Glycogen: glycogenesis, glycogenolysis, glycogen storage diseases

Carbohydrate digestion in the gastrointestinal tract

The main dietary carbohydrates are starch, sucrose, and lactose. Starch is a glucose polymer whose residues are linked by α-1,4 and α-1,6 glycosidic bonds. Digestion begins in the oral cavity under the action of salivary α-amylase, which hydrolyzes starch into dextrins. Carbohydrate cleavage practically does not occur in the stomach due to the absence of relevant enzymes and the acidic environment.

In the duodenum, pancreatic α-amylase acts to break down starch into disaccharides—maltose (α-1,4) and isomaltose (α-1,6). The final hydrolysis of disaccharides is carried out by brush-border enzymes of the small intestine:

• sucrase-isomaltase complex — hydrolyzes sucrose, maltose, isomaltose;
• β-glycosidase complex — breaks down a range of β-glycosides;
• lactase — breaks down lactose into galactose and glucose.

Lactase activity is maximal in infants and decreases with age, which underlies lactase deficiency.

Absorption of monosaccharides and their transport into tissues

Monosaccharides enter enterocytes via two pathways. Facilitated diffusion is characteristic of fructose (via GLUT5), as well as partially for glucose and galactose. Secondary active transport involving the Na⁺-dependent transporter SGLT1 moves glucose and galactose against a concentration gradient; energy is provided by the activity of the Na⁺/K⁺-ATPase.

Monosaccharides exit enterocytes into the blood via facilitated diffusion. In tissues, glucose is taken up by GLUT family proteins. Of particular importance is GLUT4, the insulin-dependent transporter of muscle and adipose tissue.

Glucose phosphorylation and the fate of glucose-6-phosphate

Within the cell, glucose is immediately phosphorylated. The reaction is catalyzed by:

• hexokinase — low Km (~0.1 mmol/L), inhibited by the product, glucose-6-phosphate;
• glucokinase — high Km (~10 mmol/L), operates in the liver, induced by insulin.

Glucose-6-phosphate is used for glycogen synthesis, in the pentose phosphate pathway, for the synthesis of other monosaccharides and amino acids, and undergoes catabolism to CO₂ and H₂O or to lactate with ATP generation.

Glycogenesis: glycogen synthesis

Glycogen synthesis occurs in the absorptive state (1–2 hours after a meal). Stages:

1. Glucose → glucose-6-phosphate (hexokinase/glucokinase).
2. Glucose-6-phosphate → glucose-1-phosphate under the action of phosphoglucomutase.
3. Glucose activation: glucose-1-phosphate + UTP → UDP-glucose + pyrophosphate (enzyme UDP-glucose pyrophosphorylase).
4. Glycogen synthase transfers a glucose residue from UDP-glucose to a primer (≥4 residues), forming an α-1,4 glycosidic bond.
5. After elongation of the chain to 11–12 residues, the branching enzyme (amylo-1,4→1,6-glucosyltransferase) transfers a fragment of 5–6 residues, forming an α-1,6 bond—a branch point.

Glycogenolysis: glycogen mobilization

Glycogen breakdown is activated in the postabsorptive state and during physical exertion. The key enzyme is glycogen phosphorylase, which phosphorolytically cleaves α-1,4 bonds to yield glucose-1-phosphate. The enzyme stops 4 residues away from a branch point. Next, the debranching enzyme operates:

• oligosaccharide transferase transfers a triglucose fragment to an adjacent chain;
• α-1,6-glucosidase hydrolyzes the α-1,6 bond, releasing free glucose.

Glucose-1-phosphate is converted into glucose-6-phosphate. In muscles, it enters glycolysis. The liver contains glucose-6-phosphatase, which dephosphorylates glucose-6-phosphate to free glucose, which enters the bloodstream and maintains glycemia.

Regulation of glycogen metabolism

Simultaneous synthesis and breakdown are prevented by the reciprocal regulation of glycogen synthase and glycogen phosphorylase. Active forms:

• glycogen synthase — dephosphorylated;
• glycogen phosphorylase — phosphorylated.

The ratio is determined by the insulin-glucagon ratio (IGR).

Insulin (high IGR) activates glycogen particle protein phosphatase, which dephosphorylates both enzymes: glycogen synthase is activated, and glycogen phosphorylase is inactivated. Additionally, insulin activates GLUT4, induces glucokinase, and activates phosphodiesterase, which lowers cAMP levels.

Glucagon (in the liver) and adrenaline (via β2-receptors) turn on the adenylate cyclase system: G-protein → adenylate cyclase → cAMP → protein kinase A. PKA phosphorylates glycogen synthase (inactivation) and phosphorylase kinase, which activates glycogen phosphorylase.

Adrenaline via α1-adrenergic receptors activates the inositol phosphate system: phospholipase C → IP₃ → Ca²⁺ efflux → Ca²⁺–calmodulin–phosphorylase kinase complex activates glycogen phosphorylase. Protein kinase C additionally phosphorylates and inactivates glycogen synthase.

In muscles during moderate exercise, glycogen phosphorylase is allosterically activated by AMP. During intense exercise, nerve impulses (Ca²⁺-calmodulin pathway) and adrenaline (cAMP-dependent pathway) are recruited.

Glycogen storage diseases (glycogenoses)

Glycogenoses are hereditary diseases caused by defects in enzymes of glycogen synthesis or breakdown. They are accompanied by the accumulation of abnormal amounts or structurally altered glycogen in the liver, muscles, and kidneys. Clinically, they manifest as fasting hypoglycemia, hepatomegaly, muscle weakness, and exercise intolerance. Glucose-6-phosphatase deficiency (Von Gierke disease), debranching enzyme deficiency, muscle phosphorylase deficiency (McArdle disease), and branching enzyme deficiency are the most studied forms.

Key points

• Starch is broken down by salivary and pancreatic α-amylases; final disaccharide hydrolysis occurs at the brush border (sucrase-isomaltase, lactase).
• Glucose is transported into enterocytes via SGLT1 (secondary active transport with Na⁺) and enters tissues via GLUT proteins; GLUT4 is insulin-dependent.
• Within the cell, glucose is phosphorylated by hexokinase or glucokinase; glucose-6-phosphate is a central metabolite.
• Glycogen synthesis requires glucose activation to UDP-glucose; key enzymes are glycogen synthase and the branching enzyme.
• Breakdown proceeds phosphorolytically: glycogen phosphorylase + debranching enzyme (transferase + α-1,6-glucosidase).
• Only the liver is capable of releasing free glucose into the blood due to glucose-6-phosphatase.
• Insulin stimulates synthesis (enzyme dephosphorylation), while glucagon and adrenaline stimulate glycogen breakdown via cAMP/PKA and Ca²⁺-dependent pathways.
• Hereditary defects in glycogen metabolism enzymes lead to glycogenoses characterized by hypoglycemia and liver and muscle damage.