s'erum Lipids and Lipoproteins in Insulin-dependent ... - Diabetes Care

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MARJA-RI1TTA TASKINEN, ESKO A. NIKKILA, AND ANNELI OLLUS. The response of blood glucose and serum lipids and lipoproteins to a high-carbohydrate, ...
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'erum Lipids and Lipoproteins in Insulin-dependent Diabetic Subjects During High-Carbohydrate, High-Fiber Diet MARJA-RI1TTA TASKINEN, ESKO A. NIKKILA, AND ANNELI OLLUS

The response of blood glucose and serum lipids and lipoproteins to a high-carbohydrate, high-fiber, low-fat diet was assessed in 10 insulin-dependent diabetic subjects. The diet contained approximately 60% of calories as carbohydrate (CHO) and 20% as fat. The patients were followed for 2 wk in a metabolic ward and subsequently for 4 wk at home without changing insulin dosage. During this 6-wk period, the fasting blood glucose fell from 10.6 ± 1.1 to 8.9 ± 1.3 mmol/L (NS); HbA, fell from 11.7 ± 0.5 to 11.0 ± 0.7% (P < 0.05). Serum total triglyceride and very-low-density lipoprotein levels remained unchanged. After 2 wk in the ward on a high-CHO diet, total cholesterol fell by 15% (P < 0.01), LDL cholesterol by 16% (P < 0.001), and HDL cholesterol by 10% (P < 0.05). The fall of HDL cholesterol was due to a decrease of HDL3 cholesterol only. After the 4-wk home period on a high-CHO diet, the observed lipoprotein changes were reversed. Heparin-releasable adipose tissue LPL activity was not influenced by a high-CHO diet. In conclusion, a high-carbohydrate, high-fiber, lowfat diet did not deteriorate the diabetic control, and it had no unfavorable effects on serum lipids or lipoproteins. DIABETES CARE 6:224-230, MAY-JUNE 1983.

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igh-carbohydrate (CHO) low-fat diets have been reported to improve the diabetic control in both insulin-dependent1 5 and non-insulin-dependent diabetic patients.6"9 The mechanisms underlying this favorable effect are not fully understood but may be related to the high-fiber content of CHO-rich diets.1011 Recent dietary recommendations for diabetic subjects advocate diets providing 50-60% of total energy intake as CHO and only 15-20% as fat.12 However, the usefulness and benefits of the CHO-rich diet in the treatment of diabetes has also been questioned.13 The major concern has been the possible adverse effects of such diets on serum lipid and lipoprotein levels. In normal subjects a high-CHO, low-fat diet increases serum triglyceride concentration due to stimulation of hepatic VLDL synthesis and secretion.14"17 A high-CHO diet also consistently reduces HDL cholesterol in healthy subjects.17 21 From the point of view of atherosclerosis, these effects of a high-CHO, low-fat diet are less desirable. When a high-CHO diet is recommended for diabetic patients, it does not include sugar but is rich in fiber. This type of diet does not elevate serum triglyceride levels22"23 but it still reduces HDL cholesterol.4'23 In most studies comparing high- versus low-CHO diets,M>8 the P/S ratio and cholesterol

224

content have been changed concomitantly with the amount of CHO. This makes it difficult to assess the role of dietary CHO on the results. Therefore, we studied the effects of a high-CHO, highfiber, low-fat diet with constant P/S ratio and cholesterol content on serum lipids and lipoproteins in insulin-dependent diabetic patients in the metabolic ward and at home.

MATERIAL AND METHODS

Patients Ten patients with insulin-dependent diabetes volunteered for the study. There were six women and four men between the ages of 17 and 42 yr. The relative body weight (RBW) varied from 90% to 122% (mean ± SEM: 103 ± 4%). The average duration of the diabetes was 15 yr (range: 6-30 yr). All patients had normal blood pressure and serum creatinine (69 ± 4 mmol/L) and only one subject showed occasional proteinuria. Five patients showed signs of nonproliferative background retinopathy. All subjects were otherwise healthy and had normal working capacity. Apart from insulin the patients did not receive any medication. Only one smoked regularly.

