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Boden, Guenther, Xinhua Chen, and T. Peter Stein. gluconeogenesis (GNG) (7, 8, 26, 28, 32, 41). The valid-ity of
Gluconeogenesis in moderately and severely hyperglycemic patients this widely accepted concept, however, can be questioned.
with type 2 diabetes mellitus. Am J Physiol Endo-crinol Metab 280: First, the notion that postabsorptive EGP is uniformly elevated
E23±E30, 2001.ÐWe tested the generally accepted concept that in hyperglycemic patients has recently come under attack (1,
increased gluconeogenesis (GNG) and endogenous glucose
17). Second, the data that were the basis for the thesis that
production (EGP) are the main reasons for postabsorptive
hyperglycemia in patients with type 2 diabetes mellitus (T2DM). patients with high fasting plasma glucose (FPG) had increased
GNG was measured with the 2H2O method by use of both the C5-to- rates of GNG were obtained with methods that, for several
C2 ratio (C5/C2, with gas chromatography-mass spectrometry) and reasons, did not allow quantitative measurements of GNG.
the C5-to-2H2O ratio (C5/2H2O, with isotope ratio mass Usually only one (or at most two) GNG precursor was used.
To determine total GNG would have re-quired extrapolation
spectrometry), and EGP was measured with 3-[ 3H]glucose in 27
patients with T2DM [13 with fasting plasma glucose (FPG) .10 mM
from the conversion to GNG from one to all precursors. This
and 14 with FPG ,10 mM] and in 7 weight- and age-matched is dif®cult, because it has been shown that infusion of some
nondiabetic controls. The results showed 1) that GNG could be precursors (for in-stance glycerol) decreased the fractional
determined accurately with 2H2O by using either C5/C2 or C5/2H2O; conversion of other precursors (for instance amino acids) (16,
2) that whereas after an overnight fast of 16 h, GNG was higher in 38). Another, more serious problem was that the hepatic GNG
the entire group of patients with T2DM than in controls (6.4 vs. 5.0 precursor speci®c activity was unknown, because the label
mmolz kg21 z min21 or 60.4 vs. 51.4% of EGP, P , 0.02), GNG was was diluted in the oxaloacetate pool, which is shared by GNG
within normal limits (less than the mean 6 2 SD of controls or , and the tricarboxylic acid cycle (19). This usually resulted in a
65.3%) in 11/14 (79%) patients with mild to moderate hyperglycemia systematic underestimation of GNG (19). Recently, new
(FPG ,10 mM) and in 5/13 (38%) of patients with severe methods have become available that for the ®rst time have
hyperglycemia (FPG 10±20 mM); 3) that elevated GNG in T2DM allowed quantita-tive in vivo determination of GNG in human
was asso-ciated with a 43% decrease in prehepatic insulin secretion, subjects (13, 20, 22, 23, 33).
i.e., with hepatic insulin de®ciency; and 4) that FPG corre-lated
signi®cantly with glucose clearance (insulin resistance) (r 5 0.70)
and with GNG (r 5 0.50) or EGP (r 5 0.45). We conclude 1) that 2
peripheral insulin resistance is at least as important as GNG (and In the current study, we used the H2O technique, which
EGP) as a cause of postabsorptive hyperglycemia in T2DM and 2) was recently developed and validated by Landau and
that GNG and EGP in T2DM are increased under conditions of colleagues (22, 23). Major advantages of this method are that
signi®cant hepatic insulin de®ciency and thus probably represent a it determines GNG from all precursors (including glycerol)
late event in the course of T2DM. and that it avoids the problems, related to unknown precursor
speci®c activity in the liver, that have plagued all previous
endogenous glucose production; insulin resistance; prehe-patic isotopic methods. We used this new method to examine the
insulin secretion; deuterated water method hypothesis that GNG was elevated in patients with type 2
diabetes (T2DM) and was responsible for their postabsorptive
hyperglycemia. To this end, we measured GNG in 27 patients
HYPERGLYCEMIA AFTER AN OVERNIGHT FAST is
a major hall- with T2DM fasted for 16 h who were subdi-vided into two
mark and an important diagnostic criterion of diabe-tes. groups, those who had either mild to moderate (,10 mM) or
Postabsorptive hyperglycemia of .7.8 mM in dia-betic patients severe (.10 mM) postabsorp-tive hyperglycemia.
