Vol. 277, Issue 5, E905-E914, November 1999
Ethnicity affects the postprandial regulation of
glycogenolysis
Ashok
Balasubramanyam1,
Siripoom
McKay1,2,
Prashant
Nadkarni1,
Arun S.
Rajan1,
Armandina
Garza3,
Valory
Pavlik3,
J. Alan
Herd4,
Farook
Jahoor2, and
Peter J.
Reeds2
1 Division of Endocrinology and
4 Section on Atherosclerosis,
Department of Medicine,
2 Department of Pediatrics,
Children's Nutrition Research Center, and
3 Department of Community
Medicine, Baylor College of Medicine, Houston, Texas
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ABSTRACT |
We investigated the
effect of nutrient intake on glucose metabolism in normal
Mexican-Americans (n = 6) and
European-Americans (n = 6). Subjects
were studied after an 18-h fast and after 5-6 h of ingestion of
hourly meals that supplied 6.35 or 12.75 µmol glucose · kg
1 · min1.
Endogenous glucose production (EGP), gluconeogenesis (GNG), and
glycogenolysis (GLY) were estimated by mass isotopomer analysis with
[U-13C]glucose
infusions. Fasting EGP, GNG, and GLY did not differ between the groups.
Food ingestion lowered the molar rate of GNG by only 31%. However,
while consuming the lower quantity of nutrients, Mexican-Americans had
higher plasma glucose (P < 0.05), a
39% higher rate of EGP (P < 0.05), and a 68% (P < 0.025) higher rate of GLY than the European-Americans. At the higher
intake, EGP and GLY were suppressed completely in both groups. There
was a linear relationship between insulin concentrations, EGP, and GLY in both groups, but the slope of the line was significantly
(P < 0.05) greater in the
European-Americans. We conclude that the sensitivity of GLY to nutrient
intake differs between ethnic groups and that this may play a role in
the increased predisposition of Mexican-Americans to type II diabetes.
Mexican-American; type II diabetes; gluconeogenesis
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INTRODUCTION |
ENDOGENOUS GLUCOSE PRODUCTION (EGP) plays a dominant
role in determining the hyperglycemia of type II diabetes in both the fasting (10, 15, 16, 20, 32-34, 40) and postprandial (19, 20, 34)
states. The increased predisposition of certain ethnic groups to type
II diabetes raises the important question as to whether genetic factors
affect the regulation and rates of fasting and postprandial EGP and of
its components, gluconeogenesis and glycogenolysis. One way to approach
this question is to compare these rates during fasting, and the degree
of their suppression during feeding, in apparently normal members of
ethnic groups who collectively have either a high or a low prevalence
of type II diabetes.
Despite an active and ongoing debate regarding the most appropriate way
to calculate the results (31, 46), the isotopic technique of mass
isotopomer distribution analysis, in which a multiply labeled tracer
can be distinguished from labeled molecules of the same tracer that
have been resynthesized by the subject (27, 28, 30, 45, 46), presents
an attractive approach to quantifying the various glucose carbon
interactions and to measuring the rate of glucose carbon cycling in
vivo during fasting and feeding. We have utilized this approach in the
present study, employing intravenous infusions of uniformly labeled
[13C]glucose
([U-13C]glucose) to
quantify total EGP, gluconeogenesis, glycogenolysis, and glucose carbon
recycling in the fasting and fed states. We have compared these rates
in healthy, glucose-tolerant American men of Mexican descent, who
belong to an ethnic group with a high prevalence of type II diabetes,
with those in normal American men of Northern European extraction, who
belong to an ethnic group with a significantly lower prevalence of type
II diabetes. Our initial hypothesis was that subjects of Mexican origin
would have higher rates of glucose production (specifically, of
gluconeogenesis) irrespective of their short-term feeding status.
