HUN3224 Ch. 3 Carbohydrate Digestion & Absorption

Why is the *rate of FRUCTOSE absorption* by enterocytes *much SLOWER* vs the rate of glucose & galactose absorption?

b/c unlike glucose/galactose absorption, fructose uptake by enterocytes is a *FACILITATED DIFFUSION* process that *can proceed only down a conc. gradient* (vs active transport powered by ATP for glu/gal)

*Metabolism* of *fructose* & *galactose* in the *LIVER* (following uptake by hepatocytes)

both *converted ==> GLUCOSE derivatives*, then share *same fate as glucose*

Lactase

brush border disaccharidase that degrades *lactose ==> glucose + galactose*

Maltase

brush border disaccharidase that degrades *maltose ==> glucose + glucose*

Sucrase

brush border disaccharidase that degrades *sucrose ==> glucose + fructose*

*FACILITATED diffusion* (i.e. facilitated transport)

diffusion of a molecule across a semi-permeable membrane that *requires a CARRIER PROTEIN* (integral membrane protein that functions as a transporter) but still *no energy*

*PASSIVE diffusion*

diffusion of a solute through a membrane that *does NOT require energy*, but is driven/limited by a *concentration gradient*: small molecules & solutes will flow from areas of *HIGHER conc.==> LOWER conc.* until equilibrium is reached

Carb digestion in the *SI*

digestion of carbs (temporarily inhibited in the stomach) continues in the small intestine w/ *pancreatic secretions* & *BB enzyme* action

Trehalase

disaccharidase that degrades a(1-1) bonds in *trehalose ==> glucose + glucose*

*Salivary amylase*

enzyme produced by salivary glands to *begin carb. digestion in the mouth*; breaks *a(1-4)* bonds i.e. those in *amylose* & other a(1-4) polysaccharide linkages -action *continues in the stomach* *until* penetration of the food bolus by *HCl* lowers pH to a level that sufficiently *inactivates the enzyme* -canNOT digest a(1-6) bonds in amylopectin or b(1-4) bonds in lactose/cellulose

*Pancreatic a-amylase*

enzyme secreted by the pancreas into the small intestine that breaks a(1-4) bonds in *amylose & amylopectin* -same function as salivary amylase, but DIFF. LOCATIONS; breaks *long-chain starches (polysacch.) ==> shorter oligosaccharides + disaccharides*`

*GLUTs*

family of *protein carriers (glucose transporters)* involved in the *transport of glucose across the plasma membrane* of cells; 14 highly-specific GLUT isoforms have been identified, each w/ a distinct tissue distribution & biochemical properties

GLUT*1*

glucose absorption into *RBCs* & placenta

Where in the GIT does *CHO (polysaccharide) digestion BEGIN*?

in the *MOUTH*--with salivary amylase (digests amylose in starch)

*ACTIVE transport*

like facilitated diffusion, this transport mechanism *requires a carrier protein*, however it *also requires ENERGY* (ATP, unlike F.D.) b/c pumping *AGAINST a concentration gradient* (from low conc. to high conc.)

What is the major function of the liver, skeletal muscle, & adipose tissue (which collectively account for the majority of tissues in the body)?

maintenance of blood glucose levels

Summary of CHO digestion:

nearly all dietary starches/disaccharides are hydrolyzed completely by specific glycosidases into their constituent monosaccharide units, which together w/ small amounts of remaining disaccharides can then be absorbed by the intestinal mucosal cells

The binding of insulin to specific I-receptors on the cell membranes of skeletal muscle, adipose tissue, & cardiac muscle cells requires the activation of

phosphatidylinositol-3-kinase (PI3-kinase)

*SGLT1*

sodium-glucose transporter 1, responsible for uptake of *glucose & galactose* from the lumen of the SI into enterocytes (i.e. at *apical membrane of enterocytes*, powered by Na+/K+-ATPase active transport)

