Carbohydrate assimilation and it's applied with emphasis on SGLT and GLUT

receptors

The main source of energy in most of the Indian diets is carbohydrates which provide 50-80%* of

daily energy intake. About 80%* of this carbohydrate is the plant polysaccharide starch, and most of the

remainder consists of the disaccharides sucrose (table sugar) and lactose (milk sugar). Only small amounts

of monosaccharides (glucose, fructose) are usually present in the diet.

There are two different types of glucose polymers in starch, which is significant because they

require different enzymes to digest them fully. About 25% of starch consists of amylose, which is

comprised of simple, straight chain polymers of glucose linked by α-1,4-glycosidic bonds. The remainder

portion of starch consists of amylopectin, which is is similar to amylose; however, in addition to 1,4-

linkages there is a 1,6- linkage for every 20 to 30 glucose units.

Carbohydrate digestion begins in the mouth and continues through to the small intestine. Cellulose

and certain other complex polysaccharides found in vegetable matter, referred to as fibre, are not broken

down by the enzymes in the digestive tract and are partially metabolised by bacteria.

*(Nutrient requirements and recommended dietary allowances for Indians: A Report of the Expert Group of

the Indian Council of Medical Research 2009)

Digestion of Carbohydrates

Salivary and Pancreatic Amylase

Food gets mixed with saliva during mastication in the oral cavity and bolus is formed. Saliva

contains the digestive enzyme ptyalin (α-amylase), secreted mainly by the parotid glands. This enzyme

hydrolyses starch into the disaccharide maltose and other small polymers of glucose that contain three to

nine glucose molecules.

Digestion of carbohydrates by salivary α-amylase is of relatively limited importance, as the food

remains in the mouth only for a short time, so not more than 5 percent of all the starches are hydrolysed,

by the time the food is swallowed. However, the salivary amylase does assume an important role in

specific situations. For example, in infants, there is a developmental delay in the production of pancreatic

enzymes, and so the salivary enzyme assumes a proportionately greater role. Salivary amylase is also an

important backup in patients with pancreatic insufficiencies, such as in the setting of cystic fibrosis.

The optimum pH for the action of α-amylase is 5.6–6.9 and, therefore, it is inactivated in the

stomach by gastric juice, which has a pH as low as 1.0. However, it has been demonstrated that amylase

activity can be protected if its substrate occupies the active site of the enzyme. Thus starch digestion

sometimes continues in the body and fundus of the stomach for as long as 1 hour before the food becomes

mixed with the stomach secretions. On an average 30-40% of the starches can get hydrolysed, before food

and its accompanying saliva becomes completely mixed with the gastric secretions.

The gastric contents reach the small intestine where the alkaline content of the pancreatic and

biliary secretions results in a pH equal to 7.8. Pancreatic secretion, like saliva, contains a large quantity of

α-amylase (94% homologous to salivary amylase) which is almost identical in its function with the salivary

amylase but is several times more powerful. It has an optimum pH of about 7.1. Human salivary and

pancreatic amylases have optimum activities near neutral pH and are activated by chloride (Cl–).

α-Amylase is an endoenzyme that hydrolyses internal α-1,4 linkages. α-Amylase does not cleave

terminal α-1,4 linkages, α-1,6 linkages (i.e., branch points), or α-1,4 linkages that are immediately adjacent

to α-1,6 linkages. As a result, starch hydrolysis products are maltose, maltotriose, and α-limit dextrin.

Maltose is composed of two glucose molecules in the α-1,4 linkage, maltotriose consists of three glucose

molecules in the α-1,4 linkage, and α-dextrin has both α-1,6 and α-1,4 links. Because α-amylase has no

activity against terminal α-1,4 linkages, glucose is not a product of starch digestion. The intestine cannot

absorb these products of amylase digestion of starch, and thus further digestion is required to produce

substrates (i.e., monosaccharides) that the small intestine can absorb by specific transport mechanisms.

