Effects of a Novel Palatinose Based Enteral Formula (MHN-01) Carbohydrate-Adjusted Fluid Diet in Improving the Metabolism of Carbohydrates and Lipids in Patients with Esophageal Cancer

Effects of a Novel Palatinose Based Enteral Formula (MHN-01)Carbohydrate-adjusted Fluid Diet in Improving the Metabolism ofCarbohydrates and Lipids in Patients with Esophageal Cancer

Complicated by Diabetes MellitusToshiya Fujiwara, M.D.,* Yoshio Naomoto, M.D., Ph.D.,*,1 Takayuki Motoki, M.D.,*

Kaori Shigemitsu, M.D., Ph.D.,§ Yasuhiro Shirakawa, M.D., Ph.D.,* Tomoki Yamatsuji, M.D., Ph.D.,*Masafumi Kataoka, M.D., Ph.D.,§ Minoru Haisa, M.D., Ph.D.,¶ Toshiyoshi Fujiwara, M.D., Ph.D.,!

Maritoki Egi, M.D.,‡ Hiroshi Morimatsu, M.D.,‡ Motohiko Hanazaki, M.D., Ph.D.,‡Hiroshi Katayama, M.D., Ph.D.,‡ Kiyoshi Morita, M.D., Ph.D.,‡ Kenji Mizumoto, Ph.D.,#

Takanobu Asou, Ph.D.,# Hirofumi Arima, Ph.D.,# Hajime Sasaki, Ph.D.,# Motoi Matsuura, Ph.D.,#Mehmet Gunduz, M.D., Ph.D.,† and Noriaki Tanaka, M.D., Ph.D.*

*Department of Gastroenterological Surgery, Transplant and Surgical Oncology, †Department of Oral Pathology and Medicine,‡Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama

University, Okayama, Japan; §Department of Surgery, Okayama Saiseikai General Hospital, Okayama, Japan; ¶Department of Surgery,Okayama City General Hospital, Okayama, Japan; !Center for Gene and Cell Therapy, Okayama University Hospital, Okayama, Japan;

and #Meiji Dairies Corporation, Kanagawa, Japan

Submitted for publication December 12, 2005

Background. During perioperative management ofpatients with gastrointestinal cancer complicated bydiabetes mellitus, adequate alimentation is required,but we often face difficulties associated with hypergly-cemia and other accompanying complications. Re-cently, we investigated the effects of a novel palati-nose based enteral formula (MHN-01) in suppressingpost-prandial hyperglycemia and improving lipid me-tabolism in experimental animals and perioperativemanagement of patients with esophageal cancer com-plicated by diabetes mellitus.

Materials and methods. We gave normal rats and ratswith type 2 diabetes mellitus a single oral dose of fluiddiet, and analyzed comparatively the time course ofblood glucose level in each group until 3 h after the dose.In both the normal rat group and the type 2 diabetesgroup, peak blood glucose level after the MHN-01 dosewas significantly lower than after a dose of ordinaryfluid diet and was comparable to the peak level after adose of a fluid diet rich in MUFA (monounsaturated fattyacid). We allowed normal mice free access to fluid diet

for 43 days, and measured their body fat levels. Fat ac-cumulation was significantly lower in mice givenMHN-01 than in mice given ordinary fluid diet. We alsoanalyzed the respiratory quotient and resting energyexpenditure of normal Sprague-Dawley rats fed byMHN-01 or an ordinary fluid diet. The respiratory quo-tient of the MHN-01 group was significantly lower thanthe ordinary fluid group, although the resting energyexpenditure of both groups was almost the same level.The effect of MHN-01 was estimated to be based on im-provement of lipid metabolism.

Results. Between 2003 and 2005, among 164 patientswho underwent radical thoracic esophagectomyand/or reconstruction for esophageal carcinoma atOkayama University Hospital, nine patients (5.5%)were diagnosed with diabetes mellitus in pre-operative screening and were treated with MHN-01.Clinical courses of two cases with severe status ofdiabetes mellitus were presented as successful casereports of MHN-01.

