[Abstract unavailable

Autophagy is an evolutionarily conserved machinery for bulk degradation of cytoplasmic components. Here, we report upregulation of autophagosome formation in pancreatic beta cells in diabetic db/db and in nondiabetic high-fat-fed C57BL/6 mice. Free fatty acids (FFAs), which can cause peripheral insulin resistance associated with diabetes, induced autophagy in beta cells. Genetic ablation of atg7 in beta cells resulted in degeneration of islets and impaired glucose tolerance with reduced insulin secretion. While high-fat diet stimulated beta cell autophagy in control mice, it induced profound deterioration of glucose tolerance in autophagy-deficient mutants, partly because of the lack of compensatory increase in beta cell mass. These findings suggest that basal autophagy is important for maintenance of normal islet architecture and function. The results also identified a unique role for inductive autophagy as an adaptive response of beta cells in the presence of insulin resistance induced by high-fat diet.

During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing β-cells1–3. However, the exact mechanisms by which the lactogenic hormones drive β-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive β-cell proliferation. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in β-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked β-cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gαq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gαi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked β-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking β-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes4.

gp130 is a common signal transducer for the interleukin-6-related cytokines. To delineate the gp130-mediated growth signal, we established a series of pro-B cell lines expressing chimeric receptors composed of the extracellular domain of the granulocyte colony-stimulating factor receptor and the transmembrane and cytoplasmic domains of gp130. The second tyrosine (from the membrane) of gp130, which was required for the tyrosine phosphorylation of SHP-2, its association with GRB2, and activation of a MAP kinase, was essential for mitogenesis, but not for anti-apoptosis. On the other hand, the tyrosine in the YXXQ motifs essential for STAT3 activation was required for bcl-2 induction and anti-apoptosis. Furthermore, dominant-negative STAT3 inhibited anti-apoptosis. These data demonstrate that two distinct signals, mitogenesis and anti-apoptosis, are required for gp130-induced cell growth and that STAT3 is involved in anti-apoptosis.

Oxidative stress is produced under diabetic conditions and possibly causes various forms of tissue damage in patients with diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate the potential usefulness of antioxidants in the treatment of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine [NAC], vitamins C plus E, or both) was started at 6 weeks of age; its effects were evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose tolerance test, the treatment with NAC retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Vitamins C and E were not effective when used alone but slightly effective when used in combination with NAC. No effect on insulin secretion was observed when the same set of antioxidants was given to nondiabetic control mice. Histologic analyses of the pancreases revealed that the beta-cell mass was significantly larger in the diabetic mice treated with the antioxidants than in the untreated mice. As a possible cause, the antioxidant treatment suppressed apoptosis in beta-cells without changing the rate of beta-cell proliferation, supporting the hypothesis that in chronic hyperglycemia, apoptosis induced by oxidative stress causes reduction of beta-cell mass. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. Furthermore, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), a beta-cell-specific transcription factor, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. In conclusion, our observations indicate that antioxidant treatment can exert beneficial effects in diabetes, with preservation of in vivo beta-cell function. This finding suggests a potential usefulness of antioxidants for treating diabetes and provides further support for the implication of oxidative stress in beta-cell dysfunction in diabetes.

The regenerative process in the pancreas is of particular interest because diabetes results from an inadequate number of insulinproducing beta cells and pancreatic cancer may arise from the uncontrolled growth of progenitor/stem cells. Continued and substantial growth of islet tissue occurs after birth in rodents and humans, with additional compensatory growth in response to increased demand. In rodents there is clear evidence of pancreatic regeneration after some types of injury, with proliferation of preexisting differentiated cell types accounting for some replacement. Additionally, neogenesis or the budding of new islet cells from pancreatic ducts has been reported, but the existence and identity of a progenitor cell have been debated. We hypothesized that the progenitor cells are duct epithelial cells that after replication undergo a regression to a less differentiated state and then can form new endocrine and exocrine pancreas. To directly test whether ductal cells serve as pancreatic progenitors after birth and give rise to new islets, we generated transgenic mice expressing human carbonic anhydrase II (CAII) promoter: Cre recombinase (Cre) or inducible CreER TM to cross with ROSA26 loxP-Stop-loxP LacZ reporter mice. We show that CAII-expressing cells within the pancreas act as progenitors that give rise to both new islets and acini normally after birth and after injury (ductal ligation). This identification of a differentiated pancreatic cell type as an in vivo progenitor of all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replenishment therapy for diabetes.diabetes ͉ islets of Langerhans ͉ lineage tracing

OBJECTIVEExogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonists such as an exendin-4 has direct beneficial effects on the cardiovascular system. However, their effects on atherosclerogenesis have not been elucidated. The aim of this study was to investigate the effects of GLP-1 on accumulation of monocytes/macrophages on the vascular wall, one of the earliest steps in atherosclerogenesis.RESEARCH DESIGN AND METHODSAfter continuous infusion of low (300 pmol · kg−1 · day−1) or high (24 nmol · kg−1 · day−1) dose of exendin-4 in C57BL/6 or apolipoprotein E–deficient mice (apoE−/−), we evaluated monocyte adhesion to the endothelia of thoracic aorta and arteriosclerotic lesions around the aortic valve. The effects of exendin-4 were investigated in mouse macrophages and human monocytes.RESULTSTreatment with exendin-4 significantly inhibited monocytic adhesion in the aortas of C57BL/6 mice without affecting metabolic parameters. In apoE−/− mice, the same treatment reduced monocyte adhesion to the endothelium and suppressed atherosclerogenesis. In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of tumor necrosis factor-α and monocyte chemoattractant protein-1, and suppressed nuclear translocation of p65, a component of nuclear factor-κB. This effect was reversed by either MDL-12330A, a cAMP inhibitor or PKI14-22, a protein kinase A–specific inhibitor. In human monocytes, exendin-4 reduced the expression of CD11b.CONCLUSIONSOur data suggested that GLP-1 receptor agonists reduced monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages, and that this effect may contribute to the attenuation of atherosclerotic lesion by exendin-4.

Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-␤ (TGF-␤) signaling plays an important role in PDAC progression, as indicated by the fact thatSmad4, which encodes a central signal mediator downstream from TGF-␤, is deleted or mutated in 55% and the type II TGF-␤ receptor (Tgfbr2) gene is altered in a smaller subset of human PDAC. Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (Kras G12D) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus. Pancreas-selective Tgfbr2 knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific Kras G12D activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with Kras G12D expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with Kras G12D expression also developed PDAC, which indicated a haploinsufficiency of TGF-␤ signaling in this genetic context. The clinical and histopathological manifestations of the combined Kras G12D expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-␤ signaling and activated Ras signaling cooperate to promote PDAC progression.[Keywords: Kras; pancreas-specific knockout; pancreatic ductal adenocarcinoma; Ptf1a; TGF-␤; type II TGF-␤ receptor] Supplemental material is available at http://www.genesdev.org. Pancreatic cancer is one of the leading causes of cancer death in many countries, and also is one of the most lethal diseases, with a <5% 5-yr survival rate (Warshaw and Fernandez-del Castillo 1992;Hezel et al. 2006;Jemal et al. 2006). Poor survival is likely because most of the patients are already at an unresectable stage when diagnosed. Moreover, even with a successful resection, most patients have recurrence within a year, and the tumors are resistant to all forms of conventional therapies. Since the most common form is pancreatic ductal adenocarcinoma (PDAC), to establish a good animal model that recapitulates aggressive full-blown human PDAC is of high importance for a better understanding of this disease, and for development of better means of early detection and treatment.Previous histological and molecular studies have suggested a model of disease evolution through a preinvasive state, termed pancreatic intraepithelial neoplasia (PanIN), along with accumulating specific genetic alterations (Hruban et al. 2001). An activating point mutation of the Kras proto-oncogene is found in PanIN lesions and with increasing frequency at later stages, and in >90% of