The Physiology of the Intestinal Absorption of Sugars - ACS Publications

1 The Physiology of the Intestinal Absorption of Sugars ROBERT K. CRANE

Downloaded by 80.82.77.83 on May 23, 2017 | http://pubs.acs.org Publication Date: June 1, 1975 | doi: 10.1021/bk-1975-0015.ch001

College of Medicine and Dentistry of New Jersey, Rutgers Medical School, Department of Physiology, Piscataway, N. J. 08854

This review has to do with the physiology of the intestinal absorption of sugars and should properly begin with a brief discussion of the components of the physiological system which carries out this indispensable task. The small intestine where the absorption of sugars takes place is a tube connecting to the stomach at its upper end and to the large intestine at its lower. In the human adult the tube is about 280 cm (9 feet) in length and an average 4 cm (1-1/2 inches) in internal diameter. The area of the inner surface of the tube is much greater than implied by these two measurements because the inner surface is heavily folded and everywhere on the folds there are to be found numerous projec tions called v i l l i (1). Villi are readily seen under a micro scope of low power and there are perhaps as many as 25,000,000 v i l l i in all. As indicated in Figure 1, each villus is covered by a sheet of absorptive epithelial cells punctuated at intervals by the so-called goblet cells which supply protective mucous. Between the v i l l i are to be found crypts within which the cells are produced and from which they migrate outward along the sur face of a villus during a short 3-4 days of active life before being extruded into the lumen of the gut where they disintegrate and are digested. The v i l l u s i s the working u n i t o f the s m a l l i n t e s t i n e . I t i s on t h i s s t r u c t u r e t h a t the i n n e r ends of the a b s o r p t i v e c e l l s are brought i n t o c l o s e p r o x i m i t y t o the blood and lymph which must p i c k up absorbed n u t r i e n t s and c a r r y them t o the other p a r t s of the body. The outer ends of the a b s o r p t i v e c e l l s are i n contact w i t h the contents of the i n t e s t i n e and are s p e c i a l i z e d to perform t h e i r necessary work. The outer end of each c e l l i s a "brush border" made up o f c l o s e l y packed, p a r a l l e l c y l i n d r i c a l processes c a l l e d m i c r o v i l l i . The l i m i t i n g plasma membrane of t h e c e l l f o l l o w s the contours o f the m i c r o v i l l i . J u s t beneath the brush border along the s i d e s of the c e l l s are t o be found s p e c i a l i z e d j u n c t i o n a l s t r u c t u r e s by means of which the absorpt i v e c e l l s are h e l d together i n t o a more or l e s s continuous sheet. 2 Jeanes and Hodge; Physiological Effects of Food Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1975.


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Expanding our h o r i z o n t o i n c l u d e the whole of the i n t e s t i n a l s u r f a c e w h i l e r e t a i n i n g our view o f i t s microscopic appearance i t i s c l e a r t h a t , so f a r as concerns d i g e s t i o n and a b s o r p t i o n , t h e c o l l e c t i v e brush borders of the e p i t h e l i a l sheet form a j u n c t i o n a l b a r r i e r between the o u t s i d e of the body and the i n s i d e through which n u t r i e n t s must pass i n order t o reach the c i r c u l a t i o n and enter metabolism. The c o l l e c t i v e brush borders separate t h e d i g e s t i v e f u n c t i o n s of t h e i n t e s t i n a l lumen c o n t r i b u t e d by the secreted enzymes of the pancreas from t h e metabolic f u n c t i o n s c o n t r i b u t e d by t h e c e l l s . The brush borders a l s o c o n t r i b u t e d i g e s t i v e f u n c t i o n s o f t h e i r own as w e l l as t h e s e l e c t i v i t y , energy t r a n s d u c t i o n and other p r o p e r t i e s of a b s o r p t i o n a n t i c i pated f o r a c e l l membrane occupying t h i s p a r t i c u l a r l o c a t i o n . The brush border membrane acts as a b i l a y e r l i p o i d a l m a t r i x composed of t h e f a t t y chains of p h o s p h o l i p i d s and glycosphingol i p i d s i n t e r s p e r s e d w i t h c h o l e s t e r o l ( 2 ) and p e r f o r a t e d here and there by aqueous channels through which water and s m a l l molecules may pass by d i f f u s i o n . L i p i d s o l u b l e molecules of most any s i z e d i f f u s e r e a d i l y across the m a t r i x of the membrane. However, t h e membrane i s a s u b s t a n t i a l b a r r i e r t o the r a p i d d i f f u s i o n o f large, h i g h l y water s o l u b l e molecules l i k e the hexoses because these do not enter the m a t r i x and the dimensional p r o p e r t i e s of the aqueous channels are too s m a l l , being e q u i v a l e n t only t o those o f pores o f 4-5 £ i n r a d i u s (3), ( 4 ) . There a r e a l s o aqueous channels between the c e l l s because t h e j u n c t i o n a l complexes o f the i n t e s t i n a l e p i t h e l i u m ' a r e n o t t i g h t {5). However, these channels are a l s o too s m a l l f o r the r a p i d passage of hexoses. Those hexoses which do g e t across the brush border membrane r a p i d l y and i n q u a n t i t y ; and t h i s group n a t u r a l l y i n c l u d e s the major d i e t a r y hexoses, glucose, g a l a c t o s e , and f r u c t o s e , do so because they f i t the s p e c i f i c i t y requirements and are able t o b i n d t o membrane t r a n s p o r t c a r r i e r s ( 6 ) . The a c t u a l mode of o p e r a t i o n o f c a r r i e r s i s c u r r e n t l y unknown. However, t h e i r apparent mode o f o p e r a t i o n , i n s o f a r as we can know i t from k i n e t i c s , i s most e a s i l y described as l i k e t h a t of a f e r r y b o a t , capable of s h u t t l i n g water s o l u b l e molecules across the l i p o i d a l matrix. C a r r i e r f u n c t i o n i s diagrammed i n F i g u r e 2 where t h e upper p a r t i s an o p e r a t i o n a l model and t h e lower p a r t i s a k i n e t i c model of a simple s o - c a l l e d f a c i l i t a t e d d i f f u s i o n type of c a r r i e r t o which constants may be assigned as i n d i c a t e d . The assumptions are few and simple. Substrate i n t e r a c t s w i t h the b i n d i n g s i t e o f a c a r r i e r on e i t h e r s i d e of the membrane and i s t r a n s l o c a t e d i n a s s o c i a t i o n w i t h the c a r r i e r . The b i n d i n g s i t e of the c a r r i e r can t r a n s l o c a t e whether or not i t c a r r i e s substrate. A l l i n t e r a c t i o n s are u s u a l l y assumed t o be symmetrical and e q u i l i b r i u m i s then achieved a t equal transmembrane concentrations or a c t i v i t i e s . F o r the most p a r t , f r u c t o s e crosses the brush border membrane by means of a c a r r i e r w i t h these p r o p e r t i e s ( 7 , 8, 9 ) .