Conclusion. MHN-01 was very useful in periopera-tive management of patients complicated by diabetesmellitus, unable to ingest food p.o. such as esophagealcancer or other diseases. © 2006 Elsevier Inc. All rights reserved.

Key Words: MHN-01; diabetes; perioperative hyper-glycemia; esophageal cancer.

1 To whom correspondence and reprint requests should be ad-dressed at Department of Gastroenterological Surgery, Transplantand Surgical Oncology, Graduate School of Medicine, Dentistry andPharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho,Okayama 700-8558, Japan. E-mail: [email protected].

Journal of Surgical Research xx, xxx (2006)doi:10.1016/j.jss.2006.06.025

1 0022-4804/06 $32.00© 2006 Elsevier Inc. All rights reserved.

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INTRODUCTION

The prevalence of diabetes for all age-groups world-wide was estimated to be 2.8% in 2000 and 4.4% in2030 [1]. We often face difficulties associated with hy-perglycemia and other various accompanying compli-cations during perioperative management of patientswith gastrointestinal cancer in which adequate ali-mentation is required.

It has been reported that the increase in plasma glu-cose and insulin after ingestion of palatinose (isomaltu-lose), which is known as a component of honey, is signif-icantly smaller than that of sucrose [2]. Furthermore,palatinose has been reported as an insulin-sparing ca-loric sweeter with a lower glycemic index than sucrose intype 2 diabetic patients and streptozotocin-diabetic ani-mals [3]. A novel palatinose-based enteral formula des-ignated as MHN-01 was developed for the preventionof post-prandial hyperglycemia and hyperinsulinemia.MHN-01 is a carbohydrate-adjusted fluid diet contain-ing the disaccharide palatinose as a major carbohy-drate that Meiji Dairies Corporation currently distrib-utes under the brand name Inslow. In a recent study,we evaluated the effects of MHN-01 in suppressingpost-prandial hyperglycemia and improving lipid me-tabolism in experimental animals [4]. Furthermore, weused MHN-01 for perioperative management of pa-tients with esophageal cancer complicated by diabetesmellitus. We verify the effects of MHN-01 in suppress-ing hyperglycemia and improving lipid metabolism inexperimental animals and recently used this novelfluid diet for perioperative management of nine pa-tients with esophageal cancer complicated by diabetesmellitus. This diet proved useful in all of these cases, asreported below.

MATERIALS AND METHODS

Composition of Carbohydrate-Adjusted Fluid Diet MHN-01

The novel carbohydrate-adjusted fluid diet MHN-01 was preparedby the replacement of dextrin in ordinary enteral liquid diet with55.7% palatinose among carbohydrates (Table 1). MHN-01 containspalatinose, branched dextrin, xylitol, and other carbohydrates con-

taining dietary fiber and mixed carbohydrates from raw material asthe principal carbohydrates, and the percentages of protein, fat, andcarbohydrates in the formula are 20.0, 29.7, and 50.3%, respectively.The fluid diet of an ordinary composition (ordinary fluid diet), fluiddiet rich in monounsaturated fatty acid (MUFA-rich fluid diet) thatwere used for comparison contains dextrin and sucrose as the prin-cipal carbohydrates, and the percentages of protein, fat, and carbo-hydrates are 16.0, 25.2, and 58.8%, and 16.4, 49.2, and 34.4%, re-spectively. MHN-01 has another feature with the milk-derivedphospholipids containing phosphatidylethanolamine, phosphatidyl-choline, and sphingomyeline. Spray-dried powder versions of MHN-01, ordinary fluid diet and MUFA-rich fluid diet were prepared foruse in this study.

Palatinose is a disaccharide, like sucrose, but differs from thelatter in the binding site of two sugars. Palatinose is formed by thebinding of position-1 carbon of glucose to position-6 carbon of fruc-tose. This bond is considered relatively stable, resulting in slowdigestion and absorption in vivo (Fig. 1).