*GLUT5* (intestinal absorption)

specific transporter for *FRUCTOSE* located at the *apical membrane of enterocytes* for fructose transport into cells of intestinal mucosa; *high affinity for fructose* & is not influenced by the presence of glucose -independent of active Na+-ATPase-dependent transport of glucose by SGLT1 (i.e. is a *Na+-independent tranpsorter*)

Carb. digestion in the *stomach*

stomach serves as a *holding tank* for carbs where *digestion is temporarily halted* by the *inactivation* of *salivary amylase* by *HCl* (secreted by parietal cells, denatures proteins incl. enzymes like salivary amylase)

GLUT*3*

supplies glucose to the *brain*/neurons

GLUT*6*

supplies glucose to the *spleen* & leukocytes (WBCs), *brain*

Insulin

the *ANABOLIC hormone* secreted by the islets (endocrine, beta cells) of the pancreas that is central in *regulating BG levels* during periods of *feeding/fasting* -involved in *glucose, lipid, & amino acid/protein metabolism*

What is the *major site of metabolism* of *galactose* & *fructose* in the body?

the *LIVER*: galactose & fructose are readily *taken up* by the liver via specific hepatocyte receptors (GLUT2, 9 & 10) via *facilitated transport* (no ATP required) & are *subsequently metabolized*

*Alpha-dextrinase* (*isomaltase*, sucrase-isomaltase, dextrinase)

the ONLY intestinal enzyme that will hydrolyze *a(1-6) bonds*, which is attached to the BB membrane in the small intestine -contains *2 active sites*, one (sucrase) for *a(1-4)* linkages & other (isomaltase) for *BOTH a(1-4) & a(1-6)* linkages -*degrades limit dextrins* & other partially-digested poly-/oligosaccharides ==> disaccharides

GLUT*9/10*

uptake of glucose by *hepatocytes (LIVER)*, also proximal kidney tubules & placenta

Describe the anatomic advantage of the SI wall that allows for highly efficient carb. absorption of almost all monosaccharides by end of the jejunum:

villi-microvilli structure of the intestinal wall creates an enormous surface area that is accessible to intestinal contents to facilitate absorption, giving it a huge absorptive capacity for monosaccharide carb. units

T/F: *Free monosaccharides* are present in the diet in *significant amt.'s*.

*FALSE*--exc. *some free Glu & Fru* present in honey, some fruits, & carbs added to processed foods i.e. HFCS

Aside from certain absorptive cells (i.e. epithelial cells of *SI & renal tubule*, *Na+/K+-ATPase symport* system w/ *SGLT1*), glucose is admitted to nearly all cells in the body by what carrier-mediated transport mechanism?

*Facilitated (carrier-mediated) diffusion* via *GLUT transporters* -mech. that does NOT require energy, but instead uses a large number of transport proteins (GLUTs) to facilitate the movement of specific substrates across cellular membranes into specific cells

GLUT*4*

*INSULIN-STIMULATED* uptake of glucose at *muscle, heart, & adipocytes*; only transporter that is insulin-responsive (primary means by which insulin is responsible for cellular uptake of glucose in muscle & adipose tissue) **insulin ==> stimulates translocation of GLUT4 from GLUT4 storage vesicles (GSV) within the cell ==> membrane

*Absorption* process *of carbs* into the blood is restricted to

*MONOSACCHARIDES* (only form of carbs that enterocytes can absorb) -therefore polysaccharides, trisaccharides (oligosaccharides), & disaccharides must first be hydrolyzed

Where in the body does the *absorption & transport* of *CHOs* occur?

*SI*

T/F: *ALL body cells* express *at least 1 GLUT isoform* on their plasma membrane!

