1 Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University Hospital, Philadelphia, Pennsylvania 19140; and the 2 Department of Surgery, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, New Jersey 08084
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ABSTRACT |
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We tested the generally accepted
concept that increased gluconeogenesis (GNG) and endogenous glucose
production (EGP) are the main reasons for postabsorptive hyperglycemia
in patients with type 2 diabetes mellitus (T2DM). GNG was measured with
the 2H2O method by use of both the C5-to-C2
ratio (C5/C2, with gas chromatography-mass spectrometry) and the
C5-to-2H2O ratio
(C5/2H2O, with isotope ratio mass
spectrometry), and EGP was measured with 3-[3H]glucose in
27 patients with T2DM [13 with fasting plasma glucose (FPG) >10 mM
and 14 with FPG <10 mM] and in 7 weight- and age-matched nondiabetic
controls. The results showed 1) that GNG could be determined
accurately with 2H2O by using either C5/C2 or
C5/2H2O; 2) that whereas after an
overnight fast of 16 h, GNG was higher in the entire group of
patients with T2DM than in controls (6.4 vs. 5.0 µmol · kg1 · min
1 or 60.4 vs. 51.4% of EGP, P < 0.02), GNG was within normal
limits (less than the mean ± 2 SD of controls or <65.3%) in
11/14 (79%) patients with mild to moderate hyperglycemia (FPG <10 mM)
and in 5/13 (38%) of patients with severe hyperglycemia (FPG
10-20 mM); 3) that elevated GNG in T2DM was associated
with a 43% decrease in prehepatic insulin secretion, i.e., with
hepatic insulin deficiency; and 4) that FPG correlated
significantly with glucose clearance (insulin resistance)
(r = 0.70) and with GNG (r = 0.50) or
EGP (r = 0.45). We conclude 1) that
peripheral insulin resistance is at least as important as GNG (and EGP)
as a cause of postabsorptive hyperglycemia in T2DM and 2)
that GNG and EGP in T2DM are increased under conditions of significant
hepatic insulin deficiency and thus probably represent a late event in
the course of T2DM.
endogenous glucose production; insulin resistance; prehepatic insulin secretion; deuterated water method
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INTRODUCTION |
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HYPERGLYCEMIA AFTER AN OVERNIGHT FAST is a major hallmark and an important diagnostic criterion of diabetes. Postabsorptive hyperglycemia of >7.8 mM in diabetic patients is generally believed to be due to increased endogenous glucose production (EGP), which in turn is believed to be caused by increased rates of gluconeogenesis (GNG) (7, 8, 26, 28, 32, 41). The validity of this widely accepted concept, however, can be questioned. First, the notion that postabsorptive EGP is uniformly elevated in hyperglycemic patients has recently come under attack (1, 17). Second, the data that were the basis for the thesis that patients with high fasting plasma glucose (FPG) had increased rates of GNG were obtained with methods that, for several reasons, did not allow quantitative measurements of GNG. Usually only one (or at most two) GNG precursor was used. To determine total GNG would have required extrapolation from the conversion to GNG from one to all precursors. This is difficult, because it has been shown that infusion of some precursors (for instance glycerol) decreased the fractional conversion of other precursors (for instance amino acids) (16, 38). Another, more serious problem was that the hepatic GNG precursor specific activity was unknown, because the label was diluted in the oxaloacetate pool, which is shared by GNG and the tricarboxylic acid cycle (19). This usually resulted in a systematic underestimation of GNG (19). Recently, new methods have become available that for the first time have allowed quantitative in vivo determination of GNG in human subjects (13, 20, 22, 23, 33).
In the current study, we used the 2H2O technique, which was recently developed and validated by Landau and colleagues (22, 23). Major advantages of this method are that it determines GNG from all precursors (including glycerol) and that it avoids the problems, related to unknown precursor specific activity in the liver, that have plagued all previous isotopic methods. We used this new method to examine the 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 with T2DM fasted for 16 h who were subdivided into two groups, those who had either mild to moderate (<10 mM) or severe (>10 mM) postabsorptive hyperglycemia.
