bims-glecem 2022-05-22 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–05–22
thirteen papers selected by
Dipsikha Biswas, Københavns Universitet

Development of minimally invasive 13C-glucose breath test to examine different exogenous carbohydrate sources in patients with glycogen storage disease type Ia.
The biallelic novel pathogenic variants in AGL gene in a chinese patient with glycogen storage disease type III.
Muscle Glycogen in Elite Soccer - A Perspective on the Implication for Performance, Fatigue, and Recovery.
GSK-3β Inhibition in Birds Affects Social Behavior and Increases Motor Activity.
Molecular docking analysis of glycogen phosphorylase with inhibitors from Cissampelos pareira Linn.
Antihyperglycemic and antidyslipidemic Effect of Moricandia suffruticosa in Normal and Streptozotocin-Induced Diabetic Rats.
miR-23b-3p rescues cognition in Alzheimer's disease by reducing tau phosphorylation and apoptosis via GSK-3β signaling pathways.
CircLIFR suppresses hepatocellular carcinoma progression by sponging miR-624-5p and inactivating the GSK-3β/β-catenin signaling pathway.
Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells.
Beta 2 adrenergic receptor and mu opioid receptor interact to potentiate the aggressiveness of human breast cancer cell by activating the glycogen synthase kinase 3 signaling.
Trafficking regulator of GLUT4-1 (TRARG1) is a GSK3 substrate.
Oxidative stress-induced damage to the developing hippocampus is mediated by GSK3beta.
Glucagon, cyclic AMP, and hepatic glucose mobilization: A half-century of uncertainty.

Mol Genet Metab Rep. 2022 Jun;31 100880

Development of minimally invasive 13C-glucose breath test to examine different exogenous carbohydrate sources in patients with glycogen storage disease type Ia.

Abrar Turki, Sylvia Stockler, Sandra Sirrs, Ramona Salvarinova, Gloria Ho, Jennifer Branov, Annie Rosen-Heath, Taryn Bosdet, Rajavel Elango.

   Background: Glycogen storage disease type Ia (GSD Ia) is an autosomal recessive disorder caused by deficiency of glucose-6-phosphatase (G6Pase), resulting in fasting hypoglycemia. Dietary treatment with provision of uncooked cornstarch (UCCS) or a novel modified cornstarch (Glycosade®) is available to treat hypoglycemia, yet choice of carbohydrate to achieve a desirable glycemic control is debated.13C-glucose breath test (13C-GBT) can be used to examine glucose metabolism from different carbohydrate sources via 13CO2 in breath.
Objectives: Our objectives were: 1) establishing the use of a minimally invasive 13C-GBT to examine in vivo glucose metabolism in healthy adults, and 2) using 13C-GBT to measure utilization of the standard UCCS vs. Glycosade® in GSD Ia and healthy controls.
Design: Experiment 1- Ten healthy adults (6F: 4 M, 22-33y) underwent 13C-GBT protocol twice as a proof-of-principle, once with oral isotope dose (glucose 75 g + [U-13C6] d-glucose 75 mg) and once without isotope (only glucose 75 g) to test sensitivity of natural 13C-enrichment. Breath samples were collected at baseline and every 20 min for 240 min. Rate of CO2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Experiment 2- Three GSD Ia (12y, 13y, and 28y) and six healthy controls (2F: 4 M, 10-32y) underwent 13C-GBT protocol twice: with UCCS or Glycosade® (based on their current prescribed dose 42-100 g) after ~4 h fast based on our GSD Ia patients with fasting tolerance.
Results: Findings 1- Maximum 13C-enrichments occurred at 200 min without and with [U-13C6] d-glucose in all healthy adults, suggesting natural enrichment is sensitive for the 13C-GBT. Findings 2- Glycosade® utilization was lower than UCCS utilization in 12y and 13y GSD Ia, but was similar in the 28y GSD Ia.
Conclusions: 13C-GBT is a novel minimally invasive functional test to examine glucose metabolism in GSD Ia, and test new products like Glycosade®, which has the potential to improve nutritional management and individualized carbohydrate supply in GSD.