Jeanes and Hodge; Physiological Effects of Food Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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O F FOOD

CARBOHYDRATES

BRUSH BORDER MEMBRANE

CELL CONTENTS

INTESTINAL CONTENTS

+ C ^ c s Figure 2.

^

C+ c s

Schematic of a facilitated diffusion (monofunctional) carrier. Ρ is the permeability coefficient.


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Glucose and g a l a c t o s e , however, use a c a r r i e r which though i t i s somewhat the same i s a l s o somewhat and i m p o r t a n t l y d i f f e r ent. The glucose-galactose c a r r i e r , depicted i n F i g u r e 3 both as an o p e r a t i o n a l model and as a k i n e t i c model, i s an e q u i l i b r a t i n g , symmetrical c a r r i e r l i k e the f r u c t o s e c a r r i e r except t h a t i t has two b i n d i n g s i t e s i n s t e a d o f one. The glucoseg a l a c t o s e c a r r i e r r e q u i r e s N a f o r i t s e f f i c i e n t o p e r a t i o n and cotransports N a i n a t e r n a r y complex along w i t h the sugar ( 6 ) . The p a r t i c u l a r v e r s i o n of the Na -dependent c a r r i e r shown i n F i g u r e 3 i n d i c a t e s t h a t the b i n d i n g s i t e can t r a n s l o c a t e e i t h e r empty o r i n a t e r n a r y complex w i t h both o f i t s s u b s t r a t e s , b u t not w i t h sugar alone. There are other v e r s i o n s w i t h other assumptions about the requirements f o r t r a n s l o c a t i o n but the e s s e n t i a l f e a t u r e s are very s i m i l a r ( 1 0 ) . In an i s o l a t e d system, a c a r r i e r w i t h two b i n d i n g s i t e s i s an e q u i l i b r a t i n g c a r r i e r l i k e the c a r r i e r w i t h one b i n d i n g s i t e . The c a r r i e r i t s e l f can serve only t o d i s s i p a t e g r a d i e n t s and the s t a t i o n a r y s t a t e would f i n d equal concentrations o f sugar and equal concentrations of N a on the two s i d e s o f the membranes. In the c e l l u l a r system, however, the'Na -dependent glucoseg a l a c t o s e c a r r i e r i s able t o transduce metabolic energy and t o achieve " u p h i l l " o r a g a i n s t t h e g r a d i e n t t r a n s p o r t by coupling t o the t r a n s c e l l u l a r f l u x of Na . The system i n the i n t e s t i n e seems t o work as suggested by the diagram i n F i g u r e 4. M e t a b o l i c energy i n the form of ATP i s put i n t o a sodium pump i n the basol a t e r a l membranes of the a b s o r p t i v e c e l l s t o d r i v e a t r a n s c e l l u l a r f l u x of N a from the brush border end t o the basol a t e r a l end (12). The glucose-galactose c a r r i e r couples sugar entry to t h i s f l u x by being a route f o r the entry of sodium i o n at the brush border membrane and achieves an " u p h i l l " c e l l u l a r accumulation o f sugar a t the expense o f the " d o w n h i l l " f l u x of Na . I n t a c t d i - and higher saccharides do not get across the brush border membrane i n q u a n t i t y and we thus i n f e r t h a t the needed c a r r i e r s do not e x i s t (13). Tiny amounts o f d i e t a r y d i - and o l i g o s a c c h a r i d e s are sometimes found i n the u r i n e o f i n d i v i d u a l s under study but these t i n y amounts are a t t r i b u t a b l e t o d i f f u s i o n o f these l a r g e compounds through regions o f the i n t e s t i n e where the normal b a r r i e r has been broken down by i n j u r y or by disease. Recently our l a b o r a t o r y has i d e n t i f i e d a route of c e l l u l a r e n t r y of monosaccharides i n a d d i t i o n t o t h a t provided by the N a dependent c a r r i e r s , o f F i g u r e s 3 and 4 (14, 15.)· * ^ t o be b r i e f l y d e s c r i b e d l a t e r i s r e l a t e d t o the a c t i v i t y o f those hydrolases which are an i n t r i n s i c p a r t o f the brush border mem brane. As i s discussed a t f u r t h e r l e n g t h by Dr. Gary Cray i n t h i s Symposium and as i s shown i n Table I , there are imbedded i n the outer surface o f the brush border membrane a s u b s t a n t i a l l i s t of b o n d - s p e c i f i c h y d r o l y t i c o r t r a n s f e r a c t i v i t i e s . The +

+


+

+

+

+

+

+

+

T h

s

n

e

w

γ ο ι 1


θ

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BRUSH BORDER MEMBRANE

INTESTINAL CONTENTS

Να pump


G

1+

C —

k.Jfk-, ΝαΙ + C-G

kJfk2

2

C +| G

k|ik4

4

C-G+lNa

kjfik-s

C-G-Na^C-G-Να Figure 3.

