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Glycogen synthase

Glycogen synthase is a key glycosyltransferase enzyme that catalyzes the rate-limiting step in glycogen biosynthesis, transferring glucose residues from the activated donor UDP-glucose to the non-reducing ends of existing glycogen chains via α-1,4-glycosidic linkages, thereby elongating the linear glucose polymer that serves as the primary energy storage form of glucose in animals.^[1] This process requires a protein primer called glycogenin and works in concert with glycogen branching enzyme to create the branched structure of glycogen, enhancing its solubility and rapid mobilization during energy demands.^[2] In mammals, glycogen synthase exists in two isoforms encoded by distinct genes: GYS1, which is ubiquitously expressed but predominantly in skeletal muscle and heart, and GYS2, which is liver-specific and responsible for hepatic glycogen storage to maintain blood glucose homeostasis.^[1] Both isoforms share approximately 70% sequence identity and exhibit similar tetrameric structures, each subunit comprising two Rossmann-like domains for substrate binding and a C-terminal domain for oligomerization, enabling efficient processive synthesis that contributes to glycogen molecules containing up to 55,000 glucose units.^[1]^[3] The enzyme's activity is intricately regulated to match cellular energy needs, primarily through allosteric activation by glucose-6-phosphate (G6P), which binds to an interdomain site and promotes a conformation favoring UDP-glucose binding, and through reversible phosphorylation at multiple serine residues (e.g., Ser641, Ser8) by kinases such as GSK3, PKA, and AMPK, which inhibit activity, countered by dephosphorylation via protein phosphatase 1 (PP1).^[1]^[2] Insulin signaling enhances dephosphorylation and activation, while glucagon and epinephrine promote inhibitory phosphorylation, ensuring glycogen accumulation postprandially and breakdown during fasting.^[2] Defects in GYS1 or GYS2 cause glycogen storage disease type 0 (GSD 0), an autosomal recessive disorder characterized by impaired glycogen synthesis leading to hypoglycemia, ketosis, and in muscle cases, cardiomyopathy; GSD 0a (liver) results from GYS2 mutations, while GSD 0b (muscle) stems from GYS1 variants.^[4]^[5]

Role in Metabolism

Glycogen Synthesis Pathway

Glycogen synthase, classified under EC 2.4.1.11, functions as a glycosyltransferase that catalyzes the incorporation of glucosyl residues from the donor molecule UDP-glucose onto the non-reducing terminus of an existing glycogen chain, thereby extending it through the formation of α-1,4-glycosidic linkages.^[6] This enzymatic activity is essential for the elongation phase of glycogen biosynthesis, enabling the efficient polymerization of glucose units into branched polysaccharide structures.^[2] Within the broader context of glycogenesis, glycogen synthase occupies a pivotal position, becoming activated in the post-feeding state to facilitate the storage of excess glucose as glycogen primarily in hepatic and skeletal muscle tissues.^[2] The pathway commences with glucose phosphorylation to glucose-6-phosphate by hexokinase (in muscle) or glucokinase (in liver), followed by isomerization to glucose-1-phosphate via phosphoglucomutase. Glucose-1-phosphate then combines with UTP, catalyzed by UDP-glucose pyrophosphorylase, to generate UDP-glucose, the activated substrate that glycogen synthase utilizes for chain elongation.^[2] This sequential process ensures the directed assembly of glycogen granules, serving as an intracellular energy reserve. By promoting the conversion of surplus circulating glucose into an osmotically inert storage polymer, glycogen synthesis via this pathway plays a critical role in maintaining systemic energy homeostasis and averting postprandial hyperglycemia.^[2] As the rate-limiting enzyme in glycogenesis, glycogen synthase's activity is precisely modulated to synchronize glycogen accumulation with fluctuating energy requirements, preventing wasteful overstorage or depletion.^[7] The muscle-specific isoform GYS1 and liver-specific isoform GYS2 both mediate this core pathway, differing mainly in their tissue distribution.^[8]

