Triglyceride-integrated concentration: Relationship to insulin-integrated concentration

Triglyceride-Integrated Concentration: Relationship Insulin-Integrated Concentration*

to

John T. Hayford, Mark M. Danney, and Robert G. Thompson The relationship triglyceride ations

was

subjects. either

between

plasma insulin and plasma

concentrations studied

Four

45%

in

in response eight

isocaloric

or 65%

healthy

formula

of total

to diet alteradult

diets,

energy

male

providing

from

carbohy-

drate and, using either sucrose or corn syrup as the carbohydrate Latin

source, were ingested for 10 days in a

Square

sequence.

insulin responses

Plasma

in blood samples after overnight obtained nique,

by a 24-hr

the

mean

were

concentrations

concentration tration

during

designated and

as

withdrawal

tech-

of plasma

insulin

the 24-hr

the

centrations

were

triglyceride

integrated

Nlean

45%

insulin

to

57%

higher

of analogous

change

carbohydrate

the insulin integrated

of the eight subjects concentrations integrated ods

(r

subject

associated

ranged

from

between

integrated

significantly Seven

insulin-integrated lower

triglyceride-

during the four diet peri-

-. 536

had a positive

of total energy

concentration.

with

mean

19% to 27%

not

had higher

concentrations

was a statistically tionship

did

con-

and

diets containing

sucrose. Increases in the percentage as

of

concen-

integrated

concentrations

lower during ingestion supplied

period

insulin-integrated

triglyceride-integrated

respectively.

and

were assessed

fast and in samples

continuous

and plasma triglyceride study

triglyceride

to diet alterations

to

-.777),

correlation

significant

while

(+.324).

(p < .Ol

)

inverse

one

There rela-

the mean insulin- and triglyceride-

concentrations

during the four diet peri-

ods.

REGULATION of circulating T HEtriglyceride concentrations is a

plasma complex process reflecting exogenous and endogenous factors that control triglyceride influx into and

From the Department of Pediatrics, University of Iowa, College of Medicine, Iowa City, Iowa. Supported in part by grants AM-18439. HL-14230. Atherosclerosis Specialized Center for Research from the NIH and a grant-in-aid from the Amstar Corporation. Patients were studied in the Clinical Research Center, Grant RR59, Division of Research Resources, National Institutes of Health. Dr. Hayford was supported by Nationa/ Research Service Award T32-AM07018. Address reprint requests to Robert G. Thompson, M.D., Division of Pediatric Endocrinology, Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242. *The opinions expressed in this paper are those of the authors and do not represent the opinions of the United States Air Force. 01979 by Grune & Stratton, Inc. 0026-0495~79/2811-$0002$01.00/0

1078

triglyceride clearance from the vascular compartment. The carbohydrate and fat composition of the diet is the primary external regulator of triglyceride metabolism. Circulating hormone concentrations are postulated to be a major internal regulator of triglyceride metabolism, controlling both triglyceride synthesis and triglyceride clearance. Several polypeptide hormones, including insulin,ld glucagon,‘-* and growth hormone’,” have been shown to regulate aspects of triglyceride synthesis and clearance. Both in vivo and in vitro studies have shown that insulin plays a pivotal role in the control of triglyceride ingress and egress from the circulating triglyceride pool. Insulin has been shown to influence triglyceride metabolism by regulation of precursor substrate concentration,” regulation of the activity of hepatic glyceride esterification pathways,‘2-‘4 and regulation of degradation and extravascular storage of triglyceride.“-‘* Although relative or absolute insulinopenia can lead to dramatic increases in circulating plasma triglyceride concentration secondary to decreased triglyceride clearance by lipoprotein lipase, clinical states associated with insulin excess or augmented insulin secretory response to provocative stimul~l.6.19-ZZ frequently are associated with elevated fasting concentrations of plasma triglyceride. However, the-relationship between triglyceride and insulin concentrations assessed over 24 hr has not been evaluated to determine if the observations in the fasting state can be extrapolated to 24 hr. This report describes our observations in a population of healthy, normolipemic young males of plasma insulin and plasma triglyceride responses to diet alterations. The goal was to evaluate the relationship between mean 24-hr insulin and triglyceride concentrations obtained during ingestion of the four test diets. In addition to this difference in methods of assessing the hormone and lipid response to the test diets, this study differs from previous reports in that comparisons are possible between diet responses within individual subjects rather than being limited to evaluations between subjects.

