Diabetes-induced oxidative stress can lead to protein misfolding and degradation by the ubiquitin-proteasome system. This study examined protein ubiquitination in pancreatic sections from Zucker diabetic fatty rats. We observed large aggregates of ubiquitinated proteins (Ubproteins) in insulin-expressing ␤-cells and surrounding acinar cells. The formation of these aggregates was also observed in INS1 832/13 ␤-cells after exposure to high glucose (30 mmol/l) for 8 -72 h, allowing us to further characterize this phenotype. Oxidative stress induced by aminotriazole (ATZ) was sufficient to stimulate Ub-protein aggregate formation. Furthermore, the addition of the antioxidants N-acetyl cysteine (NAC) and taurine resulted in a significant decrease in formation of Ub-protein aggregates in high glucose. Puromycin, which induces defective ribosomal product (DRiP) formation was sufficient to induce Ub-protein aggregates in INS1 832/13 cells. However, cycloheximide (which blocks translation) did not impair Ub-protein aggregate formation at high glucose levels, suggesting that long-lived proteins are targeted to these structures. Clearance of Ub-protein aggregates was observed during recovery in normal medium (11 mmol/l glucose). Despite the fact that 20S proteasome was localized to Ub-protein aggregates, epoxomicin treatment did not affect clearance, indicating that the proteasome does not degrade proteins localized to these structures. The autophagy inhibitor 3MA blocked aggregate clearance during recovery and was sufficient to induce their formation in normal medium. Together, these findings demonstrate that diabetes-induced oxidative stress induces ubiquitination and storage of proteins into cytoplasmic aggregates that do not colocalize with insulin. Autophagy, not the proteasome, plays a key role in regulating their formation and degradation. To our knowledge, this is the first demonstration that autophagy acts as a defense to cellular damage incurred during diabetes. Diabetes 56:930 -939, 2007

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The objectives of this paper were (1) to review recent research on the actions of vitamin D as a steroid derivative with neuroactive properties and (2) to highlight clinical relevance and need for more research. Our methods included review of research from current journals, Medline, and Cochrane Reviews; theoretical discussion. Scientific research has had a justifiably strong emphasis on how vitamin D affects calcium metabolism and bone. This appears to have eclipsed its fundamental actions on several other important systems, including the central nervous system. Vitamin D as a neuroactive compound, a prohormone, is highly active in regulating cell differentiation, proliferation, and peroxidation in a variety of structures, including the brain. Vitamin D insufficiency is not rare. Historically, focus has been on bone metabolism, which appears to have caused research bias and evidence bias, distorting physiological importance. The central nervous system is increasingly recognized as a target organ for vitamin D via its wide-ranging hormonal effects, including the induction of proteins such as nerve growth factor. We need more research on this important neuroactive substance because it may play a role as a relatively safe and inexpensive pharmaceutical in the prevention and treatment of a number of common neuropsychiatric conditions.

Király MA, Bates HE, Kaniuk NA, Yue JT, Brumell JH, Matthews SG, Riddell MC, Vranic M. Swim training prevents hyperglycemia in ZDF rats: mechanisms involved in the partial maintenance of ␤-cell function. Am J Physiol Endocrinol Metab 294: E271-E283, 2008. First published November 20, 2007 doi:10.1152/ajpendo.00476.2007.-Exercise improves glucose tolerance in obese rodent models and humans; however, effects with respect to mechanisms of ␤-cell compensation remain unexplained. We examined exercise's effects during the progression of hyperglycemia in male Zucker diabetic fatty (ZDF) rats until 19 wk of age. At 6 wk old, rats were assigned to 1) basal-euthanized for baseline values; 2) exercise-swam individually for 1 h/day, 5 days/wk; and 3) controls (n ϭ 8 -10/group). Exercise (13 wk) resulted in maintenance of fasted hyperinsulinemia and prevented increases in fed and fasted glucose (P Ͻ 0.05) compared with sham-exercised and sedentary controls (P Ͻ 0.05). ␤-Cell function calculations indicate prolonged ␤-cell adaptation in exercised animals alone. During an intraperitoneal glucose tolerance test (IPGTT), exercised rats had lower 2-h glucose (P Ͻ 0.05) vs. controls. Area-under-the-curve analyses from baseline for IPGTT glucose and insulin indicate improved glucose tolerance with exercise was associated with increased insulin production and/or secretion. ␤-Cell mass increased in exercised vs. basal animals; however, mass expansion was absent at 19 wk in controls (P Ͻ 0.05). Hypertrophy and replication contributed to expansion of ␤-cell mass; exercised animals had increased ␤-cell size and bromodeoxyuridine incorporation rates vs. controls (P Ͻ 0.05). The relative area of GLUT2 and protein kinase B was significantly elevated in exercised vs. sedentary controls (P Ͻ 0.05). Last, we show formation of ubiquitinated protein aggregates, a response to cellular/oxidative stress, occurred in nonexercised 19 wk-old ZDF rats but not in lean, 6 wk-old basal, or exercised rats. In conclusion, improved ␤-cell compensation through increased ␤-cell function and mass occurs in exercised but not sedentary ZDF rats and may be in part responsible for improved glucoregulation.Zucker diabetic fatty; exercise; diabetes; glycemia; insulin; C-peptide; ␤-cell mass; ␤-cell function; glucose transporter 2; protein kinase B; apoptosis; proliferation; islet morphology OBESITY IS THE MOST COMMON metabolic disease in North America (38) and along with its comorbidities is currently responsible for ϳ15% of the annual health care expenditure (38). One such comorbidity is type 2 diabetes mellitus (T2DM), which develops in ϳ35-40% of the obese adult population (38). The cause of T2DM is unknown but is predominantly associated with obesity (38), a progressive decline in peripheral insulin sensitivity, and corresponding decrements in glucose disposal in skeletal muscle, fat, and the liver (15). T2DM, however, is not defined solely by decreased hepatic and peripheral insulin action; ␤-cell defects with respect to insulin production and/or secretion mus...

Brain injuries are too common. Most people are unaware of the incidence of and horrendous consequences of traumatic brain injury (TBI) and mild traumatic brain injury (MTBI). Research and the advent of sophisticated imaging have led to progression in the understanding of brain pathophysiology following TBI. Seminal evidence from animal and human experiments demonstrate links between TBI and the subsequent onset of premature, psychiatric syndromes and neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Objectives of this summary are, therefore, to instill appreciation regarding the importance of brain injury prevention, diagnosis, and treatment, and to increase awareness regarding the long-term delayed consequences following TBI.