Showing papers by "Subbiah Pugazhenthi published in 2012"
TL;DR: Transplantation of human islets transduced with adenoviral CREB and treated with exendin-4 showed improved glycemic control over a 30-d period in diabetic athymic nude mice, which has significant implications in the therapeutic potential of exendIn-4 and CREB in the islet transplantation setting as well as in preserving β-cell mass of diabetic patients.
Abstract: Islets isolated from cadaveric donor pancreas are functionally viable and can be transplanted in diabetic patients to reduce insulin requirements. This therapeutic approach is less efficient because a significant portion of functional islets is lost due to oxidative stress, inflammation, and hypoxia. Exendin-4, a glucagon-like peptide-1 receptor agonist, is known to improve islet survival through activation of the transcription factor, cAMP response element binding protein (CREB). However, isolated human islets are exposed to several stresses known to down-regulate CREB. The objective of the present study was to determine whether the cytoprotective actions of exendin-4 in human islets can be augmented by increasing the levels of CREB. Simulation of ischemia/reperfusion injury and exposure to hypoxic conditions in cultured human islets resulted in decreased CREB activation and induction of apoptosis. Islets were transduced with adenoviral CREB followed by exposure to exendin-4 as a strategy for improving their survival. This combination increased the levels of several proteins needed for β-cell survival and function, including insulin receptor substrate-2, Bcl-2, and baculoviral IAP repeat-containing 3, and suppressed the expression of proapoptotic and inflammatory genes. A combination of CREB and exendin-4 exerted enhanced antiapoptotic action in cultured islets against hypoxia and cytokines. More significantly, transplantation of human islets transduced with adenoviral CREB and treated with exendin-4 showed improved glycemic control over a 30-d period in diabetic athymic nude mice. These observations have significant implications in the therapeutic potential of exendin-4 and CREB in the islet transplantation setting as well as in preserving β-cell mass of diabetic patients.
50 citations
TL;DR: The findings suggest that GLP‐1‐based therapies can decrease the incidence of Alzheimer's disease among aging diabetic population.
Abstract: Glucagon-like peptide-1 (GLP-1)-based therapies are currently available for the treatment of type 2 diabetes, based on their actions on pancreatic β cells. GLP-1 is also known to exert neuroprotective actions. To determine its mechanism of action, we developed a neuron-rich cell culture system by differentiating human neuroprogenitor cells in the presence of a combination of neurotrophins and retinoic acid. The neuronal nature of these cells was characterized by neurogenesis pathway-specific array. GLP-1 receptor expression was seen mainly in the neuronal population. Culture of neurons in the presence of Aβ oligomers resulted in the induction of apoptosis as shown by the activation of caspase-3 and caspase-6. Exendin-4, a long-acting analog of GLP-1, protected the neurons from apoptosis induced by Aβ oligomers. Exendin-4 stimulated cyclic AMP response element binding protein phosphorylation, a regulatory step in its activation. A transient transfection assay showed induction of a reporter linked to CRE site-containing human brain-derived neurotrophic factor promoter IV, by the growth factor through multiple signaling pathways. The anti-apoptotic action of exendin-4 was lost following down-regulation of cAMP response element binding protein. Withdrawal of neurotrophins resulted in the loss of neuronal phenotype of differentiated neuroprogenitor cells, which was prevented by incubation in the presence of exendin-4. Diabetes is a risk factor in the pathogenesis of Alzheimer's disease. Our findings suggest that GLP-1-based therapies can decrease the incidence of Alzheimer's disease among aging diabetic population.
36 citations
TL;DR: Research studies centered on the biology, regeneration, and transplantation of islets continue to shed significant understanding on the development of different forms of diabetes and provide further impetus for the quest to find a “cure.”
Abstract: Research studies centered on the biology, regeneration, and transplantation of islets continue to shed significant understanding on the development of different forms of diabetes and provide further impetus for the quest to find a “cure.” Diabetes is a manifestation of an inadequate mass of insulin-producing pancreatic beta-cells. While type 1 is characterized by complete loss of beta-cells due to autoimmune attack on them, type 2 is characterized by a relative deficiency of beta-cells due to a decreased compensation for insulin resistance [1, 2]. Restoring beta-cell mass and reversing diabetes can be accomplished by two approaches: either by endogenous regeneration of beta-cells or transplantation of beta-cells from exogenous sources; recent advancements in science and technology have facilitated progress in both. In the first approach, while efforts to expand mature beta-cells in vitro have been met with limited success, regeneration of beta-cells from embryonic and adult stem cells, or pancreatic progenitor cells, has shown promise [2]. Understanding the role of beta-cell-specific transcription factors in the transdifferentiation to beta-cell phenotype is critical to further progress. Pharmacological approaches, employing growth factors, hormones, and small molecules, have also been shown to boost beta-cell proliferation and function.