors associated with short-term abstinence from alcohol.. Prospective, observational study.. Single tertiary centre.. Healthy subjects were recruited based on intention to: (1) abstain from alcohol for 1 month (abstinence group), or (2) continue to drink alcohol (control group). Inclusion criteria were baseline alcohol consumption >64 g/week (men) or >48 g/week (women). Exclusion criteria were known liver disease or alcohol dependence.. The primary outcome was change in insulin resistance (homeostatic model assessment (HOMA) score). Secondary outcomes were changes in weight, blood pressure (BP), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and liver function tests. Primary and secondary outcomes were adjusted for changes in diet, exercise and cigarette smoking.. The abstinence group comprised 94 participants (mean age 45.5 years, SD ±1.2) and the control group 47 participants (mean age 48.7 years, SD ±1.8). Baseline alcohol consumption in the abstinence group was 258.2 g/week, SD ±9.4, and in the control group 233.8 g, SD ±19.0. Significant reductions from baseline in the abstinence group (all p<0.001) were found in: HOMA score (-25.9%, IQR -48.6% to +0.3%), systolic BP (-6.6%, IQR -11.8% to 0.0%), diastolic BP (-6.3%, IQR -14.1% to +1.3%), weight (-1.5%, IQR -2.9% to -0.4%), VEGF (-41.8%, IQR -64.9% to -17.9%) and EGF (-73.9%, IQR -86.1% to -36.4%). None of these changes were associated with changes in diet, exercise or cigarette smoking. No significant changes from baseline in primary or secondary outcomes were noted in the control group.. These findings demonstrate that abstinence from alcohol in moderate-heavy drinkers improves insulin resistance, weight, BP and cancer-related growth factors. These data support an independent association of alcohol consumption with cancer risk, and suggest an increased risk of metabolic diseases such as type 2 diabetes and fatty liver disease.

Topics: Adult; Alcohol Drinking; Alcoholism; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Ethanol; Fatty Liver; Female; Humans; Insulin Resistance; Liver; Liver Function Tests; Male; Middle Aged; Neoplasms; Prospective Studies; Risk Factors; Vascular Endothelial Growth Factor A

To compare the serum proangiogenic biomarkers in diabetic patients suffering from with and without diabetic retinopathy (DR).. An observational study.. Arif Memorial Teaching Hospital, Lahore, Pakistan and Institute of Molecular Biology and Biotechnology/Centre for Research in Molecular Medicine, The University of Lahore, Lahore, Pakistan, from March to December 2017.. Forty patients with DR were included in group A and 15 patients without retinopathy (controls) were included in group B. Twelve serum pro-angiogenic biomarkers [Angiopoietin 2, Human Growth Factor (HGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), Placental Growth Factor (PLGF), Vascular Endothelial Growth Factor-A and C (VEGF-A and VEGF-C), Bone Morphogenetic Protein 9 (BMP9), Follistatin, Leptin, Interleukin-8 (IL8), Endothelin (ET)] were analysed by xMAP flow cytometry technique, results were compared between the two groups and statistical analysis was done using Mann-Whitney U test.. Serum ET, Follistatin and EGF were significantly raised in group A as compared to group B having p-values of 0.001, <0.001, and 0.033, respectively. Serum BMP9, Leptin, HGF, FGF and VEGF-C had p <0.001, 0.023, 0.020, and 0.009, respectively and were higher in group B than group A.. Serum ET, Follistatin and EGF were significantly higher in DR patients as compared to those without DR and should be considered to be significant biomarkers of retinal complications in diabetes mellitus.

Topics: Adult; Aged; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Endothelins; Epidermal Growth Factor; Female; Flow Cytometry; Follistatin; Humans; Male; Middle Aged; Pakistan; Vascular Endothelial Growth Factor A

