Physiological Effects of Food Carbohydrates

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The Metabolism of Infused Maltose and Other Sugars ELEANOR A. YOUNG and ELLIOT WESER Division of Gastroenterology, Department of Medicine, The University of Texas Health Science Center, San Antonio, Tex. 78284

Introduction

Provision of adequate nutrition when oral feeding or tubefeeding is difficult or impossible, can be achieved if essential nutrients and calories are introduced directly into the vein. For over three hundred years, man has searched for ways to provide life-dependent nutrients intravenously. As early as 1656 Sir Christopher Wren had already utilized a goose quill attached to a pig's bladder to introduce ale, wine and opium into dog veins (1). Richard Lower of Oxford, in 1662 reported intravenous injections into animals, and Jean B. Davis, a French physician in Paris, transfused lamb blood into man in 1667 (1). In 1843, almost two centuries later, Claude Bernard first infused sugars into animal veins (2), and in 1896, Biedl and Kraus reported the intravenous infusion of dextrose solutions in man (3). Perhaps one of the most exciting and challenging developments in modern medicine, has been the achievement of providing total parenteral nutrition to man. This has been possible largely as a result of advances in the knowledge of the nutritional require ments of man, availability of essential nutrients, and means of parenteral delivery over extended periods of time. Several re views (4,5,6) and national and international symposia (7,8,9,10, 11,12) attest to the distinguished achievements made within the past decade, largely as a result of numerous clinical trials in which calories and all essential nutrients...amino acids, carbo hydrates, fats, vitamins and minerals...have been effectively de livered intravenously to man. Numerous c l i n i c a l s i t u a t i o n s a r i s e i n which p a r e n t e r a l nut r i t i o n may not only be t h e r a p e u t i c , but e s s e n t i a l t o l i f e . Some of these are summarized i n Table 1. Notwithstanding the recent progress made i n p a r e n t e r a l a l i m e n t a t i o n , current problems focus on s u p e r i o r vena cava c a t h e r i z a t i o n v i a the s u b c l a v i a n v e i n ; i n f e c t i o n and s e p s i s i n v o l v i n g catheter e n t r y s i t e , contamination of the catheter and s o l u t i o n ; and hyperglycemic, hyperosmolar dehyd r a t i o n (13). 73 Jeanes and Hodge; Physiological Effects of Food Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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TABLE I INDICATIONS FOR INTRAVENOUS FEEDING Malnutrition Chronic diarrhea Chronic vomiting G.I. obstruction Bowel resection Inflammatory bowel disease G.I. fistulas and anomalies Malignant disease Anorexia nervosa Coma Preoperative preparation Postsurgical support

The Search For C a l o r i e Sources From a n u t r i t i o n a l p o i n t of view, the search f o r s u i t a b l e c a l o r i e sources has been of fundamental importance. As seen i n Table I I , a v a r i e t y of compounds have been e x p l o r e d . T A B L E II CALORIE SOURCES FOR INTRAVENOUS FEEDING Glucose Fructose Xylitol Sorbitol Ethanol Maltose Fat emulsions Amino Acids

I t i s the purpose o f t h i s paper to review b r i e f l y the carbohydrate c a l o r i e sources s t u d i e d t o date, and f i n a l l y t o summarize the p o s s i b i l i t i e s o f the d i s a c c h a r i d e , maltose, as a carbohydrate subs t r a t e i n intravenous f e e d i n g . Glucose. Since glucose i s the carbohydrate normally found i n the b l o o d , i t would seem t o be the obvious and i d e a l choice of c a l o r i e s . Glucose i s an economic and r e a d i l y a v a i l a b l e carbohyd r a t e , i s e f f i c i e n t l y u t i l i z e d p h y s i o l o g i c a l l y and a l s o has the h i g h e s t u t i l i z a t i o n r a t e i n normal man. Notwithstanding the advantages o f glucose as an intravenous source of c a l o r i e s , i t