Schematic of a sodium-dependent bifunctional carrier

American Journal of Clinical Nutrition

Figure 4. Schematic of energy transduction between the baso-hteral sodium pump and brush border Να"-dependent carriers by means of the Na through flux (11) +


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TABLE I BRUSH BORDER ENZYME ACTIVITIES*


Oligopeptidase γ-glutamyl t r a n s p e p t i d a s e Enterokinase Glucoamylase ( o l i g o s a c c h a r i d a s e ) Maltase Sucrase Isomaltase (α-dextrinase) Lactase Trehalase P h l o r i z i n Hydrolase ( g l y c o s y l c e r a m i d a s e ) A l k a l i n e Phosphatase as o f 1974 according t o Crane (16 ). saccharidases among these enzymes; namely, glucoamylase (which i s h i g h l y a c t i v e a g a i n s t o l i g o s a c c h a r i d e s ) maltase, sucrase, i s o maltase, (which Gray would p r e f e r t o c a l l α-dextrinase a f t e r t h e n a t u r a l s u b s t r a t e found as a product o f p a n c r e a t i c amylase a c t i o n ) l a c t a s e , t r e h a l a s e , and p h l o r i z i n hydrolase share the work o f p o l y s a c c h a r i d e d i g e s t i o n w i t h p a n c r e a t i c amylase as suggested i n F i g u r e 5. Digestive-Sequence Polysaccharides P a n c r e a t i c Amylase

^ Oligosaccharides and D i s a c c h a r i d e s

Brush Border Saccharidases

^ Monosaccharides

Figure 5.

Sequential roles in carbohydrate digestion of pancreatic amylase and brush border saccharidases

In t h e a d u l t , p a n c r e a t i c amylase s p l i t s amylose o n l y as f a r as m a l t o t r i o s e and maltose (17) and amylopectin t o m a l t o t r i o s e , maltose and a - d e x t r i n s (18). The brush border saccharidases then take over t o cleave~Tree glucose from these products. The brush border enzymes a l s o c o n t r i b u t e d i r e c t l y the d i g e s t i v e



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c a p a c i t y of t h e i n t e s t i n e f o r d i e t a r y d i s a c c h a r i d e s . A good d e a l o f work has made i t c l e a r t h a t t h e brush border membrane i s a d i g e s t i v e - a b s o r p t i v e surface on which the monosaccharide s u b s t r a t e s f o r t h e c a r r i e r s a r e formed by t h e a c t i o n of d i - and o l i g o s a c c h a r i d a s e s , i f they are not provided i n f r e e form i n t h e d i e t ( 1 9 ) · There i s a c l o s e p r o x i m i t y a t the brush border membrane between the s e q u e n t i a l processes of d i g e s t i o n and absorption and because of t h i s only a r e l a t i v e l y s m a l l amount of monosaccharide accumulates i n t h e lumen during t h e d i g e s t i o n of a d i s a c c h a r i d e . I n Figure 6, taken from Gray and Santiago ( 2 0 ) , i t i s seen t h a t only 10 percent of the glucose formed by brush border h y d r o l y s i s of sucrose over a 30 cm segment o f i n t e s t i n e was found i n the lumen; 90 percent having been absorbed. The experience w i t h l a c t o s e and maltose was s i m i l a r . Fructose was l e s s w e l l absorbed than glucose formed a t t h e same time from sucrose because i t s d i f f e r e n t t r a n s p o r t system i s l e s s e f f i c i e n t at equal concentrations. Galactose was l e s s w e l l absorbed than glucose formed a t the same time from l a c t o s e because i t has t o compete w i t h t h a t glucose f o r the same t r a n s p o r t system and has a lower a f f i n i t y f o r i t . O v e r a l l , i t i s c l e a r t h a t the absorption of t h e monosaccharide products of d i s a c c h a r i d e d i g e s t i o n i s e f f i c i e n t . I n p a r t , as already mentioned, t h i s may be explained by the c l o s e f u n c t i o n a l p r o x i m i t y of the membrane d i g e s t i v e enzymes t o t h e membrane t r a n s p o r t systems; a p r o x i m i t y that we have l a b e l e d " k i n e t i c advantage" (19). A l s o i n p a r t t h i s may be explained by a f u n c t i o n of theïïTsaccharidasesas a route f o r the d i r e c t t r a n s l o c a t i o n of some of t h e i r products without the i n t e r v e n t i o n of t h e normal c a r r i e r mechanisms, as r e c e n t l y documented i n publ i c a t i o n s from our l a b o r a t o r y (14·, 15) and f u l l y corroborated by D i e d r i c h ( 2 1 ) . However, there i s no r e l i a b l e evidence t o support the i d e a t h a t the a b s o r p t i o n o f t h e monosaccharide products of d i s a c c h a r i d e s can be s u b s t a n t i a l l y more e f f i c i e n t than the a b s o r p t i o n o f the f r e e monosaccharides themselves. For t h e past 15 years, a concept has been f l o a t i n g about t o the e f f e c t t h a t there may be an advantage f o r absorption t o feed sugars i n the form of d i s a c c h a r i d e s r a t h e r than as f r e e monosaccharides. T h i s concept got i t s s t a r t w i t h some i n v i t r o experiments of Chain and h i s colleagues (22). Our s t u d i e s (19) d i d nothing t o d e t r a c t from the i d e a and d i r e c t i n v i v o experimental support f o r a s m a l l e f f e c t seemed t o be provided by human s t u d i e s c a r r i e d out by Ian MacDonald ( 2 3 ) . The most recent work on humans does n o t support the i d e a . I n f a c t , i t i s p o s s i b l e t h a t t h e i d e a has f i n a l l y been l a i d t o r e s t by the c a r e f u l s t u d i e s of Cook (24) who has found a b s o l u t e l y no d i f f e r e n c e i n the p o r t a l blood l e v e l s o f f r u c t o s e and glucose whether i t i s sucrose t h a t i s placed i n the lumen o f the i n t e s t i n e or whether i t i s an equimolar mixture of glucose and f r u c t o s e .



