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Mechanism and Effects of Glucose Absorption during an Oral Glucose

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Mechanism and Effects of Glucose Absorption during an Oral Glucose Tolerance
Test Among Females and Males
Christian Anderwald, Amalia Gastaldelli, Andrea Tura, Michael Krebs, Miriam Promintzer-Schifferl, Alexandra
Kautzky-Willer, Marietta Stadler, Ralph A. DeFronzo, Giovanni Pacini and Martin G. Bischof

J. Clin. Endocrinol. Metab. 2011 96:515-524 originally published online Dec 8, 2010; , doi: 10.1210/jc.2010-1398

To subscribe to Journal of Clinical Endocrinology & Metabolism or any of the other journals published by The Endocrine
Society please go to: http://jcem.endojournals.org//subscriptions/

Copyright © The Endocrine Society. All rights reserved. Print ISSN: 0021-972X. Online
 ORIGINAL ARTICLE

E n d o c r i n e R e s e a r c h

Mechanism and Effects of Glucose Absorption during

an Oral Glucose Tolerance Test Among Females and
Males

Christian Anderwald, Amalia Gastaldelli, Andrea Tura, Michael Krebs,

Miriam Promintzer-Schifferl, Alexandra Kautzky-Willer, Marietta Stadler,
Ralph A. DeFronzo, Giovanni Pacini, and Martin G. Bischof
Division of Endocrinology and Metabolism (C.A., M.K., M.P.-S., A.K.-W., M.G.B.), Department of
Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria; Metabolic Unit (C.A., A.T.,
G.P.), Institute of Biomedical Engineering, National Research Council, I-35127 Padova, Italy; National
Research Council Institute of Clinical Physiology (A.G.), I-56124 Pisa, Italy; Third Medical Department of
Metabolic Diseases and Nephrology (M.S.) and Karl Landsteiner Institute of Metabolic Diseases and
Nephrology (M.S.), Hietzing Hospital, A-1130 Vienna, Austria; Department of Medicine/Diabetes
(R.A.D.), University of Texas Health Science Center, San Antonio, Texas 78207; and Medical Direction
(M.G.B.), St. Elisabeth Hospital, A-1030 Vienna, Austria

Background: Several epidemiological studies revealed sex-specific differences during oral glucose
tolerance tests (OGTTs), such as higher prevalence of glucose intolerance (i.e. increased glucose at
the end of the OGTT) in females, which was not yet explained. Thus, we aimed to analyze sex-
related distinctions on OGTT glucose metabolism, including gut absorption, in healthy humans.

Methods: Females (n ⫽ 48) and males (n ⫽ 26) with comparable age (females, 45 ⫾ 1 yr; males, 44 ⫾
2 yr) and body mass index (both, 25 ⫾ 1 kg/m2) but different height (females, 166 ⫾ 1 cm; males,
180 ⫾ 2 cm; P ⬍ 0.000001), all normally glucose tolerant, as tested by frequently sampled, 3-h (75-g)
OGTTs, underwent hyperinsulinemic [40 mU/(min 䡠 m2)] isoglycemic clamp tests with simultaneous
measurement of endogenous glucose (D-[6,6-2H2]glucose) production (EGP). EGP and glucose dis-
appearance during OGTT were calculated from logarithmic relationships with clamp test insulin
concentrations. After reliable model validation by double-tracer technique (r ⫽ 0.732; P ⬍ 0.007),
we calculated and modeled gut glucose absorption (ABS).

Results: Females showed lower (P ⬍ 0.05) fasting EGP [1.4 ⫾ 0.1 mg/(kg 䡠 min)] than males [1.7 ⫾
0.1 mg/(kg 䡠 min)] but comparable whole-body insulin sensitivity in clamp tests [females, 8.1 ⫾ 0.4
mg/(kg 䡠 min); males, 8.3 ⫾ 0.6 mg/(kg 䡠 min)]. Plasma glucose OGTT concentrations were higher
(P ⬍ 0.04) from 30 – 40 min in males but from 120 –180 min in females. Glucose absorption rates were
21– 46% increased in the initial 40 min in males but in females by 27– 40% in the third hour (P ⬍
0.05). Gut glucose half-life was markedly higher in females (79 ⫾ 2 min) than in males (65 ⫾ 3 min,
P ⬍ 0.0001) and negatively related to body height (r ⫽ ⫺0.481; P ⬍ 0.0001).

Conclusions: This study in healthy, glucose-tolerant humans shows for the first time different ABS
rates during OGTT in women and men and a negative relationship between body height and gut
glucose half-life. Prolonged ABS in females might therefore contribute to higher plasma glucose
concentrations at the end of OGTT. (J Clin Endocrinol Metab 96: 515–524, 2011)

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2011 by The Endocrine Society
doi: 10.1210/jc.2010-1398 Received June 18, 2010. Accepted October 26, 2010.
First Published Online December 8, 2010
Abbreviations: ABS, Gut glucose absorption; AUC, area under the concentration curve;
BMI, body mass index; EGP, endogenous glucose production; FFA, free fatty acids; HDL,
high-density lipoprotein; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; M,
M-value (clamp test); MPE, mole percent excess; OGIS, oral glucose insulin sensitivity index;
OGTT, oral glucose tolerance test; Rd, rate of glucose disappearance.