Dependence on Glycogenin

Glycogenin functions as a self-glucosylating protein that initiates glycogen synthesis by covalently attaching the first glucose residues to a specific tyrosine residue on itself, typically adding 8-12 glucose units to form an oligosaccharide primer. This autoglucosylation process requires UDP-glucose and divalent cations such as Mn²⁺ or Mg²⁺, establishing a short glucan chain that serves as the foundation for further elongation.^[9] Without this primer, glycogen synthase cannot initiate de novo glycogen particle formation, highlighting glycogenin's essential role in priming the pathway.^[10] Glycogen synthase binds directly to the C-terminal region of glycogenin once the primer is formed, allowing the synthase to extend the glucan chain by adding additional glucose units from UDP-glucose. This interaction is mediated by specific protein-protein contacts, with the synthase's binding affinity enhanced by the primed oligosaccharide, ensuring efficient transfer of the growing chain. In the absence of glycogenin, glycogen synthase remains inactive for chain initiation, preventing glycogen accumulation and underscoring the synthase's strict dependence on this primer protein.^[11] The association between glycogen synthase and glycogenin operates in a dynamic cycle: after priming, glycogen synthase elongates the chain until it reaches approximately 12 glucose units, at which point the synthase detaches, permitting further maturation of the glycogen particle by branching enzymes and additional synthase molecules.^[9] Glycogenin then re-primes by initiating a new oligosaccharide on another molecule or site, facilitating the formation of multiple glycogen particles. This cyclical process ensures controlled nucleation and growth of glycogen structures. This dependence on glycogenin is evolutionarily conserved across eukaryotes, where it uniquely enables primed glycogen synthesis, in contrast to prokaryotes that lack glycogenin and instead use glycogen synthase for direct self-priming without a dedicated protein primer.^[12] Experimental evidence from glycogenin knockout studies in mice demonstrates that its deficiency results in abnormal glycogen particles lacking covalently bound protein, accompanied by excessive glycogen accumulation in striated muscle and impaired muscle function, confirming glycogenin's critical role in maintaining normal glycogen structure and metabolism.^[10]

Isoforms

GYS1 (Muscle Isoform)

GYS1, the gene encoding the muscle isoform of glycogen synthase, is located on human chromosome 19q13.33 and produces a protein of approximately 84 kDa.^[13]^[8] This isoform shares the core catalytic function of elongating glycogen chains by transferring glucose from UDP-glucose to the non-reducing ends of α-1,4-linked glucan primers.^[8] GYS1 is predominantly expressed in skeletal muscle, heart muscle, and brain, with notably low levels in the liver, where the GYS2 isoform predominates.^[14]^[1] In these tissues, the enzyme operates primarily as a homotetramer, facilitating efficient glycogen biosynthesis.^[8]^[1] Physiologically, GYS1 supports the storage of glucose as glycogen in muscle to fuel contractions during physical activity, serving as a readily accessible energy reserve.^[15] Post-exercise, its activation enables rapid replenishment of depleted glycogen stores, aiding recovery and maintaining endurance capacity.^[16] This isoform demonstrates heightened sensitivity to cellular energy status indicators, such as elevated glucose-6-phosphate levels, which promote swift glycogen synthesis in response to metabolic demands in muscle.00358-X)

GYS2 (Liver Isoform)

GYS2 is the gene encoding the liver isoform of glycogen synthase, located on chromosome 12p12.2. It produces a protein of approximately 80 kDa consisting of 703 amino acids, sharing about 70% sequence identity with the muscle isoform GYS1. Like GYS1, GYS2 belongs to the GT3 superclass of glycosyltransferases. This isoform is specifically expressed in the liver, with no detectable presence in skeletal muscle or other tissues where GYS1 predominates. In the liver, GYS2 facilitates the storage of excess glucose as glycogen following meals, thereby preventing hyperglycemia and maintaining systemic blood glucose levels. During fasting, it supports glucose homeostasis indirectly through the balanced regulation of glycogen synthesis and subsequent breakdown, ensuring steady glucose release into the circulation. GYS2 utilizes UDP-glucose as its primary substrate to elongate glycogen chains, but its kinetic properties are optimized for the high hepatic glucose flux, enabling efficient incorporation into glycogen under postprandial conditions. Compared to GYS1, GYS2 exhibits a greater capacity to synthesize and associate with larger glycogen particles, which are characteristic of hepatic stores and better suited for buffering blood glucose over extended periods. Expression of GYS2 in the liver increases significantly postnatally, coinciding with the transition from fetal to neonatal metabolism and enabling adaptation to intermittent feeding patterns. This developmental upregulation supports the maturation of hepatic glycogen storage capacity, crucial for maintaining euglycemia during early life.

