Carbohydrates

Carbohydrates are neutral compounds composed of carbon, hydrogen, and oxygen that serve as the primary sources of energy in the human body. They can be divided into simple carbohydrates, which include monosaccharides (e.g., glucose, fructose, galactose) and disaccharides (e.g., sucrose, lactose), and complex carbohydrates, which comprise starch and nonstarch polysaccharides (e.g., starch, glycogen, cellulose). While monosaccharides are directly absorbed by enterocytes, disaccharides and polysaccharides require degradation into monosaccharides for absorption by hydrolytic enzymes, which are secreted by the salivary glands in the mouth (salivary amylase), intestinal villi (maltase, lactase), and pancreas (pancreatic amylase). Conditions that decrease the secretion of these enzymes result in malabsorption and maldigestion. Glucose and galactose are absorbed via Na⁺-glucose-cotransporters (SGLT) in the intestinal epithelial cells and translocated into the circulation via glucose transporter 2 (GLUT2). Fructose is absorbed into enterocytes via glucose transporter 5 (GLUT5) through facilitated diffusion. The uptake of glucose into other cells is mediated by glucose transporters 1 to 5 (GLUT1–5). Intracellularly, the monosaccharides are further metabolized by a series of enzymatic reactions to release adenosine triphosphate (ATP).

For details on the carbohydrate glucose, see glucose metabolism (synthesis and breakdown) and glycogen metabolism (storage).

Definitions

• Carbohydrates: Compounds consisting of carbon, oxygen, and hydrogen that are classified as either simple (e.g., glucose, fructose, sucrose) or complex sugars (e.g., starch).
• Monosaccharide: a simple carbohydrate that cannot be further broken down by simple hydrolysis
  • Examples: glucose, fructose, or galactose
• Disaccharide: formed by the union of two monosaccharides linked by a glycosidic bond
  • Examples: sucrose, maltose, or lactose (see table below)
• Polysaccharide: formed by many monosaccharides bound by glycosidic bonds
  • Examples: glycogen, cellulose, starch, peptidoglycans, glycosaminoglycans
• Glycosidic bond: linkage between a carbohydrate and another molecule (e.g., carbohydrate, alcohol)
  • Two forms:
    • 1,4 α-glycosidic bond (OH group below the plane of the ring)
      • Example: maltose
    • 1,4 β-glycosidic bonds (OH above the plane of the ring)
      • Examples: lactose and cellulose

Lactase is the only enzyme in the human body that can cleave β-glucosidic bonds, but only those of the disaccharide lactose. There are no enzymes in the digestive tract that can cleave β-glycosidic bonds of polysaccharides. Cellulose therefore remains undigested in the intestine and is referred to as fiber!

Important disaccharides
Name	Composed of
Sucrose Common table sugar	Glucose + fructose
Maltose	Glucose + glucose
Lactose Milk sugar	Glucose + galactose

Carbohydrates in food

• Sources: table sugar, cereals, fruits, and vegetables
  • About ⅔ in the form of starch (polysaccharide)
  • About ⅓ in the form of disaccharides (e.g., lactose, sucrose)

Digestion

• Monosaccharides: absorbed directly by enterocytes
• Polysaccharides: broken down by enzymes into monosaccharides via hydrolytic cleavage of α-glycosidic bonds

Enzyme	Site	Chemical reaction
α-Amylase	Saliva (mouth) Pancreas	Polysaccharides → maltose, isomaltose, maltotriose, other oligosaccharides
Lactase	Intestinal microvilli	Lactose → galactose + glucose
Sucrase-isomaltase		Maltose, isomaltose, maltotriose, saccharose → glucose + fructose
Maltase-glucoamylase		Polysaccharides, oligosaccharides, disaccharides → glucose

• Lactase production decreases after breastfeeding, which leads to many individuals developing lactose intolerance.

Absorption

Glucose enters intestinal epithelial cells and proximal renal tubular cells via Na⁺-glucose-cotransporters (SGLT). In all other cells of the body, glucose uptake occurs through specific membranous glucose transporters (GLUT).

• Intestinal glucose absorption
  • Sodium-dependent glucose cotransporter 1 (SGLT1)
    • Specific transporter on the luminal side of mucosa cells, as well as the proximal straight tubule in the kidney
    • The driving force is a sodium concentration gradient, which is maintained by basal Na⁺/K⁺ ATPase by transporting sodium out of the cell (secondary active transport).
    • Sodium moves down its concentration gradient into the cell and takes a glucose molecule with it each time.
    • Also absorbs galactose.
• Transport into blood: via GLUT2 and circulates unbound in blood
• Glucose uptake into cells
  • Glucose transporter (GLUT)
    • Group of specific glucose transporters that are present in the plasma membranes of almost all cells of the body.
    • Passive transport via facilitated diffusion
• Renal glucose reabsorption
  • Free filtration of glucose by the kidneys
  • Complete reabsorption in the proximal tubules via 2 types of SGLT → urine normally glucose free
    • SGLT2: reabsorbs ∼ 98% of urinary glucose in the proximal convoluted tubule (PCT)
      • One molecule of glucose is absorbed together with one molecule of sodium.
    • SGLT1: reabsorbs the remaining glucose (∼ 2%) as well as galactose in the PST
      • One molecule of glucose is absorbed together with two molecules of sodium.
    • Fructose is absorbed via GLUT5 (glucose transporter).
    • Reabsorption also relies on a sodium concentration gradient via Na⁺/K⁺ ATPase.

