Glutamine prevents pancreatic atrophy and fatty liver during elemental feeding

JOURNAL OF SURGICAL RESEARCH 48,297-303(1990)

Glutamine Prevents Pancreatic Atrophy and Fatty Liver during Elemental Feeding

W. S. HELTON, M.D.,* R. J. SMITH, M.D.,? J. ROUNDS, B.S.,* AND D. W. WILMORE, M.D.*

*Department of Surgery, Laboratory for Surgical Metabolism and Nutrition, and TJoslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115

Presented at the Annual Meeting of the Association for Academic Surgery, Louisville, Kentucky, November 15-18, 1989

Rats fed an elemental, enteral diet (STD) developed pancreatic atrophy and hepatic steatosis following 60% jejunoileal intestinal resection. An isonitrogenous, isocaloric 2 g/100 ml glutamine-supplemented diet (GLN) significantly attenuated the development of pancreatic atrophy and hepatic steatosis associated with elemental feeding. Pancreatic weight, DNA, and protein were 27, 22, and 40% increased, respectively, in GLN animals. The pancreata of all animals appeared normal by light and electron microscopic examination. GLN animals had 12% less total liver wet weight, 3% less hepatic water content, and 47% less hepatic fat relative to STD rats. Histologic examination of the liver revealed extensive centrilobular fatty vacuolization in STD animals whereas GLN rats had normal looking hepatic parenchyma. Glu- tamine should be viewed as an important nutrient in elemental diets with trophic effects on the pancreas and protective effects against the development of hepatic steatosis. 0 1990 Academic Press, Inc.

INTRODUCTION

Chemically defined, elemental enteral diets adversely effect both the normal structure and the function of the gastrointestinal tract. For example, rats fed elemental diets develop pancreatic and intestinal atrophy [3,4] and hepatic steatosis [l-4]. These alterations are related to the absence of several nutrient and nonnutrient compo- nents from the diet such as dietary amines [5], fiber, and glutamine [4]. Glutamine is an important respiratory fuel for both enterocytes [6] and pancreatic acinar cells [7], plays an important role in the interorgan transfer of nitrogen [8], and influences hepatic metabolism [g-12]. The addition of glutamine to standard intravenous diets attenuates intestinal [13-X] and pancreatic atrophy [16] especially after small bowel resection [ 14, 161. In addition, glutamine-enriched intravenous [12] and enteral [4] diets significantly attenuate hepatic steatosis.

This study was undertaken to determine whether the addition of glutamine to an elemental diet would attenuate

the development of pancreatic atrophy and hepatic steatosis following small bowel resection.

MATERIALS AND METHODS

Animals and Operative Procedures

The studies reported herein conform to the guidelines for the care and use of laboratory animals established by the Animal Care Committee of Harvard Medical School.

Twenty male Wistar rats (200 + 15 g) were anesthetized with intraperitoneal pentobarbital (45 mg/kg) and their fur was clipped from the neck, back, and abdomen. After alcohol and povidone-iodine preparation, the abdomen was opened using sterile technique and an x60% mid jejunoileal intestinal resection performed by transecting the small bowel 20 cm distal to the ligament of Treitz and 20 cm proximal to the ileocecal junction. Bowel continuity was reestablished by end to end anastomosis. A silastic catheter (internal diameter of 0.03 in., external diameter of 0.06 in.) was placed in the fundus of the stomach and secured with a double purse string suture. The proximal end of the gastrostomy catheter was brought through the lateral abdominal wall and tunneled subcutaneously to the interscapular space where it was exteriorized through a stainless-steel button and secured to the deep fascia. Ten milliliters of warm 0.9% normal saline was instilled intraperitoneally at the completion of the procedure.