Keywords:  13C-GBT, 13C-glucose breath test; 13C-glucose; APE, atom percent excess; AUC, area under the curve; BIA, bioelectrical impedance analysis; BMI, body mass index; Breath test; CGM, continuous glucose monitor; CREU, clinical research and evaluation unit; Cmax, maximum peak enrichment in 13CO2 oxidation; F13CO2, rate of glucose oxidation; FCO2, CO2 production rate using indirect calorimetry; FFM, fat free mass; FM, fat mass; G6P, glucose-6-phosphate; G6Pase, glucose-6-phosphatase; GSD I, glycogen storage disease type I; GSD Ia, glycogen storage disease type Ia; Glucose-6-phosphatase; Glycogen storage disease type Ia; Glycosade®; HSCT, hematopoietic stem cell transplantation; OGTT, oral glucose tolerance test; PKU, phenylketonuria; REE, resting energy expenditure; UCCS, uncooked cornstarch; Uncooked cornstarch; VCO2, rate of carbon dioxide production; tmax, time to reach maximum 13CO2 oxidation

DOI:  https://doi.org/10.1016/j.ymgmr.2022.100880
BMC Pediatr. 2022 May 16. 22(1): 284

The biallelic novel pathogenic variants in AGL gene in a chinese patient with glycogen storage disease type III.

Jing Wang, Yuping Yu, Chunquan Cai, Xiufang Zhi, Ying Zhang, Yu Zhao, Jianbo Shu.

   BACKGROUND: Glycogen storage disease type III (GSD III) is a rare autosomal recessive glycogenolysis disorder due to AGL gene variants, characterized by hepatomegaly, fasting hypoglycemia, hyperlipidemia, elevated hepatic transaminases, growth retardation, progressive myopathy, and cardiomyopathy. However, it is not easy to make a definite diagnosis in early stage of disease only based on the clinical phenotype and imageology due to its clinical heterogeneity.
CASE PRESENTATION: We report a two-year-old girl with GSD III from a nonconsanguineous Chinese family, who presented with hepatomegaly, fasting hypoglycemia, hyperlipidemia, elevated levels of transaminases. Accordingly, Sanger sequencing, whole‑exome sequencing of family trios, and qRT-PCR was performed, which revealed that the patient carried the compound heterogeneous variants, a novel frameshift mutation c.597delG (p. Q199Hfs*2) and a novel large gene fragment deletion of the entire exon 13 in AGL gene. The deletion of AGL was inherited from the proband's father and the c.597delG variant was from the mother.
CONCLUSIONS: In this study, we identified two novel variants c.597delG (p. Q199Hfs*2) and deletion of the entire exon 13 in AGL in a Chinese GSD III patient. We extend the mutation spectrum of AGL. We suggest that high-throughput sequencing technology can detect and screen pathogenic variant, which is a scientific basis about genetic counseling and clinical diagnosis.

Keywords:  AGL gene; Frameshift variant; Glycogen storage disease type III; Novel variant; Whole-exome sequencing

DOI:  https://doi.org/10.1186/s12887-022-03252-y
Front Sports Act Living. 2022 ;4 876534

Muscle Glycogen in Elite Soccer - A Perspective on the Implication for Performance, Fatigue, and Recovery.

Magni Mohr, Jeppe F Vigh-Larsen, Peter Krustrup.

