Augmentedβ-Cell Function and Mass in Glucocorticoid-Treated Rodents Are Associated with Increased Islet Ir-β/AKT/mTOR and Decreased AMPK/ACC and AS160 Signaling

Glucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increasedβ-cell function is associated with increased insulin signaling that has the protein kinase B (AKT) substrate with 160 kDa (AS160) as an important downstream AKT effector. In muscle, both insulin and AMP-activated protein kinase (AMPK) signaling phosphorylate and inactivate AS160, which favors the glucose transporter (GLUT)-4 translocation to plasma membrane. Whether AS160 phosphorylation is modulated in islets from GC-treated subjects is unknown. For this, two animal models, Swiss mice and Wistar rats, were treated with dexamethasone (DEX) (1 mg/kg body weight) for 5 consecutive days. DEX treatment induced IR, hyperinsulinemia, and dyslipidemia in both species, but glucose intolerance and hyperglycemia only in rats. DEX treatment caused increased insulin secretion in response to glucose and augmentedβ-cell mass in both species that were associated with increased islet content and increased phosphorylation of the AS160 protein. Protein AKT phosphorylation, but not AMPK phosphorylation, was found significantly enhanced in islets from DEX-treated animals. We conclude that the augmentedβ-cell function developed in response to the GC-induced IR involves inhibition of the islet AS160 protein activity.

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Over-expression of AMP-activated protein kinase impairs pancreatic β-cell function in vivo

Journal of Endocrinology ◽

10.1677/joe.1.06413 ◽

2005 ◽

Vol 187 (2) ◽

pp. 225-235 ◽

Cited By ~ 66

Author(s):

S K Richards ◽

L E Parton ◽

I Leclerc ◽

G A Rutter ◽

R M Smith

Keyword(s):

Insulin Secretion ◽

Protein Kinase ◽

Islet Transplantation ◽

Cell Function ◽

Cell Mass ◽

Β Cell ◽

Over Expression ◽

Β Cell Function ◽

Amp Activated Protein Kinase

Treatment of type 1 diabetes by islet transplantation is currently limited by loss of functional β-cell mass after transplantation. We investigated here whether adenovirus-mediated changes in AMP-activated protein kinase (AMPK) activity, previously shown to affect insulin secretion in vitro, might affect islet graft function in vivo. In isolated mouse and rat islets, insulin secretion stimulated by 17 (vs 3) mmol/l glucose was inhibited by 36.5% (P<0.01) and 43% (P<0.02) respectively after over-expression of constitutively-active AMPK- (AMPK CA) versus null (eGFP-expressing) viruses, and glucose oxidation was decreased by 38% (P<0.05) and 26.6% (P<0.05) respectively. Increases in apoptotic index (terminal deoxynucleotide transferase-mediated deoxyuridine trisphosphate biotin nick end-labelling) (TUNEL)) were also observed in AMPK CA- (22.8 ± 3.6% TUNEL-positive cells, P<0.001), but not AMPK DN- (2.72 ± 3.9%, positive cells, P=0.05) infected islets, versus null adenovirus-treated islets (0.68 ± 0.36% positive cells). Correspondingly, transplantation of islets expressing AMPK CA into streptozotocin-diabetic C57 BL/6 mice improved glycaemic control less effectively than transplantation with either null (P<0.02) or AMPK-DN-infected (P<0.01) islets. We conclude that activation of AMPK inhibits β-cell function in vivo and may represent a target for therapeutic intervention during islet transplantation.

