A High-Monounsaturated-Fat/Low-Carbohydrate Insulin Sensitivity in Non-Insulin-Dependent M. Parillo,

A.A.

Rivellese,

A.V. Ciardullo,

B. Capaldo,

A. Giacco,

Diet Improves Peripheral Diabetic Patients S. Genovese,

and G. Riccardi

It is commonly believed that high-carbohydrate (CHO) diets improve peripheral insulin sensitivity; however, this concept is based on anecdotal evidence. Furthermore, it has been demonstrated that in non-insulin-dependent diabetic patients treated with insulin, a high-monounsaturated-fat (MUFA) diet is more effective than a high-complex-CHO diet in reducing blood glucose levels. The aim of our study was to compare the effect of a high-MUFA diet and a high-CHO diet on peripheral insulin sensitivity and metabolic control in non-insulin-dependent diabetic patients. Ten non-insulin-dependent diabetic patients aged 52 2 8 years with a body mass index (BMI) of 26.7 ? 3.5 kg/m2 who were being treated with diet alone (n = 5) or with diet plus glibenclamide (n = 5) were randomly assigned to a 15-day period of either a high-MUFAllow-CHO diet (CHO, 40%; fat, 40%; protein, 20%; fiber, 249) or a low-MUFA/high-CHO diet (CHO, 60%; fat, 20%; protein, 20%; fiber, 249) and were then crossed-over to the ether diet. Diets were similar in their content of monosaccharides, disaccharides, and saturated fats, and were administered to the patients in a metabolic ward. The dosage of hypoglycemic drugs was maintained at a constant level throughout the study. With the high-MUFA/low-CHO diet, a decrease in both postprandial glucose (8.76 f 2.12 Y 10.08 2 2.76 mmol/L; P < .05) and plasma insulin (195.0 f 86.4 Y 224.4 f 75.6 pmol/L; P < .02) levels was observed. Furthermore, fasting plasma triglyceride levels were reduced after the high-MUFA fat/low-CHO diet (1.16 f 0.59 Y 1.37 + 0.59 mmol/L; P < .Ol). Insulin-mediated glucose disposal, evaluated with the euglycemic hyperinsulinemic (470 pmol/L) clamp, was significantly higher with the high-MUFA/low-CHO diet (5.8 f 2.1 v 4.6 + 1.8 mg/kg/min; P = .02). This study demonstrates that a high-MUFA/low-CHO diet has clinical and metabolic benefits in non-insulin-dependent diabetic patients. Copyright 8 1992 by W.B. Saunders Company

I

MPAIRED PERIPHERAL insulin sensitivity represents a key feature of non-insulin-dependent diabetes mellitus. It plays a crucial role in the pathogenesis of the disease and may also contribute to the development of cardiovascular complications in non-insulin-dependent diabetic patients.‘.’ Therefore, in these patients any therapeutic maneuver should aim not only at improving blood glucose control, but also at increasing peripheral insulin sensitivity. High-complex-carbohydrate (CHO)/low-fat diets have long been advocated for the treatment of non-insulindependent diabetes mellitus. 4-5Among the reasons for this is the assumption that this type of diet would improve peripheral insulin sensitivity. However, this assumption is based on anecdotal evidence, since only a few studies have evaluated the effects of different amounts of CHO and fat on insulin sensitivity in humans. Besides, a number of methodological problems make the interpretation of previous data difficult. Actually, in previous studies dietary variations were often extreme (the high-CHO diet contained 85% CHO and 0% fat), and the diet was either of liquid formula type6-7 or included variations not only in the amount of CHO, but also in other dietary components that are likely to affect glucose metabolism (fiber, type of fat, sucrose, etc.).8-12 Furthermore, the method used to assess peripheral insulin sensitivity was often far from adequate (oral glucose tolerance test, insulin infusion test, etc.).h-‘l Another reason to recommend high-complex-CHOilow-fat diets for the treatment of non-insulin-dependent diabetic patients is their alleged efficacy in improving blood glucose control and in reducing the concentration of atherogenic lipoproteins.13 However, this finding is also questionable, since it has recently been shown that, at least in non-insulin-dependent diabetic patients treated with insulin, a high-monounsaturated-fat (MUFA) diet seems to be more effective than a highMetabolism,

Vol41, No 12 (December), 1992: pp 1373-1378

complex-CHO diet in reducing blood glucose levels and improving the overall lipoprotein profile.‘” Against this background, we have undertaken the present study to reexamine the issue of the optimal amount of CHO and fat in the diabetic diet, taking into consideration its effects on plasma glucose and lipoprotein concentrations and on peripheral insulin sensitivity. These aspects are of crucial importance in basing dietary recommendations for diabetic patients on sound scientific evidence. PATIENTS AND METHODS