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SERUM LIPIDS AND L1POPROTE1NS IN IDDM SUBJECTS DURING HIGH-CHO, HIGH-FIBER DIET/M.-R. TASK1NEN AND ASSOCIATES

Study Design The patients were admitted to the metabolic ward. The diabetic control was assessed daily and the insulin dose was adjusted until fasting blood glucose was less than 14.0 mmol/ L and daily urinary glucose excretion did not exceed 50 g. Thus, we did not deliberately aim for strict diabetic control. The insulin dose was increased in three and decreased in six cases during 4-14 days (average: 7 days). After the adjustment period the insulin dose was not changed. The average dose was 36 ± 4 U/day, ranging from 22 to 56 U/day. The protocol included a 7-day period on a basal diet (I), a subsequent 14-day period on a high-CHO, low-fat diet in the metabolic ward (II), and finally a period of 4 wk on a similar diet at home (III). During the last period, the subjects were studied after 2 and 4 wk in the ward. One subject failed to complete the home study period. Body weight was monitored regularly and it remained constant during all diet periods. The subjects were instructed to keep their daily activities similar to those before the experiment. Alcohol was not allowed during the study. Diets Upon admission the subjects were placed on an isocaloric sucrose-free diet providing approximately 45% of calories as CHO, 35% as fat, and 20% as protein (see Table 1). The calculated polyunsaturated to saturated fatty acid ratio (P/S) was around 0.4, and the cholesterol content averaged about 400 mg/day. The diet contained 25-28 g of fiber per 2000 kcal. The high-CHO, low-fat diet contained about 60% of calories as CHO (sugar-free) and 20% as fat, with P/S ratio and cholesterol similar to those of the basal diet. The average fiber content was estimated as 55 g/2000 kcal. The content of fibers in different foodstuffs was calculated as dietary fiber according to Paul and Southgate.24 The adherence to the diet was assessed from the calculations based on dietary records kept by the patients for 2 days before each control visit. The percent of calories derived from carbohydrate averaged 62 ± 1% on first control and 61 ± 2% on second control. The estimated daily amount of fiber and cholesterol in the at-home diet was 58 ± 6 g and 366 ± 47 mg, respectively, on first control and 54 ± 4 g and 430 ± 39 mg (NS), respectively, on second control. The estimated P/S ratio averaged 0.63 ± 0.10 on the first visit and 0.60 ± 0.10 on the second visit. Methods During the hospital stay the diabetic control was assessed by daily blood glucose determinations taken before breakfast and at 4 p.m. and by daily urinary glucose output. In addition, 24-h blood glucose was monitored at intervals of 4 h before and after basal and high-CHO diets (periods I and II) and again at 2 and 4 wk of home diet period. Serum lipids and lipoproteins and blood HbA] were measured upon admission, and then before and after the basal diet period and again after the high-CHO diet periods in the metabolic ward and at home. Adipose tissue biopsies for the assay of LPL activity were carried out before the high-CHO diet period and re-

TABLE 1 Examples of daily amounts of food served on basal and high-CHO, lowfat diets Basal diet (g) Breakfast Milk Fat-free sourmilk Wholemeal bread (wheat) Vegetable margarine Homemade cheese Lean meat Lettuce, paprika Coffee Mid-morning snack Wholemeal bread (rye) Crispbread Vegetable margarine Lettuce, tomato Lunch Lean meat (raw weight) Potatoes Carrots Lettuce + pineapple Soya oil Wholemeal bread (rye) Vegetable margarine Milk Fat-free sourmilk Apricots Mid-afternoon snack Wholemeal bread (wheat) Crispbread Vegetable margarine Lean meat Egg Cucumber Coffee Orange Dinner Lean meat Potatoes Cauliflower Cucumber, lettuce Soya oil Wholemeal bread (rye) Vegetable margarine Milk Fat-free sourmilk Orange Blueberries Potato starch Bedtime snack Wholemeal bread (rye) Vegetable margarine Low-fat cheese Lettuce, tomato Apple Skimmed milk Tea

DIABETES CARE, VOL. 6 NO. 3, MAY-JUNE 1983

200 — 25 10

25 —

High-CHO diet (fi)