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Antidiabetic and Antihyperlipidemic Effects ofClitocybe nudaon Glucose Transporter 4 and AMP-Activated Protein Kinase Phosphorylation in High-Fat-Fed Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/981046 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Mei-Hsing Chen ◽

Cheng-Hsiu Lin ◽

Chun-Ching Shih

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Glucose Transporter ◽

Body Weight Gain ◽

Glucose Production ◽

Hypolipidemic Effect ◽

Glucose Transporter 4 ◽

High Fat ◽

Hepatic Expression ◽

Amp Activated Protein Kinase

The objective of this study was to evaluate the antihyperlipidemic and antihyperglycemic effects and mechanism of the extract ofClitocybe nuda(CNE), in high-fat- (HF-) fed mice. C57BL/6J was randomly divided into two groups: the control (CON) group was fed with a low-fat diet, whereas the experimental group was fed with a HF diet for 8 weeks. Then, the HF group was subdivided into five groups and was given orally CNE (including C1: 0.2, C2: 0.5, and C3: 1.0 g/kg/day extracts) or rosiglitazone (Rosi) or vehicle for 4 weeks. CNE effectively prevented HF-diet-induced increases in the levels of blood glucose, triglyceride, insulin (P<0.001,P<0.01,P<0.05, resp.) and attenuated insulin resistance. By treatment with CNE, body weight gain, weights of white adipose tissue (WAT) and hepatic triacylglycerol content were reduced; moreover, adipocytes in the visceral depots showed a reduction in size. By treatment with CNE, the protein contents of glucose transporter 4 (GLUT4) were significantly increased in C3-treated group in the skeletal muscle. Furthermore, CNE reduces the hepatic expression of glucose-6-phosphatase (G6Pase) and glucose production. CNE significantly increases protein contents of phospho-AMP-activated protein kinase (AMPK) in the skeletal muscle and adipose and liver tissues. Therefore, it is possible that the activation of AMPK by CNE leads to diminished gluconeogenesis in the liver and enhanced glucose uptake in skeletal muscle. It is shown that CNE exhibits hypolipidemic effect in HF-fed mice by increasing ATGL expression, which is known to help triglyceride to hydrolyze. Moreover, antidiabetic properties of CNE occurred as a result of decreased hepatic glucose production via G6Pase downregulation and improved insulin sensitization. Thus, amelioration of diabetic and dyslipidemic states by CNE in HF-fed mice occurred by regulation of GLUT4, G6Pase, ATGL, and AMPK phosphorylation.

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AMPK activation with AICAR provokes an acute fall in plasma [K+]

AJP Cell Physiology ◽

10.1152/ajpcell.00464.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. C126-C135 ◽

Cited By ~ 21

Author(s):

Dan Zheng ◽

Anjana Perianayagam ◽

Donna H. Lee ◽

M. Douglas Brannan ◽

Li E. Yang ◽

...

Keyword(s):

Protein Kinase ◽

Infusion Rate ◽

Extracellular Fluid ◽

Ampk Activation ◽

Conscious Rats ◽

Significant Fall ◽

Ampk Phosphorylation ◽

Atp Levels ◽

Ampk Activity ◽

Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK), activated by an increase in intracellular AMP-to-ATP ratio, stimulates pathways that can restore ATP levels. We tested the hypothesis that AMPK activation influences extracellular fluid (ECF) K+ homeostasis. In conscious rats, AMPK was activated with 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) infusion: 38.4 mg/kg bolus then 4 mg·kg−1·min−1 infusion. Plasma [K+] and [glucose] both dropped at 1 h of AICAR infusion and [K+] dropped to 3.3 ± 0.04 mM by 3 h, linearly related to the increase in muscle AMPK phosphorylation. AICAR treatment did not increase urinary K+ excretion. AICAR lowered [K+] whether plasma [K+] was chronically elevated or lowered. The K+ infusion rate needed to maintain baseline plasma [K+] reached 15.7 ± 1.3 μmol K+·kg−1·min−1 between 120 and 180 min AICAR infusion. In mice expressing a dominant inhibitory form of AMPK in the muscle (Tg-KD1), baseline [K+] was not different from controls (4.2 ± 0.1 mM), but the fall in plasma [K+] in response to AICAR (0.25 g/kg) was blunted: [K+] fell to 3.6 ± 0.1 in controls and to 3.9 ± 0.1 mM in Tg-KD1, suggesting that ECF K+ redistributes, at least in part, to muscle ICF. In summary, these findings illustrate that activation of AMPK activity with AICAR provokes a significant fall in plasma [K+] and suggest a novel mechanism for redistributing K+ from ECF to ICF.