J Clin Endocrinol Metab, February 2011, 96(2):515–524 jcem.endojournals.org 515

516 Anderwald et al. Sex-Specific Differences in Glucose Absorption
s recommended by the World Health Organization,
A the standardized, 75-g oral glucose tolerance test
(OGTT) is used for diagnosis of impaired fasting glucose
(IFG) and impaired glucose tolerance (IGT) as well as (ges-
tational) diabetes mellitus, for all of which plasma glucose
measurements at fasting and after 2 h, and for pregnant
women also after 1 h, are required. Impaired glucose metab-
olism is associated not only with higher probability to de-
velop type 2 diabetes mellitus but also with simultaneously in-
creasedcardiovascularrisk(1–3).Interestingly,epidemiological
studiesthroughouttheentireworldconsistentlypointatgender-
related differences in OGTT abnormalities; females show
higher prevalence of IGT, which means elevated glucose con-
centrations at the end of the OGTT, whereas males more fre-
quently display IFG (3–8). However, the causes for these dif-
ferences have not been sufficiently explained yet.
For better interpretation of those population-based, sex-
specific differences in OGTTs (3– 8), we studied quite a large
cohort of healthy females and males, with comparable body
mass index (BMI) and age as well as normal fasting glucose
and glucose tolerance. Our study participants were precisely
characterized undergoing prolonged (3 h), frequently sam-
pled OGTTs and 2-h hyperinsulinemic clamp tests with si-
multaneous infusion of deuterated glucose for measurement
of glucose metabolism and whole-body insulin sensitivity
with endogenous glucose production (EGP), respectively.
Our aim was to elucidate possible physiological causes of the
expected, gender-related differences in plasma glucose ex-
cursions during the OGTT, focusing on glucose absorption
from the gastrointestinal tract. For this approach, we created
three novel methods including a new mathematical model,
which account for the main processes to control blood glu-
cose during the OGTT. This novel model was validated in
humans by applying the double-tracer technique.
Subjects and Methods
Study participants
All 74 participants, 48 females and 26 males, were recruited by
means of local advertising. They had been instructed to refrain from
excessive physical exercise and to ingest an isocaloric carbohydrate-
rich diet 3 d before baseline examination with OGTT (study d 1)
and the clamp test (study d 2). All participants gave informed con-
sent to the protocol, which was approved by the Institutional Ethics
Board. All recruited volunteers with normal fasting glucose levels
and glucose tolerance were included in this study. Females were
examined in the first phase of their menstrual cycle (i.e. 5–12 d after
the period) if they were not postmenopausal.
Study d 1
After an overnight fast for at least 12 h, the participants un-
derwent a complete medical history and a thorough clinical ex-
amination to confirm their excellent health, followed by anthro-
pometric measurements, a resting electrocardiogram, and a
J Clin Endocrinol Metab, February 2011, 96(2):515–524
routine laboratory check analyzed in our hospital’s Clinical
Institute of Medical and Chemical Laboratory Diagnostics
(www.kimcl.at). Sitting blood pressure was measured three
times (Omron 705cp; Omron Healthcare Europe, Hoofddorp,
The Netherlands). Body weight and fat mass were measured by
the Tanita bioimpedance balance (TBF-300 body composition
analyzer; Tanita International Division, Yiewsley, UK). None of
the participants was on regular intake of any medication known
to affect insulin sensitivity.
Anthropometric characteristics (Table 1)
Females and males were similar in age and BMI (each P ⬎
0.61). Males were 8% (P ⬍ 10⫺12) taller and heavier by 15%
(P ⬍ 0.003), whereas women displayed 62% higher fat mass and
88% increased fat mass relative to total body weight, but 29%
lower fat-free mass (each P ⬍ 0.0001). Of note, the mean values
of body height in both genders very closely approach the respec-
tive average values of the Austrian population (females, 167 cm;
males, 180 cm) (http://en.wikipedia.org/wiki/Human_height).
Oral glucose tolerance test
The participants drank 75 g glucose (Gluco-Drink75; Roche
Diagnostics, Vienna, Austria) within 2 min. Blood samples for
determination of plasma glucose, insulin and free fatty acids
(FFA) were drawn at 0, 10, 20, 30, 40, 60, 90, 120, 150, and 180
min, immediately kept on ice for 10 min, and then centrifuged
(10 min, 4 C, 3634 ⫻ g). The supernatant was separated to be
stored at ⫺80 C until further analysis (9 –12). The participants
remained in supine position throughout the entire OGTT.
Study d 2
In females and males, examinations were performed 34 ⫾ 2 and
35 ⫾ 3 d, respectively, after the OGTT. After another overnight fast
for at least 12 h, two catheters (Vasofix; Braun, Melsungen, Ger-
many) were inserted into an antecubital vein of the left and right arm
for blood sampling and infusions, respectively. A primed continu-
ous infusion [from ⫺120 to ⫺115 min at 4 mg/(min 䡠 kg) fat-free
mass (obtained from Tanita measure) and from ⫺115 to 15 min at
0.04 mg/(min 䡠 kg) fat-free mass] of D-[6,6-2H2]glucose (98% en-
riched; Cambridge Isotope Laboratories, Andover, MA) was given
in 44 participants (59% of the study population: 29 females and 15
males) before and until 15 min after the start of the clamp test to
determine fasting EGP (9, 12–14). To obtain stable tracer concen-
trations during varying glucose infusion rates, the 20% glucose
infusions were enriched with D-[6,6-2H2]glucose to approximately
2 mole percent excess (MPE), as previously described (9, 12, 13).
The two subgroups receiving deuterated glucose infusion were also
representative for the respective entire groups, because they did not
differ in major anthropometric characteristics, such as age or BMI
(each P ⬎ 0.64).
The isoglycemic clamp glucose target was determined from
the mean value of three fasting plasma glucose measurements, as
described (12, 13, 15, 16). However, in case of a mean value
lower than 80 mg/dl, the glucose clamp target was set to 80
mg/dl, and at a mean glucose value above 100 mg/dl, the clamp
goal was 100 mg/dl.
Hyperinsulinemic-isoglycemic clamp tests were performed for
120 min, with primed (0 – 4 min, 4-fold; 5–7 min, 2-fold rate) con-
tinuous insulin (Actrapid; NovoNordisk, Bagsvaerd, Denmark) in-
fusion at a rate of 40 mU/(min 䡠 m2) body surface area and 20%
glucose solutions at variable rates (9, 12, 13, 16). Blood for deter-
J Clin Endocrinol Metab, February 2011, 96(2):515–524 jcem.endojournals.org 517