Meraboiism,Vol. 28, No. 11,

(November), 1979

INSULIN

TRIGLYCERIDE

MATERIALS The criteria

AND

of subject

METHODS

selection.

the dietary

the sequence of diet administration, continuous

blood sampling

over the 24-hr

in a previous

publication.*’

healthy

normolipemic

young

formula

a balanced (Table

Latin

Square

carbohydrate calories

As can be noted

received

The

the 4

comparison

calories

a mixture

by

diets

derived

from

of monoaccharide

with a dextrose

in Table

are identical

in all

respects.

between

the diet

45% or 65% of total to the percentage

energy

except

diets (B and D)

carbohydrate

formulations

source.

providing

from carbohydrate

of energy from dietary

contribution

equivalence

I, the 45% carbohydrate

diets (A and C) and the 65%’ carbohydrate

tionate

are

(45% and 65%)) and the source of carbohydrate

and short chain glucose polymers

Differences

period

each of the 8

subjects

of total

(sucrose or corn syrup.

of 42).

for the

of diet being governed

design).

in percent

study

Briefly,

male

diets (sequence

I) altered

formulation,

and the protocol

detailed isocaloric

1079

RELATIONSHIP

either

are confined

fat and the propor-

of each fat source to the total dietary

fat

content. After

the 9-day period of diet consumption.

admitted of

to the Clinical

continuous

collected

blood

as 48 half-hour

later triglyceride latory

Research aliquots,

and insulin

and encouraged

so far as possible. subjects continued

Center

withdrawal.

subjects

for a 24-hr period

Blood

samples

to maintain the

their 24-hr

for

were ambu-

usual activity withdrawal

to receive the designated

as three meals and an evening

were

plasma being harvested

assay. The subjects

During

were

level period,

diet. apportioned

snack. until

IO:00 p.m. when

they began to fast. A blood sample was obtained

by separate

venepuncture

observation

period

at the completion

to assess fasting

to the

triglyceride

24.hr

and insulin

concentra-

tion. insulin

double-antibody

variation

were assayed

immunoassay

concentrations subject

was measured

within

7 days of sampling.

concentrations collection

for

the

were analyzed within

four

in triplicate

technique.24 test diets

concurrently

a test subject.

The

hormone

fed to a particular

to eliminate

Plasma

using a

triglyceride

interassay concen-

are corrected

Triglyceride expressed

and insulin

mean

concentrations during

of the

the 24-hr

one-half

for

the

27% dilution

due to

solution.

concentration,

plasma

of constant

which

triglyceride

and

hormone

Since blood

and all sampling

the integrated

is

represents

blood samples obtained

blood withdrawal.

continuously

hour,

assay2”

lipid and hormone

response to the diet alterations

from all of the 30-min

was withdrawn

Ruorometric

anticoagulant

by the integrated

the grand

automated The reported

in the preservative

concentration

periods

were

is equivalent

the area under the curve in a plot of concentration

to

over the

24-hr period of evaluation. Hormone

and

lipid

responses to each

analyxd

by analysis of variance for a Latin

Sources

of

sequence, effect,

variation.

residual

namely

significance

neither

diet sequence induced

diet sequence

diet accounted

nor residual

integrated

fore.

all

of insulin

done

by analysis

without

analyses partitioning

degrees

significance

for of

the previous

source of varia-

concentration integrated

concentration,

from

significant

of variance

Statistical

elect

response. Thereconcentrations

2 4 x 4 Latin freedom

comparison>

to the

between

mean

responses to the test diets wcrc made using Tukey’s comparison

diet

and direct

by the F statis-

integrated

for a statistically

tion in the insulin

diet,

did have statistical

triglyceride

were

variability.

were tested for statistical

on the diet

effect.

subject the previous

tic. Although

cffcct

test diet

Square design.*”

from

are

Squares residual insulin multiple

method.” RESULTS

Fasting Responses

ofInsulin

and Triglyceride

obtained after the IO-hr overnight fast (Table 2) showed no significant difference in the mean insulin concentration during the 4 test diets despite the alterations in either the carbohydrate source or Plasma

concentrations

by an

tration

samples from the 8 subjects

Table 1. Summary of Diet Formulations D!strlbutlonof Energy

D!et 45% Carbohydrate diets (A and C)