Ten patients (seven men and three women) with non-insulindependent diabetes mellitus were studied. The diagnosis of diabetes was based on the presence of fasting hyperglycemia levels higher than 7.8 mmol/L on repeated occasions.‘s Patients were 52.7 k 8.4 years of age (mean -CSD) and had a body mass index (BMI) of 26.7 2 3.5 kg/m?. Five patients were treated with diet alone, and the other five were treated with diet plus glibenclamide at a dosage of between 2.5 and 7.5 mg/d (Table 1). All patients were free of diabetic complications and had no clinical or biochemical evidence of renal or hepatic disease. Besides hypoglycemic treatment. none of them were taking any drugs known to affect CHO or lipid metabolism. All subjects gave their informed consent to participate in the study. The experimental protocol was approved by the Ethical Committee of the School of Medicine of the University of Naples.

From the Institute of Internal Medicine and Metabolic Diseases, Universiv “Federico II, “Naples, Italv. Supportrd by Grant No. 91.00226.PF4Ifiom the National Research Council (CNR)-Targeted Project “Prevention and Control of Disease Factors, ” subproject “Nutrition. ” Address reprint requests to M. Parillo, MD, Institute of Internal Medicine and Metabolic Diseases, University of Naples, 2nd Medical School, Via S. Pansini S, 80131 Naples, Italy. Copyright 0 I992 by W.B. Saunders Company 0026-0495/9214112-0017$03.00l0 1373

PARILLO ET AL

1374

Table 1. Patient Characteristics Diabetes Patient

Age

BMI

FBG

Duration

No.

Sex

(vd

(kg/m?

(mmollL1

1

PA

45

21.6

5.3

5

Treatment

w

2

F

53

33.4

6.2

9

Diet

3

M

61

31.0

7.0

2

Diet

4

M

52

27.3

4.8

5

Diet + G

5

F

50

27.8

11.9

15

Diet + G

6

M

62

28.0

3.9

3

Diet + G

7

M

61

25.4

5.8

15

a

F

42

24.0

7.3

4

9

M

57

22.7

6.7

17

10

M

44

26.1

7.3

9

Diet Diet + G Diet Diet + G

Means + SD

7M13F

52.7 f 8.4 26.7 + 3.5 6.6 + 2.1 8.4 2 5.5

Abbreviations: G, glibenclamide; FBG, fasting blood glucose.

Experimental Design A randomized crossover study was performed. The patients were admitted to the metabolic ward for the duration of the experiment. During a baseline period of 7 days, patients received an isocaloric diet according to the recommendation of the Diabetes and Nutrition Study Group of the EASD.S The purpose of the baseline period was to allow for estimation of the energy intake required to maintain body weight at a constant level. Afterward, the patients were randomly assigned to a 15-day period of either a high-MUFA/ low-CHO or a low-MUFAihigh-CHO diet. At the end of the first dietary period, patients were switched to the other diet; there was no wash-out period between the two diets. Six patients received the high-MUFAilow-CHO diet first, and the other four received the low-MUFA/high-CHO diet first. The dosage of hypoglycemic medication was maintained constant throughout the study period. Patients were required to maintain a constant level of physical activity (ie, walking only) for the duration of the study. Diets The composition of the diets is shown in Table 2. The highMUFA/low-CHO diet supplied 40% of its total energy content as fat and 40% as CHO. whereas the low-MUFA/high-CHO diet supplied 20% of its energy as fat and 60% as CHO. The protein content was 20% in both diets, and each diet included approximately 250 mgid cholesterol. The amount of fiber was identical in the two diets (24 g/d) and was composed mainly of insoluble fiber.