TABLE 1. Anthropometric characteristics, blood pressure, routine laboratory measurements at fasting, AUC of
glucose and insulin, glucose clearance during OGTT (OGIS), and Rd in females (n ⫽ 48) and males (n ⫽ 26)
Females Males P
Age (yr) 44.9 ⫾ 1.3 44.3 ⫾ 1.5 0.774
BMI (kg/m2) 25.2 ⫾ 0.6 24.7 ⫾ 0.6 0.611
Body weight (kg) 70 ⫾ 2 80 ⫾ 3 0.002
Body height (cm) 166 ⫾ 1 180 ⫾ 2 ⬍0.000001
Waist to hip ratio 0.86 ⫾ 0.01 0.88 ⫾ 0.01 0.494
Fat mass (kg) 24 ⫾ 1 15 ⫾ 2 ⬍0.000001
Amount of fat mass (%) 33 ⫾ 1 18 ⫾ 1 ⬍0.000001
Fat-free mass (kg) 46 ⫾ 1 66 ⫾ 2 ⬍0.000001
Blood pressure (mm Hg)
Systolic 117 ⫾ 2 118 ⫾ 2 0.609
Diastolic 77 ⫾ 1 76 ⫾ 1 0.568
Serum creatinine (mg/dl) 0.76 ⫾ 0.02 0.95 ⫾ 0.02 ⬍0.000001
Serum uric acid (mg/dl) 4.2 ⫾ 0.2 5.8 ⫾ 0.2 ⬍0.000001
Serum triglycerides (mg/dl) 81 ⫾ 6 97 ⫾ 6 0.076
Serum total cholesterol (mg/dl) 203 ⫾ 6 206 ⫾ 7 0.756
Serum HDL cholesterol (mg/dl) 63 ⫾ 2 52 ⫾ 2 0.002
Serum LDL cholesterol (mg/dl) 124 ⫾ 5 134 ⫾ 6 0.216
Serum ASAT (GOT) (U/liter) 23 ⫾ 1 24 ⫾ 2 0.811
Serum ALAT (GPT) (U/liter) 19 ⫾ 1 26 ⫾ 2 0.010
Serum ␥GT (U/liter) 18 ⫾ 3 25 ⫾ 3 0.155
HbA1c (%) 5.4 ⫾ 0.1 5.4 ⫾ 0.1 0.773
Plasma glucose (mg/dl) 89 ⫾ 1 91 ⫾ 1 0.305
OGTT glucose AUC (mg/dl 䡠 min) 19,884 ⫾ 432 19,659 ⫾ 448 0.738
OGTT insulin AUC 关0 – 60 min兴 (mU/ml 䡠 1 h) 2.12 ⫾ 0.11 2.68 ⫾ 0.18 0.008
OGIS [ml/(min 䡠 kg)] 12.2 ⫾ 0.4 12.2 ⫾ 0.5 0.977
Rd (%/min) 0.30 ⫾ 0.03 0.44 ⫾ 0.05 0.015
All data are given as mean ⫾ SE. Student’s t test compared females vs. males. ALAT, Alanine aminotransaminase; ASAT, aspartate
aminotransaminase; ␥GT, ␥-glutamyl transferase; GOT, glutamate-oxaloacetate transaminase; GPT, glutamate-pyruvate transaminase; HbA1c,
glycated hemoglobin A1c; LDL, low-density lipoprotein.

mination of plasma hormones and metabolites was drawn at ⫺5,
⫺2, 60, 90, and 120 min and processed as described above.
Plasma metabolites and hormones
Plasma glucose concentrations were measured using the glu-
cose oxidase method (Glucose Analyzer II; Beckman, Fullerton,
CA). Plasma insulin was analyzed by a commercially available
RIA from Linco Research (St. Charles, MO) and plasma FFA
with a microfluorimetric assay (Wako, Richmond, VA) (12, 17).
MPE of plasma and infusate D-[6,6-2H2]glucose was mea-
sured on a Hewlett-Packard (Palo Alto, CA) 5890 gas chromato-
graph equipped with a CP-Sil5 25 m ⫻ 0.25 mm ⫻ 0.12 ␮m
capillary column (Chrompack, Middelburg, The Netherlands)
and interfaced to a Hewlett-Packard 5971A mass selective de-
tector as described (9, 12, 13).
of glucose per minute per kilogram total body weight, during
consecutive 20-min intervals (9 –13, 15, 16). Peripheral insulin
release during the first hour was determined as the area under the
concentration curve (AUC, trapezoidal rule) in that time interval.
Glucose clearance was assessed by the parameter oral glucose
insulin sensitivity index (OGIS) calculated during OGTT, as pre-
viously described (19). Glucose disappearance rate during the
last 2 h of OGTT was calculated as the slope of the logarithm of
glucose concentrations vs. time. The rate of insulin-mediated
glucose disappearance (Rd) was calculated as the sum of M and
EGP. Insulin release in relation to prevailing plasma glucose con-
centrations was evaluated by dividing the insulin AUC (pico-
moles per liter for 2 h) by that of glucose (millimoles per liter per
for 2 h) during the first 120 min of the OGTT (insulinogenic
index), as described previously (15).