*TRUE*

T/F: *Very little (if any) Gal/Fru* is found in the *peripheral blood* (at "typical" CHO intakes)

*TRUE*--b/c at typical intakes Gal & Fru are *totally removed by the liver* (absorbed & mostly converted to Glu, therefore never enter the systemic circulation)

T/F: Virtually *NO digestion* of *disaccharides/small oligosaccharides* occurs in the *mouth, stomach*, or *SI lumen*

*TRUE*--rather, digestion of these CHOs occurs *almost entirely* within the *MICROVILLI (BB)* of the upper SI via *disaccharidase* activity

Which is the *ONLY intestinal enzyme* that can *hydrolyze a(1-6) bonds* in branched polysaccharides (e.g. amylopectin)?

*a-dextrinase*

Primary *end product* of *a-dextrinase* action (on partially-digested poly- & oligosacch.'s):

*disaccharides*

*Fructose* is *absorbed more SLOWLY* in SI vs .......... but *FASTER* vs ..........

*glucose/galactose* (b/c these are absorbed via active transport using ATP); *sugar alcohols* (b/c these absorbed via passive diffusion)

GLUT*11*

*heart* & *skeletal muscle*

*Glycosidases* (carbohydrases)

*hydrolytic enzymes* involved in the hydrolysis rxn.'s of *complex carbohydrates ==> monosaccharides* (form that can then be absorbed into the bloodstream & carried to body cells for use)

GLUT*7*

*liver ER*

GLUT*12*

*mammary gland* (breast)

*Limit dextrins*

*partially-digested carbs* resulting from *salivary & pancreatic amylase action* that has *stopped several (usually 4) residues short of the a(1-6) bonds* in the original branched polysaccharide chain; further broken down into disaccharides by *a-dextrinase* in *BB* of SI

Which are the *MOST nutritionally-important* CHOs?

*polysaccharides* & *disaccharides* (free monosaccharides are not commonly present in the diet in significant amt.'s)

CHO digestion in the *mouth*

*salivary amylase* enzyme breaks *a(1-4)* glycosidic linkages in some *polysaccharides* (produces very few mono/disaccharides b/c short period of time that the food is in the mouth before being swallowed)

After digestion by enzymes in pancreatic secretions (pancreatic amylase), *CHOs= further digested by*

*specific BB enzymes* (enzymes embedded in brush border) e.g. sucrases, lactases, & maltases

GLUT*8*

*testes* & *embryonic tissues* (i.e. REPRODUCTIVE tissues) -insulin-responsive (like GLUT4!)

*Absorption* of *Glu/Gal* into the intestinal mucosa cell (enterocytes)

-*ACTIVE TRANSPORT* (relies on conc. gradient maintained by Na+/K+ pump, also referred to as Na+/K+-ATPase) -*Sodium-dependent* (moves into the cell via *symport w/ Na+*, with Na+'s conc. gradient; binding of Na+ to SGLT1 site must happen 1st ==> inc. affinity of glucose-binding site on SGLT1 ==> binds Glu) -Transporter: *SGLT1* (Sodium-Glucose transporter 1, symporter) -glucose *==> hepatic portal system* (diffuses through basolateral membrane of the enterocyte to enter the capillaries ==> portal system ==> liver)

GLUT*2*

-*BL membrane* of *enterocytes* (glucose AND fructose, rate of transport entirely dependent on blood glucose conc.) -*Liver* -*kidney* -pancreatic b-cells

Transport of *glucose AND fructose* through the *BL membrane* of the enterocyte *==> bloodstream* (to *EHC*)

-*FACILITATED DIFFUSION* ONLY (no energy required) -Transporter: *GLUT2* (integral carrier protein) in basolateral membrane of enterocyte

T/F: the liver preferentially takes up (stores) fructose & other CHO's so it can send glucose out to other tissues for energy

TRUE

*Facilitated transport* of *glucose* NOT used by the liver into the cells of which tissues in *insulin-INdependent*?

all other body tissues; particularly the *kidneys* & *brain* (GLUT6/GLUT3 transporters)

Why can't glucose move across cellular membranes via simple diffusion?

b/c glucose is a highly polar molecule, therefore it cannot pass through the non-polar matrix of the lipid bilayer; requires a transporter (carrier/integral protein)