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Figure 6. Role of monosaccharides released by the digestion of disaccharides over a 30-cm infusion-to-collection distance in human intestine (20)


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The usefulness t o the organism o f the d i r e c t t r a n s l o c a t i o n of monosaccharides by brush border d i g e s t i v e hydrolases i s c u r r e n t l y a p h y s i o l o g i c a l p u z z l e and, f o r t h i s reason, the data base f o r t h i s new t r a n s p o r t pathway w i l l not be developed here t o any great extent. S u f f i c e i t t o say t h a t i n v i t r o s t u d i e s c a r r i e d out under c o n d i t i o n s where the normal c a r r i e r mechanisms f o r glucose t r a n s p o r t are e i t h e r s a t u r a t e d w i t h s u b s t r a t e and thus operating at a maximal r a t e or completely i n h i b i t e d by the omission of N a have demonstrated an a d d i t i o n a l component of glucose e n t r y i n t o the c e l l s when any d i s a c c h a r i d e substrate of a brush border enzyme i s provided. In the case of sucrose, f r u c t o s e as w e l l as glucose enters and accumulates i n the c e l l s . Moreover, the components of t r a n s l o c a t i o n c o n t r i b u t e d by the i n d i v i d u a l enzymes are a d d i t i v e when more than one d i s a c c h a r i d e i s used. C l e a r l y , these systems f o r d i r e c t t r a n s l o c a t i o n i n c r e a s e the t o t a l c a p a c i t y of the i n t e s t i n e f o r carbohydrate a b s o r p t i o n s u b s t a n t i a l l y over the c a p a c i t y c o n t r i b u t e d by the monosaccharide c a r r i e r mechanisms. However, the circumstances under which t h i s a d d i t i o n a l c a p a c i t y may f u l f i l l a need are f a r from obvious. The reason f o r t h i s , which i s probably not g e n e r a l l y appre c i a t e d , i s t h a t t h e c a p a c i t y of the i n t e s t i n e f o r a b s o r p t i o n of the monosaccharides, glucose, g a l a c t o s e and f r u c t o s e i s already t r u l y enormous. As shown i n Table I I , Holdsworth and Dawson ( 2 5 )


+

TABLE I I THE CAPACITY OF THE GUT TO ABSORB SUGARS Measured:

Glucose =

4

P' ^ min. χ 30 cm

Fructose = 0.9 x glucose C a l c u l a t e d : Glucose =

. °'

4 o n

x

mm. χ 30 cm

i d ^ £ i £ . 2 8 0 cm = 5374 g/day X

day

Fructose = 5374 χ 0.9 = 4#37 g/day THUS T o t a l D a i l y Capacity = 10,211 g > 22 l b . > 50,000 c a l . measured the a b s o r p t i v e c a p a c i t y over a 30 cm segment of i n t e s t i n e i n normal humans. At p e r f u s a t e sugar concentrations of 5 g/100 ml they obtained the measured values of 0.4 g/min/30 cm f o r glucose and 90 percent of t h a t value f o r f r u c t o s e . From these i t may be c a l c u l a t e d t h a t the t o t a l d a i l y c a p a c i t y i s 10,211 g of a mixture of glucose and f r u c t o s e ; an amount



