Impaired {beta}-cell compensation to dexamethasone-induced hyperglycemia in women with polycystic ovary syndrome

David A. Ehrmann,1 Elena Breda,2 Matthew C. Corcoran,1 Melissa K. Cavaghan,1 Jacqueline Imperial,1 Gianna Toffolo,2 Claudio Cobelli,2 and Kenneth S. Polonsky3

1Department of Medicine, University of Chicago, Chicago, Illinois 60637; 2Department of Electronics and Informatics, University of Padua, Padua, 35131 Italy; and 3Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Submitted 22 October 2003 ; accepted in final form 1 December 2003


    ABSTRACT
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
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Deterioration in glucose tolerance occurs rapidly in women with polycystic ovary syndrone (PCOS), suggesting that pancreatic {beta}-cell dysfunction may supervene early. To determine whether the compensatory insulin secretory response to an increase in insulin resistance induced by the glucocorticoid dexamethasone differs in women with PCOS and control subjects, we studied 10 PCOS and 6 control subjects with normal glucose tolerance. An oral glucose tolerance test (OGTT) and a graded glucose infusion protocol were performed at baseline and after subjects took 2.0 mg of dexamethasone orally. Basal ({Phi}b), static ({Phi}s), dynamic ({Phi}d), and global ({Phi}) indexes of {beta}-cell sensitivity to glucose were derived. Insulin sensitivity (Si) was calculated using the minimal model; a disposition index (DI) was calculated as the product of Si and {Phi}. PCOS and control subjects had nearly identical fasting and 2-h glucose levels at baseline. {Phi}b was higher, although not significantly so, in the PCOS subjects. The {Phi}d, {Phi}s, and {Phi} indexes were 28, 19, and 20% higher, respectively, in PCOS subjects. The DI was significantly lower in PCOS (30.01 ± 5.33 vs. 59.24 ± 7.59) at baseline. After dexamethasone, control subjects averaged a 9% increase (to 131 ± 12 mg/dl) in 2-h glucose levels; women with PCOS had a significantly greater 26% increase to 155 ± 6 mg/dl. The C-peptide-to-glucose ratios on OGTT increased by 44% in control subjects and by only 15% in PCOS subjects. The accelerated deterioration in glucose tolerance in PCOS may result, in part, from a relative attenuation in the response of the {beta}-cell to the demand placed on it by factors exacerbating insulin resistance.

insulin resistance; insulin secretion; type 2 diabetes


POLYCYSTIC OVARY SYNDROME (PCOS) affects 5–8% of reproductive-age women (17) and is associated with a substantial risk for the development of impaired glucose tolerance (IGT) and type 2 diabetes (8, 18). Insulin resistance plays a well-recognized role in the pathogenesis of glucose intolerance in this population (6, 11); more recently, alterations in insulin secretion have been shown to contribute to the development of glucose intolerance in PCOS subjects (11).

The fact that the majority of women with PCOS have normal glucose tolerance at the time of clinical presentation (1) has been taken as evidence that their ability to adequately secrete insulin in compensation for the degree of insulin resistance is retained. However, rates of decline in glucose tolerance in PCOS are high (8, 21) and exceed those recently reported from the Nurses' Health Study (15). This suggests that pancreatic {beta}-cell dysfunction may supervene earlier in the evolution of glucose intolerance in women with PCOS compared with women without PCOS. The basis for this, however, remains unclear.

It has been hypothesized (5, 22) that, in some individuals with normal glucose tolerance, subtle alterations in {beta}-cell function may be present but undetectable by standard provocative stimuli. The present study was undertaken to determine whether the compensatory insulin secretory response to an increase in insulin resistance induced by a low dose of the glucocorticoid dexamethasone differs in women with PCOS and control subjects and whether dexamethasone unmasks latent defects in insulin secretion in the women with PCOS (26). To accomplish this, we utilized a novel protocol to simultaneously quantify insulin secretion and insulin action over a broad range of plasma glucose concentrations (9).