is generally believed to be due to increased endogenous
glucose production (EGP), which in turn is believed to be
caused by increased rates of
The costs of publication of this article were defrayed in part by the payment
Address for correspondence: G. Boden, Temple Univ. Hospital, 3401 North of page charges. The article must therefore be hereby marked ``advertisement''
Broad St., Philadelphia, PA 19140 (E-mail: bodengh @tuhs.temple.edu). in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
http://www.ajpendo.org 0193-1849/01 $5.00 Copyright © 2001 the American Physiological Society E23
21 21 21 21
kg z min , P , 0.02). GNG was also higher in the (4.1 6 0.3 mmolz kg z min ) in the .10 mM glucose group,
21 21
.10 mM glucose group than in the ,10 mM glucose group 43.7 6 3.1% (3.8 6 0.4 mmolz kg z min ) in the ,10 mM
21 21 21
(64.8 6 3.3% or 8.5 6 1.1 mmolz kg z min vs. glucose group, and 48.6 6 2.6% (4.8 6 0.5 mmolz kg z
21 21 21
56 6 3.1% or 4.8 6 0.6 mmolz kg z min , P , 0.03) and in min ) in the controls. GL in all T2DM and in the .10 mM
the controls. The difference between the T2DM with ,10 mM glucose group was signi®cantly lower than GL in controls (P ,
glucose and the control group was not statistically signi®cant. 0.03).
There was a trend for GNG to rise with higher FPG, which EGP
was re¯ected in a signif-icant but modest correlation between
FPG and GNG (r 5 0.50, P , 0.005; Fig. 2). Rates of EGP were higher in the .10 mM glucose group
than in the ,10 mM glucose group (12.6 6 1.2 vs. 8.6 6 0.8
Postabsorptive GNG levels (at 16 h) were similar in the 7 21 21
mmolz kg z min , P , 0.01) and in the controls (9.8 6 0.6
elderly controls (this study) and in 12 younger (36 6 3 yr) and 21 21
mmolz kg z min , P , 0.05). The differences between all
leaner (body mass index 24.7 6 1.3) nondiabetic subjects (51.4 21 21
T2DM (10.5 6 0.8 mmolz kg z min ) and controls and
6 2.6 vs. 54.2 6 3.2%, non-signi®cant), suggesting that our between the ,10 mM glucose and control group were not
normal range was representative of that in a larger nondiabetic statistically signi®cant.
popula-tion. FPG correlated signi®cantly but modestly with EGP (r 5
0.46, P , 0.01; Fig. 2).
GL
Glucose Clearance
Rates of GL were 39.6 6 2.4% of EGP (3.9 6 0.3 mmolz
21 21 Glucose clearance was used to estimate insulin sen-sitivity.
kg z min ) in patients with T2DM, 35.2 6 3.3% Rates of glucose clearance were 1.12 6 0.10, 0.90 6 0.08, 1.33
21 21
6 0.15, and 1.79 6 0.10 mlz kg z min in all T2DM, the .10
mM and ,10 mM groups, and controls, respectively. All of
these differences were highly signi®cant (P , 0.01). Glucose
clearance corre-lated closely with FPG (r 5 0.70, P , 0.001;
Fig. 2).
Fig. 3. Rates of GNG, glucose clearance, insulin secretion (ISR), and plasma
glucagon levels in 16 patients with T2DM with normal GNG, in 11 patients Fig. 4. Plasma concentrations of glucose, ketone bodies (acetoacetate plus b-
with T2DM with high GNG (higher than mean 6 2 SD of controls), and in 7 hydroxybutyrate), and free fatty acids (FFA) in 16 patients with T2DM and
nondiabetic controls. Statistical analysis: *P , 0.05, **P , 0.001 vs. controls; normal GNG, 11 patients with T2DM and high GNG, and 7 normal controls.