Increased monocyte chemoattractant protein-1 (MCP-1) and decreased epidermal growth factor (EGF) are promising biomarkers to predict progressive decline in kidney function in non-diabetic kidney diseases. We aimed to evaluate the performance of urinary EGF, MCP-1 or their ratio in predicting rapid decline of GFR in a cohort of Type 2 diabetic patients (T2DM) with diabetic kidney disease (DKD).. T2DM patients (n = 83) with DKD at high risk for renal progression were followed up prospectively. The baseline urine values of MCP-1 to creatinine ratio (UMCP-1), EGF to creatinine ratio (UEGF), EGF to MCP-1 ratio (UEGF/MCP-1) and albumin to creatinine ratio (UACR) were measured. The primary outcome was a decline in estimated glomerular filtration rate (GFR) of ≥25% yearly from baseline.. During follow-up time of 23 months, patients with rapid decline in estimated GFR of ≥25% yearly from baseline had significantly higher baseline levels of UMCP-1, and UACR and lower UEGF and UEGF/MCP-1 ratio. All renal biomarkers predicted primary outcomes with ROC (95%CI) for UMCP-1=0.73 (0.62-0.84), UEGF=0.68 (0.57-0.80), UEGF/MCP-1=0.74 (0.63-0.85), and UACR =0.84 (0.75-0.93). By univariate analysis, blood pressure, GFR, UACR, UMCP-1, UEGF, and UEGF/MCP-1 were associated with rapid decline GFR. By multivariate analysis, UACR, systolic blood pressure, and UMCP-1 or UEGF/MCP-1 were independently associated with rapid GFR decline.. UMCP-1 or UEGF/MCP-1 ratio were associated with rapid renal progression independent from conventional risk factors in DKD.

Topics: Aged; Albuminuria; Biomarkers; Cardiovascular Diseases; Chemokine CCL2; Creatinine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Disease Progression; Epidermal Growth Factor; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prospective Studies; Risk Factors

There is a growing interest in low-grade inflammatory and metabolic alterations in patients with chronic schizophrenia (SCH).. Inflammatory (tumor-necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukins [IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10], monocyte chemo-attractant protein-1 [MCP-1]) and growth factors (vascular endothelial growth factor [VEGF], epidermal growth factor [EGF]) were measured in blood serum samples of 105 SCH patients and 148 control subjects (CS). Simultaneously the clinical biomarkers (C-reactive protein [CRP], triglycerides [TG], low-density lipoprotein [LDL-c] and high-density lipoprotein [HDL-c] cholesterol, glycated hemoglobin [HbA1c]) were measured, and body mass index (BMI) was calculated for patients.. Several cyto-/chemokines (IFN-γ, MCP-1, IL-2, IL-6, IL-8 and IL-10) were significantly (P<0.0000001) elevated in SCH patients compared to CS. Odds ratios, obtained from logistic regression analyses, were significantly elevated for IL-2, IL-6, IL-10, INF-γ, and decreased for TNF-α in SCH group. Among the patients, higher IL-2, IL-6, INF-γ and lower MCP-1 levels as well as male gender were together significant (P<0.000001) predictors of higher HbA1c levels, and TG/HDL-c parameter was associated with ratios of INF-γ/IL-10 (P=0.004), and INF-γ/IL-4 (P=0.049), HbA1c (P=0.005), INF-γ (P=0.009), as well as LDL-c (P=0.02) levels.. IL-2, IL-6, IL-10 and IFN-γ were the most significant SCH-related markers among the measured cytokines in our patient group. Furthermore, significant associations between pro-/anti-inflammatory imbalance and HbA1c as well as cardio-metabolic risk marker (TG/HDL-c) were observed, indicating higher risks of diabetes and cardiovascular diseases among SCH patients.

Topics: Adult; Cytokines; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Female; Humans; Inflammation; Male; Middle Aged; Obesity; Schizophrenia; Vascular Endothelial Growth Factor A

