bims-glecem 2023-04-30 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023‒04‒30
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?
Blood glucose trends in glycogen storage disease type Ia: A cross-sectional study.
CT findings of glycogen storage disease I complicated with pancreatitis: A case report.
Rhabdomyolysis Episode in an Individual with McArdle's Disease after Low Aerobic Exercise.
Protective effects of a novel glycogen phosphorylase inhibitor against cerebral ischemia-reperfusion injury in mice.
Late Onset Pompe's Disease: Clinical, Pathological & Molecular Analysis of Two Adolescent Patients.
GSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit.
Identification of mutations that causes glucose-6-phosphate transporter defect in tunisian patients with glycogenosis type 1b.
Repurposing Pitavastatin and L-Glutamine: Replenishing β-Cells in Hyperlipidemic Type 2 Diabetes Mouse Model.
Inhibition of GSK-3β Enhances Osteoblast Differentiation of Human Mesenchymal Stem Cells through Wnt Signalling Overexpressing Runx2.
[Glycogen phosphorylase inhibitor ameliorates pentylenetetrazole-induced acute seizure, neuroinflammation and memory impairment in rats].

Int J Mol Sci. 2023 Apr 19. pii: 7541. [Epub ahead of print]24(8):

GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?

Beatrice Balboni, Mirco Masi, Walter Rocchia, Stefania Girotto, Andrea Cavalli.

  Most kinase inhibitors are designed to bind to highly homologous ATP-binding sites, which leads to promiscuity and possible off-target effects. Allostery is an alternative approach to pursuing selectivity. However, allostery is difficult to exploit due to the wide variety of underlying mechanisms and the potential involvement of long-range conformational effects that are difficult to pinpoint. GSK-3β is involved in several pathologies. This critical target has an ATP-binding site that is highly homologous with the orthosteric sites of other kinases. Unsurprisingly, there is also great similarity between the ATP-binding sites of GSK-3β and its isomer, which is not redundant and thus would benefit from selective inhibition. Allostery would also allow for a moderate and tunable inhibition, which is ideal for GSK-3β, because this target is involved in multiple pathways, some of which must be preserved. However, despite considerable research efforts, only one allosteric GSK-3β inhibitor has reached the clinic. Moreover, unlike other kinases, there are no X-ray structures of GSK-3β in complex with allosteric inhibitors in the PDB data bank. This review aims to summarize the state of the art in allosteric GSK-3β inhibitor investigations, highlighting the aspects that make this target challenging for an allosteric approach.

Keywords:  Alzheimer’s disease; Pocketron; cancer; drug discovery; inhibitors

DOI:  https://doi.org/10.3390/ijms24087541
J Inherit Metab Dis. 2023 Apr 28.

Blood glucose trends in glycogen storage disease type Ia: A cross-sectional study.

Tokiko Fukuda, Tetsuya Ito, Takashi Hamazaki, Ayano Inui, Mika Ishige, Reiko Kagawa, Norio Sakai, Yoriko Watanabe, Hironori Kobayashi, Yosuke Wasaki, Junki Taura, Yuki Imamura, Tsutomu Tsukiuda, Kimitoshi Nakamura.