In January 2003, the official committee for enteral foods andnutrition in Okayama University Hospital approved MHN-01 as aregular enteral liquid formula for patient with diabetes mellitus.

Experimental Animals

There were 18 male normal rats (Sprague-Dawley), 8 weeks ofage, purchased from Japan SLC and 18 male rats with type 2diabetes mellitus (GK), 7 weeks of age, purchased from Clea JapanInc. and used for experiment 1-1. There were 27 mice with type 2diabetes mellitus (C57BL/Ksj-db/db Jcl), 8 weeks of age for experi-ment 1-2 and 27 male normal mice (C57BL/6N), 9 weeks of age forexperiment 2 were purchased from Clea Japan Inc. and used for thefollowing experiments. All animals were cared in accordance withthe National Institutes of Health (NIH) Guidelines for the Care andUse of Laboratory Animals.

Carbohydrate Improvement

Suppression of post-prandial blood glucose elevation. We gavenormal rats (Sprague-Dawley) and rats with type 2 diabetes mellitus(GK) a single oral dose (12 kcal/kg) of one of the following diets:powdered MHN-01, fluid diet of an ordinary composition (ordinaryfluid diet), or fluid diet rich in monounsaturated fatty acid (MUFA-rich fluid diet). The time course of blood glucose level was followeduntil 3 h after the dose (Fig. 2).

FIG. 1. Construction of palatinose (A) and sucrose (B). MHN-01is carbohydrate-adjusted fluid diet containing the disaccarhide pal-atinose as a major carbohydrate. Palatinose is formed by the bindingof position-1 carbon of glucose to position-6 carbon of fructose. G,glucose; F, fructose.

TABLE 1

Compositions of the Administered Fluid Diets

MHN-01MUFA-richfluid diet

Ordinaryfluid diet CRF

Energy (kJ/mL) 4.19 4.19 4.19 —Carbohydrates (%) 50.3 34.4 58.8 60.4Protein (%) 20.0 16.4 16.0 25.4Fat (%) 29.7 49.2 25.2 16.2

Ordinary fluid diet, the fluid diet of an ordinary composition;MUFA-rich fluid diet, fluid diet rich in monounsaturated fatty acid;CRF-1, a diet thought to allow ideal alimentation of mice.

2 JOURNAL OF SURGICAL RESEARCH: VOL. xx, NO. x, MONTH 2006

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Suppression of HbA1c elevation under long-term feeding. We al-lowed mice with type 2 diabetes mellitus (C57BL/KsJ-db/db Jcl) freeaccess to powdered MHN-01, ordinary fluid diet or MUFA-rich fluiddiet for 1 month and followed the time course of HbAlc during thisperiod. The energy intake was equal in all experimental fluid diet(Fig. 3A). MHN-01 was equivalent to MUFA-rich fluid diet, and morethan ordinary fluid diet in a body weight increases (Fig. 3B). Glu-tamic pyruvic transaminase (GPT) levels in serum and triglyceride(TG) levels in liver tissue were determined after these diets had beentaken for 1 month.

Lipid Metabolism ImprovementWe allowed normal mice (C57BL/6N) free access to powdered

MHN-01 for 1 month, and measured the body fat level in comparisonto mice given an ordinary fluid diet or CRF-1 (a diet thought to allowideal alimentation of mice). The energy intake was equal in allexperimental fluid diet (Fig. 4A). MHN-01 was equivalent to CRF,and less than ordinary fluid diet in a body weight increase (Fig. 4B).

Respiratory Quotient (RQ) and Resting EnergyExpenditure (REE)Normal Sprague-Dawley rats were starved for 18 hours, and then

12 kcal/kg of MHN-01 or ordinary fluid diet were given throughenteral tube. Using Micro-Oxymax system (Columbus Instruments,Columbus, OH), a closed circuit respirometer for small animals withhigh sensitivity, the RQ (Fig. 5A) and REE (Fig. 5B) were measuredand analyzed.

