Epidermal growth factor and platelet-derived growth factor in blood in diabetes mellitus

Epidermal and platelet-derived growth factors are potent mitogens for many types of cells, including smooth muscle cells. Epidermal growth factor in blood of humans is present both in platelets (as reflected in its serum level) and in plasma, the source(s) of which remains unknown. We assayed its level in 82 diabetic patients and 53 age-matched controls. In diabetes, epidermal growth factor level was increased in serum (191 +/- 43 vs 155 +/- 64 pmol/l, p = 0.0002) and plasma (53 +/- 9 vs 38 +/- 14 pmol/l, p less than 0.0001), without any difference between the patients with and without complications. Platelet-derived growth factor level was assayed only in serum of 19 patients with uncomplicated diabetes and found elevated (222 +/- 47) as compared with 13 controls (160 +/- 26 pmol/l), (p = 0.0002). Type of diabetes, its duration, mode of therapy, control, presence of retinopathy or albuminuria (in case of epidermal growth factor), as well as C-peptide age and sex did not correlate with epidermal or platelet-derived growth factor levels. Serum but not plasma epidermal and platelet-derived growth factor were negatively correlated with serum creatinine (correspondingly, r = -0.373, p = 0.0008 and r = -0.564, p = 0.0285). It is concluded that diabetes itself and not its complications cause increased levels of epidermal growth factor in plasma and serum and of platelet-derived growth factor in serum.     

Leukocyte myeloperoxidase deficiency and diabetes mellitus associated with Candida albicans liver abscess.

Reported here is a case of hereditary myeloperoxidase deficinecy in a diabetic patient suffering from a Candida albicans liver abscess. Peroxidase activity is completely absent from the neutrophils and monocytes although it is present in the eosinophils. The different forms of myeloperoxidase deficiency are discussed.     

Oral disorders associated with diabetes mellitus.

The protean manifestations of diabetes include various associated oral disorders such as sialosis, xerostomia, impairment of taste, and localized infections of which oral candidosis is the most commonly observed. The association of specific oral diseases and diabetes is of importance both in the detection of undiagnosed diabetes and in the elucidation of the pathogenesis of various oro-facial diseases. The clinical features and possible causes of oral disorders recognized to be associated with diabetes are reviewed with emphasis on good oral hygiene in the diabetic patient.     

Riboflavin deficiency in children with diabetes mellitus

Summary Twenty-four insulin-dependent diabetic children and 114 normal control children, all between the ages of 6 to 16 years, were investigated for riboflavin deficiency. The method used was a measurement of erythrocyte glutathione reductase activity and the results were expressed as the activity coefficient (AC). None of the children had received vitamin supplementation. The percentage of diabetic children with riboflavin deficiency was 4 fold greater than in non diabetics. Supplementation with daily oral riboflavin quickly returned all AC values to normal.     

Epidermal growth factor in the oesophagus.

Epidermal growth factor (EGF) has been implicated in mitogenesis and oncogenesis in the gastrointestinal tract. To determine the role of EGF in oesophageal disease, its quantity and distribution in the oesophageal mucosa of control subjects and patients with oesophageal disease were studied. Oesophageal biopsy specimens, taken 20-40 cm from the incisors in 72 patients, were graded histologically and adjacent specimens were taken for immunohistochemical analysis of the distribution of EGF. In patients with Barrett's columnar lined oesophagus, specimens were also taken from the gastric cardia for comparison. Twenty two biopsy specimens showed oesophagitis, 20 Barrett's mucosa, and 30 were histologically normal. EGF was found in the capillary endothelium of the normal oesophageal papillae and basal mucosa. Significantly more EGF positive papillae were found in the normal mucosa (81%) than in the inflamed mucosa (42%) (p < 0.001). The 20 patients with Barrett's mucosa showed abnormal expression of EGF in 25% of the isthmus and superficial epithelial cells. This study has shown that EGF is found only in the endothelial cells of the capillaries of the normal oesophageal mucosa and that the peptide is detectable significantly less frequently than normal in the inflamed oesophageal mucosa. EGF is also abnormally present, in large quantities, in the cytoplasm of the epithelial cells of Barrett's mucosa compared with gastric mucosa.     

Epidermal growth factor inhibitors

PURPOSE: Tyrosine kinases are implicated in the normal cellular proliferation and in malignant transformation. Among the tyrosine kinase receptors, one of best described is the Epidermal Growth Factor Receptor (EGFR), which is widely expressed in particular in epithelial cells and in many human carcinomas. CURRENT KNOWLEDGE AND KEY POINTS: Compounds have been developed that target either the extracellular ligand-binding region of EGFR (Cetuximab) or the intracellular tyrosine kinase ATP-binding (Iressa), Tarceva. Phase I studies showed that these molecules have a favorable pharmacokinetic and pharmacodynamic profile, with excellent tolerance and easy administration. Phase II and III studies are currently testing their efficacy. FUTURE PROSPECTS AND PROJECTS: Preliminary results show interesting activity in different tumors, alone or in combination with either chemotherapy or radiotherapy. If these results are confirmed in larger trials including a high number of patients, these agents might be very useful in combination with chemotherapy, radiotherapy or other biological targeting agents such as cellular cycle inhibitors or antiangiogenics.     