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METHODS |
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Subjects
Twenty-seven patients with T2DM and seven age- and weight-matched nondiabetic controls participated in this study. Thirteen of the diabetic patients had high (mean 14.2, range 10.2-19.3 mM) and 14 had either normal or moderately elevated (mean 7.2, range 4.7-9.9 mM) postabsorptive glucose levels. All patients in this group, however, had elevated glucose levels (>11.11 mM) during a 2-h oral glucose tolerance test. Some of their characteristics are given in Table 1. All patients had been treated with oral hypoglycemic agents (sulfonylureas or biguanides or both), and some had received, in addition, small doses of NPH insulin (5-20 units) at bedtime. These medications were withheld starting 3 days before the studies in all but three patients (one discontinued medications 2 days before, the other two, one day before the studies). The patients' body weights were stable for
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Experimental Design
The subjects were admitted to the Temple University Hospital General Clinical Research Center on the day before the studies. At 6 PM, the subjects ingested a meal containing 14 kcal/kg of body weight. The meal was composed of 53% carbohydrate, 15% protein, and 32% fat. They then fasted for 16 h but were allowed water ad libitum. At 11 PM, a baseline blood sample was obtained. The subjects drank 2.5 g of 2H2O (99.9% 2H; Isotec, Miamisburg, OH) per kg of body water at 11 PM and again 4 h later at 3 AM. Body water was assumed to be 50% of body weight in women and 60% of body weight in men. Additional water ingested during the fast was enriched to 0.5% with 2H2O to prevent dilution of the isotopic steady state. The studies began at 8 AM the following day with the subjects reclining in bed. A short polyethylene catheter was inserted into an antecubital vein for infusion of isotopes. Another catheter was placed into a contralateral forearm vein for blood sampling. This arm was wrapped with a heating blanket (~70°C) to arterialize venous blood. Blood samples were drawn after 16 h of fasting for determination of glucose turnover, GNG, substrates, and hormones.In a separate study, designed to determine 2H
enrichment in plasma water, the fast was extended to 24 h in 14 diabetic patients (7 with plasma glucose of >10 mM and 7 with plasma
glucose of <10 mM) and in the 7 age- and weight-matched controls.
Blood samples were collected at 16, 20, and 24 h for measurement
of 2H enrichment of plasma water (Table
2).
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Analytical Procedures
Determination of GNG. This method depends on the incorporation of 2H from 2H2O into glucose. After 2H2O administration, 2H enrichment at the glucose carbon 5 (C5) divided by 2H enrichment of plasma water or at the glucose carbon 2 (C2) equals the fractional contribution of GNG to EGP. This is so because the conversion of every molecule of pyruvate to glucose involves addition of an H from body water to C2 of the intermediate phosphoenolpyruvate. This carbon becomes C5 of glucose (22, 23).
During conversion of glycerol to glucose, one H from body water is added to C2 of glyceraldehyde 3-phosphate during isomerization with dihydroxyacetone 3-phosphate. That carbon also becomes C5 of glucose. Thus enrichment in C5 of glucose reflects glucose production from pyruvate and glycerol, i.e., from all GNG precursors (22, 23). Therefore, the ratio of 2H labeling at C5 of glucose to plasma water is a measure of GNG relative to EGP. 2H enrichment on C2 reflects glucose production from GNG and from glycogenolysis (GL). This is so because one H from body water is added to C2 of glucose 6-phosphate when fructose 6-phosphate is converted to glucose 6-phosphate during GNG. Furthermore, glucose 6-phosphate, which is also formed as an intermediate during GL, equilibrates extensively with fructose 6-phosphate, resulting in the exchange of the H bound to C2 of the glucose 6-phosphate with that in body water. There is, however, no labeling at C5 during GL. Therefore, the ratio of 2H labeling at C5 to C2 of glucose is a measure of GNG relative to EGP (22, 23). 2H enrichment of C5 and C2 was determined by gas chromatography-mass spectrometry (Hewlett-Packard 5989 MS, HP 5890 GC) as previously described (5). GNG (µmol · kg
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Glucose turnover. Glucose turnover was determined with 3-[3H]glucose. 3-[3H]glucose was infused intravenously for 2.5 h starting with a bolus adjusted proportionally to the degree of hyperglycemia (40 µCi × mM glucose/5.5) (15), followed by continuous infusion of 0.4 µCi/min. Glucose was isolated from blood for determination of 3-[3H]glucose specific activity as previously described (36). Rates of total body glucose appearance (GRa) and disappearance (GRd) were calculated using Steele's equation for non-steady-state conditions (37). The rate of EGP was equal to GRa, because no glucose was infused during these studies.