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

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nevertheless has s e v e r a l s e r i o u s l i m i t a t i o n s . I f a 5% glucose s o l u t i o n i s used as the s o l e source of c a l o r i e s , 10 l i t e r s o f s o l u t i o n would be r e q u i r e d t o provide the c a l o r i c needs o f the average a d u l t male. I n f u s i o n o f hypertonic s o l u t i o n s o f glucose i n t o p e r i p h e r a l v e i n s may lead to complications such as thrombop h l e b i t i s , and h i g h u r i n a r y l o s s e s o f the sugar w i t h a consequent osmotic d i u r e s i s (14,15,16). Furthermore, glucose, being dependent on i n s u l i n f o r i t s u t i l i z a t i o n , may be c o n t r a i n d i c a t e d i n c o n d i t i o n s i n which i n s u l i n a v a i l a b i l i t y and/or a c t i v i t y may be diminished o r absent, such as s u r g i c a l s t r e s s a s s o c i a t e d w i t h e l e vated catecholamines and g l u c o c o r t i c o i d s (17,18,19), as w e l l as i n diabetes (20,21,22,23), hypothermia (17), p a n c r e a t i t i s (20,22), and sometimes i n uremia (20,24). The problems of s i g n i f i c a n t l y impaired glucose t o l e r a n c e i n p a t i e n t s w i t h l a t e n t o r overt diabetes m e l l i t u s , p a n c r e a t i t i s , s t r e s s , s e p s i s o r shock, can o f t e n be c o n t r o l l e d i f the p a r e n t e r a l a d m i n i s t r a t i o n of h y p e r t o n i c glucose s o l u t i o n s i s i n i t i a t e d a t a slow r a t e to e x c i t e increased endogenous i n s u l i n response, o r , i f exogenous i n s u l i n i s provided (25, 26). S t i l l another l i m i t a t i o n o f glucose as an intravenous source of c a l o r i e s i s the M a i l l a r d r e a c t i o n that takes place during s t e r i l i z a t i o n and storage of combined glucose-amino a c i d s o l u t i o n s , i n a c t i v a t i n g e s s e n t i a l amino a c i d s , e s p e c i a l l y l y s i n e (27). For these reasons, other carbohydrates that might overcome some o f the l i m i t a t i o n s of glucose, have been s t u d i e d . Fructose. Comparative s t u d i e s of glucose and f r u c t o s e suggest that f r u c t o s e may be more r a p i d l y metabolized than glucose (28,29, 30), i n f u s e d v e i n s may have a higher t o l e r a n c e f o r f r u c t o s e ( 3 1 ) , and the u r i n a r y e x c r e t i o n o f f r u c t o s e i s l e s s than that o f glucose (32,33,34). The i n i t i a l uptake of f r u c t o s e and i t s subsequent phosphorylation to fructose-l-phosphate c a t a l y z e d by f r u c t o k i n a s e i n the l i v e r and adipose t i s s u e i s independent o f i n s u l i n (16,20, 31,34). Some s t u d i e s have shown t h a t f r u c t o s e i n f u s i o n s t i m u l a t e s i n s u l i n r e l e a s e (36,37), w h i l e other s t u d i e s do not confirm t h i s (20). Nevertheless, some i n f u s e d f r u c t o s e i s converted t o glucose (38,39) and consequently r e q u i r e s i n s u l i n f o r i t s f u r t h e r metabol i s m (17,32). Thus, w h i l e o v e r a l l u t i l i z a t i o n o f glucose and f r u c t o s e are s i m i l a r i n normal man, f r u c t o s e may have c e r t a i n advantages over glucose, e s p e c i a l l y f o r p a t i e n t s i n the immediate p o s t o p e r a t i v e s t a t e when there i s a known i n s u l i n antagonism (20, 30,40,41), diabetes m e l l i t u s (22,23,29), c e r t a i n l i v e r diseases (20) and i n pancreatectomy (20,22). I n s p i t e o f the advantages of f r u c t o s e as a c a l o r i e source f o r intravenous i n f u s i o n , a number of s e r i o u s l i m i t a t i o n s have been r e p o r t e d , i n c l u d i n g an increase i n l a c t i c a c i d l e v e l s i n the l i v e r (42,43), increased blood l a c t a t e l e v e l s f o l l o w i n g r a p i d i n f u s i o n (44,47), d e p l e t i o n o f high-energyphosphate as w e l l as i n o r g a n i c phosphate i n the l i v e r (48,49), r e duction o f i n o r g a n i c phosphate i n the serum (23), and h y p e r u r i c e mia (44,50). The use of intravenous f r u c t o s e can thus have s e r i ous and profound metabolic e f f e c t s under c e r t a i n circumstances,


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r a i s i n g s e r i o u s questions and c a u t i o n concerning i t s use as a c a l o r i e s u b s t r a t e i n p a r e n t e r a l a l i m e n t a t i o n (51,53). S o r b i t o l . S o r b i t o l , a hexahydric a l c o h o l with the same c a l o r i c value as glucose and f r u c t o s e (4.1 k c a l / g ) , i s not d i r e c t l y o x i d i z e d f o r energy production, but i s converted to f r u c t o s e v i a s o r b i t o l dehydrogenase, and metabolized as i s t h i s sugar (54). A second and q u a n t i t a t i v e l y l e s s important metabolic pathway i s the conversion of s o r b i t o l to glucose v i a aldose reductase (55). One advantage of s o r b i t o l i s that i t does not i n t e r a c t with amino acids i n the M a i l l a r d r e a c t i o n (56). S o r b i t o l i s not reabsorbed by the r e n a l t u b u l e s , and i f administered r a p i d l y , can provoke a d i u r e s i s (57,58). Thus, from a n u t r i t i o n a l p o i n t of view, i f the r a t e of u t i l i z a t i o n and t o l e r a n c e i s l e s s than that of glucose or f r u c t o s e , s o r b i t o l does not o f f e r any important advantage over these sugars, and shares the l i m i t a t i o n s of these two sugars as a c a l o r i e source i n intravenous feeding (31,56). Xylitol. The p e n t i o l , x y l i t o l , i s a n a t u r a l intermediate i n carbohydrate metabolism, and i s r a p i d l y o x i d i z e d to L - x y l u l o s e by s o r b i t o l dehydrogenase, and i s then shunted i n t o the pentose phosphate c y c l e . X y l i t o l s t i m u l a t e s i n s u l i n r e l e a s e only when i n f u s e d at high dosage (20,59), and shares with f r u c t o s e and s o r b i t o l , i t s p a r t i a l insulin-independence c h a r a c t e r i s t i c s (20,59), X y l i t o l can then be r e a d i l y converted to glucose (27). I n f u s i o n rates are l i m i t e d (36), and i n a d d i t i o n , x y l i t o l r a i s e s serum u r i c a c i d and b i l i r u b i n (60,62), and has adverse e f f e c t s with regard to a wide spectrum of metabolic a b n o r m a l i t i e s , i n c l u d i n g metabolic a c i d o s i s , r e n a l t u b u l a r e p i t h e l i a l - c e l l damage, i n t r a l u m i n a l dep o s i t s of calcium oxalate c r y s t a l s i n the r e n a l tubules, a l t e r e d c e r e b r a l f u n c t i o n and h e p a t o c e l l u l a r i n j u r y (60,62). Nevertheless, S p i t z et a l (59) have reported s u c c e s s f u l u t i l i z a t i o n of x y l i t o l i n healthy subjects and p a t i e n t s with r e n a l d i s e a s e , and suggest the use of t h i s c a l o r i e source i n uremia and i n other c o n d i t i o n s c h a r a c t e r i z e d by carbohydrate i n t o l e r a n c e and i n s u l i n r e s i s t a n c e . Ethanol. Ethanol contains 7.1 k c a l / g , and thus p o t e n t i a l l y i s a higher c a l o r i e source than other intravenous compounds with the exception of l i p i d s . A l c o h o l i s o x i d i z e d by a l c o h o l dehydrogenase to acetaldehyde, which i s then converted to a c e t y l CoA and shunted i n t o the t r i c a r b o x y l i c a c i d c y c l e f o r complete o x i d a t i o n . I t i s thought that i n s u l i n i s not e s s e n t i a l f o r o x i d a t i o n of a l c o h o l (63). Ethanol has some v a s o d i l a t o r a c t i o n at the s i t e of f l u i d entry and may thus reduce the i n c i d e n c e of thrombophlebitis when i t i s used i n hyperosmotic carbohydrate s o l u t i o n s (64). In a d d i t i o n ethanol provides c a l o r i e s without an accompanying osmotic l o a d , and has minimal u r i n a r y e x c r e t i o n r a t e s (64). However, the c o n c e n t r a t i o n of ethanol i n the body f l u i d s must be kept w i t h i n t o l e r a b l e l i m i t s to avoid pronounced pharmacological e f f e c t s (64). D i r e c t t o x i c e f f e c t s of ethanol on the l i v e r (65) makes the use


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questionable.

