Insulin resistance is often associated with impeded insulin signaling due either to decreased concentrations or functional modifications of crucial signaling molecules including insulin receptor substrates (IRS) in the liver. Many actions of adiponectin, a well-recognized antidiabetic adipokine, are currently attributed to the activation of two critical molecules downstream of AdipoR1 and R2: AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). However, the direct effects of adiponectin on insulin signaling molecules remain poorly understood. We show here that adiponectin upregulates IRS-2 through activation of signal transducer and activator of transcription-3 (STAT3). Surprisingly, this activation is associated with IL-6 production from macrophages induced by adiponectin through NFκB activation independent of its authentic receptors, AdipoR1 and AdipoR2. These data have unraveled an insulin-sensitizing action initiated by adiponectin leading to upregulation of hepatic IRS-2 via an IL-6 dependent pathway through a still unidentified adiponectin receptor.

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.

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Aceruloplasminemia is an interesting disease, the study of which helps elucidate how iron-induced oxidative stress is involved in neuronal cell death. In order to study the neuropathological characteristics associated with oxidative stress, we scrutinized the brains of 5 patients with aceruloplasminemia histopathologically and immunohistochemically. The pathological findings were essentially similar in all patients. In the frontal cortices, iron deposition and neuronal cell loss were trivial, but in the basal ganglia (especially in the caudate nucleus and putamen), severe iron overload and extensive neuronal loss were noted. Iron deposition was more prominent in the astrocytes than in the neurons in both regions. 4-hydroxynonenal (HNE), one of the most physiologically active lipid peroxides, was strongly detected on neurons and astrocytes by immunostaining. Markedly deformed astrocytes were observed in the striatum. These astrocytes were similar to Alzheimer type 1 astrocytes. Globular structures were seen in proportion to the degree of iron deposition. They clearly reacted with anti-glial fibrillary acidic protein (GFAP) and anti-S-100 antibodies and contained glial fibril-like filaments, but showed no or only faint immunoreactivity to antibodies for neuronal marker proteins, such as neurofilament and synaptophysin. Therefore, the globular structures presumably originated from astrocytes. The structures also reacted positively to anti-HNE and anti-ubiquitin antibodies. We conclude that astrocytic deformities and globular structures are characteristic neuropathological features of aceruloplasminemia and are closely linked to iron overload and subsequent oxidative stress.