1 Division of Endocrinology and
4 Section on Atherosclerosis, 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
Mexican-American; type II diabetes; gluconeogenesis
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.
Subjects
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
1 · min
1.
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.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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).
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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 · kgBlood 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
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(1) |
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(2) |
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(3) |
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. ![]() |
RESULTS |
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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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|
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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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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 · min
1)
in the Mexican-American group was significantly greater than that in
the European-American group (+3.33 ± 0.68 µmol · kg
1 · min
1).
As a consequence, the calculated EGP (7.12 µmol · kg
1 · min
1
in the Mexican-Americans and 5.14 µmol · kg
1 · min
1
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.
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Table 5 also shows estimated fractional gluconeogenesis (percentage of
glucose Ra) and absolute
gluconeogenesis
(µmol · kg1 · min
1).
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 · kg
1 · min
1)
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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DISCUSSION |
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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.
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ACKNOWLEDGEMENTS |
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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.
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FOOTNOTES |
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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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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
American Diabetes Association Expert Committee.
Report of the expert committee on the diagnosis and classification of diabetes mellitus.
Diabetes Care
20:
1057-1058,
1997[Medline].
2.
Arslanian, S.,
and
C. Suprasongsin.
Differences in the in vivo insulin secretion and sensitivity of healthy black versus white adolescents.
J. Pediatr.
12:
440-443,
1996.
3.
Bogardus, C.,
S. Lillioja,
B. V. Howard,
G. Reaven,
and
D. Mott.
Relationship between insulin secretion, insulin action and fasting plasma glucose concentration in nondiabetic and non-insulin-dependent diabetic subjects.
J. Clin. Invest.
74:
1238-1246,
1984[Medline].
4.
Campbell, P.,
L. Mandarino,
and
J. Gerich.
Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent diabetes mellitus.
Metabolism
37:
15-21,
1988[Medline].
5.
Capaldo, B.,
R. Napoli,
P. Di Bonito,
G. Albano,
and
L. Sacca.
Glucose and gluconeogenic substrate exchange by the forearm skeletal muscle in hyperglycemic and insulin-treated type 2 diabetic patients.
J. Clin. Endocrinol. Metab.
71:
1220-1223,
1990[Abstract].
6.
Cerda-Flores, R. M.,
G. K. Kshatriya,
T. K. Bertin,
D. Hewett-Emmett,
C. L. Hanis,
and
R. Chakraborty.
Gene diversity and estimation of genetic admixture among Mexican-Americans of Starr County, Texas.
Ann. Hum. Biol.
19:
347-360,
1992[Medline].
7.
Chiasson, J. L.,
J. E. Liljenquist,
F. E. Finger,
and
W. W. Lacy.
Differential sensitivity of glycogenolysis and gluconeogenesis to insulin infusion in dogs.
Diabetes
25:
283-291,
1976[Abstract].
8.
Chu, C. A.,
D. A. Sindelar,
D. W. Neal,
and
A. D. Cherrington.
Portal adrenergic blockade does not inhibit the gluconeogenic effects of circulating catecholamines on the liver.
Metabol. Clin. Exp.
46:
458-465,
1997.
9.
Chu, C. A.,
D. K. Sindelar,
D. W. Neal,
and
A. D. Cherrington.
Direct effects of catecholamines on hepatic glucose production in conscious dog are due to glycogenolysis.
Am. J. Physiol.
271 (Endocrinol. Metab. 34):
E127-E137,
1996
10.
Consoli, A.,
N. Nurjhan,
F. Capani,
and
J. Gerich.
Predominant role of gluconeogenesis in increased hepatic glucose production in type 2 diabetes.
Diabetes
38:
550-557,
1989[Abstract].
11.
Consoli, A.,
N. Nurjhan,
J. J. Reilly, Jr.,
D. M. Bier,
and
J. E. Gerich.
Mechanism of increased gluconeogenesis in noninsulin-dependent diabetes mellitus. Role of alterations in systemic, hepatic, and muscle lactate and alanine metabolism.
J. Clin. Invest.
86:
2038-2045,
1990[Medline].
12.
Cusi, K.,
A. Consoli,
and
R. A. DeFronzo.
Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus.
J. Clin. Endocrinol. Metab.
81:
4059-4067,
1996[Abstract].
13.
DeFronzo, R.,
D. Simonson,
and
E. Ferrannini.
Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus.
Diabetologia
23:
313-319,
1982[Medline].
14.
Diraison, F.,
V. Large,
H. Brunengraber,
and
M. Beylot.
Non-invasive tracing of liver intermediary metabolism in normal subjects and moderately hyperglycemic NIDDM subjects. Evidence against increased gluconeogenesis and hepatic fatty acid oxidation in NIDDM.