Calculations Gut glucose absorption

Baseline rates of EGP were calculated by dividing the tracer
(D-[6,6-2H2]glucose) infusion rate times tracer enrichment by the
tracer enrichment in plasma and subtracting the tracer infusion
rate (9, 12, 13). During the clamp tests, EGP was assessed using
the formula: EGP ⫽ glucose infusion rate (GIR)mean ⫻ [(enrich-
mentinf/enrichmentplasma) ⫺ 1], where GIRmean is the mean GIR
during the preceding 30 min, enrichmentinf is the MPE of glucose
in infusate, and enrichmentplasma is the MPE of plasma glucose
during steady-state conditions of the clamp (14). All EGP results
are given in milligrams of glucose per minute per kilogram total
body weight. Whole-body insulin sensitivity was calculated from
the clamp as M-value (clamp test) (M) (12, 15, 18) in milligrams
In the postprandial state, the increase of circulating glucose (dg-
luccirc) over time (dt) is the result of gain from gut glucose absorption
(ABS) and EGP and loss because of glucose uptake (Rd) (see Fig.
1A). Thus, changes in glucose concentration over time can be ex-
pressed as dgluccirc/dt ⫽ 1/VG ⫻ [BW ⫻ (EGP ⫺ Rd) ⫹ ABS] (equa-
tion 1), with initial conditions of gluc (0) ⫽ fasting glucose concen-
tration; ABS (0) ⫽ 0, and Rd (0) ⫽ EGP (0). BW is the body weight,
and VG is the oral glucose distribution volume, previously estimated
as approximately 9% of body weight (20).
Equation 1 was used to calculate ABS, once EGP and Rd were
estimated as follows. Previous work reported that both glucose
utilization and EGP suppression follow a dose-responsive curve
518 Anderwald et al. Sex-Specific Differences in Glucose Absorption J Clin Endocrinol Metab, February 2011, 96(2):515–524

levels. The relationships of Rd and EGP with

plasma insulin concentrations were better de-
scribed by a logarithmic rather than a linear (not
shown) function, as visible in Fig. 1B, inset. The
assumption that insulin is the major regulator of
both EGP suppression and Rd is therefore a plau-
sible working hypothesis.
We then used in equation 1 these logarithmic
relationships with the frequently measured OGTT
data in the 44 participants. In particular, dividing
by gender, we found (Fig. 1C) the following: EGP
in females ⫽ 1.889 ⫺ 0.342 ⫻ ln[insulin (mi-
crounits per milliliter)] (equation 2), and EGP in
males ⫽ 2.542 ⫺ 0.496 ⫻ ln[insulin (microunits
per milliliter)] (equation 3).
After insulin-mediated suppression, EGP re-
mains at that low level for at least 2 h, so equa-
tions 2 and 3 define EGP during its suppression,
which occurs within the first hour of the OGTT.
Thereafter, individual EGP was equal to the min-
imum value calculated. Using this method, EGP
was then calculated in those participants who did
not receive deuterated glucose during the clamp
to assess Rd as a function of the prevailing clamp
insulin concentrations in each of the 74 partici-
pants separately (Fig. 1D). Because insulin sen-
sitivity can be different among individuals (18),
here the average values ⫾ SE are given for both
genders: Rd in females ⫽ ⫺3.96 ⫾ 0.46 ⫹ 2.86 ⫾
0.18 ⫻ ln[insulin (microunits per milliliter)]
(equation 4), and Rd in males ⫽ ⫺3.76 ⫾ 0.53 ⫹
2.86 ⫾ 0.25 ⫻ ln[insulin (microunits per milli-
liter)] (equation 5).
For each participant, the total glucose ab-
sorbed was calculated by integrating glucose ab-
sorption rates over the 180-min OGTT. The rel-
ative retention (percent) is the amount of
absorbed glucose at each OGTT time point in
FIG. 1. A, Schematic model of glucose fate and effects during an OGTT, with relation to total glucose absorbed. Glucose half-
stimulating (⫹) and inhibiting (⫺) actions, as indicated; B, logarithmic relationship life (t ⁄ ) in the gastrointestinal tract was individ-
12

between plasma insulin concentrations over the broad range between fasting and ually determined by linear curve interpolation of
supraphysiological insulinemia and Rd and EGP (inset) in nondiabetic humans (n ⫽ 6, 䡺) relative glucose retention during the OGTT by
during three-stepped (1, 2, and 4 mU insulin/min 䡠 kg) hyperinsulinemic clamp tests
using the closest time points to cross the 50%
[other information published elsewhere (9)]; C and D, logarithmic relationship of plasma
threshold (22).
insulin concentrations with EGP in females (E, n ⫽ 29) and males (F, n ⫽ 15) (C), and
Rd in females (E, n ⫽ 48) and males (F, n ⫽ 26) (D), both measured during one-
stepped [40 mU insulin/(min 䡠 m2)] hyperinsulinemic clamp test; E–G, validation of our Mathematical modeling
model regarding EGP (E), glucose appearance (F), and glucose half-life (t ⁄ ) (F, inset) in
12
Equation 1 was implemented using Simulink
gastrointestinal tract during OGTT: f, calculated results; Œ, modeled values; 䡺, data for Matlab (MathWorks Inc., Boston, MA), and
measured with double-tracer technique during 75-g OGTT in 12 subjects. Student’s t ABS was estimated by solving nonlinear least-
test: *, P ⬍ 0.05 for females vs. males.
squares problem fitting the plasma glucose values
during the OGTT (MatLab function used
with insulin concentrations in logarithmic manner (21). We LSQNONLIN with 10,000 iterations at maximum). Every time
tested this observation in our population with an additional sample of ABS was treated as an independent parameter to be es-
study in a subgroup of nondiabetic humans (n ⫽ 6: two females timated. Common criteria of model performance (best fit, residuals,
and four males; age, 57 ⫾ 2 yr; BMI, 26 ⫾ 1 kg/m2), whose other variance-covariance Fisher’s matrix) were evaluated for accepting
characteristics were published elsewhere (9). These subjects un- the final model’s prediction. ABS is calculated as the average value
derwent three-stepped hyperinsulinemic (1, 2, and 4 mU insulin/ for each time interval between consecutive blood samples.
min 䡠 kg total body weight) normoglycemic (98 ⫾ 3 mg/dl) clamp
tests, corresponding to 40, 80, and 160 mU insulin/(min 䡠 m2)
body surface area, respectively, with simultaneous EGP mea- Model validation
surement, to allow Rd calculation over the broad range of insu- To evaluate our model’s reliability, we applied our newly
linemia from fasting to postprandial-like and supraphysiological developed equations 1–5 to the data of 12 nondiabetic humans
J Clin Endocrinol Metab, February 2011, 96(2):515–524 jcem.endojournals.org 519