Study Protocol

After operation, the animals were randomized to receive an elemental enteral nutrient solution without glutamine (STD) or a 2 g/100 ml glutamine-enriched solution (GLN) in which glutamine constituted 30% of the amino acid nitrogen. The elemental diets contained 6.1% amino acids, 26% dextrose, and appropriate concentrations of electro- lytes, vitamins, and minerals required for 180 to 200-g rats [ 171. The diets did not contain lipid or choline. The isocaloric (1.13 kcal/ml) and isonitrogenous (9.6 mg/ml) diets differed only in their composition of nonessential amino acids. The nutrient solutions were prepared in a

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298 JOURNAL OF SURGICAL RESEARCH: VOL. 48, NO. 4, APRIL 1990

TABLE 1

Body Weight and Cumulative Nitrogen Balance

Body weight (g) Cumulative

Preoper- Day 7- nitrogen Group ative Day 1 Day I Day 1 balance (g)

STD (N = 8) 209 + 3 191 + 3 191 f 3 0.7 * 2.7 2.31 + 0.01

GLN (N = 9) 202 + 3 180 + 3 182 + 3 2.1 f 2.5 2.32 f 0.01

Chow (N = 8) 197 k 5 176 ?I 6 199 + 5 22.1 + 1.8 2.29 + 0.01

laminar flow hood and were sterilized by membrane fil- tration.

The animals were housed individually in metabolic cages and their infusion catheters attached to a swivel device (Instech Labs, Inc.) that allowed unrestricted movement during continuous infusion of the nutrient solutions. In the first 16 hr following operation, animals were not allowed oral intake. All animals were given free access to tap water from the first postoperative day until the end of the study. On the first postoperative day animals received 24 ml of the STD or GLN solutions. On the second postoperative day the diets were administered at a rate of 48 ml/day and maintained at this rate throughout the study. An additional eight animals, also underwent 60% jejunoileal resection and sham gastrostomy with placement of the swivel device. These animals were fed an amount of chow roughly equivalent to the caloric intake of gastrostomy-fed animals. Chow-fed animals consumed all of the daily diet.

Measurements and Analytical Procedures

Starting on the second postoperative day, 24-hr urine samples were collected in acidified wells and stored at -20°C until analysis. Cumulative urinary nitrogen content was determined on the 6-day urine pool by pyrolu- minescence [ 181. Cumulative nitrogen balance was calculated by subtracting urinary nitrogen excretion from total nitrogen intake. In chow-fed animals urinary nitro-

TABLE 2

Plasma Glutamine and Glutamate

Group

STD (N = 8) GLN (N = 9) Chow (N = 8)

Glutamine (amole/liter)

977 f 60 1164 k 103

712 + 87

Glutamate (amole/liter)

166 + 11 182 f 15 101 f 5

gen losses were increased by 20% to account for stool losses [ 191.

Animals were weighed on the first postoperative day and following the seventh day of feeding, at which time they were anesthetized with pentobarbital(45 mg/kg ip). Cardiac blood was drawn into heparinized syringes for the measurement of plasma glutamine and glutamate [ 201. Following exsanguination, the entire liver and pancreas were rapidly excised. A small segment of distal pancreas (x3 mm3) was fixed in ice-cold, buffered 2.5% glutaral- dehyde, and stored at 4°C until processed for light and electron microscopic examination as previously described [16]. The remaining gland was weighed, diluted (l/10, w/v) in ice-cold 0.9% saline, homogenized, and sonicated. Samples were stored at -70°C until analyzed for DNA [al] and protein [22]. The liver was blotted and weighed and a small portion (x50 mg) placed in 10% buffered formalin and processed for histologic examination. All histological specimens were coded and read in a blinded fashion by a single observer. The remaining liver was placed in preweighed desiccating jars and dried in a vac- uum oven at 90°C for 72 hr. The water content of the tissue was determined as the difference between wet weight and dry weight. Desiccated liver samples were then analyzed for fat [23] and nitrogen content [ 241.

Statistical Analysis

Data are expressed as means + SEM. The data from chow animals serve as normal references and were not included in statistical comparisons between groups. Data were analyzed by Student’s t test and linear regression techniques. Statistical significance was accepted at the P = 0.05 level. All calculations and statistics were performed on a Macintosh SE computer using Statview 512 statistical software.

