the degree of saturation of fatty acids in dietary fats does not affect the metabolic response to...

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The Degree of Saturation of Fatty Acids in DietaryFats Does Not Affect the Metabolic Response toIngested CarbohydrateAngela Radulescu MDab, Youssef Hassan MDab, Mary C. Gannon PhD, FACNabc & Frank Q.Nuttall MD, PhD, MACNab

a Endocrine, Metabolism and Nutrition Section, VA Medical Center (A.R., Y.H., M.C.G.,F.Q.N.) Minneapolisb Department of Medicine, University of Minnesota (A.R., Y.H., M.C.G., F.Q.N.)Minneapolisc Minneapolis, Department of Food Science & Nutrition, University of Minnesota (M.C.G.)St. Paul, MinnesotaPublished online: 09 Jun 2013.

To cite this article: Angela Radulescu MD, Youssef Hassan MD, Mary C. Gannon PhD, FACN & Frank Q. Nuttall MD, PhD,MACN (2009) The Degree of Saturation of Fatty Acids in Dietary Fats Does Not Affect the Metabolic Response to IngestedCarbohydrate, Journal of the American College of Nutrition, 28:3, 286-295, DOI: 10.1080/07315724.2009.10719783

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Original Research

The Degree of Saturation of Fatty Acids in Dietary FatsDoes Not Affect the Metabolic Response toIngested Carbohydrate

Angela Radulescu, MD, Youssef Hassan, MD, Mary C. Gannon, PhD, FACN, Frank Q. Nuttall, MD, PhD, MACN

Endocrine, Metabolism and Nutrition Section, VA Medical Center (A.R., Y.H., M.C.G., F.Q.N.), Department of Medicine, University of

Minnesota (A.R., Y.H., M.C.G., F.Q.N.), Minneapolis, Department of Food Science & Nutrition, University of Minnesota (M.C.G.),

St. Paul, Minnesota

Key words: dietary fat, carbohydrate, glycemic index

Background: We are interested in the metabolic response to ingested macronutrients, and the interaction

between macronutrients in meals. Previously, we and others reported that the postprandial rise in serum glucose

following ingestion of 50 g carbohydrate, consumed as potato, was markedly attenuated when butter was

ingested with the carbohydrate, whereas the serum insulin response was little affected by the combination.

Objective: To determine whether a similar response would be observed with three other dietary fats

considerably different in fatty acid composition.

Design: Nine healthy subjects received lard, twelve received olive oil and eleven received safflower oil as a

test meal. The subjects ingested meals of 25 g fat (lard, olive oil or safflower oil), 50 g CHO (potato), 25 g fat

with 50 g CHO or water only. Glucose, C peptide, insulin, triacylglycerols and nonesterified fatty acids were

determined.

Results: Ingestion of lard, olive oil or safflower oil with potato did not affect the quantitative glucose and

insulin responses to potato alone. However, the responses were delayed, diminished and prolonged. All three

fats when ingested alone modestly increased the insulin concentration when compared to ingestion of water

alone. When either lard, olive oil or safflower oil was ingested with the potato, there was an accelerated rise in

triacylglycerols. This was most dramatic with safflower oil.

Conclusions: Our data indicate that the glucose and insulin response to butter is unique when compared with

the three other fat sources varying in their fatty acid composition.

INTRODUCTION

Our laboratory is interested in the metabolic response to

ingested macronutrients, and the interaction between individ-

ual macronutrients as well as the interactions in mixed meals.

Several years ago, we and others [1,2] reported that the

postprandial rise in plasma glucose following ingestion of 50 g

carbohydrate (CHO), consumed as potato, was markedly

attenuated when fat, consumed as butter, was ingested with

the CHO. The serum insulin response was little affected by the

addition of butter. Since the insulin response was the same

when the glucose response was , 40% less, the data could be

interpreted to suggest that butter had an insulin stimulatory

effect. Alternatively, the butter could have directly affected the

disposition rate of glucose. Whether these results are unique to

butter, or whether a similar response would be observed with

other dietary fat sources, became of interest.

Therefore, we determined the results obtained when other

dietary fat sources, considered to be high in either saturated,

monounsaturated or polyunsaturated fatty acids, are ingested

with and without potato. For this purpose, lard, olive oil and

safflower oil were chosen, respectively (Table 1). The study

protocol used was the same as used previously.

