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Summary: We report the sixth autopsy case of a patient with aceruloplasminemia. He was the younger brother of the first reported autopsy case of this disease. Among autopsy cases with aceruloplasminemia reported to date, he had the longest duration of neurologic disorders. The neuropathologic findings showed that the basal ganglia and dentate nuclei were most severely affected. The most striking finding in the present case was that marked iron deposition was evident in the cerebral cortex. Many enlarged or deformed astrocytes and globular structures, both of which were heavily iron loaded, were found in the cerebral cortex as well as in the basal ganglia. Pyramidal neurons in his cerebral cortex were fewer in number than observed in the previous reported cases. There was a negative correlation between the number of cortical pyramidal neurons and globular structures. The present case clearly indicates that the neuropathologic process in aceruloplasminemia extends beyond the basal ganglia to the cerebral cortex with time. [ABSTRACT FROM AUTHOR]

Summary: Type 2 diabetes is characterized by insulin resistance and pancreatic β cell dysfunction, the latter possibly caused by a defect in insulin signaling in β cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in β cells and the pik3r2 gene systemically (βDKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. β cells of βDKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca2+ influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of βDKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in β cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Recent studies using several knockout models have shown that autocrine insulin (and/or IGF-1) regulates growth and some functions of pancreatic β cells through activation of insulin receptor (IR)→insulin receptor substrate (IRS) proteins→Class IA phosphoinositide 3-kinase (PI3K). Class IA PI3K is composed of a catalytic subunit (p110) and a regulatory subunit (p85), which occurs in multiple isoforms. Among them, p85α and β are two major isoforms. P85α is derived from the Pik3rl gene that also encodes two shorter isoforms, p55α and p50α, while p85β is derived from the Pik3r2. To identify the role of Class IA P13K in β cells, we have generated β cell specific Pik3rl gene knockout (βPik3rlKO) mice using Cre-LoxP system, since the whole body Pik3rl KO mice die within 1 week after birth. To gain more insight in the PI3K pathway of β cells, we ablated the genes of two major regulatory subunits, p85α and p85β, of PI3K by crossing mice lacking Pik3rl in β cells with Pik3r2 null mice, for creating β cells-specific double knockout mice (βDKO mice). βPik3r1KO mice grew normally and were indistinguishable from control RIP-Cre transgenic mice. There was an 80% reduction of the regulatory subunits in isolated islets from βPik3rlKO mice, while p85β still remained. βPik3rlKO mice displayed modestly elevated fed glucose concentrations at 4 months of age and older, whereas fasting glucose levels were normal and they never developed diabetes during entire life. However, βPik3rlKO mice exhibited glucose intolerance and markedly suppressed glucose stimulated insulin secretion (GSIS) in vivo at 2 months and older. GSIS was also impaired using isolated islets from βPik3rlKO mice especially at lower concentrations of glucose, suggesting the existence of a defect in glucose sensing. Moreover, islet size of βPik3rlKO mouse was decreased by 30% compared to that of RIP-Cre mouse. Until a few months of age that we have observed for, βDKO mice also grew normally. However, βDKO mice showed more prominent glucose intolerance than βPik3rlKO mice due to a declined insulin secretion. Despite this, βDKO mice did not develop diabetes at this stage presumably because Pik3r2 null background is more sensitive to insulin than wild-type, as we have previously shown. These data suggest that Class IA PI3K is required for age-dependent islet growth and normal insulin secretion, and that decreased Class IA PI3K activity causes postprandial hyperglycemia. This may also provide a novel therapeutic approach for diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Adiponectin, one of the insulin-sensitizing adipokines, has been shown to activate fatty acid oxidation in liver and skeletal muscle, thus maintaining insulin sensitivity. However, the precise roles of adiponectin in fatty acid synthesis are poorly understood. Here we show that adiponectin administration acutely suppresses expression of sterol regulatory element-binding protein (SREBP) 1c, the master regulator which controls and upregulates the enzymes involved in fatty acid synthesis, in the liver of +Leprdb /+Leprdb (db/db) mouse as well as in cultured hepatocytes. We also show that adiponectin suppresses SREBP1c by AdipoR1, one of the functional receptors for adiponetin, and furthermore that suppressing either AMP-activated protein kinase (AMPK) via its upstream kinase LKB1 deletion cancels the negative effect of adiponectin on SREBP1c expression. These data show that adiponectin suppresses SREBP1c through the AdipoR1/LKB1/AMPK pathway, and suggest a possible role for adiponectin in the regulation of hepatic fatty acid synthesis. [Copyright &y& Elsevier]