| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Article |
Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna (H.S., M.K., E.B., M.G.B., M.R.), A-1090 Vienna, Austria; Department of Internal Medicine, University of Graz (W.J.S., T.L.), A-8036 Graz, Austria; and Institute of Systems Science and Biomedical Engineering, University of Padova (G.P.), I-35127 Padova, Italy
Address all correspondence and requests for reprints to: Michael Roden, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna Medical School, General Hospital of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: michael.roden{at}akh-wien.ac.at.
Abstract
In a family with agenesis of the dorsal pancreas only the mother presents with insulin-dependent diabetes mellitus, whereas her sons are glucose tolerant. We examined whether metabolic defects can be detected early in this disease. Plasma glucose profiles were obtained from patients with dorsal pancreas agenesis and from matched healthy subjects. Hepatic glycogen synthesis and breakdown were determined from the time course of glycogen concentrations using noninvasive 13C nuclear magnetic resonance spectroscopy. Gluconeogenesis was calculated from the difference between glucose production (measured with D-[6,6-2H2]glucose) and glycogen breakdown. Frequently sampled iv glucose tolerance tests were performed to assess insulin secretion and sensitivity. The mean plasma glucose level was higher (12.9 ± 0.4 vs. 5.9 ± 0.1 mmol/liter), whereas the peak plasma insulin level was lower (236 vs. 397 ± 23 pmol/liter) in the diabetic mother than in her nondiabetic sons and healthy subjects. In all patients, however, glycogen synthesis and breakdown were reduced by approximately 55% (P < 0.05) and 40% (P < 0.02), respectively. Gluconeogenesis (6.8 ± 0.8 vs. 4.2 ± 0.3 µmol/kg·min; P < 0.05) and hepatic insulin clearance (6.8 ± 1.3 vs. 2.8 ± 1.0 ml/kg·min) were increased in all patients.
In conclusion, patients with complete agenesis of the dorsal pancreas exhibit marked defects in hepatic glycogen metabolism, which are present even in the nondiabetic offspring.
IN HUMANS THE pancreas develops from the foregut endoderm as ventral and dorsal buds, which requires an integrated network of transcription factors such as insulin promotor factor-1 (IPF-1) (1, 2, 3, 4, 5, 6). Complete agenesis of the pancreas is not compatible with life (7). To date, only a few cases with agenesis of the dorsal pancreas have been reported in autopsy records (8) and in patients with diabetes mellitus, chronic pancreatitis, or duodenal obstruction (9, 10, 11).
More recently, familiar agenesis of the dorsal pancreas was described in a woman and both of her sons (8). The mother developed insulin-dependent diabetes mellitus at the age of 39 yr, whereas both sons still present with normal glucose tolerance. Endoscopic retrograde pancreaticography revealed complete agenesis of the dorsal pancreas in the mother and one son, i.e. absent corpus, tail, and uncinate process, and partial agenesis of the dorsal pancreas in the other son (12). Reduction of the dorsal pancreas will necessarily result in significant loss of ß-cell mass and thereby impaired insulin secretion capacity, because the majority of the islets are located in the tail (13), and ß-cells of the dorsal pancreas better respond to glucose stimulation (14, 15).
As even small changes in the sinusoidal insulin concentration can induce marked changes in hepatic glycogen metabolism (16, 17), postprandial and/or postabsorptive glucose metabolism could be abnormal in patients with agenesis of the dorsal pancreas. Thus, this study aims to examine 1) hepatic glycogen synthesis, glycogen breakdown, and gluconeogenesis after ingestion of a mixed meal during overnight fasting; and 2) indexes of insulin sensitivity, secretion, and clearance as assessed during an iv glucose load. To this end, we applied 13C nuclear magnetic resonance (NMR) spectroscopy, which offers a noninvasive approach for direct and continuous sampling of hepatic glycogen concentrations (18, 19, 20). The frequently sampled iv glucose tolerance test (FSIGT) was used to simultaneously obtain indexes of insulin sensitivity, secretion, and clearance by exploiting a mathematical model to interpret plasma concentration data (21, 22).