RESULTS

Experiment 1-1

In both the normal rat group and the type 2 diabetesrat group, the peak blood glucose level and the area

under the curve (AUC) after the single dose of MHN-01were significantly lower than after the single dose ofordinary fluid diet (Fig. 2). These parameters after theMHN-01 dose were comparable to those after theMUFA-rich fluid diet dose (Fig. 2).

Experiment 1-2

The peak blood glucose levels measured 3 to 4 weeksafter the start of feeding were significantly lower in theanimals given MHN-01 or MUFA-rich fluid diet thanordinary fluid diet (Fig. 3C). HbA1c levels measured 4weeks later were significantly lower in the MHN-01group than in the groups given the other two diets (Fig.3D). Further, hepatic accumulation of TG was signifi-cantly greater in the MUFA-rich diet group, and it alsoexhibited hepatopathy (Fig. 3E and 3F).

Body weight and the weight of the body after re-moval of the internal organs were significantly high inthe ordinary fluid diet group, but body weight afterremoval of subcutaneous fat tissue was almost thesame in all diet groups so the higher body weight in theordinary fluid diet group seemed attributable to lipidaccumulation (Fig. 4). Lipid accumulation in the retro-peritoneum and epididymis was significantly lower inthe MHN-01 group than in the ordinary fluid dietgroup. Triglyceride level in liver is 115 ! 11 g inMHN-01 group, 140 ! 34 g in ordinary diet group, and143 ! 30 g in CRF-1 group although serum triglyceridelevel does not show remarkable difference among three

FIG. 2. Suppression of post-prandial blood glucose elevation. Blood glucose level in Sprague-Dawley (A), AUC of blood glucose inSprague-Dawley (B), blood glucose level in GK (C), AUC of blood glucose in GK (D). The time course of blood glucose level was followed until3 h after the dose of MHN-01 (●), MUFA-rich fluid diet (!) and ordinary fluid diet (□). In both group, the peak blood glucose level and thearea under the curve after the single dose of MHN-01 were significantly lower than after the single dose of ordinary fluid diet (*P " 0.05).Values are the means of n # 9 for each group; bars, SD.

3FUJIWARA ET AL.: CARBOHYDRATE-ADJUSTED FLUID DIET IN ESOPHAGEAL CANCER WITH DIABETES

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diet groups. Serum protein and albumin are slightlyhigher in MHN-1 group (Fig. 4I and 4J), which dem-onstrating that MHN-01 does not induce malnutritionnor dysfunction on metabolism. MHN-01 was equiva-lent or superior to the CRF-1 diet in terms of all pa-rameters analyzed, suggesting that MHN-01 can serveas an adequate source of energy and regulate lipidaccumulation in tissues.

RQ and REE

As shown in Fig. 5A, the RQ of the MHN-01 group wassignificantly lower than the ordinary fluid group. On theother hand, the REE of both groups was almost the samelevel and showed no difference, suggesting that MHN-01is absorbed and metabolized normally. These data dem-

onstrate that the benefit of MHN-01 is the lower RQ thatis involved in lower fat deposits.

Clinical Case Reports

Patients

Between January 2003 and December 2005, among164 patients who underwent radical thoracic esopha-gectomy and/or reconstruction for esophageal carci-noma at Okayama University Hospital, nine patients(5.5%) were diagnosed with diabetes mellitus in pre-operative screening. Informed consent was obtainedfrom each patient and all treatment modalities wereapproved by the Institutional Review Board ofOkayama University Hospital. Operations were per-

