How the body takes up sugars: transporters, the gut and the liver

Sugars released by digestion reach the blood and the cells only through protein transporters, because a water-soluble sugar cannot cross the oily membrane around a cell on its own. Two families of transporters do that work, and their members sit in different tissues. Glucose and fructose cross the lining of the small intestine by different routes, and the liver takes up much of the sugar arriving from the gut before it reaches the rest of the body.

Sugars and the cell membrane

Glucose is the sugar green plants make in photosynthesis, which makes it one of the most important fuels in nature. ¹ It is also the main sugar in the blood and the primary fuel of many cells, red blood cells and brain cells among them. ¹

Glucose, galactose and fructose are hexoses, six-carbon sugars with the same formula, C6H12O6. ² Each arranges its hydrogen and hydroxyl groups differently, which gives it slightly different chemical properties and is why the body handles each hexose differently. ²

Hexoses are polar molecules: neutral overall, but with their charge distributed lopsidedly, negative near the strongly electronegative oxygen atoms and positive near the hydrogens bound to them. ² Because of this polarity, hexoses crystallise well: the positive areas of one molecule are attracted to the negative areas of others, so the molecules pack together in an orderly crystal. ² Like other strongly polar molecules, glucose is highly soluble in water. ² Water molecules are strongly polar too, so glucose molecules are more attracted to them than to one another, and glucose crystals dissolve readily in water, at least until the solution is saturated. ^{2, 3} Glucose therefore dissolves easily in plasma, the watery fraction of blood, and is easily carried in the bloodstream. ^{3, 1}

Because simple sugars such as glucose, fructose and galactose are highly polar, they cannot dissolve in the oily membrane that surrounds each cell. ^{4, 1} A sugar molecule therefore enters or leaves a cell only through a gap made by a protein called a transporter. ^{1, 5}

Hexose transporters

Humans have two families of hexose transporters. ⁶ The 14 facilitative hexose transporters, GLUT1 to GLUT14, allow passive transport: a sugar flows downhill with its concentration or voltage gradient until its concentration is the same on both sides of the membrane. ^{1, 6} The at least two sodium-glucose linked transporters, SGLT1 and SGLT2, are symporters, each carrying sodium and a sugar across the membrane in the same direction at once. ^{1, 6} That co-transport is powered by the electrochemical gradient of sodium that sodium pumps create, and the pumps in turn run on ATP. ^{1, 6} The human genome encodes 11 members of the sodium/glucose co-transporter family, and some of them are multifunctional membrane transporters whose functions are still poorly understood. ⁶

The various hexose transporters play different roles in how the body manages glucose transport and controls blood glucose levels. ⁶ Some important hexose transporters, with what each carries and where it is found: ⁶

• GLUT1 carries glucose, in all cells but especially red blood cells and the blood–brain barrier.
• GLUT2 carries glucose, galactose and glucosamine, in the liver, intestine, kidney and pancreatic islet beta cells, and in the neurons, astrocytes and tanycytes of the central nervous system.
• GLUT3 carries glucose, in nerves, brain cells, embryos, white blood cells and some carcinoma cell lines.
• GLUT4 carries glucose, in heart, muscle and fat cells.
• GLUT5 carries fructose, in the intestine, testis, kidneys, skeletal muscle, fat tissue and brain.
• SGLT1 carries glucose or galactose with sodium, in enterocytes, kidneys, the parotid and submandibular glands and the heart.
• SGLT2 carries glucose with sodium, in the kidney.

^{6, 7}

Carbohydrate digestion

Some dietary carbohydrate is already simple sugar, monosaccharides such as glucose or fructose. ⁸ The rest is complex, disaccharides and polysaccharides such as lactose, sucrose and starch, and enzymes must break it into monosaccharides before it can be absorbed. ⁸ Some of these enzymes are in saliva or pancreatic secretions, and others are anchored on the surface of the enterocytes, the absorptive cells lining the small intestine. ⁸

Digesting sucrose, table sugar, yields a 50:50 mix of glucose and fructose. ⁹ Digesting starch yields pure glucose, so a high-carbohydrate meal can deliver a large load of glucose to the body. ⁹

Glucose absorption in the small intestine

The small intestine is lined with a single layer of enterocytes held together by tight junctions, so absorbed sugar has to pass through the cells rather than between them. ^{10, 4} A system of three transporters is involved in absorbing glucose from the intestine: a sodium pump, SGLT1 and GLUT2. ⁷