Glucose clearance rates were calculated as GRd/FPG.C-peptide kinetics. Approximately 1 wk before the studies, a 50-nmol intravenous bolus of biosynthetic human C-peptide (Eli Lilly, Indianapolis, IN) was administered to each subject after an overnight fast. Plasma C-peptide concentrations were then measured, and C-peptide kinetic parameters were calculated at frequent intervals for 3 h as described by Polonsky et al. (30).
Insulin secretory rates. The C-peptide kinetic parameters were used to calculate prehepatic insulin secretion rates (ISR) for each time interval between successive blood samples by deconvolution of peripheral C-peptide concentrations, according to Polonsky et al. (30) and Eaton et al. (11).
Substrate and hormone analyses.
Plasma glucose was measured with a glucose analyzer (YSI, Yellow
Springs, OH). C-peptide was determined by RIA (Linco, St. Charles, MO).
Insulin was determined after deproteinization by RIA by use of an
antiserum with minimal (<0.2%) cross-reactivity with proinsulin
(Linco). Human growth hormone and glucagon were determined by RIA.
Cortisol was measured with a kit (Diagnostic Products, Los Angeles, CA)
and epinephrine with a 3H radioenzymatic assay (Amersham,
Piscataway, NJ). Plasma free fatty acid (FFA) concentration was
determined with a kit from Wako (Richmond, VA). Plasma glycerol,
lactate, alanine, glutamine, glutamate, -hydroxybutyrate (
-OHB),
and acetoacetate (AcAc) were determined enzymatically.
Statistical Analysis
All data are expressed as means ± SE. Statistical analysis was performed using the SAS program (SAS Institute, Cary, NC). ANOVA with repeated measures was used to determine the differences in GNG, GL, and EGP across time points. Pairwise comparison to each time point was then performed if overall comparison was statistically significant. Correlations between GNG and EGP or glucose were determined by least squares regression analysis. ![]() |
RESULTS |
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Effects of a 16-h Fast
Postabsorptive (16-h) plasma glucose concentrations were 10.6 ± 0.8 mM in patients with T2DM [n = 27, 14.2 ± 0.8 (range 10.2-19.3) mM and 7.2 ± 0.4 (range 4.7-9.9) mM, respectively, in patients with FPG >10 mM (n = 13) and <10 mM (n = 14)] and were 5.5 ± 0.2 (range 4.9-6.1) mM in controls (n = 7) (Fig. 1).
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GNG
Rates of GNG were higher in patients with T2DM than in controls (60.4 ± 2.4% of EGP or 6.35 ± 0.25 µmol · kg
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Postabsorptive GNG levels (at 16 h) were similar in the 7 elderly controls (this study) and in 12 younger (36 ± 3 yr) and leaner (body mass index 24.7 ± 1.3) nondiabetic subjects (51.4 ± 2.6 vs. 54.2 ± 3.2%, nonsignificant), suggesting that our normal range was representative of that in a larger nondiabetic population.
GL
Rates of GL were 39.6 ± 2.4% of EGP (3.9 ± 0.3 µmol · kgEGP
Rates of EGP were higher in the >10 mM glucose group than in the <10 mM glucose group (12.6 ± 1.2 vs. 8.6 ± 0.8 µmol · kgFPG correlated significantly but modestly with EGP (r = 0.46, P < 0.01; Fig. 2).
Glucose Clearance
Glucose clearance was used to estimate insulin sensitivity. Rates of glucose clearance were 1.12 ± 0.10, 0.90 ± 0.08, 1.33 ± 0.15, and 1.79 ± 0.10 ml · kgHormones and Substrates
All T2DM had significantly higher plasma insulin, growth hormones, cortisol, FFA, and ketone body levels than controls (Table 4). The >10 mM glucose group had significantly higher plasma insulin and ketone body levels than the <10 mM glucose group and significantly higher plasma insulin, glucagon, FFA, ketone bodies, and GNG precursor levels than the controls.