APPLIED PHYSIOLOGY Although the action of amylase is rapid, some sources of starch contain proteins and fibre components that may slow the action of this enzyme. This means that the rise in blood glucose that eventually follows the ingestion of starch will have differing kinetics depending on the food in which the starch is contained. Some nutritional supplement manufacturers have tried to take advantage of this by isolating so-called "starch blockers", which they claim can reduce the digestion of starch by inhibiting amylase activity and thereby are useful as aids to weight loss. However, this is unlikely to be an effective approach, given the marked excess of pancreatic enzymes and the fact that the starch blockers are proteins, and therefore are themselves get digested in gut. Further, any carbohydrate that escapes assimilation in the small intestine is rapidly broken down by bacterial hydrolases in the colon. Although this may carry the price of the generation of gas and bloating, it ultimately allows the caloric content of the starch to be reclaimed.

Disaccharidases

The disaccharidases are located in the brush border cells of the small intestine mucosa. They

hydrolyse the disaccharides produced from the action of salivary and pancreatic α-amylase on

polysaccharides. Also, they act on disaccharides that were introduced directly by the diet.

The human small intestine has four brush border oligosaccharidases: lactase, glucoamylase (most

often called maltase), sucrase and isomaltase (also known as α-dextrinase or debranching enzyme).

Sucrase and isomaltase occur together as a molecular complex, there activities are actually encoded in a

single polypeptide chain with two distinct active sites, and thus the complete protein is referred to as

sucrase-isomaltase.

Lactase has only one substrate; it breaks lactose into glucose and galactose. The other three

enzymes have more complicated substrate spectra. All cleave the terminal α-1,4 linkages of maltose,

maltotriose, and α-limit dextrins. In addition, each of these three enzymes has at least one other activity.

Maltase can also degrade the α-1,4 linkages in straight-chain oligosaccharides up to nine monomers in

length. The sucrose moiety of sucrase-isomaltase is required to split sucrose into glucose and fructose. The

isomaltase moiety of sucrose-isomaltase is the only enzyme that can split the branching α-1,6 linkages of

α-limit dextrins. Thus the only products of sugar digestion are glucose (80%), galactose (10%), and fructose

(10%).

They are all water soluble and are absorbed immediately into the portal blood. The activities of the

hydrolysis reactions of sucrase-isomaltase and maltase are considerably greater than the rates at which the

monosaccharides are absorbed. Thus, uptake, not hydrolysis, is the rate-limiting step. In contrast, lactase

activity is considerably less than that of the other oligosaccharidases and is rate limiting for overall lactose

digestion-absorption.

The oligosaccharidases have a varying spatial distribution throughout the small intestine. In general,

peak oligosaccharidase distribution and activity occur in the proximal jejunum (i.e., at the ligament of

CARBOHYDRATE DIGESTION

Starch Sucrose Lactose

α-amylase sucrase lactase

α-dextrins Maltose Maltotriose Glucose Fructose Glucose Galactose

Maltase Sucrase

α-dextrinase

Glucose

Treitz). Considerably less activity is noted in the duodenum and distal ileum, and none is reported in the

large intestine. The distribution of oligosaccharidase activity parallels that of active glucose transport.

These oligosaccharidases are affected by developmental and dietary factors in different ways. In

many non-white ethnic groups, as well as in almost all other mammals, lactase activity markedly decreases

after weaning in the postnatal period. The regulation of this decreased lactase activity is genetically

determined. The other oligosaccharidases do not decrease in the postnatal period. In addition, long-term

feeding of sucrose upregulates sucrase activity. In contrast, sucrase activity is greatly reduced much more

by fasting than is lactase activity. In general, lactase activity is both more susceptible to enterocyte injury

(e.g., following viral enteritis) and is slower to recover from damage than is other oligosaccharidase

activity. Thus, reduced lactase activity (as a consequence of both genetic regulation and environmental

effects) has substantial clinical significance in that lactose ingestion may result in a range of symptoms in

affected individuals.

APPLIED PHYSIOLOGY: LACTOSE INTOLERANCE

Description of case: A 17 year old male complains of diarrhea, bloating, and gas when he drinks milk.

The physician suspects that the boy has lactose intolerance and tells him to avoid consumption of milk

products for 2 weeks and note the presence of diarrhea or excessive gas. Boy felt relieved during this

period.

Explanation of case: Patient has lactase deficiency (a partial or total absence of the intestinal brush-

border enzyme lactase), hence lactose cannot be digested to the absorbable monosaccharide forms

and intact lactose remains in the intestinal lumen. There, it behaves as an osmotically active solute: it

retains water isosmotically, and it produces osmotic diarrhea. Excess gas is caused by fermentation of

the undigested, unabsorbed lactose to methane and hydrogen gas.