The sodium pumps sit on the basolateral membrane, the side of the enterocyte facing the bloodstream. ^{11, 7} They are Na+/K+-ATPase antiporters, which carry two substances at once in opposite directions. ^{11, 7} Using energy from ATP, each pump expels three sodium ions from the enterocyte while pulling two potassium ions in, both against their concentration gradients. ^{11, 7} The pumps keep the sodium concentration inside the enterocyte lower than in the intestinal lumen, and that intracellular deficit powers the co-transport of sodium ions and glucose into the cell. ^{11, 7}

SGLT1 sits on the apical membrane, the side facing the food in the lumen. ¹² When it binds a sodium ion, it changes shape to form a pocket that can hold a glucose or galactose molecule. ¹² When the sugar enters the pocket, the transporter changes shape again and carries both across the membrane to face the inside of the cell. ¹² It releases the sodium ion inside the cell, which triggers release of the sugar, and then flips back so that the cycle can repeat. ¹²

Bringing glucose into the enterocyte lets its glucose concentration exceed that in the blood, so glucose can diffuse passively out into the bloodstream through GLUT2 on the basolateral surface. ^{13, 7} Once through the lining of the intestine, sugars can diffuse into the blood flowing through its small blood vessels. ⁴

Fructose absorption

Fructose enters the enterocyte through GLUT5 on the apical membrane, passively, because its concentration is higher in the intestine than in the blood. ^{14, 7} The enterocytes convert much of it to glucose or other substances. ¹⁴ When they take in more than they can metabolise, the excess can pass into the blood through GLUT2 on the basolateral side. ^{14, 7}

Fructose uptake from food is limited by the number of GLUT5 transporters. ¹⁴ People with relatively few, for genetic reasons or because the lining of the intestine is damaged, have a limited ability to absorb fructose. ¹⁴ If they eat a lot of fructose, whether from fruit, table sugar or high-fructose corn syrup, they may suffer from fructose malabsorption, with bloating, flatulence and watery diarrhoea, similar to those of lactose intolerance. ¹⁴

Sugar uptake by the liver

Blood from the gastrointestinal tract travels by the hepatic portal vein to the liver, where glucose and fructose can flow into the liver cells through GLUT2. ¹⁵ Liver cells can convert glucose to a starch called glycogen. ¹⁵ Most of the incoming fructose is converted to glucose, much of which is then used to make glycogen. ¹⁵ About a quarter of the fructose becomes lactate, which various cells throughout the body can use as fuel, and a small fraction becomes triglyceride, a fat, most of which is released into the blood. ¹⁵ As the liver converts glucose and fructose into these substances, both can continue to flow passively into the liver cells through GLUT2, until their levels are the same on both sides of the cell membrane. ¹⁵ Through this process the liver usually takes up practically all the fructose and galactose and much of the glucose arriving by the hepatic portal vein, before the blood rejoins the systemic circulation. ^{15, 1, 4}

When a person is fasting, the liver can release glucose to make it available to the rest of the body. ¹⁵ It can raise or lower blood sugar as needed because hormones from the pancreas control its actions. ^{15, 1} Insulin, made by the beta cells of the pancreas, encourages the liver to convert glucose to glycogen, which lowers the glucose concentration inside the liver cells, so more glucose can diffuse passively in through GLUT2. ¹⁵ Glucagon, made by the alpha cells of the pancreas, stimulates the liver cells to convert glycogen back to glucose and to make glucose from non-carbohydrates, which raises that concentration, so glucose can flow passively out through the same transporters. ¹⁵ The liver plays an important role in keeping blood sugar from rising too high after a meal, and it keeps blood sugar from dropping too low when a person is fasting or eating a low-carbohydrate diet. ⁴ It can perform this role because of signals from the pancreas and other endocrine glands. ⁴

Insulin and glucose entry into cells

Many people believe insulin is needed for glucose to enter cells, but if it were, people with severe insulin deficiency, as in untreated type 1 diabetes, would not be able to absorb glucose from their food. ¹⁶ Only one glucose transporter, GLUT4, on fat, heart and muscle cells, is associated with insulin receptors and affected by insulin signalling. ^{16, 1, 6}