Why is the *transport of glucose/galactose* into the cell via *SGLT1 considered ACTIVE*?

b/c the carriers needed are *dependent on the concentration gradients achieved by the action of Na+/K+-ATPase* at the *BL membrane*

*Disaccharidases*

*BB enzymes* incl. *lactase, sucrase, trehalase, & maltase* that digest specific disaccharides into their monosaccharide components to immediately enter enterocytes w/ facilitation of specific transporters

*Absorption* of *Fructose* into enterocytes (i.e. at *apical membrane*)

-*FACILITATED TRANSPORT* only (no ATP required) -Transporter: *GLUT5* -*some fructose* is *converted ==> glucose* INSIDE enterocyte (to be used for energy by enterocyte) -*much slower rate of absorption* vs. glucose/galactose (however rate is *inc. when GLUT2 is present at the apical membrane* of enterocyte after high-carb meals) -once in enterocyte, transported into bloodstream (w/ glucose & galactose) by GLUT2 transporter in basolateral membrane ==> EHC ==> liver

A portion of the starch in beans/certain vegetables & other resistant starches are not fully digested due to

-accessibility of the food to enzyme alpha-dextrinase in the brush border -naturally-occurring amylase inhibitors in some foods

Why is the action of *salivary amylase* (which begins *carb. digestion in the mouth*) *INCOMPLETE*?

-cannot break a(1-6) or b(1-4) bonds -*short time spent in the mouth*

Explain the mechanism by which insulin regulates glucose uptake by skeletal muscle & adipose tissue cells

-inc. BG levels ==> stimulates insulin release from beta cells of the pancreas -====> inhibition of gluconeogenesis in the liver (stops production of more glucose from non-carb. sources) -====> insulin binds w/ specific insulin receptors on the cell membrane that causes GSV (GLUT4 storage vesicles in the cell) to translocate to the cell membrane (to become gLUT4 transporters to inc. uptake of glucose into muscle/fat cells) -*exercise also causes similar translocation of GLUT4 from GSVs to cell membrane but mechanism is poorly understood

*GLUT2* (intestinal transport)

-integral carrier protein located at the *BL membrane* of *enterocytes* that is primarily responsible for the movement of *glucose/fructose* across the basolateral membrane *into the bloodstream* to be transported to the liver via the *enterohepatic circulation* -has *high affinity* for BOTH *Glu & Fru* -HOWEVER: at times of *high glucose conc.* in the *intestinal mucosa* (i.e. after a large carb-rich meal), more *glucose (& fructose)* are *transported into the enterocyte* at the *APICAL membrane* via *facilitated transport w/ GLUT2* (that has been translocated from storage in intracellular vesicles ==> apical membrane in response to [luminal Glu]>[BG]) than by active transport via SGLT1 -high insulin levels ==> GLUT2 leaves plasma membrane of enterocyte to return to storage vesicles w/i cell so that blood glucose does not become too high (hyperglycemic)

*Pancreatic secretions* (that facilitate carb digestion in the SI)

1) *Bicarbonate*--neutralizes HCl to *inc. pH* of chyme that has entered the SI to a level in that is *optimal for enzymatic activity* 2) *Pancreatic a-amylase*--enzyme that continues to hydrolyze *a(1-4)* glycosidic bonds in *both amylose & amylopectin* ==> -oligosaccharides (dextrins/limit dextrins) -maltose -& maltotriose (trisaccharide)

*Products* of *pancreatic amylase* action on polysacch.'s in SI lumen (3):

1) *Oligosacch.'s* (dextrins & branched "limit dextrins") 2) *Maltotriose* (Glu-Glu-Glu) 3) *Maltose* (Glu-Glu)

*Facilitated transport* of *glucose* into the cells of which tissues is *Insulin-DEPENDENT* (i.e. insulin-"responsive")?