Treatment: Apparently, this defect is specific only for lactase; the other brush-border enzymes are

normal in this patent. Therefore, only lactose must be eliminated from his diet by having him avoid milk

products. Alternatively, lactase tablets can be ingested along with milk to ensure adequate digestion of

lactose to monosaccharides.

Dietary fibre, although not digestible, benefits gastrointestinal function

Humans lack enzymes that hydrolyse β-1,4 linkages. Thus, humans are incapable of digesting cellulose,

a major constituent of vegetables that consists of glucose residues in β-1,4. Dietary fibre, also known as

roughage, consists of non-starch polysaccharides, such as cellulose, waxes, and pectin. Although it is not

digestible, consuming dietary fibre offers several advantages to gastrointestinal function. It increases

bulk, softens stools, and shortens transit time in the intestinal tract, all of which facilitates motility and

prevents constipation. For example, many fruits and vegetables are rich in fibre, and their frequent

ingestion greatly decreases intestinal transit time. Dietary fibre has also been shown to reduce the

incidence of colon cancer by shortening gastrointestinal transit time. A shortened transit time inhibits

the formation of carcinogenic bile acids, such as lithocholic acid, as well as reducing the contact time of

ingested carcinogens to act on tissue. Another benefit of dietary fibre is the lowering of blood

cholesterol. This is accomplished by dietary fibre binding with bile acids, which are formed from

cholesterol. Thus, fibre consumption lowers blood cholesterol by promoting excretion.

Absorption of Carbohydrates

The three monosaccharide products of carbohydrate digestion, i.e., glucose, galactose, and fructose

are absorbed by the small intestine in a two-step process involving their uptake across the apical

membrane into the epithelial cell and their coordinated exit across the basolateral membrane.

The sodium glucose transporter 1 (SGLT1) is the membrane protein responsible for glucose and

galactose uptake at the apical membrane. Fructose uptake across the apical membrane is mediated by

GLUT5 (glucose transporter 5). The exit of all three monosaccharides across the basolateral membrane

uses a facilitated sugar transporter (GLUT2).

Glucose uptake across the apical membrane through SGLT 1, occurs against the glucose

concentration gradient and is energised by the electrochemical Na+ gradient, which, in turn, is maintained

by the extrusion of Na+ across the basolateral membrane by the Na+-K+ pump. The cotransport of sodium

and glucose forms the physiological basis of the treatment of diarrhoea, i.e., administration of oral

rehydration solutions containing both NaCl and glucose.

The affinity of SGLT1 for glucose is markedly reduced in the absence of Na+. The varied affinity of

SGLT1 for different monosaccharides reflects its preference for specific molecular configurations. SGLT1

has two structural requirements for monosaccharides: (1) a hexose in a D-configuration and (2) a hexose

that can form a six-membered pyranose ring. SGLT1 does not absorb L-glucose, which has the wrong

stereochemistry, and it does not absorb D-fructose, which forms a five-membered ring.

The evolutionary significance of partly luminal and partly surface digestion of carbohydrates is not

understood. It may be that the absence of monosaccharides in the intestinal lumen makes bacterial

proliferation there more difficult. There may be a kinetic advantage to diffusion of oligosaccharides rather

than monosaccharides through the unstirred water layer coating the mucosa. Oligosaccharides are then

hydrolysed at apical membrane promoting there transport

Glucose-Galactose Malabsorption

In patients with glucose- galactose malabsorption

(or monosaccharide malabsorption) diarrhea

occurs when they ingest dietary sugars that are

normally absorbed by SGLT1. Defect in Na+

coupled monosaccharide absorption results in

diarrhea due to the osmotic effects of unabsorbed

monosaccharides. Eliminating the

monosaccharides (glucose and galactose), as well

as the disaccharide lactose (i.e., glucose +

galactose), from the diet eliminates the diarrhea.

Fructose, which crosses the apical membrane

through GLUT5, does not induce diarrhea.