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e q u i v a l e n t t o over 22 pounds o f sugar and more than 50,000 c a l o r i e s . Although not a l l p a r t s o f the i n t e s t i n e have the same c a p a c i t y as the p a r t s t u d i e d by Holdsworth and Dawson, t h e e x t r a p o l a t e d maximal r a t e was n e a r l y twice t h a t of the value assumed i n Table I I ; namely 0.73 g/min/30 cm and the t o t a l capaci t y c a l c u l a t e d i s probably a reasonable compromise. Galactose, t e s t e d alone, was absorbed even more r a p i d l y than glucose. Such a c a p a c i t y f o r sugar absorption i s ten times more than would be needed t o provide f o r even the most unreasonable i n d i v i d u a l c a l o r i c requirements s i n c e foods i n a d d i t i o n t o sugars are g e n e r a l l y a l s o eaten and i t s great s i z e i n d i c a t e s t h a t cont r o l of sugar absorption i s not exerted a t the l e v e l of the processes of d i g e s t i o n and absorption a t the brush border membrane. C o n t r o l i s exerted by a negative feedback mechanism i n v o l v i n g receptors i n the upper i n t e s t i n e and the m o t i l i t y o f the stomach. The r e l a t i o n s h i p s between the stomach and the i n t e s t i n e s are diagrammed i n Figure 7. The d i g e s t i v e f e a t u r e s above the stomach and o f the stomach i t s e l f are not i n c l u d e d because i t i s a matter o f f a c t t h a t the r e a l l y indispensable f u n c t i o n of the stomach i s t o serve as a r e s e r v o i r f o r f o o d s t u f f s and t o provide f o r t h e i r r e l e a s e i n s m a l l increments i n t o the s m a l l i n t e s t i n e through the i n t e r m i t t e n t opening o f the p y l o r i c v a l v e . The s m a l l i n t e s t i n e d i g e s t s and absorbs these increments as they are r e c e i v e d but i t s a b i l i t y t o do so depends upon c e r t a i n p h y s i o l o g i c a l l i m i t a t i o n s . Perhaps most important i s the f a c t t h a t the mucosal surface o f the s m a l l i n t e s t i n e i s osmoresponsive. That i s t o say, when the contents of the stomach are r e l e a s e d i n t o the upper s m a l l i n t e s t i n e water s h i f t s between the e x t r a c e l l u l a r f l u i d spaces o f the body and the lumen o f the i n t e s t i n e so as t o balance the osmotic a c t i v i t i e s across the mucosal membrane (26). Normally, the process i s g r o s s l y unremarkable and goes unnoticed. Under abnormal circumstances, however, such as f o l l o w i n g surgery of the stomach so extensive as t o e l i m i n a t e i t s r e s e r v o i r funct i o n , the simple a c t o f e a t i n g may l e a d t o sudden and excessive hyperosmolarity i n the upper i n t e s t i n e w i t h consequent water s h i f t s l a r g e enough t o r e s u l t i n the p h y s i o l o g i c a l response known as the "dumping dyndrome" wherein there can be s e r i o u s vasomotor disturbances i n c l u d i n g sweating, nausea, d i a r r h e a , a f a l l i n blood pressure and weakness (27). S i m i l a r l y , the l a r g e i n t e s t i n e i s a l s o osmoresponsive (28) but i t cannot absorb sugars. Thus when, due t o disease o r surgery, the s m a l l i n t e s t i n a l c a p a c i t y f o r sugar d i g e s t i o n o r a b s o r p t i o n i s so g r e a t l y reduced t h a t a s u b s t a n t i a l amount of unabsorbed sugar enters the large, i n t e s t i n e , d i a r r h e a w i l l ensue owing t o the osmotic p r o p e r t i e s o f the sugar i t s e l f as w e l l as t o any i n c r e a s e i n o s m o t i c a l l y a c t i v e molecules through b a c t e r i a l breakdown o f the sugar t o l a c t i c and other acids (2S). I t takes o n l y 54 grams of glucose t o produce one l i t e r of the osmotic equivalent of the e x t r a c e l l u l a r f l u i d s and, thus, a t l e a s t one



12

PHYSIOLOGICAL

EFFECTS

OF

FOOD

CARBOHYDRATES

l i t e r o f excess e x c r e t i o n . Under normal circumstances the system i s under c o n t r o l and such untoward e f f e c t s do not happen. Foodstuffs i n general, f a t s , e s p e c i a l l y , but p r o t e i n s a l s o as w e l l as carbohydrates, when they enter the i n t e s t i n e through the p y l o r i c v a l v e e l i c i t responses which slow g a s t r i c emptying. The case of sugars i s shown i n F i g u r e 8 by a summation o f many s t u d i e s c a r r i e d out by J. N. Hunt and h i s colleagues. An i n i t i a l "meal" of 750 ml of a s o l u t i o n of c i t r a t e was placed by tube i n t o the stomach. Most of t h e "meal" was del i v e r e d t o the i n t e s t i n e over the next 20 minutes. The volume d e l i v e r e d i n the same span o f time was reduced by the a d d i t i o n of glucose and the degree t o which the d e l i v e r e d volume was r e duced i n c r e a s e d as the glucose c o n c e n t r a t i o n i n c r e a s e d . C l e a r l y , r e c e p t o r s i n the l i n i n g o f the s m a l l i n t e s t i n e respond t o t h e e n t e r i n g glucose i n p r o p o r t i o n t o i t s c o n c e n t r a t i o n and a c t t o reduce g a s t r i c m o t i l i t y presumably by hormonal mechanisms. The r e c e p t o r s f o r glucose are osmoreceptors and they are sugar specific. Fructose g e n e r a l l y d i d not e l i c i t an i n h i b i t o r y response at low c o n c e n t r a t i o n s . C l e a r responses t o f r u c t o s e r e q u i r e d concentrations o f about 300 m i l l i m o l e s / l i t e r and more. Sucrose, or a mixture of glucose and f r u c t o s e , as might be expected, were intermediate i n t h e i r e f f e c t s . Once t h e process of stomach emptying s t a r t s the stomach d e l i v e r s i t s contents a t a r a t e roughly p r o p o r t i o n a l t o t h e i r n u t r i t i v e d e n s i t y ( k c a l / m l ) ( J . N. Hunt, p e r s o n a l communication) and i n a p r e d i c t a b l e and e x p o n e n t i a l f a s h i o n u n t i l the stomach i s very n e a r l y empty. During t h i s process, monosaccharides, i n the d i e t or produced by d i g e s t i o n , are moving i n t o and down t h e i n t e s t i n e and are being absorbed by the c a r r i e r mechanisms e a r l i e r mentioned; f r u c t o s e by means of a f a c i l i t a t e d d i f f u s i o n c a r r i e r , glucose and g a l a c t o s e by means of a Na -dependent cotransport c a r r i e r . I t may be asked, why? What i s the value t o the economy o f the organism t h a t these p a r t i c u l a r mechanisms are used and t h a t d i f f e r e n t mechanisms are used f o r d i f f e r e n t kinds of sugar. An answer may be t h a t the needs are best matched i n t h i s way. The fundamental d i f f e r e n c e between the two c a r r i e r systems i s t h a t the one, the Na -dependent c a r r i e r , can be energized t o produce a c t i v e ( a g a i n s t t h e c o n c e n t r a t i o n g r a d i e n t ) t r a n s p o r t whereas the other, the f a c i l i t a t e d d i f f u s i o n c a r r i e r cannot. This d i f f e r e n c e would seem t o match the energy demands of t h e r e s p e c t i v e a b s o r p t i v e problems. In the case of f r u c t o s e , f r u c t o s e l e v e l s i n the blood during i t s absorption are low, being only one-tenth those of glucose during i t s a b s o r p t i o n , (10-15 mg % as against 150-200 mg %) and f r u c t o s e i s r a p i d l y metabolized reducing the l a t e - or p o s t a b s o r p t i v e blood f r u c t o s e t o very low l e v e l s . Consequently, there i s no l a r g e s t a b l e b l o o d - t o - i n t e s t i n a l lumen gradient of f r u c t o s e c o n c e n t r a t i o n and there may simply be no need f o r +