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Elevated vs. Normal GNG
To gain insight into factors responsible for the increased rates of GNG, we compared the 11 patients (8 from the >10 mM, 3 from the <10 mM group) who had GNG >65.3% (i.e., higher than the mean + 2 SD of controls) with the remaining 16 T2DM patients and with the 7 controls who had normal GNG. Compared with the 16 patients with normal GNG, the 11 patients with high GNG had significantly lower prehepatic ISR (101 ± 18 vs. 178 ± 32 pmol/min, P < 0.05) but the same glucose clearance (1.13 ± 0.12 vs. 1.14 ± 0.15 ml · kg
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DISCUSSION |
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Can GNG be Accurately Quantitated in T2DM with 2H2O?
To assess its role in the pathogenesis of elevated FPG in patients with T2DM, we measured GNG with the recently developed 2H2O method (22, 23). This method determines GNG from all precursors (including glycerol) and avoids the problems related to unknown precursor specific activity in the liver that have previously prevented quantitative determination of GNG. The method has been extensively validated in normal subjects (5, 23) and has been used in pregnant women (18) and in patients with cirrhosis of the liver (29). So far, it has not been used in diabetic patients. In this study, GNG was determined in patients with T2DM and in nondiabetic controls by use of C5/C2 and C5/H2O. C5/C2 does not require steady-state conditions, only sufficient 2H enrichment to measure C5 and C2. C5/2H2O does need complete mixing of 2H and body water. This is obtained ~1 h after the last 2H2O ingestion (23). Not surprisingly, therefore, we found that 2H enrichment in plasma water did not change between 16 and 24 h, indicating that a steady state existed at 16 h (Table 2). Confirming a previous report from our laboratory, 2H enrichment on C2 of glucose and in plasma water was the same in nondiabetic subjects (5). In diabetic patients, 2H enrichment of plasma water was slightly but not significantly higher than that on C2, resulting in GNG rates that were 3-5% higher when C5/C2 was used instead of C5/H2O (Table 2). Both methods can therefore be used to quantitate GNG in patients with T2DM. For this study, C5/C2 as well as C5/H2O was obtained for all data points, and the results were pooled.GNG in T2DM
We found that patients with T2DM, as a group, had higher rates of GNG than controls (60.4 ± 2.4 vs. 51.4 ± 2.6%, P < 0.03). In one of the two other studies in which GNG was quantitatively determined [with 13C nuclear magnetic resonance spectroscopy (NMR)], Magnusson et al. (24) reported rates of GNG of 88 ± 2% of EGP in seven patients with T2DM (FPG 14.6 ± 1.2 mM) and of 70 ± 6% in five nondiabetic controls. Although both studies agreed that GNG was elevated in T2DM, the GNG values in the Magnusson study were higher than those in our study. The differences, however, were more apparent than real when the differences in methodology are considered. Magnuson et al. determined mean rates of GL and obtained GNG by subtraction of GL from EGP. There are several reasons why this method could underestimate GL and therefore overestimate GNG. 1) The NMR spectroscopy method does not detect renal GL. This may be inconsequential in nondiabetic subjects, whose kidneys contain only trivial amounts of glycogen (2). Patients with T2DM, however, accumulate glycogen in their kidneys and are able to produce glucose by GL (2). This alone could account for much of the difference between the two studies.1 2) In the Magnusson study, liver glycogen concentrations were much lower in diabetic patients than in controls (131 vs. 282 mmol/l), possibly due to differences in prestudy food intakes. Because GL depends on glycogen levels (40), this could have been a reason for low GL and high GNG rates in the diabetic patients. 3) Magnuson et al. determined average rates of GL from changes in hepatic glycogen concentrations based on NMR measurements obtained between 4 and 22.5 h after the last meal. Therefore, to provide accurate rates of GL, the first NMR measurement needed to coincide with the peak of postmeal hepatic glycogen accumulation. If hepatic glycogen increased after the first NMR measurement (4 h after the meal), which may occur in diabetic patients who not infrequently have delayed absorption, GL would have been underestimated and GNG overestimated. 