Combination of C a l o r i e Sources. Because no s i n g l e c a l o r i e source seems to be i d e a l , s e v e r a l i n v e s t i g a t o r s are c u r r e n t l y searching f o r appropriate combinations of carbohydrate and p o l y a l c o h o l that can be used i n t r a v e n o u s l y . I t i s p o s t u l a t e d that c a p i t a l i z i n g on the most d e s i r a b l e c h a r a c t e r i s t i c s of each i n d i v i d u a l source, some r a t i o of combined sources may prove to be a more s u i t a b l e means of p r o v i d i n g energy s u b s t r a t e (66). I t i s a l s o of importance to note that d i f f e r e n t carbohydrates have varying i n s u l i n o g e n i c p o t e n t i a l . The s t i m u l a t i o n of i n s u l i n i s a maj o r key to anabolism and may thus i n f l u e n c e the choice of carbohydrate s u b s t r a t e i n p a r e n t e r a l feeding. U t i l i z a t i o n of Intravenous Disaccharides as a Source of C a l o r i e s A f t e r o r a l i n g e s t i o n of l a c t o s e , sucrose or maltose, only s m a l l amounts of these d i s a c c h a r i d e s are absorbed i n t a c t . Thus, under normal circumstances c i r c u l a t i n g l e v e l s as w e l l as u r i n a r y e x c r e t i o n of these sugars i s minimal. For these reasons, the i n f u s i o n of the double sugars has r e c e i v e d l i m i t e d c o n s i d e r a t i o n as a p o s s i b l e source of c a l o r i e s i n intravenous n u t r i t i o n . W i t h i n the past decade a v a r i e t y of animal and human s t u d i e s suggest that i n fused maltose, u n l i k e the other d i s a c c h a r i d e s , may be s u i t a b l e as a carbohydrate s u b s t r a t e i n intravenous n u t r i t i o n . Animal S t u d i e s . When r a d i o l a b e l e d l a c t o s e or sucrose are adm i n i s t e r e d i n t r a v e n o u s l y i n the r a t , o n l y s m a l l amounts of isotope appear i n the e x p i r e d CO2 over a 24-hr p e r i o d , w h i l e 62-68% i s exc r e t e d i n the u r i n e (Table I I I ) (67). This confirms previous s t u d i e s which showed that when these two d i s a c c h a r i d e s are admini s t e r e d p a r e n t e r a l l y i n the r a t , they are r a p i d l y and almost quant i t a t i v e l y excreted i n the u r i n e (68,69). In c o n t r a s t , 55-59% of i n t r a v e n o u s l y administered l a b e l e d maltose appears as 14c02> w i t h minimal u r i n a r y e x c r e t i o n of l ^ C . The recovery of l a b e l e d from maltose was comparable to that from i n j e c t i o n of l a b e l e d g l u cose or other monosaccharide mixtures (67). The extensive metabolism of i n j e c t e d maltose to ^C02 suggested a p o s s i b l e r e c i r c u l a t i o n through the i n t e s t i n a l mucosa w i t h subsequent o x i d a t i o n of maltose by i n t e s t i n a l maltases, o r , the p o s s i b i l i t y t h a t t i s s u e s other than s m a l l bowel mucosa might possess maltase a c t i v i t y . As seen i n Table IV, the h y d r o l y s i s and subsequent metabolism of i n t r a v e n o u s l y administered maltose was not s i g n i f i c a n t l y i n f l u e n c e d by s e l e c t i v e removal of the s m a l l bowel, kidneys, or 70% of the l i v e r (67). A n a l y s i s of maltase act i v i t y i n s e l e c t e d r a t organs (Table V) i n d i c a t e s the presence of maltase i n a v a r i e t y of t i s s u e s (67). Other estimates of r a t t i s sue maltase a c t i v i t y are comparable (70,71,72). I t t h e r e f o r e seems u n l i k e l y that c i r c u l a t i o n of i n j e c t e d maltose to s m a l l bowel mucosa p l a y s a s i g n i f i c a n t r o l e i n i t s o v e r - a l l metabolism, or


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TABLE 1

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4

No. animals

Glucose-1- C Glucose-U- C Glucose-1- C + galactose** Glucose-U- C + fructose-U- Ct Maltose-1- C Maltose-U- C Lactose-1- C l4

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Metabolism of C-labeled disaccharides iv administration in the rat*

Sugar

O F FOOD

1 4

C0

after

Urine

2

1

4

C

% dose/24 hours 5.3 ± 4.7 14.8 ± 10.3

5 5

62.0 ± 11.6 64.0 ± 12.0

4

52.0 ± 9.7

5 5 5 6 5

50.7 54.6 58.6 6.2 7.6

l4

9.8 ± 6.6

14

14

l4

14

14

Sucrose-U- C 14

± ± ± ± ±

19.3 4.8 3.2 62.1 68.4

7.9 7.0 5.8 2.7 2.4

± ± ± ± ±

4.6 3.9 3.0 13.5 10.8

* Animals received 5 mg of suger in 0.5 ml (1 μο per ml). * * M i x t u r e contained 2.5 mg of each sugar and 0.5 μο g l u c o s e - 1 - C . tMixture contained 2.5 mg and 0.25 μο of each sugar. 14

Journal of Clinical Investigation (67)


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T A B L E IV Oxidation

of

1

4

l 4

C-labeled sugars t o C 0 after iv injection in partially eviscerated rats 2

1 4

Organ removed

l4

l4

48.3 46.2 50.1 45.0

2

Glucose-1- C

Maltose-1- C

Sham Kidneys Liver (70%) Small bowel

C0

% dose/24 hours 55.3 ± 19.5 (3) 45.5 ± 17.6 (3) 43.9 ± 4.7 (3)