Subjects and Methods
Participants
Three members of one family with agenesis of the dorsal pancreas and three healthy volunteers were studied. The diabetic mother [age, 49 yr; body mass index (BMI), 22.3 kg/m2; hemoglobin A1c (HbA1c), 7.5%; low-density lipoprotein cholesterol (LDL-C), 148 mg/dl; triglycerides (TG), 151 mg/dl] requires therapy with a short-acting insulin analog (
22 IU/d), of which the last dose was administered 24 h before the NMR measurements. She had neither a history of hypoglycemic episodes for 4 wk before the study nor diabetes-related late complications. Her sons (age, 21 and 25 yr; BMI, 22.2 and 21.7 kg/m2; HbA1c, 5.5% and 5.0%; LDL-C, 118 and 107 mg/dl; TG, 166 and 196 mg/dl) are neither diabetic nor taking any medication. One female (age, 49 yr; BMI, 21.8 kg/m2; HbA1c, 5.5%; LDL-C, 146 mg/dl; TG, 135 mg/dl) and two male healthy volunteers (age, 26 and 26 yr; BMI, 24.9 and 23.1 kg/m2; HbA1c, 5.7% and 5.2%; LDL-C, 86 and 121 mg/dl; TG, 87 and 87 mg/dl) did not have a family history of diabetes, suffer from any other disease, or take any medication. No other selection criteria besides matching for age, body weight, BMI, and plasma lipids were adopted to have a reflection of the general healthy population. All participants gave informed and written consent to the protocol, which had been approved by the local ethical board according to the 1975 Declaration of Helsinki.
Experimental protocol
All participants were on a carbohydrate-rich, weight-maintaining diet and refrained from strenuous physical exercise for at least 3 d before the study. Patients arrived at the metabolic ward on the afternoon before the first study day and fasted overnight for 12 h before the beginning of the experiments. At 0745 h, a Teflon catheter was inserted into an antecubital vein for blood sampling.
Three standard mixed meals (60% carbohydrate, 20% protein, and 20% fat) were served at 0800 h (720 kcal solid), 1230 h (710 kcal solid), and 1700 h (800 kcal liquid) (23). From all participants blood was drawn every 15 min for plasma glucose measurement between 0800 and 2300 h and when appropriate during the night. Blood samples for measurements of metabolites and hormones were taken before dinner and at timed intervals thereafter. At 1900 h, participants were transferred to the MR unit, and 13C NMR spectroscopy was performed from 1930 h until the plateau was reached (2230 h) as well as from 0200 h until 0300 h and from 0630 h until 0730 h (23). At 0245 h, a second catheter was inserted into the contralateral antecubital vein, and a bolus-continuous [0.03 (mg/kg) x body weight (kg)/(min)] D-[6,6-2H2]glucose infusion (Cambridge Isotope Laboratories, Andover, MA) was performed from 0300–0600 h (19, 24). For measurement of 2H enrichments in glucose, blood samples were taken every 15 min during the last 45 min of the infusion (25).
FSIGT
At 0800 h on the following day, baseline blood samples were collected, and then glucose (300 mg/kg body weight) was infused iv within 30 sec. Regular insulin (0.03 U/kg; Actrapid, Novo-Nordisk, Denmark) was injected at 20 min. From a different vein blood samples for measuring glucose, insulin, and C-peptide were taken at 3, 4, 5, 6, 7, 10, 14, 19, 22, 27, 30, 35, 40, 50, 70, 100, 140, and 180 min as previously described in detail (26).
Plasma analyses
Plasma glucose was measured on a glucose analyzer II (Beckman, Fullerton, CA). Plasma free fatty acids (FFA; Wako Chemicals, Neuss, Germany) were quantified enzymatically. Plasma insulin (Pharmacia-Upjohn, Uppsala, Sweden), C-peptide (CIS, Gif-Sur-Yvette, France), glucagon (Serono Diagnostics, Freiburg, Germany), GH (Sorin Biomedica, Saluggia, Italy), and leptin (Linco Research, Inc., St. Charles, MO) were measured by RIA. Plasma cortisol was quantified after extraction and charcoal-dextran separation by RIA (27). Plasma norepinephrine was analyzed by reverse phase HPLC (28, 29). Measurements of serum total cholesterol, high-density lipoprotein cholesterol, LDL-C, and TG were performed by automated enzymatic assays (CHOD-Pap and GPO-Pap, Hitachi, Tokyo, Japan) in the routine laboratory.
Gas chromatography-mass spectrometry
After deproteinization and derivatization the glucose-pentaacetate was assayed for 2H enrichments on a Hewlett-Packard 5890 gas chromatograph (Hewlett-Packard Co., Palo Alto, CA) interfaced to a Hewlett-Packard 5971A mass selective detector as previously described (25, 30).
