Retinopathy is the most common microvascular diabetes complication and represents a major threat to the eyesight. The aim of this study was to address the role of pro- and anti-angiogenic molecules in diabetic retinopathy in the aqueous humor of the eye. Aqueous humor was collected at cataract surgery from 19 diabetic patients and from 13 age- and sex-matched normoglycemic controls. Levels of pro-angiogenic vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) were determined. Angiogenic activity of the aqueous humor was quantified by measuring its effect on the migration of capillary endothelial cells.In the aqueous fluid, VEGF levels were increased in diabetics (mean values: 501 vs. 367 pg/ml; p = 0.05), compared to controls. PEDF was found to be decreased in diabetics (mean values: 2080 vs. 5780 ng/ml; p = 0.04) compared to controls. In seven diabetic patients with proliferative retinopathy, the most profound finding was a significant decrease of the PEDF level (mean value: 237 ng/ml), whereas VEGF levels were comparable to diabetic patients without proliferation (mean value: 3153; p = 0.003). Angiogenic activity in samples of patients from the control group was generally inhibitory due to PEDF, and inhibition was blocked by neutralizing antibodies to PEDF. Likewise, in diabetics without proliferation, angiogenic activity was also blocked by antibodies to PEDF.We will demonstrate here that the level of the natural ocular anti-angiogenic agent PEN is inversely associated with proliferative retinopathy. PEN is an important negative regulator of angiogenic activity of aqueous humor. Our data may have implications for the development of novel regimens for diabetic retinopathy.

Objective: Growth hormone and insulin-like growth factor- have been implicated as strong promoters of proliferative diabetic retinopathy. We studied reduction of bleeding and preservation of visual acuity by treatment with the long-acting somatostatin analogue, octreotide, in diabetic patients at an advanced stage of proliferative diabetic retinopathy. Research Design and Methods: Randomized trial in a University hospital setting. Reading ophthalmologists were masked for octreotide use, diabetologists were aware of that treatment. Nine patients received 100 mug tid octreotide (verum) subcutaneously for a maximum of 36 months. Nine diabetics served as controls, no placebo treatment was used. Episodes of vitreous hemorrhages were counted, measurement of visual acuity, estimation of neovascularization by stereoscopic fundus photography and fluorescein angiography were carried out. Results: After 3 years of treatment, the incidence of vitreous hemorrhages and the need for vitreoretinal surgery was significantly lower (log rank test p = 0.002) in the octreotide-treated patients. Visual acuity was preserved and significantly better in the octreotide treated group compared to controls (p=0.05). Conclusions: In diabetics with high-risk proliferative retinopathy after full scatter laser coagulation, octreotide reduced the number of vitreous hemorrhages, preserving visual acuity.

In patients with diabetic retinopathy, elevated serum levels of total circulating insulin-like growth factor-I (IGF-I) have been implicated as an important mediator of the disease. There is no study, however, measuring free IGF-I levels in patients with diabetic retinopathy which mediate the biological effects of IGF-I and are modulated by a complex system of six specific IGF binding proteins (IGFBPs) and several IGFBP proteases.

Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single-strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5' region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.

BACKGROUND:Growth factors like IGF-I have been implicated in the pathogenesis of diabetic retinopathy. To investigate the role and bioavailability of IGF-I we measured not only total but also free serum levels of IGF-I in diabetic patients.METHODS:A total of 159 patients with and without diabetic retinopathy were investigated (60 diabetic patients without and 99 with clinically and angiographically diagnosed diabetic retinopathy). One hundred ten healthy volunteers served as controls. The data were analyzed by Student's t-test, analysis of variance and correlation; P < 0.05 was considered statistically significant.RESULTS:Diabetic patients with retinopathy showed significantly lower serum levels of free IGF-I than diabetics without retinopathy. Free IGF-I was negatively correlated with glycosylated hemoglobin 1c. IGFBP-3 levels were diminished in type 2 patients with diabetic retinopathy, while type 1 patients with diabetic retinopathy showed higher IGFBP-1 levels.CONCLUSION:Diabetic patients with retinopathy showed significantly reduced serum levels of free IGF-I. Low IGF-I was associated with poor metabolic control.