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From the Clinical Research Centers |
Division of Pediatric Endocrinology, Metabolism, and Diabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Silva A. Arslanian, M.D., Division of Endocrinology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue at DeSoto Street, Pittsburgh, Pennsylvania 15213. E-mail: arslans{at}chplink.chp.edu
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Abstract |
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Hepatic glucose production was significantly higher in IGT vs. NGT. Insulin-stimulated glucose disposal was not different between the two groups. The first phase insulin level was lower in IGT (207.9 ± 21.0 vs. 357.0 ± 62.9 µu/mL; P = 0.025; 1247 ± 126 vs. 2142 ± 377 pmol/L) without a difference in second phase insulin. The glucose disposition index (product of insulin sensitivity x first phase insulin) was lower in IGT vs. NGT (278 ± 40 vs. 567 ± 119 mg/kg·min; P = 0.023; 1546 ± 223 vs. 3249 ± 663 µmol/kg·min). The glucose disposition index correlated inversely with OGTT glucose concentrations at 30, 60, and 120 min. Adolescents with PCOS-IGT lacked the normal nocturnal decline in blood pressure.
We conclude that in obese adolescents with PCOS, glucose intolerance is associated with 1) decreased first phase insulin secretion, 2) decreased glucose disposition index, and 3) increased hepatic glucose production. These metabolic abnormalities are precursors of type 2 diabetes and are present early in the course of PCOS. Furthermore, the absence of nocturnal dipping in blood pressure may herald the early expression of cardiovascular disease risk in these adolescents.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Even though PCOS is not as extensively studied in adolescents as it is in older women, it is postulated that the disorder begins at menarche, and its characteristics do not change with age (5). Adolescents less than 18 yr old with PCOS have comparable clinical, neuroendocrine, and ultrasonographic features as adult women with PCOS (6). We recently demonstrated that adolescents with PCOS are severely insulin resistant compared with a control group matched for body composition and abdominal obesity (7). The aim of the present study was to investigate the balance between insulin secretion and insulin sensitivity in adolescents with PCOS with normal vs. abnormal glucose tolerance and identify the early risk factors for type 2 diabetes and cardiovascular disease (CVD).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-one adolescents with PCOS participated in the study. They
were referred to the endocrine service for evaluation of irregular
menses, hirsutism, and acne. The diagnosis of PCOS was made after
excluding other causes of hyperandrogenism according to the recommended
standards developed at the 1990 conference of the NIH (8).
Eleven girls (4 black and 7 white) had abnormal glucose tolerance (9
impaired and 2 type 2 diabetes) and 10 (5 black and 5 white) had normal
glucose tolerance based on 2-h plasma glucose level during an oral
glucose tolerance test (OGTT). None of the participants was symptomatic
for diabetes, and none was receiving any medication at the time of
investigation. The studies were approved by the human rights committee
of Children’s Hospital of Pittsburgh. Research participants and
parents gave written informed consent after explanation and before
initiation of research studies. The clinical characteristics of the
study subjects are summarized in Table 1
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Metabolic studies
In vivo insulin secretion was assessed during a 2-h hyperglycemic clamp (225 mg/dL; 12.5 mmol/L) described by us previously (9). Fasting hepatic glucose production was measured with a primed (2.8 µmol/kg) constant infusion (0.28 µmol/kg·min) of [6,6-2H2]glucose for 2 h as reported by us previously (10). Turnover calculations were made over the last 30 min of the basal 2-h infusion period. In vivo insulin sensitivity was measured during a 3-h hyperinsulinemic-euglycemic clamp in conjunction with indirect calorimetry. The insulin infusion rate was 80 mu/m2·min. Plasma glucose was clamped at approximately 100 mg/dL (5.5 mmol/L) with a variable rate infusion of 20% dextrose in water. Blood was sampled every 10–15 min for determination of insulin concentrations and every 5 min for measuring glucose levels. Indirect calorimetry was performed for 30 min at baseline and at the end of the 3-h euglycemic clamp (10).
Body composition and abdominal adiposity
Body composition was assessed by dual energy x-ray absortiometry, and abdominal fat was determined by computed tomography scan as we previously described (10).