In addition, the concentration of NEFAs was determined.

To our knowledge the above data, obtained in a highly

controlled fashion, are not available in the literature. Such data

Address reprint requests to: Frank Q. Nuttall, M.D., Ph.D., Endocrine, Metabolism and Nutrition Section (111G), VA Medical Center, Minneapolis, MN 55417. E-mail:

[email protected]

The study was supported in part by funds from the Department of Veterans Affairs and a grant from the National Pork Board.

Journal of the American College of Nutrition, Vol. 28, No. 3, 286–295 (2009)

Published by the American College of Nutrition

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are of intrinsic value. The information also is important for

patients and health care providers in understanding the

anticipated metabolic effects of the various dietary fat sources

when ingested with a carbohydrate in a mixed meal. Current

data indicate that these nutrients should be considered not

solely as a source of energy but also as regulators of fuel

homeostasis.

MATERIALS AND METHODS

Nine healthy subjects, four females and five males,

received lard as a test meal, twelve healthy subjects, six

females and six males, received olive oil as a test meal and

eleven healthy subjects, six females and five males, received

safflower oil as a test meal. All subjects gave informed consent

before participating in the study and the study was approved by

the Minneapolis Department of Veterans Affair Medical

Center and the University of Minnesota Committee on Human

Subjects. The mean age of the subjects was 25 years (range

18–38), the mean BMI was 23 kg/m2 (range 19–29) with mean

lean body mass of 54 kg (range 37–67). Lean body mass was

determined using a portable body impedance analyzer (RJL

Systems, Clinton Township, MI). All participants had normal

thyroid, liver, kidney function, lipid profiles and glycated

hemoglobin.

Subjects were studied in a Special Diagnostic and

Treatment Unit, which is similar to a Clinical Research

Center. After an overnight fast of 12 hours, an indwelling

catheter was inserted into an antecubital or forearm vein and

kept patent with intravenous saline. Subjects ingested a test

meal consisting of lard, olive oil or safflower oil with or

without mashed potatoes or mashed potatoes alone. On a

separate occasion, they received water only. Each subject

completed all four arms of the study. Generally, the 4-day

study was conducted over a 2–3 week period.

Boiled, peeled white potatoes (250 g raw weight) were

given in an amount to equal 50 g starch [3]. They were cooked

10–15 minutes in a microwave oven before being served. The

amount of fat consumed either alone or mixed with potatoes

was 25 g. The meals were given in a random order at 8:15 AM.

Patients were allowed to consume water and coffee ad libitum.

Although the amount of water was not quantified, when

questioned, the subjects indicated that similar amounts of

water/coffee were consumed for all three test meals. Baseline

blood samples were obtained at 7:45, 8:00 and 8:15 AM. The

test meal was ingested at 8:15 AM. Blood was collected every

15 minutes after the beginning of each meal for the first two

hours, then every 30 minutes for the third and fourth hours.

After the study period, subjects were asked to complete a

satiety index. The satiety index consisted of the following 4

questions: (1) How strong is your desire to eat? (2) How

hungry do you feel? (3) How full do you feel? (4) How much

food do you think you can eat? In addition they were asked

how pleasant they found the test meals. Answers were

quantified on a linear scale of 1 to 100, with 1 being the

least and 100 being the most. At the end of the study period,

subjects were served a regular mixed meal.

Serum glucose concentrations were determined by a

hexokinase method using an Abbott Architect analyzer (Abbott

Laboratories, Abbott Park, Illinois). Serum immunoreactive

insulin was measured using an automated chemiluminescent

assay on DPC’s IMMULITE machine (Diagnostic Products

Corp., Los Angeles, California). Triglycerides were deter-

mined using an EktaChem Analyzer (Eastman Kodak,

Rochester, New York). C peptide was measured initially with

RIA kits from Diasorin (Stillwater, Minnesota). Subsequently,

because the Diasorin RIA kit production was discontinued, the

C peptide was measured with RIA kits from Diagnostic

Systems Laboratories (Webster, Texas). A conversion coeffi-

cient was established by assaying serum specimens with both

assays in order to obtain comparable data. Serum nonesterified

fatty acids were determined by an enzymic colorimetric assay

using kits produced by Wako Pure Clinical Industries, Ltd,

Japan. For all data, the net integrated 240 minute area

responses, using the fasting values as baseline, were calculated

using a computer program based on the trapezoid rule.