Diet Component

PerCent of Total Energy

Diet Components (Percentof Carbohydrate,Proteinor Fat Prowded) FormulaComponent

Protein

Fat

Carbohydrate

45

Sucrose or corn syrup*

99

0

Protem

15

Casec

0

95

2

Fat

40

Peanut 011

0

0

65

Cocoa butter

0

0

26

Egg yolk mix

1

5

7

100

100

0

100

Total 65% Carbohydrate diets (B and D)

CHO

0

Carbohydrate

65

Sucrose or corn syrup*

99

0

Protein

15

Casec

0

95

4

Fat

20

Peanut 011

0

0

64

Cocoa butter

0

0

18

Egg yolk mix

1

5

14

100

100

Total *Diets A and B prowded carbohydrate as source and diets C and D as corn syrup.

100

HAYFORD. DANNEY,

1080

Table 2. Plasma Insulin and Triglyceride

AND THOMPSON

Response to Diet Diet

Variable

45% SlKr0se (Al

65% SlKr0ss (8)

45% Corn Syrup (C)

65% Corn Syrup 0)

12.7

14.7

14.1

19.2

4.03

13.06

38.5

36.6

55.7

57.4

4.91

20.60

5.06

16.40

6.54

21.19

SEM

Critical Value p < .05

Mean fasting insulin concentration ($/ml) Mean insulin integrated concentration (rlJ/mll Mean fasting triglyceride 77

concentration (mg/dl)

116

71

128.6

90.9

118

Mean triglycende Integrated 112.1

concentration (mg/dll

percentage of total energy derived from carbohydrate. Analysis of variance showed that all differences in mean fasting insulin response were related to the heterogeneity of subject’s response, direct diet effects were not significant (p > .05). The mean fasting triglyceride concentration was increased during the 65% carbohydrate diets compared to 45% diets (Table 2). There was no significant difference in fasting triglyceride concentration between diets with common Mean Seauential

7AM

12 Noon

94.0

source of carbohydrate but different percent of total calories derived from carbohydrate. Additional details relating to these observations have been previously reported.24 Mean Sequential Insulin and Triglyceride Responses The mean sequential plasma insulin concentration of the 8 subjects during the 24 hr of continuous sampling (Fig. 1) demonstrated the more spiking nature of insulin secretion during

Insulin Concentration

5 PM

10 PM

LI

I

I

I

7AM

12 Noon

5 PM

10 PM

Clock Time

3AM

I

3AM

Fig. 1. The mean insulin concentration of the 48 sequential blood samples for the 8 study subjects had greater meal associated variation on diets formulated with corn syrup (diets C and D) compared to diets formulated with sucrose (diets A and 8). This occurred when these carbohydrates provided either 45% (upper panell or 85% (lower panel) of total energy. The corn syrup diets, in addition, induced higher insulin concentrations than sucrose diets. This difference was confirmed primarily to the postprandial periods. there being no significant difference during the overnight fast starting at 10:00 p.m.

1081

INSULIN TRIGLYCERIDE RELATIONSHIP Mean Sequential Plasma Triglyceride

7AM

12Noon

5PM

10 PM

3 AM

Concentration

6AM

200 .:

The mean triglyceride concentration of Fig. 2. the 48 sequential blood samples for the 8 study subjects shows that the sucrose diets (A and 8) had higher or equivalent plasma triglyceride concentration than the corn syrup diets. ihe diets formulated with 45% of total calories as carbohydrate (upper panel) showed greater meal associated variation compared to 85% carbohydrate diets (lower panel). reflecting the higher dietary fat content of the 45% carbohydrate diets (Reproduced with permission from the American Journal of Clinical Nutrition, 32:1870-1678.1979).

the ingestion of corn syrup (diets C and D) compared to sucrose (diets A and B). The mean insulin concentration during each 30-min period was generally lower during the ingestion of the sucrose containing diets compared to corn syrup diets. This difference was noted both with diets providing 45% of total energy as carbohydrate (upper panel) and with diets providing 65% of total energy as carbohydrate (lower panel). The difference between the insulin response to the two carbohydrate sources was most marked during the period of diet consumption, there being no significant difference in mean plasma insulin concentration during the overnight fasting period starting at 1O:OOp.m. The mean plasma triglyceride responses in the sequential samples (Fig. 2) were higher during the sucrose diets than corn syrup diets. The diets with the higher fat content (diets A and C, upper panel) showed more meal associated variation in plasma triglyceride concentration and no signifi-

-

.*\

-* B 65% Sucrose D 65% Corn Syrup

..