4) Liver volume (to calculate glycogen content from glycogen concentration) was determined once (14.5 h after the last meal). It was assumed that the decrease in liver volume [observed previously to be 23% over 67 h of fasting (33)] was linear over time. It appears more likely, however, that liver glycogen decreases dose dependently, i.e., at a faster rate during the early hours of the fast than later (14). Assuming a linear decrease would therefore result in underestimation of the glycogen content and GL and overestimation of GNG during the initial 15 h of fasting. In another study, Tayek and Katz (39), using mass isotopomer [U-13C]glucose analysis, reported GNG rates of 48.8 ± 5.7% of EGP in nine patients with T2DM (FPG 11.8 ± 1.3 mM) and 46.6 ± 4.0% in eight controls (P < 0.05).When we studied 27 patients with T2DM, it became apparent that there was considerable variation in their rates of GNG. For instance, GNG was elevated infrequently in patients with FPG <10 mM; in fact, only 1 of 14 (7%) had GNG exceeding the mean + 3 SD of controls, whereas 3 of 14 (21%) exceeded the mean + 2 SD. Elevated GNG was more common in patients with more severe hyperglycemia (FPG >10 mM). Here 5 of 13 (38%) exceeded the mean + 3 SD and 8 of 13 (61.5%) exceeded the mean + 2 SD of controls. This also meant, however, that GNG remained within normal limits in more than one-third (5 of 13) of even severely hyperglycemic patients (FPG 10.2-19.3 mM). One patient in this group had discontinued his Glipizide medication only 1 day before being studied. It is, therefore, possible that this patient's GNG (49.5%) might have been slightly higher had the drug been discontinued 2 days earlier. Thus, whereas there was a trend for GNG to rise with rising FPG levels, the correlation between GNG and FPG was modest (r = 0.50, P < 0.005).
GNG and Insulin
To learn why GNG was high in some diabetic patients but not in others, we compared the 11 patients with elevated GNG (> mean + 2 SD of controls) with the remaining 16 patients who had normal GNG (Fig. 3). This comparison revealed that the patients with elevated GNG had similar plasma levels of the major GNG-promoting hormones and substrates, including glucagon, epinephrine, cortisol, FFA, and GNG precursors (lactate, alanine, glutamate, glutamine, and glycerol; Table 5). In addition, they were as insulin resistant (as judged by their glucose clearance) as the patients with normal GNG. Noteworthy, however, their livers were exposed to ~40% less insulin (as judged by a ~40% reduction in prehepatic ISR). This suggested that hepatic insulin deficiency was a major cause for the increased GNG in these patients, because insulin is known to suppress GNG (34), and insulin deficiency is known to increase gene transcription of at least three of the four key GNG enzymes (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose 1,6-biphosphatase) (12).
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Insulin is also a powerful suppressor of ketone body formation
(27). Presence of insulin deficiency in these patients was further supported by the finding that their plasma -OHB levels were
higher, whereas their FFA levels (i.e., the ketone body precursors) were similar compared with those of the diabetic patients with normal GNG.
GNG and FPG
Whether EGP (or GNG) is elevated in mildly to moderately hyperglycemic patients with T2DM has remained controversial. Older studies have frequently reported greatly increased rates of EGP, which has led to the conclusion that elevated levels of FPG in T2DM were primarily the result of increased EGP (3, 4, 10, 21). More recently, however, it has become clear that in most of these studies, EGP was overestimated in proportion to the degree of the patient's hyperglycemia. The main reason for this was incomplete equilibration of the labeled and nonlabeled glucose in the expanded glucose pool. In studies in which an isotopic steady state was achieved, EGP was usually found to be elevated only in patients who had FPG ofOur results did not support the currently popular concept that EGP and GNG were primarily responsible for the fasting hyperglycemia >7.8 mM in patients with T2DM (28). Approximately 40% of patients with severe fasting hyperglycemia (10.2-19.3 mM) and all patients with FPG <10 mM had normal rates of EGP. In addition, neither EGP nor GNG correlated closely with FPG. In fact, the correlation coefficients of 0.46 and 0.50 suggested that not more than 20-25% of the hyperglycemia was due to increased EGP or GNG, respectively. On the other hand, of the eight patients in the group with high rates of GNG, six (75%) also had high rates of EGP.