± 7.7(4)* ± 11.3 (4) ± 9.2 (5) ± 2.7 (3)

Lactose-1- C 14

2.9 ± 0.9 (3) 16.9 ± 5 . 9 (3) 2.4 (1)

* Number of rats is given in parenthesis. Journal of Clinical Investigation (67)

TABLE V Maltase activity in homogenates of rat organs

Maltase Organ

Intestinal mucosa Kidney Brain Liver Pancreas Spleen Muscle Serum Human serum

1

2

3

U*

U 390 61

205 73

485 17 14 2

U

1.6 4

1 0.1 9.1 0.3

0.1 0.3 12.5 0.1

4.0 1.7 5.6 0.2 0.3 8.9 0.2

*One U equals 1 μιτιοΐβ maltose hydrolyzed per minute per g protein. Journal of Clinical Investigation (67)


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that a s i n g l e t i s s u e maltase was r e s p o n s i b l e f o r maltose o x i d a t i o n . I t i s more probable that c i r c u l a t i n g maltose, u n l i k e l a c tose o r sucrose, may be hydrolyzed by e x t r a i n t e s t i n a l maltases i n s e v e r a l t i s s u e s and subsequently metabolized. To explore whether m a l t o s y l o l i g o s a c c h a r i d e s were a l s o metab o l i z e d i n v i v o , the o x i d a t i o n of a t r a c e r dose of u n i f o r m l y l a beled - ^ C - m a l t o t r i o s e to -^CC^ a f t e r intravenous i n j e c t i o n i n the r a t was measured (73). As seen i n F i g u r e 1, t r a c e r doses of u n i formly l a b e l e d ^ C - m a l t o t r i o s e , as w e l l as u n i f o r m l y l a b e l e d 1*0maltose may be o x i d i z e d to xC>2 a f t e r intravenous i n j e c t i o n i n the r a t as e f f i c i e n t l y as U - C - g l u c o s e , w i t h 64.2 + 4.2%, 65.5 + 8.3% and 60.5 + 4.8% of the i n f u s e d dose recovered as 1*0)2, r e s p e c t i v e l y (73). When i n s u l i n i s s i m u l t a n e o u s l y administered w i t h g l u c o s e 1-14 maltose-l--^C to r a t s , the percentage of i n j e c t e d -^C ex p i r e d as ^CC>2 was the same as the recovery of 14C02 from adminis t r a t i o n of the sugar without i n s u l i n (74). A f t e r intravenous i n j e c t i o n of glucose-l-l^C., 49.3 + 8.2% of the i s o t o p e appeared i n the e x p i r e d CO2 over a 6-hr p e r i o d . When i n s u l i n was added to the i n j e c t i o n s o l u t i o n , 47.5 + 6.6% of the l a b e l e d glucose was e x p i r e d as The f r a c t i o n of i n j e c t e d l^C recovered as 14(χ>2 f o l l o w i n g m a l t o s e - l - l ^ C i n j e c t i o n , w i t h and without i n s u l i n was a l s o the same, these values being 59.7 + 4.9 and 59.7 + 5.0%, r e s p e c t i v e l y . L i k e w i s e , when the two sugars are compared, there was no s i g n i f i cant d i f f e r e n c e i n the amount of glucose or maltose o x i d i z e d to CO2 w i t h or without i n s u l i n . As seen i n F i g u r e s 2 and 3, i n s u l i n d i d cause a more r a p i d o x i d a t i o n of both sugars to 1^C02« S p e c i f i c a c t i v i t y curves showed s i g n i f i c a n t l y e a r l i e r peaks when i n s u l i n was given w i t h e i t h e r glucose or maltose, than when these sugars were administered alone. When the peak e x c r e t i o n curves a f t e r maltose and glucose a d m i n i s t r a t i o n are compared, i t i s c o n s i s t e n t l y observed t h a t the peak o x i d a t i o n time a f t e r maltose i s delayed, suggesting a "precursor-product" r e l a t i o n s h i p which r e q u i r e s time f o r maltose to be hydrolyzed to glucose. I n s u l i n a l s o enhances the i n c o r p o r a t i o n of i n t r a v e n o u s l y i n j e c t e d glucose and maltose i n t o r a t epididymal l i p i d s (Figure 4 ) . The s p e c i f i c a c t i v i t y of e x t r a c t e d l i p i d s of r a t epididymal l i p i d s f o l l o w i n g intravenous i n f u s i o n of glucose p l u s i n s u l i n was 37% g r e a t e r than when glucose was i n f u s e d alone. Of p a r t i c u l a r i n t e r e s t i s the s i m i l a r response noted when i n s u l i n was i n j e c t e d w i t h maltose, r e p r e s e n t i n g a 29% i n c r e a s e over i n c o r p o r a t i o n observed when maltose was given alone. Rat epididymal t i s s u e was e q u a l l y i n s u l i n - s e n s i t i v e when e i t h e r glucose or maltose was the sugar donating i t s l a b e l e d carbon to the s y n t h e s i s of l i p i d s (74). These s t u d i e s i n d i c a t e t h a t glucose and maltose respond s i m i l a r l y to i n s u l i n stimulation. The o x i d a t i o n of i n t r a v e n o u s l y administered t r e h a l o s e has a l s o been s t u d i e d (75). This double sugar was s e l e c t e d f o r study because i t c l o s e l y resembles maltose, c o n s i s t i n g of two glucose molecules j o i n e d i n a n / - 1 , 1 l i n k a g e . Figure 5 p l o t s the 14

o r


YOUNG

AND WESER

Infused Maltose

ro

ο X

Minutes Biochimica et Biophysica Acta

Figure 1. Oxidation of uniformly labeled [ C] maltotriose, [ C] malt ose, and [ C] glucose to C0 after intravenous injection in the rat. Each point represents the mean value of five animate (73). 14

14

14

14

2

Time (Hours) Endocrinology 14

Figure 2. Effect of insulin on the oxidation of circulating maltose-l- C to C0 . Specific activity curve following maltose (50 mg) iv (O); maltose (50 mg) plus insulin (0.2 U)iv(m) (74).