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MATERIALS AND METHODS |
Subjects
After approval was obtained from the Baylor Affiliated Hospitals
Institutional Review Board, six adult Mexican-American men and six
adult European-American men were recruited for the study. The ages of
the subjects ranged from 33-64 yr among the Mexican-Americans and
from 35-64 yr among the European-Americans. Ethnicity was determined by the ethnic self-identification of the subject and by the
ethnicity of each of his parents and grandparents. All of the
Mexican-American subjects, except one, were long-term (>10 yr)
residents of Houston, TX. None had a first- or second-degree relative
known to have type II diabetes or a parent or grandparent who could be
identified as European. The European-Americans were all of Northern
European extraction and were also long-term (>10 yr) residents of
Houston, TX. None had a first-degree relative known to have type II
diabetes or a parent or grandparent who could be identified as Native
American or Mexican-American in ethnicity.
The Mexican-American subjects were matched for age with the
European-American subjects. They were also matched for body mass index
(BMI), which ranged from 24-30 for the Mexican-American subjects
and 23-27 for the European-Americans. (The reasons for the slight
disparity in the upper end of the BMI range may be traced to the
characteristic adult body habitus of persons of these ethnic groups, as
described in the DISCUSSION section). All subjects had normal levels of glycosylated hemoglobin (HbA1c) and
thyroid-stimulating hormone (TSH) (Table
1). Before the subjects were recruited into
the study, measurements of plasma glucose were made while they were
fasting at 8 AM, as well as 0.5 and 2 h after an oral
load of 75 g glucose (Sun-Dex 75, Curtis Matheson Scientific, Houston,
TX). All were found to have glucose tolerance within normal limits
(Table 1) according to both the criteria of the National Diabetes Data
Group (24) and the more recent recommendations of the American Diabetes
Association (1).
Infusion Protocol
Each subject participated in three studies, once while fasting
("fasting study") and twice while consuming at hourly intervals a
balanced protein- and lipid-containing enteral formula (Ensure, Ross
Products Division, Abbott Laboratories, Columbus, OH) that provided
different doses of ingested glucose:
1) 6.38 µmol · kg1 · min1,
calculated to only partially suppress a fasting level of EGP ("low-fed study"); and 2)
12.75 µmol · kg1 · min1,
calculated to fully suppress a fasting level of EGP ("high-fed study"). For two days before each study, the subjects consumed Ensure in an amount that supplied 35 cal · kg1 · day1
[22% from fat, 64% from carbohydrate (85% from glucose and
15% from fructose), and 14% from protein] and 1.2 g
protein · kg1 · day1.
The isotope infusion was performed on the third day. The fasting study
commenced after a 12-h overnight fast. A blood sample was taken for
measurement of the baseline labeling of plasma glucose and lactate, and
the subject then received, via a superficial hand vein, a 6-h primed
constant intravenous infusion of
[U-13C]glucose. The
[U-13C]glucose was
purchased from Cambridge Isotope Laboratories (Woburn, MA). The
abundance of the
13C6-isotopomer
was 92%, and 7% of the labeled glucose was
13C5.
For the fasting study, the target priming dose was 12.5 µmol/kg and
the infusion rate was 0.20 µmol · kg1 · min1.
Samples of blood were obtained at half-hour intervals during the
infusion. The protocols for the fed studies were identical to that of
the fasting study, with the exception that:
1) beginning 2 h before the start of
the [U-13C]glucose
infusion, and every 60 min (low-fed study) or 30 min (high-fed study) thereafter for 8 h (until the end of the 6-h infusion), the subjects consumed 30 ml of Ensure. This protocol was
calculated to supply 7.5 µmol of
carbohydrate · kg1 · min1
(6.38 µmol of
glucose · kg1 · min1)
for the low-fed study or 15 µmol of
carbohydrate · kg1 · min1
(12.75 µmol of glucose · kg1 · min1)
for the high-fed study; and 2) the
target priming dose of
[U-13C]glucose was 20 µmol/kg, with an infusion rate of 0.30 µmol · kg1 · min1.
The measured infusion rates are shown in
RESULTS (see Table 5).