0: iz : 3 4

50

t

L 7AM

12Noon

5PM

Clock

10 PM

3 AM

0AM

Time

cant difference in triglyceride concentration during the period of overnight fasting. An analogous pattern was observed during ingestion of test diets with the low fat content (diets B and D, lower panel), although meal associated changes in plasma triglyceride concentration were dampened and plasma triglyceride concentrations obtained during the 10 hr of overnight fasting were more disparate. Twenty-Four-Hour Integrated Insulin and Triglyceride Responses The plasma integrated insulin concentrations for each of the eight study subjects while receiving each diet formulation are shown in Table 3. With the exception of two subjects, the insulin integrated concentrations range from 19.0 to 58.0 &J/ml. The reason for the consistently elevated integrated insulin concentrations observed in subject 2 is unclear. The diurnal pattern of insulin secretion in subject 2 was not

HAYFORD. DANNEY, AND THOMPSON

1082

Table 3. Plasma Insulin (I. = plJ/ml) and Triglyceride 45%

Subject

Mean

I

(T. = mg/dl)

65%

integrated

Concentrations

45%

65%

SUCKlSe

SUCrOSe

Corn Syrup

Corn Syrup

IA)

(6)

(C)

(Dl

T

I

T

I

T

I

CotrelatIon Coefficient insulin vs T

16.1

74

19.4

93

26.4

74

35.2

65

127.6

156

102.5

154

138.4

141

142.9

122

Tr!glycerfde

-

,639

-.730

14.1

130

19.1

100

85.8

66

33.5

70

-.750

36.8

137

27.9

177

35.6

121

53.3

123

-.7Ol

38.8

109

25.3

156

42.5

91

55.9

122

- ,536

19.7

70

30.7

109

47.8

74

57.4

103

+.324

28.8

91

39.1

76

35.4

57

46.2

61

~ ,662

26.3

130

28.8

164

33.5

103

34.9

86

-.777

38.5

112

36.6

129

55.7

91

57.4

94

- ,936

different from that observed in the other study subjects. No insulin binding antibodies, which might be responsible for spuriously elevated insulin concentrations in the immunoassay used, were detectable. No history of adult onset or juvenile onset diabetes in first degree relatives was elicited. In addition, this subject demonstrated no evidence of glucose intolerance by either the criteria of Fajans and Conn29 or of the University Group Diabetes Program.3o The etiology of the exaggerated response in insulin integrated concentration in subject 3 to the 45% sucrose diet is likewise unclear. No abnormality in glucose tolerance, as monitored by mean 24-hr plasma glucose concentration or by plasma glucose response to a 100-g oral glucose tolerance test, accompanied this exaggerated insulin response. lnterassay variation was eliminated since insulin concentrations for all four diets were assessed in a single assay and intraassay variation was ruled out by repeat insulin immunoassay. The remainder of the subjects had insulin integrated concentrations consistent with this laboratory’s experience in a healthy young adult population consuming self-selected diets mean insulin integrated concentra(n = 18, tions -t SD = 32.42 * 13.8 pU/ml. range 11.256.0 pU/ml). Statistically significant direct diet effects on insulin integrated concentration (p < ,025) were documented by analysis of variance. In addition, statistically significant sources of variation were associated with the response within Latin Squares (p < .OOOS) and differences in subject response (p < .005). The sequence in which diets were administrated has no significant effect (p > .10) on observed insulin response.