14

2


PHYSIOLOGICAL

EFFECTS

O F FOOD

CARBOHYDRATES

Time (Hours) Endocrinology 14

14

Figure 3. Effect of insulin on the oxidation of circulating glucose-l- C to C0 L Specific activity curve following glucose (50 mg) iv (O); glucose (50 mg) plus insulin(0.2)iv{%) (74). 2

GLUCOSE

GLUCOSE INSULIN

MALTOSE

MALTOSE INSULIN Endocrinology

Figure 4. Effect of insulin on the incorporation of r e labeled glucose, glucose plus insulin, maltose and maltose plus insulin into rat epididymal tissue. Bars represent the means and S.D. for 6, 7, 6 and 6 animals, respectively (74).


5.

YOUNG

AND WESER

Infused Maltose

83

o x i d a t i o n o f u n i f o r m l y l a b e l e d glucose, maltose, sucrose and t r e halose f o l l o w i n g intravenous a d m i n i s t r a t i o n i n the r a t . A f t e r the i n j e c t i o n o f trehalose-U-l^C and sucrose-U-l^C only 5 . 2 6 + 0 . 8 8 % and 8.11 + 1.25% o f the i s o t o p e appeared i n the expired C02, r e s p e c t i v e l y . I n c o n t r a s t , a f t e r maltose o r glucose i n j e c t i o n , 59.60 + 2.30% and 49.30 + 3.50% r e s p e c t i v e l y , was excreted as 1*C02. Only 3 t o 5% o f the i n f u s e d maltose and glucose was excreted i n the u r i n e , w h i l e 40 to 47% o f the t r e h a l o s e and sucrose was excreted (75). The r e s u l t s o f t h i s study i n d i c a t e that w h i l e t r e halose and maltose both c o n s i s t o f two glucose molecules, t h e i r metabolic f a t e i s q u i t e d i f f e r e n t . U n l i k e maltose, t r e h a l o s e i s m i n i m a l l y o x i d i z e d t o CO2 and l a r g e l y excreted i n the u r i n e . I t has been suggested that the absence o f t r e h a l a s e and sucrase i n r a t serum and kidney (71,72,76,77) probably accounts f o r the m i n i mal o x i d a t i o n o f these sugars. I n c o n t r a s t , maltase i s r e l a t i v e l y high i n r a t kidney (67,77,78) and serum (67,77) which would exp l a i n the d i f f e r e n c e i n the metabolism o f these d i s a c c h a r i d e s when given p a r e n t e r a l l y . I t i s p o s t u l a t e d that t r e h a l a s e and maltase a c t i v i t y i n mammalian kidney may p l a y a r o l e i n t u b u l a r reabsorpt i o n o f t r e h a l o s e and maltose, as w e l l as glucose (79). Rat k i d ney s l i c e s have been shown to o x i d i z e l^C-maltose and l^C-maltot r i o s e t o ^C02 more than other t i s s u e s , w i t h the exception of s m a l l bowel mucosa (78). A f t e r the intravenous a d m i n i s t r a t i o n o f u n i f o r m l y l a b e l e d t r e h a l o s e and sucrose, the kidney t i s s u e accumulates the h i g h e s t cpm/g t i s s u e when compared to recovery o f the l a b e l i n other t i s s u e s (75). These s t u d i e s lend f u r t h e r support to the suggestion t h a t the presence of the d i s a c c h a r i d a s e i n the r e n a l t u b u l a r t i s s u e may be a major determinant o f the e f f i c i e n c y of d i s a c c h a r i d e metabolism subsequent t o intravenous i n f u s i o n . I n an animal such as the r a b b i t w i t h h i g h t r e h a l a s e a c t i v i t y i n the kidney (72,78), 64% o f i n t r a v e n o u s l y administered trehalose-U-l^C was o x i d i z e d t o ^*C02> w h i l e l e s s than 2% was excreted i n the u r i n e (75). The recovery o f 1*C as ^C02 a f t e r i n f u s i o n o f t r e halose i n the r a b b i t i s seen i n Figure 6. The e f f i c i e n t o x i d a t i o n o f i n t r a v e n o u s l y administered maltose poses a question concerning the entry o f t h i s sugar i n t o the c e l l p r i o r to i t s metabolism. A comparative study of the uptake of maltose and other sugars i n t o r a t diaphragm c e l l s i n d i c a t e d that at e q u i l i b r i u m a l l sugars entered c e l l s by d i f f u s i o n (80). A t a l l equimolar c o n c e n t r a t i o n s , d i s a c c h a r i d e t r a n s p o r t i n t o i n t r a c e l l u l a r water was e q u a l , but o n l y 50% that o f monosaccharides. When i n t r a c e l l u l a r sugar was c a l c u l a t e d on a weight b a s i s (mg/ml) t r a n s p o r t of a l l d i s a c c h a r i d e s and monosaccharides was equal (80). In c e l l s that possess i n t r a c e l l u l a r d i s a c c h a r i d a s e a c t i v i t y , h y d r o l y s i s o f d i s a c c h a r i d e s and monosaccharides would account f o r t h e i r subsequent metabolism. The slow 24-hr i n f u s i o n s o f n u t r i e n t s o l u t i o n c o n t a i n i n g 25% maltose hydrate, amino a c i d s , v i t a m i n s and e l e c t r o l y t e s i n r a t s over a 14 day p e r i o d r e s u l t e d i n severe weight l o s s e s and up t o 52% u r i n a r y e x c r e t i o n of the i n f u s e d maltose. S i m i l a r i n f u s i o n s



14

14

2

14

14

14

Comparative Biochemistry and Physiology

Figure 5. Oxidation of intravenously administered glucose-U- C, maltose-U- C, sucrose-U- C, and trehalose-U- C to C0 in rats over a 6-hour period. Each point represents the mean value for 6, 6, 4 and 7 animals respectively (75).

HOURS


Figure 6. 2

Comparative Biochemistry and Physiology

Oxidation of circulating trehalose to C0 in the rabbit. Points represent mean ± S.D. for one animal (75).

