bims-glecem 2023-10-22 papers

Issue of 2023–10–22
four papers selected by
Dipsikha Biswas, Københavns Universitet

Am J Physiol Endocrinol Metab. 2023 Oct 18.

Post-exercise muscle glycogen synthesis with glucose, galactose and combined galactose-glucose ingestion.

Tim Podlogar, Brandon J Shad, Alex P Seabright, Oliver J Odell, Samuel O Lord, Rafael B Salgueiro, Rita Civil, Emma L Shepherd, Patricia F Lalor, Yasir S Elhassan, Yu-Chiang Lai, David S Rowlands, Gareth A Wallis.

Ingested galactose can enhance post-exercise liver glycogen repletion when combined with glucose but effects on muscle glycogen synthesis are unknown. In this double-blind randomised study participants (7 men, 2 women; VO2max: 51.1 (8.7) ml·kg-1·min-1) completed 3 trials of exhaustive cycling exercise followed by a 4-h recovery period, during which carbohydrates were ingested at the rate of 1.2 g·kg-1·h-1 comprising glucose (GLU), galactose (GAL) or galactose+glucose (GAL+GLU; 1:2 ratio). The increase in vastus lateralis skeletal-muscle glycogen concentration during recovery was higher with GLU relative to GAL+GLU (contrast: +50 mmol∙(kg DM)-1; 95%CL 10, 89; p=0.021) and GAL (+46 mmol∙(kg DM)-1; 95%CL 8, 84; p=0.024) with no difference between GAL+GLU and GAL (-3 mmol∙(kg DM)-1; 95%CL -44, 37; p=0.843). Plasma glucose concentration with GLU was not significantly different vs GAL+GLU (+0.41 mmol∙L-1; 95%CL -0.13, 0.94) but was significantly lower in GAL (-1.16 mmol∙L-1; 95%CL -0.53, -1.80) and lower in GAL vs GLU (-0.75 mmol∙L-1; 95%CL -1.34, 0.17). Plasma insulin was higher in GLU+GAL and GLU compared to GAL but not different between GLU+GAL and GLU. Plasma galactose concentration was higher in GAL compared to GLU (3.35 mmol∙L-1; 95%CL 3.07, 3.63) and GAL+GLU (3.22 mmol∙L-1; 95%CL 3.54, 2.90) with no difference between GLU+GAL (0.13 mmol∙L-1; 95%CL -0.11, 0.37) and GLU. Compared to galactose or a galactose+glucose blend, glucose feeding was more effective in post-exercise muscle glycogen synthesis. Comparable muscle glycogen synthesis was observed with galactose-glucose co-ingestion and exclusive galactose-only ingestion.

Keywords: exercise; nutrition; recovery; sugars

DOI: https://doi.org/10.1152/ajpendo.00127.2022

Endocr Metab Immune Disord Drug Targets. 2023 Oct 18.

Metabolic Myopathies: Experience of a Reference Center of Inherited Metabolic Diseases.

Mafalda Rebelo, Madalena Pires, Laura Azurara, Lara Câmara, Márcia Pereira, Augusto Ribeirinho, Gonçalo Padeira, Patrícia Gaspar Silva, Sandra Jacinto, José Pedro Vieira, Ana Cristina Ferreira.

INTRODUCTION: Metabolic myopathies (MM) are a heterogeneous group of genetic disorders affecting metabolic pathways involved in energy production during rest, exercise and physiologic stress (fever, fasting, …). Impairments in the pathways of glycolysis/ glycogenolysis, fatty acid transport/oxidation or in the mitochondrial respiratory chain present primarily with exercise intolerance, myalgias, weakness, cramps, or rhabdomyolysis. Depending on aetiology, the diagnosis can be made through neonatal screening, pre-symptomatic or in the set of clinical manifestations for which a high level of suspicion is important.
METHODS: Retrospective descriptive study of the clinical, biochemical, and molecular features of patients with a confirmed diagnosis of MM followed by the multidisciplinary team of the Reference Center of Inherited Metabolic Diseases of Centro Hospitalar Universitário de Lisboa Central from 2009 to 2022.
RESULTS: Twenty-three patients with MM were included: 9 (39%) glycogen storage diseases (7 McArdle and 2 Pompe), 7 (30%) fatty acid oxidation disorders (3 CPT2, 3 LCHAD and 1 MAD deficiencies), 6 (26%) mitochondrial disease with significant muscle involvement (2 Pearson, 1 Kearns Sayre, 1 VARS2, 1 SUCLA2 and 1 MT-TL1 deficiencies), and 1 myoadenylate deaminase deficiency. Ages varied from 15 months to 35 years. Eighteen (78%) patients were diagnosed by clinical symptoms, 3 by newborn screening (LCHAD) and 2 were asymptomatic (1 Pompe and 1 McArdle). Frequent symptoms were rhabdomyolysis triggered by illness or exercise 12 (52%), fatigue 11 (48%), exercise intolerance 10 (43%), and myalgia 9 (43%). Eight (35%) patients (LCHAD and mitochondrial) had multisystemic involvement. In 20 (87%) patients, the diagnosis was confirmed by biochemical and/or genetic analysis and 3 (McArdle) by muscle biopsy.
CONCLUSION: MM are a heterogeneous set of disorders, but a careful history may guide the differential diagnosis among biochemical pathways and other etiologies. Nowadays, molecular testing has become a powerful tool for diagnosis confirmation, surpassing muscular biopsy in most cases. Accurate diagnosis is important to identify who may benefit from specific therapeutic options, such as enzyme replacement therapy, restricted diets, emergency regime and cofactors. All patients benefit from adequate lifestyle modifications, individualized exercise prescription, nutritional intervention, and genetic counselling.