+


1.

CRÂNE

13


SMALL

STOMACH

LARGE INTESTINE

INTESTINE

J ' BACTERIAL

„

DIGESTION and ABSORPTION


Γ—ι

1

1

r

Ί

FERMENT ATION

Figure 7. Schematic of the relationships between the stomach and the intestines

VOLUME PLACED IN STOMACH

100 Ο >

200

MILLIMOLES/LITER

300

400

500

OF MONOSACCHARIDE

Figure 8. Effect of carbohydrate con tent on the rate of stomach emptying of a test meal. Drawn from data published in graph ic form by Hunt and Knox (29).



PHYSIOLOGICAL

EFFECTS

O F FOOD

CARBOHYDRATES

MINUTES Figure 9. Time course of glucose absorption from a loop of rabbit intestine, in vivo. Drawn from data published in graphic form by Barany and Sperber (30).


1.

CRÂNE


15

f r u c t o s e t o be absorbed by an energized t r a n s p o r t system. Hence, the f a c i l i t a t e d d i f f u s i o n c a r r i e r s u f f i c e s . The case i s d i f f e r ent f o r glucose. The blood i n h e a l t h always contains a p p r e c i able (80-90 mg %) glucose and one may be c e r t a i n t h a t a q u a n t i t a t i v e l y important p a r t o f the absorption o f a load o f glucose w i l l r e q u i r e the p a r t i c i p a t i o n of an energized c a r r i e r because t h a t p a r t o f a b s o r p t i o n w i l l n e c e s s a r i l y be " u p h i l l " from the lumen t o the blood. What takes p l a c e i n the i n t e s t i n e f o l l o w i n g a l o a d of g l u cose i s w e l l i l l u s t r a t e d by the experiments o f Barany and Sperber (30) w i t h l i v e r a b b i t s as shown i n F i g u r e 9. These workers placed a c e r t a i n volume o f a concentrated glucose s o l u t i o n i n t o a c l o s e d loop of the r a b b i t s i n t e s t i n e and sampled the contents o f the loop a t the i n t e r v a l s t h e r e a f t e r . Initially the c o n c e n t r a t i o n o f glucose i n the i n t e s t i n e was higher than glucose i n the blood. Consequently, a b s o r p t i o n during t h i s p e r i o d took place down the c o n c e n t r a t i o n g r a d i e n t and n e t t r a n s f e r of sugar from the i n t e s t i n e t o the blood stream would r e q u i r e no energy input other than d i f f u s i o n a l . This i s the " d o w n h i l l " component. L a t e r , as a b s o r p t i o n progressed, the c o n c e n t r a t i o n of glucose i n the i n t e s t i n e became lower than i n the blood. Continued absorption consequently took p l a c e " u p h i l l " a g a i n s t t h e c o n c e n t r a t i o n g r a d i e n t and would r e q u i r e the i n p u t o f energy other than d i f f u s i o n a l . At t h e o u t s e t , one might suppose t h a t two d i f f e r e n t c a r r i e r s are used; one f o r the d o w n h i l l component and another f o r the uph i l l . However, t h i s i s not the case. The evidence says t h a t the same c a r r i e r s are used f o r both components. I f these c a r r i e r s were t o have the requirement f o r the consumption o f metabolic energy i n the u p h i l l mode b u i l t i n t o t h e biochemical mechanisms they would be w a s t e f u l when o p e r a t i n g i n the d o w n h i l l mode. In Table I I I are compared four types of membrane t r a n s p o r t which are e i t h e r known or have been proposed t o occur i n animal cells. These a r e : ( l ) F a c i l i t a t e d d i f f u s i o n which f o r present purposes i s viewed as having the c h a r a c t e r i s t i c s o f a symmetrical biochemical r e a c t i o n i n which the s t a t i o n a r y s t a t e achieved w i l l be a 1/1 e q u i l i b r i u m between f r u c t o s e i n s i d e and f r u c t o s e o u t s i d e the c e l L F a c i l i t a t e d d i f f u s i o n can operate only " d o w n h i l l " . (2) V e c t o r i a l biochemical r e a c t i o n s of t h e k i n d envisaged i n the phosphorylation-dephosphorylation hypothesis of the 1930 s - 1950*s ( 31) wherein i t was proposed t h a t the energy f o r accumulation was d e l i v e r e d t o the s u b s t r a t e , glucose, by the t r a n s f e r o f phosphate from ATP w i t h subsequent h y d r o l y s i s t o r e l e a s e f r e e sugar. Roseman and h i s colleagues and Kaback have s t u d i e d systems i n b a c t e r i a l membranes which are of t h i s g e n e r a l type except t h a t phosphorylated sugar and n o t f r e e sugar i s accumulated (32). The asymmetry of the biochemical r e a c t i o n s i n such systems i s obvious. ( 3 ) C o v a l e n t l y energized c a r r i e r s which a r e l i k e the