  Based on extrapolation of current trends in modern soccer, physiological loading has increased markedly, and the game will continue to become even more demanding in the future, which will exacerbate fatigue at the end of a game and between games. Soccer is a glycogen consuming activity due to its high-intensity intermittent nature, and muscle glycogen is a key factor associated with fatigue late in a game, as well as in determining recovery after a game or an intense training session. Low glycogen in individual muscle fibers and subcellular compartments in the muscle cell is likely to negatively affect several essential steps in the excitation-contraction coupling such as action potential propagation, calcium handling and cross-bridge cycling through reductions in muscle ATP which are suggested sites of muscle function impairment inducing muscle fatigue. Recovery of physical performance and muscle glycogen after a soccer game is a slow process, which challenges the reality in modern elite soccer with increased game and training frequency and physiological loading. We suggest a markedly higher prioritization of fitness training modalities, nutritional approaches and general recovery strategies that optimizes muscle glycogen storage prior to games and training sessions. Also, the soccer community including the governing bodies of the sport must acknowledge and plan according to the high and increasing demands of the modern game, as well as the consequences this has on fatigue and recovery. These aspects are paramount to consider in the planning of training and games, as well as in the process of structuring soccer tournaments and developing competitive regulations in the future to optimize performance and player health.

Keywords:  carbohydrates; football; nutrition; resynthesis; training

DOI:  https://doi.org/10.3389/fspor.2022.876534
Front Physiol. 2022 ;13 881174

GSK-3β Inhibition in Birds Affects Social Behavior and Increases Motor Activity.

Stan Moaraf, Ido Rippin, Joseph Terkel, Hagit Eldar-Finkelman, Anat Barnea.

  Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine/threonine protein kinase that plays a central role in a wide variety of cellular processes, cognition and behaviour. In a previous study we showed that its α and β isozymes are highly conserved in vertebrates, however the α gene is missing in birds. This selective loss offers a unique opportunity to study the role of GSK-3β independently. Accordingly, in the present study we aimed to investigate the role of GSK-3β in social behaviour, motivation, and motor activity in zebra finches (Taeniopygia guttata). We did that by selective inhibition of GSK-3β and by using tests that were specifically designed in our laboratory. Our results show that GSK-3β inhibition: 1) Affected social recognition, because the treated birds tended to move closer towards a stranger, unlike the control birds that stood closer to a familiar bird. 2) Caused the treated birds to spend more time in the more middle parts of the cage compared to controls, a behaviour that might indicate anxiety. 3) As the experiment progressed, the treated birds took less time to make a decision where to stand in the cage compared to controls, suggesting an effect on decision-making. 4) Increased in the motor activity of the treated birds compared to the controls, which can be regarded as hyperactivity. 5) Caused the treated birds to pass through a barrier in order to join their flock members faster compared to controls, and regardless of the increase in the level of difficulty, possibly suggesting increased motivation. Our study calls for further investigation, because GSK-3 is well acknowledged as a central player in regulating mood behaviour, cognitive functions, and neuronal viability. Therefore, studying its impact on normal behaviour as we did in the current study, unlike most studies that were done in diseases models, can advance our understanding regarding GSK-3 various roles and can contribute to the discovery and development of effective treatments to repair cognition and behaviour.

Keywords:  GSK-3; birds; cognition; motor activity; sociability; zebra finches

DOI:  https://doi.org/10.3389/fphys.2022.881174
Bioinformation. 2021 ;17(10): 866-869

Molecular docking analysis of glycogen phosphorylase with inhibitors from Cissampelos pareira Linn.

Kirubhanand Chandrashekar, Ponnulakshmi Rajagopal, Shazia Fathima Jh, Saravanan Radhakrishnan, Vijaya Prakash Krishnan Muthaiah, Bharat Ramrao Sontakke, Vishwajit Ravindra Deshmukh, Vijayalakshmi Periyasamy, Gayatri Girish Muthiyan, Aaditya Madhusudan Tarnekar, T S Gugapriya, Patil Ashlesh Laxman, Satyendra Chandra Tripathi, Selvaraj Jayaraman.

