Metabolic regulation in mammals requires communication between multiple organs and tissues. The rise in the incidence of obesity and associated metabolic disorders, including type 2 diabetes, has renewed interest in interorgan communication. We used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiological compensation for insulin resistance. We found that hepatic activation of extracellular regulated kinase (ERK) signaling induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.

We studied the kinetics of mutation induction in skin epidermis and dermis of UVA-irradiated transgenic Muta mice and analyzed the sequence changes in 80 lacZ transgene mutants from the irradiated epidermis. The mutant frequency increased linearly in both the epidermis and dermis up to 240 kJ/m2 UVA, twice as efficiently in the epidermis as in the dermis, without provoking any inflammatory reactions in the exposed skin. The 83 mutations detected in the UVA-exposed epidermis were dominated by C-->T transitions (88%), found almost exclusively at dipyrimidine sites, and specified by four occurrences of CC-->TT tandem substitutions, suggesting that UV-specific photoproducts induced in DNA have a major role in the genotoxicity. No T-->G transversions, which have been considered as a UVA signature mutation, and few mutations suggesting the relevance of oxidative damage were recovered in the present study. An analysis of the bases adjacent to the mutated cytosines revealed that the 3'-cytosine of dipyrimidine sites is the preferred target of UVA-induced C-->T transition. Moreover, C-->T transitions were induced at dipyrimidine sites associated with CpG much more frequently by UVA than by UVB, forming hotspots at several of these sites. These results suggest that UVA contributes more to the formation of recurrent or hotspot mutations at methylated CpG sites in the mammalian genome than UVB, since methylation of the CpG motif is observed entirely in the lacZ transgenes and is known to enhance the formation of cyclobutane pyrimidine dimers by longer wavelength UV.

A small portion of Type 2 diabetes mellitus (T2DM) is familial, but the majority occurs as sporadic disease. Although causative genes are found in some rare forms, the genetic basis for sporadic T2DM is largely unknown. We searched for a copy number abnormality in 100 early-onset Japanese T2DM patients (onset age <35 years) by whole-genome screening with a copy number variation BeadChip. Within the 1.3-Mb subtelomeric region on chromosome 4p16.3, we found copy number losses in early-onset T2DM (13 of 100 T2DM versus one of 100 controls). This region surrounds a genome gap, which is rich in multiple low copy repeats. Subsequent region-targeted high-density custom-made oligonucleotide microarray experiments verified the copy number losses and delineated structural changes in the 1.3-Mb region. The results suggested that copy number losses of the genes in the deleted region around the genome gap in 4p16.3 may play significant roles in the etiology of T2DM.

Interferon (IFN) therapies, including IFN, peginterferon (PEG-IFN)