Diabetologia
41:
212-220,
1998[Medline].
15.
Efendic, S.,
S. Karlander,
and
M. Vranic.
Mild type II diabetes markedly increases glucose cycling in the postabsorptive state and during glucose infusion irrespective of obesity.
J. Clin. Invest.
81:
1953-1961,
1988[Medline].
16.
Efendic, S.,
A. Wajngot,
and
M. Vranic.
Increased activity of the glucose cycle in the liver: early characteristic of type 2 diabetes.
Proc. Natl. Acad. Sci. USA
82:
2965-2969,
1985[Abstract].
17.
Eriksson, J.,
A. Franssila-Kallunki,
A. Ekstrand,
C. Saloranta,
E. Widen,
C. Schalin,
and
L. Groop.
Early metabolic effects in persons at increased risk for non-insulin-dependent diabetes mellitus.
N. Engl. J. Med.
321:
337-343,
1989[Abstract].
18.
Ferrannini, E.,
D. C. Simonson,
L. D. Katz,
G. Reichard, Jr.,
S. Bevilacqua,
E. J. Barrett,
M. Olsson,
and
R. A. DeFronzo.
The disposal of an oral glucose load in patients with non-insulin-dependent diabetes.
Metabolism
37:
79-85,
1988[Medline].
19.
Firth, R. G.,
P. M. Bell,
H. M. Marsh,
I. Hansen,
and
R. A. Rizza.
Postprandial hyperglycemia in patients with non-insulin-dependent diabetes mellitus. Role of hepatic and extrahepatic tissues.
J. Clin. Invest.
77:
1525-1532,
1986[Medline].
20.
Gerich, J. E.,
and
N. Nurjhan.
Gluconeogenesis in type 2 diabetes.
Adv. Exp. Med. Biol.
234:
253-258,
1993.
21.
Giaccari, A.,
L. Morviducci,
L. Pastore,
D. Zorretta,
P. Sbraccia,
E. Maroccia,
A. Buongiorno,
and
G. Tamburrano.
Relative contribution of glycogenolysis and gluconeogenesis to hepatic glucose production in control and diabetic rats. A re-examination in the presence of euglycemia.
Diabetologia
41:
307-314,
1996.
22.
Haffner, S. M.,
H. Miettinen,
and
M. P. Stern.
Nondiabetic Mexican-Americans do not have reduced insulin responses relative to nondiabetic non-Hispanic whites.
Diabetes Care
19:
67-69,
1996[Abstract].
23.
Hall, S. E. H.,
J. T. Braaten,
J. B. R. McKendry,
T. Bolton,
D. Foster,
and
M. Berman.
Normal alanine-glucose relationships and their changes in diabetic patients before and after insulin treatment.
Diabetes
28:
737-745,
1979[Medline].
24.
Hanis, C. L.,
R. E. Ferrell,
S. A. Barton,
L. Aguilar,
A. Garza-Ibarra,
B. R. Tulloch,
C. A. Garcia,
and
W. J. Shull.
Diabetes among Mexican Americans in Starr County, Texas.
Am. J. Epidemiol.
118:
659-672,
1983[Abstract].
25.
Harris, M.,
G. Cahill,
and
members of NIH Diabetes Data Group Workshop.
A draft classification of diabetes mellitus and other categories of glucose tolerance.
Diabetes
28:
1039-1057,
1979[Medline].
26.
Jeng, C. Y.,
W. H. H. Sheu,
M. M. T. Fuh,
Y. D. I. Chen,
and
G. M. Reaven.
Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with type 2 diabetes.
Diabetes
43:
1440-1444,
1994[Abstract].
27.
Katz, J.,
W. N. P. Lee,
P. A. Wals,
and
E. A. Bergner.
Studies of glycogen synthesis and the Krebs cycle by mass isotopomer analysis with [U-13C]glucose in rats.
J. Biol. Chem.
264:
12994-13004,
1989
28.
Kelleher, J. K.,
and
T. M. Masterson.
Model equations for condensation biosynthesis using stable isotopes and radioisotopes.
Am. J. Physiol.
262 (Endocrinol. Metab. 25):
E221-E227,
1992.
29.
Kolterman, O. G.,
R. S. Gray,
J. Griffin,
P. Burstein,
J. Insel,
F. A. Scarlett,
and
J. M. Olefsky.
Receptor and post-receptor defect contribute to the insulin resistance in non-insulin-dependent diabetes mellitus.
J. Clin. Invest.
69:
957-969,
1981.
30.
Landau, B. R.
Estimating gluconeogenic rates in type 2 diabetes.
Adv. Exp. Med. Biol.