Statistics were determined using Student’s t test for paired

variates or Wilcoxon’s signed rank with the Microsoft Office

Excell 2007 program (Microsoft Corporation, Richmond,

Washington) for PC. A p value of ,0.05 was criterion for

significance. Data are presented as means +/2 SEMs.

RESULTS

Glucose Response (Fig. 1)

Following the ingestion of potato, the results were similar

in all three studies. The mean plasma glucose increased and

reached a peak at 30–45 minutes. It then returned to a basal

concentration at 1.75 hr, decreased to a nadir at 2.5 hr and re-

approached the baseline at the end of the study period.

After the ingestion of the combination meals, the initial rise

in glucose was delayed by approximately 15 minutes. The

Table 1. Composition of Dietary Fats*

Monounsaturated

fatty acids

(%)

Polyunsaturated

fatty acids

(%)

Saturated

fatty acids

(%)

Lard 45.1 11.2 39.2

Olive Oil 72.96 10.52 13.8

Safflower Oil 14.36 74.62 6.20

* Database is Agriculture Handbook No.8-11

United States Department of Agriculture.

Metabolic Response to Dietary Fats

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subsequent glucose response was diminished and prolonged.

Following ingestion of potato + lard, potato + olive oil or

potato + safflower oil, the peak was 89 %, 86 % and 78 %

respectively of that following ingestion of potato alone (123 6

8 mg/dl vs. 138 6 8 mg/dl, 119 6 6.6 mg/dl vs. 139 6

7.8 mg/dl and 114 6 5 mg/dl vs. 143 6 8.7 mg/dl).

The 4 hr integrated area response was not different for any

potato + fat combination meal when compared to the potato

Fig. 1. Time course of serum glucose concentrations. Time points are means +/2 SEM. Inserts: net integrated areas under the curve after test meal

ingestion. Bars with different letters indicate data are statistically significantly different (p,0.05).


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meal alone (21 6 8.5 mg?hr/dl vs. 21 6 6 mg?hr/dl, 42.9 6

6.9 mg?hr/dl vs 37.4 6 9.5 mg?hr/dl and 30.8 6 6 mg?hr/dl vs

41.4 6 8.9 mg?hr/dl, for lard, olive oil and safflower oil,

respectively).

When only fat was ingested alone, the glucose response

was not different from when only water was ingested. In all

cases, it decreased modestly.

Insulin Response (Fig. 2)

The initial mean fasting insulin concentrations ranged from

4.2–6.6 mU/ml (25–40 pmol/L). After ingestion of potato

alone, the serum insulin concentration increased, reached a

peak at 45 minutes and returned to the baseline value by

3 hours. When lard, olive oil or safflower oil was ingested with

potato, the initial insulin rise was delayed 15 minutes.

Subsequently, the insulin response was reduced and prolonged,

similar to the glucose response. The insulin concentration

increased slightly when fats were ingested alone, compared to

water ingestion.

As with the glucose response, the ingestion of lard, olive oil

and safflower oil with potato did not significantly change the

insulin area response when compared with potato alone (58 6

14.1 mU?hr/ml vs. 66 6 13 mU?hr/ml, 58 6 5.6 mU?hr/ml vs.

51.8 6 9.6 mU?hr/ml and 49.7 6 13 mU?hr/ml vs. 55.4 6

10.2 mU?hr/ml, respectively). The insulin area response was

slightly negative after the water challenge. When lard, olive oil

or safflower oil were ingested alone, the insulin area response

was small, positive and significantly increased when compared

with water [0.86 6 0.78 mU?min/ml vs. 25.17 6 1.24 mU?min/ml

(p,0.001), 2.46 6 1 mU?hr/ml vs. 22.6 6 1 mU?hr/ml

(p, 0.005) and 2.9 6 0.9 mU?hr/ml vs. 23.9 6 1 mU?hr/ml

(p,0.002) ].

C Peptide Response

The increase in C Peptide concentration confirmed that the

insulin results represented an increase in insulin secretion (data

not shown).