Molecular Structure

Overall Architecture

Glycogen synthase in eukaryotes is classified within the GT3 family of glycosyltransferases and typically comprises 737 amino acids in the human muscle isoform (GYS1), with a molecular weight of approximately 84 kDa per subunit.^[8] The liver isoform (GYS2) shares this GT3 architecture but is slightly shorter at 703 amino acids and ~80 kDa.^[17] These enzymes exhibit a GT-B fold, characterized by two Rossmann-like domains that form the core structure.^[18] A key structural feature is the division into an N-terminal regulatory domain, which is susceptible to phosphorylation, and a C-terminal catalytic domain that adopts a Rossmann fold for nucleotide binding.^[18] In eukaryotes such as yeast and humans, glycogen synthase assembles into tetramers, which enhance enzymatic stability through interfaces stabilized by hydrophobic interactions.^[19] This oligomeric state is conserved across species and supports efficient glycogen biosynthesis.^[20] In contrast, prokaryotic glycogen synthases serve as analogs and belong to the GT5 family, exemplified by the enzyme from Agrobacterium tumefaciens, which has ~480 amino acids and a molecular weight of ~50 kDa per subunit. These bacterial forms utilize ADP-glucose as the substrate and exist as monomers, as observed in crystal structures resolved at 2.3 Å resolution.^[21] Evolutionarily, the GT3 family in animals has developed intricate regulation, including phosphorylation and allosteric control, whereas GT5 enzymes in bacteria (glycogen synthases) and plants (starch synthases) generally lack such tight regulatory mechanisms.^[21]

Active Site Features

The active site of glycogen synthase is situated within a deep cleft formed between the two Rossmann-like domains characteristic of the GT-B fold in its catalytic core. This architecture positions the nucleotide-sugar substrate and the glycogen acceptor in proximity for glycosyl transfer, with the cleft allowing access to both substrates. Structural studies, including crystal structures of the bacterial homolog and cryo-EM structures of human GYS1, reveal an open conformation that undergoes interdomain closure upon substrate binding to facilitate catalysis.^[21]^[22] The UDP-glucose binding pocket is located on the C-terminal side of the cleft, where the nucleotide moiety interacts through hydrogen bonds with conserved lysine and arginine residues, such as Lys15 and Arg299 and equivalents in eukaryotic isoforms, while the uracil base stacks against Tyr354. The glucose moiety of UDP-glucose is oriented toward the acceptor binding region, coordinated by aspartic and asparagine residues that stabilize the sugar for transfer, as observed in structural models of eukaryotic glycogen synthases. An extended groove adjacent to this pocket accommodates the non-reducing end of the glycogen chain, binding up to seven glucose units via hydrophobic interactions, including π-stacking with aromatic residues like Tyr507 and Phe558 in the site-4 binding region.^[21]^[23] Conformational flexibility in the active site is evident from multiple structures, including cryo-EM reconstructions of the human GYS1 isoform showing transitions between closed (inactive) and open states, with domain rotations of approximately 20° to expose the cleft for substrate entry. These states have been captured in human complexes at 3.4–3.5 Å, highlighting the dynamic positioning of the interdomain linker. Insights into inhibitor design stem from these structures, where glucose analogs occupy the glucose-binding subsite, mimicking the substrate and blocking the transfer position, as seen in binding pockets lined by residues like Asn246 and Asp138 in rabbit GS.^[21]^[22]

Catalytic Mechanism

Reaction Catalysis

Glycogen synthase catalyzes the elongation of glycogen chains by transferring the glucosyl moiety from the donor substrate UDP-glucose to the non-reducing end of an existing α-1,4-linked glucan chain, forming a new α-1,4-glycosidic bond and releasing UDP as a byproduct. The overall reaction can be represented as:

\text{UDP-glucose} + (\text{glucose})_n \rightarrow \text{UDP} + (\text{glucose})_{n+1}

