Objectives Hyperamylinemia, a common pancreatic disorder in obese and insulin resistant patients, is known to cause amylin oligmerization and cytotoxicity in pancreatic islets leading to β-cell mass depletion and development of type-2 diabetes. Recent data revealed that hyperamylinemia also affects the vascular system, heart and kidneys. We, therefore, hypothesized that oligomerized amylin might accumulate in cerebrovascular system and brain parenchyma of diabetic patients. Methods Amylin accumulation in the brain of diabetic patients with vascular dementia or Alzheimer’s disease (AD), non-diabetic patients with AD, and age-matched healthy controls was assessed by quantitative real-time PCR, immunohistochemistry, western blot and ELISA. Results Amylin oligomers and plaques were identified in the temporal lobe gray matter from diabetic patients, but not controls. In addition, extensive amylin deposition was found in blood vessels and perivascular spaces. Intriguingly, amylin deposition was also detected in blood vessels and brain parenchyma of patients with late-onset AD without clinically apparent diabetes. Mixed amylin and Aβ deposits were occasionally observed. However, amylin accumulation leads to amyloid formation independent of Aβ deposition. Tissues infiltrated by amylin show increased interstitial space, vacuolation, spongiform change, and capillaries bended at amylin accumulation sites. Unlike the pancreas, there was no evidence of amylin synthesis in the brain. Interpretations Metabolic disorders and aging promote accumulation of amylin amyloid in cerebrovascular system and gray matter altering microvasculature and tissue structure. Amylin amyloid formation in the wall of cerebral blood vessels may also induce failure of elimination of Aβ from the brain, thus contributing to the etiology of AD.

DeVerse JS, Bailey KA, Jackson KN, Passerini AG. Shear stress modulates RAGE-mediated inflammation in a model of diabetes-induced metabolic stress.

Glycemic regulation improves myocardial function in diabetic patients, but finding optimal therapeutic strategies remains challenging. Recent data have shown that pharmacological inhibition of soluble epoxide hydrolase (sEH), an enzyme that decreases the endogenous levels of protective epoxyeicosatrienoic acids (EETs), improves glucose homeostasis in insulin-resistant mice. Here, we tested whether the administration of sEH inhibitors preserves cardiac myocyte structure and function in hyperglycemic rats. University of California-Davis-type 2 diabetes mellitus (UCD-T2DM) rats with nonfasting blood glucose levels in the range of 150-200 mg/dl were treated with the sEH inhibitor 1-(1-acetypiperidin-4-yl)-3-adamantanylurea (APAU) for 6 wk. Administration of APAU attenuated the progressive increase of blood glucose concentration and preserved mitochondrial structure and myofibril morphology in cardiac myocytes, as revealed by electron microscopy imaging. Fluorescence microscopy with Ca(2+) indicators also showed a 40% improvement of cardiac Ca(2+) transients in treated rats. Sarcoplasmic reticulum Ca(2+) content was decreased in both treated and untreated rats compared with control rats. However, treatment limited this reduction by 30%, suggesting that APAU may protect the intracellular Ca(2+) effector system. Using Western blot analysis on cardiac myocyte lysates, we found less downregulation of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), the main route of Ca(2+) reuptake in the sarcoplasmic reticulum, and lower expression of hypertrophic markers in treated versus untreated UCD-T2DM rats. In conclusion, APAU enhances the therapeutic effects of EETs, resulting in slower progression of hyperglycemia, efficient protection of myocyte structure, and reduced Ca(2+) dysregulation and SERCA remodeling in hyperglycemic rats. The results suggest that sEH/EETs may be an effective therapeutic target for cardioprotection in insulin resistance and diabetes.

that couples the motions of three b strands (b1, b13 and b14) at the trimeric interface of the ligand binding domain (LBD) and the motion of the pore-forming helix (TM2) of the transmembrane domain (TMD) was identified. The resulting widening of the fenestrations above the TMD and the opening of the TMD pore are in close agreement with observed signatures of channel activation. Four charged residues implicated in ATP binding are located in b1, b13 and b14. P2X4 activation was further investigated by MD simulations in explicit water. ATP was placed near the putative binding site in two opposite orientations, with the adenine either promixal or distal to the TMD. In simulations with proximal adenine, the adenine ring inserted between b1 and b13 and the phosphate group moved downward. At the same time b1 and b14 approached each other to close in on the ATP, allowing close interactions with the four charged residues. The motions of these b strands are similar to those in the normal mode putatively representing channel activation. In simulations with distal adenine, the ATP hindered the closure between b1 and b14, perhaps representing a desensitized state. Our computational studies produced the first complete model, supported by electrophysiological data, for how ATP binding leads to P2X4 channel activation. The detailed gating mechanism will be essential for the rational drug design.

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