Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes.

Despite growing interest in the relationship between autophagy and systemic metabolism, how global changes in autophagy affect metabolism remains unclear. Here we show that mice with global haploinsufficiency of an essential autophagy gene (Atg7(+/-) mice) do not show metabolic abnormalities but develop diabetes when crossed with ob/ob mice. Atg7(+/-)-ob/ob mice show aggravated insulin resistance with increased lipid content and inflammatory changes, suggesting that autophagy haploinsufficiency impairs the adaptive response to metabolic stress.

Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes.

Islet amyloid accumulation is a hallmark of human type 2 diabetes (T2D). In contrast to human islet amyloid polypeptide (hIAPP), murine islet amyloid polypeptide (mIAPP) does not exhibit amyloidogenic propensity. Because autophagy is important in the clearance of amyloid-like proteins, we studied transgenic mice with β cell-specific expression of hIAPP to evaluate the contribution of autophagy in T2D-associated accumulation of hIAPP.

Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin-proteasome system in pancreatic beta cell dysfunction.

To shed light on islet cell molecular phenotype in human type 2 diabetes (T2D), we studied the transcriptome of non-diabetic (ND) and T2D islets to then focus on the ubiquitin-proteasome system (UPS), the major protein degradation pathway. We assessed gene expression, amount of ubiquitinated proteins, proteasome activity, and the effects of proteasome inhibition and prolonged exposure to palmitate. Microarray analysis identified more than one thousand genes differently expressed in T2D islets, involved in many structures and functions, with consistent alterations of the UPS.

A novel dipeptidyl peptidase IV inhibitor DA-1229 ameliorates streptozotocin-induced diabetes by increasing β-cell replication and neogenesis.

We studied the effect of a novel dipeptidyl peptidase IV (DPP IV) inhibitor, DA-1229, on blood glucose profile and pancreatic β-cell mass in established diabetes after streptozotocin (STZ) treatment. Mice that developed diabetes after administration of STZ 100mg/kg were treated with DA-1229 for 13 weeks. DA-1229 significantly reduced plasma DPP IV activity, and enhanced glucagon-like peptide 1 (GLP-1) levels.

Role of JNK activation in pancreatic beta-cell death by streptozotocin.

c-Jun N-terminal kinase (JNK) is activated by cellular stress and plays critical roles in diverse types of cell death. However, role of JNK in beta-cell injury is obscure. We investigated the role for JNK in streptozotocin (STZ)-induced beta-cell death.

Loss of mitochondrial DNA enhances angiogenic and invasive potential of hepatoma cells.

Mitochondrial DNA (mtDNA) mutations are frequently found in a variety of tumors. However, the role of mtDNA mutations in tumor behavior is poorly understood. We explored the effects of mtDNA mutations on tumor phenotype employing mtDNA-depleted SK-Hep1 rho0 hepatoma cells.

Metastasis-associated protein 1 inhibits p53-induced apoptosis.

Metastasis-associated protein 1 (MTA1) is highly upregulated in cancer cells with metastatic potential; however, the molecular mechanism by which MTA1 increases the metastatic potential of cancer cells is far from clear. We characterized the functional consequences of MTA1 overexpression on p53-induced apoptosis of cancer cells. MTA1 was associated with p53 in a co-immunoprecipitation assay.

Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1alpha.

Metastasis-associated protein 1 (MTA1) is highly upregulated in cancer cells with metastatic potential; however, the molecular mechanism by which MTA1 increases the metastatic potential of cancer cells is unknown. We characterized the functional consequences of MTA1 overexpression in cancer cells with an emphasis on its potential role as a deacetylator of hypoxia-inducible factor-1alpha (HIF-1alpha). MTA1 increased the expression of HIF-1alpha protein, but did not increase the expression of its mRNA.

Cellular aging of mitochondrial DNA-depleted cells.

We have reported that mitochondrial DNA-depleted rho(0) cells are resistant to cell death. Because aged cells have frequent mitochondrial DNA mutations, the resistance of rho(0) cells against cell death might be related to the apoptosis resistance of aged cells and frequent development of cancers in aged individuals. We studied if rho(0) cells have features simulating aged cells.