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EXENATIDE, AN INCRETIN HORMONE & AMP-ACTIVATED PROTEIN KINASE, AN ENERGY SENSOR, EMERGE AS NOVEL INSULIN-SENSITIZING AGENTS by Dan Zheng ___________________________________________________________ A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHYSIOLOGY AND BIOPHYSICS) December 2008 Copyright 2008 Dan Zheng
|Title||Exenatide, an incretin hormone & AMP-activated protein kinase, an energy sensor, emerge as novel insulin-sensitizing agents|
|Author email@example.com; firstname.lastname@example.org|
|Degree||Doctor of Philosophy|
|Degree program||Physiology & Biophysics|
|School||Keck School of Medicine|
|Advisor (committee chair)||Bergman, Richard N.|
|Advisor (committee member)||
Watanabe, Richard M.
Watts, Alan G.
Buchanan, Thomas A.
Youn, Jang H.
|Abstract||The present dissertation focuses on two novel metabolic players: exenatide, an incretin mimetic, and AMP-activated protein kinase, a cell energy sensor.; Exenatide is a long-acting mimetic of the incretin hormone glucagon-like peptide-1 and has been shown to lower glycemia in diabetic animal models and subjects. Recent progress suggests that exenatide might lower glycemia independent of an increase in beta-cell response or suppression of gastrointestinal motility. The overall aim of the exenatide studies was to investigate whether exenatide directly stimulates glucose turnover in insulin-responsive tissues dependent or independent of insulinemia. We utilized an "intraportal glucose infusion-glucose clamp" to measure glucose turnover so as to potentially activate with exenatide the putative glucose/GLP-1 sensor in the porto-hepatic circulation. We first performed the modified glucose clamp in the presence of postprandial hyperinsulinemia and hyperglycemia with either exenatide (EX) or saline (SAL) injected at time 0 min (study 1). We measured a significant increase in total glucose turnover by ~30%, as indicated by portal glucose infusion rate (PoGinf, SAL 15.9 ± 1.6 vs. EX 20.4 ± 2.1 mg/kg/min, P < 0.001), resulting from increased whole-body glucose disposal (Rd, ~20%) as well as increased net hepatice uptake of exogenous glucose (~80%). Reducing systemic hyperglycemia to euglycemia (study 2), exenatide still increased total glucose turnover by ~20% (PoGinf, SAL 13.2 ± 1.9 vs. EX 15.6 ± 2.1 mg/kg/min, P < 0.05) in the presence of elevated insulinemia, accompanied by smaller increments in Rd (12%) and net hepatic uptake of exogenous glucose (45%). In contrast, reducing hyperinsulinemia to basal levels (study 3), exenatide-increased glucose turnover was completely abolished despite of the presence of hyperglycemia (PoGinf, SAL 2.9 ± 0.6 vs. 2.3 ± 0.3 mg/kg/min, P = 0.29). It appears that hyperinsulinemia is a prerequisite of exenatide-mediated glucose disposal, suggesting an insulin-sensitizing effect of exenatide.; We conclude that exenatide also directly stimulates glucose turnover by enhancing insulin-mediated whole-body glucose disposal and increasing uptake of exogenous glucose by the liver, contributing to its overall action to lower postprandial glucose excursion.; AMP-activated protein kinase (AMPK) is a serine/threonine protein kianse that is activated during metabolic stresses and regulates metabolic pathways to maintain energy balance. Notably, AMPK promotes membrane nutrient (glucose) and ion (Na+, Cl-) transport. We hypothesized that AMPK stimulates cellular K+ uptake while it promotes glucose uptake during stresses, such as exercise and ischemia, which is reminiscent of insulin's dual actions on glucose and K+ in a postprandial condition. We administered AICAR (an AMPK activator; 38.4 mg/kg + 4 mg/kg/min, 3 hr) to rats with normal, elevated, or depressed plasma K+ level. We found that AICAR infusion simultaneously induced plasma glucose and K+ clearance. AICAR-stimulated glucose turnover was compensated by giving exogenous glucose so euglycemia was maintained throughout. Plasma K+ was allowed to change and AICAR led to an average of 20% decrease in plasma K+ despite the difference in basal K+ levels (all P < 0.05; in eukalemic rats: 4.1 ± 0.1 mM basal vs. 3.2 ± 0.04 mM AICAR 150-180 min). AICAR's K+-lowering effect appears to result from a stimulation of net cellular K+ uptake because no increase was found in urinary K+ excretion with AICAR. The temporal change in plasma K+ during AICAR infusion was well correlated with skeletal muscle AMPK phosphorylation and activation (R = 0.87, P < 0.0001). Thus, skeletal muscle AMPK activity appears to mediate AICAR's effect on K+. Na+, K+-ATPase activity and content are altered with K+ overload or deficiency, which in turn alters cellular K+ uptake mediated by the pump. The observation that AMPK's K+-lowering effect is maintained in rats on either positive K+ balance (basal K+ elevated) or negative K+ balance (basal K+ hypokalemic) suggests that Na+ pump might not be involved in AMPK's effect on K+. In other words, AMPK might lower plasma K+ by inhibiting K+ efflux through a channel.; AMPK appears to be a potent hypokalemic agent and capable of restoring plama K+ homeostasis in muscle contraction since a lowering of plasma K+ to 3.2 mM in eukalemic rats was only previously observed with the maximal dose of insulin. AMPK also appears to be the most recent example of simultaneous stimulation of membrane glucose and K+ transport, which can be an indication of a novel concept that K+ channel activity is involved in membrane glucose transport. In conclusion, the present AMPK studies have clearly shown a novel action of AMPK to stimulate net cellular K+ uptake coincident with its action to increase cellular glucose uptake. Such an effect might be physiologically important in extracellular K+ homeostasis during exercise or ischemia and/or skeletal muscle glucose disposal.|
|Keyword||exenatide; insulin action; AMP-activated protein kinase|
|Part of collection||University of Southern California dissertations and theses|
|Publisher (of the original version)||University of Southern California|
|Place of publication (of the original version)||Los Angeles, California|
|Publisher (of the digital version)||University of Southern California. Libraries|
|Provenance||Electronically uploaded by the author|
|Legacy record ID||usctheses-m1739|
|Contributing entity||University of Southern California|
|Repository name||Libraries, University of Southern California|
|Repository address||Los Angeles, California|
|Contributing entity||University of Southern California|
|Full text||EXENATIDE, AN INCRETIN HORMONE & AMP-ACTIVATED PROTEIN KINASE, AN ENERGY SENSOR, EMERGE AS NOVEL INSULIN-SENSITIZING AGENTS by Dan Zheng ___________________________________________________________ A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHYSIOLOGY AND BIOPHYSICS) December 2008 Copyright 2008 Dan Zheng|