Pancreatic ductal adenocarcinoma (PDAC) is one of the most potent and perilous diseases known, with a median survival rate of 3-5 months due to the combination of only advanced stage diagnosis and ineffective therapeutic options. Metformin (1,1-Dimethylbiguanide hydrochloride), the leading drug used for type 2 diabetes mellitus, emerges as a potential therapy for PDAC and other human cancers. Metformin exerts its anticancer action via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)- dependent and/or AMPK-independent mechanisms. We present data here showing that metformin downregulated pancreatic transcription factor pancreatic duodenal homeobox-1 (PDX-1), suggesting a potential novel mechanism by which metformin exerts its anticancer action. Metformin inhibited PDX-1 expression at both protein and mRNA levels and PDX-1 transactivity as well in PDAC cells. Extracellular signal-regulated kinase (ERK) was identified as a PDX-1-interacting protein by antibody array screening in GFP-PDX-1 stable HEK293 cells. Co-transfection of ERK1 with PDX-1 resulted in an enhanced PDX-1 expression in HEK293 cells in a dose-dependent manner. Immunoprecipitation/Western blotting analysis confirmed the ERK-PDX-1 interaction in PANC-1 cells stimulated by epidermal growth factor (EGF). EGF induced an enhanced PDX-1 expression in PANC-1 cells and this stimulation was inhibited by MEK inhibitor PD0325901. Metformin inhibited EGF-stimulated PDX-1 expression with an accompanied inhibition of ERK kinase activation in PANC- 1 cells. Taken together, our studies show that PDX-1 is a potential novel target for metformin in PDAC cells and that metformin may exert its anticancer action in PDAC by down-regulating PDX-1 via a mechanism involving inhibition of ERK signaling.

Topics: Adenocarcinoma; Carcinoma, Pancreatic Ductal; Cell Line; Cell Line, Tumor; Diabetes Mellitus, Type 2; Down-Regulation; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; Genes, Homeobox; HEK293 Cells; Homeodomain Proteins; Humans; MAP Kinase Signaling System; Metformin; Pancreas; Pancreatic Neoplasms; Protein Kinase Inhibitors; Signal Transduction; Trans-Activators

Pharmacoepidemiologic studies provide evidence that use of metformin, a drug commonly prescribed for type II diabetes, is associated with a substantial reduction in cancer risk. Experimental models show that metformin inhibits the growth of certain neoplasms by cell autonomous mechanisms such as activation of AMP kinase with secondary inhibition of protein synthesis or by an indirect mechanism involving reduction in gluconeogenesis leading to a decline in insulin levels and reduced proliferation of insulin-responsive cancers. Here, we show that metformin attenuates paraquat-induced elevations in reactive oxygen species (ROS), and related DNA damage and mutations, but has no effect on similar changes induced by H(2)0(2), indicating a reduction in endogenous ROS production. Importantly, metformin also inhibited Ras-induced ROS production and DNA damage. Our results reveal previously unrecognized inhibitory effects of metformin on ROS production and somatic cell mutation, providing a novel mechanism for the reduction in cancer risk reported to be associated with exposure to this drug.

Topics: Adenylate Kinase; Animals; Cell Line; Diabetes Mellitus, Type 2; DNA Damage; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Fibroblasts; Flow Cytometry; Humans; Hydrogen Peroxide; Hypoglycemic Agents; Insulin; Male; Metformin; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Mutagenesis; Mutation; NADP; Reactive Oxygen Species

Diabetes is increasing in the world and causes severe cardiovascular complications. Diabetes-induced limb ischemia leads to foot amputation and therapeutic remedies are urgently needed. Here we report that local injection of mesenchymal stem cells (MSCs) prestimulated with epidermal growth factor (EGF) restored blood flow and vasculogenesis in the ischemic hind-limb of type II diabetic (db(-)/db(-)) mice. Bone marrow cells from db(-)/db(-) mice are altered as evidenced by increased oxidative stress and reduced Akt and adhesion molecules when compared with control (db(-)/db(+)). Femoral artery ligation-induced ischemia was performed in the hind-limb of db(-)/db(-) and db(-)/db(+) mice for 28 days. Enhanced green fluorescent protein (EGFP)-MSCs stimulated+/-exogenous EGF for 24 h were injected locally into the ischemic muscle. Blood flow measured with MoorLDI-Laser and microangiography assessed with X-ray showed 100% recovery in db(-)/db(+) compared to 50% recovery in db(-)/db(-) mice. Interestingly, db(-)/db(-) mice had 60 and 96% blood flow recovery and 61 and 98% of vasculogenesis when treated with MSCs alone or MSCs modified with EGF, respectively. Western blot analysis of hind-limb muscles revealed an increase in Akt and vascular endothelial growth factor receptor phosphorylation and hypoxia-inducible factor) expression in db(-)/db(-) mice injected with MSCs or MSCs+EGF compared to db(-)/db(-) mice. Fluorescent microscopic images show that EGFP-MSCs differentiate into new microvessels. Adhesion and migration of MSCs on cultured endothelial cells were ICAM1-, VCAM1- and Akt-dependent mechanism and elevated when MSCs were prestimulated with EGF compared with nonstimulated MSCs. Our novel study data provide evidence that in type II diabetes, stimulated MSCs with EGF enhance the recovery of blood flow and angiogenesis.