This process is the core of glycogen biosynthesis and occurs with high specificity for the linear extension of the polymer.^[24] The catalytic mechanism involves a retaining stereochemical course at the anomeric C1 carbon of the transferred glucose, proceeding through an oxocarbenium ion-like transition state consistent with retaining glycosyltransferases. In this step, the hydroxyl oxygen at the C4 position of the terminal glucose residue in the glycogen chain acts as the nucleophile, attacking the electrophilic C1 of UDP-glucose and displacing the UDP leaving group. A divalent metal ion, typically Mg²⁺ or Mn²⁺, coordinates the diphosphate moiety of UDP-glucose to enhance the electrophilicity of C1 and stabilize the transition state. Active site residues, including conserved aspartate and glutamate, further assist by binding the metal ion and positioning the substrates.^[25]^[21] Upon formation of the new glycosidic bond, the UDP product dissociates rapidly, while the extended glycogen chain remains associated with the enzyme, promoting processive catalysis that allows the sequential addition of hundreds of glucose units in a single binding event. This processivity enhances the efficiency of glycogen assembly under physiological conditions.^[26] The enzyme exhibits Michaelis-Menten kinetics with respect to UDP-glucose, characterized by a Km value typically ranging from 0.1 to 1 mM, which can vary based on the phosphorylation state and isoform; Vmax values differ similarly, often reaching 20-50 units per mg in the activated form. Isotope labeling experiments, including measurements of secondary deuterium kinetic isotope effects at C1 (kH/kD ≈ 1.23 for Vmax), have supported an oxocarbenium ion-like transition state with some SN2 character, consistent with the retaining mechanism of glycogen synthase.^[27]^[28]

Structural Conformational Changes

Glycogen synthase undergoes significant conformational transitions from an inactive to an active state, primarily involving the N-terminal region and allosteric interactions. In the inactive form, phosphorylation introduces disorder in the N-terminus, stabilizing inhibitory interactions such as those between phospho-Ser641 and arginine residues like Arg588 and Arg591, which maintain a tense (T) conformation with a closed active site cleft.^[1] Binding of glucose-6-phosphate (G6P) to an allosteric site triggers a shift to the relaxed (R) state, inducing a ~35° outward rotation of subunits and an ~18.6 Å translation that stabilizes the active tetrameric assembly, thereby opening the active site for substrate access.^[1]^[29] During catalysis, glycogen synthase exhibits dynamic changes to facilitate the glycosyl transfer reaction. Upon substrate binding, including UDP-glucose and glycogen, the interdomain cleft narrows, promoting the retaining glycosidic bond formation mechanism.^[1]^[30] This is accompanied by a ~10–20° rotation of the Rossmann-fold domain 1 relative to domain 2. Recent cryo-electron microscopy (cryo-EM) studies have provided high-resolution insights into these open and closed conformations. In the open form (T state), resolved at ~3.0 Å, the enzyme accommodates substrate entry with a wide cleft, while the closed form (R state), at ~3.5–3.7 Å resolution, supports the catalytic transfer by compacting the active site.^[1]^[30] These structures reveal three distinct states—tense (T), relaxed (R), and super-relaxed (super-R)—highlighting the enzyme's adaptability during the synthesis cycle.^[1] Allosteric site movements in glycogen synthase are spatially distinct from the catalytic site, enabling signal transmission without direct interference. G6P binds to pockets at the oligomeric interface, involving arginine clusters (e.g., Arg579, Arg582, Arg586), which propagate conformational changes to the active site via intersubunit rearrangements.^[1]^[30] This separation allows independent modulation of activity while maintaining the GT-B fold integrity. Structurally, glycogen synthase shares the GT-B fold with glycogen phosphorylase, including similar Rossmann domains and predicted interdomain closures of ~20–25° during catalysis, but lacks the phosphorolytic reversal capability of phosphorylase due to its use of nucleoside-diphospho-glucose substrates.^[21] These conformations support the enzyme's retaining mechanism for α-1,4-glycosidic bond formation without overlapping the chemical steps of catalysis.^[1]

Regulation

Phosphorylation Control

Glycogen synthase activity is primarily inhibited through covalent modification by phosphorylation at multiple serine and threonine residues, predominantly located in the N-terminal regulatory domain. In the muscle isoform (GYS1), there are at least nine such sites, including Ser8 (site 2), Ser11 (site 2a), and several in the C-terminal region like Ser641 (site 3a); phosphorylation at these sites can reduce enzymatic activity by 80-90% by increasing the Km for UDP-glucose and decreasing sensitivity to glucose-6-phosphate.^[1] Both isoforms share multiple conserved phosphorylation sites, reflecting tissue-specific regulatory needs for glycogen storage.^[1] Key kinases responsible include protein kinase A (PKA), which targets sites 1a and 1b; glycogen synthase kinase-3 (GSK-3), which phosphorylates C-terminal sites such as 3a, 3b, 3c, and 3d; phosphorylase kinase (PhK), which targets site 2a; and AMP-activated protein kinase (AMPK), which phosphorylates site 2.^[1] Phosphorylation often proceeds sequentially, with GSK-3 requiring prior "priming" phosphorylation at nearby sites (e.g., site 5 by casein kinase 2) to access its targets efficiently, creating a hierarchical control mechanism that amplifies inhibition. This results in the enzyme existing in an active, dephosphorylated I-form or an inactive, phosphorylated D-form, where the latter predominates under conditions favoring glycogen breakdown.^[1] Dephosphorylation, mediated by protein phosphatase 1 (PP1), reverses this inhibition and restores activity, with PP1 targeting key sites like 3a and 3b; insulin signaling enhances PP1 activity to promote this shift.^[1] Overall, phosphorylation induces a conformational change that locks the enzyme in an inactive state, preventing substrate access until dephosphorylated.^[1]

