Carbohydrate-Rich, Fat-Poor Dietin Diabetes*

INGRID ERNEST, M.D., ERIK LINNBR, M.D . and ALVAR SVANBORG, M.D .

Gothenburg, Sweden

EXPERIENCE with an earlier short-term studyon the effect of different isocaloric diets in

diabetes showed that even diets of extremecomposition can be used-at least for sometime-without clinical complications or note-worthy discomfort to the patient [ 11 .

A carbohydrate-rich, fat-poor diet was chosenfor further long-term study . This choice wasbased on both theoretical and clinical considera-tions. The diabetic state is a broad disturbancein the metabolism of carbohydrate, fat andprotein but the insufficiency of glucose oxidationis of central importance in this disease . De-creased glucose oxidation will result in disturb-ances also in the oxidation, synthesis and mobili-zation of lipids . From this point of view thetherapeutic efforts should aim at increasing theoxidation of glucose to a normal rate . The intakeof carbohydrate, therefore, should be kept high.Furthermore, a decrease in the fat content of thefood would be expected to diminish the tendencyto ketoacidosis . Such a diet, including largeamounts of vegetables with a low caloric content,also counteracts the risk of obesity, which is un-suitable for diabetic subjects.

The aim of the present investigation was tostudy the effect of a carbohydrate-rich, fat-poordiet on various vascular lesions in diabetes . Itwas reported by van Eck [2j that a low fat dietis well tolerated by patients with diabetes andhas a good effect on diabetic retinopathy . Wehave been investigating the possibility of nor-malizing some of the diabetic changes which,according to general clinical experiences, areunlikely to improve spontaneously . We were nottrying to evaluate a possible slowing down of therate of progress of the disease ; in order to do thisa greater number of patients than studied herewould be required, with satisfactory controls .

MATERIAL

Nine patients (two women and seven men) wereincluded in the study . None of them had arterialhypertension, all had diabetic retinopathy . Protein-uria was taken as evidence of diabetic nephropathywhen repeated investigations failed to demonstrateother diseases of the kidneys or urinary tract .

CASE 1 . This man, born in 1917, had had diabetessince 1927 . Earlier he had very unstable diabetes withrepeated hypoglycemic accidents but never ketoacido-sis .

CASE 2 . This man, born in 1933, had had diabetessince 1937 and angina pectoris since 1954. At a workload of 600 kg. per minute on a bicycle ergometersigns of coronary insufficiency appeared in the elec-trocardiogram . An angiogram showed pronouncedand widespread coronary arteriosclerosis .

CASE 3. This woman was born in 1922 and hadhad diabetes since 1942 .

CASE 4 . This man was born in 1922 and had haddiabetes since 1946

CASE 5. This woman was born in 1937 and hadhad diabetes since 1939 . Slight proteinuria had beenpresent since 1957, with repeated urinary tract infec-tions . The serum creatinine concentration was withinnormal limits.

CASE 6 . This man was bom in 1931 and had haddiabetes since 1945, which was unstable with repeatedepisodes of hypoglycemia or ketoacidosis . Since 1958there had been signs of diabetic neuropathy andperipheral arterial insufficiency in both legs . Thearteriogram showed widespread atheromatosis in thevessels of the leg and an occlusion in the right tibialartery. After the first year this patient was livingabroad and returned for follow-up studies .

CASE 7 . This man, born in 1929, had had diabetessince 1943 . Slight proteinuria had been present since1956 ; the serum creatinine was within normal limits .

-From the Medical Clinic II and the Department of Ophthalmology, University of Gothenburg, Gothenburg,Sweden . This study was presented at the meeting ofthe Swedish Society for Internal Medicine in Gothenburg, October,19, 1963 . Manuscript received October 6, 1964 .

594

AMERICAN JOURNAL OF MEDICINE

CASE 8 . This man was born in 1930 and had haddiabetes since 1932 .

CASE 9 . This man, born in 1928, had had diabetessince 1945 . Slight proteinuria had been present since1961 ; the serum creatinine was within normal limits .