The two diets were also similar with respect to monosaccharides and disaccharides and saturated fat content. The composition of the diets was calculated with standard tables of food composition? both diets consisted exclusively of solid natural foods. The increase in fat content of the high-MUFAilow-CHO diet was achieved by increasing the consumption of olive oil (rich in MUFA), while the increase in CHO in the low-MUFAihigh-CHO diet was achieved by using starch-rich foods, especially bread. Five daily menus were prepared for each diet (Table 3); all meals were cooked in the metabolic kitchen. They were eaten at 8:00 AM, 1:00 PM, and 8:00 PM in the presence of a dietitian and contained IO%, 50%, and 40% of the total daily caloric intake, respectively. Blood Sampling and Analysis On day 14 of each diet period, blood samples for glucose, insulin, nonesterified fatty acids (NEFA), cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol determinations were collected from each patient after a 12- to 14-hour overnight fast. On the same day, glucose, insulin, and NEFA levels were also measured before and 2 hours after lunch and dinner. On day 15, a euglycemic hyperinsulinemic clamp was performed”; a polyethylene cannula was inserted into an antecubital vein for infusion of the test substances. A second cannula was placed retrogradely into a hand vein for intermittent blood sampling; the hand was kept warm in a heated box (60°C) to ensure arterialization of venous blood. Then, regular human insulin was administered intravenously at a rate of 1.2 mU/kg/min to increase peripheral insulin concentration to approximately 470 pmol/L. A variable amount of a 20% glucose solution was also infused to maintain blood glucose concentration at approximately 5.6 mmol/L. The glucose infusion rate was adjusted according to plasma glucose levels, which were measured at 5-minute intervals on a Beckman glucose analyzer (Beckman Instruments, Fullerton, CA). Since our patients’ fasting plasma glucose level was approximately 6.5 mmol/L. no glucose was infused until plasma glucose levels decreased to 5.6 mmol/L; when this value was reached, it was clamped for 2 hours. The time required to achieve euglycemia did not differ between the two dietary treatments (32 ? 24 minutes with the high-MUFAilowCHO diet and 28 ? 20 minutes with the low-MUFAihigh-CHO diet). At -150 minutes, a primed (45 FCi) continuous (0.3 uCi/min) infusion of o3-H-3-glucose (Amersham, Buckinghamshire, England) was started and continued throughout the study to Table 3. Sample Menu of Study Diets High-MUFA/Low-CHO

Skimmed milk Table 2. Composition of Diets

Simple

Low-MUFAiHigh-CHO

Breakfast 150 Whole milk

Toasted bread

10

Macaroni with tomato

80

%Energy

CHO

(g)

Toasted bread

(g)

150 30

Lunch

High-MUFAI

Low-MUFAI

Low-CHO

High-CHO

Macaroni with tomato

sauce

110

sauce

40

60

Turkey cock breast

160

Beef

130

15

14

Eggplants

200

Tomato salad

100

25

46

Bread

40

20

Apples

250

29

13

Sole (fish)

220

4

Mullet

2

170

Lettuce

Protein

100

20

Peppers

20

200

Bread

Fiber (9)

24

24

50 190

Bread

135

Apples

250

230

250

Complex Fat Saturated MUFA Polyunsaturated

Cholesterol fmg)

5

NOTE Calculations are based on standard tables of food composition.16

50

Bread Tangerines

90 200

Dinner

Bananas

Seasoning Olive oil

75

Olive oil

20

HIGH-MUFA

DIET IMPROVES

INSULIN SENSITIVITY

measure hepatic glucose production. Arterialized blood samples were taken in the basal state and every 20 to 30 minutes during the clamp for insulin, NEFA, and glucose specific activity measurements. Plasma glucose concentrations were measured by the glucoseoxidase method (Boehringer Biochemia Robbin, Mannheim, Germany),ls and plasma insulin levels were determined by radioimmunoassay (lZsI insulin; Sclavo. Milan, Italy).19 The intraassay coefficient of variation for insulin was 4.1% and the specific activity was 150 to 200 pCi/pg. Plasma NEFA,*O cholesterol,z’ and triglyceride” levels were measured by standard enzymaticcalorimetric methods (Boehringer). HDL cholesterol level was assayed by precipitation using a combination of dextran sulfate 500 (70 g/L) and magnesium chloride (2 mol/L).23 o3-H-3-glucose specific activity was measured on Somogy extracts of plasma samples after evaporation of radiolabeled water. The amount of glucose metabolized by the whole body was calculated as the mean value of glucose infused during the last 40 minutes of the clamp. Hepatic glucose production was calculated using the Steele equations. as previously described.24 Since this model is known to give frequently negative numbers in the presence of high insulin levels, He assumed that negative values indicated complete suppression of hepdtic glucose output. StatisticalAnalysis All data are expressed as the mean 2 SD and were analyzed with the SPSS statistical analysis. The differences between the two dietdry treatments were evaluated by Student’s paired t test, with the level of significance at P = .05 (two-tailed).Z5 RESULTS

The palatability of the two diets was very good and all patients were able to comply with the administered menus. No effect of diet sequence on the results was observed.