Allosteric Modulation

Glycogen synthase is primarily activated allosterically by glucose-6-phosphate (G6P), which binds to a specific site distinct from the catalytic domain and enhances enzyme activity by promoting a conformational shift toward the active state. This binding overcomes the inhibitory effects of phosphorylation, thereby allowing the enzyme to function even when covalently modified. In the phosphorylated form, G6P significantly boosts glycogen synthesis rates under physiological conditions.^[31] The allosteric binding site for G6P is located at the interface of the C-terminal domains within the enzyme's tetrameric structure, involving key residues such as Arg579, Arg582, and Arg586 that coordinate the phosphate group, along with interactions from His287 and Gln294 for the glucose moiety. This site is unique to eukaryotic glycogen synthases and leverages an insertion domain (helices α15–α16) that mediates subunit interactions in the tetramer. Upon G6P binding, the tetramer undergoes a substantial rearrangement, including a ~35° rotation of subunits and ordering of a regulatory loop (residues 278–284), which stabilizes the active conformation and facilitates access to the catalytic cleft.^[1] Other metabolites also modulate glycogen synthase activity through allosteric mechanisms. Inorganic phosphate (Pi) acts as an inhibitor by competing with substrates or stabilizing inactive conformations, while ATP and ADP exert inhibitory effects that reflect cellular energy charge, with higher ATP levels suppressing activity to prevent unnecessary glycogen accumulation. These inhibitors typically reduce Vmax or increase substrate Km values, fine-tuning the enzyme in response to metabolic status.^[32] G6P exhibits synergistic effects with the enzyme's phosphorylation state: it amplifies the activity of the dephosphorylated form by further enhancing catalytic efficiency, while partially activating the phosphorylated form to restore substantial but not maximal activity. This allows G6P to counter the inhibitory impact of phosphorylation in a dose-dependent manner. Experimental analyses reveal cooperativity in G6P activation, indicating positive allosteric interactions that contribute to the enzyme's sensitivity to fluctuating G6P levels in vivo.^[1]

Clinical and Pathological Aspects

Glycogen Storage Diseases

Glycogen storage disease type 0 (GSD 0) encompasses rare autosomal recessive disorders caused by deficiencies in glycogen synthase, leading to impaired glycogen synthesis in specific tissues. Unlike most glycogen storage diseases, which involve excessive glycogen accumulation due to breakdown defects, GSD 0 results in depleted glycogen stores because of reduced synthesis. The condition is isoform-specific, with the liver isoform (GYS2) affected in GSD 0a and the muscle isoform (GYS1) in GSD 0b.^[5]^[33] GSD 0a, resulting from biallelic mutations in the GYS2 gene on chromosome 12p12.1, manifests primarily in the liver and presents with postprandial hyperglycemia followed by fasting hypoglycemia and hyperketonemia, often in infancy or early childhood. Affected individuals may experience morning seizures, drowsiness, or convulsions due to low blood glucose levels after overnight fasting, with elevated post-meal lactate and ketones reflecting metabolic imbalance. A notable example is the homozygous R484X nonsense mutation in GYS2, which abolishes enzyme activity and has been identified in multiple families. The liver form was first described in 1966.^[5]^[34]^[35] GSD 0b, caused by biallelic mutations in the GYS1 gene on chromosome 19q13.33, affects skeletal and cardiac muscle, leading to exercise intolerance, myopathy, and cardiomyopathy. In severe childhood-onset cases, symptoms include arrhythmia, heart failure, and risk of sudden cardiac death, as seen in initial reports of three affected siblings with dilated cardiomyopathy. Adult-onset variants present with milder muscle weakness, myalgia, and fatigue without cardiac involvement. Fewer than 20 cases of GSD 0b have been reported worldwide, highlighting its extreme rarity.^[33]^[36]^[37] The pathophysiology of GSD 0 involves deficient glycogen synthase activity, preventing the polymerization of glucose into glycogen and resulting in inadequate energy reserves during fasting or exertion. In the liver, this causes rapid depletion of glucose stores, promoting ketogenesis and hypoglycemia without hepatomegaly or glycogen buildup. In muscle, low glycogen levels impair ATP production, contributing to contractile dysfunction and cardiac complications, distinct from other GSDs with lysosomal or cytoplasmic accumulation.^[38]^[39] Diagnosis of GSD 0 typically requires a combination of clinical evaluation, biochemical assays, and genetic confirmation. Enzyme activity assays on liver or muscle biopsy demonstrate reduced or absent glycogen synthase function, while biopsies reveal glycogen depletion rather than excess. Genetic sequencing of GYS2 or GYS1 identifies causative variants, enabling prenatal or carrier testing in families. Prevalence is estimated at less than 1 in 1,000,000 individuals, accounting for under 1% of all glycogen storage diseases.^[40]^[41]^[42]