METHODS

Did . The caloric intake was adjusted to a level atwhich the patient maintained a normal and constantbody weight . Three alternatives were provided, theamount of calories, carbohydrate, fat and protein inthe diet varying as shown in Table L. Most of thecarbohydrate consisted of starch-rich vegetables andfruits . Pure sugars were avoided . Bread was restrictedto 150 mg ., milk to 0.5 L . of skim milk and potatoes to200 gm . per day . The diet included adequate amountsof minerals and vitamins. Three meals of cooked foodand three between-meal snacks were given every day .Breakfast included 460 to 630 calories, lunch 480 to670 calories and dinner 560 to 780 calories .

At the time of the present report three patients(Cases 1, 2 and 3) have adhered to the diet for twoand a half years, three (Cases 4, 5 and 6) for two yearsand three (Cases 7, 8 and 9) for one and a half years .As it was thought desirable to keep the patients

under close control during the first diet period, theywere hospitalized during the first two to six months .Except for the first weeks in the hospital, the malepatients were allowed to do their usual work duringtheir stay in the hospital . When the patients left thehospital, they received detailed diet lists for everymeal during a three week period . A special dieticianwas available to them during the whole study .

In addition to the regular clinical examinations,which as a rule were made at least every secondmonth, the following examinations were made beforethe diet period and at different times during thestudy : electrocardiography, exercise tolerance test ona bicycle ergometer [31, x-ray examination of theheart, blood flow measurements in the calf of the legby conventional venous occlusion plethysmography.Both resting blood flow and maximal blood flow weremeasured and calculated per 100 nil . of tissue perminute. To obtain maximal blood flow, repeated5-minute periods of complete ischemia, combinedwith exercise of the calf muscles during the latter partof the ischemia, were induced until the blood flowcould not be increased any further .

Also recorded were the rate and extent of the in-crease in temperature in the toes when the patientwas exposed to strong indirect heating (body in warmwater of 42°c .) after being in a temperature-regulatedroom at 15°c., with controlled moisture. Rectaltemperature and heart rate were recorded as an indexof the efficiency of indirect heating . This test was usedin order to trace changes in reactivity of the apicalcutaneous vessels which usually appear as early signsof diabetic vasopathologic changes . Repeated tests

VOL . 39, OCTOBER 1965

Diet in Diabetes-Ernesi el al .

Cal-ories

2,0202,2202,420

Protein

TABLE ICOMPOSITION OF DIETS

595

Fat

Carbohydrate

were performed and the results compared with therate and extent of increase in the temperature ofnormal subjects exposed to the same carefully stand-ardized procedure for causing inhibition of vasocon-striction fibre activity in the skin by indirect heating .

The plasma creatininc level was determined re-peatedly. In six patients the renal clearance of inulinand para-aminohippuric acid was measured beforethe diet period and at the time of the follow-upstudy. In Cases 1 and 2 the bladder was catheterizedduring the clearance determinations . In no case wereobvious signs of disturbance in the dynamics of theurinary bladder present .

The diabetic lesions of the fundus were examinedregularly by direct ophthalmoscopy with the pupildilated . Pictures were also taken with a Zeiss funduscamera using Ectachrome® color film . Since it wasdifficult to obtain clear and reproducible photographsof the diabetic lesions showing all the details observedophthalmoscopically, the ophthalmoscopic findingswere considered conclusive for the evaluation. Thedevelopment and changes of three different lesions ofthe fundus specifically followed were : (1) small,round, distinctly outlined red dots-both micro-aneurysms and small, deep punctate hemorrhageswere included ; (2) deep sharply outlined hard exu-dates-all hard retinal exudates were included in thisgroup because a clear and consistent classification ofdifferent types was not always possible ; the soft exu-dates similar to these found in hypertensive retin-opathy were not included ; (3) proliferative lesionscharacterized by newly formed vessels and fibroustissue .

The postabsorptive levels of plasma total fat, totalcholesterol, phospholipids, glycerides and free fattyacids were analyzed according to methods describedearlier [4J. During the hospitalization period bloodlipid levels were analyzed at least once a week, afterthat the analyses were performed once every monthas a rule .