Plasma glucose concentration is the result of glucose production and
utilization. Because elevated glucose production did not seem to be
predominantly responsible for the hyperglycemia, the data suggested
that the elevated FPG had to be due also to impaired glucose
disappearance, as had previously been suggested by others (6,
9). This notion was supported by a negative correlation (r
= 0.70) between FPG and glucose clearance (Fig. 2).
It needs to be pointed out, however, that the patients in the >10 mM glucose group had not only grossly elevated plasma glucose but also abnormally high serum insulin levels, both of which should have depressed EGP (31, 35). The fact that in over 50% of these patients EGP was within normal limits instead of reduced indicated that these patients had hepatic as well as peripheral insulin resistance.
In summary, our data showed 1) that the deuterated water method (either C5/C2 or C5/H2O) can be used to accurately measure GNG in patients with T2DM; 2) that GNG was infrequently (~20%) elevated in patients with FPG <10 mM but was commonly elevated (~60%) in patients with FPG >10 mM; 3) that hepatic insulin deficiency seemed to be a major reason for increased GNG; and 4) that peripheral insulin resistance together with inappropriate glucose production caused the development of fasting hyperglycemia. On the basis of these findings, we conclude that the widely held concept that FPG of >7.8 mM is mainly due to increased EGP or GNG overemphasizes the importance of EGP/GNG and underemphasizes the importance of insulin resistance.
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ACKNOWLEDGEMENTS |
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We thank the nurses of the General Clinical Research Center for help with the studies and for excellent patient care, Karen Kresge and Maria Mozzoli for outstanding technical assistance, and Constance Harris Crews for typing the manuscript.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants R01-AG-07988, R01-AA-10221 (to G. Boden), R01-AG-14098 (to T. P. Stein), and RR-349 (to the General Clinical Research Center).
1
For instance, if the kidneys contributed 25% of
total EGP, as has been reported by Meyer et al. (25), and
if 50% of this renal EGP was from GL (a reasonable assumption), then
1.39 µmol · kg1 · min
1 of
a total EGP of 11.1 µmol · kg
1 · min
1 in the
Magnusson study (24) would have been renal GL. Hepatic plus renal GL would have been 2.7 µmol · kg
1 · min
1, i.e.,
24% of EGP, and GNG would have been 76%, the same as the 75% that we
found in seven patients with comparable FPG after 24 h of fasting
(this study).
Address for correspondence: G. Boden, Temple Univ. Hospital, 3401 North Broad St., Philadelphia, PA 19140 (E-mail: bodengh{at}tuhs.temple.edu).
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. Section 1734 solely to indicate this fact.
Received 20 March 2000; accepted in final form 6 September 2000.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Beck-Nielsen, H,
Hother-Nielsen O,
Vaag A,
and
Alford F.
Pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus: the role of skeletal muscle glucose uptake and hepatic glucose production in the development of hyperglycemia. A critical comment.
Diabetologia
37:
217-221,
1994[ISI][Medline].
2.
Biava, C,
Grossman A,
and
West M.
Ultrastructural observations on renal glycogen in normal and pathologic human kidneys.
Lab Invest
15:
330-356,
1996.
3.
Bogardus, C,
Lillioja S,
Howard BV,
Reaven G,
and
Mott D.
Relationships 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[ISI][Medline].
4.
Campbell, PJ,
Mandarino LJ,
and
Gerich JE.
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[ISI][Medline].
5.
Chen, X,
Iqbal N,
and
Boden G.
The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects.
J Clin Invest
103:
365-372,
1999
6.
Chen, YDI,
Jeng CY,
Hollenbeck CB,
Wu MS,
and
Reaven G.
Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes.
J Clin Invest
82:
21-25,
1988[ISI][Medline].
7.
Consoli, A,
Nurjhan N,
Reilly JJ, Jr,
Bier DM,
and
Gerich JE.
