bims-glecem 2023-12-17 papers

Issue of 2023–12–17
six papers selected by
Dipsikha Biswas, Københavns Universitet

J Pak Med Assoc. 2023 Dec;73(12): 2473-2475

Exercise induced muscle weakness in a young adult: McArdle's disease unusual presentation.

Hira Kalsoom, Haseeb Mukhtar, Rizwana Kitchlew Latif.

McArdle's disease (Glycogen storage disease type V) is a rare inherited autosomal recessive disease involving defect in enzyme, glycogen phosphorylase (PYGM) which results in accumulation of glycogen mainly affecting skeletal muscles. It commonly presents in childhood and rarely in adults with symptoms like exercise intolerance, muscle weakness, cramps and fatigue. Herein, we report an unusual case of a 22 years old male in Pakistan with probable McArdle's Disease presenting with repeated episodes of generalized cramping muscle pain, exercise intolerance and haematuria. The diagnostic approach to identifying this disease as well as the differentials of other rare types of skeletal muscle disorders that should be kept in mind while dealing with a similar clinical picture, irrespective of the age of presentation, have been discussed.

Keywords: Glycogen Storage Disease Type V, Myoglobinuria.

DOI: https://doi.org/10.47391/JPMA.8401

J Int Med Res. 2023 Dec;51(12): 3000605231216633

Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review.

Zhuolin Wang, Ruiqin Zhao, Xiaoyun Jia, Xiaolei Li, Li Ma, Haiyan Fu.

Glycogen storage disease type 1b (GSD1b) is a rare genetic disorder, resulting from mutations in the SLC37A4 gene located on chromosome 11q23.3. Although the SLC37A4 gene has been identified as the pathogenic gene for GSD1b, the complete variant spectrum of this gene remains to be fully elucidated. In this study, we present three patients diagnosed with GSD1b through genetic testing. We detected five variants of the SLC37A4 gene in these three patients, with three of these mutations (p. L382Pfs*15, p. G117fs*28, and p. T312Sfs*13) being novel variants not previously reported in the literature. We also present a literature review and general overview of the currently reported SLC37A4 gene variants. Our study expands the mutation spectrum of SLC37A4, which may help enable genetic testing to facilitate prompt diagnosis, appropriate intervention, and genetic counseling for affected families.

Keywords: Glycogen storage disease type 1b; SLC37A4 gene; genetic variant; hypoglycemia; inflammatory bowel disease; neutropenia

DOI: https://doi.org/10.1177/03000605231216633

Int J Biol Macromol. 2023 Dec 05. pii: S0141-8130(23)05435-1. [Epub ahead of print]257(Pt 1): 128536

Glycogen for lysosome-targeted CpG ODNs delivery and enhanced cancer immunotherapy.

Huijie Zhang, Li Lai, Zhiqing Wang, Jiawen Zhang, Jianzhu Zhou, Yao Nie, Jinghua Chen.

CpG oligodeoxynucleotides (ODNs) strongly activate the immune system after binding to toll-like receptor 9 (TLR9) in lysosome, which demonstrated significant potential in cancer immunotherapy. However, their therapeutic efficacy is limited by drawbacks such as rapid degradation and poor cellular uptake. Although encouraging progress have been made on developing various delivery systems for CpG ODNs, safety risks of the synthetic nanocarriers as well as the deficient CpG ODNs release within lysosome remain big obstacles. Herein, we developed a novel nanovector for lysosome-targeted CpG ODNs delivery and enhanced cancer immunotherapy. Natural glycogen was simply aminated (NH2-Gly) through grafting with diethylenetriamine (DETA), which was spherical in shape with diameter of approximately 40 nm. NH2-Gly possessed good biocompatibility. Cationic NH2-Gly complexed CpG ODNs well and protected them from nuclease digestion. NH2-Gly significantly enhanced the cellular uptake of CpG ODNs. Efficient CpG ODNs release was observed in the presence of α-glucosidase that mimicking the environment of lysosome. Consequently, NH2-Gly/CpG complexes triggered potent antitumor immunity and effectively inhibit the tumor growth without causing any toxic effect or tissue damages. This work highlights the promise of glycogen for lysosome-targeted on-command delivery of CpG ODNs, which brings new hope for precision cancer immunotherapy.