1) *Skeletal & cardiac muscle* 2) *Adipose tissue* via GLUT4 transporter

What *factors* determine the *RATE of facilitated diffusion* of a molecule across a membrane?

1) *concentration gradient* (always moves from high ==> low conc.) 2) *amount* of *carrier protein available* to bind molecules for transport 3) *rapidity of solute/carrier interaction* (how quickly can the door open/close for that solute?) 4) *rapidity of conformation change of carrier*

*Glucose* that has been taken up from the enterohepatic circulation & *entered the hepatocytes* is either:

1) *stored* as liver *glycogen *(glycogenesis) 2) *returned to the bloodstream* to maintain circulating BG levels (& to be taken up by extrahepatic tissues to use for energy) 3) or *catabolized for energy* according to liver's energy demand (i.e. to meet LIVER energy needs)

*Each GLUT transporter* has a *distinct*............ & .............

1) *tissue distribution* 2) & biochemical properties (but all have somewhat similar structures!)

*Mechanisms* of *nutrient transport* (i.e. for absorption into enterocytes/bloodstream) incl.:

1) Passive diffusion 2) *Facilitated transport/diffusion* 3) *Active transport*

Glucose levels are maintained within a narrow range by a balance among:

1) glucose absorption from the intestine 2) glucose production by the liver (glycogenolysis/gluconeogenesis) 3) uptake & metabolism of glucose by peripheral tissues

Glucose that is NOT taken up by the liver is either

1) taken up by *skeletal muscle & adipose tissue* via facilitated, *INSULIN-DEPENDENT* transport -taken up by *kidneys/brain*/other tissues via facilitated, *insulin-INDEPENDENT* transport

*SGLT1* (Sodium-glucose transporter 1)

Carrier protein (integral transport protein located at *apical membrane* of the *enterocyte*, at the peak of the microvilli) in the BB, required for *glucose & galactose transport* into the enterocyte (Absorption): -symporter that *simultaneously transports Na+ & Glu/Gal* in the same direction (into the enterocyte *moving down Na+'s conc. gradient*, which is maintained by Na+/K+ -ATPase) --NOTE: glucose binding site is not available unless the transport protein has already bound a Na+ (this inc. the protein's affinity for glucose)

What happens to *fructose* once it gets to the *liver* (via EHC)?

Fructose is efficiently *absorbed by the liver* & then is *phosphorylated* to become *TRAPPED in hepatocytes*

*Uptake of glucose, galactose, & fructose* by the *liver* following enterohepatic portal circulation occurs by facilitated diffusion that is facilitated by which *transport protein*?

GLUT*9/10*

*GLUT4* activity in *insulin-resistant states/low insulin* levels

GLUT4 *stays in the GSV* & *DEC. presence in cell membrane* ==> hyperglycemia characteristic of diabetes

*Metabolization of GLUCOSE* in the *liver* vs. fructose/galactose:

Glucose is extensively metabolized in the liver but its *removal here is not as complete* as in the case of fructose/galactose--rather, *glucose remaining in the liver passes to the SYSTEMIC BLOOD* supply ==> *distributed among other extrahepatic tissues* (i.e. muscle, kidney, brain, & adipose tissue) which it enters via facilitate transport

Ex. of active transport mechanism

The *Na+-K+ pump*--has both a facilitated diffusion & an active transport component: --F.D.: SGLT1 transporter moves glucose into cell w/ Na+ in direction of conc. gradient (no energy required) --active transport: in order to maintain the conc. gradient of higher Na+ conc. outside the cell vs. inside so that glucose can continue to move with Na+ inside the cell via facilitated diffusion, the Na+-K+ uses ATP to continuously pump 3 Na+ out of the cell & 2 K+ into the cell against their conc. gradients

To be used by the body's cells, dietary carbohydrates must first be

absorbed from the GI tract into the bloodstream

GLUT*5*

absorption of *FRUCTOSE* into *enterocytes* (*apical* membrane) in SI