14

HOURS

86

PHYSIOLOGICAL

EFFECTS

OF

FOOD

CARBOHYDRATES

of glucose s o l u t i o n s r e s u l t e d i n weight maintenance and l i t t l e o r no u r i n a r y e x c r e t i o n (81). While t h i s study concludes that l o n g term p a r e n t e r a l maltose cannot serve as a t o t a l c a l o r i c s u b s t i t u t e f o r glucose i n complete p a r e n t e r a l n u t r i t i o n , r e s u l t s are l i m i t e d to observations i n only two animals. A d d i t i o n a l long-term parent e r a l s t u d i e s are needed. Human S t u d i e s . A f t e r l a c t o s e o r sucrose i n f u s i o n i n man, these d i s a c c h a r i d e s are l a r g e l y excreted i n the u r i n e (67,82). As seen i n Table V I , only s m a l l q u a n t i t i e s o f i n f u s e d maltose appear i n the u r i n e , suggesting that t h i s d i s a c c h a r i d e i s metabolized (67). O x i d a t i o n curves o f i n t r a v e n o u s l y administered maltose to h e a l t h y , normal s u b j e c t s are seen i n F i g u r e 7 (83). When 10 g maltose c o n t a i n i n g 5 u C i maltose-U-l^C given i n t r a v e n o u s l y , t h i s d i s a c c h a r i d e was r e a d i l y metabolized to CO2, w i t h 60% of the administered r a d i o a c t i v i t y recovered i n the e x p i r e d a i r over a 6 hr p e r i o d . Less than 8% o f the r a d i o a c t i v e carbon was recovered i n the u r i n e e i t h e r as maltose or as glucose (83). The metabolic response o f intravenous i n f u s i o n of maltose and glucose t o normal s u b j e c t s i s compared i n F i g u r e 8. Blood glucose concentrations d i d not i n c r e a s e s i g n i f i c a n t l y a f t e r maltose i n f u s i o n , although a s i g n i f i c a n t r i s e i n t o t a l reducing substances was noted, i n d i c a t i n g the presence of t h i s d i s a c c h a r i d e i n the blood. This suggests t h a t e x t r a c e l l u l a r h y d r o l y s i s of maltose to glucose i s minimal. Since human serum c o n t a i n s almost no maltase a c t i v i t y (67,72), i t i s probable t h a t maltose enters t i s s u e c e l l s i n t a c t and i s subsequently metabolized. I n i t i a l l y , there was a f o u r f o l d i n c r e a s e i n serum i n s u l i n c o n c e n t r a t i o n a f t e r glucose and a t h r e e f o l d i n c r e a s e a f t e r maltose i n f u s i o n . T h e r e a f t e r , serum i n s u l i n c o n c e n t r a t i o n s g r a d u a l l y d e c l i n e d i n a s i m i l a r manner f o r both sugars. Data from t h i s study (83) demonstrates t h a t maltose i s r e a d i l y a v a i l a b l e as a metabolic s u b s t r a t e , and may provide the r e q u i r e d m e t a b o l i t e ( s ) necessary t o i n i t i a t e i n s u l i n s e c r e t i o n . The plasma f r e e f a t t y a c i d s a t 15 min decreased 371 u E q / l i t e r a f t e r glucose and 338 u E q / l i t e r a f t e r maltose i n f u s i o n . The r e s u l t s of t h i s study i n d i c a t e t h a t the u t i l i z a t i o n o f i n f u s e d maltose e l i c i t s s i m i l a r metabolic e f f e c t s as glucose i n the normal subject. Table V I I shows the s p e c i f i c a c t i v i t y (counts/minute per m i l l i g r a m ) of serum glucose and maltose a f t e r intravenous admini s t r a t i o n of 55 u C i maltose-U-^C i one s u b j e c t . Although there was no change i n serum glucose c o n c e n t r a t i o n , the s p e c i f i c a c t i v i t o f glucose s l o w l y i n c r e a s e d d u r i n g the 60 min p e r i o d , l i k e l y r e p r e s e n t i n g r e e n t r y o f l a b e l e d glucose from t i s s u e sources. On the other hand, the s p e c i f i c a c t i v i t y o f the i n j e c t e d maltose r e mained r e l a t i v e l y constant (83). The metabolism of maltose and glucose a f t e r intravenous i n j e c t i o n was compared i n normal and m i l d l y d i a b e t i c s u b j e c t s (84). The recovery o f as ^ 0 0 2 i normal s u b j e c t s was s i m i l a r a f t e r w

a

s

n

n


YOUNG

A N D WESER

Infused Maltose

T A B L E VI Disaccharide recovered in 24-hour urine sample, after iv administration of 10 g in adult humans

Disaccharide infused Subject

Lactose

Sucrose

Maltose

g

9

9

J.S. I.R. B.B. B.G.

10.5

7.2

0.09

4.8

0.12

Mean±SD

8.7 ± 1 . 8

7.1

0.08

8.6

6.8

0.15

6.3 ± 1 . 3

0.11

± 0 . 0 3

Journal of Clinical Investigation ( 6 7 )

T A B L E VII Specific Activity of Serum Glucose and Maltose after Intravenous Administration of 10g Maltose-U- C* 14

Specific activity

Minutes

Serum glucose

Estimated maltose

mg/100 ml

mg/100 ml

Maltose

Glucose

cpm/mg

0

87

0

0

0

15

92

61

209

5773

30

90

50

487

6153

45

90

34

878

5933

60

94

31

1000

6975

* 5 5 MCI Maltose-U- C. 14

Journal of Clinical Investigation ( 8 3 )


PHYSIOLOGICAL

EFFECTS

OF FOOD

CARBOHYDRATES

180'

MINUTES Journal of Clinical Investigation 14

Figure 7. Fraction of injected C recovered as expired C0 per millimole C0 over a 6-hr period after the intravenous administration of 10 g C-hbeled maltose. Points are mean values for five subjects (83). 14

2

2

14


5.