Keywords: CpG ODNs; Drug delivery; Glycogen; Nanocarrier; cancer immunotherapy

DOI: https://doi.org/10.1016/j.ijbiomac.2023.128536

bioRxiv. 2023 Nov 28. pii: 2023.11.28.568950. [Epub ahead of print]

Drosophila Neuronal Glucose 6 Phosphatase is a modulator of Neuropeptide Release that regulates muscle glycogen stores via FMRFamide signaling.

Tetsuya Miyamoto, Sheida Hedjazi, Chika Miyamoto, Hubert Amrein.

Neuropeptides (NPs) and their cognate receptors are critical molecular effectors of diverse physiological processes and behaviors. We recently reported of a non-canonical function of the Drosophila Glucose-6-Phosphatase ( G6P ) gene in a subset of neurosecretory cells in the CNS that governs systemic glucose homeostasis in food deprived flies. Here, we show that G6P expressing neurons define 7 groups of neuropeptide secreting cells, 5 in the brain and 2 in the thoracic ganglia. Using the glucose homeostasis phenotype as a screening tool, we show that one such group, located in the thoracic ganglia and expressing FMRFamide ( FMRFa G6P ) neuropeptides, is necessary and sufficient to maintain systemic glucose homeostasis in starved flies. We further show that the receptor for FMRFamides (FMRFaR) is one key target of G6P dependent NP signaling and essential for the build-up of glycogen stores in the jump muscle. Lastly, measurements of the Golgi apparatus of FMRFa G6P neurons and neuropeptide released into the hemolymph suggests that G6P enhances FMRFa signaling by increasing the capacity of the neurosecretory system. We propose a general model in which the main role of G6P is to counteract glycolysis in peptidergic neurons for the purpose of optimizing the intracellular environment best suited for the expansion of the Golgi apparatus, boosting release of neuropeptides, which through the activation of specific neuropeptide receptors, enhances signaling in respective target tissues.

DOI: https://doi.org/10.1101/2023.11.28.568950

Nat Metab. 2023 Dec 08.

Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes.

Cotadutide is a dual glucagon-like peptide 1 and glucagon receptor agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes mellitus (T2DM) and chronic kidney disease. Non-alcoholic steatohepatitis is a complex disease with no approved pharmacotherapies, arising from an underlying state of systemic metabolic dysfunction in association with T2DM and obesity. Cotadutide has been shown to improve glycaemic control, body weight, lipids, liver fat, inflammation and fibrosis. We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. The primary endpoints were change from baseline to day 28 of treatment in postprandial hepatic glycogen (part A) and to day 35 of treatment in fasting hepatic glycogen (part B) with cotadutide versus placebo. Secondary endpoints in part B were changes in fasting hepatic glycogen with cotadutide versus the mono glucagon-like peptide 1 receptor agonist, liraglutide, and change in hepatic fat fraction. The trial met its primary endpoint. We showed that cotadutide promotes greater reductions in liver glycogen and fat compared with placebo and liraglutide. Safety and tolerability findings with cotadutide were comparable to those of previous reports. Thus, this work provides evidence of additional benefits of cotadutide that could be attributed to glucagon receptor engagement. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994 .

DOI: https://doi.org/10.1038/s42255-023-00938-0

Cell Rep. 2023 Dec 04. pii: S2211-1247(23)01547-4. [Epub ahead of print]42(12): 113535

Epinephrine inhibits PI3Kα via the Hippo kinases.

The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.

Keywords: CP: Metabolism; CP: Molecular biology; Hippo kinases; PI3K signaling; epinephrine signaling; glucose metabolism; glycogen metabolism; insulin sensitivity; liver

DOI: https://doi.org/10.1016/j.celrep.2023.113535