TABLE 3

Indices of Pancreatic Mass

Chow Standard N=8 N=8

Glutamine N=9

Weight mg

Protein mg mg/g pancreas

DNA w mg/g pancreas

Protein/DNA mdmg

547 + 38 343 k 19 439 f 15*

79 + 11 37 + 3 52 + 5t 140 k 11 111 f 10 118 + 11

1.85 -+ 0.25 1.48 + 0.13 1.79 + 0.19 3.31 + 0.32 4.39 L 0.41 4.03 f 0.35

43 * 2.2 26.0 2~ 2.5 30.0 f 2.1

Note. Pancreatic weight, DNA, and protein are expressed per 100 g of body weight.

* P < 0.001 and tP < 0.05 vs STD.

HELTON ET AL.: GLUTAMINE, THE PANCREAS AND LIVER 299

TABLE 4

Liver Weight and Composition

Group Wet weight

woo d Dry weight

woo Ii9 Nitrogen

hdd Fat

(mg/d

STD (N = 8) 5.44 zk 0.21 1.67 + 0.11 0.718 f 0.006 26.52 AI 0.49 79.0 k 12.9 GLN (N = 9) 4.77 z!Y 0.12* 1.40 1 0.08 0.694 + O.OlOt 27.78 + 0.48 42.2 f 7.8* Chow (N = 8) 4.52 f 0.26 1.24 + 0.07 0.726 f 0.001 31.63 f 0.87 28.7 ? 0.9

Note. Liver wet and dry weights are expressed per 100 g of body weight. H,O, nitrogen, and fat are expressed per gram of wet liver tissue. *P< 0.05 vs STD. tP = 0.06 vs STD.

RESULTS

The study was completed in 90% of the animals entered. Three animals died, two in the STD group and one in the GLN group, from peritonitis secondary to anastamotic leak. There was no evidence of bowel obstruction, peritonitis, or pancreatitis in any of the surviving animals. There was no difference in nitrogen balance or the change in body weight between the STD and the GLN groups; weight gain appeared less in the enterally fed animals than in chow-fed animals (Table 1). Previous studies have demonstrated that a large portion of the increased weight associated with chow feeding is related to food and stool within the intestinal tract.

Plasma Glutamine and Glutamate

There was a trend toward increased plasma glutamine concentration in the GLN group in comparison with the STD group that approached but did not reach statistical significance (1164 f 103 vs 977 ? 60 pmole/liter, GLN vs STD, P = 0.14) (Table 2). Plasma glutamate concentration was similar in both groups (182 f 15 vs 165 f 11 pmole/liter, GLN vs STD, P = 0.38).

6

5

6 2 4

0 3 I H20 8 = NITROGEN r 2 I FAT

UJ 0 ASH 1

0 CHOW STD GLN

FIG. 1. Amount of water, nitrogen, fat, and ash per total liver (cor- rected for body weight). Water was calculated from the difference among wet and dry weights, fat content by methanol/chloroform extraction of desiccated liver, and nitrogen by macroKjeldah1 distillation of desiccated liver. Ash content was calculated to be that left over after subtracting water, nitrogen, and fat from liver wet weight.

Pancreatic Indices

Both groups receiving the defined diets developed pancreatic atrophy as evidenced by the lower pancreatic wet weight and protein and DNA contents in comparison to those of the chow-fed animals (Table 3). However, the glutamine-supplemented animals had a 28% increase in pancreatic weight (P < 0.001) and a 40% increase in pancreatic protein content (P < 0.05) relative to those of the animals fed the STD diet. Mean pancreatic DNA content was increased by 21%, although this difference did not reach statistical significance (P = 0.20). There was no difference in the pancreatic DNA or protein content per gram of pancreatic tissue or the protein to DNA ratio.

Exocrine and endocrine pancreatic tissues appeared normal by light and electron microscopy. There was no histologic evidence of edema, inflammation, or changes in acinar cell size or zymogen content in any of the animals.

Liver Indices

The liver wet weight in STD animals was 14% greater than the liver wet weight in the GLN group (P < 0.05) (Table 4). This increase in liver weight was related to an

80

70

60

50

40

30

20

10

0

I H20 i Mt:ogen

0 Ash

CHOW STD GLN

FIG. 2. Water, nitrogen, fat, and ash expressed as a percentage of total liver wet weight. Water, nitrogen, fat, and ash weights were determined as described in the text and Fig. 1.