  Cissampelos pareira Linn. is a climbing herb known in Indian traditional medicine as laghupatha. It belongs to the Menispermaceae family. The enzyme glycogen phosphorylase (GP) is a promising target for the treatment of type-2 diabetes (T2DM). A variety of natural product inhibitors with both pharmaceutical and nutraceutical potential have been reported in the search for powerful, selective and drug-like GP inhibitors that could lead to hypoglycemic medicines. Therefore, it is of interest to document the molecular docking analysis data of glycogen phosphorylase with compounds from Cissampelos pareira Linn. We report the optimal binding features of 4 compounds namely Trans-N-feruloyltyramine, Coclaurine, Magnoflorine, and Curine with the target protein for further consideration in the context of T2DM.

Keywords:  Cissampelos pareira; Diabetes mellitus; Glycogen phosphorylase; Molecular docking

DOI:  https://doi.org/10.6026/97320630017866
Cardiovasc Hematol Disord Drug Targets. 2022 May 13.

Antihyperglycemic and antidyslipidemic Effect of Moricandia suffruticosa in Normal and Streptozotocin-Induced Diabetic Rats.

Amine Azzane, Ayoub Amssayef, Mohamed Eddouks.

   AIMS OF THE STUDY: The present work aimed to assess the antihyperglycemic and antohyperlipidemic effects ofMoricandia suffruticosa.
BACKGROUND: Moricandia suffruticosa (M. suffruticosa) is used in traditional medicine.
OBJECTIVE: The present study investigated the antihyperglycemic and antidyslipidemic effects of M. suffruticosa and its effect on glycogen content in normoglycemic and hyperglycemic rats.
METHODS: The effect of the aqueous extract of M. suffruticosa (AEMS) at a two doses of 100 and 140 mg/kg on blood glucose levels, lipid, lipoprotein profile, and glycogen content was examined in normal and streptozotocin(STZ)-induced diabetic rats. On the other hand, a preliminary phytochemical screening and quantification of phenolic, flavonoid, and tannin contents were carried out.
RESULTS: The results demonstrated that AEMS exhibits antihyperglycemic activity in diabetic rats during both acute and subchronic essays. Furthermore, AEMS revealed an antidyslipidemic effect concerning the level of triglycerides, total cholesterol, very-low density lipoprotein (VLDL), and non-high density lipoproteins (Non-HDL). In contrast, AEMS has not affected the value of glycemia, lipids, and lipoproteins in normal rats. In addition, AEMS is rich in several phytochemical compounds. Furthermore, AEMS revealed an important in vitro antioxidant activity.
CONCLUSION: In conclusion, the study demonstrates that M. suffruticosa exhibits an important antihyperglycemic effect in diabetic rats.

Keywords:  Diabetes mellitus; Moricandia suffruticosa; antihyperglycemia; diabetes; glycogen content; streptozotocin

DOI:  https://doi.org/10.2174/1871529X22666220513124452
Mol Ther Nucleic Acids. 2022 Jun 14. 28 539-557

miR-23b-3p rescues cognition in Alzheimer's disease by reducing tau phosphorylation and apoptosis via GSK-3β signaling pathways.

Hailun Jiang, Jianghong Liu, Shuilong Guo, Li Zeng, Zhongdi Cai, Junxia Zhang, Linlin Wang, Zhuorong Li, Rui Liu.

  Dysregulated microRNA (miRNA) expression in the brain can contribute to cognitive dysfunction and aberrant tau hyperphosphorylation in Alzheimer's disease (AD). Several studies have reported a role for microRNA-23b-3p (miR-23b-3p) in various neurologic disorders; however, its involvement in cognition-related functions remains unclear. In the present study, we investigated the potential therapeutic effects and mechanisms of miR-23b-3p in AD. miRNA profiles in the cortex of amyloid precursor protein (APP)/presenilin 1 (PS1) double transgenic mice (APP/PS1 mice) demonstrated that miR-23b-3p was reduced. This decrease was verified in APPswe cells, SAMP8 mouse brains, and plasma from AD patients. Furthermore, glycogen synthase kinase-3β (GSK-3β), a major tau kinase implicated in tau pathology, was identified as a target of miR-23b-3p. Functional in vivo studies demonstrated that intracerebroventricular delivery of miR-23b-3p in APP/PS1 mice ameliorated cognitive deficits, histopathological changes, and tau phosphorylation immunoreactivity at several sites by inhibiting GSK-3β expression and activation. Similarly, the upregulation of miR-23b-3p in APPswe cells inhibited GSK-3β-mediated tau hyperphosphorylation, Aβ1-42 generation, and neuronal apoptosis, resulting in the suppression of the GSK-3β/p-tau and Bax/caspase-3 pathways. Collectively, our findings strongly support the hypothesis that miR-23b-3p plays a neuroprotective role in AD, thereby identifying miR-23b-3p as a promising therapeutic target for AD.