Keywords: fatty acid; fatty acid oxidation disorders; glycogenosis; metabolic myopathies; mitochondrial diseases; rhabdomyolysis

DOI: https://doi.org/10.2174/0118715303279208231012051937

Int J Biol Macromol. 2023 Oct 13. pii: S0141-8130(23)04272-1. [Epub ahead of print]253(Pt 7): 127375

A review of Glycogen Synthase Kinase-3 (GSK3) inhibitors for cancers therapies.

Riya Thapa, Gaurav Gupta, Asif Ahmad Bhat, Waleed Hassan Almalki, Sami I Alzarea, Imran Kazmi, Shakir Saleem, Ruqaiyah Khan, Najla Altwaijry, Harish Dureja, Sachin Kumar Singh, Kamal Dua.

The intricate molecular pathways governing cancer development and progression have spurred intensive investigations into novel therapeutic targets. Glycogen Synthase Kinase-3 (GSK3), a complex serine/threonine kinase, has emerged as a key player with intricate roles in various cellular processes, including cell proliferation, differentiation, apoptosis, and metabolism. Harnessing GSK3 inhibitors as potential candidates for cancer therapy has garnered significant interest due to their ability to modulate key signalling pathways that drive oncogenesis. The review encompasses a thorough examination of the molecular mechanisms underlying GSK3's involvement in cancer progression, shedding light on its interaction with critical pathways such as Wnt/β-catenin, PI3K/AKT, and NF-κB. Through these interactions, GSK3 exerts influence over tumour growth, invasion, angiogenesis, and metastasis, rendering it an attractive target for therapeutic intervention. The discussion includes preclinical and clinical studies, showcasing the inhibitors efficacy across a spectrum of cancer types, including pancreatic, ovarian, lung, and other malignancies. Insights from recent studies highlight the potential synergistic effects of combining GSK3 inhibitors with conventional chemotherapeutic agents or targeted therapies, opening avenues for innovative combinatorial approaches. This review provides a comprehensive overview of the current state of research surrounding GSK3 inhibitors as promising agents for cancer treatment.

Keywords: GSK3; Inflammation; Inhibitors; Lung cancer; Renal cancer; Thyroid cancer

DOI: https://doi.org/10.1016/j.ijbiomac.2023.127375

Endocr Metab Immune Disord Drug Targets. 2023 Oct 19.

Neonatal Glycogen Storage Disease Type IA: A Rare Presentation.

Joana Tenente, Teresa Campos, Carla Vasconcelos, Helena Santos, Marisa Carvalho, Altina Ramos, Laura Vilarinho, Esmeralda Rodrigues, Elisa Leão Teles.

Glucose homeostasis is essential for energy production and the central nervous system function, depending on glycogen metabolism. Glycogen storage diseases (GSD) are caused by enzymatic defects of the glycogen degradation and mainly involve the liver since the inhibition of hepatic glycogen breakdown results in its excessive storage and hepatomegaly. Other findings are hypoglycemia and hyperlactatemia and consequent neurological symptoms. GSD Type Ia is a severe disease with clinical manifestations usually occurring in the first months. Morbidity and mortality are high, when not treated. The patient was a male newborn, with nonconsanguineous couple, born by eutocic delivery and weight 3760 g. On Day 2, weight loss >10% and jaundice were noticed, and physical examination was as normal. The investigation showed low glucose that only respond to iv glucose, metabolic acidosis, hyperlactatemia and elevated liver enzymes. Considering his inherited metabolic disease, he was transferred to the Reference Center. Complementary tests showed hypertriglyceridemia and absence of ketone bodies. Abdominal US revealed a liver in the upper limit of normal. Most likely clinical diagnosis was GSD type Ia, confirmed by genetic test. He needed iv glucose, but then stabilized with formula without galactose, supplemented with dextrin every 2 hours. He is now 7 months old, has flash glucose self-monitoring system, maintaining frequent feedings, with sporadic hypoglycemia with normal physical development and no hepatomegaly. Hypoglycemia and early weight loss in newborns are red flags for metabolic diseases or other conditions. When accompanied by other metabolic findings, such as hyperlactatemia and metabolic acidosis, associated with short fasting periods, glycogen metabolism disorders must be considered. Patients with GSD Type Ia generally appear normal at birth and an early presentation is not frequent within the first hours after birth. Moreover, avoiding fasting and hypoglycemia are of vital importance for better cognitive outcome, global prognosis, and prevention of other metabolic abnormalities.

Keywords: Hypoglycemia; glucose; glycogen storage disease; hyperlactatemia; ketone bodies.

DOI: https://doi.org/10.2174/0118715303278622231006102118