Patients with glucose-galactose malabsorption do

not have glycosuria (i.e., glucose in the urine),

because glucose reabsorption by the proximal

tubule normally occurs through both SGLT1 and

SGLT2

Glucose Transport Pathways

Because the lipid bilayer of the eukaryotic plasma membrane is impermeable to hydrophilic

molecules, glucose is transported across the plasma membrane by membrane-associated carrier proteins,

glucose transporters. There are 2 different types of transporter proteins, which mediate the transfer of

glucose and other sugars through the lipid bilayer: Sodium-dependent glucose cotransporters (SGLT) and

Facilitative glucose transporters (GLUT).

The SGLT family

There are twelve members of the human SGLT family in the human genome (gene name SLC5A)1. The

SGLT family comprises Na+-dependent glucose co-transporters (SGLT1 and SGLT2), the glucose sensor

SGLT32, the widely distributed inositol and multivitamin transporters SGLT4 and SGLT6, and the thyroid

iodide transporter SGLT53.

1. Wright EM, Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 2001; 280:F10-F18

2. Berry GT, Mallee JJ, Kwon HM, et al. The human osmoregulatory Na+/myo-inositol cotransporter gene (SLC5A3): molecular cloning

and localization to chromosome 21. Genomics. 1995;25: 507-513.

3. Balamurugan K, Ortiz A, Said AM. Biotin uptake by human intestinal and liver epithelial cells: role of the SMVT system. Am J Physiol

Gastrointest Liver Physiol. 2003;285: G73-G77.

SGLTs are secondary active cell membrane symporters that transfer sodium down its concentration

gradient, usually into the cell, in conjunction with the inward transfer of specific hexose sugars or some

other molecules against their concentration gradient. An electrochemical gradient that allows sodium to

enter the cell is generated by the active transport of sodium out of the cell at another location within the

cell membrane hence the term secondary active.

Genes, substrates, and main sites for expression of sodium-glucose cotransporters

SGLT NAME SUBSTRATE APPARENT AFFINITY FOR GLUCOSE K0.5mM

DISTRIBUTION

SGLT1 (SLC5A1) Glucose, galactose 0.4 Intestine, trachea,

kidney, heart, brain,

testes, prostate

SGLT2 (SLC5A2) Glucose 2 Kidney, brain, liver,

thyroid, muscle, heart

SGLT4 (SLC5A9) Glucose, mannose 2 Intestine, kidney, liver,

brain, lung, trachea,

pancreas, uterus

SGLT5 (SLC5A10) Glucose Not determined Kidney’s cortex

SGLT6 (SLC5A11) Myo-inositol, glucose 35 Brain, kidney, intestine

SMIT1 (SLC5A3) Myo-inositol, glucose >35 Brain, heart, kidney, lung

Source: Abd A Tahrani et al, SGLT inhibitors in management of diabetes. www.thelancet.com/diabetes-endocrinology Published online August 13, 2013. http://dx.doi.org/10.1016/S2213-8587(13)70050-0

The main SGLTs are SGLT1, which is responsible for glucose absorption from the small intestine, and

SGLT2, which accounts for reabsorption of most of the glucose filtered by the kidney. SGLT1 is a high-

affinity (K0.5 of about 0∙4 mM for glucose and about 3∙0 mM for sodium), low-capacity glucose transporter

with a 2:1 coupling ratio for sodium and glucose. Conversely, SGLT2 is a low-affinity (K0.5 of about 2∙0 mM

for glucose and about 0∙1 mM for sodium), high-capacity glucose transporter with a 1:1 coupling for

sodium and glucose4,5.

4. Hediger MA, Rhoads DB. Molecular physiology of sodium-glucose cotransporters. Physiol Rev 1994; 74: 993–1026.

5. Wright EM, Loo DDF, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev 2011; 91: 733–94.

SGLT3 is expressed in human skeletal muscle and small intestine. Immunofluorescence microscopy

indicated that in the small intestine the protein was expressed in cholinergic neurons in the submucosal

and myenteric plexuses, but not in enterocytes. Functional studies have shown that human SGLT3 is

incapable of sugar transport, leading to the conclusion that SGLT3 is not a Na+/glucose cotransporter but

instead a glucose sensor in the plasma membrane of cholinergic neurons, skeletal muscle, and other

tissues.6

6. Diez-Sampedro A et al., A glucose sensor hiding in a family of transporters. Proc Natl Acad Sci U S A. 2003; 100:11753-8

The GLUT family

The human genome contains 14 members of the GLUT family, which can be divided into 3 subfamilies

according to sequence similarities and characteristic elements7.

