History of changes to: The role of glucose 6-phosphate in regulating glycogen synthase & the establishment of a molecular physiology laboratory
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Nov. 27, 2023, 2:13 p.m. Added 35 {"external_links": []}
Nov. 20, 2023, 2:03 p.m. Added 35 {"external_links": []}
Nov. 13, 2023, 1:34 p.m. Added 35 {"external_links": []}
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Jan. 28, 2023, 11:09 a.m. Created 43 [{"model": "core.projectfund", "pk": 29193, "fields": {"project": 6411, "organisation": 49, "amount": 879707, "start_date": "2007-03-31", "end_date": "2012-02-29", "raw_data": 47903}}]
Jan. 28, 2023, 10:52 a.m. Added 35 {"external_links": []}
April 11, 2022, 3:48 a.m. Created 43 [{"model": "core.projectfund", "pk": 21326, "fields": {"project": 6411, "organisation": 49, "amount": 879707, "start_date": "2007-03-31", "end_date": "2012-02-29", "raw_data": 29865}}]
April 11, 2022, 3:48 a.m. Created 41 [{"model": "core.projectorganisation", "pk": 80642, "fields": {"project": 6411, "organisation": 567, "role": "COLLAB_ORG"}}]
April 11, 2022, 3:48 a.m. Created 41 [{"model": "core.projectorganisation", "pk": 80641, "fields": {"project": 6411, "organisation": 8132, "role": "LEAD_ORG"}}]
April 11, 2022, 3:48 a.m. Created 40 [{"model": "core.projectperson", "pk": 49783, "fields": {"project": 6411, "person": 9076, "role": "PI_PER"}}]
April 11, 2022, 1:48 a.m. Updated 35 {"title": ["", "The role of glucose 6-phosphate in regulating glycogen synthase & the establishment of a molecular physiology laboratory"], "description": ["", "\nWe aim to understand the molecular mechanism by which excess blood glucose is stored in muscle and liver cells. This will help in developing a new drug for type 2 diabetes.||Glucose is the primary fuel used by most cells in the body to generate the energy that is needed to carry out cellular processes. Normally, blood glucose levels are tightly controlled by hormone insulin. When the blood glucose rises after a meal, insulin is released from the pancreas to signal the body to lower the glucose levels. Insulin commands liver and muscle cells to uptake glucose and switch on the action of several enzymes, including a protein called glycogen synthase (GS). By the key action of GS, glucose molecules are converted to its polymer form glycogen for energy storage. The mechanism by which GS is switched on is a coordinated event, which involves binding of a glucose derivative to the protein and removal of phosphate from multiple positions on the protein.||We have developed genetic models to work out the relative contribution of these two molecular events in controlling the action of GS and storage of glycogen in muscle and liver cells.\n\n"], "extra_text": ["", "\nTechnical Abstract:\nSkeletal muscle is the major site of insulin-stimulated glucose uptake, with the majority of glucose that enters muscle fibres in response to insulin being stored as glycogen. Thus muscle glucose uptake and glycogen synthesis play a critical role in the regulation of whole-body glucose homeostasis. In skeletal muscle of type 2 diabetic subjects, both glucose uptake and the activity of glycogen synthase (GS) with insulin are impaired, and this is thought to play a major role in the development of insulin resistance and type 2 diabetes. GS is a rate-limiting enzyme in glycogen synthesis in muscle and liver cells. GS is regulated by covalent phosphorylation which inhibits the enzyme, and by the allosteric activator G6P. The relative contribution of these two regulatory mechanisms in controlling GS in vivo is not defined. Insulin is thought to enhance GS activity through the activation of PKB and subsequent phosphorylation and deactivation of GSK3, which functions to dephosphorylate GS at a cluster of C-terminal residues. In support of this we have recently reported that insulin was unable to promote dephosphorylation of GS at residues targeted by GSK3 and activation of GS in the muscle of knock-in mice expressing constitutively active mutant forms of GSK3 in which the PKB phosphorylation sites on GSKa (Ser21) and GSK3b (Ser9) were changed to Ala. However, unexpectedly, the levels of glycogen in muscle were similar in wild-type and GSK3 knock-in mice. This could be explained if activation of GS by the allosteric activator, G6P, plays a key role in glycogen synthesis, compensating for the lack of insulin-induced dephosphorylation of GS in the GSK3 knock-in mice. The aim of the proposed research is, (1) to investigate the role that allosteric regulation GS plays and (2) to work out the relative contribution of phosphorylation versus allosteric regulations of GS in glycogen synthesis in vivo. We have identified a key residue that is important for G6P binding to GS and recently generated a knock-in mouse in which GS is mutated to render it incapable of activation by G6P. We are analyzing these mice along with GSK3 knock-in mice to provide information about the relative roles of G6P and phosphorylation in controlling activity of GS and the level of glycogen in vivo and to define their role in regulating whole body glucose homeostasis. This study will provide mechanistic insights into how insulin promotes glycogen synthesis in vivo and will help in developing a new drug for type 2 diabetes.\n\n\n\n"], "status": ["", "Closed"]}
April 11, 2022, 1:48 a.m. Added 35 {"external_links": [23598]}
April 11, 2022, 1:48 a.m. Created 35 [{"model": "core.project", "pk": 6411, "fields": {"owner": null, "is_locked": false, "coped_id": "e6c21816-f4b6-47f0-b181-8c41a1ae6aa3", "title": "", "description": "", "extra_text": "", "status": "", "start": null, "end": null, "raw_data": 29851, "created": "2022-04-11T01:43:10.190Z", "modified": "2022-04-11T01:43:10.190Z", "external_links": []}}]