1

f



C + ATP C * Ρ + ADP C * Ρ + Go + HOH C + Gi + Ρ

C + Nao C-Na C-Na + Go C-Na-G C-Na-G «r+ C-Na + G i C'Na C + Nai t o pump

(3) C o v a l e n t l y Energized Reaction

(4) Cotransport Energized Carrier

[Gi] > [Go] [Nai] > [Nao]

no

yes

both

[Gi] > [Go]

both

yes

both

[ F i ] = [Fo]

[Gi] > [Go]

no

Downhill only

Stationary State

C = c a r r i e r , F = f r u c t o s e , G = glucose, Ρ = phosphate, ο = o u t s i d e , i = i n s i d e .

C-G6P + ADP C + Gi + Ρ

C + Go + ATP C-G6P + HOH

( 2 ) V e c t o r i a l Biochemical Reaction

C + Fi

C + Fo

C-F

Reaction Involved

(1) Symmetrical Biochemical Reaction ( F a c i l i t a t e d Diffusion)

D e s c r i p t i v e Name

I s Bond Energy Consumed i n Downhill Mode

Downhill or Uphill Transport Capability

Reactions Involved i n and Energy U t i l i z a t i o n by V a r i o u s H y p o t h e t i c a l Types o f Membrane Transport

TABLE I I I


1.

CRÂNE


17

v e c t o r i a l b i o c h e m i c a l r e a c t i o n s i n t h a t they are fundamentally asymmetrical but which d i f f e r i n t h a t t h e energy f o r accumulation i s d e l i v e r e d t o t h e c a r r i e r r a t h e r than t o the s u b s t r a t e . Perhaps the best example of a c o v a l e n t l y energized c a r r i e r i s the c e l l membrane sodium pump which expresses i t s e l f as an Na^K " a c t i vated ATPase (33). (4) Cotransport energized c a r r i e r s o f the k i n d already d e s c r i b e d above. I n the absence o f a N a f l u x t h e r e a c t i o n s o f these c a r r i e r s a r e symmetrical. I n t h e presence o f a N a f l u x t h e r e a c t i o n s are, as i n d i c a t e d , asymmetrical. As a consequence of t h i s d u a l i t y the cotransport energized system i s the o n l y one o f t h e f o u r which i s not only capable o f both u p h i l l as w e l l as d o w n h i l l t r a n s p o r t but which a l s o does n o t have an absolute requirement t o u t i l i z e bond energy i n the d o w n h i l l mode. The c o t r a n s p o r t energized system i s capable o f a d j u s t i n g energy use t o energy need and i s thus c o n s e r v a t i v e . The a b i l i t y of the i n t e s t i n e t o absorb such enormous q u a n t i t i e s o f f o o d s t u f f as c a l c u l a t e d above i s what one might expect o f an organ which evolved i t s f u n c t i o n s under c o n d i t i o n s o f l i m i t e d food supply where s t r e s s would be expected on developing a system w i t h the a b i l i t y t o capture every l a s t a v a i l a b l e molecule. Under t h e same c o n d i t i o n s there would seem t o be an advantage t o a t r a n s p o r t mechanism which d i d n o t waste t h i s precious food i n prov i d i n g energy merely t o s a t i s f y t h e needs o f the mechanism and not the needs of the work. 4

+


+

Summary The f o l l o w i n g p o i n t s can be r e i t e r a t e d i n summary. 1. Sugar i s absorbed i n t h e form o f monosaccharides by means o f s p e c i f i c brush border membrane c a r r i e r s which are i n c l o s e f u n c t i o n a l p r o x i m i t y t o the brush border d i g e s t i v e h y d r o l ases or by means o f an h y d r o l a s e - r e l a t e d d i r e c t t r a n s l o c a t i o n . 2. There i s normally no advantage f o r a b s o r p t i o n t o provide sugar i n t h e form o f d i s a c c h a r i d e . 3. The t o t a l c a p a c i t y of the s m a l l i n t e s t i n e f o r sugar a b s o r p t i o n i s enormous. 4. The r a t e o f carbohydrate a b s o r p t i o n i s c o n t r o l l e d by negative feed-back t o stomach emptying from s u g a r - s p e c i f i c osmor e c e p t o r s l o c a t e d i n t h e upper i n t e s t i n e . The r e c e p t o r s are l e s s responsive t o f r u c t o s e than t o glucose. 5. The a b s o r p t i o n o f glucose and g a l a c t o s e can take p l a c e both up as w e l l as down a c o n c e n t r a t i o n g r a d i e n t from i n t e s t i n e t o blood. The same c a r r i e r s are used i n both the d o w n h i l l and the u p h i l l modes. 6. The c a r r i e r s f o r glucose and g a l a c t o s e are energized by the cotransport of N a thus p r o v i d i n g a p o s s i b l e advantage f o r energy conservation i n t h a t bond energy need not be consumed i n the d o w n h i l l mode. +