Blood samples were collected in precooled vacutainers, placed on ice,
and centrifuged to separate plasma. Plasma was stored at
70°C for later analysis.
Sample Preparation and Analysis
Plasma samples were acidified with an equal volume of 1 M acetic acid
and applied to a Dowex 50×8
(H+) cation exchange resin. The
sample front and a 2-bed volume water wash were dried and used for
glucose and lactate analysis.
Mass spectrometry was performed on a Hewlett Packard 9890A gas
chromatograph quadrupole mass spectrometer with helium as the carrier
gas and methane as the ionizing gas. Isotopomers of glucose were
measured by positive chemical ionization of their pentaacetate derivatives with a DB 29 column, which separates the acetates of
glucose and fructose. Lactate was measured by negative chemical ionization of its pentafluorobenzyl derivative with a DB 25 column. We
monitored ions with a mass-to-charge ratio of 331-337 for glucose and 87-90 for lactate.
Plasma insulin concentrations were measured in duplicate samples by RIA
with a kit from Linco Research (St. Charles, MO). Plasma glucose
concentrations were measured by the glucose oxidase reaction with a
COBOS clinical analyzer. TSH was measured by a standard double-antibody
radioimmunoassay. HbA1c was measured by electrophoresis.
Calculations
The crude ion abundances of all metabolite tracers were converted to
fractional abundances with the matrix approach, with, as baseline, the
ion spectrum of glucose isolated from each subject before the start of
the [U-13C]glucose infusion.
The entry rate of glucose (glucose
Ra) was calculated as
![R<SUB>a</SUB> = R × <FENCE><FR><NU><AR><R><C>fractional abundance of</C></R><R><C>infused [<SUP>13</SUP>C<SUB>6</SUB>]glucose</C></R></AR></NU><DE><AR><R><C>fractional abundance of</C></R><R><C>[<SUP>13</SUP>C<SUB>6</SUB>] glucose in plasma</C></R></AR></DE></FR> − 1</FENCE>](/content/vol277/issue5/fulltext/E905/img001.gif)
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(1)
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in
which R is the molar rate of glucose infusion. In the fasting study,
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(2)
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In the
fed study
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(3)
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There is continuing controversy regarding the calculation of
the gluconeogenic rate from the recycling of
13C during a
[U-13C]glucose
infusion. Because at this stage we did not wish to enter into this
debate, in the present paper we elected to utilize the equations of
both Tayek and Katz (46) and Landau et al. (31). Both equations provide
an estimate of the fractional contribution of gluconeogenesis
(GNGF) to the glucose
Ra, so that the molar rate of
gluconeogenesis (GNGA) was
calculated as GNGA = glucose Ra × GNGF (31, 46).
Glycogenloysis was then calculated by subtracting the value for
GNGA from EGP as calculated with
Eq.
.
Statistics
The data are expressed as means ± SD. The glucose kinetic and
metabolic cycling data were initially analyzed by two-way ANOVA with
ethnicity and feeding status as the independent variables. Post hoc
testing of ethnic differences within a given study was by grouped
t-tests. A value of two-tailed
P < 0.05 was taken as statistically
significant. Plasma glucose and insulin concentrations were analyzed by
one-way ANOVA, and a value of one-tailed
P < 0.05 was taken as statistically significant.
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RESULTS |
Subject Characteristics
Table 1 outlines physical and biochemical characteristics of the
subjects. Age ranges were similar for the two groups. Values for HbA1c,
fasting or stimulated plasma glucose concentrations, and TSH were in
the normal range for all subjects and similar for the two groups. BMI
ranges overlapped, and mean BMIs were not significantly different for
the two groups.
One Mexican-American subject declined to participate in the high-fed
study. Therefore, the results described below are for n = 6 in each group for every study
except the high-fed study, in which n = 5 in the Mexican-American group.