150 60 — —

25

25 — 5



100 100 100 100 5 25

80 150 100 25 15 25 — — 150 —

5 150 — 150

25 — 10

25 —

50 —

50 — —



45



150

50 100 100

100 100



25 5 150 — 150 — —

50

40

10 25 — 150 — 100

5

10 25

80 5 —

100 —

_.. 150

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SERUM L1PIDS AND LIPOPROTE1NS IN 1DDM SUBJECTS DURING HIGH-CHO, HIGH-FIBER DIET/M.-R. TASKINEN AND ASSOCIATES

peated after 2 wk of the ward diet and 4 wk of the home diet. The biopsies were taken at 8 a.m. after an overnight fast and at 1 p.m., 1 h after lunch. Heparin test for the assay of postheparin plasma lipase activities was carried out before and after the 2-wk high-CHO diet period in the metabolic ward. Analytic methods. Blood glucose was determined from vevous blood using a commercial kit (GLOX, Kabi Diagnostica, Sweden).25 Concentrations of cholesterol (enzymatic colorimetric method, cat. no. 187313, Boehringer Mannheim GmbH, Diagnostica) and triglyceride26 (kit no. 297771, Boehringer Mannheim GmbH, Diagnostica) were measured from the whole serum and from VLDL, LDL, and HDL. The HDL subfractions were additionally analyzed for cholesterol, phospholipids,27 total protein,28 and apoproteins AI and AIL29 Glycosylated hemoglobin (HbA^ levels were assayed using the method of Groop et al.30 The lipoproteins were separated by sequential ultracentrifugation31 in a Beckman L-70 ultracentrifuge (Beckman Instruments, Inc., Palo Alto, California) using a Beckman Type 50 Ti rotor. VLDL was separated at a solvent density of 1.006 g/ml by centrifugation for 18 h at 40,000 rpm, +4°C. For separation of LDL the density of the bottom fraction was adjusted to 1.063 g/ml and centrifuged at 42,000 rpm, +4°C for 24 h. The LDL in the top layer was removed and the HDL2 and HDL3 were separated by spinning at 48,000 rpm, +4°C for 48 h at densities of 1.125 and 1.210 g/ml, respectively. The recoveries of cholesterol and triglyceride in lipoprotein fractions averaged 91 ± l%and 101 ± 2% (mean ± SEM), respectively. Assay of lipoprotein lipase and hepatic lipase activities. Sub-

cutaneous adipose tissue was taken by needle aspiration from the gluteal region. Heparin-releasable lipoprotein lipase (LPL) activity of adipose tissue was assayed immediately using a radioactive triolein substrate.32 The results are expressed as jxmol FFA released from the substrate by 1 g of adipose tissue in 1 h.

For the assay of postheparin plasma lipase activities, 100 IU heparin/kg body wt (Vitrum, Sweden) was injected intravenously. Blood was collected 15 min after the injection into chilled heparinized tubes. Assays of lipoprotein and hepatic lipase activities were carried out from postheparin plasma using a specific immunochemical method.33 Statistical methods. Data were analyzed in Honeywell Bull 66/20 computer using standard programs for nonpaired and paired t tests and also by using a nonparametric test for paired differences (Wilcoxon). Linear regression analysis and calculation of correlation coefficients also were carried out by computer programs. RESULTS

Diabetic Control Table 2 shows that the daily blood glucose level was not changed during basal diet period or during the high-CHO, low-fat diet in the metabolic ward. The individual responses were variable. Six of ten patients had a lower mean daily blood glucose level on a high-CHO diet than before it. The urinary glucose output decreased significantly during the highCHO diet. The frequency of hypoglycemic episodes was similar before and during the high-CHO diet. After 4 wk on the high-CHO diet at home, the daily blood glucose profile was slightly lower than that achieved on the basal diet (Table 2). After the home diet period, eight of the diabetic patients showed lower HbA, value than those on the basal diet, and the mean HbAi was significantly decreased (Table 2). Serum Lipoproteins Metabolic ward studies. Total and VLDL triglyceride concentrations were not changed during basal or high-CHO, low-fat diets (Table 3). Total cholesterol, LDL cholesterol, and HDL cholesterol concentrations remained constant during the basal diet period (Table 3). In contrast, during the high-CHO, low-fat diet, total cholesterol fell in each patient;