Mechanism of increased gluconeogenesis in non-insulin-dependent diabetes mellitus: role of alterations in systemic, hepatic, and muscle lactate and alanine metabolism.
J Clin Invest
86:
2038-3045,
1990[ISI][Medline].
8.
DeFronzo, RA,
Bonadonna RC,
and
Ferranini E.
Pathogenesis of NIDDM: a balanced overview.
Diabetes Care
15:
316-368,
1992.
9.
DeFronzo, RA,
Ferrannini E,
and
Simonson DC.
Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake.
Metabolism
38:
387-395,
1989[ISI][Medline].
10.
DeFronzo, RA,
Simonson D,
and
Ferrannini E.
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[ISI][Medline].
11.
Eaton, RP,
Allen RC,
Schade DS,
Erickson KM,
and
Standefer J.
Prehepatic insulin production in man: kinetic analysis using peripheral connecting peptide behavior.
J Clin Endocrinol Metab
51:
520-528,
1980[Abstract].
12.
Hanson, RW,
and
Patel YM.
Phosphoenolpyruvate carboxykinase (GTP): the gene and the enzyme.
Adv Enzymol
69:
203,
1994[ISI][Medline].
13.
Hellerstein, MK,
Neese RA,
Linfoot P,
Christiansen M,
Turner S,
and
Letscher A.
Hepatic gluconeogenic fluxes and glycogen turnover during fasting in humans. A stable isotope study.
J Clin Invest
100:
1305-1319,
1997
14.
Hers, HG.
The control of glycogen metabolism in the liver.
Annu Rev Biochem
45:
167-189,
1976[ISI][Medline].
15.
Hother-Nielsen, O,
and
Beck-Nielsen H.
On the determination of basal glucose production rate in patients with type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-3H-glucose infusion.
Diabetologia
33:
603-610,
1990[ISI][Medline].
16.
Jahoor, F,
Peters EJ,
and
Wolfe RR.
The relationship between gluconeogenic substrate supply and glucose production in humans.
Am J Physiol Endocrinol Metab
258:
E288-E296,
1990
17.
Jeng, CY,
Sheu WHH,
Fuh MMT,
Chen YDI,
and
Reaven GM.
Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM.
Diabetes
43:
1440-1444,
1994[Abstract].
18.
Kalhan, S,
Rossi K,
Gruca L,
Burkett E,
and
O'Brien A.
Glucose turnover and gluconeogenesis in human pregnancy.
J Clin Invest
100:
1775-1781,
1997
19.
Katz, J.
Determination of gluconeogenesis in vivo with 14C-labeled substrates.
Am J Physiol Regulatory Integrative Comp Physiol
248:
R391-R399,
1985
20.
Katz, J,
and
Tayek JA.
Gluconeogenesis and the Cori cycle in 12-, 20-, and 40-h-fasted humans.
Am J Physiol Endocrinol Metab
275:
E537-E542,
1998
21.
Kolterman, OG,
Gray RS,
Griffin J,
Brunstein P,
and
Insel J.
Receptor and postreceptor defects contribute to the insulin resistance in non-insulin-dependent diabetes mellitus.
J Clin Invest
68:
957-969,
1981[ISI][Medline].
22.
Landau, BR.
Stable isotope techniques for the study of gluconeogenesis in man.
Horm Metab Res
29:
334-336,
1997[ISI][Medline].
23.
Landau, BR,
Wahren J,
Chandramouli V,
Schumann WC,
Ekberg K,
and
Kalhan SC.
Contributions of gluconeogenesis to glucose production in the fasted state.
J Clin Invest
98:
378-385,
1996
24.
Magnusson, I,
Rothman DL,
Katz LD,
Shulman RG,
and
Shulman GI.
Increased rate of gluconeogenesis in type II diabetes mellitus.
J Clin Invest
90:
1323-1327,
1992[ISI][Medline].
25.
Meyer, C,
Stumvoll M,
Nadkarni V,
Dostou J,
Mitrakou A,
and
Gerich J.
Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus.
J Clin Invest
102:
619-624,
1998
26.
Nurjhan, N,
Consoli A,
and
Gerich J.
