The relevance of AMP-activated protein kinase in insulin-secreting β cells: a potential target for improving β cell function?

Szkudelski, Tomasz; Szkudelska, Katarzyna

doi:10.1007/s13105-019-00706-3

Cited by 30 publications

(23 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the same study, transplantation of islets expressing the constitutively active AMPK into streptozotocin-induced diabetic mice improved glycemic control less effectively than transplantation with control islets. In contrast, other studies concluded that activation of AMPK by AICAR increases insulin secretion [4,5]. The effects of AMPK on glucose-stimulated insulin secretion may be influenced by experimental conditions, such as the glucose concentrations in cell culture media and during the insulin secretion assays.…”

Section: Ampk In the β-Cellmentioning

confidence: 97%

“…Intuitively, activation of AMPK in the β-cell should not accompany the stimulatory action of glucose on insulin secretion, the former resulting from low energy state and the latter being associated with robust ATP production. However, the numerous studies on these actions are somehow contradictory, as extensively reviewed by others [4,5]. Here, we will address the effects of metabolic stresses on the expression of the key components of the AMPK system.…”

Section: Ampk and Glucose Homeostasismentioning

confidence: 98%

“…Molecular targets of AMPK in the β-cell, as well as their potential roles, have been documented and reviewed by others [3][4][5]. Several studies have reported that AMPK negatively regulates β-cell insulin exocytosis in primary rat islets and β-cell lines [14,18,19].…”

Section: Ampk In the β-Cellmentioning

confidence: 99%

See 2 more Smart Citations

AMPK Profiling in Rodent and Human Pancreatic Beta-Cells under Nutrient-Rich Metabolic Stress

Brun

Jiménez‐Sánchez

Madsen

et al. 2020

IJMS

View full text Add to dashboard Cite

Chronic exposure of pancreatic β-cells to elevated nutrient levels impairs their function and potentially induces apoptosis. Like in other cell types, AMPK is activated in β-cells under conditions of nutrient deprivation, while little is known on AMPK responses to metabolic stresses. Here, we first reviewed recent studies on the role of AMPK activation in β-cells. Then, we investigated the expression profile of AMPK pathways in β-cells following metabolic stresses. INS-1E β-cells and human islets were exposed for 3 days to glucose (5.5–25 mM), palmitate or oleate (0.4 mM), and fructose (5.5 mM). Following these treatments, we analyzed transcript levels of INS-1E β-cells by qRT-PCR and of human islets by RNA-Seq; with a special focus on AMPK-associated genes, such as the AMPK catalytic subunits α1 (Prkaa1) and α2 (Prkaa2). AMPKα and pAMPKα were also evaluated at the protein level by immunoblotting. Chronic exposure to the different metabolic stresses, known to alter glucose-stimulated insulin secretion, did not change AMPK expression, either in insulinoma cells or in human islets. Expression profile of the six AMPK subunits was marginally modified by the different diabetogenic conditions. However, the expression of some upstream kinases and downstream AMPK targets, including K-ATP channel subunits, exhibited stress-specific signatures. Interestingly, at the protein level, chronic fructose treatment favored fasting-like phenotype in human islets, as witnessed by AMPK activation. Collectively, previously published and present data indicate that, in the β-cell, AMPK activation might be implicated in the pre-diabetic state, potentially as a protective mechanism.

show abstract

Section: Ampk In the β-Cellmentioning

confidence: 97%

Section: Ampk and Glucose Homeostasismentioning

confidence: 98%

See 1 more Smart Citation

AMPK Profiling in Rodent and Human Pancreatic Beta-Cells under Nutrient-Rich Metabolic Stress

Brun

Jiménez‐Sánchez

Madsen

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…AMPK, as the main target of metformin, regulates the function of hepatic glucose metabolism and pancreatic b-cell [8,11,26]. It has been widely agreed that the phosphorylation of AMPK is induced by metformin, although the speci c route is not clear yet.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of PRKAA2 Genetic Variation on Metformin Efficacy as an Initial Therapy Among Drug-Naïve Patients With Type II Diabetes Mellitus