FIG. 3. Suppression of HbA1c elevation under long-term feeding. Energy intake (A), changes of body weight (B), blood glucose levels inserum (C), HbA1c levels in serum (D), TG levels in liver tissue (E), GPT levels in serum (F). We allowed C57BL/KsJ-db/db Jcl free access topowdered fluid diet MHN-01 (●), MUFA-rich fluid diet (!) and ordinary fluid diet (□) for 1 month and followed the time course of HbAlc duringthis period. Glutamic pyruvic transaminase (GPT) levels in serum and triglyceride (TG) levels in liver tissue were determined after thesediets had been taken for 1 month. HbA1c level measured 3 to 4 weeks after the start of feeding was significantly lower in the animals givenMHN-01 than in the animals given the other two diets (*P " 0.05). Further, hepatic accumulation of TG was significantly greater in theMUFA-rich diet group, and it also exhibited hepatopathy (*P " 0.05). Values are the means of n # 9 for each group; bars, SD.


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FIG. 4. Lipid metabolism improvement. Energy intake (A), changes of body weight (B), body weight (C), body weight after removal of theinternal organs (D), subcutaneous fat tissue (E), the body weight after removal of the internal organs and subcutaneous fat tissue (F),epididymal fat tissue (G), retroperitoneal fat tissue (H), total serum protein (I), and serum albumin (J). We allowed C57BL/6N free accessto powdered MHN-01 (●) for 1 month, and measured body fat level in comparison to mice given an ordinary fluid diet (!) or CRF-1 (□). Bodyweight and the weight of the body after removal of the internal organs were significantly high in the ordinary fluid diet group, but body weightafter removal of subcutaneous fat tissue was almost the same in all diet groups (*P " 0.05). Lipid accumulation in the retroperitoneum andepididymis was significantly lower in the MHN-01 group than in the ordinary fluid diet group (*P " 0.05). Values are the means of n # 9for each group; bars, SD.


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formed on each patient, jejunostomy were performedfor continuous tube feeding. Three days after each op-eration, tube feeding using MHN-01 was started. Thedose of MHN-01 was increased gradually up to 1500 or1750 kcal. Glucose in blood and urine was monitored.Outcome measures were blood and urine glucose andthe required dosage of insulin (Table 2).

The effects of MHN-01 were evaluated in clinicalcases of perioperative management for patients withesophageal cancer complicated by diabetes mellitus. 2representative cases of nine patients treated withMHN-01 are presented as case reports (Fig. 7 and 8).

Case 1

Disease History

Case 1 presented a 59-year-old male with alcoholicpancreatitis and acute pancreatitis. The patient beganreceiving insulin therapy (bi-phasic insulin 12 U/day)at age 49, based on a diagnosis of diabetes mellitus.Around November 2002, the patient began to feel dif-ficulty swallowing solid food. On December 30 of thesame year, he received upper digestive tract endoscopyat a nearby clinic and was diagnosed as having cancerof the middle thoracic segment of the esophagus. Hewas referred and admitted to our hospital on January17, 2003. The patient now shows no signs of anemia orjaundice. No superficial lymph nodes are palpable.

Course

Detailed examination before surgery for cancer ofthe middle thoracic segment of esophagus allowed adiagnosis of severe diabetes mellitus secondary tochronic pancreatitis. Laboratory results during thehospital stay showed HbA1c was controlled relativelywell (6.8%). Daily urinary glucose elimination was ab-normally high at 34.4 g, while urinary CPR, an indica-tor of endogenous insulin, was markedly low.

Circadian variation in blood glucose level examinedpre-operatively showed very high blood glucose levels2 h after meals (536 mg/mL). Insulin administration

was required for this reason. This resulted in a sharpfall in blood glucose level to 60 mg/mL (Fig. 6) Wedecided it was impossible to continue the test. Thispatient was diagnosed as having secondary diabetesmellitus attributable to intensely disturbed pancreaticendocrine function because of chronic pancreatitis. Theplanned surgery was postponed.