appearance during OGTT also showed a satis-

factory conformity (Fig. 1F), although displaying
our models to give higher values between 90 and
150 min. To validate our model’s prediction
power for the individual glucose absorption ve-
locity, we calculated glucose t ⁄ in the gastroin-
12

testinal tract and found tight correlations (cal-

culated method: r ⫽ 0.674, P ⬍ 0.02; modeling:
r ⫽ 0.732, P ⬍ 0.007; see Fig. 1F, inset).

Statistics
Before further analysis, normal distribution of
the variables was tested by applying the Kolmog-
orov-Smirnov test for the entire study population
and each (sub)group separately (12). This test
showed that the continuous variables were nor-
mally distributed, except alanine aminotransami-
nase and ␥-glutamyl transferase, which were loga-
rithmically transformed; statistical tests were
applied to the transformed variables (12).
Comparisons between groups were per-
formed by the two-sided Student’s t test for un-
paired data, and the data are given as means ⫾
SEM. Pearson’s product-moment correlation was
used to estimate linear relationships between
variables. Differences were considered statisti-
cally significant at P ⬍ 0.05.

Results
Routine laboratory measurements
(Table 1)
In the routine laboratory check, males
showed 25–36% higher serum creatinine,
uric acid, and alanine aminotransaminase en-
zyme activity than females, who displayed
21% increased high-density lipoprotein (HDL)
cholesterol concentrations (each P ⬍ 0.01).

Oral glucose tolerance test (Fig. 2, A–D)

FIG. 2. Plasma concentrations (means ⫾ SE) during OGTT (A–D) and the hyperinsulinemic Fasting plasma glucose concentrations
clamp test (E–G) of glucose (A and E), insulin (B and F), C-peptide (C) and FFA (D and G) and glucose AUC were comparable in fe-
as well as clamp EGP (H) and M for total body weight (I) in females (E, n ⫽ 48) and
males (F, n ⫽ 26). Student’s t test: *, P ⬍ 0.05 for females vs. males.
males and males (Table 1). Between 30 and
40 min after the start of the OGTT, males
(42 ⫾ 4 yr; BMI, 30 ⫾ 1 kg/m2; eight females and four males) showed 11–12% higher plasma glucose
who, after an overnight fast, underwent a double-tracer OGTT than females (each P ⬍ 0.01), whereas females had ele-
consisting of a primed constant infusion of [3-3H]glucose (0.25 vated glucose concentrations from 120 –180 min by
Ci/min) starting 120 min before the OGTT (75 g glucose diluted
9 –18% (each P ⬍ 0.04). Plasma insulin AUC was higher
in water containing 75 Ci D-[1-14C]glucose), as described pre-
viously (23). Because a hyperinsulinemic clamp test was not per- in males during the first hour (Table 1) but increased in
formed, we estimated M from OGTT data, as described by Stum- females at 150 and 180 min by 52– 64% (each P ⬍ 0.03)
voll et al. (24). As visible in Fig. 1E, inset, we observed a very close (Fig. 2B). Plasma C-peptide was 26% higher in males at 40
parallelization of our calculated (black boxes with broken line) min and in females at 150 min (each P ⬍ 0.03). From 0 –20
EGP with EGP data from double-tracer experiments (rectangles
with continuous line). The comparison of measured (rectangles
min, females showed 31–35% elevated plasma FFA con-
with continuous line) with calculated (black boxes with broken centrations (each P ⬍ 0.005), whereas they were higher in
line) and modeled (triangles with broken line) rate of glucose males from 120 min onward by 59 –190% (each P ⬍
520 Anderwald et al. Sex-Specific Differences in Glucose Absorption J Clin Endocrinol Metab, February 2011, 96(2):515–524

males (P ⫽ 0.03) but fell similarly during the

clamp test in both genders. Fasting EGP was
17% lower in females (P ⬍ 0.05), whereas
during the clamp test, EGP decrease by in-
sulin was comparable in both genders. Fe-
males and males did not show any differ-
ences in M at any of the 20-min intervals of
the clamp test. However, when adjusting M
for lean body weight, females [11.6 ⫾ 0.6
mg/(min 䡠 kg)] were slightly more (P ⬍ 0.05)
insulin sensitive than males [9.6 ⫾ 0.7
mg/(min 䡠 kg)].