Topics: Animals; Bone Marrow Cells; Cell Adhesion; Cell Movement; Diabetes Mellitus, Type 2; Endothelial Cells; Epidermal Growth Factor; Hindlimb; Hypoxia-Inducible Factor 1; Ischemia; Male; Mesenchymal Stem Cell Transplantation; Mice; Mice, Inbred C57BL; Multipotent Stem Cells; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A

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

Serum glucocorticoid regulated kinase (SGK-1) is induced in the kidney in diabetes mellitus. However, its role in the proximal tubule is unclear. This study determined the expression and functional role of SGK-1 in PTCs in high glucose conditions. As the epidermal growth factor (EGF) receptor is activated by both EGF and other factors implicated in diabetic nephropathy, the relationship of SGK-1 with EGFR activity was assessed.. mRNA and protein expression of SGK-1 and mRNA expression of the sodium hydrogen exchanger NHE3 were measured in human PTCs exposed to 5 mmol/L (control) and 25 mmol/L (high) glucose. The effects of SGK-1 on cell growth, apoptosis, and progression through the cell cycle and NHE3 mRNA were examined following overexpression of SGK-1 in PTCs. The role of EGFR activation in observed changes was assessed by phospho-EGFR expression, and response to the EGFR blocker PKI166. SGK-1 expression was then assessed in vivo in a model of streptozotocin-induced diabetes mellitus type 2.. A total of 25 mmol/L glucose and EGF (10 ng/mL) increased SGK-1 mRNA (P < 0.005 and P < 0.002, respectively) and protein (both P < 0.02) expression. High glucose and overexpression of SGK-1 increased NHE3 mRNA (P < 0.05) and EGFR phosphorylation (P < 0.01), which were reversed by PKI166. SGK-1 overexpression increased PTC growth (P < 0.0001), progression through the cell cycle (P < 0.001), and increased NHE3 mRNA (P < 0.01), which were all reversed with PKI166. Overexpression of SGK-1 also protected against apoptosis induced in the PTCs (P < 0.0001). Up-regulation of tubular SGK-1 mRNA in diabetes mellitus was confirmed in vivo. Oral treatment with PKI166 attenuated this increase by 51%. No EGF protein was detectable in PTCs, suggestive of phosphorylation of the EGFR by high glucose and downstream induction of SGK-1.. The effects of high glucose on PTC proliferation, reduced apoptosis and increased NHE3 mRNA levels are mediated by EGFR-dependent up-regulation of SGK-1.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epidermal Growth Factor; ErbB Receptors; Glucose; Humans; Immediate-Early Proteins; Kidney Tubules, Proximal; Phosphorylation; Protein Serine-Threonine Kinases; Rats; RNA, Messenger; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Up-Regulation

We evaluated the content of EGF in platelet lysates obtained from 49 patients with non-insulin-dependent diabetes mellitus (NIDDM)(18 males, 31 females, age 58 +/- 13 years) and from 23 clinically healthy control subjects (11 males, 12 females, age 53 +/- 18 years). Platelets were collected from platelet-rich plasma and lysed. EGF was determined by radioimmunoassay. The immunoreactive EGF content in the platelet lysates in diabetic patients significantly exceeded that of control subjects (44.9 +/- 18.5 pg/mm3platelet vs. 34.2 +/- 7.8 pg/mm3platelet, mean +/- SD p < 0.008). In performing multiple regression analysis with ten clinical parameters, urinary albumin excretion (F = 16.1, r = 0.551, p < 0.001), duration of diabetes (F = 13.0, r = 0.511, p < 0.001) and the presence of diabetic proliferative retinopathy (F = 8.8, p < 0.01) were significantly associated with irEGF content in platelet lysates. These observations suggest that the amount of EGF in platelets may increase with the progression of diabetic complications. The mechanism for the increase of EGF in platelets remains to be clarified.