RESULTS

The clinical experiences with this special dietwere good. The patients tolerated the diet well .

I

gm./day

ories

%ofcal-

gm./day

oof

cal-Cries 'ones

agm./

ofday

cal-

104 21

16 .7 8 351

71112 21

17 .8 ! 7 389 72119 20

19 .1 7 428 73

596

TABLE DINSULIN DOSE AND BODY WEIGHT BEFORE DIET PERIOD

AND AT FOLLOW-UP

Ketoacidosis was not observed. After an initialperiod of weight reduction the patients readilymaintained a low normal and relatively con-stant body weight . (Table ii,)Hypoglycemic episodes were uncommon and

hypoglycemic coma appeared only once in onepatient (Case 1) when his lunch was delayed .Maintaining the sugar in the blood and urine atthe same or lower levels was easier than withearlier diets. In most patients the need for insulindecreased (Table it), especially in those who lostconsiderable weight .

The electrocardiographic findings and theresults of the exercise tolerance test did notchange significantly during the dietary period,not even in the patient who, at the beginning ofthis study, had advanced coronary sclerosis andanginal pectoris (Case 2) .Normal resting and maximal blood flow

values in the calf were found in those patients inwhom the measurements were performed . Com-parison of the values obtained before the specialdiet was instituted and those obtained aftervarious periods of the diet regimen did not, ingeneral, reveal any significant change in the rateand extent of the increase in temperature in thetoes upon indirect, standardized heating .

The results of the renal clearance studies werenormal and did not change significantly with thespecial diet. (Table in.)

In the patients with high plasma levels ofcholesterol and phospholipids and,/or trigly-cerides before the diet period, a reduction wasobserved as early as the first weeks of the diet .

Diet in Diabetes-Ernest et al .

Later on the level of these lipids remained rela-tively unchanged and not significantly differentfrom the normal level [4,51 for the population inthis part of Sweden . (Fig . 1-4 .)

A schematic description of the course of thelesions in the fundus will be given for each pa-tient separately .

CASE I . Before the diet period the right eye showeda haze in the central part of the vitreous, following avitreous hemorrhage . Some newly formed vessels andsome hard exudates around the macular area could befaintly observed. The left eye showed several micro-aneurysms and punctate retinal hemorrhages, alsoseveral hard exudates in the posterior part of thefundus. During the following year recurrent vitreoushemorrhages occurred in the right eye and a periph-eral preretinal hemorrhage developed in the left eye .In the left eye only a few hard exudates remained .After one and a half years a large vitreous hemorrhagedeveloped in the left eye, which was only partiallyabsorbed . During the last year of observation a pos-terior cataract began to appear in both eyes. There-after the diabetic lesions could not be evaluated ac-curately .

CASE 2. Before the diet period both eyes showednumerous microaneurysms and punctate retinalhemorrhages as well as hard exudates around themacular area. The macular area in the left eye wasnearly covered by an old pigmented lesion . No prolif-erative retinopathy was present . During the followingyear the number of red dots and exudates diminished .In the last year of observation there remained about20 to 30 red dots, but only one exudate in the righteye and but a few exudates in the left eye . A fine net-work of newly formed vessels appeared in the leftfundus .

CASE 3- Before the diet period there was a thickhaze in the central part of the vitreous following a

AMERICAN JOURNAL OF MEDICINE

Insulin Dose(1-U./day) Body Weight (kg .)

CaseNo . Before

DietPeriod

Follow-At

up

I -

BeforeDiet

Period

AtFollow .

up

I1 56 36 68 .7 63 .0I2 36 32 57 .7 59 .1

3 48 48 64 .6 62 .94 32 32 68 .5 68 .95 24 16 53 .7 48 .06 68 84 62 .3 637 56 36 70 .3 62 .58 64 64 58 .3 56 .79 48 28 66 .0 61 .7

TABLE IIIRENAL CLEARANCE OF INULIN AND PAH BEFORE DIET

PERIOD AND AT FOLLOW-UP

Inulin Clearance(ml./min,/1 .73 M' .