Triacylglycerols (TAG) Response (Fig. 3)

The serum TAG concentration decreased slightly over the

4 hours of the experiment when water was ingested. When

only potato was ingested, the TAG concentrations remained

similar to those when only water was ingested. Following

ingestion of lard alone, the mean TAG concentration did not

begin to increase until the 1.25 hr time point. It subsequently

increased and it was still elevated at the end of the study.

Following ingestion of olive oil or safflower oil alone, the

mean TAG concentration began to increase at 1 hr, reached a

maximum at 3 hr and remained elevated above baseline at the

end of the study. Following ingestion of potato + lard, potato +olive oil or potato + safflower oil, the TAG concentration

increased more rapidly than when the fats were ingested

independently and it remained constantly elevated throughout

the study period.

The net integrated area response after ingestion of each fat

alone was not different when compared to the area response

following the ingestion of potato + fat. The area response after

lard, olive oil, safflower oil, potato + lard, potato + olive oil and

potato + safflower oil were statistically higher than after the

potato or water ingestion [lard vs. potato (p,0.007), lard vs.

water (p,0.04), potato + lard vs. potato (p,0.005), potato +lard vs. water(p,0.001), olive oil vs. potato (p, 0.0002), olive

oil vs. water (p,0.016), potato + olive oil vs. potato (p,0.0007)

and potato + olive oil vs. water (p,0.003), safflower oil vs.

potato (p,0.007), safflower oil vs. water (p,0.01), potato +safflower oil vs. potato (p,0.04) and potato + safflower oil vs.

water (p,0.04)]. The area responses to potato alone vs. water

were not statistically significantly different.

Non-Esterified Fatty Acids (NEFA) Response (Fig. 4)

When compared to water, the ingestion of fats alone did not

quantitatively change the NEFA response. Ingestion of potato,

alone or with any of the fats, resulted in a transient decrease in

NEFA concentration. The changes in NEFAs concentrations

are as expected with the increased insulin concentration.

The integrated NEFA area responses were lower for all

meals containing potato compared with the areas resulting

from ingestion of water or fats alone. The area responses were

not different between potato alone and potato ingested with

lard, olive oil or safflower oil. The differences between the net

areas following water, lard, olive oil or safflower oil ingestion

were not statistically significantly different.

Satiety Index (Fig. 5)

The subjects desire to eat, the degree of hunger, and the

proposed food intake were significantly higher and their degree

of fullness was less after subjects ingested lard when compared

with potato or potato plus lard. The responses to potato alone

vs potato plus lard were essentially identical.

Both olive oil and safflower oil ingested alone had a similar

effect on the desire to eat, degree of hunger and proposed

intake as after potato alone or potato plus olive oil or safflower

oil, respectively. The degree of fullness was less after the

ingestion of olive oil alone when compared with potato alone

or potato plus olive oil. Safflower oil did not change the degree

of fullness when compared with potato alone or potato plus

safflower oil. The desire to eat, the degree of hunger, the

degree of fullness and the proposed intake were similar after

potato and after potato plus olive oil or potato plus safflower

oil respectively.

The ingestion of fat alone was considered unpleasant

regardless of the fat source. The pleasantness of potato and



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potato plus lard or potato and potato plus safflower oil were

similar. When compared with potato alone, the taste was

significantly less pleasant when olive oil was added to the

potato.

Thus, overall the ingestion of lard or olive oil alone was

less satisfying than when potato with or without these fats were

ingested. This was not the case for safflower oil. Safflower oil

alone was not less satisfying.

Fig. 2. Time course of serum insulin concentrations. Time points are means +/2 SEM. Inserts: net integrated areas under the curve after test meal



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Of some interest, when fats were added to the potato, there

was no change in the overall satiety index, even though the

food energy intake was more than twice as great as when

potato was ingested.

DISCUSSION

We [1], and others [2], have determined that butter

dramatically reduces the blood glucose with little or no

Fig. 3. Time course of serum triacylglycerols concentrations. Time points are means +/2 SEM. Inserts: net integrated areas under the curve after test

meal ingestion. Bars with different letters indicate data are statistically significantly different (p,0.05).



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change in insulin concentration when ingested with potato as

a source of carbohydrate. The addition of butter also did not

delay the rise in glucose. Given these results, we were

interested in determining whether lard, olive oil and safflower

oil, i.e. dietary fats considerably different in fatty acid

composition, would have a similar effect. For comparative

purposes, potato again was used as a carbohydrate source.

