Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.

Vascular endothelial growth factor (VEGF), a major mediator of vascular permeability and angiogenesis, may play a pivotal role in mediating the development and progression of diabetic retinopathy. In the present study, we examined the genetic variations of the VEGF gene to assess its possible relation to diabetic retinopathy in type 2 diabetic patients. Among seven common polymorphisms in the promoter region, 5-untranslated region (UTR) and 3UTR of the VEGF gene, genotype distribution of the C(؊634)G polymorphism differed significantly (P ‫؍‬ 0.011) between patients with (n ‫؍‬ 150) and without (n ‫؍‬ 118) retinopathy, and the C allele was significantly increased in patients with retinopathy compared with those without retinopathy (P ‫؍‬ 0.0037). The odds ratio (OR) for the CC genotype of C(؊634)G to the GG genotype was 3.20 (95% CI 1.45-7.05, P ‫؍‬ 0.0046). The ؊634C allele was significantly increased in patients with nonproliferative diabetic retinopathy (non-PDR) (P ‫؍‬ 0.0026) and was insignificantly increased in patients with proliferative diabetic retinopathy (PDR) (P ‫؍‬ 0.081) compared with patients without retinopathy, although frequencies of the allele did not differ significantly between the non-PDR and PDR groups. Logistic regression analysis revealed that the C(؊634)G polymorphism was strongly associated with an increased risk of retinopathy (P ‫؍‬ 0.0018). Furthermore, VEGF serum levels were significantly higher in healthy subjects with the CC genotype of the C(؊634)G polymorphism than in those with the other genotypes. These data suggest that the C(؊634)G polymorphism in the 5UTR of the VEGF gene is a novel genetic risk factor for diabetic retinopathy.

Diabetes mellitus associated with the A-->G mutation at position 3243 of mitochondrial leucine transfer RNA represents a subtype of diabetes found in both patients with IDDM and patients with NIDDM in Japan.

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We have revised a part of the diagnostic criteria for fulminant type 1 diabetes. The new criteria were set both to express the essence of this disease of rapid increase of patients' blood glucose and to be highly sensitive to reduce the misdiagnosis. After analyzing the data of 382 patients with newly-diagnosed fulminant type 1 diabetes, we adopted the glycated hemoglobin (HbA 1c ) level of 8.7% (National Glycohemoglobin Standardization Program [NGSP] value). The new criterion indicates 100% of sensitivity and the best value by receiver operating characteristic curve analysis. In addition, we added a comment that 'This value (HbA 1c <8.7% in NGSP) is not applicable for patients with previously diagnosed glucose intolerance' in the new criteria and also a comment that 'Association with human leukocyte antigen DRB1*04:05-DQB1*04:01 is reported' as a related finding. We did not revise the screening criteria and the other part of the diagnostic criteria, because they are still reliable. (J Diabetes Invest