FIG. 3. Histology of the liver from a rat fed a glutamine-free elemental diet for 7 consecutive days following 60% resection of the jejunoileum. There is extensive fatty vacuolization of hepatocytes predominantly located around the hepatic veins.

expansion in the total water content of the liver (3.77 + 0.11 vs 3.42 + 0.10 g/100 g body weight, STD vs GLN, P < 0.05) and in total liver lipid content (441 f 88 mg vs 240 -+ 52 mg/lOO g body weight, STD vs GLN, P = 0.06) (Fig. 1). When expressed as a percentage of total liver wet weight (Table 4, Fig. 2), the livers of STD animals had an 88% increase in fat content relative to GLN animals (7.9 +- 1.3 vs 4.2 + 0.8%, STD vs GLN, P < 0.05). When expressed as a percentage of dry liver weight, STD animals still had a significantly greater percentage of liver weight from fat relative to GLN animals (25 -t 3 vs 16 +- 2%, STD vs GLN, P < 0.05). The dry liver weight of STD animals was increased 16% or approximately 270 mg over GLN animals (P = 0.06) (Table 4). Extractable fat accounted for 200 mg of this increase in liver dry weight. The percentage of liver weight as water and fat was highly correlated (r = 0.98, P -e 0.0001) as was the percentage of liver nitrogen and fat (r = 0.88, P < 0.0001). When expressed as total organ content, liver nitrogen and liver fat were also positively related (r = 0.71, P < 0.002).

Light microscopy demonstrated normal hepatic architecture and no evidence of hepatocellular necrosis. STD

animals had significant fatty infiltration and vacuolization with fat deposition occurring almost uniformily in centrilobular zones; periportal regions were normal in ap- pearance (Fig. 3). Liver parenchyma appeared normal in chow and GLN animals with little to no evidence of fatty infiltration (Fig. 4).

DISCUSSION

Feeding an elemental diet to rats following small bowel resection resulted in a decrease in pancreatic weight and DNA and protein contents and an increase in total hepatic lipid content relative to chow-fed animals. Very similar structural and compositional changes have been observed in nonresected rodents fed elemental diets [l-4]. The decrease in pancreatic weight and DNA and protein contents of STD animals suggests that pancreatic atrophy results primarily from changes in acinar cell size, number, and protein content. These morphological changes are quantitatively and qualitatively identical to those observed in both normal and intestinally resected rodents maintained on parenteral feeding [ 16, 251. Because the enteral route of feeding is believed to be the most important trophic


FIG. 4. Histology of the liver from a rat fed a 2 g/100 ml glutamine-supplemented elemental diet for 7 consecutive days following 60% resection of the jejunoileum. Hepatic architecture is normal with little evidence of fatty infiltration of hepatocytes.

stimulus for intestinal and pancreatic growth following intestinal resection, we anticipated that the differences in pancreatic growth in response to the STD and GLN enteral diets would not be as great as when these diets were administered intravenously [16]. In fact, the difference was even greater with the enteral diets. In the current study, the GLN group had a 27% increase in pancreatic weight and a 40% increase in pancreatic protein relative to the STD group whereas, when the same diets were administered intravenously, there was a 17% increase in pancreatic weight and a 31% increase in pancreatic protein in animals receiving the GLN diet. Thus, our data demonstrate that the lack of dietary glutamine is more important than the route of feeding for pancreatic growth.

Because changes in body weight and nitrogen balance were identical between STD and GLN animals, the trophic effects of glutamine on the pancreas could not be attributed to a generalized improvement in nutritional status of GLN animals. The addition of glutamine to elemental diets may therefore provide an important sub- strate for acinar cell metabolism and specifically preserve the protein synthetic capacity of acinar cells [7]. Gluta- mine and glutamate may also indirectly stimulate pan-

creatic growth through stimulating humoral, cholinergic, and/or GABAergic pathways. These potential mechanisms have been previously discussed in detail [ 161.