More data points were obtained in the present study, which

Fig. 4. Time course of serum NEFAs concentrations. Time points are means +/2 SEM. Inserts: net integrated areas under the curve after test meal



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increases the precision of the quantitative measurements of

the net area.

In contrast to the dramatic decrease in glucose response

when butter was ingested with potato [1,2] when lard, olive oil

or safflower oil were ingested with potato, the glucose rise was

slower and the maximum was less. However, when integrated

over 4 hours, the net areas resulting from potato alone or

potato ingested with any fat were virtually identical. The rise

in insulin concentration followed the rise in glucose. The

insulin net area response correlated in all cases.

A delayed gastric emptying induced by fats has been well

documented [4,5,6] and this potentially could account for the

blunted and prolonged blood glucose increase observed

following ingestion of potato + lard, potato + olive oil or

potato + safflower oil.

Thus, the results were similar to one another but all were

different from those observed after butter ingestion. Why the

modification in glucose and insulin response was different

when compared with butter is unknown. The observation that

the glucose area response decreased when potato was ingested

with butter but not when ingested with the other fats, could

have been due to the increased insulin response relative to the

glucose response or could be due to an independent mechanism

which directly stimulated the glucose removal rate. Also

unknown is if the butter-stimulated insulin effect is due to a

direct effect on the beta cell of the absorbed products in butter

or is mediated through an incretin effect. In any regard, a

difference in fatty acid composition of the triacylglycerols

present in the fat sources, most likely is the explanation for the

difference.

Butter contains a higher proportion of saturated long-chain

fatty acids and a lower proportion of mono- and polyunsatu-

rated fatty acids. In this regard, in an in vitro islet cell

preparation, addition of fatty acids potentiated a glucose-

stimulated release of insulin. The stimulation increased with

increasing chain length and the degree of saturation of the fatty

acids [7]. In a perfused rat pancreas preparation, long chain

fatty acids also stimulated insulin secretion. Again the longer

the chain length and the lower the number of double bonds, the

greater the effect [8]. In rats maintained on a highly saturated

lard oil diet for 4 weeks, plasma insulin concentrations

measured during a hyperglycemic clamp were augmented

when compared to results in animals receiving a low fat diet or

a diet enriched with an unsaturated fat [9].

Fatty acids cannot be infused in humans because of a

potential toxic effect. An artificial way of increasing the non-

esterified free fatty acid (NEFA) concentration in plasma is by

giving an intravenous lipid emulsion followed by heparin

administration in order to activate a lipoprotein lipase which

promotes the release of fatty acids from triacylglycerols. In

humans, this maneuver to increase the NEFA concentration

facilitated insulin secretion in the presence of an elevated

glucose concentration [10] [11]. Thus, raising the plasma long

chain fatty acid concentration indirectly by giving a fat

emulsion intravenously followed by heparin in humans, as well

as in vitro data, suggest that a raised fatty acid concentration

facilitates insulin secretion in the presence of an elevated

glucose concentration. Saturated long chain fatty acids make

up a large proportion of the fatty acids in triacylglycerols

found in butter and lard.

In other studies, absorption of chylomicrons after oral

ingestion of fats including butter has resulted in an increase in

NEFAs [12–14]. However, that an increase in long-chain fatty

acid concentration is not important in stimulating insulin

secretion when ingested with glucose is demonstrated in

another study in which normal and obese women were given

100 g butter orally. Two hours later, a hyperglycemic clamp

was introduced. There was a highly significant increase in

insulin secretion when compared to that induced by the

hyperglycemic clamp in the absence of preloading with butter

[15]. Nevertheless, following the ingestion of butter the total

NEFAs were not increased. That is, the increase in insulin

concentration was independent of a rise in NEFAs. It is

possible that there was a selective increase in certain long

Fig. 5. Satiety Index. Average response on a scale of 1–100 with 1

being the least and 100 the most. See Materials and Methods for more

detail. Statistical significance is denoted by the following symbols:

* p,0.05 Fat vs Potato or Fat vs Potato + Lard {p,0.05 Olive Oil

vs Potato + Olive Oil.



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chain fatty acids and that these were responsible for the increase

in insulin concentration. This would appear to be unlikely.

