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 include starch polysaccharides (e.g., starch, glycogen) and nonstarch polysaccharides (e.g., glucan, cellulose). Monosaccharides are directly absorbed by enterocytes. Disaccharides and polysaccharides require degradation into monosaccharides to be absorbed 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 sodium-glucose linked transporters (SGLTs) 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. Intracellularly, monosaccharides are further metabolized by a series of enzymatic reactions that release ATP.

For details on the carbohydrate glucose, see “Glycolysis and gluconeogenesis” and “Glycogen metabolism.”

• Carbohydrates
  • Compounds consisting of carbon, oxygen, and hydrogen
  • Classified as 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 (e.g., glucose, fructose, galactose)
• Disaccharide: two monosaccharides linked by a glycosidic bond (e.g., sucrose, maltose, or lactose)
• Polysaccharide: multiple monosaccharides bound by glycosidic bonds (e.g., glycogen, cellulose, starch, peptidoglycans, glycosaminoglycans)
• Glycosidic bond: linkage between a carbohydrate and another molecule (e.g., carbohydrate and alcohol)
  • Two forms:
    • 1,4-α-glycosidic bond (OH group below the plane of the ring), e.g., maltose
    • 1,4-β-glycosidic bonds (OH above the plane of the ring), e.g., lactose, cellulose

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

Carbohydrates in food

• Sources: table sugar, cereals, fruits, and vegetables
  • Approx. ⅔ of carbohydrates in food are in the form of starch (polysaccharide).
  • Approx. ⅓ of carbohydrates in food are 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

• Lactase production decreases after breastfeeding, which leads to many individuals developing lactose intolerance. ^[1]

Absorption of glucose

Glucose enters intestinal epithelial cells and proximal renal tubular cells via SGLT. In all other cells of the body, glucose uptake occurs via specific membranous glucose transporters (e.g., GLUT2, GLUT5).

• Transporters
  • Sodium-dependent glucose cotransporter 1 (SGLT1): a specific transporter, located on the luminal side of mucosa cells and the proximal straight tubule in the kidney
  • Glucose transporters (GLUTs): a group of specific glucose transporters that are present in the plasma membranes of almost all cells of the body
• Intestinal glucose absorption: via SGLT1
  • Secondary active transport: The driving force of absorption is a sodium concentration gradient maintained by basal Na⁺/K⁺ ATPase, which transports sodium out of the cell.
  • Sodium moves down its concentration gradient into the cell, taking a glucose molecule with it each time.
• Transport into the blood: via GLUT2 (circulates unbound in the blood)
• Glucose uptake into cells: passive transport via facilitated diffusion
• Renal glucose reabsorption
  • Free filtration of glucose by the kidneys
  • Complete reabsorption (urine normally is glucose-free) in the proximal tubules via two types of SGLT
    • A membrane protein that mediates glucose and sodium transport across apical cell membranes in the small intestine and kidneys.
    • Utilizes the energy provided by the sodium gradient across the cell membrane for active glucose transport.
    • SGLT1
      • Reabsorbs the remaining glucose (∼ 2%) as well as galactose in the PCT
      • One molecule of glucose is absorbed together with two molecules of sodium
    • SGLT2
      • Reabsorbs ∼ 98% of urinary glucose in the proximal convoluted tubule (PCT)
      • One molecule of glucose is absorbed together with one molecule of sodium.
  • Reabsorption also relies on a sodium concentration gradient via Na⁺/K⁺ ATPase.

“Only GLUT4 has a need 4 insulin.”

BRICK LIPS: Brain, RBCs, Intestine, Cornea, Kidney, Liver, Islet cells, Placenta, Spermatocytes (insulin-independent glucose uptake)

Specific insulin-independent glucose transporters: GLUT1 and GLUT3 for BBB (blood-brain barrier); GLUT2 transports in both directions; GLUT5 (five) is a fructose transporter.

Metabolism of glucose

• See “Breakdown and synthesis of glucose“ for:
  • Glucose degradation
    • Glycolysis
    • Hexose monophosphate shunt (pentose phosphate pathway)
  • Glucose synthesis: See “Gluconeogenesis.”
• See “Glycogen metabolism“ for glucose storage.
• See “Sources of ATP synthesis” for ATP synthesis pathways and caloric values.

Absorption of galactose

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

1. Lactose is cleaved in the small intestine by lactase.
2. Free galactose is absorbed by enterocytes via SGLT1.
3. Free galactose is transported into blood via GLUT2.
4. Galactose circulates to the liver for further metabolism.

Breakdown of galactose

1. Galactokinase activates galactose: galactose + ATP → galactose-1-P + ADP
2. Galactose-1-phosphate uridyltransferase: 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 in the enzyme galactose-1-phosphate uridyltransferase (classical galactosemia), galactose and lactose (galactose + glucose) have to be removed from their 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 breakdown reactions

Absorption of fructose

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

Breakdown of fructose (fructolysis)

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. Trioses are converted 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 (e.g., due to hereditary fructose intolerance), both fructose and sucrose (fructose + glucose) have to be removed from the diet.

Fructose synthesis

• Fructose can be produced from glucose via sorbitol (osmotically active sugar alcohol) without using ATP.
• In the body, fructose is the primary source of energy for spermatozoa.
• Enzymes
  • Aldose reductase
    • Reduces glucose to sorbitol: glucose + NADPH → sorbitol
    • Can convert galactose to galactitol (a sugar alcohol) when galactose levels in blood are high
  • Sorbitol dehydrogenase oxidates sorbitol to fructose: sorbitol + NAD⁺ → fructose
• Tissues that have both aldose reductase and sorbitol dehydrogenase (liver, ovaries, seminal vesicles) will not accumulate sorbitol.
• Tissues/cells 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.

No LOVE for sorbitol in the Liver, Ovaries, and seminal VEsicles.

• Maldigestion and malabsorption
  • Lactose intolerance
  • Fructose intolerance
  • Sucrose malabsorption (sucrase-isomaltase deficiency)
  • Sorbitol malabsorption
• Disorders of glucose metabolism
  • Diabetes mellitus type 1, diabetes mellitus type 2
  • Glycogen storage disorders (GSD)
• Disorders of galactose metabolism: galactosemia
• Disorders of fructose metabolism
  • Hereditary fructose intolerance (autosomal recessive defect of aldolase B)
  • Essential fructosuria (autosomal recessive defect of fructokinase)