Glucose absorption
In the first phase of the OGTT, ABS rates
were higher (each P ⬍ 0.05) in males by
between 84 and 191 mg/min, whereas in the
last part of the 180-min OGTT, glucose ab-
sorption rates were increased (each P ⬍
0.05) in women by 59 – 68 mg/min (Fig. 3A).
When adjusting for body weight, males had
higher glucose absorption from 10 –20 min
[7.2 ⫾ 0.4 mg/(min 䡠 kg) vs. 5.7 ⫾ 0.3 mg/
(min 䡠 kg) in females, P ⬍ 0.002], but fe-
males showed higher absorption through-
out the second half of the OGTT (90 –120
min, ⫹24%; 120 –150 min, ⫹50%; 150 –
180 min, ⫹66%; each P ⬍ 0.05). The total
amount of the calculated glucose ab-
sorbed during the 75-g OGTT was similar
(P ⫽ 0.62) among females (60 ⫾ 3 g) and
males (62 ⫾ 4 g) (Fig. 3B), reproducing
FIG. 3. A, ABS (milligrams per minute) averaged for each interval derived from
80 ⫾ 4 and 83 ⫾ 6%, respectively, of the
mathematical modeling; B, amount of total glucose absorbed; C, relative glucose total glucose load. The relative retention
retention; D, half-life of glucose (t ⁄ ) in the gastrointestinal tract during the OGTT; E and
12
of glucose in the gastrointestinal tract was
F, relationship of glucose t ⁄ with body height (E) and fat-free mass (F) in females (E,
greater (each P ⬍ 0.0001) in women than
12

n ⫽ 48) and males (F, n ⫽ 26). Student’s t test: *, P ⬍ 0.05; #, P ⬍ 0.00001 for
females vs. males. men from 10 –150 min (Fig. 3C). Thus, the
half-life of glucose in the gastrointestinal
tract was 14 min greater (P ⬍ 0.00001) in
0.04). Glucose disappearance rate was higher in males, females than in males (Fig. 3D). Also when pair match-
whereas glucose clearance, as determined by OGIS, was ing all studied males and selected females (n ⫽ 26;
virtually the same in both sexes (Table 1). The insulino- BMI ⫽ 25 ⫾ 1 kg/m2; P ⫽ 0.9 vs. males) for fat-free
genic index was similar in females (4.4 ⫾ 0.7) and males mass-adjusted M [9.6 ⫾ 0.6 mg/(min 䡠 kg) in females,
(4.8 ⫾ 1.0) during the first 120 min. P ⫽ 1.0 vs. males], ABS curves remained the same (data
not shown), as did the difference in glucose half-life in
Hyperinsulinemic clamp test (Fig. 2, E–I) the gut (80 ⫾ 2 min in females vs. 65 ⫾ 3 min in males,
Plasma glucose was not different before and during the P ⬍ 0.0001).
clamp test, except at 80 min, when it was 5% higher in
males (P ⫽ 0.04). At fasting, plasma insulin was compa- Correlation analyses
rable (7.4 ⫾ 0.7 ␮U/ml in females vs. 7.2 ⫾ 0.5 ␮U/ml in In all participants, glucose t ⁄ correlated negatively
12