Keywords:  Alzheimer’s disease; MT: Oligonucleotides: Therapies and Applications; cognition; glycogen synthase kinase-3β; microRNA therapy; tau protein

DOI:  https://doi.org/10.1016/j.omtn.2022.04.008
Cell Death Dis. 2022 May 17. 13(5): 464

CircLIFR suppresses hepatocellular carcinoma progression by sponging miR-624-5p and inactivating the GSK-3β/β-catenin signaling pathway.

Lei Yang, Wenliang Tan, Yingcheng Wei, Zhiqin Xie, Wenxin Li, Xiaowu Ma, Qingbin Wang, Huilong Li, Ziyu Zhang, Changzhen Shang, Yajin Chen.

Circular RNAs have been reported to play essential roles in the tumorigenesis and progression of various cancers. However, the biological processes and mechanisms involved in hepatocellular carcinoma (HCC) remain unclear. Initial RNA-sequencing data and qRT-PCR results in our cohort showed that hsa_circ_0072309 (also called circLIFR) was markedly downregulated in HCC tissues. Kaplan-Meier analysis indicated that higher levels of circLIFR in HCC patients correlated with favorable overall survival and recurrence-free survival rates. Both in vitro and in vivo experiments indicated that circLIFR inhibited the proliferation and invasion abilities of HCC cells. We therefore conducted related experiments to explore the mechanism of circLIFR in HCC. Fluorescence in situ hybridization results revealed that circLIFR was mainly located in the cytoplasm, and RNA immunoprecipitation assays indicated that circLIFR was significantly enriched by Ago2 protein. These results suggested that circLIFR may function as a sponge of miRNAs to regulate HCC progression. We further conducted bioinformatics prediction as well as dual-luciferase reporter assays, and the results of which showed that circLIFR could sponge miR-624-5p to stabilize glycogen synthase kinase 3β (GSK-3β) expression. Loss and gain of function experiments demonstrated that regulation of the expression of miR-624-5p or GSK-3β markedly affected HCC progression induced by circLIFR. Importantly, we also proved that circLIFR could facilitate the degradation of β-catenin and prevent its translocation to the nucleus in HCC cells. Overall, our study demonstrated that circLIFR acts as a tumor suppressor in HCC by regulating miR-624-5p and inactivating the GSK-3β/β-catenin signaling pathway.

DOI: https://doi.org/10.1038/s41419-022-04887-6
Sci Adv. 2022 May 20. 8(20): eabm8786

Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells.

Long He, Jennifer Endress, Sungyun Cho, Zhongchi Li, Yuxiang Zheng, John M Asara, John Blenis.

Serine/one-carbon metabolism provides critical resources for nucleotide biosynthesis and epigenetic maintenance and is thus necessary in cancer cell growth, although the detailed regulatory mechanisms remain unclear. We uncover a critical role of glycogen synthase kinase 3 (GSK3) in regulating the expression of serine/one-carbon metabolic enzymes. Nuclear enrichment of GSK3 significantly suppresses genes that mediate de novo serine synthesis, including PHGDH, PSAT1, PSPH, and one-carbon metabolism, including SHMT2 and MTHFD2. FRAT1 promotes nuclear exclusion of GSK3, enhances serine/one-carbon metabolism, and, as a result, confers cell vulnerability to inhibitors that target this metabolic process such as SHIN1, a specific SHMT1/2 inhibitor. Furthermore, pharmacological or genetic suppression of GSK3 promotes serine/one-carbon metabolism and exhibits a significant synergistic effect in combination with SHIN1 in suppressing cancer cell proliferation in cultured cells and in vivo. Our observations indicate that inhibition of nuclear GSK3 signaling creates a vulnerability, which results in enhanced efficacy of serine/one-carbon metabolism inhibitors for the treatment of cancer.