334:
209-220,
1993[Medline].
31.
Landau, B. R.,
J. Wahren,
K. Ekberg,
S. F. Previs,
D. Yang,
and
H. Brunengraber.
Limitations in estimating gluconeogenesis and Cori cycling from mass isotopomer distributions using [U13C6]glucose.
Am. J. Physiol.
274 (Endocrinol. Metab. 37):
E954-E961,
1998
32.
Magnusson, I.,
D. L. Rothman,
D. P. Gerard,
L. D. Katz,
and
G. I. Shulman.
Contribution of hepatic glycogenolysis to glucose production in humans in response to a physiological increase in plasma glucagon concentration.
Diabetes
44:
185-189,
1995[Abstract].
33.
Mitrakou, A.,
D. Kelley,
M. Mokan,
T. Veneman,
T. Pangburn,
J. Reilly,
and
J. Gerich.
Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance.
N. Engl. J. Med.
326:
22-29,
1992[Abstract].
34.
Mitrakou, A.,
D. Kelley,
T. Veneman,
T. Henssen,
T. Pangburn,
J. Reilly,
and
J. Gerich.
Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in non-insulin-dependent diabetes mellitus.
Diabetes
39:
1381-1390,
1990[Abstract].
35.
Moore, M. C.,
C. C. Connolly,
and
A. D. Cherrington.
Autoregulation of hepatic glucose production.
Eur. J. Endocrinol.
138:
240-248,
1998[Medline].
36.
Morrison, J. A.,
M. P. Alfaro,
P. Khoury,
B. B. Thornton,
and
S. R. Daniels.
Determinants of resting energy expenditure in young black girls and young white girls.
J. Pediatr.
129:
637-642,
1996[Medline].
37.
Mueller, W. H.,
S. K. Joos,
C. L. Hanis,
A. N. Zavaleta,
J. Eichner,
and
W. J. Schull.
The Diabetes Alert Study: growth, fatness and fat patterning, adolescence through adulthood in Mexican Americans.
Am. J. Phys. Anthropol.
64:
389-399,
1984[Medline].
39.
Periello, G.,
S. Pampanelli,
P. Del Sindaco,
C. Lalli,
M. Ciofetta,
E. Volpi,
S. Santeusanio,
P. Brunetti,
and
G. B. Bolli.
Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM.
Diabetes
46:
1010-1016,
1997[Abstract].
40.
Petersen, K. F.,
T. Price,
G. W. Cline,
D. L. Rothman,
and
G. I. Shulman.
Contribution of net hepatic glycogenolysis to glucose production during the early postprandial period.
Am. J. Physiol.
270 (Endocrinol. Metab. 33):
E186-E191,
1996
41.
Rossetti, L.,
D. Massillon,
N. Barzilai,
P. Vuguin,
W. Chen,
M. Hawkins,
J. Wu,
and
J. Wang.
Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action.
J. Biol. Chem.
272:
27758-27763,
1998
42.
Sindelar, D. K.,
J. H. Balcom,
C. A. Chu,
D. W. Neal,
and
A. D. Cherrington.
A comparison of the effects of selective increases in peripheral or portal insulin on hepatic glucose production in the conscious dog.
Diabetes
45:
1594-1604,
1996[Abstract].
43.
Sindelar, D. K.,
C. A. Chu,
P. Venson,
E. P. Donahue,
D. E. Neal,
and
A. D. Cherrington.
Basal hepatic glucose production is regulated by the portal vein insulin concentration.
Diabetes
47:
523-529,
1998[Abstract].
44.
Tataranni, P. A.,
L. Christin,
S. Snitker,
G. Paolisso,
and
E. Ravussin.
Pima Indian males have lower beta-adrenergic sensitivity than Caucasian males.
J. Clin. Endocrinol. Metab.
83:
1260-1263,
1998
45.
Tayek, J. A.,
and
J. Katz.
Glucose production, recycling, and gluconeogenesis in normals and diabetics: a mass isotopomer [U13C]glucose study.
Am. J. Physiol.
270 (Endocrinol. Metab. 33):
E709-E717,
1996
46.
Tayek, J. A.,
and
J. Katz.
Glucose production, recycling, Cori cycle, and gluconeogenesis in humans: relationship to serum cortisol.
Am. J. Physiol.
272 (Endocrinol. Metab. 35):
E476-E484,
1997
47.
Zawadzki, J. K.,
R. R. Wolfe,
D. M. Mott,
S. Lillioja,
B. V. Howard,
and
C. Bogardus.
Increased rate of Cori cycle in obese subjects with type 2 diabetes and effect of weight reduction.
Diabetes
37:
154-159,
1986[Abstract].
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