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Myeloid deletion and therapeutic activation of AMP-activated protein kinase (AMPK) do not alter atherosclerosis in male or female mice

10.1101/2020.07.15.204487 ◽

2020 ◽

Author(s):

Nicholas D. LeBlond ◽

Peyman Ghorbani ◽

Conor O’Dwyer ◽

Nia Ambursley ◽

Julia R. C. Nunes ◽

...

Keyword(s):

Protein Kinase ◽

First Generation ◽

Western Diet ◽

Daily Injection ◽

Catalytic Subunits ◽

Male And Female ◽

Ampk Signaling ◽

Female Mice ◽

Amp Activated Protein Kinase ◽

Progression Of Atherosclerosis

AbstractObjectiveThe dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis.Approach and ResultsWe aimed to clarify the role of myeloid-specific AMPK signaling by using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), in male and female mice made acutely atherosclerotic by PCSK9-AAV and Western diet-feeding. After 6 weeks of Western diet feeding, half received daily injection of either the AMPK activator, A-769662 or a vehicle control for a further 6 weeks. After 12 weeks, myeloid cell populations were not different between genotype or sex. Similarly, aortic sinus plaque size, lipid staining and necrotic area were not different in male and female MacKO mice compared to their littermate floxed controls. Moreover, therapeutic intervention with A-769662 had no effect. There were no differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area or markers of autophagy showed no effect of either lacking AMPK signaling or systemic AMPK activation.ConclusionsOur data suggest that while defined roles for each catalytic AMPK subunit have been identified, global deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Moreover, we show that intervention with the first-generation AMPK activator, A-769662, was not able to stem the progression of atherosclerosis.Highlights- The deletion of both catalytic subunits of AMPK in myeloid cells has no significant effect on the progression of atherosclerosis in either male or female mice- Therapeutic delivery of a first-generation AMPK activator (A-769662) for the last 6 weeks of 12-week study had no beneficial effect in either male or female mice- Studying total AMPK deletion may mask specific effects of each isoform and highlights the need for targeted disruption of AMPK phosphorylation sites via knock-in mutations, rather than the traditional “sledgehammer” knockout approach

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Roles for AMP-Activated Protein Kinase in RPE Cell Function

Retinal Degenerative Diseases - Advances in Experimental Medicine and Biology ◽

10.1007/978-1-4614-0631-0_95 ◽

2011 ◽

pp. 745-751 ◽

Cited By ~ 1

Author(s):

Suofu Qin

Keyword(s):

Protein Kinase ◽

Cell Function ◽

Amp Activated Protein Kinase

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AMP-activated protein kinase (AMPK) signaling in GnRH neurons links energy status and reproduction

Metabolism ◽

10.1016/j.metabol.2020.154460 ◽

2021 ◽

Vol 115 ◽

pp. 154460

Author(s):

D. Franssen ◽

A. Barroso ◽

F. Ruiz-Pino ◽

M.J. Vázquez ◽

D. García-Galiano ◽

...

Keyword(s):

Protein Kinase ◽

Energy Status ◽

Ampk Signaling ◽

Gnrh Neurons ◽

Amp Activated Protein Kinase

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AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress

Journal of Biological Chemistry ◽

10.1074/jbc.m300643200 ◽

2003 ◽

Vol 278 (33) ◽

pp. 31000-31006 ◽

Cited By ~ 259

Author(s):

Daisuke Nagata ◽

Masaki Mogi ◽

Kenneth Walsh

Keyword(s):

Endothelial Cells ◽

Protein Kinase ◽

Hypoxic Stress ◽

Ampk Signaling ◽

Amp Activated Protein Kinase

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Octaphlorethol A, a marine algae product, exhibits antidiabetic effects in type 2 diabetic mice by activating AMP-activated protein kinase and upregulating the expression of glucose transporter 4