  BACKGROUND: Glycogen storage disease type Ia (GSDIa) is caused by biallelic pathogenic variants in the glucose-6-phosphatase gene (G6PC) and mainly characterized by hypoglycemia, hepatomegaly, and renal insufficiency. Although its symptoms are reportedly mild in patients carrying the G6PC c.648G>T variant, the predominant variant in Japanese patients, details remain unclear. Therefore, we examined continuous glucose monitoring (CGM) data and daily nutrition intake to clarify their associations in Japanese patients with GSDIa with G6PC c.648G>T.METHODS: This cross-sectional study enrolled 32 patients across 10 hospitals. CGM was performed for 14 days, and nutritional intake was recorded using electronic diaries. Patients were divided according to genotype (homozygous/compound heterozygous) and age. The durations of biochemical hypoglycemia and corresponding nutritional intake were analyzed. Multiple regression analysis was performed to identify factors associated with the duration of biochemical hypoglycemia.
RESULTS: Data were analyzed for 30 patients. The mean daily duration of hypoglycemia (<4.0 mmol/L) in the homozygous group increased with age (2-11 years [N = 8]: 79.8 min; 12-18 years [5]: 84.8 min; ≥19 years [10]: 131.5 min). No severe hypoglycemic symptoms were recorded in the patients' diaries. The mean frequency of snack intake was approximately three times greater in patients aged 2-11 years (7.1 times/day) than in those aged 12-18 years (1.9 times/day) or ≥19 years (2.2 times/day). Total cholesterol and lactate were independently associated with the duration of biochemical hypoglycemia.
CONCLUSION: Although nutritional therapy prevents severe hypoglycemia in patients with GSDIa with c.648G>T, patients often experience asymptomatic hypoglycemia. This article is protected by copyright. All rights reserved.

Keywords:  G6PC gene; continuous glucose monitoring; glucose-6-phosphatase (G6Pase); glycemic control; glycogen storage disease type Ia

DOI:  https://doi.org/10.1002/jimd.12610
Medicine (Baltimore). 2023 Apr 25. 102(17): e33668

CT findings of glycogen storage disease I complicated with pancreatitis: A case report.

Shuo Chen, Feng Chen, Fei Cheng, Xiao Xu.

RATIONALE: The incidence of glycogen storage disease type I (GSD I) in the overall population is 1/100,000.[1] Hyperlipidemia in patients with GSD I can induce pancreatitis. Three cases of GSD I complicated with pancreatitis have been reported.[2] Here, the computed tomography (CT) features of GSD I complicated with pancreatitis are reported for the first time.PATIENT CONCERNS: A 22-year-old female presents with growth retardation for 20 years and recurrent epigastric pain for 3 years. No abnormality in physical examination. Laboratory examination: GPT 81 U/L, GOT 111 U/L, DBIL 1.7 umol/L, TBIL 0.7 umol/L, Albumen 41.4 g/L, blood ammonia 54 umol/L, fasting blood glucose 3.02 mmol/L, G6PD 1829 U/L, lactic acid 7.9 mmol/L, triglyceride 18.79 mmol/L, TCH 9.46 mmol/L, uric acid 510 umol/L, urinary protein +++ (3.0) g/L.
DIAGNOSIS: The CT findings of the upper abdomen show that the liver is obviously enlarged, and the density of the liver is obviously uneven on plain scan. Unclear boundaries and increased blood vessels of the pancreas are found, especially in the head of the pancreas. The patient is diagnosed with GSD I complicated with pancreatitis.
INTERVENTIONS: The patient undergoes split liver transplantation and splenectomy under general anesthesia in our hospital.
OUTCOMES: Upper abdominal CT is reexamined half a month and 2 and a half months after the operation. It is found that the transplanted liver is not enlarged and the density is not abnormal. The pancreas shrinks, its boundary is clear, and its blood vessels decrease, especially in the head of the pancreas.
LESSONS: The density of the liver depends on the relative amount of glycogen and fat, which can be increased, normal, or decreased. Hyperlipidemia in patients with GSD I can induce pancreatitis.

DOI: https://doi.org/10.1097/MD.0000000000033668
Saudi J Kidney Dis Transpl. 2022 Feb;33(Supplement): S91-S99

Rhabdomyolysis Episode in an Individual with McArdle's Disease after Low Aerobic Exercise.

Guilherme Henrique Mattos Dantas, Artur Luís Bessa de Oliveira, Pablo Jorge Marcos-Pardo, Vanessa Franco Ferreira Coutinho, Felipe Cassau de Sá Freire, Juliana Brandão Pinto de Castro, Rodrigo Gomes de Souza Vale.