In vivo 13C NMR spectroscopy
Liver glycogen concentrations were measured on a 3-Tesla spectrometer (Medspec 30/80-DBX system, Bruker Medical, Ettlingen, Germany) as previously detailed (19, 23). Briefly, subjects were lying in the supine position in the magnet with a double-tuned 1H/13C circular coil positioned over the lateral aspect of the liver. The liver borders were determined by percussion, and the correct position of the coil was confirmed with a multi-slice gradient echo image. Magnetic field homogeneity was optimized on the water signal to a line width of 60–80 Hz. Spectra were acquired using a modified 1D-ISIS sequence without 1H decoupling (18, 19, 23). Two blocks of spectra, each consisting of 5000 scans, were added together, yielding a final time resolution of about 26 min. The glycogen concentration was calculated by integration of the C1 glycogen doublet at 100.5 ppm using the same frequency bandwidth for all spectra (±300 Hz). Absolute quantification of the hepatic glycogen concentration was obtained by comparing the peak integral with that of a glycogen standard obtained under identical conditions.
Liver volume
Liver volumes were measured in a 1.5-Tesla Vision imager (Siemens, Munich, Germany) using a body array coil and in-phase and post-phase multislice FLASH imaging sequences. Slice number and position were chosen to cover the whole organ. Liver tissue was manually segmented, and the area of each region of interest was measured in each slice. Areas were added and multiplied by the sum of slice thickness and interslice distance.
Calculations
Incremental areas under the concentration-time curves (AUC) corrected for baseline concentrations were for calculated for insulin and C-peptide after the dinner meal using the trapezoidal rule. Rates of endogenous glucose production (EGP) were calculated from the infusion rate of D-[6,6-2H2]glucose and its enrichment divided by the average percent enrichment of plasma D-[6,6-2H2]glucose less the infusion rate (31). Isotopic steady state was confirmed by repeated measurements of 2H enrichments at 15-min intervals.
Rates of net glycogen synthesis and breakdown were calculated for each individual from linear regression of the glycogen concentration-time curves between 1930 and 2230 h and from 2230–0800 h, respectively (19, 23). Individual data of body weight and liver volume were used to calculate net rates of glycogen synthesis and glycogen breakdown as well as gluconeogenesis. Rates of gluconeogenesis were calculated as the difference between EGP and the net rates of hepatic glycogen breakdown (18, 19, 23).
FSIGT data analysis
The glucose tolerance index, KG (percentage per minute), was calculated as the slope of the natural logarithm of glucose concentration vs. time during the early phase from 10–20 min, KG [10–20], and after insulin injection from 20–40 min, KG [20–40]. The integral over 180 min of C-peptide concentration (AUCCP; nanograms per milliliter in 180 min) describes total ß-cell secretion per unit volume, whereas AUCCP [0–10] (minutes per nanograms per milliliter) reflects the early ß-cell response immediately following glucose stimulation. Other parameters related to insulin secretion are the average suprabasal systemic insulin concentration, 
AIRG (microunits per milliliter) and the area under the insulin curve during the early response from 3–10 min, AUCIns [0–10] (minutes per milliunits per milliliter). The index of insulin clearance was assessed by dividing the insulin dose by the area under the suprabasal insulin concentration from 20–180 min (32). FSIGT data were submitted to the computer program MINMOD (21, 26), which calculates metabolic parameters by fitting glucose data to the minimal models of glucose disappearance as previously described (21, 26). The model accounts for the effect of insulin and glucose on glucose disappearance and provides the insulin sensitivity index, SI [minutes per (microunits per milliliter)] (22), and the index of glucose effectiveness, SG (minutes-1) (33). The product SI x AIRG gives the disposition index, which gives integrated figure of the effect of insulin sensitivity and insulin secretion in assessing the degree of whole body glucose disposal capacity (34). This index is of relevance for understanding the physiological adaptation in insulinemia to the ambient insulin sensitivity. However, this adaptation requires an adaptive alteration in insulin secretion, which is executed at the level of the ß-cell. This process is quantified by the so-called ß-cell adaptation index (35), obtained by multiplying SI by AUCCP [0–10]; the adaptation index includes the ß-cell sensitivity to glucose obtained by C-peptide data.
All data are presented as the mean ± SEM. Statistical comparisons between the different groups and within the time courses of the experiments were performed using unpaired and paired t tests, respectively. Statistical significance was considered at P < 0.05. All calculations were made using the SigmaStat software package (Jandel Corp., San Rafael, CA).