There was no change in body weight after the two diets; body weights were 68.7 t 1I.6 kg after the high-MUFAilowCHO diet and 68.9 c 11.9 kg after the low-MUFA/highCHO diet. The high-MUFA/low-CHO diet produced a significantly lower postprandial plasma glucose concentration (8.71, 2 2.12 v 10.08 t 2.76, P < .05; average of the samples taken 2 hours after lunch and dinner; Fig l), while no difference was observed for fasting plasma glucose level (6.38 2 1.97~ 6.74 ? 2.28 mmol/L). Similarly, postprandial plasma insulin levels were significantly lower after the high-MUFAilow-CHO diet compared with the low-MUFAI high-CHO diet (195.0 2 86.4 v 224.4 ? 75.6 pmol/L, P < .02; Fig 1). No significant difference was observed in fasting plasma insulin levels between the two diets (43.2 ? 14.4 v 51.6 ? 23.4 pmol/L). Both fasting (0.43 + 0.2 v 0.43 +- 0.2 mEq/L) and postprandial (0.21 * 0.1 v 0.19 f 0.1 mEq/L) plasma NEFA concentrations were similar after the high-MUFA/low-CHO and the lowMUFAihigh-CHO diet, respectively. The high-MUFA/low-CHO diet also induced a significant decrease in fasting plasma triglyceride levels (1.16 2 0.59 v 1.37 t 0.59 mmol/L; P < .Ol), while no difference was found in plasma total cholesterol (4.68 -+ 1.01 v 4.52 2 0.96 mmol/L) and HDL cholesterol (0.99 t 0.2 v 0.95 5 0.2 mmol/L) levels between the two diets. Blood glucose was clamped at the same level with the

1375

Fig 1.

Postprandial blood glucose and plasma insulin levels after

the high-MUFA/low-CHO

and low-MUFA/high-CHO

diets.

high- and low-MUFA diet (5.6 t 0.2 v 5.8 ? 0.2 mmol/L), with a coefficient of variation of less than 5%. Mean plasma insulin concentrations during the clamp were 455 5 107 and 478 + 118 pmol/L with the high- and low-MUFA diets, respectively. NEFA levels were similar in the basal state and decreased to the same extent during the clamp with both diets. The amount of glucose metabolized by the whole body during the insulin clamp was significantly higher with the high-MUFAilow-CHO diet (5.8 2 2.1 mg/kg/min) than with the low-MUFA/high-CHO diet (4.6 t 1.8 mgikgimin, P = .02; 95% confidence interval for the difference, 0.22 to 2.34 mg/kg/min). The individual values for each subject arc shown in Fig 2. In eight of 10 patients, insulin-stimulated glucose utilization was ameliorated, while in the remaining two patients no change or a slight decrease was demonstrable. Hepatic glucose output was similar in the basal state during the two treatment periods (2.1 ? 0.2 v 2.0 2 0.3 mg/kg/min) and was totally and equally suppressed during the clamp. DISCUSSION

This study clearly shows that a reduction in the consumption of complex CHO associated with an increase in the consumption of MUFA improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients. This improvement, although not impressive, is almost of the same magnitude as that achieved with insulin therapy or hypoglycemic medications.ZblZ7 This finding is somehow unexpected; it is generally believed, in fact, that a diet rich in fat and low in CHO would worsen insulin sensitivity rather than improve it. However, this concept is not based on any solid evidence, since the few studies in both animals and humans quoted in support of this idea suffer from major methodological problems that do not allow a clear interpretation of the resu]ts.6-l

I.?X.?Y

For this reason, the present study adopts experimental

PARILLO ET AL

p’

0.02

Fig 2. Whole-body glucose disposal during euglycemic hyperinsulinemic clamp after the two dietary periods.

methodologies that overcome such problems and are therefore able to prevent major flaws in the interpretation of the results. First, patients were hospitalized in order to closely supervise their food intake; second, the two diets were given to the same individuals in random order, according to a controlled design; and finally, peripheral insulin sensitivity was evaluated by a widely accepted method. Moreover, the change in the ratio of CHO/fat did not reflect extreme, nonrealistic conditions, but was chosen to resemble the range of variations in diet composition achievable in the usual clinical setting. To this end, foods used in this study are ordinary solid foods included in the everyday menu of the diabetic diet. Finally, apart from the complementary changes in the amount of complex CHO and MUFA, the composition of the two diets was remarkably similar. Therefore, no interference with the results of this study can be suspected by any other dietary component known to influence CHO metabolism, ie, sucrose, fiber, protein, type of fat, etc. MUFA was chosen to partially replace complex CHO in the low-CHO diet, in view of the beneficial effects of these fats on the cardiovascular risk factor profile in both diabetic30 and nondiabetic individuals3’ Moreover, the use of olive oil (rich in MUFA) in Mediterranean countries is associated with low mortality rates from both cardiovascular disease and all other causes of death.32