McArdle's disease, known as blockage of muscle glycogen metabolism, is characterized by glycogen accumulation of chains in skeletal striated muscles. One of the typical symptoms of the disease is the feeling of intolerance to exercise. Severe muscle cram and contracture, which often cause stiffness, occur due to a lack of muscle energy substrate during the exercise. These factors can lead to muscle damage, myoglobinuria, and, in severe cases, renal failure and rhabdomyolysis. Rhabdomyolysis is a syndrome that presents injury and necrosis of muscle cells leading to the release of intracellular material to the circulatory system. The present study aimed to report rhabdomyolysis in an individual with McArdle's disease after exercise of walking with low intensity. Patient, aged 33 years, was treated in the emergency room of a hospital located in the State of Rio de Janeiro, Brazil. After performing a full lap on the block of home (~500 m in ~4 min 37 s), walking at a moderate speed (~6.5 km/h), the individual felt sick and was rescued, later being hospitalized. The examinations collected presented hematocrit (HCT) compatible with chronic disease anemia and myoglobinuria. The patient was discharged from the intensive care center on the 3rd day, after a 45% drop in creatine kinase. The patient described in the present study achieved full recovery. Attention to symptoms, early diagnosis, and immediate treatment made it possible to interrupt the development of complications caused by rhabdomyolysis, not allowing progression to acute renal failure.

DOI: https://doi.org/10.4103/1319-2442.374387
Future Med Chem. 2023 Apr 25.

Protective effects of a novel glycogen phosphorylase inhibitor against cerebral ischemia-reperfusion injury in mice.

Zhiwei Yan, Shuai Li, Youde Wang, Yachun Guo, Liying Zhang.

  Aim: To evaluate the effects of a novel glycogen phosphorylase inhibitor (NGPI) on cerebral ischemia-reperfusion injury (CIRI). Methods: Cerebral ischemia was induced in mice using a modified bilateral common carotid artery ligation model. To assess the effects of NGPI against CIRI, mice which had been administered with different doses of NGPI (1.25, 2.5, 5 mg/kg/day) for 7 days before the injury were evaluated for infarct volume, the apoptosis level of brain tissue, integrity of brain tissue and oxidative stress level. Results: NGPI effectively improved the infarct area, apoptosis of neurons, integrity of brain tissue and oxidative stress level of mice with CIRI. Conclusion: NGPI could effectively improve CIRI and deserves further study.

Keywords:  cerebral infarction; cerebral ischemia–reperfusion injury; glycogen phosphorylase inhibitor; neuroprotective; oxidative stress

DOI:  https://doi.org/10.4155/fmc-2023-0038
J Assoc Physicians India. 2023 Jan;71(1): 1

Late Onset Pompe's Disease: Clinical, Pathological & Molecular Analysis of Two Adolescent Patients.

Arun Sree Parameswaran, Singh, Lokesh Saini, Divya Aggarwal.

INTRODUCTION: The estimated global prevalence of late onset Pompe's disease is 1/57000 live birth(1). We present the case of two patients diagnosed to have Pompe's disease with a rare association of cardiomyopathy.MATERIALS: Two siblings born out of non consanguineous marriage presented with proximal myopathy of 5 years duration. Patient 1 - 19 year female, there was atrophy and weakness of face, neck, girdle and limbs. Her Echocardiogram showed LV dilation with low ejection fraction, ECG showed LV hypertrophy with incomplete LBBB. Her CK-NAC values came to be 918 U/L. Patient 2 - 16 year male; progression, distribution and severity slightly different to his sister but had exertional dyspnea since last one year. His echocardiogram showed LV diastolic dysfunction, ECG showed short PR interval partial LBBB and his CK-NAC came to be 2347 U/L. His skeletal muscle biopsy showed deposition of glycogen. Genetic analysis revealed pathogenic mutation in GAA gene (c.2040G>A) in both patients.
RESULT: Late onset Pompe disease is of less severity but progressive. The involvement of heart is less likely compared to infantile onset(2). It is also interesting that the same variant presents differently in both patients.
CONCLUSION: Genetic diseases manifest as rare phenotype which in itself is a clinical puzzle. When rare disease present with a rare manifestation of itself, this pose a great diagnostic challenge. Pompe's disease is one of the very few inherited disorder which has definitive treatment- enzyme replacement therapy. Molecular characterization of the variant is absolutely necessary before initiating therapy. References Ausems MG, Verbiest J, Hermans MM, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 1999;7(6):713-716. Van der Beek NA, Soliman OI, Van Capelle CI, et al. Cardiac evaluation in children and adults with Pompe disease sharing the common c.-32-13T>G genotype rarely reveals abnormalities. J Neurol Sci 2008;275(1-2):46-50.
Biochim Biophys Acta Mol Basis Dis. 2023 Apr 22. pii: S0925-4439(23)00090-X. [Epub ahead of print] 166724

GSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit.

Prachi Umbarkar, Sulivette Y Ruiz Ramirez, Angelica Toro Cora, Sultan Tousif, Hind Lal.

  Glycogen synthase kinase-3 (GSK-3) is a family of serine/threonine kinases. The GSK-3 family has 2 isoforms, GSK-3α and GSK-3β. The GSK-3 isoforms have been shown to play overlapping as well as isoform-specific-unique roles in both, organ homeostasis and the pathogenesis of multiple diseases. In the present review, we will particularly focus on expanding the isoform-specific role of GSK-3 in the pathophysiology of cardiometabolic disorders. We will highlight recent data from our lab that demonstrated the critical role of cardiac fibroblast (CF) GSK-3α in promoting injury-induced myofibroblast transformation, adverse fibrotic remodeling, and deterioration of cardiac function. We will also discuss studies that found the exact opposite role of CF-GSK-3β in cardiac fibrosis. We will review emerging studies with inducible cardiomyocyte (CM)-specific as well as global isoform-specific GSK-3 KOs that demonstrated inhibition of both GSK-3 isoforms provides benefits against obesity-associated cardiometabolic pathologies. The underlying molecular interactions and crosstalk among GSK-3 and other signaling pathways will be discussed. We will briefly review the specificity and limitations of the available small molecule inhibitors targeting GSK-3 and their potential applications to treat metabolic disorders. Finally, we will summarize these findings and offer our perspective on envisioning GSK-3 as a therapeutic target for the management of cardiometabolic diseases.

Keywords:  Cardiometabolic disease; Fibrosis; Glycogen synthase kinase; Heart failure; Hypertrophy; Myocardial infarction; Obesity

DOI:  https://doi.org/10.1016/j.bbadis.2023.166724
Diabetol Metab Syndr. 2023 Apr 28. 15(1): 86

Identification of mutations that causes glucose-6-phosphate transporter defect in tunisian patients with glycogenosis type 1b.

Latifa Chkioua, Yessine Amri, Chayma Sahli, Ferdawes Ben Rhouma, Amel Ben Chehida, Neji Tebib, Taieb Messaoud, Hassen Ben Abdennebi, Sandrine Laradi.

  BACKGROUND: Glycogen storage disease type 1b (GSD1b) is an autosomal recessive lysosomal storage disease caused by defective glucose-6-phosphate transporter encoded by SLC37A4 leading to the accumulation of glycogen in various tissues. The high rate of consanguineous marriages in Tunisian population provides an ideal environment to facilitate the identification of homozygous pathogenic mutations. We aimed to determine the clinical and genetic profiles of patients with GSD1b to evaluate SLC37A4 mutations spectrum in Tunisian patients.METHODS: All exons and flanking intron regions of SLC37A4 gene were screened by direct sequencing to identify mutations and polymorphisms in three unrelated families with GSD1b. Bioinformatics tools were then used to predict the impacts of identified mutations on the structure and function of protein in order to propose a function-structure relationship of the G6PT1 protein.
RESULTS: Three patients (MT, MB and SI) in Families I, II and III who had the severe phenotype were homoallelic for the two identified mutations: p.R300H (famillies I, II) and p.W393X (Family III), respectively. One of the alterations was a missense mutation p.R300H of exon 6 in SLC37A4 gene. The analysis of the protein structure flexibility upon p.R300H mutation using DynaMut tool and CABS-flex 2.0 server showed that the reported mutation increase the molecule flexibility of in the cytosol region and would probably lead to significant conformational changes.
CONCLUSION: This is the first Tunisian report of SLC37A4 mutations identified in Tunisia causing the glycogenosis type Ib disease. Bioinformatics analysis allowed us to establish an approximate structure-function relationship for the G6PT1 protein, thereby providing better genotype/phenotype correlation knowledge.