Results
Plasma glucose profiles (Fig. 1
)
In the diabetic mother, E.H., plasma glucose concentrations ranged from 10.1–18.6 mmol/liter (57 measurements), with a mean of 12.9 ± 0.4 mmol/liter over 24 h, which was markedly higher than that of her sons (6.1 ± 0.1 mmol/liter; P < 0.0001) and that of healthy subjects (5.6 ± 0.1 mmol/liter; P < 0.0001). Both sons had normal fasting (5.5 mmol/liter) and postprandial peak (8.0 mmol/liter) plasma glucose concentrations, which decreased rapidly to approximately 5.2 mmol/liter in B.H., but more slowly to about 7.5 mmol/liter in C.H. within 1 h.
|
)
Plasma insulin and C-peptide concentrations were not different between patients with agenesis of the dorsal pancreas and healthy subjects before dinner. Postprandial peak plasma insulin was 236 pmol/liter in the diabetic mother, but levels were 404 ± 16 and 369 ± 26 pmol/liter in her sons and in controls, respectively. Likewise, postprandial peak plasma C-peptide was 1059 pmol/liter in the diabetic mother, but levels were 2714 ± 264 and 1854 ± 119 pmol/liter in her sons and in controls, respectively. Thereafter, plasma insulin and C-peptide were similar in all participants. The AUCs of insulin and C-peptide were not different between patients and healthy subjects (Table 1).
|
Plasma glucagon concentrations were similar (23 pmol/liter) in all participants before meal ingestion, increased by 35% (P < 0.05), and returned to baseline values within 3 h without any difference between patients and healthy subjects. Plasma concentrations of FFA (0.25 mmol/liter), cortisol (210 nmol/liter), GH (3.1 µg/liter), norepinephrine (1.35 nmol/liter), and leptin (0.37 pmol/liter) were similar in patients and healthy subjects throughout the study.
Hepatic glycogen metabolism
Maximum liver glycogen concentrations were reached at 5.5 h after dinner in both groups (P < 0.005 vs. measurements at 3 h) and were markedly lower (P < 0.0001) in patients than in healthy subjects (Fig. 2A). Glycogen concentrations were higher in one of the patients (C.H.), who also had higher peak plasma C-peptide concentrations during meal ingestion (Fig. 1C) and less reduction in pancreas mass (12). Thereafter, hepatic glycogen concentrations decreased (P < 0.005) linearly (r2 = 0.94; P < 0.0001) until about 0700 h.
|
). Rates of net glycogen breakdown from 2230–0700 h were about 40% lower (P < 0.02) in the patients (107 ± 7 µmol/liter·min; 2.6 ± 0.1 µmol/kg·min) vs. healthy subjects (184 ± 19 µmol/liter·min; 4.2 ± 0.7 µmol/kg·min). EGP and rates of net gluconeogenesis
EGP was slightly higher (P < 0.001) in the patients (9.4 ± 0.3 µmol/kg·min) vs. the healthy subjects (8.4 ± 0.2 µmol/kg·min; Fig. 2C). Using the individual data of body weight and liver volume (patients, 1.70 ± 0.03 liters; healthy subjects, 1.65 ± 0.14 liters) made it possible to calculate net rates of gluconeogenesis. Gluconeogenesis was also higher (P < 0.05) in the patients (6.8 ± 0.8 µmol/kg·min) vs. the healthy subjects (4.2 ± 0.3 µmol/kg·min) and contributed to EGP by 72 ± 2% vs. 51 ± 6%.
Insulin sensitivity and secretion
Individual FSIGT data of the patients and pooled data of healthy subjects are shown in Fig. 3. The glucose time course changed markedly after insulin injection, as shown by a KG [20–40] that was much greater than the KG [10–20] (Table 1). Glucose tolerance was nonetheless impaired in the diabetic mother in the presence of elevated concentrations of exogenous insulin. In this subject the reduced glucose disappearance rate was due to a combination of impaired index of insulin sensitivity (SI) and early phase insulin response (AUCIns [0–10]), as also indicated by the lowest disposition and adaptation indexes. Endogenous insulin levels in general were lower in the patients than in control subjects, as reflected by AIRG and AUCIns [0–10] (Table 1). This was not due to reduced ß-cell secretion, because AUCCP [0–10] was not different between groups, but was due to an approximately 2.5-fold increased index of insulin clearance (P < 0.02) in the patients, particularly in the diabetic mother. The similar total ß-cell secretion is also reflected by comparable AUCCP [0–180] values. Finally, indexes of insulin sensitivity and secretion were not different between the two sons and the healthy subjects.
|
This study demonstrates marked defects in liver glycogen metabolism in a family with agenesis of the dorsal pancreas. Interestingly, these defects occurred in the diabetic mother and both of her sons independently of their glucose tolerance state.