In the present study, the ingestion of the three fats with CHO

did not increase the NEFA concentration over the 4 hr of the

study. Rather, the NEFA concentration decreased and the decrease

correlated with the change in insulin concentration, as expected.

Butter is unique in that it contains short-chain and medium-

chain fatty acids, as well as a small proportion of trans-fatty

acids not found in lard, olive oil or safflower oil. Thus, it is

possible that their presence in the stomach or gut or their

absorption played a role in the reduced glucose response and

the relatively greater insulin response previously observed.

To our knowledge, the circulating concentrations of short

and medium chain fatty acids have not been determined in any

study. Previous data have suggested that short and medium

chain fatty acids are converted into ketone bodies and these

stimulate insulin secretion by the beta cells [16,17]. The keto

acid concentrations have not been determined after butter

ingestion, but an increase in the presence of a high circulating

insulin concentration would be unlikely. The possibility that

short and/or medium chain fatty acids directly stimulate insulin

secretion and/or accelerate glucose removed remains an

interesting possibility.

Although ingestion of lard, olive oil or safflower oil did not

facilitate a reduction in glucose response or stimulate an

increase in insulin when ingested with potato, all three fats

when ingested alone did modestly increase the insulin

concentration when compared to ingestion of water alone.

The C-peptide data confirmed that this represented a

stimulation of insulin secretion. The mechanism is totally

unknown. Pi-Sunyer et al. [18] described a small rise in insulin

after the ingestion of corn oil in man. Others [16,19–21]

reported no change after fat ingestion but the studies were not

done with a water control. However, similar to the results of

our study, in a study where water was used as a control, Carr et

al. [22] reported that the ingestion of olive oil increased insulin

secretion without affecting glucose levels. In the present study

our data extend the stimulation of insulin secretion to other

dietary fat sources as well. Thus, all three macronutrients i.e.

carbohydrates, proteins and fats, have now been shown to

stimulate insulin secretion. The observation that the plasma

glucose did not change is compatible with an induced insulin

resistance. Nevertheless, our data indicate that the glucose and

insulin response to butter is unique when compared with the

three other fat sources varying in their fatty acid composition.

Resent data indicate that the response to fats ingested with

carbohydrate is different than in people without diabetes. In

patients with type 2 diabetes, we [12] and others [23] have

reported that ingestion of butter with a CHO source resulted in

an increase in insulin area response without a change in

glucose area response. Thomsen et al [24] reported a similar

increase in insulin concentration without a change in glucose

concentration when olive oil was ingested with a CHO source.

Although, it should be noted that larger amounts of fat were

ingested in the studies reported by Thomsen et al, [23,24].

Thus, information obtained in non-diabetic subjects can not

directly be applied to people with type 2 diabetes. It should be

noted that we previously have reported that the insulin

response in non diabetic and type 2 diabetic subjects to

ingested protein with or without glucose also is considerably

different. The insulin responses were relatively more vigorous

in the subjects with diabetes [12,13]. Overall, these data

strongly suggest that the beta cell response to all macro-

nutrients is different in people with type 2 diabetes.

In the present study when either lard, olive oil or safflower

oil was ingested with the potato, there was an accelerated rise in

TAG concentration. This was most dramatic with safflower oil.

The increase occurred 1.5 hr earlier. The reason why the

ingestion of fats with potato resulted in the more rapid rise in

TAG is unknown and has never been reported to our knowledge.

In summary, in normal subjects it has been reported [1,2],

that butter decreases the glucose concentration but does not

change the insulin response. In contrast, in the present study,

three other dietary fats had no effect on either the glucose or

insulin quantitative area responses when ingested with a CHO

source. They did delay, decrease the maximum response, and

prolong the elevation of both. They independently stimulate a

modest increase in insulin concentration. The presence of a

carbohydrate source also accelerates a rise in TAGs when

ingested with a fat source. The mechanism is unclear.

ACKNOWLEDGEMENTS

The authors thank the subjects for participating in the study,

the staff of the Special Diagnostic and Treatment Unit, the staff

of the Clinical Chemistry Laboratory, the staff of the Nuclear

Medicine Department for their assistance, Heidi Hoover RD,

MS for help with food preparation and Linda Hartich, MT, for

technical advice and laboratory assistance.

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the degree of saturation of fatty acids in dietary fats does not affect the metabolic response to...

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