1P , 0.05, 11P , 0.001 vs. T2DM with normal GNG. Statistical analysis: *P , 0.05, **P , 0.005 vs. controls; 1P , 0.05 vs. T2DM
with FPG ,10 mM.
resulting in GNG rates that were 3±5% higher when C5/C2 was linear over time. It appears more likely, however, that
was used instead of C5/H2O (Table 2). Both methods can liver glycogen decreases dose dependently, i.e., at a faster rate
therefore be used to quantitate GNG in patients with T2DM. during the early hours of the fast than later (14). Assuming a
linear decrease would therefore result in underestimation of
For this study, C5/C2 as well as C5/H2O was obtained for all
the glycogen content and GL and overestimation of GNG
data points, and the re-sults were pooled. during the initial 15 h of fasting. In another study, Tayek and
13
Katz (39), using mass isotopomer [U- C]glucose analysis,
GNG in T2DM
reported GNG rates of 48.8 6 5.7% of EGP in nine patients
We found that patients with T2DM, as a group, had higher with T2DM (FPG 11.8 6 1.3 mM) and 46.6 6 4.0% in eight
rates of GNG than controls (60.4 6 2.4 vs. 51.4 6 2.6%, P , controls (P , 0.05).
0.03). In one of the two other studies in which GNG was When we studied 27 patients with T2DM, it became
13
quantitatively determined [with C nuclear magnetic apparent that there was considerable variation in their rates of
resonance spectroscopy (NMR)], Magnusson et al. (24) GNG. For instance, GNG was elevated infre-quently in
reported rates of GNG of 88 6 2% of EGP in seven patients patients with FPG ,10 mM; in fact, only 1 of 14 (7%) had
with T2DM (FPG 14.6 6 1.2 mM) and of 70 6 6% in ®ve GNG exceeding the mean 1 3 SD of controls, whereas 3 of 14
nondiabetic controls. Although both studies agreed that GNG (21%) exceeded the mean 1 2 SD. Elevated GNG was more
was elevated in T2DM, the GNG values in the Magnusson common in patients with more severe hyperglycemia (FPG .10
study were higher than those in our study. The differences, mM). Here 5 of 13 (38%) exceeded the mean 1 3 SD and 8 of
however, were more apparent than real when the dif-ferences 13 (61.5%) exceeded the mean 1 2 SD of controls. This also
in methodology are considered. Magnuson et al. determined meant, however, that GNG remained within normal limits in
mean rates of GL and obtained GNG by subtraction of GL more than one-third (5 of 13) of even severely hyper-glycemic
from EGP. There are several reasons why this method could patients (FPG 10.2±19.3 mM). One patient in this group had
underestimate GL and there-fore overestimate GNG. 1) The discontinued his Glipizide medication only 1 day before being
NMR spectroscopy method does not detect renal GL. This studied. It is, therefore, possi-ble that this patient's GNG
may be incon-sequential in nondiabetic subjects, whose (49.5%) might have been slightly higher had the drug been
kidneys con-tain only trivial amounts of glycogen (2). Patients discontinued 2 days earlier. Thus, whereas there was a trend
with T2DM, however, accumulate glycogen in their kidneys for GNG to rise with rising FPG levels, the correlation
and are able to produce glucose by GL (2). This alone could between GNG and FPG was modest (r 5 0.50, P , 0.005).
1
account for much of the difference between the two studies.
2) In the Magnusson study, liver glycogen concentrations were GNG and Insulin
much lower in diabetic patients than in controls (131 vs. 282
mmol/l), possibly due to differences in prestudy food intakes. To learn why GNG was high in some diabetic pa-tients but
Because GL de-pends on glycogen levels (40), this could have not in others, we compared the 11 patients with elevated GNG
been a reason for low GL and high GNG rates in the diabetic (. mean 1 2 SD of controls) with the remaining 16 patients
patients. 3) Magnuson et al. determined average rates of GL who had normal GNG (Fig. 3). This comparison revealed that
from changes in hepatic glycogen concentrations based on the patients with elevated GNG had similar plasma levels of
NMR measurements obtained between 4 and 22.5 h after the the major GNG-promoting hormones and substrates, including
last meal. Therefore, to provide accu-rate rates of GL, the ®rst glucagon, epinephrine, cortisol, FFA, and GNG precur-sors
NMR measurement needed to coincide with the peak of (lactate, alanine, glutamate, glutamine, and glyc-erol; Table 5).
postmeal hepatic glycogen accumulation. If hepatic glycogen In addition, they were as insulin resis-tant (as judged by their
increased after the ®rst NMR measurement (4 h after the glucose clearance) as the patients with normal GNG.
