Glucose stimulated insulin secretion (GSIS) involves a series of metabolic and cationic events, leading to translocation of insulin-laden secretory granules from a distal site toward the plasma membrane for fusion and release of insulin into circulation. Vesicular transport and fusion events are tightly regulated by signals which coordinate between vesicle- and membrane-associated docking proteins. It is now being accepted that reactive oxygen species [ROS] plays a second messenger role in islet â-cell function. Further, evidence from multiple laboratories suggests a tonic increase in ROS generation is necessary for GSIS and fatty acid-induced insulin secretion. On the other hand, excessive ROS generated during glucolipotoxic / exposures to cytokines and ceramide have proved to be detrimental for islet â-cells. Recent studies have shown activation of phagocyte-like NADPH oxidase [Nox] to be underlying cause for increased ROS generation observed under the above pathological conditions.
The overall objective of the present study is to i) determine potential mechanism[s] underlying nutrient-induced generation of ROS; ii) contributory roles of Tiam1-Rac1-Nox signaling in free fatty acid (e.g., palmitate) and cytokines- induced â-cell dysfunction. Findings from current study suggest that posttranslational prenylation is a requisite for signaling G-proteins involved in the activation of Nox and generation of ROS for nutrient-induced insulin secretion from islet â-cells. Studies with pertussis toxin [Ptx] suggested that glucose-induced Nox-mediated ROS generation is regulated by inhibitory class of G-proteins [Go/Gi]. Our next set of studies, directed towards understanding the mechanism of Nox activation under chronic exposure to high palmitate, cytokines and C2-ceramide implicate increased expression of Nox subunits to precede the functional activation of the holoenzyme and excessive ROS generation resulting in mitochondrial dysfunction. This study also provide first evidence for a critical modulatory role of Tiam1, a guanine nucleotide exchange factor [GEF] in Rac1-Nox signaling axis.
The next set of studies validated the above observations in Zucker Diabetic Fatty [ZDF] rat model, which mimics type2 diabetes in humans, characterized by obesity, hyperinsulinemia, hyperglycemia and gradual decline in â-cell function. The results obtained were comparable with clonal â-cells. Islets derived from ZDF-rats presented high levels of Nox subunit expression [p47phox, gp91phox, Rac1] which constitutively activated Nox-holoenzyme and augmented ROS levels. The increased oxidative stress under conditions of diabetes activated Jun-N-terminal kinases [JNK 1/2, stress-activated kinases] leading to mitochondrial abnormalities and eventual demise of islet â cells. A similar pattern of induction in Nox subunit expression/activation, ROS generation and JNK 1/2 were also observed in type 2 diabetes human islets. Taken together, herein I propose that high levels of oxidative stress, activation of stress-activated kinases [JNK1/2] and mitochondrial abnormalities underlies pancreatic â-cell dysfunction[s] during diabetes. Additional studies are needed to understand the precise regulatory roles for Tiam1-Rac1-Nox-ROS-JNK1/2 signaling to develop therapeutic strategies in the treatment of metabolic disorder.
","abstract_html":"<p>Glucose stimulated insulin secretion (GSIS) involves a series of metabolic and cationic events, leading to translocation of insulin-laden secretory granules from a distal site toward the plasma membrane for fusion and release of insulin into circulation. Vesicular transport and fusion events are tightly regulated by signals which coordinate between vesicle- and membrane-associated docking proteins. It is now being accepted that reactive oxygen species [ROS] plays a second messenger role in islet â-cell function. Further, evidence from multiple laboratories suggests a tonic increase in ROS generation is necessary for GSIS and fatty acid-induced insulin secretion. On the other hand, excessive ROS generated during glucolipotoxic / exposures to cytokines and ceramide have proved to be detrimental for islet â-cells. Recent studies have shown activation of phagocyte-like NADPH oxidase [Nox] to be underlying cause for increased ROS generation observed under the above pathological conditions.</p> <p>The overall objective of the present study is to i) determine potential mechanism[s] underlying nutrient-induced generation of ROS; ii) contributory roles of Tiam1-Rac1-Nox signaling in free fatty acid (e.g., palmitate) and cytokines- induced â-cell dysfunction. Findings from current study suggest that posttranslational prenylation is a requisite for signaling G-proteins involved in the activation of Nox and generation of ROS for nutrient-induced insulin secretion from islet â-cells. Studies with pertussis toxin [Ptx] suggested that glucose-induced Nox-mediated ROS generation is regulated by inhibitory class of G-proteins [Go/Gi]. Our next set of studies, directed towards understanding the mechanism of Nox activation under chronic exposure to high palmitate, cytokines and C2-ceramide implicate increased expression of Nox subunits to precede the functional activation of the holoenzyme and excessive ROS generation resulting in mitochondrial dysfunction. This study also provide first evidence for a critical modulatory role of Tiam1, a guanine nucleotide exchange factor [GEF] in Rac1-Nox signaling axis.