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Many factors are involved in the pathogenesis of diabetic nephropathy. A single gene abnormality may be prerequisite but insufficient to the disease to manifest. It is therefore only when a second or sometimes a third damage is associated that the consequences of pathogenic phenotypes become evident. We generated the triple transgenic mice overexpressing megsin (a novel glomerular-specific serpin), a receptor for advanced glycation end products (RAGE), and inducible nitric oxide synthase (iNOS). Compared with the single- or two-gene transgenic mice, the triple transgenic mice developed, at an early age (16 weeks), severe albuminuria and renal damage with all of the characteristics of human diabetic nephropathy (i.e., glomerular hypertrophy, diffuse mesangial expansion, inflammatory cell infiltration, and interstitial fibrosis). Interestingly, 30-40% of glomeruli exhibit nodule-like lesions. Oxidative and carbonyl stress makers (pentosidine, N[sup e]-carboxymethyllysine, and 8-hydroxy-deoxyguanosine) were significantly higher in the triple transgenic mice. The iNOS transgenic mice have a diabetes phenotype, the renal consequences of which are moot, and the superimposition of RAGE leads to more conspicuous manifestations. By additional overexpression of megsin, a gene known to be involved in mesangial proliferation and expansion, these local consequences become dramatically manifest and approximate those observed in human pathology. This multiple hit approach is of interest in consideration of the sequential events during development of diabetic nephropathy. Diabetes 55:356-366, 2006 [ABSTRACT FROM AUTHOR]

We tested the hypothesis that green tea prevents diabetes-related tissue dysfunctions attributable to oxidation. Diabetic rats were treated daily with tap water, vitamins C and E, or fresh Japanese green tea extract. After 12 months, body weights were decreased, whereas glycated lysine in aorta, tendon, and plasma were increased by diabetes (P < 0.001) but unaffected by treatment. Erythrocyte glutathione and plasma hydroperoxides were improved by the vitamins (P < 0.05) and green tea (P < 0.001). Retinal superoxide production, acellular capillaries, and pericyte ghosts were increased by diabetes (P < 0.001) and improved by green tea and the vitamins (P variable). Lens crystallin fluorescence at 370/440 nm was ameliorated by green tea (P < 0.05) but not the vitamins. Marginal effects on nephropathy parameters were noted. However, suppressed renal mitochondrial NADH-linked ADP-dependent and dinitrophenol-dependent respiration and complex III activity were improved by green tea (P variable). Green tea also suppressed the methylglyoxal hydroimidazolone immunostaining of a 28-kDa mitochondrial protein. Surprising, glycoxidation in tendon, aorta, and plasma was either worsened or not significantly improved by the vitamins and green tea. Glucosepane cross-links were increased by diabetes (P < 0.001), and green tea worsened total cross-linking. In conclusion, green tea and antioxidant vitamins improved several diabetes-related cellular dysfunctions but worsened matrix glycoxidation in selected tissues, suggesting that antioxidant treatment tilts the balance from oxidative to carbonyl stress in the extracellular compartment. [ABSTRACT FROM AUTHOR]

Presents a perspective on the oxidative stress hypothesis on the origin of diabetic complications. Historical overview for advanced glycation end product (AGE) hypothesis; Explanation for increased glycoxidation and lipoxidation of tissue proteins in diabetes; Distinction between oxidative and carbonyl stress.