Blood pressure monitoring
In healthy normotensive subjects, there is a circadian rhythm in blood pressure. Blood pressure readings fall during the night and increase during the daytime. This decrease during the night is called the nocturnal dip (11, 12). The absence of this nocturnal dipping is an early expression of risk of future CVD (12, 13). To assess overnight blood pressure change, measurements were made during one of the General Clinical Research Center admissions. Blood pressure was measured when the patients were resting in the recumbent position in bed. Measurements were performed every 10 min for 1 h between 2200–2300 h before the patients fell asleep and between 0600–0700 h before awakening with an automated sphygmomanometer. The mean of seven measurements during each hour was the outcome for statistical analysis to assess the nocturnal dip (i.e. 2200–2300 h vs. 0600–0700 h). Two patients in the normal glucose tolerance (NGT) group did not have complete data, because in one the 2200–2300 h measurement was lacking and in the other the 0600–0700 h measurement was lacking.
Biochemical measurements
Plasma glucose was measured by the glucose oxidase method with a glucose analyzer (YSI, Inc., Yellow Springs, OH). Plasma insulin was analyzed by RIA (14). Total and free testosterone were measured by RIA at Endocrine Sciences, Inc. (Calabasas Hills, CA). Plasma lipid levels were measured using the standards of the Centers for Disease Control and Prevention as described previously (15). Plasma free fatty acids were quantitated by an enzymatic colorimetric method with the use of the nonesterified fatty acid C test kit (Wako, Osaka, Japan) (16). Urinary nitrogen was measured by the Kjeldahl method (14). Deuterium enrichment of glucose in the plasma was determined on a Hewlett-Packard Co. 5971 mass spectrometer (Palo Alto, CA) coupled to a 5890 series II gas chromatograph as we previously reported (10). Plasma samples were deproteinized with methanol. The aldolnitrile pentaacetate derivative of glucose was analyzed for 2H enrichment in the electron impact mode. Selective ion monitoring software was used to monitor the mass to charge ratio for (m/z) 200 and 202, reflecting unlabeled and labeled glucose. Standard curves of known enrichments were performed with each assay.
Calculations
Glucose turnover at baseline was calculated during the last 30 min of the fasting 2-h isotopic infusion period according to steady state tracer dilution equations reported by us previously (10). Insulin-stimulated glucose disposal (Rd) was calculated during the last 30 min of the 80 mu/m2·min hyperinsulinemic clamp. Basal and insulin-stimulated carbohydrate oxidation rates and lipid oxidation rates were calculated from indirect calorimetric data by averaging the data over the 30 min of measurements during each period according to Frayn formulas (16). Glucose storage or nonoxidative glucose disposal during hyperinsulinemia was estimated by subtracting glucose oxidation from total glucose disposal. Insulin sensitivity was calculated by dividing insulin-stimulated glucose disposal by the steady state plasma insulin concentration during the hyperinsulinemic clamp as described previously (17).
During the hyperglycemic clamp, the first phase insulin concentration was calculated as the mean of five determinations every 2.5 min during the first 15 min of the clamp, and the second phase concentration was calculated as the mean of eight determinations from 15–120 min (9). The glucose disposition index was calculated as the product of insulin sensitivity index and the first phase insulin concentration (18).
Statistical analysis
Comparisons between IGT and NGT patients were made using
Student’s t test. Least squares regression analysis was
used for univariate relationships, and multiple regression analysis was
applied to assess multivariate relationships. Data are presented as the
mean ± SEM. Statistical significance was
considered at P 
0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and Tables 1
and 2)
Figure 1 depicts plasma glucose and insulin concentrations during
OGTT in adolescents with PCOS (IGT vs. NGT groups). The 2-h
glucose levels in PCOS-IGT vs. PCOS-NGT were (171 ± 9
vs. 110 ± 8 mg/dL; P = 0.0001;
9.5 ± 0.5 vs. 6.1 ± 0.4 mmol/L), and
those in PCOS-IGT vs. type 2 diabetes (159 ± 5
vs. 225 ± 3 mg/dL; P = 0.0004;
8.8 ± 0.3 vs. 12.5 ± 0.2 mmol/L). Both
groups were obese, but the two groups did not differ in body
composition, abdominal adiposity, or serum testosterone level (Table 1). Similarly, the fasting lipid profile was not different between the
two groups (Table 2).