</p> <p>The next set of studies validated the above observations in Zucker Diabetic Fatty [ZDF] rat model, which mimics type2 diabetes in humans, characterized by obesity, hyperinsulinemia, hyperglycemia and gradual decline in â-cell function. The results obtained were comparable with clonal â-cells. Islets derived from ZDF-rats presented high levels of Nox subunit expression [p47phox, gp91phox, Rac1] which constitutively activated Nox-holoenzyme and augmented ROS levels. The increased oxidative stress under conditions of diabetes activated Jun-N-terminal kinases [JNK 1/2, stress-activated kinases] leading to mitochondrial abnormalities and eventual demise of islet â cells. A similar pattern of induction in Nox subunit expression/activation, ROS generation and JNK 1/2 were also observed in type 2 diabetes human islets. Taken together, herein I propose that high levels of oxidative stress, activation of stress-activated kinases [JNK1/2] and mitochondrial abnormalities underlies pancreatic â-cell dysfunction[s] during diabetes. Additional studies are needed to understand the precise regulatory roles for Tiam1-Rac1-Nox-ROS-JNK1/2 signaling to develop therapeutic strategies in the treatment of metabolic disorder.</p>","abstract_has_math":false,"creators":["Syed, Ismail"],"institution":null,"degree_name":"Ph.D.","degree_level":"Open Access Dissertation","degree_discipline":"Pharmaceutical Sciences","degree_department":null,"school":null,"contributors":["ANJANEYULU KOWLURU"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-01-01T08:00:00Z","date_published":"2011-01-01T08:00:00Z","updated_at":"2026-07-24T05:58:57Z","subjects":["NOX","Rac1","ROS","T2DM","Tiam1","ZDF","Medicinal Chemistry and Pharmaceutics","Pharmacology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.wayne.edu/oa_dissertations/332","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["ANJANEYULU KOWLURU"]},{"key":"dc:creator","label":"Author","values":["Syed, Ismail"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2012-12-15T08:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmaceutical Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Open Access Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["NOX","Rac1","ROS","T2DM","Tiam1","ZDF","Medicinal Chemistry and Pharmaceutics","Pharmacology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.wayne.edu/oa_dissertations/332"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Glucose stimulated insulin secretion (GSIS) involves a series of metabolic and cationic events, leading to translocation of insulin-laden secretory granules from a distal site toward the plasma membrane for fusion and release of insulin into circulation. Vesicular transport and fusion events are tightly regulated by signals which coordinate between vesicle- and membrane-associated docking proteins. It is now being accepted that reactive oxygen species [ROS] plays a second messenger role in islet â-cell function. Further, evidence from multiple laboratories suggests a tonic increase in ROS generation is necessary for GSIS and fatty acid-induced insulin secretion. On the other hand, excessive ROS generated during glucolipotoxic / exposures to cytokines and ceramide have proved to be detrimental for islet â-cells. Recent studies have shown activation of phagocyte-like NADPH oxidase [Nox] to be underlying cause for increased ROS generation observed under the above pathological conditions.
The overall objective of the present study is to i) determine potential mechanism[s] underlying nutrient-induced generation of ROS; ii) contributory roles of Tiam1-Rac1-Nox signaling in free fatty acid (e.g., palmitate) and cytokines- induced â-cell dysfunction. Findings from current study suggest that posttranslational prenylation is a requisite for signaling G-proteins involved in the activation of Nox and generation of ROS for nutrient-induced insulin secretion from islet â-cells. Studies with pertussis toxin [Ptx] suggested that glucose-induced Nox-mediated ROS generation is regulated by inhibitory class of G-proteins [Go/Gi]. Our next set of studies, directed towards understanding the mechanism of Nox activation under chronic exposure to high palmitate, cytokines and C2-ceramide implicate increased expression of Nox subunits to precede the functional activation of the holoenzyme and excessive ROS generation resulting in mitochondrial dysfunction. This study also provide first evidence for a critical modulatory role of Tiam1, a guanine nucleotide exchange factor [GEF] in Rac1-Nox signaling axis.