Increased lipolysis and its consequences on gluconeogenesis in non-insulin-dependent diabetes mellitus.
J Clin Invest
89:
169-175,
1992[ISI][Medline].
27.
Owen, OE,
Trapp VE,
Reichard GA, Jr,
Mozzoli MA,
Smith R,
and
Boden G.
Effects of therapy on the nature and quantity of fuels oxidized during diabetic ketoacidosis.
Diabetes
29:
365-372,
1980[ISI][Medline].
28.
Perriello, G,
Pampanelli S,
Del Sindaco P,
Lalli C,
Ciofetta M,
Volpi E,
Santeusanio F,
Brunetti P,
and
Bolli GB.
Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM.
Diabetes
46:
1010-1016,
1997[Abstract].
29.
Petersen, KF,
Krssak M,
Navarro V,
Chandramouli V,
Hundal R,
Schumann WC,
Landau BR,
and
Shulman GI.
Contributions of net hepatic glycogenolysis and gluconeogenesis to glucose production in cirrhosis.
Am J Physiol Endocrinol Metab
276:
E529-E535,
1999
30.
Polonsky, KS,
Licinio-Paixao J,
Given BD,
Pugh W,
Rue P,
Galloway J,
Karrison T,
and
Frank B.
Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type 1 diabetic patients.
J Clin Invest
77:
98-105,
1986[ISI][Medline].
31.
Prager, R,
Wallace P,
and
Olefsky JM.
In vivo kinetics of insulin action on peripheral glucose disposal and hepatic glucose output in normal and obese subjects.
J Clin Invest
78:
472-481,
1986[ISI][Medline].
32.
Puhakainen, I,
Koivisto VA,
and
Yki-Jarvinen H.
Lipolysis and gluconeogenesis from glycerol are increased in patients with non-insulin-dependent diabetes mellitus.
J Clin Endocrinol Metab
75:
789-794,
1992[Abstract].
33.
Rothmann, DL,
Magnusson I,
Katz LD,
Shulman RG,
and
Shulman GI.
Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR.
Science
254:
573-576,
1991[ISI][Medline].
34.
Ruderman, NB,
Aoki TT,
and
Cahill GF, Jr.
Gluconeogenesis and its disorders in man.
In: Gluconeogenesis: Its Regulation in Mammalian Species, edited by Hanson RW,
and Mehlman MA. New York: Wiley, 1976, p. 515-530.
35.
Sacca, L,
Hendler R,
and
Sherwin RS.
Hyperglycemia inhibits glucose production in man independent of changes in glucoregulatory hormones.
J Clin Endocrinol Metab
47:
1160-1167,
1978[Abstract].
36.
Shimoyama, R,
Savage CR, Jr,
and
Boden G.
In vivo and in vitro effects of antiinsulin receptor antibodies.
J Clin Endocrinol Metab
59:
916-923,
1984[Abstract].
37.
Steele, R,
Wall JS,
DeBodo RC,
and
Altszuler N.
Measurement of size and turnover rate of body glucose pool by the isotope dilution method.
Am J Physiol
187:
15-24,
1956[ISI].
38.
Steele, R,
Winkler B,
and
Altszuler N.
Inhibition by infused glycerol of gluconeogenesis from other precursors.
Am J Physiol
221:
883-888,
1971[ISI][Medline].
39.
Tayek, JA,
and
Katz J.
Glucose production, recycling, and gluconeogenesis in normals and diabetics: a mass isotopomer [U-13C]glucose study.
Am J Physiol Endocrinol Metab
270:
E709-E717,
1996
40.
Wise, S,
Nielsen M,
and
Rizza R.
Effects of hepatic glycogen content on hepatic insulin action in humans: alteration in the relative contributions of glycogenolysis and gluconeogenesis to endogenous glucose production.
J Clin Endocrinol Metab
82:
1828-1833,
1997
41.
Zawadski, J,
Wolfe R,
Mott D,
Lillioja S,
Howard B,
and
Bogardus C.
Increased rate of Cori cycle in obese subjects with NIDDM and effects of weight reduction.
Diabetes
37:
154-159,
1988[Abstract].