We managed this case with continuous MHN-01 al-imentation via tube and continuous subcutaneous in-sulin infusion. Immediately after the start of MHN-01dosing, daily urinary glucose elimination became neg-ative and blood glucose control improved (Fig. 7), al-lowing the patient to undergo surgery for cancer about1 month later. After surgery, the patient developedpneumonia, disturbing the control of blood and urinaryglucose temporarily. However, blood and urinary glu-cose control improved rapidly as inflammatory reac-tions subsided.

Case 2

Disease History

A 68 years old male patient has been receivingalpha-glucosidase inhibitor therapy based on the diag-nosis of diabetes mellitus since he was in his 40s. InNovember 2001, the patient was referred to our hospi-tal owing to cancer in the middle and lower thoracicsegments of the esophagus. On January 11, 2002, heunderwent coronary artery bypass grafting (CABG) totreat coronary artery stenosis caused by marked ath-erosclerosis secondary to diabetes mellitus. On April 22of the same year, we performed a partial esophagec-tomy. Because of post-operative anastomotic failure, hereceived additional esophagectomy. On May 12 of thesame year, we performed percutaneous trans-gallbladderdrainage (PTGBD) to deal with acute cholecystitis. Sincethen, we have used enteric alimentation with ordinaryfluid diet (1700 kcal/day) to improve his systemic condi-tion. No signs of anemia or jaundice are visible now. Nosuperficial lymph nodes are palpable.

FIG. 5. RQ and REE. Normal Sprague-Dawley rats were starved for 18 h, and then 12 kcal/kg of MHN-01 (●) or ordinary fluid diets (!)were given through enteral tube. The RQ (A) and REE (B) were measured and demonstrated. Values are the means of n # 10 for each group;bars, SD.


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Course

We used long-term tube feeding to deal with compli-cations. During this period, diabetes mellitus was con-trolled relatively well, with HbA1c kept at 6.6% anddaily urinary glucose elimination at 0.1 g/day (Fig. 8).

Infection developed after esophageal reconstructionbecause of anastomosis, making blood and urinary glu-cose control difficult. To deal with this condition, weperformed continuous MHN-01 alimentation via tubeand continuous intravenous insulin infusion. Soon af-ter the start of this therapy, control of blood and uri-nary glucose improved.

Shown in Table 2, we performed perioperative man-agement of nine patients with MHN-01. Two of thenine patients, cases 1 and 2 showed over 20 g of urineglucose per day (34.4 and 25.6 g/day). Although theirdiabetes mellitus was very severe, the clinical outcomeusing MHN-01 was positive. We presented these twocases in Figs. 6, 7, and 8 as successful cases of MHN-01. Four of nine cases showed remarkable decline ofurine glucose and required dosage of insulin. All nineof the patients had no specific complication induced bythe usage of MHN-01.

As historical controls, we surveyed 155 patients whounderwent esophagectomy for esophageal carcinomaat Okayama University Hospital from 2000 to 2002.Among them, six patients (3.9%) were diagnosed withdiabetes mellitus in pre-operative screening and treatedwith regular carbohydrate diets in perioperative periods.In these all cases, we could not find the decrease of bloodand/or urine glucose or required dose of insulin.

Compared with these historical controls, we con-firmed that MHN-01 was very useful in perioperativemanagement of patients unable to ingest food p.o.

FIG. 6. Circadian variation in blood glucose level (case 1). Bloodglucose level 2 h after meals went up to a very high value of 536mg/dl. Insulin administration was required for this reason, causing asharp fall in blood glucose level to 60 mg/dl.

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Surgical operation for esophageal cancer is some-times accompanied by severe complications. On theother hand, patients with diabetes mellitus possessmajor risks for perioperative complications because oftheir immunosuppressive status induced by diabetes.

We demonstrate that MHN-01 enables patients withdiabetes mellitus to reduce the urine glucose, to haveenough nutritional energy and to minimize the risk ofperioperative complications for surgical treatment ofesophageal carcinoma.