Glucose and Insulin Concentrations
Plasma glucose and insulin concentrations were measured in samples
taken before the start of the
[U-13C]glucose
infusion, as well as every half hour during the infusion. The values
over the last 2 h of each tracer infusion are shown in Figs.
1 and 2, and
the data are summarized in Table 2. Over the last 2 h of the fasting study, the European-Americans had significantly higher plasma glucose levels than the Mexican-Americans (P < 0.05), a similar (but
nonsignificant) difference having been found in the fasting samples,
taken as part of the initial screening test for glucose tolerance
(Table 1). In both groups, plasma glucose concentrations declined
significantly over the course of the infusion in the fasting study:
from 5.28 ± 0.39 to 4.94 ± 0.22 mmol/l in the Mexican-Americans
and from 5.72 ± 0.44 to 5.28 ± 0.33 mmol/l in the
European-Americans (Fig. 1). In contrast to the fasted state, during
the last 2 h of the low-fed study infusion, the Mexican-Americans had
significantly (P < 0.05) higher plasma glucose levels than the European-Americans. Although a similar
difference in glucose concentrations persisted during the high-fed
study, it was not significant (Mexican-Americans: 6.67 ± 0.33 mmol/l vs. European-Americans: 6.33 ± 0.33 mmol/l; P = 0.064).
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Fig. 1.
Plasma glucose concentrations during final hours of
[U-13C]glucose
infusions when metabolic measurements were made.
A: fasting study.
B: low-fed study (6.38 µmol
glucose · kg1 · h1).
C: high-fed study (12.75 µmol
glucose · kg1 · h1).
Each point is mean plasma glucose concentration ± SD.  ,
Mexican-Americans;  , European-Americans.
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Fig. 2.
Plasma insulin concentrations during final hours of
[U-13C]glucose
infusions, when metabolic measurements were made.
A: fasting study.
B: low-fed study (6.38 µmol
glucose · kg1 · h1).
C: high-fed study (12.75 µmol
glucose · kg1 · h1).
Each point is mean plasma insulin concentration ± SD. ,
Mexican-Americans; , European-Americans.
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Figure 2 shows mean plasma insulin concentrations for each group over
the last 2 h of each study, i.e., during the period when the metabolic
measurements were made. Plasma insulin concentrations were maintained
at a steady level in each group while fasting (within 2-3 µU/ml)
and at each level of feeding (within 2-5 µU/ml). There was a
trend (P = 0.062) for the
Mexican-American group to have higher plasma insulin concentrations
while fasting (Table 2). This ethnic difference became statistically
significant in the fed state (low intake difference = 6.0 ± 2.4 µU/ml; P < 0.05; high intake
difference = 6.4 ± 1.8 µU/ml, P < 0.025).
Glucose Kinetics and Metabolic Recycling
Time course of glucose labeling.
Figure 3,
A-C,
shows the isotopic labeling of the
13C3-
and
13C6-isotopomers
of glucose and of the
13C3-isotopomer
of lactate in the fasting (Fig. 3A),
low-fed (Fig. 3B), and high-fed
(Fig. 3C) studies. Between 4 and 6 h
of infusion during the fasting study, the labeling of
[13C6]glucose
was at steady state as adjudged both by a slope that was not
significantly different from zero and by a within-subject standard
deviation of 3.2-5.4% of the mean value. The
13C3-isotopomers
of glucose and lactate also showed little or no systematic change in
their fractional abundances between 4 and 6 h. The mean values for the
[M+1] to
[M+3] isotopomers of
glucose and lactate as well as the
[M+6]glucose isotopomer
enrichment are shown in Table 3
([M+1],
[M+3], and
[M+6] refer to percentages of glucose molecules with 1, 3, and 6 13C-atoms, respectively, or
lactate molecules with 1 and 3 13C-atoms, respectively). There
were no significant differences between the fractional abundances of
the two groups for any of the labeled isotopomers, except for
[13C6]glucose
during the low-fed study, in which the fractional abundance of
[13C6]glucose
was significantly lower in the Mexican-Americans
(P < 0.01), indicating a
significantly higher glucose Ra
(P < 0.01) in the Mexican-Americans
at this glucose intake. The ratio of [M+3]lactate to
[M+6]glucose, a measure of
the glycolytic metabolism of glucose, rose significantly when subjects
were fed, from 0.36 ± 0.04 in the fasted state to a mean value of
0.49 ± 0.05 (P < 0.025) in the
fed state. This was reflected in a highly significant fall
(P < 0.01) in the dilution factor (D
in Table 4) used in the calculation of
gluconeogenesis by the Landau method. The other factor in this
calculation, the contribution of recycling to glucose labeling
(presented as F in Table 4), also fell highly significantly (P < 0.001) with feeding. Neither
the lactate labeling nor the fractional recycling of tracer showed a
significant ethnic difference.