The insulin integrated concentrations for each subject induced by diets containing sucrose compared to corn syrup are variable in magnitude but are consistent in the direction of change (Table 3). Generally, higher insulin integrated concentrations were observed during consumption of the two diets in which corn syrup was the source of carbohydrate calories. Only in the case of subject 4 was the insulin integrated concentration less while receiving the diet with 45% of calories from corn syrup than while receiving the diet with 45% of calories from sucrose. As noted previously, subject 3 had an exaggerated insulin response associated with the 45% corn syrup diet. The mean of the insulin integrated concentrations for all study subjects was 44% to 56% greater during ingestion of diets containing corn syrup than during ingestion of diets containing sucrose. Comparisons of the mean insulin integrated concentrations to the diet formulations are summarized in Table 2. The mean insulin integrated concentration with 65% corn syrup is significantly greater (p < .05) than that observed with the 65% sucrose diet. None of the other comparisons of mean insulin integrated concentrations with diet alterations achieved statistical significance (p > .05). The comparison of insulin integrated concentration with the diets providing 45% of calories from the two carbohydrate sources did not achieve statistical significance, although the insulin integrated concentration was 44% greater with corn syrup than with sucrose. The percent of total calories derived from carbohydrate did not influence the observed insulin integrated concentration response to a given source of carbohydrate.

1083

INSULIN TRIGLYCERIDE RELATIONSHIP

Integrated triglyceride concentrations for the eight subjects are shown in Table 3. Although observations pertinent to this presentation are summarized below, a more detailed analysis of the triglyceride response to the diet alternations is to be presented in a separate publication.*‘The integrated concentrations of plasma triglyceride were higher during consumption of sucrosecontaining diets than during consumption of the corn syrup-containing diets (Table 2). The triglyceride integrated concentration was 22%’ greater (p < .05) when subjects consumed 45%’ of total energy from sucrose than when corn syrup was the source of carbohydrate. whereas triglyceride integrated concentration was 36% greater (p > .005) when sucrose provided 65% of total energy than when corn syrup was the carbohydrate source. Although the diets formulated with the higher percent of energy provided as carbohydrate tended to induce higher triglyceride-integrated concentrations, these differences were not statistically significant and the pattern of triglyceride variation is distinctly different. This latter observation has led us to restrict the comparisons of the integrated triglyceride concentration between diets to those diets with an equal percentage of total carbohydrate calories.

night period during whichinsulinconcentrations were not significantly different showed no difference in plasma triglyceride concentration. Although differences in mean triglyceride-integrated concentration could be skewed by qualitative differences in the pattern of meal associated variation in triglyceride concentration due to inequalities in dietary fat content, this possibility is eliminated by restriction of comparisons to diets with equivalent fat content and composition. This trend toward an inverse relationship between the mean insulin and triglyceride integrated concentration was also observed when analyzing the insulin and triglyceride integrated concentrations in individual subjects. The insulin and triglyceride integrated concentrations were inversely related in 7 of the 8 subjects when the 4 test diets were evaluated (Table 3). All subjects had higher integrated concentrations of insulin and lower integrated concentrations of triglyceride during ingestion of the 65% corn syrup diet than during consumption of the 65% sucrose diet. A similar change was noted in the insulin response of 7 of 8 subjects and in the triglyceride response of 6 of 8 subjects when the 2 45% carbohydrate diets are compared. DISCUSSION

Relationship Triglyceride

Between Diet-Induced and Insulin Responses

Inspection of the mean triglyceride integrated concentration and mean insulin integrated concentration observed on either the 45% or 65%) carbohydrate diet (Table 2) suggests an inverse relationship between insulin- and triglycerideintegrated concentration. The diets that provided all carbohydrate as sucrose had higher mean triglyceride integrated concentrations and lower mean insulin integrated concentration than the diets that provided all carbohydrate as corn syrup. This relationship was also seen during the 48 half-hour samples obtained during the continuous sampling. The 45% and 65% corn syrup diets induced both a higher insulin concentration and a lower or equivalent triglyceride concentration at each of the 48 periods of sampling (Figs. I and 2). This relationship was consistently observed both with the fasting periods and with the prandial and postprandial periods. In the 2 45% carbohydrate diets, the over-