Increased plasma basic fibroblast growth factor is associated with coronary heart disease in adult type 2 diabetes mellitus

Basic fibroblast growth factor (bFGF) is a potent endothelial and smooth muscle cell mitogen that does not normally circulate. Plasma bFGF-like bioactivity was increased in association with persistent microalbuminuria (a risk marker for cardiovascular disease) in adult type 2 diabetes mellitus. In the present study, we tested whether baseline plasma bFGF immunoreactivity (IR) predicts the occurrence of a subset of cardiovascular disease outcomes in adults with advanced type 2 diabetes mellitus from the Veterans Affairs Diabetes Trial (mean: age, 59 years; diabetes duration, 11 years; baseline hemoglobin A_1c, 9.5%). Plasma bFGF-IR was determined with a sensitive and specific 2-site enzyme-linked immunoassay in 399 patients at the baseline visit. These results were then evaluated as possible predictors of the occurrence of prespecified cardiovascular or coronary heart disease end points. There was a borderline-significant association (P = .07) between plasma bFGF-IR and the main study cardiovascular disease outcome (myocardial infarction, congestive heart failure, cerebrovascular accident, amputation, cardiovascular death, coronary, cerebrovascular or peripheral revascularization, and inoperable coronary artery disease). Plasma bFGF-IR was significantly associated with the occurrence of coronary heart disease (P = .01). After adjusting for clinical risk factors, bFGF (hazard ratio [HR], 1.013; 95% confidence interval [CI], 1.007-1.019; P < .0001), prior macrovascular event (HR, 3.55; 95% CI, 2.154-5.839; P < .0001), and duration of diabetes (HR, 1.041; 95% CI, 1.012-1.071; P = .0055) were all significantly associated with time to first postrandomization coronary heart disease occurrence. These results suggest that increased plasma bFGF-IR may be a novel risk marker for coronary heart disease occurrence in adult men with advanced type 2 diabetes mellitus.     

Insulin-dependent diabetes mellitus associated with pentamidine

Insulin-dependent diabetes mellitus occurred following intravenous pentamidine treatment of two AIDS patients with Pneumocystis carinii pneumonia. Both patients also experienced drug-induced nephrotoxicity. Patients receiving pentamidine must be observed for multisystem dysfunction, including the onset of severe diabetes mellitus. Dosage adjustment or alternative therapy should be considered with the onset of toxicity.     

Elevated hepatocyte growth factor in sera from patients with insulin-dependent diabetes mellitus

Hepatocyte growth factor (HGF) is a pleiotropic cytokine known to be involved in tissue regeneration and repair. We measured serum levels of HGF in patients with insulin-dependent diabetes mellitus (type 1). The patients were divided into four groups: (1) 10 patients at clinical presentation before insulin treatment; (2) 19 patients with newly diagnosed type 1 diabetes (diabetes duration 1/2–3 years); (3) 14 patients with long-standing type 1 diabetes without renal involvement (diabetes duration >10 years, and urinary albumin excretion (UAER) <20 μg/ min); and (4) 20 patients with long-standing type 1 diabetes with renal involvement (diabetes duration >10 years and UAER 20–500 μg/min). Sera from 24 age- and sex-matched healthy blood donors constituted a control group. The HGF levels of the four groups were (mean±SD); group 1, 0.74±0.14; group 2, 0.78±0.40; group 3, 0.86±0.42; group 4, 0.79±0.27 ng/ml, compared to 0.43±0.24 ng/ml in the control group (P<0.0008). HGF levels were not significantly different between the four patient groups. The elevated serum HGF levels did not correlate with complications related to type 1 diabetes, such as UAER, retinopathy and macrovascular complications, suggesting that HGF levels were not associated with the type 1 diabetes complications. In conclusion, our results show that type 1 diabetic patients have increased serum HGF levels compared with controls and that HGF is elevated to the same extent in newly diagnosed as well as in long-standing type 1 diabetes. Received: 29 November 1997 / Accepted in revised form: 11 March 1998     

Epidermal growth factor receptors in the oesophagus.

The quantity and distribution of epidermal growth factor receptors (EGF-R) in oesophageal mucosa was studied in the oesophagus in order to determine its role in oesophageal disease. Fifty five biopsies were taken from different levels of the oesophagus in 25 consecutive patients undergoing endoscopy. Another group of eight patients with histologically proven Barrett's oesophagitis had a biopsy taken from the area of columnar lined oesophagus. A peripheral, membranous pattern was seen predominantly confined to the basal and immediately suprabasal cells in all of the first group of patients. In the superficial cells a few granular cytoplasmic structures were positive. All patients with Barrett's oesophagitis showed EGF-R staining of the surface epithelium. A computerised planimeter was used to determine the proportion of stained areas of squamous cells which were expressed as a percentage of the total area of squamous cells. The difference in the area of cells stained for EGF-R between normal and inflamed oesophageal mucosa (29.5% and 43.1% respectively) was significant (p less than 0.001).     