Differences between the current study and other studies in which glutamine-supplemented elemental diets failed to increase pancreatic weight may be explained by specific differences in the diets. For example, Young and associ- ates observed less pancreatitic and intestinal mass in rats fed Vivonex (which contains glutamine at 14% of total amino acids) when compared with other refined formula diets [l, 21. The lack of effectiveness of Vivonex relative to Vivonex HN and other refined diets [l] may result from its lower fat content and the absence of di- and tri- peptides present in the other formulas. In addition, glutamine constitutes only 14% of the total dietary nitrogen in Vivonex whereas glutamine represents 30% of the dietary nitrogen content in the current study, and in other studies reported from our laboratory [17--191. We have previously observed that both body weight and intestinal mucosal cellularity increase in rats following intestinal resection proportional to dietary glutamine content, with maximal effects observed when glutamine constitutes 25- 30% of the amino acids [26].


Rats fed the STD diet developed significant hepatic fat accumulation. Quantitatively, the amount of fat measured was similar to that reported in rodents fed balanced amino acids and hypertonic dextrose whether administered by the intravenous [12, 19, 27-311 or enteral route [l-4]. The distribution of hepatic fat differed from that reported by Li et al. [28] who noted periportal fat vacuolization. In the current study, periportal hepatocytes appeared normal and fat vacuolization occurred predominantly in hepatocytes surrounding the hepatic veins (Fig. 3). The basis for this distribution remains unknown.

Our data are consistent with previous studies which have shown that supplementation of hypertonic dextrose feedings with glutamine attenuates the development of hepatic steatosis [4,12,29]. The mechanism(s) accounting for hepatic fat accumulation in rats during hypertonic glucose has been attributed by Hall et al. [30] to four abnormalities: increased hepatic fat synthesis, impaired hepatic fat mobilization, increased hepatic fat uptake, and reduced hepatic fat oxidation. Hepatic steatosis has also been demonstrated to be related to the absence of choline from elemental diets [5]. However, because choline was absent from both the STD and the GLN diets, the inhib- itory effect of glutamine on hepatic steatosis cannot be attributed to a choline-dependent process.

This study does not establish the mechanism by which glutamine prevents hepatic steatosis. Other studies have demonstrated that enteral and intravenous infusions of glutamine can decrease peripheral lipolysis [ll, 321 and fat uptake by the liver [ 111 independent of insulin and glucagon. Glutamine also can decrease the portal insulin/ glucagon ratio coincident with decreased fatty infiltration of the liver [29]. Increased circulating levels of glucagon enhance hepatic glutamine utilization [ 331, possibly due to the stimulation of hepatic glutaminase activity. It is possible that increased glutamine metabolism by hepatocytes in the periportal region, which contain high levels of glutaminase, may somehow alter lipid uptake and/or metabolism [31]. Thus the prevention of hepatic steatosis by glutalmine may derive from both glucagon-dependent and glucagon-independent mechanisms.

In the current study, glutamine-fed animals also had decreased liver wet and dry weights relative to animals fed a glutamine-free diet. The decrease in liver dry weight can be explained by a slight decrease in total liver nitrogen and a significant decrease in liver fat. The explanation for the decrease in total liver water content is not appar- ent, although there was a correlation between nitrogen and liver water content (r = 0.88, P < 0.05). In contrast to the current study, Barber et al. [4] reported an increase in total liver wet weight in animals fed a glutamine-enriched enteral diet.

In summary, elemental glutamine-free enteral feedings with hypertonic dextrose resulted in pancreatic atrophy and hepatic steatosis in rats following small bowel resection. The addition of glutamine to the elemental diet sig-

nificantly attenuated pancreatic atrophy and hepatic water and fat accumulation. The significant effects of enteral glutamine on pancreatic mass and liver composition il- lustrate that glutamine is important for the maintenance of visceral tissues other than the gut. These observations suggest that the efficacy of chemically defined diets on visceral growth and metabolism, particularly following small bowel resection, could be enhanced by the inclusion of glutamine.

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Glutamine prevents pancreatic atrophy and fatty liver during elemental feeding

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