    SUBJECTS AND METHODS
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects

PCOS. PCOS subjects were recruited from the Endocrinology Clinics of the University of Chicago. All were ≥2 yr postmenarche and not >40 yr of age. A diagnosis of PCOS required the presence of criteria previously defined (10): 1) oligo/amenorrhea; 2) hyperandrogenemia, with a plasma free testosterone level ≥34.7 pmol/l; 3) hyperandrogenism, as evidenced by infertility, hirsutism, acne, or androgenetic alopecia; and 4) exclusion of nonclassic 21-hydroxylase deficiency congenital adrenal hyperplasia, Cushing's syndrome, hypothyroidism, or significant elevations in serum prolactin. In addition to meeting these diagnostic criteria for PCOS, often referred to as the "NIH consensus criteria" (27), each subject had hormonal evidence of ovarian androgen overproduction, documented by an abnormal 17-hydroxyprogesterone response to gonadotropin-releasing hormone agonist administration or a supranormal plasma free testosterone level after administration of dexamethasone (10). For ≥2 mo before study, subjects had not taken steroid preparations (including oral contraceptives) or medications known to alter insulin secretion and/or action.

Control subjects. Control subjects had normal menstrual cyclicity, normal oral glucose tolerance, and no evidence of hirsutism, acne, or elevation in androgen levels. Control subjects were matched as closely as possible to the subjects with PCOS for age, body mass index (BMI), and race. The PCOS group of women comprised six Caucasians, three African-Americans, and one Hispanic; among control subjects there were three Caucasians, two African-Americans, and one Hispanic.

None of the controls had a first-degree relative with type 2 diabetes. No subjects had taken steroid preparations (including oral contraceptives) or medications known to alter insulin secretion and/or action for ≥2 mo before study. Women with significant systemic illness, including renal, cardiac, hepatic, or malignant disease, were excluded from study.

The Institutional Review Board of the University of Chicago approved all studies, and written informed consent was obtained from each subject.

Experimental Protocols

The experimental protocol is schematized in Fig. 1. Briefly, each subject had a standard oral glucose tolerance test (OGTT) at baseline. Subjects who had either IGT or diabetes were excluded from further study. Those with normal glucose tolerance had a graded glucose infusion (GGI) procedure 2–3 days after the OGTT. One and two weeks later, respectively, the OGTT and GGI were repeated after oral administration of dexamethasone, 1 mg at 11 PM on the night before study and 1 mg at 8 AM on the morning of study.



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Fig. 1. Schematic of study protocol. Circled numbers refer to study day number. OGTT, oral glucose tolerance test; GGI, graded glucose infusion; IGT, impaired glucose tolerance. OGTT and GGI protocols were performed at baseline and again after oral administration of dexamethasone, 1 mg at 11 PM the night before study and 1 mg at 8 AM on the morning of study.

 
All tests were performed after an overnight fast. Intravenous catheters were placed into antecubital veins. Where appropriate, one catheter was used for administration of intravenous glucose, while the catheter in the contralateral forearm was used for blood sampling. The blood sampling arm was heated to obtain arterialized venous samples.

OGTT. Blood samples were obtained at baseline and at 30-min intervals for 3 h for measurement of glucose and insulin after ingestion of a 75-g glucose load. Glucose tolerance was evaluated using the criteria of the American Diabetes Association (23).

GGI. Details of this protocol have been previously described (9). Briefly, after normal saline was infused for 30 min, a glucose infusion was started beginning at a rate of 1 mg·kg–1·min–1. To achieve a progressive increase ("step-up") in the plasma glucose concentration, every 5 min the glucose infusion rate was increased by 1 mg·kg–1·min–1 to a maximum of 16 mg·kg–1·min–1. To achieve a progressive decrease ("step-down") in plasma glucose, the infusion rates were subsequently reduced in a parallel manner from 16 mg·kg–1·min–1 down to infusion of normal saline. Blood was sampled throughout the study at the end of each 5-min interval, just before the subsequent dose change, for measurement of glucose, insulin, and C-peptide levels.