Until now, few cases of agenesis of the dorsal pancreas have been reported. Most reports describe single, but not familiar, patients who were diagnosed because of jaundice (36), pancreatitis (11), weight loss, and diabetes mellitus (10). Partial agenesis of the dorsal pancreas like that in the older son has been reported (37), but was not familiar.
The present study of one family with pancreas agenesis is limited by the number of patients, but offers the opportunity to examine a morphological homogenous form of the disease. Interestingly, despite different metabolic states all three afflicted patients exhibited identical defects in hepatic glycogen metabolism. Furthermore, although the younger of the brothers has complete and the other only partial agenesis of the dorsal pancreas (12), both presented with comparable reduction in liver glycogen synthesis and the parameter of the first phase of insulin secretion as derived from the FSIGT. Marked defects in net hepatic glycogen synthesis after a mixed meal in type 1 diabetic patients (38) and increased gluconeogenesis in type 2 diabetic patients have been demonstrated by both splanchnic balance (39) and 13C NMR spectroscopic techniques (40). Recently, we reported that net hepatic glycogen breakdown is also reduced in type 1 diabetic patients (23). The patients of the present study exhibited a comparable degree of impaired glycogen synthesis and glycogenolysis compared with diabetic patients of previous studies. Despite the small number of patients the magnitude of a 40–60% decrease was sufficient to detect significant differences compared with age- and BMI-matched subjects. These defects might contribute to the development of glucose intolerance and ultimately lead to a diabetic metabolic state in such patients.
Whereas the metabolic defects were not surprising in the diabetic mother, we can only speculate about the potential reasons for the similar reduction in glycogen synthesis and breakdown and the increase in gluconeogenesis in her glucose-tolerant sons. It is of note that these latter alterations resulted in a small (10%), but significant, rise in EGP to a degree that can be found in overt type 2 diabetes (40, 41, 42). The observed defects could result from 1) peripheral insulin resistance, 2) isolated hepatic defects, and/or 3) altered pancreatic ß-cell activity.
Defects in peripheral glucose disposal or insulin sensitivity are unlikely to have caused the alterations in hepatic glucose metabolism, because both sons had normal insulin sensitivity, as indicated by normal SI. Actually, their SI values are in the higher range of those in control subjects, as they had to compensate for the relatively lower insulinemia (see their AIRG) with respect again to controls, resulting in normal disposition and adaptation indexes. Also, all other parameters related to glucose disappearance (both KG values and glucose effectiveness, SG) were within the normal range.
Mutations of the homeobox gene HLXB9 (3, 4) and defects of the transcription factor IPF-1 (IDX-1) (43) were identified to cause pancreas agenesis and were linked to the development of maturity-onset diabetes of the young, MODY (44). In one family, a frameshift mutation in the IPF-1 gene was shown to cause pancreas agenesis when homozygous (1) and to cause MODY 4 when heterozygous (2). A number of different mutations in the IPF-1 gene were identified and may predispose for type 2 diabetes, MODY, and pancreas agenesis, with the phenotype depending on the severity of the mutation (45, 46). Thus, DNA of the mother and her sons were screened (Dr. Martine Vaxillaire, Laboratory Dr. Froguel, Department of Human Genetics of Biology, Lille, France), but no mutations, particularly of HNFIb, p48-PTF, HlXb9, or LRH1 genes, were detected.