Keywords:  Bioinformatics tool; Glucose-6-phosphate transporter (SLC37A4); Glycogenosis; Mutations

DOI:  https://doi.org/10.1186/s13098-023-01065-2
Life (Basel). 2023 Apr 01. pii: 929. [Epub ahead of print]13(4):

Repurposing Pitavastatin and L-Glutamine: Replenishing β-Cells in Hyperlipidemic Type 2 Diabetes Mouse Model.

Sayantani Pramanik Palit, Roma Patel, Nishant Parmar, Nirali Rathwa, Nilay Dalvi, A V Ramachandran, Rasheedunnisa Begum.

  Type 2 diabetes (T2D) is associated with obesity and declining β-cells. L-glutamine has been implicated in the amelioration of T2D by virtue of its incretin secretagogue property while, there are mixed reports on pitavastatin's adiponectin potentiating ability. We aimed to investigate the effect of pitavastatin (P), L-glutamine (LG), and combination (P + LG) on glycemic control and β-cell regeneration in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2D mouse model. C57BL6/J mice treated with HFD + STZ were divided into four groups: diabetes control (HFD + STZ), P, LG, and P + LG, while the control group (NCD) was fed with the normal-chow diet. Significant amelioration was observed in the combination therapy as compared to monotherapies in respect of (i) insulin resistance, glucose intolerance, lipid profile, adiponectin levels, and mitochondrial complexes I, II, and III activities, (ii) reduced phosphoenolpyruvate carboxykinase, glucose 6-phophatase, glycogen phosphorylase, and GLUT2 transcript levels with increased glycogen content in the liver, (iii) restoration of insulin receptor 1β, pAkt/Akt, and AdipoR1 protein levels in skeletal muscle, and (iv) significant increase in islet number due to β-cell regeneration and reduced β-cell death. L-glutamine and pitavastatin in combination can ameliorate T2D by inducing β-cell regeneration and regulating glucose homeostasis.

Keywords:  GLP-1; adiponectin; mitochondrial biogenesis; obesity; β-cell regeneration

DOI:  https://doi.org/10.3390/life13040929
Int J Mol Sci. 2023 Apr 12. pii: 7164. [Epub ahead of print]24(8):

Inhibition of GSK-3β Enhances Osteoblast Differentiation of Human Mesenchymal Stem Cells through Wnt Signalling Overexpressing Runx2.

Nihal AlMuraikhi, Sarah Binhamdan, Hanouf Alaskar, Amal Alotaibi, Sumaiya Tareen, Manikandan Muthurangan, Musaad Alfayez.