The next set of studies validated the above observations in Zucker Diabetic Fatty [ZDF] rat model, which mimics type2 diabetes in humans, characterized by obesity, hyperinsulinemia, hyperglycemia and gradual decline in â-cell function. The results obtained were comparable with clonal â-cells. Islets derived from ZDF-rats presented high levels of Nox subunit expression [p47phox, gp91phox, Rac1] which constitutively activated Nox-holoenzyme and augmented ROS levels. The increased oxidative stress under conditions of diabetes activated Jun-N-terminal kinases [JNK 1/2, stress-activated kinases] leading to mitochondrial abnormalities and eventual demise of islet â cells. A similar pattern of induction in Nox subunit expression/activation, ROS generation and JNK 1/2 were also observed in type 2 diabetes human islets. Taken together, herein I propose that high levels of oxidative stress, activation of stress-activated kinases [JNK1/2] and mitochondrial abnormalities underlies pancreatic â-cell dysfunction[s] during diabetes. Additional studies are needed to understand the precise regulatory roles for Tiam1-Rac1-Nox-ROS-JNK1/2 signaling to develop therapeutic strategies in the treatment of metabolic disorder.
"]},{"key":"dc:title","label":"Title","values":["Mechanisms of regulation of islet function by nadph oxidase"]}]}],"canonical_facts":{"dc:contributor":["ANJANEYULU KOWLURU"],"dc:creator":["Syed, Ismail"],"dc:date.available":["2012-12-15T08:00:00Z"],"dc:description.abstract":["Glucose stimulated insulin secretion (GSIS) involves a series of metabolic and cationic events, leading to translocation of insulin-laden secretory granules from a distal site toward the plasma membrane for fusion and release of insulin into circulation. Vesicular transport and fusion events are tightly regulated by signals which coordinate between vesicle- and membrane-associated docking proteins. It is now being accepted that reactive oxygen species [ROS] plays a second messenger role in islet â-cell function. Further, evidence from multiple laboratories suggests a tonic increase in ROS generation is necessary for GSIS and fatty acid-induced insulin secretion. On the other hand, excessive ROS generated during glucolipotoxic / exposures to cytokines and ceramide have proved to be detrimental for islet â-cells. Recent studies have shown activation of phagocyte-like NADPH oxidase [Nox] to be underlying cause for increased ROS generation observed under the above pathological conditions.
The overall objective of the present study is to i) determine potential mechanism[s] underlying nutrient-induced generation of ROS; ii) contributory roles of Tiam1-Rac1-Nox signaling in free fatty acid (e.g., palmitate) and cytokines- induced â-cell dysfunction. Findings from current study suggest that posttranslational prenylation is a requisite for signaling G-proteins involved in the activation of Nox and generation of ROS for nutrient-induced insulin secretion from islet â-cells. Studies with pertussis toxin [Ptx] suggested that glucose-induced Nox-mediated ROS generation is regulated by inhibitory class of G-proteins [Go/Gi]. Our next set of studies, directed towards understanding the mechanism of Nox activation under chronic exposure to high palmitate, cytokines and C2-ceramide implicate increased expression of Nox subunits to precede the functional activation of the holoenzyme and excessive ROS generation resulting in mitochondrial dysfunction. This study also provide first evidence for a critical modulatory role of Tiam1, a guanine nucleotide exchange factor [GEF] in Rac1-Nox signaling axis.
The next set of studies validated the above observations in Zucker Diabetic Fatty [ZDF] rat model, which mimics type2 diabetes in humans, characterized by obesity, hyperinsulinemia, hyperglycemia and gradual decline in â-cell function. The results obtained were comparable with clonal â-cells. Islets derived from ZDF-rats presented high levels of Nox subunit expression [p47phox, gp91phox, Rac1] which constitutively activated Nox-holoenzyme and augmented ROS levels. The increased oxidative stress under conditions of diabetes activated Jun-N-terminal kinases [JNK 1/2, stress-activated kinases] leading to mitochondrial abnormalities and eventual demise of islet â cells. A similar pattern of induction in Nox subunit expression/activation, ROS generation and JNK 1/2 were also observed in type 2 diabetes human islets. Taken together, herein I propose that high levels of oxidative stress, activation of stress-activated kinases [JNK1/2] and mitochondrial abnormalities underlies pancreatic â-cell dysfunction[s] during diabetes. Additional studies are needed to understand the precise regulatory roles for Tiam1-Rac1-Nox-ROS-JNK1/2 signaling to develop therapeutic strategies in the treatment of metabolic disorder.
"],"dc:identifier":["https://digitalcommons.wayne.edu/oa_dissertations/332"],"dc:subject":["NOX","Rac1","ROS","T2DM","Tiam1","ZDF","Medicinal Chemistry and Pharmaceutics","Pharmacology"],"dc:title":["Mechanisms of regulation of islet function by nadph oxidase"],"thesis:degree_discipline":["Pharmaceutical Sciences"],"thesis:degree_level":["Open Access Dissertation"],"thesis:degree_name":["Ph.D."]},"updated_at":"2026-07-24T05:58:57Z"}