Dendrogram of the family of human sugar transporter facilitators. Numbers at the branches of the tree

indicate percentage of identity7

7. Scheepers A, Joost HG, Schürmann A. The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant

function. J Parenter Enteral Nutr 28: 364–371, 2004

Among 14 GLUT genes in the human genome, 11 have been shown to catalyse sugar transport [7,8]. The

individual isotypes exhibit different substrate specificity, kinetic characteristics, and expression profiles,

thereby allowing a tissue-specific adaptation of glucose uptake through regulation of their gene

expression[8,9].

8. Zhao F-Q, Keating AF, Functional properties and genomics of glucose transporters. Current Genomics, 2007; 113-128

9. Bell GI et al., Molecular biology of mammalian glucose transporters. Diabetes Care 1990; 13:198-208

CLASS I SUGAR TRANSPORT FACILITATORS:

The class I facilitative glucose transporters comprise the thoroughly characterised isoforms GLUT1

to 4 and the recently identified GLUT14.

GLUT1 is expressed in most tissues10, though its highest expression levels are in erythrocytes and

endothelial cells of the brain. It is responsible for the basic supply of glucose to the cells. GLUT1 is a high-

affinity glucose transporter with a Km for glucose of around 3-7 mM11. The Km value for GLUT proteins is

the concentration of blood glucose at which transport into the cell takes place at half its maximum rate. A

Km of 3-7 mM is below or equal to the average blood glucose concentration of 5-7 mM, enabling tissues to

take up glucose at a significant rate, regardless of the amount present in the blood.

GLUT2 is a high-capacity, low-affinity glucose transporter with a Km, around 15-20 mM.12 Its

predominant expression is in pancreatic β-cells, liver, kidney, and small intestine (basolateral membrane).

In all these tissues, the uptake of glucose is not dependent on the number and activity of the glucose

transporters, but on the blood glucose concentration13 i.e., the amount of incoming glucose in these

tissues is proportional to the amount of glucose in the blood. The presence of GLUT2 ensures that glucose

is taken up rapidly by the liver only when it is abundant and enables pancreatic β cells to monitor blood

glucose levels directly, and regulate insulin secretion. The presence of GLUT2 in the small intestine and the

kidney reflects its role in the transport of glucose across the serosal surface of the epithelial cells which line

the intestine and the nephron, after glucose absorption across their luminal surface via the sodium-linked

glucose transporter SLGT1. Thus, transport activity of GLUT2 cannot be saturated by physiologic blood

glucose concentrations. In addition to glucose, GLUT2 is able to transport fructose14, with higher affinity,

glucosamine15.

GLUT3 is a high-affinity glucose transporter with a Km for glucose of around 2 mM, much less than

the average blood glucose concentration of 5-7 mM, enabling most tissues to take up glucose at a constant

rate, regardless of the amount present in the blood . Its predominant expression is in tissues with a high

glucose requirement (e.g., brain)16.

GLUT4 is a high-affinity glucose transporter, with a Km around 5 mM. It is expressed in insulin-

sensitive tissues (heart, skeletal muscle, adipose tissue)17. The level of this transporter on the surface of

these cells is rapidly regulated by insulin, which stimulates the translocation of GLUT4 from intracellular

membranes to the plasma membrane, resulting in an immediate 10- to 20-fold increase in glucose

transport18-20. In skeletal muscle translocation of GLUT-4 can be induced by muscle contraction and

hypoxia21,22.

GLUT14 is exclusively expressed in testis.

GLUT1, GLUT3, and GLUT4 have been described to also transport dehydroascorbic acid (DHAA). DHAA a

stable oxidation product of ascorbate, which is transported by specific sodium-ascorbic acid cotransporters

and mainly stored in skeletal muscle and brain.

10. Mueckler M, Caruso C, Baldwin SA, et al. Sequence and structure of a human glucose transporter. Science. 1985;229:941-945.

11. Burant CF, Bell GI, Mammalian facilitative glucose transporters: evidence for similar substrate recognition sites in functionally

monomeric proteins. Biochemistry 1992; 31:10414-20.