The results of this study fail to confirm the previously reported positive correlation between plasma insulin concentrations obtained after an overnight fast or in response to a glucose or meal challenge and triglyceride concentrations obtained in the fasting state. In fact, as seen in Figs. I and 2, insulin and triglyceride responded in opposite directions to the dietary changes included in this study and comparisons of changes within individuals resulted in a negative. rather than positive, correlation between these variables. Multiple explanations are possible for the discrepancy between these results and the earlier reported positive correlation between insulin and triglyceride concentrations. The normal population included in this study differs markedly from earlier studies which included heterogenous and frequently abnormal populations comprised of subjects with hyperlipidemia,‘,“,6.“,3? premature atherosclerotic disease, 1.4.11.31 and abnormal carbohydrate tolerance.‘.h Eaton et al.’ have suggested obesity,‘,3”

HAYFORD, DANNEY, AND THOMPSON

1084

that these study ~pulations are not homogenous with respect to their insulin-triglyceride relationship. Our study was limited to normal subjects and our results should not be interpreted as being applicable to subjects with obesity or abnormalities of lipid and/or carbohydrate tolerance. The methods used to characterize insulin responses to dietary changes in this study differ from earlier studies that used a variety of insulin stimulatory tests, including insulin response to oral glucose,‘.4-6*‘9.3’-34 intravenous glucose,20~22 and formula feedings,6 to assess insulin homeostasis. In contrast, this study evaluated insulin both in response to an oral glucose tolerance test and continuously over an entire 24-hr period that included ingestion of the test diets. As reported earlier,23 the insulin responses to the glucose tolerance tests during the sucrose-containing diets were equivalent to, or slightly higher than the insulin responses to oral glucose during consumption of diets that contained corn syrup. Thus, the results of the oral glucose tolerance test do not accurately reflect the integrated concentrations of insulin that were significantly higher during the corn syrup containing diets than during the ingestion of the diets that contained sucrose. This apparent lack of specificity of insulin stimulatory tests may contribute to the discrepancy between the results of this study and earlier reports. The results of this study may differ from earlier reports of a positive correlation between insulin and triglyceride because of the major differences in the control of fasting triglyceride concentrations compared to prandial and postprandial triglyceride concentrations. If insulin is positively correlated with triglyceride only after an overnight fast, while the two variables are either not correlated or negatively correlated during the remainder of the day, a question of the significance of the positive correlation must be raised. The mean sequential triglyceride patterns during ingestion of the diets that provided 65% of energy from carbohydrate (Fig. 2) suggests that the fasting concentration of triglyceride accurately reflects the triglyceride

concentrations only at that specific time. Even during ingestion of the diets that provided 45% of energy from carbohydrate, the fasting concentrations reflected the actual triglyceride concentrations for only a brief period of time. To our knowledge, there are no data that suggest that the triglyceride concentrations that occur over the brief period of time reflected by the fasting sample are of more physiologic importance than 24-hr triglyceride concentrations. The data of Olefsky et a1.35 demonstrate that significant changes of total and VLDL triglyceride concentrations occur for up to 6 hr postprandially, a response obviously ignored in fasting lipid determinations. The negative ~rrelation between integrated concentrations of insulin and triglyceride should not be interpreted as proving that higher integrated concentrations of insulin uniformly result in lower integrated concentrations of triglyceride. It is possible that the insulin and triglyceride changes were both secondary to the dietary changes and were not related to each other. The fructose component of sucrose is known to be less insulinogenic than glucose.3h Similarly, fructose and/or sucrose are associated with higher triglyceride concentrations than equivalent amounts of glucose.*’ This study does not allow resolution of whether this inverse relationship is a function of the insulin response, dietary components (especially the fructose component) or a combination of the two. In conclusion, this study differs so significantly in methodology from previous studies that direct comparisons are not possible. Although the negative correlation does not imply that high integrated concentrations of insulin caused reduction of the integrated concentrations of triglyceride, it is clear that elevated integrated concentrations of insulin do not play a dominant role in elevating integrated concentrations of triglyceride in normal subjects. ACKNOWLEDGMENT The technical assistance of Timothy Osweiler and secretarial assistance of Aline Autenrieth and Jan Megonigle are gratefully acknowi~g~.

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2. Nikkila

EA, Taskinen

MR: Hypertriglyceridemia

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in Jones RJ

Proceedings of Second International

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1085

INSULIN TRIGLYCERIDE RELATIONSHIP

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