males) and similarly rose after insulin infusion in females with body height (r ⫽ ⫺0.481; P ⬍ 0.0001) (Fig. 3E) and
and males up to 71.8 ⫾ 2.8 and 72.5 ⫾ 3.0 ␮U/ml, re- fat-free mass (r ⫽ ⫺0.401; P ⬍ 0.001) (Fig. 3F) but not
spectively. Fasting plasma FFA were 23% higher in fe- with BMI.
J Clin Endocrinol Metab, February 2011, 96(2):515–524
To ascertain these relationships not to be spurious, we
also performed correlation analyses in the smaller valida-
tion group (n ⫽ 12), finding glucose t ⁄ negatively asso-
12
ciated with both body height (r ⫽ ⫺0.581; P ⬍ 0.05) and
fat-free mass (r ⫽ ⫺0.699; P ⬍ 0.02) as well (individual
data not shown). Plasma concentrations of insulin and
glucose positively correlated with each other, both at fast-
ing (r ⫽ 0.268; P ⬍ 0.03) and more closely at all OGTT
time points from 10 –180 min (r range ⫽ 0.373– 0.559;
each P ⬍ 0.002) in all participants.
Discussion
We recruited a cohort of females and males similar in age
and BMI to avoid as much as possible confounders in this
study. Females showed lower fasting EGP and decreased
plasma glucose levels during the early course of the OGTT
but higher plasma glucose concentrations from 120 –180
min. The novelty of our work is the determination of glu-
cose absorption rates, which were higher in males in the
initial phase of the OGTT and elevated in females in the
final part of the 180-min OGTT. The best-suited value to
describe OGTT glucose absorption velocity is glucose
half-life in the gut, which was prolonged in females in
comparison with males. In all participants, glucose half-
life was negatively related to body height and fat-free
mass. Three novel methods, i.e. calculation of both EGP
and rate of glucose disappearance (Rd) from plasma insu-
lin in logarithmic manner as well as description of its
mechanism by introduction of five equations were neces-
sary to establish a model of ABS during an OGTT. This
model was then evaluated in nondiabetic humans during
double-tracer OGTT and proven for reliability. Thereaf-
ter, this model was used in quite a large cohort of healthy
humans (n ⫽ 74) to reveal whether glucose absorption
could play a role in the mechanisms of gender-related dif-
ferences in glucose metabolism.
Oral glucose tolerance test
Fasting glucose is the glucose concentration after an
overnight fast and mostly reflects EGP, whereas postload
hyperglycemia reflects the acute increase in blood glucose
after a glucose challenge (6). Several epidemiological in-
vestigations from many European countries (3, 6), Aus-
tralia (4, 7), some Asian countries (8), and Mauritius (5)
report that females, when compared with males, have de-
creased IFG prevalence, but more frequently IGT. In those
studies (3– 8), the prevalence of IFG at an age similar to our
study participants (⬃45 yr) was between 3 and 5% in
females but consistently higher, between 5 and 12%, in
males. In this study, the higher fasting EGP in males by
jcem.endojournals.org 521
approximately 0.3 mg/(min 䡠 kg) (Fig. 2H) compared with
females yields, when calculated for 12 h, an elevated over-
night EGP by 26 g. However, fasting glucose concentra-
tions were similar in both genders (Table 1). This is not
surprising, because EGP is positively related to fasting
glucose only in diabetic patients with severely reduced
insulin sensitivity in the whole body, including the liver,
but not in nondiabetic humans (9). It appears therefore
conceivable that in the early stage of diabetes, the pro-
gression of (hepatic) insulin resistance with concomi-
tant inability of insulin to suppress EGP and use glucose,
favors the rise of fasting glucose in those humans with a
somewhat higher EGP, who are presumably males. This
might explain the higher IFG incidence in men (3– 8).
To date, the gender-related differences in IGT incidence
have still been under debate; Sicree et al. (7) reported
higher IGT prevalence also in Australian women (10.1%)
in comparison with men (6.5%) and ascribed this obser-
vation to differences in height between both genders. In
addition, Sicree et al. (7) supposed that taller persons
(mostly males) have more muscle mass, which is the major
tissue involved in glucose uptake, so that the differences in
postload glucose seen probably reflect more tissue for up-
take/metabolism of glucose against the fixed glucose load
of 75 g. Certainly, also in our study, the male participants
had more muscle mass, because they showed increased
fat-free mass and serum creatinine (Table 1). The latter is
directly related to muscle mass as its major source (11, 25).
Insulin-stimulated glucose utilization, when given in rela-
tion to full body weight, was comparable in both sexes
(Fig. 2I) but would be increased in the 15% heavier males
when considered for the whole body. Nevertheless, the
higher total capacity for glucose uptake in men cannot
explain the elevated glucose concentrations in the early
OGTT period (Fig. 2A), because it would have rather re-
sulted in decreased glucose concentrations.
Glucose absorption
To assess glucose absorption, which in humans is not
directly, i.e. invasively, measurable, we developed a novel
approach, based on mathematical modeling and the de-
convolution method (Fig. 3B) to mimic absorptive condi-
tions at the intestine site. Our method allows the estima-
tion of ABS rates, the total glucose absorbed, ABS, and
half-life in the gastrointestinal tract. The validity of our
novel model was checked by using manifold-labeled glu-
cose tracers, the gold standard of glucose absorption mea-
surement (23, 26, 27). We could provide evidence that our
model is capable of revealing an absorption pattern from
a simple OGTT that satisfactorily resembles conditions
under labor-intensive application of isotopes. However,
the use of isotopes requires considerable experience and
522 Anderwald et al. Sex-Specific Differences in Glucose Absorption
expensive equipment and cannot be employed easily in a
larger cohort of humans. In particular, both point-to-
point calculation and modeling result in a tight association
between estimated and measured gut glucose t ⁄ . Thus, we
12
show that mathematical modeling seems a valid alterna-
tive to study nondirectly accessible processes.
In the present work, we also used a deuterated glucose
infusion at fasting and during hyperinsulinemia for mea-
suring whole-body insulin sensitivity and EGP with the
hyperinsulinemic clamp test (11, 18). In line with a pre-
vious report (21), we were able to reconfirm the logarith-
mic association between plasma insulin concentrations
and both the rate of insulin-mediated glucose disappear-
ance and EGP (Fig. 1B) over a very broad range of insu-
linemia, from approximately 6 – 400 ␮U/ml, which en-
tirely covered that of our study participants during the
OGTT (⬃7– 65 ␮U/ml). Therefore, EGP inhibition and
the Rd in each individual were calculated by applying these
logarithmic relationships obtained from the clamp test to
OGTT data.
It should be mentioned that EGP inhibition and glucose
utilization is mediated not only by insulin but also by el-
evated glucose; nonetheless, glucose was not included in
the formula of the current model. Henriksen et al. (28)
performed pancreatic clamp tests at near-fasting insulin
concentrations (⬃10 ␮U/ml), comparing euglycemic
(⬃100 mg/dl) with markedly hyperglycemic (⬃230 mg/dl)
conditions, and showed a rise in glucose-mediated glucose
disposal by 2.2 mg/(min 䡠 kg) fat-free mass, corresponding
to 1.7 mg/(min 䡠 kg) total body weight, in insulin-sensitive
humans as well as an EGP reduction by 0.2 mg/(min 䡠 kg).
Because the association of glucose-mediated glucose dis-
posal increases with prevailing glucose concentrations in
a linear manner, as shown in dogs (29), we estimated the
role of glucose effectiveness in this study by linear inter-
polation of our peak glucose levels using the data from
Henriksen et al. (28). Glucose effectiveness, at the maxi-