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Fig. 3.
[U-13C]glucose,
[13C3]glucose,
and
[13C3]lactate
labeling during steady state in the final 2 h of the
[U-13C]glucose
infusion when metabolic measurements were made.
A: fasting study.
B: low-fed study (6.38 µmol
glucose · kg1 · h1).
C: high-fed study (12.75 µmol
glucose · kg1 · h1).
Fractional abundances of all isotopomers were quantitatively very
similar in the 2 groups during fasting and high caloric feeding
(high-fed study). Fractional abundance of
[M+6] glucose was
significantly lower in Mexican-Americans during the low caloric feeding
(low-fed study), indicating a significantly higher rate of glucose
production in this group. Filled symbols, Mexican-Americans; open
symbols, European-Americans.
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Glucose metabolism. Table 4 shows the
factors used in the calculation of gluconeogenesis by the two
approaches, and Table 5 shows the estimates
of glucose Ra, glucose production,
gluconeogenesis, and glycogenolysis. Glucose
Ra in the fasted state was not
significantly different between the two groups and was increased by
feeding in both groups. With the lower intake, however, the increase in glucose Ra (+5.34 ± 0.71 µmol · kg1 · min1)
in the Mexican-American group was significantly greater than that in
the European-American group (+3.33 ± 0.68 µmol · kg1 · min1).
As a consequence, the calculated EGP (7.12 µmol · kg1 · min1
in the Mexican-Americans and 5.14 µmol · kg1 · min1
in the European-Americans) differed significantly
(P < 0.01) between the two groups at
the lower intake. At the higher intake, glucose
Ra was not only similar between
the two groups of subjects but was very close to the calculated intake
of glucose.
Table 5 also shows estimated fractional gluconeogenesis (percentage of
glucose Ra) and absolute
gluconeogenesis
(µmol · kg1 · min1).
In the fasted state, as expected, the two methods of calculating these
parameters gave different results (fractional gluconeogenesis was 70 ± 5% for the Tayek and Katz method and 45 ± 12% for the Landau method), but there was no ethnic difference. Indeed neither fractional nor absolute gluconeogenesis showed an ethnic effect at
either level of feeding. Although the proportional contribution of
gluconeogenesis (GNGF) to
glucose Ra was significantly
(P < 0.001) lower in the
fed studies (60% in both groups and by both methods),
strikingly, when calculated in molar terms, feeding inhibited GNG to
only a small extent (31%) that barely achieved statistical
significance. As a consequence of the higher glucose Ra accompanied by unaltered
gluconeogenesis, the calculated rate of glycogenolysis during the
low-fed study was substantially higher in the Mexican-Americans than in
the European-Americans. Once again, both methods of calculation,
although yielding different values, led to the same overall conclusion,
i.e., that in the Mexican-Americans the lower rate of feeding had had
virtually no effect on the contribution of glycogenolysis to glucose
Ra.