18

PHYSIOLOGICAL

EFFECTS

OF

FOOD

CARBOHYDRATES

Acknowledgments The work o f the author c i t e d i n t h i s review was supported bygrants from the N a t i o n a l Science Foundation and the N a t i o n a l I n s t i t u t e of A r t h r i t i s , Metabolism and D i g e s t i v e Diseases. Mr. R. M i l t o n prepared the i l l u s t r a t i o n s . Literature Cited


1. Bloom, W. and Fawcett, D. W. "A Textbook of Histology", 9th

Edition, pp. 560-568, W. B. Saunders Co., Philadelphia, 1968. 2. Forstner, G. and Wherrett, J. R. Biochim. Biophys. Acta. (1973) 306, 446-459. 3. Lindemann, B. and Solomon, A. K. J. Gen. Physiol. (1962) 45, 801-810. 4. Fordtran, J. S., Rector, F. C., Jr., Ewton, M. F., Soter, N. and Kinney, J. J. Clinical Invest. (1965) 44, 1935-1944. 5. Fromter, E. and Diamond, J. Nature New Biology (1972) 235, 9-13. 6. Crane, R. K. in Code, C. F. Editor "Handbook of Physiology, Section 6. Alimentary Canal, Volume 3. Intestinal Absorption," pp. 1323-1351, American Physiological Society, Washington, 1968. 7. Schultz, S. G. and Strecker, C. K. Biochim. Biophys. Acta. (1970) 211, 586-588. 8. Gracey, Μ., Burke, V. and Oshin, A. Biochim. Biophys. Acta. (1972) 266, 397-406. 9. Honegger, P. and Semenza, G. Biochim. Biophys. Acta. (1973) 318, 390-410. 10. Schultz, S. G. and Curran, P. F. Physiol. Revs. (1970) 50, 637-718. 11. Crane, R. K. Amer. J. Clinical Nutrition (1969) 22, 242-249. 12. Diamond, J. M. Federation Proc. (1971) 30, 6-13. 13. Crane, R. K. in M. Florkin and E. Stotz, Editors, "Compre hensive Biochemistry, Vol. 17, Carbohydrate Metabolism", pp. 1-14, Elsevier,Amsterdam, 1969. 14. Malathi, P., Ramaswamy, K., Caspary, W. F. and Crane, R. K. (1973) Biochim. Biophys. Acta. 307, 613-622. 15. Ramaswamy, Κ., Malathi, P., Caspary, W. F. and Crane, R. K. (1974) Biochim. Biophys. Acta. 345, 39-48. 16. Crane, R. K. in T. Z. Csaky, Editor, "Intestinal Absorption and Malabsorption", Raven, Press, New York, in press. 17. Messer, M. and Kerry, K. R. (1967) Biochim. Biophys. Acta. 132, 432-443. 18. Walker, G. J. and Whelan, W. J. (1960) Biochem. J. 76, 257-263. 19. Crane, R. K. in Κ. B. Warren, Editor, Symposia of the International Society for Cell Biology, Vol. 5, Intracellular Transport, pp. 71-102, Academic Press, New York, 1966.



1.

CRANE

Intestinal

Absorption

of

Sugars

19

20. Gray, G. M. and Santiago, N. A. (1966) Gastroenterology 51, 489-498. 21. Diedrich, D. F. and Hanke, D. W. in T. Z. Csaky, Editor, Intestinal Absorption and Malabsorption", Raven Press, New York, in press. 22. Chain, Ε. B., Mansford, K. R. L. and Pocchiari, F. (1960) J. Physiol. 154, 39-51. 23. MacDonald, I. and Turner, L. J. (1968) The Lancet 1, 841-843. 24. Cook, G. C. (1970) Clinical Sci. 38, 687-697. 25. Holdsworth, C. D. and Dawson, A. M. (1964) Clinical Sci. 27, 371-379. 26. Code, C. F., Bass, P., McClary, G. B., Jr., Newnum, R. L. and Orvis, A. L.(1960)Amer. J. Physiol. 199, 281-288. 27. MacDonald, J. M., Webster, M.M., Jr., Tennyson, C. H. and Drapanas, T. (1969) Amer. J. Surgery 117, 204-213. 28. Phillips, S. F. (1972) Gastroenterology 63, 495-518. 29. Hunt, J. N. and Knox, M. T. in Code, C. F., Editor, Handbook of Physiology, Section 6: Alimentary Canal, Vol. 4, Motility, pp. 1917-1935, American Physiological Society, Washington, 1968. 30.Bárány,E. and Sperber, E. (1939) Skand. Arch. Physiol. 81, 290-299. 31. Crane, R. K.(1960)Physiol. Revs. 40, 789-825. 32. Kaback, H. R. in Tosteson, D. C., Editor, The Molecular Basis of Membrane Function, pp. 421-444, Prentice-Hall, Inc., Englewood Cliffs, 1969. 33. Caldwell, P. C. in Bittar, Ε. E., Editor, Membranes and Ion Transport, Vol. 1, pp. 433-461, Wiley-Interscience, New York, 1970.


The Physiology of the Intestinal Absorption of Sugars - ACS Publications

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