meal), which may occur in diabetic patients who not Noteworthy, however, their livers were exposed to ;40% less
infrequently have delayed absorption, GL would have been insulin (as
under-estimated and GNG overestimated. 4) Liver volume (to
calculate glycogen content from glycogen concentra-tion) was
determined once (14.5 h after the last meal). It was assumed Table 5. Plasma GNG precursor levels in subjects with
that the decrease in liver volume [observed previously to be normal and high rates of GNG
23% over 67 h of fasting (33)]
Normal GNG
Controls T2DM High GNG T2DM
(n _ 7) (n _ 16) (n _ 11)
1
For instance, if the kidneys contributed 25% of total EGP, as has Lactate 8456 74 1,148 6 156 1,138 6 148
been reported by Meyer et al. (25), and if 50% of this renal EGP was Alanine 2896 21 412 6 43 355 6 29
from GL (a reasonable assumption), then 1.39 mmolz kg21 z min21 of a Glutamate 896 9 79 6 10 91 6 24
total EGP of 11.1 mmolz kg21 z min21 in the Magnusson study (24) Glutamine 5416 36 478 6 36 380 6 52*
would have been renal GL. Hepatic plus renal GL would have been Glycerol 1166 18 91 6 10 84 6 11
2.7 mmolz kg21 z min21, i.e., 24% of EGP, and GNG would have been Total precursors 1,8326 114 2,208 6 191 2,048 6 158
76%, the same as the 75% that we found in seven patients with
comparable FPG after 24 h of fasting (this study). Values are means 6 SE. *P _ 0.05 vs. controls.
judged by a ;40% reduction in prehepatic ISR). This suggested It needs to be pointed out, however, that the patients in the .
that hepatic insulin de®ciency was a major cause for the 10 mM glucose group had not only grossly elevated plasma
increased GNG in these patients, because insulin is known to glucose but also abnormally high se-rum insulin levels, both
suppress GNG (34), and insulin de®ciency is known to of which should have de-pressed EGP (31, 35). The fact that in
increase gene transcription of at least three of the four key over 50% of these patients EGP was within normal limits
GNG enzymes (phosphoenol-pyruvate carboxykinase, instead of reduced indicated that these patients had hepatic as
glucose-6-phosphatase, and fructose 1,6-biphosphatase) (12). well as peripheral insulin resistance.
Insulin is also a powerful suppressor of ketone body In summary, our data showed 1) that the deuterated water
formation (27). Presence of insulin de®ciency in these method (either C5/C2 or C5/H 2O) can be used to accurately
patients was further supported by the ®nding that their plasma measure GNG in patients with T2DM; 2) that GNG was
b-OHB levels were higher, whereas their FFA levels (i.e., the infrequently (;20%) elevated in pa-tients with FPG ,10 mM
ketone body precursors) were sim-ilar compared with those of but was commonly elevated (;60%) in patients with FPG .10
the diabetic patients with normal GNG. mM; 3) that hepatic insulin de®ciency seemed to be a major
reason for increased GNG; and 4) that peripheral insulin resis-
tance together with inappropriate glucose production caused
GNG and FPG the development of fasting hyperglycemia. On the basis of
Whether EGP (or GNG) is elevated in mildly to moderately these ®ndings, we conclude that the widely held concept that
hyperglycemic patients with T2DM has remained FPG of .7.8 mM is mainly due to increased EGP or GNG
controversial. Older studies have frequently reported greatly overemphasizes the impor-tance of EGP/GNG and
increased rates of EGP, which has led to the conclusion that underemphasizes the impor-tance of insulin resistance.
elevated levels of FPG in T2DM were primarily the result of
increased EGP (3, 4, 10, 21). More recently, however, it has We thank the nurses of the General Clinical Research Center for help with
become clear that in most of these studies, EGP was the studies and for excellent patient care, Karen Kresge and Maria Mozzoli for
overestimated in pro-portion to the degree of the patient's outstanding technical assistance, and Con-stance Harris Crews for typing the
manuscript.
hyperglycemia. The main reason for this was incomplete This work was supported by National Institutes of Health Grants R01-AG-
equilibration of the labeled and nonlabeled glucose in the 07988, R01-AA-10221 (to G. Boden), R01-AG-14098 (to T. P. Stein), and
expanded glucose pool. In studies in which an isotopic steady RR-349 (to the General Clinical Research Center).
state was achieved, EGP was usually found to be ele-vated
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