  Small-molecule-inhibitor-based bone differentiation has been recently exploited as a novel approach to regulating osteogenesis-related signaling pathways. In this study, we identified 1-Azakenpaullone, a highly selective inhibitor of glycogen synthase kinase-3β (GSK-3β), as a powerful inducer of osteoblastic differentiation and mineralization of human mesenchymal stem cells (MSCs). GSK-3β is a serine-threonine protein kinase that plays a major role in different disease development. GSK-3β is a key regulator of Runx2 activity in osteoblastic formation. We evaluated alkaline phosphatase activity and staining assays to assess osteoblast differentiation and Alizarin Red staining to assess the mineralization of cultured human MSCs. Gene expression profiling was assessed using an Agilent microarray platform, and bioinformatics were performed using Ingenuity Pathway Analysis software. Human MSCs treated with 1-Azakenpaullone showed higher ALP activity, increased in vitro mineralized matrix formation, and the upregulation of osteoblast-specific marker gene expression. Global gene expression profiling of 1-Azakenpaullone-treated human MSCs identified 1750 upregulated and 2171 downregulated mRNA transcripts compared to control cells. It also suggested possible changes in various signaling pathways, including Wnt, TGFβ, and Hedgehog. Further bioinformatics analysis employing Ingenuity Pathway Analysis recognized significant enrichment in the 1-Azakenpaullone-treated cells of genetic networks involved in CAMP, PI3K (Complex), P38 MAPK, and HIF1A signaling and functional categories associated with connective tissue development. Our results suggest that 1-Azakenpaullone significantly induced the osteoblastic differentiation and mineralization of human MSCs mediated by the activation of Wnt signaling and the nuclear accumulation of β-catenin, leading to the upregulation of Runx2, a key transcription factor that ultimately promotes the expression of osteoblast-specific genes. Thus, 1-Azakenpaullone could be used as an osteo-promotor factor in bone tissue engineering.

Keywords:  GSK-3β inhibition; Runx2; Wnt; human mesenchymal stem cells; osteoblast differentiation

DOI:  https://doi.org/10.3390/ijms24087164
Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2022 Sep;38(5): 406-411

[Glycogen phosphorylase inhibitor ameliorates pentylenetetrazole-induced acute seizure, neuroinflammation and memory impairment in rats].

Xiao-Yue Deng, Nian-Nian Shuai, Shi-Yan Liu, Li-Li Hou, Shao-Wen Tian.

  OBJECTIVE: In the present study, we determined whether the glycogen phosphorylase(GP)inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) ameliorates pentylenetetrazole (PTZ)-induced acute seizure, neuroinflammation and memory impairment in rats.METHODS: In experiment 1, rats were randomly divided into the Vehicle (n=5) and PTZ (n=5) groups, and received intraperitoneal injection of saline or PTZ (70 mg/kg), respectively. Hippocampal tissues were collected 30 min after drug injection. Western blot was used to examine the levels of GP expression. Colorimetric assay was used to determine the levels of lactate. In experiment 2, rats were randomly divided into the Vehicle+Vehicle (n=18), DAB+Vehicle (n=18), Vehicle+PTZ (n=19) and DAB+PTZ (n=18) groups. Rats received intracerebroventricular injection of PBS or DAB (50 μg/2 μl) 15 min before receiving intraperitoneal injection of saline or PTZ (70 mg/kg). Behavioural assays and the Racine scale were used to evaluate seizure severity. Western blot was used to examine the levels of targeted protein of hippocampal tissues. Novel object recognition test was used to assess memory performance.
RESULTS: ① Compared with the Vehicle group, the levels of GP and lactate in the hippocampal tissues of the PTZ group were increased significantly (both P＜0.01). ② Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of myoclonic body jerk latency, forelimb clonus latency and tonic-clonic seizure latency were increased significantly (all P＜0.01), while the duration of seizure and seizure scores were decreased significantly (both P＜0.01). ③ Compared with the Vehicle+Vehicle group, in the Vehicle +PTZ group, the levels of IL-1β, IL-6, TNF-α, IBA-1 and GFAP in the hippocampal tissues were increased significantly (all P＜0.01), and the discrimination index in the novel object recognition test was decreased significantly (P＜0.01). Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of IL-1β, TNF-α, IBA-1 and GFAP in the hippocampal tissues were decreased significantly (all, P＜0.01), while the discrimination index in the novel object recognition test was increased significantly (P＜0.01).
CONCLUSION: DAB ameliorates PTZ-induced seizure, neuroinflammation and memory impairment in rats, suggesting that DAB may serve as a novel agent for potential clinical treatment of epilepsy.

Keywords:  DAB; astrocyte; epilepsy; glycogen phosphorylase; lactate; rat

DOI:  https://doi.org/10.12047/j.cjap.6283.2022.076