Modeling Analysis

Indexes. Indexes of insulin secretion during the GGI were calculated as previously described by using the minimal model of C-peptide secretion and kinetics (25). Briefly, a two-compartment model is assumed for C-peptide kinetics, whereas pancreatic secretion is described as the sum of three components, which are related, respectively, to the basal state, controlled by basal glucose concentration, to the production of new insulin, controlled by glucose above basal (static control), and to the release of stored insulin, controlled by the rate of glucose increase (dynamic control). From model parameters, three indexes were defined to quantify pancreatic sensitivity to glucose during the three phases, namely basal ({Phi}b), static ({Phi}s), and dynamic ({Phi}d). Finally, a global index of pancreatic sensitivity to glucose was calculated ({Phi}), representing the average increase above basal of pancreatic secretion over the average glucose stimulus, as indicated in Ref. 4. The minimal model of glucose disposal (3) was applied to glucose and insulin concentrations, and an estimate of insulin sensitivity (Si; 10–5 min–1·pmol–1·l–1) was derived for each subject. To adjust insulin secretion for the degree of insulin sensitivity, a disposition index (DI) was calculated as the product of Si and {Phi}. This parameter is analogous to the DI defined for the IVGTT (frequently sampled intravenous glucose tolerance test) protocol as the product of Si and a measure of {beta}-cell function, either the acute insulin response to glucose (16) or model-derived pancreatic sensitivities (3). Individuals who are able to maintain normal glucose tolerance in response to a decrease in Si demonstrate a constant DI (16).

Model identification. C-peptide kinetic parameters were fixed to standard values by the method proposed in Ref. 25. Secretory parameters were estimated, together with a measure of their precision, by using SAAM II software (2). By use of the same software, parameters of the minimal model of glucose disposal were estimated. Measurement errors were assumed to be independent, Gaussian, with zero mean. Errors in C-peptide measurements were assumed with a constant but unknown variance; errors in glucose measurements were assumed with a fractional standard deviation equal to 1.5%.

Statistical Analysis

The significance of differences between groups was determined by the nonparametric Mann-Whitney U-test and the Wilcoxon test. For all analyses, a two-tailed P value of <0.05 was considered to indicate statistical significance. All results are expressed as means ± SE. Statistical analysis was performed using StatView 5.0 (SAS Institute, Cary, NC).

Assay Methods

Plasma glucose was measured immediately using a glucose analyzer (YSI Model 2300 STAT, Yellow Springs Instruments, Yellow Springs, OH). The coefficient of variation (CV) of this method is <2%. Glycosylated hemoglobin was measured by boronate affinity chromatography with an intra-assay CV of 4% (Bio-Rad, Hercules, CA). Serum insulin was assayed by a double-antibody technique (20), with a lower limit of sensitivity of 20 pmol/l and an average intra-assay CV of 6%. The cross-reactivity of proinsulin in the radioimmunoassay for insulin is ~40%. Plasma C-peptide was measured as previously described (12). The lower limit of sensitivity of the assay is 0.02 pmol/ml, and the intra-assay CV averaged 6%.


    RESULTS
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 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
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Baseline Clinical and Metabolic Characteristics of Study Subjects

The clinical and metabolic characteristics of PCOS and control groups were similar at baseline (Table 1). Compared with control subjects, the mean body weight (109.9 ± 7.8 vs. 92.4 ± 4.6 kg) and mean BMI (39.3 ± 3.0 vs. 33.7 ± 1.2 kg/m2) tended to be higher in the PCOS subjects, but these differences were not statistically significant. The two groups were similar in age (27.9 ± 1.7 vs. 28.2 ± 3.4 yr) and had similar glycohemoglobin levels (5.0 ± 0.1 vs. 4.9 ± 0.1%). The two groups did not differ with respect to racial and ethnic composition.


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Table 1. Clinical characteristics and results of OGTT and GGI protocols in study subjects

 
Four of the ten PCOS subjects had a first-degree relative (parent) with type 2 diabetes, consistent with the expectedly high prevalence of type 2 diabetes in PCOS families (8, 24). These four subjects were indistinguishable from the six PCOS subjects without a family history of diabetes in all measures, including demographic, OGTT, and GGI results at baseline and in response to dexamethasone. The data from the 10 PCOS subjects were therefore pooled for comparison with control subjects.