DOI: https://doi.org/10.1126/sciadv.abm8786
Breast Cancer Res. 2022 May 14. 24(1): 33

Beta 2 adrenergic receptor and mu opioid receptor interact to potentiate the aggressiveness of human breast cancer cell by activating the glycogen synthase kinase 3 signaling.

Bénédicte Rousseau, Sengottuvelan Murugan, Ajay Palagani, Dipak K Sarkar.

   BACKGROUND: Opioid and beta-adrenergic receptors are recently shown to cross talk via formation of receptor heterodimers to control the growth and proliferation of breast cancer cells. However, the underlying cell signaling mechanism remained unclear.
METHODS: To determine the effect of the interaction of the two systems in breast cancer, we employed triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468, CRISPR or chemical inhibition or activation of beta-adrenergic receptors (B2AR) and mu-opioid receptors (MOR) gene, and PCR array technology and studied aggressive tumor phenotype and signaling cascades.
RESULTS: We show here that in triple-negative breast cancer cells, the reduction in expression B2AR and MOR by genetic and pharmacological tools leads to a less aggressive phenotype of triple-negative breast cancer cells in vitro and in animal xenografts. Genomic analysis indicates the glycogen synthase kinase 3 (GSK3) pathway as a possible candidate messenger system involved in B2AR and MOR cross talk. GSK3 inactivation in MDA-MB-231 and MDA-MB-468 cells induced similar phenotypic changes as the inhibition of B2AR and/or MOR, while a GSK3 activation by wortmannin reversed the effects of B2AR and/or MOR knockdown on these cells. GSK3 inactivation also prevents B2AR agonist norepinephrine or MOR agonist DAMGO from affecting MDA-MB-231 and MDA-MB-468 cell proliferation.
CONCLUSIONS: These data confirm a role of B2AR and MOR interaction in the control of breast cancer cell growth and identify a possible role of the GSK3 signaling system in mediation of these two receptors' cross talk. Screening for ligands targeting B2AR and MOR interaction and/or the GSK3 system may help to identify novel drugs for the prevention of triple-negative breast cancer cell growth and metastasis.

Keywords:  Beta-adrenergic receptor; GSK3 signaling; Gene knockdown; Growth and metastasis; Mu-opioid receptor; Pharmacological agents; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s13058-022-01526-y
Biochem J. 2022 May 20. pii: BCJ20220153. [Epub ahead of print]

Trafficking regulator of GLUT4-1 (TRARG1) is a GSK3 substrate.

Xiaowen Duan, Dougall M Norris, Sean Humphrey, Pengyi Yang, Kristen C Cooke, Will P Bultitude, Ben Parker, Olivia J Conway, James G Burchfield, James R Krycer, Frances Brodsky, David James, Daniel J Fazakerley.

  Trafficking regulator of GLUT4-1, TRARG1, positively regulates insulin-stimulated GLUT4 trafficking and insulin sensitivity. However, the mechanism(s) by which this occurs remain(s) unclear. Using biochemical and mass spectrometry analyses we found that TRARG1 is dephosphorylated in response to insulin in a PI3K/Akt-dependent manner and is a novel substrate for GSK3. Priming phosphorylation of murine TRARG1 at serine 84 allows for GSK3-directed phosphorylation at serines 72, 76 and 80. A similar pattern of phosphorylation was observed in human TRARG1, suggesting that our findings are translatable to human TRARG1. Pharmacological inhibition of GSK3 increased cell surface GLUT4 in cells stimulated with a submaximal insulin dose, and this was impaired following Trarg1 knockdown, suggesting that TRARG1 acts as a GSK3-mediated regulator in GLUT4 trafficking. These data place TRARG1 within the insulin signaling network and provide insights into how GSK3 regulates GLUT4 trafficking in adipocytes.