mum glucose level during the OGTT, would have reduced
EGP by 0.05– 0.07 mg/(min 䡠 kg) but elevated Rd by 0.6 –
0.7 mg/(min 䡠 kg), both representing a relatively small de-
viation of absorption by maximally 10%. Thus, in theory,
an overestimation of EGP nadir and underestimation of Rd
peak in our modeling cannot be ruled out but, if existing,
appear to be rather small. Importantly, it should be stated
that we did validate our novel model and show it to be
reliable, because the measured and modeled glucose half-
life are closely related to each other. In addition, inclusion
of glucose effectiveness in our model would have blurred
the shape of the absorption curve (figure not shown).
From equation 1, the calculation of total glucose ab-
sorbed yielded approximately 60 g in both groups (Fig.
3B), with appearance of approximately 80% of the entire
J Clin Endocrinol Metab, February 2011, 96(2):515–524
75-g glucose load. This again indicates a suitable repro-
duction of the glucose challenge by our modeling, because
about 20% of gut carbohydrate is thought to escape ab-
sorption (30).
When adjusted for lean body weight, females were slightly
more insulin sensitive than males; thus, we carefully per-
formed a pair match, which gave similar results for gut ab-
sorption and strengthens our findings. We also evaluated
glucose clearance during OGTT (OGIS, Table 1) and found
a virtually identical glucose clearance in both sexes. From
this, it appears that the alterations of circulating OGTT glu-
cose concentrations in females and males are not the result of
different clearance but exist rather because of different ab-
sorption from the gastrointestinal tract.
Relationship of glucose absorption to
anthropometric measures
A close and negative relationship of gut glucose t ⁄ with12
body height and fat-free mass (Fig. 3, E and F) was found.
To confirm our novel findings, we could present this re-
lationship also in the validation group using the measured
glucose t ⁄ .
12
Possible mechanisms
We can only observe and analyze how glucose appears
in the peripheral bed without evidence for what happens
before its absorption. Thus, it is not easy to give reasons for
the higher gut absorption velocity in taller persons, which
could be because of 1) increased active transport capacity
and/or 2) elevated intestinal surface area. By ingesting ra-
dioactive, chelated 111indium, it was shown that liquids
empty from the stomach more slowly in women, with ap-
proximately 20 min reduced half-emptying time (31). This
reflects the differences found in gut glucose t ⁄ in this
12
study. Thus, prolonged gastric emptying might contribute
to slower glucose absorption. Alternatively, absorption
may also be affected by mucosal surface, which, however,
cannot be measured in intact humans. Of note, also cal-
cium absorptive efficiency rises in taller persons (32). We
totally agree with the suggestions by Barger-Lux and
Heaney (32) that the effect of body size on absorptive
kinetics is purely physical rather than physiological, be-
cause it appears likely that larger individuals have more
intestinal surface for more rapid and efficient absorption.
Regardless of the exact mechanism, our observations of an
association between glucose absorption velocity and body
size rather points from a gender-related effect on IGT in-
cidence to the stronger influence of body tallness, which
also differs between females and males. In all ethnic groups
throughout the world, women are on average shorter than
men (http://en.wikipedia.org/wiki/Human_height) by ap-
proximately 15 cm (33), like in this study (Table 1). Deter-
J Clin Endocrinol Metab, February 2011, 96(2):515–524
mination of body height in a single individual mostly results
from genetic and environmental factors (34) but also from
sexual dimorphism during pubertal growth with distinctions
in GH secretion in response to sex steroid release (35, 36).
Sex-specific differences
In the early phase of the OGTT, males had markedly
increased glucose absorption rates by approximately 200
mg/min from the gastrointestinal tract, whereas in the fi-
nal phase of the 180-min OGTT, females absorbed ap-
proximately 60 mg/min more glucose (Fig. 3, A and B).
These differences in glucose absorption with an approx-
imately 14-min longer gut glucose half-life in women (Fig.
3D) could serve to explain higher glucose concentrations
at the end of the OGTT in females (Fig. 2A). However, it
also should be taken into account that females have lower
peripheral insulin release (and thus lower concentration)
during the first 60 min of the OGTT. This fact, given the
known delay of insulin action on peripheral tissues, may
result in a lower glucose disappearance rate after 60 min.
This period of lower glucose disappearance rate includes
the 2-h data point characterized by higher glucose level in
females. Therefore, IGT prevalence in women may depend
on a concomitant effect of insulin release and glucose
absorption.
At fasting (Table 1), females had decreased liver en-
zymes, lower creatinine and uric acid concentrations with
a trend toward reduced triglycerides, but higher HDL-
cholesterol and body fat (mass), which are generally seen
as gender-related differences because of the direct effects
by sex hormones (25, 37– 40). Interestingly, females dis-
played lower fasting EGP than males, despite higher fast-
ing plasma FFA concentrations, confirming our findings
in the isolated perfused rat liver (17), in which we did not
see a direct effect by FFA on hepatic glucose production,
whereas others described an association between elevated
FFA and increased EGP (41).
Limitations
It should be emphasized that this analysis holds true for
healthy, nondiabetic subjects with normal glucose toler-
ance or at least for subjects with fasting glucose within
normal ranges (i.e. normal fasting EGP) and is worthy of
being used for large cohorts, whereas individuals might
have slightly different profiles.
Conclusions
This study in healthy, glucose-tolerant humans shows
for the first time different ABS rates during an OGTT in
women and men, which contribute to higher OGTT
plasma glucose at 120 min in females, and a negative re-
lationship between body height and gut glucose half-life.
jcem.endojournals.org 523
Finally, evaluating ABS in IGT populations could contrib-
ute to clarify the higher prevalence of glucose intolerance
in females as observed in several epidemiological studies
worldwide.
Acknowledgments
We are grateful to all volunteers for participation and to H.
Lentner and A. Hofer, from the Metabolic Unit of the Vienna
Medical University, for skillful care of the subjects. We also
thank P. Nowotny and the staff of the Lab of the Division of
Endocrinology and Metabolism/Vienna Medical School for pre-
cise hormone and metabolite analyses, including GC-MS mea-
surements. After giving informed consent, many of the study
participants were also included in the EGIR-RISC project
[www.egir.org (15), head: Prof. Dr. E. Ferrannini, University
of Pisa, Pisa, Italy; Vienna subcontractors, 2001–2005: Prof.
Dr. W. Waldhäusl, since 2005: Prof. A. Luger &C.A.].
Address all correspondence and requests for reprints to: Chris-
tian Anderwald, M.D., M.Pharm., M.B.A., Associate Professor of
Internal Medicine, Division of Endocrinology and Metabolism, De-
partment of Internal Medicine III, Medical University of Vienna,
Waehringer Guertel 18 –20, A-1090 Vienna, Austria, or Metabolic
Unit, Istituto di Ingegneria Biomedica-Consiglio Nazionale delle
Ricerche (ISIB-CNR), Corso Stati Uniti 4, I-35127 Padova, Italy.
E-mail: christian-heinz.anderwald@meduniwien.ac.at.
Some of the study participants were simultaneously included
in the EGIR RISC project (www.egir.org). RISC is supported by
EU contract QLG1-CT-2001-01252 and by AstraZeneca.
Disclosure Summary: The authors have nothing to declare.
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