OGTT. PCOS and control subjects had nearly identical fasting (95 ± 2 vs. 94 ± 2 mg/dl) and 2-h (124 ± 5 vs. 120 ± 7 mg/dl) glucose levels at baseline (Fig. 2; Table 1). Likewise, the area under the glucose response curve was similar between the groups (23,319 ± 414 vs. 21,860 ± 631 mg·min–1·dl). In contrast, insulin and C-peptide levels tended to be higher in PCOS than in control subjects. The fasting insulin and C-peptide levels in PCOS subjects were approximately twice those of control subjects (170 ± 3 vs. 85 ± 12 pmol/l and 0.94 ± 0.14 vs. 0.54 ± 0.04 pM, respectively; Fig. 2). These differences approached, but did not reach, statistical significance.



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Fig. 2. Glucose (A) and insulin (B) concentrations obtained during a 75-g OGTT in polycystic ovary syndrome (PCOS) subjects at baseline ({circ}) and after dexamethasone ({bullet}), and in control subjects at baseline ({triangleup}) and after dexamethasone ({blacktriangleup}). Glucose levels (fasting, 2 h, and area under the curve) did not differ significantly between PCOS and control subjects at baseline. After administration of 2 mg of dexamethasone, both fasting and 2-h glucose levels increased significantly in both PCOS and control subjects, but the difference between the groups was significant only at 2 h. Insulin levels in PCOS subjects were approximately twice those of control subjects at baseline; after dexamethasone, insulin levels increased in both groups. Although the PCOS subjects had a significant rise from baseline in absolute terms, it is important to note that there was only a 42% rise in insulin levels relative to baseline in PCOS, whereas control subjects had a 61% increase in this measure. See text and Table 1 for details.

 
The areas under the curve (AUC) during the OGTT for both insulin (169,370 ± 31,583 vs. 77,210 ± 8,670 pM·min; P < 0.05) and C-peptide (439 ± 3 vs. 317 ± 7 pM·min; P < 0.05) were, however, significantly higher in PCOS than in control subjects. These findings are in accord with previous studies in which PCOS subjects demonstrate disproportionate elevations in insulin levels for the degree of obesity compared with control subjects (7, 11).

GGI. Glucose and C-peptide profiles obtained during the GGI studies are depicted in Fig. 3. Women with PCOS were more insulin resistant than control subjects at baseline (Si 2.06 ± 0.59 vs. 3.65 ± 0.51 10–5 min–1/pM), although the difference in Si between PCOS and control subjects just fails to reach significance (P = 0.083). This difference was not significant even after adjustment for body weight or BMI.



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Fig. 3. Glucose (A) and C-peptide (B) levels obtained in PCOS and control subjects at baseline and postdexamethasone during the GGI protocol. The magnitude of the rise in glucose after dexamethasone was similar between PCOS and control subjects; in contrast, the incremental rise in C-peptide after dexamethasone was greater in control than in PCOS subjects. These results parallel those observed during the OGTT. PCOS subjects at baseline ({circ}) and after dexamethasone ({bullet}); control subjects at baseline ({triangleup}) and after dexamethasone ({blacktriangleup}).

 
Indexes of pancreatic sensitivity to glucose in the basal state ({Phi}b) were higher, although not significantly so, in the PCOS compared with control subjects (8.96 ± 1.41 vs. 5.69 ± 0.67 10–9 min–1). The differences between PCOS and control subjects in dynamic ({Phi}d), static ({Phi}s), and total ({Phi}) indexes were less pronounced, being 28, 19, and 20% higher, respectively, in PCOS subjects. The product of the total pancreatic index {Phi} and Si, i.e., the so-called DI, was significantly lower in PCOS compared with control subjects (30.01 ± 5.33 vs. 59.24 ± 7.59) at baseline.

Postdexamethasone Responses

OGTT. After oral administration of 2 mg of dexamethasone, fasting glucose levels increased significantly in both PCOS and control subjects. Control subjects increased their fasting glucose level from 94 ± 2 to 105 ± 4 mg/dl (P < 0.05); those with PCOS went from a fasting glucose of 95 ± 2 to 105 ± 3 mg/dl after dexamethasone (P < 0.05). The postdexamethasone fasting glucose levels did not, however, differ between PCOS and control subjects (105 ± 3 vs. 105 ± 4 mg/dl).