TABLE 2 Diabetic control on a basal and high-CHO, low-fat diet

High-CHO diet

Basal diet Hospital

Blood glucose (mmol/L) Fasting Mean of daily values§ Mean for 7 days|| 24-h urinary glucose (g) Mean value for 7 daysT HbA,

Admission

Before

12.5 ± 1.5 — — 49 ± 15 — 12.9 ± 1.0

8.1 ± 1.6* 8.9 ± 1.3 — 28 ± 16t — —

After

10.6 9.0 8.1 20 32 11.7

± ± ± ± ± ±

1.1 0.7 1.1 10 8

0.5t

Hospital

Home

2 wk

4 wk

9.9 9.1 9.1 12 29 11.2

± ± ± ± ± ±

1.2 0.8 1.0 4* 7 0.6

8.9 ± 1.3 7.9 ± 0.7

— 15

± 5

— 11.0 ± 0.7*

The results are expressed as mean ± SEM. *P < 0.05 for difference from the values at the end of the basal diet period; IP < 0.05, $P < 0.01 for difference from respective values on admission. SMean of daily blood glucose values taken at intervals of 4 h. ||Mean of fasting blood glucose values of last seven consecutive mornings on basal and high-CHO diet. HMean of 24-h urinary glucose values of last seven consecutive days on basal and high-CHO diet.

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TABLE 3 Lipoprotein cholesterol and triglyceride concentrations before and after a high-CHO, low-fat diet Basal diet

High-CHO diet

Hospital Befo Triglyceride (mg/dl) Total VLDL LDL HDL Cholesterol (mg/dl) Total VLDL LDL HDL

After

87 ± 35 ± 32 ± 20 ±

10 5 4 2

81 31 31 19

203 ± 8± 146 ± 49 ±

7

192 7 134 51

1

12 3

± ± ± ±

Hospital

Home

After 2 wk

After 4 wk

82 ± 34 ± 30 ± 16 ±

10 5 3 4

5 5 1 1

± 6

165 ± 6t

± 2

7 ± 1

± 6

112 ± 5t 46 ± 3*

±

3

84 ± 9 37 ± 5 29 ± ) 18 ± 2 189 8 131 50

± ± ± ±

5 2 4 3

The results are expressed as mean ± SEM. id of the basal diet 'P < 0.05, tP < 0.01, tP < 0.001 for the difference from values at the end

the mean change was —14% (P < 0.01). This reduction was mainly due to a decrease in LDL cholesterol; however, HDL cholesterol also fell slightly (Table 3). The HDL/LDL cholesterol ratio remained constant during the high-CHO diet (0.39 ± 0 . 1 1 versus 0.42 ± 0.11). Table 4 shows the concentrations of triglyceride, phospholiptds, cholesterol, total proteins, and their sum (nearly equivalent to the mass of particles) in HDL2 and HDL3 before and after high-CHO, low-fat diet. After 2 wk on the high-CHQ diet, the total concentration of HDL2 increased in seven patients; the average rise was 13%. This change was accounted for by a

significant rise of HDL2 protein and triglyceride concentrations. After 2 wk on the high-CHO diet, the concentrations of apo AI and All in HDL2 were similar to those of patients on the basal diet (Table 4). The HDL2 apo AI/A1I ratio was not modified by the high-CHO diet. The HDL3 concentration decreased in 9 of the 10 subjects on a high-CHO diet; the average change was —17% (P < 0.01). This change was due to a significant fall of cholesterol, phospholipid, and protein concentrations in HDLV However, HDL3 apo AI and All levels were not influenced by the high-CHO diet (Table 4). The HDL, apo AI/AII

TABLE 4 HDL2 and HDLi components before and after a high-CHO, low-fat diet Basal diet

HDL2 (mg/dl) Triglyceride Cholesterol Phospholipids Protein apo AI apo All Total mass HDL, (mg/dl) Triglyceride Cholesterol Phospholipids Protein apo AI apo All Total mass