Hepatocyte growth factor levels are associated with the results of I-metaiodobenzylguanidine myocardial scintigraphy in patients with type 2 diabetes mellitus

Elevated hepatocyte growth factor (HGF) levels and cardiovascular autonomic dysfunction are associated with a high mortality rate in patients with type 2 diabetes mellitus. We tested the hypothesis that elevated HGF is associated with insulin resistance and cardiovascular autonomic dysfunction in patients with type 2 diabetes mellitus not receiving insulin treatment. The study group consisted of 21 type 2 diabetes mellitus patients with high HGF levels (>0.26 ng/mL, 58 ± 5 years old, high-HGF group). The control group consisted of 25 type 2 diabetes mellitus patients with normal HGF levels (≤0.26 ng/mL, 58 ± 9 years old, normal-HGF group). Cardiovascular autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations, and cardiac ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy. Early and delayed ¹²³I-MIBG myocardial uptake values were lower (P < .005 and P < .01, respectively) and the percentage of washout rate of ¹²³I-MIBG was higher (P < .001) in the high-HGF group than in the normal-HGF group. The fasting plasma insulin concentrations (P < .0001) and the homeostasis model assessment index values (P < .0001) were higher in the high-HGF group than in the normal-HGF group. Multiple regression analysis revealed that the level of HGF was independently predicted by the homeostasis model assessment index values and the myocardial uptake of ¹²³I-MIBG at the delayed phase. Our results demonstrate that high levels of HGF are associated with depressed cardiovascular autonomic function and insulin resistance in patients with type 2 diabetes mellitus.     

Epidermal growth factor stimulates substrate-selective protein-tyrosine-phosphatase activity.

This study investigates the regulation of protein-tyrosine-phosphatase (PTPase; EC 3.1.3.48) activity by epidermal growth factor (EGF). Cytosol from EGF-treated A-431 human epidermoid carcinoma cells was used as a source of PTPase activity, and tyrosine-phosphorylated ErbB2, EGF receptor, phospholipase C-gamma 1, and the Ras GTPase-activating protein were used as substrates to monitor PTPase activity. EGF stimulated PTPase activity that was selective toward these substrates, as it dephosphorylated ErbB2 and the EGF receptor, but not phospholipase C-gamma 1 and the Ras GTPase-activating protein. EGF stimulated PTPase activity in several cell lines, regardless of EGF receptor number, and the activity was localized in the cytosol. The dephosphorylation activity in vitro was dependent on the presence of reducing agents and was inhibited by orthovanadate. Agonists such as phorbol 12-myristate 13-acetate, isoproterenol, or ATP were unable to stimulate PTPase activity. Physiological relevance is indicated by experiments showing that EGF treatment of a human mammary cancer cell line rapidly induced the dephosphorylation of ErbB2.     

Excess mortality associated with diuretic therapy in diabetes mellitus.

OBJECTIVE. To determine whether the high mortality among diabetic patients receiving treatment for hypertension can be explained by associated risk factors or must be attributed to a deleterious effect of antihypertensive treatment. DESIGN. Cohort analytic study with a median follow-up of 4.5 years. SETTING. Outpatients with diabetes and severe retinopathy who were enrolled in a multicenter, randomized clinical trial of laser treatment to prevent blindness had ophthalmologic examinations every 4 months and annual medical examinations that included measurement of blood pressure and recording of anti-hypertensive treatment. Only 5.5% of the patients were unavailable for follow-up. When a patient died, the circumstances surrounding the death were reviewed and classified by a mortality review committee. PARTICIPANTS.--There were 759 participants in the study; they were white, were aged 35 to 69 years, and had normal serum creatinine levels at the baseline examination. MEASUREMENTS AND MAIN RESULTS.--Patients were classified into five groups according to information recorded at the baseline and first annual follow-up examinations: normotensive (diastolic blood pressure less than 90 mm Hg), untreated hypertensive, hypertensive treated by diuretics alone, hypertensive treated by other agents alone, and hypertensive treated by both agents. Cardiovascular mortality was higher in patients treated for hypertension than in patients with untreated hypertension. The excess was primarily found in patients treated with diuretics alone, although that group had the lowest blood pressure with treatment. After adjusting for differences in risk factors, cardiovascular mortality was 3.8 times higher in patients treated with diuretics alone than in patients with untreated hypertension (P less than .001). CONCLUSIONS.--In individuals with diabetes, intervention with diuretics to reduce hypertension is associated with excess mortality. Until there is a clinical trial showing a beneficial effect of diuretic treatment in diabetic patients, there is urgent need to reconsider its continued usage in this population.