Patients with long-standing diabetes commonly develop cognitive impairment and dementia, defined as diabetic encephalopathy. Enhanced susceptibility of brain neurons to oxidative and carbonyl stress is a contributing factor. Glucagon-like peptide (GLP)-1 is a brain-gut peptide, and recently became an attractive treatment modality for patients with diabetes. GLP-1 readily enters the brain, prevents neuronal cell apoptosis, and improves learning and memory impairment in Alzheimer's disease. Therefore, in the current study, we investigated whether GLP-1 could protect against hyperglycemic- and carbonyl stress- induced neuronal cell apoptosis. Rat pheochromocytoma cell line (PC12), which is used commonly as a neuronal cell model, was exposed to 25 mM glucose and/or 500 µM methylglyoxal (MG) with or without 0.1 nM GLP-1, and cell apoptosis, protein expression and phosphorylation of epidermal growth factor receptor (EGFR)/Akt/mTOR/glutamate-L-cysteine ligase (GCL) were determined. The mechanism of GLP-1-mediated EGFR transactivation was also examined. Hyperglycemia and MG induced PC 12 apoptosis as well as mitochondrial cytochrome c release, caspase-9 and -3 activation, and PARP cleavage. GLP-1 protected against hyperglycemic- and MG- induced PC12 apoptosis, which corresponded to the phosphorylation of EGFR, PI3K, Akt, mTOR, and the upregulation of GCL. Inhibitors of EGFR (14C10), EGFR ligands (anti-HB-EGF-Ab, anti-amphiregulin (AR)-Ab), a metalloproteinase which acts as EGFR ligand shedding (KB-R7785), PI3K (wortmannin, LY294002), Akt (AktI), and mTOR (rapamycin) abrogated the GLP-1 cytoprotective effect. In sum, hyperglycemic and carbonyl stress induces neuronal cell apoptosis through mitochondrial apoptotic signaling. GLP-1 treatment affords neuroprotection by enhancing PI3K/Akt/mTOR/GCL signaling through EGFR transactivation via GLP-1 receptor-mediated EGFR ligand (HB-EGF, AR) shedding, and thus represents a promising treatment modality for diabetic encephalopathy. [ABSTRACT FROM AUTHOR]

The article presents abstracts on medical topics, which include studies on such topics as the immunodulatory effects of dental pulp stem cells on diabetic polyneuropathy in streptozotocin-induced diabetic rats, exercise-induced genetic alterations in high-fat prediabetic mouse dorsal root ganglia, and the effect of nocturnal antyhypertensive treatment in type 1 diabetic patients with autonomic neuropathy.

Presents information on several studies related to complications in atherosclerotic cardiovascular disease (CVD) and human diabetes to be presented at the 65th Scientific Sessions of the American Diabetes Association at the San Diego Convention Center in California from June 10 to 14, 2005. Relationship between central obesity and several CVD risk factors; Comparison on the effects of doxazosine GITS and atenolol on left ventricular hypertrophy; Evaluation of PAF-acetylhydrolase activity in patients with type 1 diabetes.

Presents the abstracts of studies to be presented at poster sessions in the 63rd Scientific Sessions of the American Diabetes Association. Adipocyte biology; Clinical therapeutics; Insulin delivery systems.

Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-kappaB in vitro, we observed a long-lasting sustained activation of NF-kappaB in the absence of decreased IkappaBalpha in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-kappaBp65. A comparable increase in NF-kappaBp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-beta peptide (Abeta) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-kappaB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a beta-globin reporter transgene under control of NF-kappaB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-kappaB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-kappaB activation by ligands of RAGE was mediated by initial degradation of IkappaB proteins followed by new synthesis of NF-kappaBp65 mRNA and protein in the presence of newly synthesized IkappaBalpha and IkappaBbeta. These data demonstrate that ligands of RAGE can induce sustained activation of NF-kappaB as a result of increased levels of de novo synthesized NF-kappaBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-kappaB activation observed in hyperglycemia and possibly other chronic diseases. [ABSTRACT FROM AUTHOR]

Presents information on several studies related to signal transduction of cytokines and apoptosis to be presented at the 65th Scientific Session of the American Diabetes Association at the San Diego Convention Center in California from June 10 to 14, 2005. Vulnerability of the rat pheochromocytoma cell line under various glycemic status to methyglyoxal; Ways how insulin-like growth factor-1 regulates the expression of laminin and cyclin D1; Circulation of inducible heat shock protein 70 concentrations in type 2 diabetic monkeys.