In this study, the intake of complex CHO and MUFA was modified in a complementary fashion. Therefore, it is not possible to evaluate separately the contributions of a low-CHO and high-MUFA intake to the improvement of peripheral insulin sensitivity. However, in our opinion this has little relevance in practice. As CHO and fat are the major components of the diet (in terms of energy), in isoenergetic diets it is almost impossible to modify one component without altering the other. We have therefore assessed the metabolic effects of changes in the ratio of CHO/fat in a group of non-insulindependent diabetic patients. Strictly speaking, the results of this study cannot be extrapolated to individuals with normal glucose tolerance. However, impaired insulin sensitivity is not only a characteristic feature of non-insulin-dependent diabetes mellitus, but it represents a metabolic derangement underlying many cardiovascular risk factors.‘” Because of this, it is tempting to speculate that the adoption of a low-CHO/high-MUFA diet would also improve peripheral insulin sensitivity in nondiabetic individuals, and therefore possibly reduce their risk of developing both diabetes and cardiovascular disease. The improvement in peripheral insulin sensitivity was not the only beneficial effect of the high-MUFA/low-CHO diet in non-insulin-dependent diabetic patients. This diet, in fact, also improved blood glucose control (mainly in the postprandial period) and the cardiovascular risk factor profile (lower plasma insulin and triglyceride levels without significant changes in low-density lipoprotein and HDL cholesterol). This finding-obtained in a group of patients reasonably well controlled with diet and/or sulfonylureas (which represents the most common situation for noninsulin-dependent diabetes mellitus)-confirms and extends the results of a previous study performed in a group of non-insulin-dependent diabetic patients treated with insulin.r4 The identification of the mechanisms responsible for the improvement in peripheral insulin sensitivity was beyond our aim. However, several possibilities should be considered. The better peripheral insulin sensitivity achieved with the high-MUFAilow-CHO diet is associated with other metabolic effects, namely, improvement of blood glucose control and reduction in plasma insulin and triglyceride concentrations. Therefore, it is likely that the improvement in insulin sensitivity might be at least partially mediated by those changes. This hypothesis is in agreement with previous studies showing that in diabetic patients the improvement of blood glucose control is followed by a increase in insulin sensitivity. 33,34Also, hyperinsulinemia is known to deteriorate insulin sensitivity, possibly via a down-regulation of insulin receptors.35,3h Therefore, a reduction in plasma insulin levels may also contribute to the improvement of peripheral insulin sensitivity. Finally, it is well known that glucose and lipids compete at the level of the oxidative pathway. Therefore, it is likely that the reduction in the concentration of plasma triglycerides, which in human vessels are readily transformed into free fatty acids,

HIGH-MUFA

DIET IMPROVES

INSULIN SENSITIVITY

1377

also contribute to the improvement of peripheral insulin sensitivity.“’ In conclusion, this study demonstrates that the partial replacement of CHO-rich food with MUFA in the diet of

it is well known that some of them, either because of their high fiber content or their physical-chemical properties, exert a much lower postprandial response in terms of

non-insulin-dependent

clinical

it cannot

on

shown here could be drastically reduced or even reversed if fiber-rich or low glycemic index foods were preferentially used in the highCHO diet. This aspect deserves to be properly evaluated before sound recommendations can be given to patients with non-insulin-dependent diabetes mcllitus.

may

and

metabolic

diabetic benefits.

This

patients conclusion

has

clear

is based

the

evidence that this dietary maneuver improves not only blood glucose control and cardiovascular risk factor profile, but also peripheral insulin sensitivity. However, CHO-rich foods cannot be considered to be equivalent in terms of their metabolic effects. In particular,

plasma MUFA

levels be diet

of glucose, excluded over

insulin, that

the

the high-CHO

and

lipids.3X-4n Therefore,

advantages

of

the

high-

diet

REFERENCES

1. Reaven

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37. Randle PJ, Garland PB, Hales CN, et al: The glucose fatty-acid cycle: Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785-789,1963 38. Jenkins DJA, Wolever TMS, Jenkins AL, et al: The glycaemic response to carbohydrate foods. Lancet 2:388-391,1984 39. Parillo M, Giacco R, Riccardi G, et al: Different glycemic responses to pasta, bread and potatoes in diabetic patients. Diabetic Med 2:374-377, 1985 40. Rivellese A, Riccardi G, Giacco A, et al: Effect of dietary fibre on glucose control and serum lipoproteins in diabetic patients. Lancet 2:447-450, 1980