12. Fukumoto H, Seino S, Imura H, et al. Sequence, tissue distribution, and chromosomal localization of mRNA encoding a human glucose

transporter-like protein. Proc Natl Acad Sci USA.1988; 85:5434-5438

13. Gould GW, Holman GD. The glucose transporter family: structure, function and tissue-specific expression. Biochem J. 1993; 295:329-

341

14. Wood S, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr. 2003; 89:3-9.

15. Uldry M, Ibberson M, Hosokawa M, Thorens B. GLUT2 is a high affinity glucosamine transporter. FEBS Lett. 2002;524:199-203

16. Kayano T, Fukumoto H, Eddy RL, et al. Evidence for a family of human glucose transporter-like proteins: sequence and gene

localization of a protein expressed in fetal skeletal muscle and other tissues. J Biol Chem. 1988;263:15245-15248.

17. Fukumoto H, Kayano T, Buse JB, et al. Cloning and characterization of the major insulin-responsive glucose transporter

18. Simpson LA, Cushman SW. Hormonal regulation of mammalian glucose transport. Annu Rev Biochem. 1986;55:1059-1089

19. Sheperd PR, Kahn BB. Glucose transporters and insulin action implications for insulin resistance and diabetes mellitus. N Engl J Med.

1999;341:248-257.

20. Bryant NJ, Govers R, James DE. Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol. 2002;3;267-277.

21. Cartee GD, Douen AG, Ramlal T, Klip A, Holloszi JO. Stimulation of glucose transport in skeletal muscle by hypoxia. J Appl Physiol.

1991;70:1593-1600.

22. Lund S, Holman GD, Schmitz O, Pederson O. Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle

through a mechanism distinct from that of insulin, Proc Natl Acad Sci USA. 1995;92:5817-5821

CLASS II SUGAR TRANSPORT FACILITATORS:

The class II glucose transporters include the fructose-specific transporters GLUT5 and 3 related

proteins, GLUT7, GLUT9, and GLUT11.

GLUT5 mRNA is predominantly expressed in small intestine, testis, and kidney. GLUT5 exhibits no

glucose transport activity and is responsible for the uptake of fructose23.

GLUT7 is a high-affinity transporter for glucose and fructose. GLUT7 mRNA can be detected in small

intestine, colon, testis, and prostate; within the small intestine, GLUT7 is predominately expressed in the

enterocytes brush border membrane24.

GLUT9 exhibits highest expression levels in kidney and liver; lower mRNA levels were detected in

small intestine, placenta, lung, and leukocytes25.

GLUT11 is suggested to be a fructose transporter with low affinity to glucose. GLUT11 is expressed

predominantly in pancreas, kidney, and placenta and also moderate expression in heart and skeletal

muscle.26

23. Kayano T, Burant CF, Fukumoto H, et al. Human facilitative glucose transporters: isolation, functional characterization, and gene

localization of cDNAs encoding an isoform (GLUT5) expressed in small intestine, kidney, muscle, and adipose tissue and an unusual

glucose transporter pseudogene-like sequence (GLUT6). J Biol Chem. 1990;265:13276-13282.

24. Li Q, Manolescu A, Ritzel M, et al. Cloning and functional characterization of the human GLUT7 isoform (SLC2A7) from the small

intestine. Am J Physiol Gastrointest Liver Physiol, 2004;284:G236-G242.

25. Phay JE, Hussain HB, Moley JF. Strategy for identification of novel glucose transporter family members by using internet based

genomic databases. Surgery. 2000;128:946-951.

26. Sasaki T, Minoshima S, Shiohama A, et al. Molecular cloning of a member of the facilitative glucose transporter gene family GLUT11

(SLC2A11) and identification of transcription variants. Biochem Biophys Res Commun. 2001;289:1218-1224

CLASS III SUGAR TRANSPORT FACILITATORS:

Class III comprises of GLUT6, GLUT8, GLUT10, GLUT12, and HMIT.

GLUT6 is a low-affinity glucose transporter, expressed predominantly in brain, spleen, and

peripheral leukocytes27.