FIG. 7. Perioperative course of case 1. Case 1 was pre-operatively managed with continuous MHN-01 alimentation with a tube andcontinuous subcutaneous insulin infusion. Soon after the start of therapy, urinary glucose elimination discontinued and blood glucose controlimproved, allowing the patient to undergo surgery. OF, ordinary fluid diet; HF, hospital food.

FIG. 8. Post-operative course of case 2. Case 2 was managed with continuous MHN-01 alimentation with a tube and continuousintravenous insulin infusion to deal with anastomotic failure. Soon after the start of this therapy, control of blood and urinary glucoseimproved.


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DISCUSSION

During perioperative management of patients withgastrointestinal cancer complicated by diabetes melli-tus, adequate alimentation is essential [5, 6]. Thesecases, however, often develop hyperglycemia and var-ious accompanying complications. Particularly in casesof cancer of the thoracic segment of the esophagus,patients are exposed to high operative stress, and ifmultiple-stage operation requires long-term tube feed-ing or leads to the onset of complications, it is oftendifficult to control blood and urinary glucose [5, 6].

According to our departmental policy, we carry outsurgery under general anesthesia on diabetic patientsif their daily urinary glucose elimination does not ex-ceed 10 g/day. If daily urinary glucose elimination doesexceed 10 g/day, post-operative complications are inev-itable. In such high-risk cases, we make it a rule to applystrict pre-operative management or to replace surgerywith IVR and/or chemotherapy. However, these casesoften require long-term control, making surgery with op-timal timing difficult or even impossible.

When performing esophageal cancer surgery on high-risk patients such as patients with complications orelderly patients, we select multiple-stage operations toavoid post-operative complications. Tube or intrave-nous alimentation is required for patients undergoingmultiple-stage operations during the period from resec-tion to reconstruction. In such cases, irrespective ofwhether or not the patient has been pre-operativelydiagnosed as having diabetes mellitus, intravenous, orenteric alimentation can cause various problems, suchas poor blood glucose control, hepatic dysfunction, lipidaccumulation, or diarrhea because of the enteric nutri-tional preparation. The patient’s condition will furtherdeteriorate if these problems are accompanied by post-operative complications.

A deficiency in early insulin secretion in patientswith type 2 diabetes contributes to post-prandial hy-perglycemia and subsequent delayed hyperinsulin-emia, causing retinopathy, neuropathy, nephropathy,cardiovascular disease, obesity, infection, and othercomplications [7–10]. To resolve these problems, it isadvisable to develop new enteric nutritional prepara-tions that affect blood glucose control favorably.

MHN-01 is a carbohydrate-adjusted fluid diet that con-tains palatinose, a disaccharide, as a major carbohydrate.In a recent study conducted jointly with Meiji DairiesCorporation, we evaluated the effects of MHN-01 in sup-pressing post-prandial hyperglycemia and improvinglipid metabolism in experimental animals. Further, weused MHN-01 for perioperative management of 9 pa-tients with esophageal cancer complicated by diabetesmellitus.

MHN-01 can be characterized by the use of palati-nose as a source of carbohydrate and milk phospholip-ids as a source of fat. Its energy balance is as follows:

carbohydrate 50%, protein 20%, and lipid 30%. Palati-nose is a natural sugar contained in sugar cane andhoney. Research and development of palatinose as asweetener of natural origin have been conducted inmany countries [4, 11, 12]. Various toxicological stud-ies have established the safety of palatinose. The Jap-anese authorities have authorized palatinose as a spe-cial health promotion food [4, 11]. Palatinose is adisaccharide, like sucrose, but differs from the latter inthe binding site of two sugars. Palatinose is formed bythe binding of position-1 carbon of glucose to position-6carbon of fructose [13]. This bond is considered rela-tively stable, resulting in slow digestion and absorptionin vivo [11, 13]. The degradation rate of palatinose isabout one-fifth of that of sucrose [2, 3, 14]. Furthermore,when ingested independently, palatinose is known tosuppress elevation of blood glucose levels, and apart fromthis, is also believed to suppress elevation of bloodglucose levels caused by concomitantly ingested sugarwhen ingested together with sucrose or glucose. Stud-ies for other functions of palatinose is being researchedand it is determined that palatinose has cariostaticeffect and that palatinose-based oligomers improvemineral absorption and retention, and etc. [15–19].