I PAH Clearance(nil ./min./1 .73 M',

CaseBSA) BSA)

No.BeforeDiet

Period

AtFollow-

up

BeforeDietPeriod

AtFollow-

up

1 84 127 758 6292 96 89 583 4664 141 175 535 6955 76 87 491 5087 95 103 561 5029 92 138 552 683

mgll00ml.

0

6

12

16

24

30

36 Months

FIG. 1 . Plasma total cholesterol level during the periodof observation.

vitreous hemorrhage in the right eye . In the left eyeproliferative fibrous tissue extended up and down fromthe disc. Several hard exudates could be seen in themacular area. During the following year the vitreoushemorrhage in the right eye was partially absorbedand fibrous tissue covering the disc and a few hardexudates could be seen . A vitreous hemorrhage oc-curred in the left eye . In both eyes the vitreous opac-ities cleared up to some extent . The exudates disap-peared and only a few red dots were seen . The prolif-erative lesions increased .

CASE 4. In both eyes several microaneurysms andpunctate, retinal hemorrhages and hard exudateswere present in the posterior part of the fundus . Noproliferative retinopathy was seen, The lesions re-mained essentially the same during the whole periodof study .

CASE 5 . In both eyes several microaneurysms,punctate retinal hemorrhages and hard exudates werepresent in the posterior part of the fundus . Therewere newly formed vessels close to the disc in botheyes. Under treatment, the red dots remained es-sentially the same, the exudates were somewhat re-duced, and theproliferativelesionsincreased markedly .

CAsE 6 . In both eyes there were numerous micro-aneurysms, punctate retinal hemorrhages and hardexudates, with some newly formed vessels in the rightand a few in the left eye. The number of red dots andexudates were reduced in both eyes under dietarytreatment. The newly formed vessels increased andthere was increased formation of fibrous tissue in botheyes.

Diet in Diabetes---Ernest et al .

m000 mL

of plasma

400

100

0

6

16

24

30

36 Months

Fm. 2. Plasma phospholipid level during the periodof observation.

mq/loomL

a plasma

300,

0

C

6

597

6

12

16

24

30

36 Months

Fro . 3 . Plasma glyceride level during the period ofobservation .

12 is

34

30

36 Months

CASE 7 . Several diffusely scattered microaneu-

Fm. 4 . Plasma free fatty acid level during the periodrysms and punctate retinal hemorrhages were present

of observation .

von . 39, OCTOBER 1965

598

TABLE IVOPHTHALMOSCOPIC FINDINGS

initially in both eyes, with a few hard exudates in theright fundus and a somewhat greater number in theleft fundus . In the periphery of the left fundus a small,preretinal fibrous membrane could be seen . Duringthe first year the number of exudates diminished butnewly-formed vessels developed in the left eye . Newly-formed vessels with delicate strands of connectivetissue developed in the right eye . The red dots re-mained essentially unchanged in both eyes .

CASE 8 . In both eyes there were some microaneu-rysms, punctate retinal hemorrhages and a few exu-dates around the macular area . The lesionsdiminishedand at the end of the period of observation there re-mained only two red dots in each eye and one hardexudate in the left eye .

CASE 9 . In the right fundus there were numerousmicroaneurysms, punctate retinal hemorrhages andhard exudates, with no proliferative lesions . In theleft eye there was a greater number of microaneu-rysms, punctate retinal hemorrhages and hard exu-dates, but with no proliferative lesions . The red dotsremained essentially the same in both eyes . The exu-dates were reduced, leaving only a few in the righteye and none in the left eye when the observationswere concluded. Newly-formed vessels near the discdeveloped in the right eye during the first year and inthe left eye during the second year .

The changes in red dots, exudates or prolifera-tive lesions are schematically demonstrated inTable tv. The red dots showed no strikingchanges in five patients and the same probablyoccurred in Case 1, in which a vitreous hemor-rhage obscured the details of the fundus . In theremaining three patients (Cases 2, 6 and 8) thenumber of red dots diminished .The hard exudates showed a tendency to

Diet in Diabetes-Ernest et al .

disappear more or less completely in seven cases(Fig. 5) and probably also in Case 1 (fundusobscured by vitreous haze) . In one instance(Case 4) the exudates remained essentially un-changed .