GLUT8 is a high-affinity glucose transporter, expressed predominantly expressed in testis, and

lower amounts of GLUT8 mRNA were detected in most other tissues, including insulin-sensitive tissues like

heart and skeletal muscle28. Moreover, GLUT8 was reported to mediate insulin-stimulated glucose uptake

in preimplantation embryos29. In testis, the protein was associated with the acrosomal region of mature

spermatozoa30. In addition, GLUT8 may play a role in glucose uptake of adipocytes; its expression was

found to be regulated by the metabolism of these cells31.

GLUT10 is predominantly expressed in the liver and pancreas32.

GLUT12 is predominantly expressed in heart and prostate33. GLUT12 seems to sustain the increased

glucose consumption in prostate carcinoma and breast cancer34.

The H+-coupled myo-inositol transporter HMIT64 is expressed predominantly in the brain. It specifically

transports myo-inositol and related stereoisomers but lacks any sugar transport activity35.

27. Doege H, Bocianski A, Joost H-G, Schtirmann A. Activity and genomic organization of human glucose transporter 9 (GLUT9), a novel

member of the family of sugar transport facilitators predominantly expressed in brain and leucocytes. Biochem J.2000;350:771-776.

28. Doege H, Schtirmann A, Bahrenberg G, Brauers A, Joost H-G. GLUT8, a novel member of the sugar transport facilitator family with

glucose transport activity. J Biol Chem. 2000;275:16275-16280,

29. Carayannopoulos MO, Chi MM, Cui Y, et al. GLUT8 is a glucose transsporter responsible for insulin-stimulated glucose uptake in the

blastocyst. Proc Natl Acad Sci USA. 2000;97:7313-7318.

30. Schurmann A, Axer H, Scheepers A, Doege H, Joost H-G. The glucose transport facilitator GLUT8 is predominantly associated with the

acrosomal region of mature spermatozoa. Cell Tissue Res;2002;307:237-242.

31. Scheepers A, Doege H, Joost H-G, Schurmann A. Mouse GLUT8: genomic organization and regulation of expression in 3T3-L1

adipocytes by glucose. Biochem Biophys Res Commun. 2001;288:969-74.

32. MrVie-Wylie AJ, Lamson DR, Chen YT. Molecular cloning of a novel member of the GLUT family of transporters, SLC2A10 (GLUT10),

localized on chromosome 20ql3.1: a candidate gene for NIDDM susceptibility. Genomics. 2001;72:113-117.

33. Macheda ML, Kelly DJ, Best JD, Rogers S. Expression during rat fetal development of GLUT12-a member of the class III hexose

transporter family. Anat Embryol. 2002;205:441-452.

34. Chandler JD, Williams ED, Slavin JL, Best JD, Rogers S. Expression and localization of GLUT1 and GLUT12 in prostate carcinoma.

Cancer. 2003;97:2035-2042

35. Uldry M, Ibberson M, Horisberger J-D, Chatton J-Y, Riederer BM, Thorens B. Identification of a mammalian H+ myo-inositol symporter

expressed predominantly in the brain. EMBO J. 2001;20:4467-4477

Glucose Transporters as Components of the Glucosensing Machinery

A constant monitoring of blood glucose concentrations by specific glucosensing mechanisms is

required for the maintenance of the whole-body glucose homoeostasis. The best-described glucose

detection system is that of pancreatic beta cells, which control the insulin secretion. This sensor machinery

includes glucose transporters (GLUT2), the enzyme glucokinase, and the ATP-sensitive K+ channel. When

the extracellular glucose concentration increases, more glucose enters the beta cell via the low-affinity

glucose transporter GLUT2 and is phosphorylated by glucokinase. Glycolytic and oxidative metabolism of

glucose raises the ATP-to-ADP ratio, causing ATP to bind to the ATP-sensitive K+ channel complex. This

inactivates the channel and leads to membrane depolarization, influx of calcium, and insulin secretion.

Intracellular mechanisms through which glucose stimulates insulin secretion. Glucose is metabolised within the β- cell to

generate ATP, which closes ATP - sensitive potassium channels in the cell membrane. This prevents potassium ions from leaving

the cell, causing membrane depolarization, which in turn opens voltage - gated calcium channels in the membrane and allows

calcium ions to enter the cell. The increase in cytosolic calcium initiates granule exocytosis.