Therapeutic Developments

Recent advances in therapeutic strategies targeting glycogen synthase (GS) have focused on modulating its activity to address glycogen storage disorders and metabolic conditions like diabetes. In Pompe disease, a glycogen storage disease type II caused by acid alpha-glucosidase deficiency leading to lysosomal glycogen accumulation, substrate reduction therapy (SRT) via inhibition of glycogen synthase 1 (GYS1), the muscle isoform, has emerged as a promising approach to limit excess glycogen synthesis. Preclinical studies in Pompe mouse models demonstrated that small-molecule GYS1 inhibitors, such as MZE001, effectively reduced muscle glycogen levels to those observed in healthy controls without significant off-target effects on liver glycogen, suggesting potential as a monotherapy or adjunct to enzyme replacement therapy.^[3]^[43] A first-in-human phase 1 trial of MZE001 (NCT05249621) in healthy volunteers, completed in 2022, confirmed its safety and tolerability at doses up to 480 mg twice daily, with pharmacokinetic data showing sustained plasma exposure sufficient for GYS1 inhibition. Muscle biopsies from participants revealed a dose-dependent reduction in glycogen content by up to 40% after 10 days of treatment, supporting its mechanism in lowering glycogen stores. Building on this, a phase 2 trial (NCT07123155), sponsored by Shionogi (under the name S-606001), is planned to evaluate MZE001 as an add-on to enzyme replacement therapy in late-onset Pompe patients, assessing safety, pharmacodynamics, and preliminary efficacy on muscle function and glycogen levels over 24 weeks, with recruitment expected to begin in late 2025.^[44]^[45]^[46] For diabetes management, where impaired GS activation contributes to reduced glycogen storage and insulin resistance, glycogen synthase kinase-3 (GSK-3) inhibitors have been investigated to indirectly enhance GS activity by preventing inhibitory phosphorylation. These agents promote hepatic glycogen synthesis and improve glucose homeostasis in preclinical models of type 2 diabetes. Tideglusib, a selective GSK-3β inhibitor, has shown potential in early studies to boost insulin sensitivity and lower blood glucose, though its clinical trials (e.g., phase 2 for Alzheimer's disease, NCT01350362) have primarily targeted neurodegenerative conditions; diabetes-specific applications remain preclinical or exploratory, with challenges in achieving tissue-specific effects without neurotoxicity.^[47] Key challenges in GS-targeted therapies include achieving isoform selectivity—GYS1 for muscle disorders like Pompe versus GYS2 for liver conditions—to avoid disrupting systemic glucose homeostasis and risking hypoglycemia from excessive inhibition. Ongoing phase 1/2 trials for Pompe, such as NCT07123155, emphasize dose optimization to balance glycogen reduction with metabolic safety, highlighting the need for biomarkers to monitor GS activity in real-time.^[3]^[46]

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A Phase 2, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Investigate the Safety, Pharmacodynamics, and Preliminary Efficacy of S-606001 ...
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Advances in targeting glycogen synthase kinase 3β for diabetes ...
Sep 30, 2025 · It leads to increased glucose production and decreased insulin sensitivity by inhibiting glycogen synthase. These findings indicate that studies ...
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Gene therapy has reversed disease involvement of both liver and muscle GSDs and continues to be developed as a new therapy for these disorders.