Interestingly, the index of insulin clearance was markedly increased in the patients, particularly in the diabetic mother, compared with the healthy subjects. It is conceivable that elevated insulin degradation could have resulted from increased turnover of insulin receptors, which, in turn, will reduce the ability of insulin to stimulate postprandial hepatic glycogen synthesis, because insulin primarily stimulates flux through hepatic glycogen synthase (17, 47). However, after ingestion of the dinner, the AUCs of insulin and C-peptide were not different between patients and healthy subjects, indicating that the role of differences in insulin clearance observed during the FSIGT may be small. Nevertheless, we cannot exclude that the sinusoidal glucagon/insulin ratio was higher in patients than controls after ingestion of the mixed meal, which would favor glycogen cycling, i.e. simultaneous glycogen synthesis and breakdown (16). Postprandial glycogen cycling (17, 42) could therefore be increased during the postprandial state and contribute to the differences between patients and healthy subjects. In contrast, in the postabsorptive period, i.e. overnight fasting, glycogen cycling is negligible (48) and cannot explain the observed reduction in hepatic glycogen breakdown in our patients. This is due to the lower level of glycogen synthesized, because individual net glycogenolytic rates correlate with the initial hepatic glycogen concentration in healthy (25) and type 1 diabetic subjects (23). In addition, differences in intestinal and splanchnic glucose uptake cannot be excluded.
The FSIGT does not directly assess hepatic insulin extraction, because the exogenous insulin injection does not allow the use of reliable models for estimating the differences between insulin and C-peptide under dynamic conditions (49). Nonetheless, C-peptide can be reliably used as a quantitative estimate of ß-cell secretion, because clearance of C-peptide does not differ between nondiabetic subjects and patients with impaired glucose tolerance or type 2 diabetes (50). Therefore, even in our group, the changes in parameters of C-peptide concentration can be ascribed only to ß-cell secretion. The parameter AUCCP [0–10] describes the early ß-cell response to glucose stimulation, whereas AUCCP [0–180] reflects the overall ß-cell secretion, although this may be modulated not only by the glucose stimulus, but also by the hyperinsulinemia after exogenous insulin administration.
As the majority of the islets located in the tail (13) and ß-cells of the dorsal pancreas respond better to glucose stimulation (14, 15), agenesis of the dorsal pancreas can be expected to particularly influence glucose metabolism and glucose-stimulated insulin secretion. The diabetic mother exhibited an impaired index of first phase insulin secretion, a defect less pronounced in her sons, that can obviously be related to reduced ß-cell mass. However, parameters of overall insulin secretion were not different between patients and healthy subjects, suggesting that the islets are able to produce normal amounts of insulin when adequately stimulated despite impaired rapid insulin release. This defect may contribute to, but does not completely explain, prolonged reduction in postprandial glycogen synthesis and postabsorptive glycogen breakdown in this family.
In conclusion, patients with complete agenesis of the dorsal pancreas exhibit marked defects in hepatic glycogen metabolism along with increased index of insulin clearance, which are present even in the nondiabetic offspring. These defects cannot be simply explained by impaired ß-cell function, but point to additional defects in liver and/or splanchnic glucose uptake.
Acknowledgments
Thanks are due to the staff of the Metabolic Unit (A. Hofer and O. H. Lentner) and the Endocrine Laboratory (P. Nowotny) and to Prof. E. Moser, Institute of Medical Physics, University of Vienna, for excellent cooperation.
Footnotes
This work was supported by the Austrian Science Foundation (13722-MED to M.R.) and the Austrian National Bank (ONB 9127 to H.S. and M.R.).
Abbreviations: AIRG, Average suprabasal systemic insulin concentration; AUC, area under the concentration-time curve; BMI, body mass index; EGP, endogenous glucose production; FFA, free fatty acids; FSIGT, frequently sampled iv glucose tolerance test; HbA1c, hemoglobin A1c; IPF, insulin promotor factor-1; LDL-C, low-density lipoprotein cholesterol; MODY, maturity-onset diabetes of the young; NMR, nuclear magnetic resonance; TG, triglycerides.
Received January 14, 2002.
Accepted July 12, 2002.
References
- and 18-hydroxylase deficiency associated with complete male pseudohermaphroditism and hypoaldosteronism. J Clin Endocrinol Metab 46:236–246This article has been cited by other articles:
 |
|
 |
|
  O. Kunert, H. Stingl, E. Rosian, M. Krssak, E. Bernroider, W. Seebacher, K. Zangger, P. Staehr, V. Chandramouli, B.R. Landau, et al. Measurement of Fractional Whole-Body Gluconeogenesis in Humans From Blood Samples Using 2H Nuclear Magnetic Resonance Spectroscopy Diabetes, October 1, 2003; 52(10): 2475 - 2482. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
; mean ± SEM; n = 3) after ingestion of a liquid dinner (800 kcal, 60% carbohydrate) at 1700 h. The data from patients are given as individual data of the mother (
) and her sons (
and 
).
, P < 0.05 vs. basal.