YOUNG

89

Infused Maltose

A N D WESER

300 GLUCOSE INFUSION

250-

MALTOSE INFUSION 255200175·

GLUCOSE mg/100 ml

150 I25-| 100' 75

255 H 200-| TOTAL REDUCING |75SUBSTANCES mq/IOOml | 5 Q

125· 100-I

75-1 0

50-1 40-| SERUM INSULIN pU/ml

3020· I0H

900 700

PLASMA FREE * FATTY ACIDS μ E./liter 4

~i—ι—ι 0

20

40

1

60

1

80

1

100

Γ 120 140

Figure 8. Blood glucose, total reduc ing substances, insulin and free fatty acids for six subjects following the in travenous administration of 25 g malt ose or glucose. Points represent the means ± S.E.


90

PHYSIOLOGICAL

EFFECTS

OF

FOOD

CARBOHYDRATES

the a d m i n i s t r a t i o n of l a b e l e d glucose and maltose, with 33.3 + 1.6%, 37.7 + 3.4% and 3 6 . 5 + 1 . 9 % recovered a f t e r i n f u s i o n of maltose-U-l^C., glucose-U-l^C and glucose-l-^C., r e s p e c t i v e l y (Table V I I I ) . D i a b e t i c subjects excreted 25.4 + 1.3% of administered maltose-U- C as C 0 , while a s i m i l a r amount, 28.3 + 0.7% was excreted a f t e r g l u c o s e - l - ^ C i n f u s i o n . Both normal and d i a b e t i c subjects showed a delayed peak e x c r e t i o n of approximately 100 min a f t e r maltose i n f u s i o n as compared to glucose i n f u s i o n . The l^co2 e x c r e t i o n curves f o r the d i a b e t i c subjects are shown i n Figure 9. Our s t u d i e s i n d i c a t e that d i a b e t i c subjects have a decreased c a p a c i t y to shunt a loading dose of both glucose and maltose i n t o C02 pathways. The u r i n a r y e x c r e t i o n of was somewhat greater a f t e r maltose i n f u s i o n than a f t e r glucose i n f u s i o n but t h i s d i f f e r e n c e was not s i g n i f i c a n t except f o r lower u r i n a r y exc r e t i o n a f t e r g l u c o s e - l - l ^ C . The r e n a l threshold and clearance r a t e s f o r maltose i n man have not been determined, and the a c t u a l amount of glucose and maltose appearing i n the u r i n e may depend upon the concentration and r a t e of infused sugar. Although there i s no maltase a c t i v i t y i n human serum, human kidney t i s s u e does have maltase a c t i v i t y (85). Chromatographic separation of the urinary i n d i c a t e s that some 50-55% of the excreted r a d i o a c t i v i t y f o l l o w i n g maltose i n f u s i o n i s excreted as l ^ C glucose (84). The metabolic response to the intravenous i n f u s i o n of maltose and glucose to normal and d i a b e t i c subjects i s shown i n F i g ures 10 and 11 and the s t a t i s t i c a l a n a l y s i s i s summarized i n Table IX. Serum glucose concentration a f t e r maltose i n f u s i o n r e mained l e s s than 95 mg/100 ml over the e n t i r e 2-hr p e r i o d , i n cont r a s t to the e l e v a t i o n of serum glucose f o l l o w i n g glucose administ r a t i o n . The increase i n t o t a l serum reducing substances was simi l a r a f t e r maltose and glucose a d m i n i s t r a t i o n . In normal and d i a b e t i c s u b j e c t s , there was a s i g n i f i c a n t r i s e i n serum i n s u l i n a f t e r maltose i n j e c t i o n , however t h i s increase was greater a f t e r glucose. D i a b e t i c subjects showed an abnormal i . v . glucose t o l erance t e s t and higher serum i n s u l i n l e v e l s at 60, 90, and 120 min a f t e r glucose i n f u s i o n as compared to normal s u b j e c t s . I n s u l i n disappearance curves i n both normal and d i a b e t i c subjects f o l l o w ing maltose i n f u s i o n i n d i c a t e a slow r a t e of removal of i n s u l i n from the serum. The r e l a t i o n s h i p between the delayed disappearance of serum i n s u l i n and the serum glucose concentrations (which remain below 95 mg/100 ml) i s not known. High l e v e l s of c i r c u l a t i n g maltose (as r e f l e c t e d i n the concentrations of t o t a l serum sugars) at t h i s same time i n t e r v a l may d i r e c t l y stimulate i n s u l i n r e l e a s e . I t i s not known i f i n s u l i n i s required f o r maltose entry i n t o mammalian c e l l s . Intravenously administered maltose appears to be as e f f i c i e n t l y u t i l i z e d as glucose i n m i l d l y d i a b e t i c and normal s u b j e c t s . Further s t u d i e s i n severely d i a b e t i c p a t i e n t s are needed to determine whether maltose may be e f f i c i e n t l y metabo l i z e d despite a reduced i n s u l i n response (84). Several studies i n Japan (86,87,88) have reported the use of maltose s o l u t i o n s i n a v a r i e t y of s u r g i c a l p a t i e n t s . In a study 14

1 4

2



IV. M a l t o s e - U - C (5) V . G l u c o s e - l - C (5)

Diabetic

1 4

11+ III III V IV V

14

14

14

11.0 ± 2 . 4 7.3 ± 2.0 NS ρ < 0.05 NS NS NS NS

240 ± 10 138 ± 15 ρ < 0.001 ρ < 0.001 NS ρ < 0.001 NS NS

NS NS NS NS ρ < 0.05 ρ < 0.05

Journal of Clinical Endocrinology and Metabolism (84)

t Mean ± S E . + Statistical comparisons are between groups as indicated.

