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

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

PA

45

21.6

5.3

Treatment

53

33.4

6.2

Diet

61

31.0

7.0

Diet

52

27.3

4.8

Diet + G

50

27.8

11.9

15

Diet + G

62

28.0

3.9

Diet + G

61

25.4

5.8

15

42

24.0

7.3

57

22.7

6.7

17

10

44

26.1

7.3

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 (60C) 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

Mullet

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)

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 Students 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

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

GM: Role of insulin resistance in human disease.

Diabetes 37:1595-1606,
1988
2. DeFronzo
RA: The triumvirate:
Beta-cell, muscle, liver: A
collusion responsible for NIDDM. Diabetes 37:667-687, 1988
3 Foster DW: Insulin resistance-A
secret killer? N Engl J Med
320.733734.
1989
4 American
Diabetes
Association:
Nutritional
recommendations and principles for individuals with diabetes mellitus: 1986.
Diabetes Care 10:126-132, 1987
5 Diabetes and Nutrition
Study Group of the EASD: Nutritional recommendations
for individuals
with diabetes
mellitus.
Diabetes Nutr Metab I:145148.
1988
6. Brunzell JD. Lerner
RL. Hazzard
WR, et al: Improved
glucose tolerance with high carbohydrate
feeding in mild diabetes.
N Engl J Med 284:521-524, IY71
7. Kolterman
CG. Greenfield
M, Reaven GM, et al: Effect of a
high carbohydrate
diet on insulin binding to adipocytes
and on
insulin action in vivo in man. Diabetes 28:731-736, 1979
8. Himsworth
IIP: Dietetic
factors
influencing
the glucose
tolerance
and the activity of insulin. J Physiol (Lond) 81:29-48,
1934
9. Himsworth
HP: The dietetic factor determining
the glucose
tale-ante
and sensitivity to insulin of healthy men. Clin Sci 2:67-94,
193:;
IO. Simpson RW, Mann JI, Eaton J, et al: Improved glucose
control in maturity-onset
diabetes treated with high-carbohydrate
modified fat diet. Br Med J I:l753-1756,
1979
I I Beck-Nielsen
H, Pedersen 0. Schwartz Sorensen N: Effect
oi det on the cellular insulin binding and the insulin sensitivity in
young healthy subjects. Diabetologia
15:289-296, 1978
1,. Borkman M. Campbell LV, Chisholm DJ, et al: Comparison
ot the effects on insulin sensitivity of high carbohydrate
and high
fat tliets in normal subjects. J Clin Endocrinol
Metab 72:432-437.
1991
I?. Abbott WGH, Boyce VL, Grundy SM, et al: Effects of
replacing
saturated
fat with complex carbohydrate
in diets of
subjects with NIDDM. Diabetes Care 12:102-107. 1989
14. Garg A, Bonanome
A, Grundy SM, et al: Comparison
of a
highcarbohydrate
diet with a high-monounsaturated-fat
diet in
patients with non-insulin-dependent
diabetes mellitus. N Engl J
Med 319:829-834. 1988
15. National Diabetes Data Group: Classification
and diagnosis
of diabetes
mellitus and other categories
of glucose tolerance.
Diabetes 28:1(139-1057, 1979
16. Fidanza F, Versiglione
N: Tabelle di composizione
degli
alimcnti. Napoli, Italy, Idelson. 1981
I7 De Fronzo RA, Totin JD. Andres
technique:
A method for quantifying
insulin
tance. Am J Phvsiol 237:E214-E223.
1979

R: Glucose
clamp
secretion and resis-

1X. Huggett ASG, Nixon DA: Use of glucose oxidase. peroxidase and o-dianisidine
in determination
of blond and urinary
glucose. Lancet 2:368-372, 1957
19. Roth J, Gorden P: Clinical application of the insulin assay, in
Berson SA. Yalow RS (eds): Methods in Investigative and Diagnostic Endocrinology,
vol 3B. Amsterdam.
The Netherlands.
North
Holland, 1973, pp 876-884
20. Noma A, Okaba H. Kita M: A new calorimetric
microdetermination of free fatty acid from tissue stores. Clin Chim Acta
43:317-322. 1973
21. Siedel J, Schlumberger
H. Klose S. et al: Improved reagent
for enzymatic determination
of serum cholesterol.
J Clin Chem
Clin Biochem 19838-839, lY8 I
22. Wahlefeld AW: Triglycerides
determmation
after enzymatic
hydrolysis, in Bergmeyer HU (ed): Methods of Enzymatic Analysis,
vol IV. New York, NY, Verlag Chemie. Weinheim Academic. lY74,
pp 1831-1974
23. Kostner GM: Enzymatic determination
of cholesterol
content of high density lipoprotein
fractions prepared
by polyanion
precipitation.
Clin Chem 22:695-6%. 1976
24. Steele R: Influence of glucose loading and of injected insulin
on hepatic glucose output. Ann NY Acad Sci X2420-430. 1959
25. Snedecor
GW, Cochran
Ames, IA, Iowa State University

WG: Statistical
Press, 1980

Methods

(ed 7).

26. Andrews WJ, Vasquez B, Nagulesparan

M, et al: Insulin
therapy in obese, non insulin dependent
diabetes induces improvements in insulin action and secretion that are maintained
for two
weeks after insulin withdrawal. Diabetes 33:634-637. 1984
27.
tration
in non
insulin
hepatic

Mandarin0
LJ. Gerich JE: Prolonged sulfonylurea
decreases insulin resistance and increases insulin
insulin dependent
diabetes mellitus: Evidence for
action at a postreceptor
site in hepatic as well
tissues. Diabetes Care 7:89-99. I984

adminissecretion
improved
as extra-

28. Storlien LH, James DE, Burleigh KM. et al: Fat feeding
causes widespread
in vivo insulin resistance,
decreased
energy
expenditure,
and obesity in rats. Am J PhysiolZSl:E576-E5X3,
1986
29. Chisholm K, ODea K: Effect of short term consumption
of a
high-fat, low-carbohydrate
diet on metabolic
control in insulindeficient diabetic rats. Metabolism 36:237-24X 14X7
30. Rivellese AA, Giacco R, Genovese
S. et al: Effects of
changing amount of carbohydrate
in diet on plasma lipoproteins
and apolipoproteins
in type II diabetic patients.
Diabetes Care
13:446-448, I990
31. Riccardi G, Rivellese AA, Mancini M: The use of diet to
lower plasma cholesterol
levels. Eur Heart J 879-85. 1987 (suppl
E)
32. Keys A, Menotti A, Karvonen MJ. et al: The diet and I5 year
death rate in Seven Countries Study. Am J Epidemiol 124:903-tJ15.
1986

1378

33. Rossetti L, Giaccari A, DeFronzo RA: Glucose toxicity.

Diabetes Care 13:610-630, 1990
34. Richter EA, Hansen BF, Hansen SA: Glucose-induced
insulin resistance of skeletal muscle glucose transport and uptake.
Biochem J 252:733-737,1988
35. Garvey WT, Olefsky JM, Marshall S: Insulin induces progressive insulin resistance in cultured rat adipocytes. Sequential effects
at receptor and multiple postreceptor sites. Diabetes 35:258-267,
1986
36. Olefsky JM, Kolterman OG: Mechanisms of insulin resistance in obesity and non insulin dependent (type II) diabetes. Am J
Med 70:151-168, 1981

PARILLO ET AL

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