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Fasting glucose and insulin concentrations were similar between
IGT and NGT groups (Table 2). Hepatic glucose production was higher in
IGT vs. NGT (2.2 ± 0.2 vs. 1.7 ± 0.08
mg/kg·min; P = 0.03; 12.2 ± 1.1 vs.
9.4 ± 0.4 µmol/kg·min). Fasting glucose oxidation (1.3
± 0.2 and 1.5 ± 0.2 mg/kg·min; 7.2 ± 1.1 and 8.3 ±
1.1 µmol/kg·min), fat oxidation (0.8 ± 0.1 and 0.7 ±
0.06 mg/kg·min; 3.0 ± 0.4 and 2.6 ± 0.2 µmol/kg·min),
and plasma free fatty acid levels (0.47 ± 0.04 and 0.52 ±
0.05 mmol/L) were similar between the two groups.
Hyperinsulinemic-euglycemic clamp
Steady state insulin and glucose concentrations achieved during euglycemia were similar in PCOS-IGT and PCOS-NGT (310.5 ± 17.0 and 326.8 ± 23.3 µU/mL, 99 ± 0.7 and 101 ± 0.6 mg/dL, respectively; 1863 ± 102 and 1961 ± 140 pmol/L, 5.5 ± 0.04 and 5.6 ± 0.03 mmol/L). Insulin-stimulated glucose disposal (4.1 ± 0.4 and 4.9 ± 0.6 mg/kg·min; 22.8 ± 2.2 and 27.2 ± 3.3 µmol/kg·min), oxidation (2.2 ± 0.2 and 2.4 ± 0.3 mg/kg·min; 12.2 ± 1.1 and 13.3 ± 1.7 µmol/kg·min), nonoxidative disposal (1.9 ± 0.5 and 2.5 ± 0.4 mg/kg·min; 10.6 ± 2.8 and 13.9 ± 2.2 µmol/kg·min), and insulin sensitivity (1.3 ± 0.2 and 1.6 ± 0.2 mg/kg·min per µU/mL) (1.2 ± 0.2 and 1.5 ± 0.2 µmol/kg·min per pmol/L) were comparable between the two groups. Similarly, steady state free fatty acid (0.09 ± 0.02 and 0.11 ± 0.01 mmol/L) and fat oxidation (0.38 ± 0.08 and 0.47 ± 0.08 mg/kg·min; 1.4 ± 0.3 and 1.7 ± 0.3 µmol/kg·min) were not significantly different.
Hyperglycemic clamp
The first phase insulin level was lower in IGT compared with NGT
(207.9 ± 21.0 vs. 357.0 ± 62.9 µU/mL;
P = 0.025; 1247 ± 126 vs. 2142 ±
377 pmol/L), without a difference in second phase insulin (291.4
± 26.3 vs. 307.8 ± 52.3 µU/mL; 1748 ± 158
vs. 1847 ± 314 pmol/L; Fig. 2 and 3).
The glucose disposition index, calculated as the product of insulin
sensitivity and the first phase insulin level, was lower in IGT
compared with NGT (278 ± 40 vs. 567 ± 119
mg/kg·min; P = 0.023; 1546 ± 223 vs.
3149 ± 663 µmol/kg·min; Fig. 3). The glucose disposition
index and the first phase insulin concentration correlated inversely
with plasma glucose concentrations during the OGTT; however, the
correlations were stronger for the glucose disposition index
(Table 3 and Figure 4). Results did not change when the two
patients with asymptomatic type 2 diabetes were excluded. In a multiple
regression analysis using 60 min glucose during the OGTT as the
dependent variable, the glucose disposition index and percent body fat
together explained 55% of the variability in 60 min glucose
(r2 = 0.55; P = 0.006).
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and Fig. 5)
There were no differences between systolic and diastolic blood
pressures between IGT and NGT (Table 4). In both groups diastolic blood
pressure did not show a nocturnal dip. Moreover, systolic blood
pressure did not dip overnight in the group with IGT, whereas there was
a significant drop in the group with NGT (Fig. 5). One hundred percent
of subjects in NGT group exhibited the nocturnal dip in systolic blood
pressure, whereas only 40% of the IGT group did so
(
2 = 0.02; Fig. 5).