In contrast to the average 9% increase in 2-h glucose levels after dexamethasone observed in control subjects (from 120 ± 7 to 131 ± 12 mg/dl), women with PCOS had a 26% increase (from 124 ± 5 to 155 ± 6 mg/dl), and the increase was significant only for the PCOS group. Analysis of glucose response AUC revealed a similar and significant incremental increase in both PCOS (19%) and control subjects (12%). Whereas the postdexamethasone glucose AUC was higher in PCOS compared with control subjects, this difference did not achieve statistical significance (27,601 ± 1,091 vs. 24,576 ± 1,550 mg·min–1·dl).

Insulin levels increased after dexamethasone in both groups, but only the PCOS subjects had a significant rise from baseline insulin AUC. It is important to note, however, that when expressed in relation to baseline insulin AUC, PCOS subjects had an average 42% rise, whereas control subjects had a 61% increase in this measure. This finding is paralleled by the results for the C-peptide AUC. Specifically, control subjects had a significant (44%) increase in the C-peptide AUC, whereas PCOS subjects had a 15% rise for this measure.

When expressed in relation to the prevailing glucose concentration, those with PCOS were less able to mount a sufficient insulin secretory response. This is depicted in Fig. 4 as the ratio of C-peptide to glucose during the OGTT. This difference in response between control and PCOS subjects was also observed when the post- and predexamethasone ratios of AUC C-peptide to AUC glucose were compared. Control subjects showed an average increase of 44% in this ratio after dexamethasone, compared with a 15% increase in this measure among PCOS subjects.



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Fig. 4. C-peptide-to-glucose ratios obtained during the OGTT. When expressed in relation to the prevailing glucose concentration, those subjects with PCOS were less able than control subjects to mount a sufficient {beta}-cell secretory response to an oral glucose load after dexamethasone administration. The increment in the ratio of C-peptide to glucose is significantly lower in PCOS than in control subjects. PCOS subjects at baseline ({circ}) and postdexamethasone ({bullet}); control subjects at baseline ({triangleup}) and postdexamethasone ({blacktriangleup}).

 
GGI. Results from the GGI (Fig. 3) were generally concordant with those obtained from the OGTT. There was a significant (~50%) decline in Si in both control and PCOS subjects (from 3.65 ± 0.51 to 1.76 ± 0.19 and from 2.06 ± 0.59 to 1.10 ± 0.29 10–5 min–1/pM, respectively) after dexamethasone treatment. In addition, the postdexamethasone Si was significantly lower in PCOS than in control subjects (1.10 ± 0.29 vs. 1.76 ± 0.19; P < 0.05).

Indexes of pancreatic sensitivity to glucose in the basal state did not change significantly during the GGI in either group of subjects in response to dexamethasone. The dynamic index decreased significantly, whereas the static index increased significantly after dexamethasone in control but not in PCOS subjects. The total index, which quantifies insulin secretion per unit of glucose stimulus, showed a modest increase in control (19.11 ± 2.26 vs. 16.81 ± 1.59 10–9 min–1) but not in PCOS (19.89 ± 2.76 vs. 20.09 ± 2.45 10–9 min–1) subjects after dexamethasone.

Finally, when pancreatic function was adjusted for the degree of Si, it was evident that dexamethasone impaired glucose tolerance, because the DI was significantly lower after treatment in both control (32.86 ± 3.83 vs. 59.24 ± 7.59) and PCOS (16.45 ± 2.61 vs. 30.01 ± 5.33) subjects. Moreover, PCOS subjects evidenced a significantly lower DI compared with control subjects, not only in the baseline state but also after dexamethasone administration.


    DISCUSSION
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
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Women with PCOS have an exceptionally high rate of development of impaired glucose tolerance and type 2 diabetes (8, 18), and the decline in oral glucose tolerance seems to be accelerated in this population (8, 21). Although nearly one-half of women with PCOS will ultimately develop glucose intolerance, most are able to maintain glucose levels within the normal range (8, 18). The ability to predict who among those predisposed to type 2 diabetes will evidence this deterioration in glucose tolerance has been difficult.