High-CHO diet

Hospital

Hospital

Home

After 1 wk

After 2 wk

After 4 wk

6.2 27.5 33.9 56.3 38 10.4 125

± ± ± ± ± ± ±

9.8 ± 23.3 ± 31.5 ± 94.4 ± 46 ± 18.8 ± 158 +

0.9 2.9 3.2 5.2 4 •

0.5 10 1.6 0.9 1.8 7.0 5 •

1.4 10

9.2 28.2 38.4 65.0 40 12.0 141

± ± ± ± ± ± ±

0.5t 3.3 3.5 5.0* 5 1.0 10

27.8 34.6 60.5 40 12.0 132

± ± ± ± ± ±

7.0 18.1 26.6 80.0 49 18.5 132

± ± ± ± ± ± ±

0.3 1.1* 1.0 4.4* 5 1.5 6t

6.8 21.5 30.0 95.7 55 22.0 154

± ± ± ± ± ± ±

9.2 ±

1.1

2.7 3.9

5.8 4 0.5 12 0.6 1.5 2.8 6.1

7 3 9

The results are expressed as mean ± SEM. 'P < 0.05, tP < 0.01, t? < 0.001 for the difference from values after 7 days on the basal diet.

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ratio remained constant on the high-CHO diet. Table 5 shows the relative composition of HDL subfractions before and after the high-CHO diet. Both HDL2 and HDL3 became slightly depleted of cholesterol during the diet. Home diet period. After 4 wk on a high-CHO diet at home, the total cholesterol, LDL cholesterol, and HDL cholesterol all returned to the basal level (Table 3). Also, the concentrations of triglyceride, cholesterol, phospholipid, and protein in both HDL2 and HDL3 were similar to those of patients on the basal diet (Tables 4 and 5). The concentrations of apo AI and All in both HDL subfractions remained constant. Lipoprotein Lipase and Hepatic Lipase Activities During the ward period, the high-CHO diet did not result in a change of basal or postprandial LPL activity of adipose tissue (Table 6). On the high-CHO diet at home, the basal LPL activity remained the same but the postprandial value was increased. On the other hand, the postheparin plasma LPL activity decreased during the high-CHO diet (P < 0.01).

No change occurred in the postheparin plasma hepatic lipase activity. DISCUSSION

I

n normal subjects a diet with high CHO and sugar content leads to an elevation of serum triglyceride levels due to increased synthesis and release of VLDL.14 l(1 This has raised discussion on justification on high-CHO diets in diabetic patients.13 By necessity these diets have low content of simple sugars but are rich in fiber. The present data confirm previous results422 showing that in insulin-dependent diabetic patients a high-CHO, high-fiber diet does not elevate serum total or VLDL triglyceride levels. The absence of the effect may be due to fibers, since a high-CHO, low-fiber diet has been shown to increase serum triglyceride levels.2223 Serum total, LDL, and HDL cholesterol concentrations showed a significant fall after 2 wk on a high-CHO diet, but

TABLE 5 Effect of a high-CHO, low-fat diet on the relative composition of HDL2 and HDL) fractions Basal diet

HDL2 Triglyceride (%) Cholesterol (%) Phospholipids (%) Proteins HDL, Triglyceride (%) Cholesterol (%) Phospholipids (%) Proteins (%)

High-CHO diet

Hospital

Hospital

Home

After 1 wk

After 2 wk

After 4 wk

5.9 ± 0.6 26.8 ± 0.6 46.6 ± 1.0

6.7 19.0 29.6 47.3

± ± ± ±

0.4 0.5t 0.9 1.1

7.1 21.1 25.9 45.9

± 0.7 ± 0.8 ± 1.1 ±1.5

6.4 14.8 18.9 59.9

5.7 13.6 19.1 60.9

±0.5 ± 0.6* ± 0.8 ± 0.4

4.5 13.9 19.5 62.1

± ± ± ±

21.7 ± 0.5

± ± ± ±

0.7 0.7 1.1 0.4

0.4 0.5 1.2 1.5

The results are expressed as mean ± SEM. 'P < 0.05, t P < 0.01 for the difference from values after 7 days on the basal diet.

TABLE 6 Effect of a high-CHO, low-fat diet on lipoprotein lipase (LPL) and hepatic lipase activities High-CHO diet Basal diet LPL activity Postheparin plasma (u,mol • FFA • ml"' • h" 1 ) Adipose tissue (u.mol • FFA • g~' • h" 1 ) Fasting 1-h postprandial Hepatic lipase activity Postheparin plasma (u-mol • FFA • ml"1 • h" 1 )

36.1 ±2 1.71 ±0.30 1.82 ± 0.43 18.5 ± 3

The results are expressed as mean ± SEM. "P < 0.05, t P < 0.01 for the difference from values on the basal diet.