Proliferative lesions appeared in two patients(Cases 2 and 9), in whom such lesions were notobserved at the beginning of this study . In fourpatients proliferative lesions were present andprogressed, and the same tendency probablyoccurred in Case 1 . Two patients (Cases 4 and8) remained free from proliferative lesions duringthe time of this study.

COMMENTS

The clinical experience with this diet was ingeneral favorable, and no untoward side effectswere noted. That the patients readily main-tained a normal body weight is of importancesince undesired overweight in diabetic subjectsusually is difficult to counteract . The tendencyto abnormal ketoacidosis seems to have disap-peared and was not observed even when thepatients had acute infections .

A similar type of diet was used by van Eckwho found a decrease in the serum total fat andcholesterol. In the present study the plasmalipids initially showed marked variations, as isusual in diabetic patients . During the diet periodthe variations in serum lipids decreased and inpatients with initial hyperlipernia the level wasreduced to values within normal limits . In mostcases this fall in blood lipid levels was observedas early as the first three or four weeks on thediet. This observation differs from that made inanother study, in which a diet including 30 gm.of fat per day was used for three to six weeks[1] . Presumably the difference between 30 and20 gm. of fat in the two diets was responsible forthe different effect on the blood lipid level .The possibility of spontaneous appearance

and disappearance of red dots and exudates inthe retina must be considered when variations inthe retinal lesions are evaluated . There were nostriking changes in respect to the microaneu-rysms and punctate hemorrhages, but the exu-dates diminished or disappeared in eight of thenine patients. This is a striking observation,similar to that made by van Eck . According toour experience as well as to that of others (7,8],such a uniform regression in exudates in a groupof patients cannot be ascribed to spontaneousvariation. We consider it to be related to thediet. The regression appeared after they were on

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Case Red Dots

ExudatesNo. iProliferative

Lesions

i

No change?

Regression.' Progression?2

Regression

Regression No lesion,progres-sion

3

No change Regression Progression4

No change No change No lesion5

No change Regression Progression6

Regression Regression

Progression7

No change Regression

Progression8 Regression

Regression

No lesion9 No change

Regression

No lesion,progres-sion

5A

5R

5CFTC . 5 . Case 6 . Photographs of fundus . A, October 12 . 1961 . B, April 12, 1962 . C, September 2, 1963 .

the diet for about half a year and seemed to berelated in time to the onset of the diet .

The proliferative lesions showed a progressivetendency in eight patients . It is not possible toestimate whether the rate of this progress wasinfluenced by the diet . It was, however, strikingto observe the change in opposite directions ofthese different types of lesions, regressing exu-dates and progressing proliferative lesions, in-dicating a selective effect limited to certain typesof retinal lesions. Proliferative lesions are gen-erally believed to represent the pathologicsequel to healing exudates, and unfortunately inmost cases determine the prognosis of vision .

There has been much discussion about theorigin of the exudative lesions and their possiblerelationship to an abnormal lipid accumulationin the blood and in other tissues . The hardexudates are thought to be depositions of lipidsand mucoproteins, as far as can be judged fromtheir histologic staining reactions [9-11 ] .Kempner [12] and van Eck [2] had observedearlier that retinal exudates disappear in pa-tients during treatment with a diet extremelylow in fat [2,12] . Esmann and collaborators [6],who have made an extensive survey of the fre-quency and types of exudates in diabetic reti-nopathy, have also reported that the administra-tion of para-aeninosalicylate, which lowers thelevel of plasma cholesterol and presumably alsothe level of other plasma lipids, can bring aboutdisappearance of the hard exudates [8] . Kinget al. [7] observed that normalization of theserum cholesterol and total lipids, produced bya diet high in unsaturated fat, was followed by adecrease in retinal exudates [7] . On the otherhand, primary hypercholesterolemia, primaryhyperlipemia and other nondiabetic diseases inVOL . 39, OCTOBER 1965

Diet in Diabetes-Ernest et al . 599

which plasma lipids are increased, arc not asso-ciated with hard retinal exudates ; this indicatesthat the plasma lipid level per se appears not to beresponsible for the exudates .