1 4

25.4 ± 1.3 28.3 ± 0.7

Dose ± 1.6t ± 3.4 ± 1.9

2

% Dose 11.8 ± 1.9 6.9 ± 1.2 5.1 ± 0 . 6

% 33.3 37.7 36.5

C0

1 4

C-labeled maltose or glucose to

Minutes 235 ± 10 110 ± 13 120 ± 6

4

Urinary

1

Peak C

1 4

* Number in parenthesis indicates number of subjects,

1 vs I vs II vs IV vs 1 vs II vs

1. M a l t o s e - U - C (5)* II. G l u c o s e - U - C (5) III. G l u c o s e - l - C (4)

Normal

14

Carbohydrate

after the intravenous administration of 25 g normal and diabetic subjects

Subjects

l4

Recovery of C

T A B L E VIII

PHYSIOLOGICAL

EFFECTS

O F FOOD

CARBOHYDRATES

16.0-r

14.0-

"o

I2.0H

50

100

150

200

250

300

350

400

MINUTES Journal of Clinical Endocrinology and Metabolism 14

14

Figure 9. Fraction of injected C recovered as expired C0 over a 6-hr period after the intravenous administration of 25 g glucose-l- C or maltose-U- C to five mildly diabetic subjects (84) 2

14

14


YOUNG

AND WESER

Infused Maltose 240-

MINUTES

Figure 10. Metabolic response of 14 control and five mildly diabetic subjects follounng the intravenous administration of 25 g glucose-l- C. Each point represents mean value ± S.E. 14


94

PHYSIOLOGICAL

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O F FOOD

CARBOHYDRATES

MINUTES

Figure 11. Metabolic response of 14 control and five mildly diabetic subjects to the intravenous administration of 25 g maltose-U- C. Each point represents mean value ±S.E. 14


Jeanes and Hodge; Physiological Effects of Food Carbohydrates ACS Symposium Series; American Chemical Society: Washington, DC, 1975. Journal of Clinical Endocrinology and Metabolism (84)

loading. III. Diabetic maltose loading. IV. Diabetic glucose loading.

I. Normal maltose loading. II. Normal glucose

NS NS NS NS ρ < 0.05 NS NS ρ < 0.01 NS ρ < 0.01 NS NS NS ρ < 0.01 NS NS

ρ < 0.05 ρ < 0.01 ρ < 0.05 NS

NS NS NS NS

I vs II III vs IV I vs IM II vs IV

"Statistical comparisons are between subject groups indicated:

Serum Insulin, μΙΙ/ml

NS NS NS

NS

NS

ρ < 0.01 NS NS ρ < 0.05 ρ < 0.01 NS NS ρ < 0.05

ρ < 0.01 ρ < 0.05 NS NS

NS NS NS NS

NS NS NS NS

NS NS ρ < 0.01 NS

NS

ρ < 0.05 NS NS ρ < 0.05

NS NS NS ρ < 0.05

NS NS NS ρ < 0.05

ρ < 0.05 ρ < 0.001 NS NS

120

90

ρ < 0.001 ρ < 0.001 NS NS

Minutes after infusion 60 30

NS* NS NS NS

0

15

of glucose and

I vs III

II IV III IV

I vs III vs I vs II vs

Total Serum Sugars. mg/100 ml

"Apparent Maltose/' mg/100 ml

II IV III IV

I vs III vs I vs II vs

Serum Glucose mg/100 ml

Subject groups

response to the intravenous administration

maltose to normal and diabetic subjects

Statistical comparisons of metabolic

T A B L E IX

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CARBOHYDRATES

of 67 p a t i e n t s , no secondary e f f e c t s , c l i n i c a l a b n o r m a l i t i e s , or hyperosmolar problems were recognized (84), Conclusions To date, there i s no i d e a l carbohydrate source of c a l o r i e s for parenteral alimentation. Studies of i n t r a v e n o u s l y administer ed d i s a c c h a r i d e s i n d i c a t e that maltose and glucose are e f f i c i e n t l y and s i m i l a r l y metabolized i n man and i n the r a t . Maltose, be cause of i t s c a l o r i s d e n s i t y and a b i l i t y to be metabolized, may be of importance i n p a r e n t e r a l n u t r i t i o n , and warrants f u r t h e r study. Literature Cited

1. Annan, G. L., Bull. Ν. Y. Acad. Med. (1939) 15:622. 2. Foster, M. "Claude Bernard". Longmans Green Company, New York. 1899. 3. Biedl, A. and Kraus, R., Wein Klin Wschr. (1896) 9:55. 4. Geyer, Robert P., Physiol. Rev. (1960) 40:150. 5. Law, David Η., Adv. Intern. Med. (1972) 18:389. 6. Shils, Maurice Ε., J. Amer. Med. Assoc. (1972) 220:14. 7. Wretlind, A. (Editor). "Colloquim on intravenous feeding". Colloquim held at The Royal Society of Medicine. London, May 1-2, 1962. Nutr dieta (1963) 5:295. 8. "Parenteral Nutrition Symposium". Symposium held at Kungalv, Sweden, Nov. 9-10, 1962. Acta Chir. Scand. (1964) Suppl. 325: 1. 9. Meng, H.C. and Law, David H. (Editors). "Parenteral Nutri tion". International Symposium on Parenteral Nutrition. Vanderbilt University School of Medicine, 1968. Charles C. Thomas, Springfield, 1970. 10. Cowan, G. S. M. and Scheetz, W. L. (Editors). "Intravenous Hyperalimentation". U. S. Army Institute of Surgical Research, San Antonio, Texas. 1970. Lea and Febiger, Philadelphia, 1972. 11. Wilkison, A. W. (Editor). "Parenteral Nutrition".. An Inter national Symposium in London, April 20, May 1, 1971. Williams and Wilkins Company, Baltimore, 1972. 12. American Medical Association. "Symposium on Total Parenteral Nutrition". Symposium held at Nashville, Tennessee, Jan. 1719, 1972. American Medical Association, Council on Food and Nutrition, Chicago, 1974. 13. Dudrick, S. J., Steiger, Ε., Long, J. M., Ruberg, R. L., Allen, T. R., Vars, H. M. and Rhoads, J. E. In "Intravenous Hyperalimentation", George Cowan, Jr. and Walter Scheetz, (Editors), p. 3. Lea and Febiger, Philadelphia, 1972. 14. Wyrick, W. J., Rea, W. S. and McClelland, R. Ν.,J.Amer. Med. Assoc. (1970) 211:1967. 15. Winters, R. W., Scaglione, P. R., Nahas, G. G. and Verosky, M. J. Clin. Invest. (1964) 43:647.


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Physiological Effects of Food Carbohydrates

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