Figure 4 shows the relationship between EGP
and plasma insulin concentrations for the two groups. In this figure,
only data for the fasting and low-fed studies are shown, because EGP in the high-fed state was not significantly different from zero in either
group. In both groups there was a statistically significant linear
relationship, but the slopes of the lines were different (Mexican-Americans: 0.143 ± 0.044 and European-Americans:
0.326 ± 0.130; difference in slopes
P < 0.05). The
y-intercepts (9.56 and 9.65 µmol · kg1 · min1)
were not significantly different. Figure 5
shows the relationship between the calculated rate of glycogenolysis
and plasma insulin concentrations in the fasting and low-fed studies in
the two groups. Here, as for EGP, there was a significant negative
relationship, irrespective of the method chosen to calculate the
values. Moreover, the methods yielded values that differed to only a
minor extent within each group. However, the slope of the line for the
Mexican-Americans (0.135 ± 0.060) was significantly
(P < 0.05) different from that of
the European-Americans (0.198 ± 0.059). In contrast, the
relationship between gluconeogenesis and plasma insulin concentrations
was nonsignificant and showed no ethnic effect (data not shown).
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Fig. 4.
Relationship between plasma insulin concentrations and total endogenous
glucose production. , Mexican-Americans; , European-Americans.
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Fig. 5.
Relationship between plasma insulin concentrations and calculated rate
of glycogenolysis. A:
Mexican-Americans. B:
European-Americans. , Glycogenolysis calculated by method of Tayek
and Katz (46); , glycogenolysis calculated by method of Landau et
al. (31).
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DISCUSSION |
Our results show first that there are significant ethnic variations in
glucoregulation that are manifested by a differential impact of
carbohydrate intake on the rate of glycogenolysis. Second, they show
that feeding suppresses gluconeogenesis to only a relatively small
extent. Importantly, we have arrived at these conclusions by applying
either of two equations to our glucose isotopic data. Although, as
expected from the ongoing debate regarding the relative accuracy of the
two methods (31, 46), they yielded different quantitative values for
the gluconeogenic rate, the results from both sets of calculations led
to the same physiologically and clinically significant conclusions. In
some respects this outcome is not surprising as both methods are based
on the same data, the relative abundances of the
M+1 M+3 and
M+6 isotopomers of glucose and of the
M+1 M+3 isotopomers of lactate.
A considerable body of evidence suggests that increased EGP is an
important factor affecting the fasting hyperglycemia that occurs in
persons with type II diabetes (3-5, 10, 13, 15, 16, 19, 20, 29,
34, 47). In fact, across a wide spectrum of glycemia, the rate of EGP
has been shown to be linearly related to levels of fasting blood
glucose (19, 26), and we found a similar significant relationship in
the present study of apparently normoglycemic individuals. However,
because most human beings spend the greater portion of the day in the
postprandial state, it is likely that the factors that affect EGP after
the ingestion of a meal are at least as significant to the development
of type II diabetes and to long-term glycemic control (18, 20, 32) as
those that affect fasting EGP. Indeed, Firth et al. (19) have
demonstrated a relationship between fasting blood glucose levels and
postprandial EGP in type II diabetes and have suggested that the
inability to suppress EGP after food intake is partly related to
hepatic resistance to insulin. Abnormally high rates of EGP have also
been found in persons with impaired glucose tolerance (IGT), and
Mitrakou et al. (33) have shown that this largely reflects a diminished
suppression of EGP by insulin, coupled with early blunting of the
insulin secretory response.
The present data show, for what we believe to be the first time, that
there is a difference in the rate of suppression of EGP upon feeding
between normal, glucose tolerant persons belonging to ethnic groups
with significantly different risks for type II diabetes. Although both
groups of subjects exhibited a continuous relationship between plasma
insulin and EGP, the slope of the line was ~60% steeper in the
European-American group than in the Mexican-American group. Thus,
despite higher insulin levels after low caloric feeding, the
Mexican-Americans had a higher glucose Ra than the European-Americans.