Food and Chemical Toxicology ◽

10.1016/j.fct.2016.02.022 ◽

2016 ◽

Vol 91 ◽

pp. 58-64 ◽

Cited By ~ 21

Author(s):

Seung-Hong Lee ◽

Seok-Chun Ko ◽

Min-Cheol Kang ◽

Dae Ho Lee ◽

You-Jin Jeon

Keyword(s):

Protein Kinase ◽

Marine Algae ◽

Glucose Transporter ◽

Diabetic Mice ◽

Glucose Transporter 4 ◽

Amp Activated Protein Kinase ◽

Type 2 Diabetic ◽

Antidiabetic Effects

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Regulation of multisite phosphorylation and 14-3-3 binding of AS160 in response to IGF-1, EGF, PMA and AICAR

Biochemical Journal ◽

10.1042/bj20070649 ◽

2007 ◽

Vol 407 (2) ◽

pp. 231-241 ◽

Cited By ~ 122

Author(s):

Kathryn M. Geraghty ◽

Shuai Chen ◽

Jean E. Harthill ◽

Adel F. Ibrahim ◽

Rachel Toth ◽

...

Keyword(s):

Growth Factor ◽

Protein Kinase ◽

Glucose Transporter ◽

Kinase Inhibitors ◽

Hek 293 ◽

293 Cells ◽

Ribosomal S6 Kinase ◽

Phosphoinositide 3 Kinase ◽

Amp Activated Protein Kinase

AS160 (Akt substrate of 160 kDa) mediates insulin-stimulated GLUT4 (glucose transporter 4) translocation, but is widely expressed in insulin-insensitive tissues lacking GLUT4. Having isolated AS160 by 14-3-3-affinity chromatography, we found that binding of AS160 to 14-3-3 isoforms in HEK (human embryonic kidney)-293 cells was induced by IGF-1 (insulin-like growth factor-1), EGF (epidermal growth factor), PMA and, to a lesser extent, AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside). AS160-14-3-3 interactions were stabilized by chemical cross-linking and abolished by dephosphorylation. Eight residues on AS160 (Ser318, Ser341, Thr568, Ser570, Ser588, Thr642, Ser666 and Ser751) were differentially phosphorylated in response to IGF-1, EGF, PMA and AICAR. The binding of 14-3-3 proteins to HA–AS160 (where HA is haemagglutinin) was markedly decreased by mutation of Thr642 and abolished in a Thr642Ala/Ser341Ala double mutant. The AGC (protein kinase A/protein kinase G/protein kinase C-family) kinases RSK1 (p90 ribosomal S6 kinase 1), SGK1 (serum- and glucocorticoid-induced protein kinase 1) and PKB (protein kinase B) displayed distinct signatures of AS160 phosphorylation in vitro: all three kinases phosphorylated Ser318, Ser588 and Thr642; RSK1 also phosphorylated Ser341, Ser751 and to a lesser extent Thr568; and SGK1 phosphorylated Thr568 and Ser751. AMPK (AMP-activated protein kinase) preferentially phosphorylated Ser588, with less phosphorylation of other sites. In cells, the IGF-1-stimulated phosphorylations, and certain EGF-stimulated phosphorylations, were inhibited by PI3K (phosphoinositide 3-kinase) inhibitors, whereas the RSK inhibitor BI-D1870 inhibited the PMA-induced phosphorylations. The expression of LKB1 in HeLa cells and the use of AICAR in HEK-293 cells promoted phosphorylation of Ser588, but only weak Ser341 and Thr642 phosphorylations and binding to 14-3-3s. Paradoxically however, phenformin activated AMPK without promoting AS160 phosphorylation. The IGF-1-induced phosphorylation of the novel phosphorylated Ser666-Pro site was suppressed by AICAR, and by combined mutation of a TOS (mTOR signalling)-like sequence (FEMDI) and rapamycin. Thus, although AS160 is a common target of insulin, IGF-1, EGF, PMA and AICAR, these stimuli induce distinctive patterns of phosphorylation and 14-3-3 binding, mediated by at least four protein kinases.

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