Targeting AMPK for Therapeutic Intervention in Type 2 Diabetes

Kodiha, Mohamed; Stochaj, Ursula

doi:10.5772/20930

Cited by 10 publications

(5 citation statements)

References 139 publications

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“…It could be useful to coordinate these processes in DN as they correlate with diminished AMPK activity, resulting in increases in protein synthesis that can cause diabetes-induced renal hypertrophy in hyperglycemic conditions. Thus, specifically stimulating cytoplasmic AMPK could provide a more focused approach in alleviating diabetes-induced renal damage [34] .…”

Section: The Role Of Ampk Beyond Energy Homeostasis: Regulating Metabmentioning

confidence: 99%

Adenosine monophosphate–activated protein kinase in diabetic nephropathy

Kim

Park

2016

Kidney Research and Clinical Practice

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Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and its pathogenesis is complex and has not yet been fully elucidated. Abnormal glucose and lipid metabolism is key to understanding the pathogenesis of DN, which can develop in both type 1 and type 2 diabetes. A hallmark of this disease is the accumulation of glucose and lipids in renal cells, resulting in oxidative and endoplasmic reticulum stress, intracellular hypoxia, and inflammation, eventually leading to glomerulosclerosis and interstitial fibrosis. There is a growing body of evidence demonstrating that dysregulation of 5′ adenosine monophosphate–activated protein kinase (AMPK), an enzyme that plays a principal role in cell growth and cellular energy homeostasis, in relevant tissues is a key component of the development of metabolic syndrome and type 2 diabetes mellitus; thus, targeting this enzyme may ameliorate some pathologic features of this disease. AMPK regulates the coordination of anabolic processes, with its activation proven to improve glucose and lipid homeostasis in insulin-resistant animal models, as well as demonstrating mitochondrial biogenesis and antitumor activity. In this review, we discuss new findings regarding the role of AMPK in the pathogenesis of DN and offer suggestions for feasible clinical use and future studies of the role of AMPK activators in this disorder.

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Section: The Role Of Ampk Beyond Energy Homeostasis: Regulating Metabmentioning

confidence: 99%

Adenosine monophosphate–activated protein kinase in diabetic nephropathy

Kim

Park

2016

Kidney Research and Clinical Practice

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“…Another example that illustrates the ROS-dependent activation and distribution of protein kinases is the heterotrimeric enzyme 5′-AMP activated kinase (AMPK). AMPK is an energy sensor which plays a pivotal role in the regulation of metabolic homeostasis by phosphorylating targets that are involved in glucose, carbohydrate, lipid, and protein metabolism [ 158 – 161 ]. In unstressed cells, AMPK shuttles between the nucleus and cytoplasm and this shuttling relies on the nuclear exporter Crm1 [ 116 , 162 ].…”

Section: Oxidative Stress and Nucleocytoplasmic Transportmentioning

confidence: 99%

Nuclear Transport: A Switch for the Oxidative Stress—Signaling Circuit?

Kodiha

Stochaj

2012

Journal of Signal Transduction

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Imbalances in the formation and clearance of reactive oxygen species (ROS) can lead to oxidative stress and subsequent changes that affect all aspects of physiology. To limit and repair the damage generated by ROS, cells have developed a multitude of responses. A hallmark of these responses is the activation of signaling pathways that modulate the function of downstream targets in different cellular locations. To this end, critical steps of the stress response that occur in the nucleus and cytoplasm have to be coordinated, which makes the proper communication between both compartments mandatory. Here, we discuss the interdependence of ROS-mediated signaling and the transport of macromolecules across the nuclear envelope. We highlight examples of oxidant-dependent nuclear trafficking and describe the impact of oxidative stress on the transport apparatus. Our paper concludes by proposing a cellular circuit of ROS-induced signaling, nuclear transport and repair.

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“…In the nucleolus, transcription was strongly inhibited by resveratrol, while a moderate inhibition was observed with phenformin and AICAR. Taken together, the compartment-specific phosphorylation of AMPK and downstream events are determined by the activator.acetyl-CoA-carboxylase; nucleolus; transcription 5=-AMP-ACTIVATED PROTEIN KINASE (AMPK) functions as an energy sensor that is at the center of metabolic control in all eukaryotes; this kinase regulates metabolic processes in multiple organs and tissues (8,13,20,26,29,31,32,40,43,50,53). The importance of AMPK for maintaining glucose and lipid homeostasis makes the enzyme an ideal target for the treatment of type 2 diabetes, obesity, and metabolic syndrome.…”

mentioning

confidence: 99%

Pharmacological AMP-kinase activators have compartment-specific effects on cell physiology

Kodiha

Ho-Wo-Cheong

Stochaj

2011

American Journal of Physiology-Cell Physiology

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5'-AMP-activated kinase (AMPK) regulates numerous biological events and is an essential target for the treatment of type 2 diabetes. The objectives of the present study were first to determine the compartment-specific effects of three established AMPK activators on Thr172 phosphorylation of the α-subunit, an indicator of AMPK activation. Second, we examined how cytoplasmic and nuclear processes are modulated by pharmacological AMPK activators. Specifically, the impact of phenformin, resveratrol, and 5-aminoimidazole-4-carboxamide riboside (AICAR) on Thr172 phosphorylation in the cytoplasm and nucleus was quantified by different methods. To analyze how these activators change cell physiology, we measured the inactivation of acetyl-CoA-carboxylase 1, a predominantly cytoplasmic enzyme that is crucial for lipid metabolism. As a criterion for activities associated with the nucleus, de novo RNA synthesis in nucleoli was quantified. Our studies demonstrate that pharmacological activators of AMPK can alter the balance between nuclear and cytoplasmic AMPK pools. Thus, phenformin and resveratrol caused a strong activation of AMPK in the cytoplasm, whereas the effect was less pronounced in nuclei. By contrast, AICAR elicited a comparable rise in Thr172 phosphorylation in both compartments. Notably, these activators differed drastically in their effects on physiological processes that are located in distinct subcellular compartments. All compounds led to a substantial inactivation of acetyl-CoA-carboxylase 1 in the cytoplasm, with only minor changes to the nuclear enzyme. In the nucleolus, transcription was strongly inhibited by resveratrol, while a moderate inhibition was observed with phenformin and AICAR. Taken together, the compartment-specific phosphorylation of AMPK and downstream events are determined by the activator.

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Targeting AMPK for Therapeutic Intervention in Type 2 Diabetes

Cited by 10 publications

References 139 publications

Adenosine monophosphate–activated protein kinase in diabetic nephropathy

Adenosine monophosphate–activated protein kinase in diabetic nephropathy

Nuclear Transport: A Switch for the Oxidative Stress—Signaling Circuit?

Pharmacological AMP-kinase activators have compartment-specific effects on cell physiology

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