These results complement studies that have shown differences in insulin
secretion and sensitivity between normoglycemic African-American and
white children (2), in resting energy expenditure between normal
African-American and white adolescents (36), in sympathetic nervous
system activity between normal Pima Indian and white adults (44), and,
critically, in basal and stimulated insulin levels between
normoglycemic Mexican-American and white individuals (22).
A key question is whether elevated EGP in persons with type II diabetes
or IGT reflects a disorder of gluconeogenesis, glycogenolysis, or both
pathways of glucose production and the extent to which these pathways
are sensitive to the effects of feeding. Previous studies have
emphasized the role of gluconeogenesis, in part because it is generally
believed to be the major contributor to fasting glucose production. In
the present study of normal individuals, even the method of Landau,
which gave the lower value, indicated that gluconeogenesis contributed
46% of EGP after an 18-h fast. Numerous studies have suggested that
gluconeogenesis is elevated in type II diabetes both while fasting (10,
11, 15, 16, 20, 23, 39) and in the postprandial state (19). Even so, it
should be noted that Tayek and Katz (45), who showed an elevation in
the fasting molar rate of gluconeogenesis in patients with type II
diabetes, commented that this was not associated with an increased
fractional contribution of the process but was part of an apparent
upregulation of both glycogenolysis and gluconeogenesis. Furthermore, a
recent study (14) suggests that in type II diabetic patients with
moderately elevated fasting blood glucose levels, gluconeogenic rates
are not increased compared with normal controls, despite increased
lactate turnover.
Our results showed that, irrespective of the method used to calculate
the values, there was little ethnic difference in the rate of
gluconeogenesis. Perhaps more interestingly, feeding, even at a rate
that completely suppressed EGP (as shown by the equivalence of glucose
Ra and glucose intake), produced
only a small (25-30%) suppression of gluconeogenesis, as shown
qualitatively by the continuing production of low mass isotopomers of
glucose. It appears therefore that in the fed state, hepatic glucose
synthesis from C-3 precursors and its subsequent release into the
circulation are balanced almost exactly by hepatic glucose utilization.
This conclusion is consistent with the observations of Petersen et al.
(40) who used
[13C]glucose infusions
to measure glucose Ra and NMR
spectroscopy to measure the rate of change of hepatic glycogen.
Despite extensive data in favor of gluconeogenesis as a major
contributor to hyperglycemia, glycogenolysis is also likely to
contribute significantly to the abnormal EGP in type II diabetes. Moreover, glycogenolysis may be the component of EGP that is most significantly regulated by physiological levels of insulin (7). Acute
changes in EGP in response to insulin, glucagon, catecholamines, and
leptin, as well as the effects of hepatic "autoregulation" are
predominantly due to changes in glycogenolysis (5, 21, 35, 40, 41). In
insulin clamp studies, glycogenolysis is much more sensitive to insulin
than gluconeogenesis (8, 9, 42), and the rate of fall of EGP during a
fast parallels that of glycogenolysis, not that of gluconeogenesis
(43). Finally, it has been shown that the drug metformin, which
substantially decreases EGP in patients with type II diabetes, has its
main effects on glycogenolysis rather than on gluconeogenesis (12).
The present results furnish additional proof of the importance of
glycogenolysis to glucoregulation. The dominating influence on what
appeared to be an ethnic difference in the effect of nutrient absorption and/or insulin on EGP was largely due to a less marked suppression of glycogenolysis in the Mexican-American subjects. These
results demonstrate that normal, unrelated adults who belong to an
ethnic group with a high prevalence of type II diabetes, even when they
are healthy, glucose tolerant, and specifically selected for a low
familial tendency to type II diabetes, appear to be less responsive to
the suppressive effects of ingestion of a mixed meal on glycogenolysis
than normal adults of an ethnic group with a substantially lower type
II diabetes risk. This observation raises the possibility that the
factors that regulate the rates of glycogenolysis differ significantly
between different ethnic groups and contribute to increased genetic
susceptibility to type II diabetes in groups at higher risk.