In experiments of palatinose digestion in vitro, it hasbeen shown that palatinose is degraded almost com-pletely into glucose and fructose under the catalyzingactivity of isomaltase present in the small intestineand is absorbed in these forms, without being affectedby saliva, gastric acid or pancreatic juice [11, 13]. Inhumans, isomaltase is found in the form of sucrase-isomaltase (SI) complex in the small intestine andworks to suppress diarrhea [11, 13, 20]. Palatinose isdigested and absorbed via the small intestine and doesnot work as edible fibers. Its calorie is 4 kcal/g, resem-bling other carbohydrates.

Suppression of fat accumulation by palatinose may beexplained by the following mechanism. Usually, insulinelevates the lipoprotein lipase activity (LPL) of fat tissue,thus stimulating the uptake of fat from blood [21, 22].Because the palatinose is digested and absorbed slowly itstimulates insulin secretion only slightly, resulting in thelow likelihood of simultaneously ingested fat accumulat-ing in the form of fat tissue [3, 11, 22, 23].

MHN-01 uses monounsaturated fatty acid (MUFA)as a major source of lipid. The n-6:n-3 ratio is 2.4:1 withMHN-01. This means that MHN-01 contains more n-3fatty acid than ordinary fluid diets (n-6:n-3 # 4:1).Milk-derived phospholipids are contained in MHN-01.Milk-derived phospholipids resemble soybean- or yolk-derived phospholipids in that they are composed ofphosphatidylcholine, phosphatidylserine, and phos-phatidylethanolamine. However, milk-derived phos-pholipids differ from the latter two in that the formercontains sphingomyelins [24, 25]. It seems likely that


ARTICLE IN PRESS

the combined effects of milk-derived phospholipids, n-3fatty acid and palatinose lead to marked suppression offat accumulation.

Of the cases we encountered urinary glucose disap-peared in case 1 even within two days after the start ofMHN-01 therapy, indicating the marked efficacy of thispreparation. Four of nine cases showed remarkable de-cline of urine glucose and required dosage of insulin.

As historical controls, we surveyed 155 patients whounderwent esophagectomy from 2000 to 2002 at ourinstitute. Among them, six patients (3.9%) were diag-nosed with diabetes mellitus and treated with regularcarbohydrate diets in perioperative periods. Amongthese all cases, we could not find the decrease of bloodand/or urine glucose or required dose of insulin. It isnoteworthy that this effect of MHN-01 allowed thegeneral condition of this patient with advanced cancerto improve rapidly to a level allowing surgery. MHN-01is a fluid diet that is very useful in perioperative man-agement of patients with gastrointestinal cancer com-plicated by diabetes mellitus. It seems useful also inthe management of patients with cerebral infarction,dysphasia, and intractable bedsores.

This study focused on patients with esophageal cancer,but the results may apply to other patients with poorglucose control in the post-operative period. It may alsohave broader applications for any kind of patients withpoor post-operative glucose control. Using this novel for-mula MHN-01, we would like to discover a new horizon ofclinical application for perioperative management andnutrient therapy for severe diabetes mellitus.

ACKNOWLEDGMENTS

This study is a functional collaboration between Okayama Univer-sity and Meiji Dairies Corporation. Each component of the experi-ments was performed by either Okayama University or Meiji Milk.There are no financial interests in this palatinose-based formulaMHN-01 and there was no funding from Meiji Dairies Corporation toOkayama University.

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ARTICLE IN PRESS

Effects of a Novel Palatinose Based Enteral Formula (MHN-01) Carbohydrate-Adjusted Fluid Diet in Improving the Metabolism of Carbohydrates and Lipids in Patients with Esophageal Cancer

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