Virginia¹,

Wahyuningsih²,

Nugrahaningsih³

2020

Preprint

View full text Add to dashboard Cite

Background: Metformin is the most popular oral antidiabetic agent, which is recommended as initial monotherapy. AMPK is the pivotal target of metformin molecular mechanisms. AMPK subunit a2 (encoded by PRKAA2) is a gene contributable to increase type 2 diabetes mellitus (T2DM) risk. This study aimed to evaluate PRKAA2 rs2796498, rs2746342, and rs980799 genetic variations on metformin efficacy.Methods: This study enrolled 191 newly diagnosed Indonesia T2DM patients in primary health care. Patients who received metformin as monotherapy for at least 3 months were included for genotyping. Genotyping was performed using the Taqman assay.Results: Baseline characteristics showed that BMI was higher among AA than GG+AG (p=0.04). Patients with TT genotype showed a higher FBG and HbA1c than GG+GT (p=0.02 and p=0.02, respectively). There was no significant difference in allele and genotype frequencies between responders and non-responders group in PRKAA2 rs2796498, rs9803799, and rs2746342. However, among PRKAA2 rs2796498, AG carrier had 0.32 times of responding in metformin efficacy after adjusting BMI, WC, blood pressure, lipid profiles, and eGFR. Dominant model of rs2796498 showed a significant association (OR=0.34, 95%CI=0.13 – 0.90) to metformin efficacy. Conclusions: Our findings suggest that PRKAA2 rs2796498 genetic variation may affect metformin efficacy, especially AG carrier, in drug-naïve T2DM patients.

show abstract

“…In particular, we review how the activities of the endoplasmic reticulum (ER), mitochondria, lysosomes, and autophagosomes within β -cells are influenced by chronic and sustained stimulation of two key nutrient-sensor proteins, the mechanistic target of rapamycin (mTOR) and O-linked N-acetylglucosamine transferase (OGT), and how these changes contribute to systemic β -cell failure. The catabolic nutrient sensor AMP-activated protein kinase (AMPK) is also important for β -cell function, and AMPK signaling is perturbed during T2D [ 8 , 9 ]. However, AMPK and organelle homeostasis in β -cells is understudied; this is a subject greatly in need of further research.…”

Section: Introductionmentioning

confidence: 99%

Nutrient Sensor mTOR and OGT: Orchestrators of Organelle Homeostasis in Pancreatic β-Cells

Esch

Moore

et al. 2020

Journal of Diabetes Research

View full text Add to dashboard Cite

The purpose of this review is to integrate the role of nutrient-sensing pathways into β-cell organelle dysfunction prompted by nutrient excess during type 2 diabetes (T2D). T2D encompasses chronic hyperglycemia, hyperlipidemia, and inflammation, which each contribute to β-cell failure. These factors can disrupt the function of critical β-cell organelles, namely, the ER, mitochondria, lysosomes, and autophagosomes. Dysfunctional organelles cause defects in insulin synthesis and secretion and activate apoptotic pathways if homeostasis is not restored. In this review, we will focus on mTORC1 and OGT, two major anabolic nutrient sensors with important roles in β-cell physiology. Though acute stimulation of these sensors frequently improves β-cell function and promotes adaptation to cell stress, chronic and sustained activity disturbs organelle homeostasis. mTORC1 and OGT regulate organelle function by influencing the expression and activities of key proteins, enzymes, and transcription factors, as well as by modulating autophagy to influence clearance of defective organelles. In addition, mTORC1 and OGT activity influence islet inflammation during T2D, which can further disrupt organelle and β-cell function. Therapies for T2D that fine-tune the activity of these nutrient sensors have yet to be developed, but the important role of mTORC1 and OGT in organelle homeostasis makes them promising targets to improve β-cell function and survival.

show abstract

The relevance of AMP-activated protein kinase in insulin-secreting β cells: a potential target for improving β cell function?

Cited by 30 publications

References 77 publications

AMPK Profiling in Rodent and Human Pancreatic Beta-Cells under Nutrient-Rich Metabolic Stress

AMPK Profiling in Rodent and Human Pancreatic Beta-Cells under Nutrient-Rich Metabolic Stress

Evaluation of PRKAA2 Genetic Variation on Metformin Efficacy as an Initial Therapy Among Drug-Naïve Patients With Type II Diabetes Mellitus

Nutrient Sensor mTOR and OGT: Orchestrators of Organelle Homeostasis in Pancreatic β-Cells

Contact Info

Product

Resources

About