We hypothesized that women with PCOS and normal glucose tolerance would be less able than control subjects to maintain normoglycemia in response to augmentation of insulin resistance induced by low doses of dexamethasone. The present study design allowed us to assess insulin secretion relative to the ambient level of insulin resistance at baseline and in response to a low dose of dexamethasone. The dose of dexamethasone utilized was one that is known to exacerbate insulin resistance without directly impacting upon insulin secretion (19).

In the baseline state (i.e., before the administration of dexamethasone), we found that control women and women with PCOS and normal fasting glucose concentrations (94 ± 2 vs. 95 ± 2 mg/dl) had similar glucose levels at 2 h in response to a standard 75-g oral glucose load (120 ± 7 vs. 124 ± 5 mg/dl). In this cohort of women with PCOS, the ability to compensate with sufficient insulin in response to an oral glucose challenge to keep glucose levels at 2 h within the range of normal was thus maintained (Table 1 and Fig. 5). Likewise, when faced with a reduction in Si induced by the administration of dexamethasone, women with PCOS were significantly less able than control subjects to compensate with adequate insulin secretion. This was evidenced by a relative attenuation in C-peptide levels relative to plasma glucose during the OGTT (Fig. 2) in addition to a significantly lower DI during the GGI study (Table 1 and Fig. 5). It is important to note that the relative impairment in insulin secretion in women with PCOS could result, at least in part, from inhibition of insulin secretion that is secondary to the higher glucose levels attained in women with PCOS postdexamethasone (so-called "glucose toxicity"). The present study design does not permit definitive exclusion of this possibility, although it would appear to be unlikely, since the glucose levels attained in women with PCOS were not in the range generally associated with glucose toxicity.



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Fig. 5. Disposition index (DI), derived as the product of {Phi} and insulin sensitivity (Si) obtained from the GGI protocol in PCOS and control subjects, at baseline (gray bars) and after administration of dexamethasone (black bars). P < 0.05: *baseline PCOS vs. baseline control subjects; **postdexamethasone PCOS vs. control subjects; #baseline vs. postdexamethasone PCOS; ##baseline vs. postdexamethasone control subjects.

 
In the aggregate, these data indicate that administration of dexamethasone leads to a rise in plasma glucose levels in both control and PCOS women. However, it appears that, in contrast to control women matched for age, degree of obesity, and glucose tolerance, women with PCOS are at near-maximum in their ability to secrete insulin, so that any further exacerbation in insulin resistance is met with an insufficient rise in insulin secretion and a greater degree of deterioration in oral glucose tolerance.

These findings are consistent with those reported in other diabetes-prone populations, such as nondiabetic first-degree relatives of type 2 diabetics (14), and suggest that the accelerated conversion from normal to IGT and from IGT to frank diabetes in PCOS may result, in part, from a relative attenuation in the response of the pancreatic {beta}-cell to the demand placed on it by factors exacerbating insulin resistance. As first suggested by Fajans and Conn (13), an attenuated insulin secretory response to glucocorticoid administration and the resultant deterioration in oral glucose tolerance may serve as a predictor of the subsequent development of type 2 diabetes. Prospective studies of glucose tolerance in PCOS and control subjects will be needed to determine the extent to which these responses predict the decline in glucose tolerance so often observed in PCOS.


    GRANTS
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
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These studies were supported in part by grants from the National Institutes of Health (DK-02315, DK-31842, DK-20595, HD-06308, DK-07011-17, and General Clinical Research Center MO1-RR-00055), a Clinical Research Award (to D. A. Ehrmann) from the American Diabetes Association, and a gift from the Blum-Kovler Foundation.


    FOOTNOTES
 

Address for reprint requests and other correspondence: D. A. Ehrmann, Dept. of Medicine, Section of Endocrinology, The Univ. of Chicago Pritzker School of Medicine, 5841 South Maryland Ave., MC 1027, Chicago, IL 60637 (E-mail: dehrmann{at}medicine.bsd.uchicago.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.


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