Mexican-Americans have a high prevalence and incidence of type II
diabetes (6). Hanis et al. (24) have shown that over 50% of
Mexican-American individuals older than 35 yr are directly affected by
diabetes, either by virtue of their having the disease or by being a
first-degree relative of a diabetic person. From the outset, the strong
predisposition of the Mexican-American population toward type II
diabetes and high BMI (36) was underscored by the difficulty we
experienced in identifying subjects who could satisfy all our
eligibility criteria. Indeed, we found that even the subjects who met
the criteria of relative leanness, glucose tolerance, and absence of a
family history of type II diabetes had higher insulin concentrations,
as well as a tendency to higher BMI, than the age-matched
European-American group. The observation of higher fasting
concentrations of insulin in the Mexican-Americans subjects has been
made previously in an extensive epidemiological survey in San Antonio,
TX (22). The present data extend this to show that the ethnic
difference in plasma insulin concentrations observed in the fasted
state became progressively greater and statistically more significant
as the level of glucose intake was increased. There was also a tendency
toward higher circulating glucose concentrations in the
Mexican-Americans upon feeding.
The increased BMI in the upper part of the range in our otherwise
normal Mexican-American subjects reflects the results of extensive
demographic surveys that indicate that, at comparable ages after
maturity, Mexican-Americans have more upper body fat than US
non-Hispanic whites and that by age 30, the average BMI of
Mexican-Americans in South Texas is >30 (37). This raises the
question as to whether the differences in postprandial glucose metabolism between the two groups might be explained in part by differences in body composition. We found no interindividual
correlations between BMI and rates of EGP, gluconeogenesis, or
glycogenolysis, and the mean BMIs of the two groups were not
significantly different. However, in view of the complex relationship
between ethnicity, environment, body composition, and insulin
sensitivity, it would be appropriate to say that the differences we
have found are related to some degree of interaction between ethnicity
and environment, one manifestation of which is a difference in body habitus.
Eriksson et al. (17) have shown that a defect in nonoxidative glucose
disposal (i.e., in glycogen synthesis) is perhaps the earliest defect
noted in glucose- tolerant, Northern European persons at risk for type
II diabetes. We have found that a defect in the suppression of
glycogenolysis while feeding might prove to be an important and early
marker for the predisposition of Mexican-Americans to type II diabetes.
These results warrant further investigation of the regulation of
glycogenolysis in this ethnic group, as well as more extensive and
detailed examination of interactions between ethnicity-genotype and
metabolic phenotype in type II diabetes.
| |
ACKNOWLEDGEMENTS |
We thank Dr. Glori Chauca for recruitment of subjects, Sopar
Seributra, Terry Techmanski, and the nursing and dietary staffs at the
Metabolic Research Unit, Children's Nutrition Research Center (CNRC),
and the Baylor Adult General Clinical Research Center (GCRC) for
meticulous care of the study participants, and Dr. Lisa Hung Yu and
Elizabeth Frazer for expert technical assistance in mass spectrometric analysis.
| |
FOOTNOTES |
This work was supported by a Juvenile Diabetes Foundation Career
Development Award, the Redfern Fund and a Chao Scholar Award (A. Balasubramanyam), and the United States Department of
Agriculture/Agriculture Research Service (USDA/ARS) under Cooperative
Agreement No. 5862-5-01003 (USDA/ARS CNRC, Department of Pediatrics,
Baylor College of Medicine and Texas Children's Hospital, Houston,
TX). Support was also provided by the GCRC at Texas Children's
Hospital (NIH-RR-0188).
The contents of this publication do not necessarily reflect the views
or policies of the USDA. Mention of trade names, commercial products,
or organizations does not imply endorsement by the US Government.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: A. Balasubramanyam, Division of Endocrinology, Baylor College of Medicine,
Rm. 549E, One Baylor Plaza, Houston, TX (E-mail:
ashokb{at}bcm.tmc.edu).
Received 3 March 1999; accepted in final form 11 June 1999.
| |
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ABSTRACT
INTRODUCTION