Important glucose transporters

Name	Site	Special function	Insulin-dependent
GLUT1	Most human cells RBC CNS Cornea Placenta Fetal tissue	Blood-brain barrier High affinity for glucose	No
GLUT2	Hepatocytes Pancreatic β-islet cells Kidney Small intestine	Transports all monosaccharide from the basolateral membrane of enterocytes into the blood Glucose sensor: The free flow of glucose in and out of pancreatic cells allows measuring of serum glucose levels. Low affinity (KM) for glucose → glucose only diffuses at high concentrations Bidirectional transporter: allows hepatocytes to uptake glucose for glycolysis and release glucose during gluconeogenesis	No
GLUT3	Most human cells CNS Placenta	Blood-brain barrier High affinity for glucose	No
GLUT4	Adipose tissue Striated muscle Skeletal muscle Heart muscle	Plays a key role in regulating body glucose homeostasis Insulin stimulates incorporation of GLUT4 (stored in vesicles) into plasma cell membranes of cells for controlled glucose uptake and storage Physical exercise also induces the translocation of GLUT4 into the plasma membrane of skeletal muscle (insulin-independent!)	Yes
GLUT5	Small intestinal enterocytes Spermatocytes	Fructose transporter	No

Only GLUT4 is insulin-dependent!

Maldigestion and malabsorption

• Lactose intolerance
• Fructose malabsorption
• Sucrose malabsorption (sucrase-isomaltase deficiency)
• Sorbitol malabsorption

• See breakdown and synthesis of glucose for:
  • Glucose degradation
    • Glycolysis
    • Hexose monophosphate shunt (pentose phosphate pathway)
  • Glucose synthesis: gluconeogenesis
• See glycogen metabolism for glucose storage.

Absorption of galactose

Galactose is part of lactose (found in milk products).

1. Lactose is cleaved in the small intestine by the lactase.
2. Freed galactose is absorbed by enterocytes via SGLT1.
3. Transported into blood via GLUT2
4. Circulates to the liver for further metabolism

Breakdown of galactose

Galactose metabolism converges with glucose metabolism after some intermediate steps: galactose → galactose-1-phosphate → UDP-galactose → UDP-glucose → glucose-1-phosphate (enters glycolysis).

1. Galactokinase activates galactose: galactose + ATP → galactose-1-P + ADP
2. Galactose-1-phosphate uridylyltransferase: galactose-1-P + UDP-glucose → UDP-galactose + glucose-1-P (can be fed into glycolysis)
3. UDP-galactose 4-epimerase: UDP-galactose → UDP-glucose

If an individual is deficient of the enzyme galactose-1-phosphate UDT transferase (classical galactosemia), galactose and lactose (galactose + glucose) have to be removed from the diet!

High blood levels of galactose also result in conversion to the osmotically active galactitol via aldose reductase. In individuals with galactokinase deficiency, excess galactitol forms in the lens of the eye and leads to early-onset cataracts!

Galactose synthesis

• Metabolic site: lactating breast (lactose is the main sugar of breast milk)
• Reversal of all reactions

Disorders of galactose metabolism

• Galactosemia

Absorption of fructose

Fructose is part of sucrose (a common table sugar).

1. Sucrose is cleaved in the small intestine by sucrase-isomaltase.
2. Freed fructose is absorbed into enterocytes via facilitated diffusion by GLUT5.
3. Transported into blood via GLUT2
4. Circulates to the liver for further metabolism

Breakdown of fructose (fructolysis)

Fructose metabolism converges with glucose metabolism after some intermediate steps: fructose + ATP → fructose-1-P → glyceraldehyde-3-P → glycolysis

1. Fructokinase activates fructose: fructose + ATP → fructose-1-P + ADP
2. Aldolase B splits hexose into two trioses: fructose-1-P → dihydroxyacetone-P + glyceraldehyde
3. Conversion to glyceraldehyde-3-P:
   • Triosephosphate isomerase: dihydroxyacetone-P (can directly enter glycolysis) → glyceraldehyde-3-P
   • Triose kinase: glyceraldehyde + ATP → glyceraldehyde-3-P
4. Glyceraldehyde-3-P is fed into glycolysis

If an individual is deficient in the enzyme aldolase B (hereditary fructose intolerance), both fructose and sucrose (glucose + fructose) have to be removed from the diet!

Fructose synthesis

Fructose can be produced from glucose via sorbitol (osmotically active sugar alcohol) without using ATP.

1. Aldose reductase reduces glucose to sorbitol: glucose + NADPH → sorbitol
2. Sorbitol dehydrogenase oxidates sorbitol to fructose: sorbitol + NAD⁺ → fructose
   • In liver, ovaries, seminal vesicles
   • In the body, fructose is the primary source of energy for spermatozoa.

Tissues that do not have sorbitol dehydrogenase activity (e.g., lens, retina, kidneys, Schwann cells) accumulate sorbitol. Excess sorbitol causes osmotic damage and explains changes seen in hyperglycemic diabetic patients such as diabetic cataracts, diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

Disorders of fructose metabolism

• Hereditary fructose intolerance (autosomal recessive defect of aldolase B)
• Essential fructosuria (autosomal recessive defect of fructokinase)