King et al . [7] reported that a reduction inthe amount of exudate in diabetic retinopathywas not associated with any significant improve-ment in the visual acuity . They therefore con-cluded that the exudates seem to be the endresult of a neuronal degeneration which impairsvision . According to our experience, however,improvement in visual acuity may occur inconnection with the disappearance of smallexudates . In one patient not included in thisstudy, in whom visual acuity at previous exami-nations was normal, two small exudates de-veloped in the foveola, and the visual acuity wassignificantly reduced . After dietary treatmentfor eight months these exudates disappeared andvisual acuity returned to normal . The duration,size and location of the exudates might play arole in the improvement in vision when theydisappear .

SUMMARY

A carbohydrate-rich, low-fat diet has beenused for one and a half to two and a half yearsin the treatment of nine diabetic patients withretinopathy . The marked variations in theplasma lipid levels, commonly seen in diabetes,were reduced and their level was normalized .The results of renal clearance determinationsand of studies on the coronary and cutaneouscirculation did not change significantly . In theretina, the hard exudates diminished or disap-peared but proliferative lesions showed a tend-ency to progress.

600

Acknowledgment: We would like to thank thedietician, Miss Lilian Frick, and the nurse, MissIngrid Lind, for their invaluable help . The tech-nical contributions of Mrs . Else Dahl are alsogratefully acknowledged . This study was sup-ported by grants from the Swedish Associationof Diabetics and from the Swedish NationalAssociation against Heart and Chest Diseases .

REFERENCES

1 . ERNEST, 1 ., HALLOREN, B . End SVANBORG, A .Short term study of effect of different isocaloricdiets in diabetes . Metabolism, 8: 912, 1962 .

2. VAN EOK, W . F. The effect of a low fat diet on theserum lipids in diabetes and its significance indiabetic retinopathy . Am. J. Med., 27 : 196, 1959 .

3. HOLMGRRN, A. and MATTSSON, K. M. New ergom-eter with constant work load at varying pedal-ling rate. Scandinav. J. Clin. & Lab. Invest., 6 :137, 1954 .

4. SvANsoao, A. and SVENNERHOLM, L. Plasma totallipid, cholesterol triglycerides, phospholipids andfree fatty acids in a healthy Scandinavian pop-ulation . Asia med. scandinar., 169 : 43, 1961 .

5. CRAMkR, K . Cholesterol and phospholipid contentof human-lipoprotein in different lipemic states

Diet in Diabetes-Ernest et ai .

and following myocardial infarction . J. Athero-sclerosis Res ., 1 : 317, 1961 .

6. ESMANN, V., LUNDnACK, K, and MADSEN, P . H .Types of exudates in diabetic retinopathy . Actamed. scandinav ., 174 : 375, 1963 .

7 . KING, R . C., DoBREE, J . H., Kose, D' A ., FODLDS,W. S, and DANGERFIELD, W. G. Exudativediabetic retinopathy . Brit. J. Ophth., 47 : 666,1963 .

8 . ESMANN, V ., JENSEN, H . J. and LurnnAEK, K .Disappearance of waxy Exudates in diabeticretinopathy during administration of p-amino-salicylate (PAS). Acta med, scandinav ., 174 : 99,1963 .

9 . BLOOnwoaTH, J . M. H. Diabetic retinopathy.Diabetes, 11 : 1, 1962 .

10. DIEZEL, P. B. and WILLERT, H . G. Morphologicand Histochemie der harten and weichen Exsu-date der Retina bei Diabetes mellitus und es-sentieller Hypertonic. Klin . Monatsbt. Augenhalk .,139 : 475, 1961 .

11 . WOLTER, R. Ein Beitrag zur Pathologic der Augen-veranderungen beim Diabetes . Klin. Monatsbl.Augenh., 129 : 505, 1956.

12. KEMPNER, W., PESCHEL, R . L. End SCHLAYER, C .Effect of rice diet on diabetes mellitus associatedwith vascular disease . Postgrad. Med. . 24 : 359,1958 .

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