Topics: Adult; Aged; Blood Platelets; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Platelet Count; Vascular Diseases

Morning urine samples were assayed for human EGF (hEGF) in 137 non-insulin dependent diabetic patients with normal serum creatinine and beta 2-microglobulin levels. Serving as controls, 80 age- and sex-matched healthy subjects were also examined. A significant positive correlation between hEGF excretion and the level of hemoglobin A1C (HbA1c) was present in those patients with a HbA1c value exceeding 8% (r = 0.37; p = 0.003) but not in the overall patients. The urinary hEGF level did not correlate with the concentration of glucose in urine or plasma. The mean urinary hEGF level of diabetic patients was significantly lower than that of healthy subjects. The mean urinary hEGF level was significantly lower in the patients with a diabetic history that exceeded five years as compared with those with a history below five years. The mean urinary hEGF level was significantly lower in the patients with retinopathy vs. those without retinopathy. In the patients with HbA1c value below 8%, the mean urinary hEGF level was lower in the patients whose urinary albumin level exceeded 1.7 mg/mmol.creatinine as compared with those whose urinary albumin excretion was below 1.7 mg/mmol.creatinine. These findings suggest that urinary hEGF excretion may decrease with the progression of diabetic complications in the patients with well-controlled glycemia, and that inadequate glycemic control may lead to an increased excretion of urinary hEGF in the early disease stage.

Topics: Adult; Aged; Albuminuria; Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Female; Glycosuria; Humans; Male; Middle Aged; Radioimmunoassay

The genetically diabetic db/db mouse is an excellent model to study the effect of diabetes on hormone receptors. The decrease of EGF binding sites could be detected in the hepatic microsomes of diabetic mice as early as 3 weeks of age. In addition, there was an age-related decrease in the autophosphorylating activity of EGF receptor isolated from the liver of diabetic mice. Estrone feeding (0.005%) partially restored this autophosphorylating activity. Northern blot analysis showed that the hepatic EGF receptor transcripts were dramatically decreased during the progression of diabetes and could be reversed by estrone feeding. Transfection experiments carried out on HepG2 cells using EGF receptor promoter (pERCAT-6) demonstrated that addition of 2 x 10(-8) M estrone stimulated chloramphenicol acetyltransferase activity. Our results suggest that estrone modulates EGF receptor by enhancing EGF receptor transcripts and the promoter activity of this gene.

Topics: Animals; Chloramphenicol O-Acetyltransferase; Diabetes Mellitus, Type 2; Epidermal Growth Factor; ErbB Receptors; Estrone; Female; Liver; Mice; Mice, Inbred C57BL; Phosphorylation; RNA, Messenger; Transforming Growth Factor alpha

Urinary human epidermal growth factor levels were assayed in diabetic patients and controls before and after surgery. The preoperative levels in the diabetic patients were decreased and postoperatively, did not show the trough and peak pattern which was seen in the controls.

Topics: Diabetes Mellitus, Type 2; Epidermal Growth Factor; Female; Humans; Male; Postoperative Period; Surgical Procedures, Operative

Serum very low molecular weight growth factor like-activity (S-VLMGA, molecular weight less than 3,000) and serum and urinary epidermal growth factor (S-, U-EGF) were investigated in 180 patients of non-insulin-dependent diabetes mellitus (NIDDM) by bioassay using skin fibroblast cells (CCD-27 SK) and enzyme- and radio-immunoassay, respectively. S-VLMGA was slightly elevated in NIDDM patients with retinopathy (RET) and/or neuropathy (NEU), but slightly decreased in those with nephropathy (NEP) compared with patients without complications, though the differences were not significant (without complications: 122 +/- 9, with RET and/or NEU and without NEP: 145 +/- 15, all with NEP: 110 +/- 8% of increased growth activity, mean +/- SE). The similar tendencies were seen in S- and U-EGF in the same groups. However the changes in S-EGF were small and the decrease of U-EGF in patients with NEP was remarkable (U-EGF of without complications: 22.7 +/- 2.5, with RET and/or NEU and without NEP: 24.5 +/- 4.2, all with NEP: 17.6 +/- 3.2 ng/mg creatinine, mean +/- SE). Furthermore, S-VLMGA was inversely, but U-EGF was positively related with the creatinine urinary vs serum ratio. Thus the concentrations of VLMGA and EGF in serum and urine depend on a renal permeability.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Female; Growth Substances; Humans; Male; Middle Aged; Molecular Weight

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