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Hospital

Home

30.3 ± 3t 1.54 ± 0.35 1.67 ± 0.20 17.7 ± 2

1.88 ± 0.44 2.82 ± 0.46*

SERUM LIP1DS AND L1POPROTE1NS IN IDDM SUBJECTS DURING HIGH-CHO, HIGH-FIBER DIET/M.-R. TASKINEN AND ASSCX:iATES

the values returned to the initial level after a 4-wk home diet period. A reduction of total and LDL cholesterol has also been documented in previous studies,2"422'23 particularly when the cholesterol content of the high-CHO diet has been very low (about 50 mg/day) or the P/S ratio high (above 1.0).34 It is well established that low cholesterol content and high P/S ratio separately reduce serum total and LDL cholesterol.^ 36 Previous data on the response of HDL cholesterol to a high-CHO diet are inconsistent. In diabetic subjects a highCHO, low-fat diet has been variably reported to keep the HDL unchanged3'8 or to decrease it.423 In normal subjects the high-CHO, high-sugar intake is consistently followed by a fall of HDL cholesterol.17"21 In the present study a highCHO diet caused a transient fall of total HDL cholesterol. This change was due solely to a decrease of HDL3 cholesterol. The HDL2 concentration rose and the HDL3 concentration fell, which contrasts with the effect of a high-CHO diet in nondiabetic subjects where HDL2 concentration decreases and HDL3 changes inconsistently.2021 The different response of HDL subfractions to high-CHO diets in normal and insulin-dependent diabetic subjects can be either real or caused by differences in experimental conditions. It is also possible that the different HDL response of diabetic and nondiabetic subjects is due to improvement of diabetic control, which raises HDL2.37 The HDL2 protein increased during a high-CHO diet while the HDL3 protein decreased. Since this occurred without any detectable change in the apoproteins AI and All in HDL subfractions, the diet must have induced a shift of non-A apoproteins (e.g., apo C's) from HDL3 to HDL2. In fact, an increase of apo CII in HDL2 during a high-CHO diet has been demonstrated previously in nondiabetic subjects by Kashyap et al.21 The basal activity of adipose tissue LPL was not influenced by a high-CHO, low-fat diet. In normal subjects the adipose tissue LPL activity increases in response to meals.38 During the ward period, the diabetic patients did not show any postprandial rise of LPL activity either on a basal or highCHO, low-fat diet. On the other hand, a response of adipose tissue LPL was present after the home period. This could be due to an improvement of glycemic control. The reason for the transient nature of the observed changes in serum total cholesterol, LDL and HDL cholesterol, and HDL subfractions remains open. It can only be speculated that outside the hospital some unrecorded alterations in the diet or life style occurred. The self-recorded dietary notes showed a good adherence to the diet but their reliability can always be questioned. Physical activity at home might have been higher than in the hospital, which explains the increase in HDL values during the at-home period. Also, the failure to abstain totally from alcohol at home would increase the HDL. The hospitalization may have interfered with the daily life of the patients and caused the observed transient changes; thus, they would not have been attributed to the special diet. If this is the case, the practical implication of this study is that in insulin-dependent diabetic patients a high-fiber, high-

CHO diet does not deteriorate glucose control or elevate serum lipids. Therefore, this type of diet could serve as an alternative according to individual preferences.

ACKNOWLEDGMENTS: The skillful technical assistance of Hannele Hilden, Sirkka-Liisa Runeberg, Leena Lehikoinen, and Arja Kalenius is greatly appreciated. We would like to thank Dr. Timo Kuusi for the antiserum against hepatic lipase and Dr. Christian Ehnholm for the measurements of apo AI and apo All concentrations. This study was supported by grants from the Finnish State Medical Research Council (Academy of Finland); Sigrid Juselius Foundation, Helsinki, Finland; Finnish Sugar Ltd., Helsinki, Finland; and Nordisk Insulinfond, Copenhagen, Denmark.

From the Third Department of Medicine, University of Helsinki, SF-00290 Helsinki 29, Finland. Address reprint requests to Marja-Riitta Taskinen, M.D., at the above address.

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