Keywords:  Trafficking regulator of GLUT4-1; adipocytes; glucose transport; glycogen synthase kinase; insulin signalling

DOI:  https://doi.org/10.1042/BCJ20220153
J Neurosci. 2022 May 18. pii: JN-RM-2389-21. [Epub ahead of print]

Oxidative stress-induced damage to the developing hippocampus is mediated by GSK3beta.

Joseph Abbah, Claire-Marie Vacher, Evan Z Goldstein, Zhen Li, Srikanya Kundu, Brooke Talbot, Surajit Bhattacharya, Kazue Hashimoto-Torii, Li Wang, Payal Banerjee, Joseph Scafidi, Nathan A Smith, Li-Jin Chew, Vittorio Gallo.

Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents and dentate progenitor proliferation. Post-injury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and Somatostatin, HO aberrantly activated Glycogen synthase kinase 3 beta activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 beta during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.Significance StatementPremature infants are especially vulnerable to oxidative stress, as their antioxidant defenses are underdeveloped. Indeed, high oxygen tension is associated with poor neurological outcomes. Due to its sustained postnatal development and role in learning and memory, the hippocampus is especially vulnerable to oxidative damage in premature infants. However, the role of oxidative stress in the developing hippocampus has yet to be explored. With ever-rising rates of neonatal brain injury and no universally viable approach to maximize functional recovery, a better understanding of the mechanisms underlying neonatal brain injury is needed. Addressing this need, this study utilizes perinatal hyperoxia to study cognitive deficits, pathophysiology, and molecular mechanisms of oxidative damage in the developing hippocampus.

DOI: https://doi.org/10.1523/JNEUROSCI.2389-21.2022
Physiol Rep. 2022 May;10(9): e15263

Glucagon, cyclic AMP, and hepatic glucose mobilization: A half-century of uncertainty.

Robert L Rodgers.

For at least 50 years, the prevailing view has been that the adenylate cyclase (AC)/cyclic AMP (cAMP)/protein kinase A pathway is the predominant signal mediating the hepatic glucose-mobilizing actions of glucagon. A wealth of evidence, however, supports the alternative, that the operative signal most of the time is the phospholipase C (PLC)/inositol-phosphate (IP3)/calcium/calmodulin pathway. The evidence can be summarized as follows: (1) The consensus threshold glucagon concentration for activating AC ex vivo is 100 pM, but the statistical hepatic portal plasma glucagon concentration range, measured by RIA, is between 28 and 60 pM; (2) Within that physiological concentration range, glucagon stimulates the PLC/IP3 pathway and robustly increases glucose output without affecting the AC/cAMP pathway; (3) Activation of a latent, amplified AC/cAMP pathway at concentrations below 60 pM is very unlikely; and (4) Activation of the PLC/IP3 pathway at physiological concentrations produces intracellular effects that are similar to those produced by activation of the AC/cAMP pathway at concentrations above 100 pM, including elevated intracellular calcium and altered activities and expressions of key enzymes involved in glycogenolysis, gluconeogenesis, and glycogen synthesis. Under metabolically stressful conditions, as in the early neonate or exercising adult, plasma glucagon concentrations often exceed 100 pM, recruiting the AC/cAMP pathway and enhancing the activation of PLC/IP3 pathway to boost glucose output, adaptively meeting the elevated systemic glucose demand. Whether the AC/cAMP pathway is consistently activated in starvation or diabetes is not clear. Because the importance of glucagon in the pathogenesis of diabetes is becoming increasingly evident, it is even more urgent now to resolve lingering uncertainties and definitively establish glucagon's true mechanism of glycemia regulation in health and disease.

DOI: https://doi.org/10.14814/phy2.15263