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Discussion |
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Recently, the American Diabetes Association published a consensus statement regarding the emerging problem of type 2 diabetes in children and adolescents (19). One of the well recognized features of type 2 diabetes in children is its presence in increased proportions of females, especially those with obesity and evidence of PCOS (19, 20). Over the past year, two contemporaneous publications raised awareness of increased risk of IGT (31.1% and 35%) and type 2 diabetes (7.5% and 10%) in women with PCOS (3, 4). These prevalence rates suggest that PCOS may be an important risk factor for glucose intolerance and diabetes in women. Therefore, we aimed to investigate in a group of adolescents with PCOS the metabolic impairments that would predispose them to abnormalities in glucose metabolism. In a recent publication we demonstrated that obese adolescents with PCOS have an approximately 50% reduction in peripheral tissue insulin sensitivity compared with obese nonhyperandrogenic adolescents (7). The present study takes this observation a step further to show that in obese PCOS adolescents with vs. without NGT, the difference is not in the degree of peripheral insulin resistance, but, rather, in the ability of the ß-cell to compensate for the insulin resistance. Adolescents with abnormal glucose tolerance have significantly reduced (40%) first phase insulin secretion and a 50% lower glucose disposition index in the face of comparable peripheral insulin resistance. Additionally, the group with IGT has hepatic insulin resistance with elevated hepatic glucose production. An interaction between impaired insulin secretion and impaired insulin action drives the pathophysiology of type 2 diabetes. The progression from IGT to frank type 2 diabetes in these patients may involve further deterioration in ß-cell function and insulin action, with greater elevations in hepatic glucose production leading to fasting hyperglycemia.
Even though the majority of adult women with PCOS have basal hyperinsulinemia, studies that carefully assessed ß-cell function have discovered important defects in insulin secretion (21, 22, 23). In these women, incremental insulin secretory responses to meals are markedly reduced (21). Also, the ability of the ß-cell to respond to oscillations in plasma glucose is impaired (23). Furthermore, the presence of family history of type 2 diabetes in women with PCOS increases the likelihood of inappropriate ß-cell compensation for the degree of insulin resistance (23). In the current study even though the family history of type 2 diabetes was not different between the 2 groups (8 of 11 in IGT, 8 of 10 in NGT), it was high in both, further increasing the risk of future derangements in ß-cell function over time. The low glucose disposition index observed in the present study is consistent with that in a previous study of adult women with PCOS using the frequently sampled iv glucose tolerance test (22). Both obese and nonobese PCOS women were found to have ß-cell dysfunction as well as insulin resistance. Thus, the metabolic features conducive to IGT and type 2 diabetes are present early in the course of PCOS in obese adolescents. However, only careful screening will unravel abnormalities in glucose metabolism, as none of the participants was symptomatic. Moreover, fasting glucose levels were normal in all subjects, and fasting insulin levels were indistinguishable between the group with IGT vs. those with NGT. Two adolescents converted from NGT to IGT within 6 and 9 months, respectively. Furthermore, 2 of the 11 subjects with abnormal glucose tolerance (18%) had 2-h OGTT glucose levels consistent with the diagnosis of diabetes, whereas their fasting glucose levels were normal. In a previous study the fasting glucose level was a poor predictor of diabetes in PCOS women and missed 58% of the diabetes in these women (3). In the present study the decreased glucose disposition index did not correlate with fasting glucose, but showed the highest correlation with 30 and 60 min glucose levels during the OGTT and a lower correlation with 2-h glucose. Therefore, in this high risk population of obese PCOS adolescents with a family history of type 2 diabetes, fasting glucose level may not be sufficient in making the diagnosis of diabetes. Additional studies are needed to further pursue the validity of fasting glucose vs. OGTT glucose levels in this population.
Women with PCOS are at a substantially increased risk for CVD (24, 25). These women have a 7-fold increased risk of myocardial infarction (26). Hypertension is highly prevalent especially in older women with PCOS who are obese (27). However, blood pressure is generally within the normal range in young women with PCOS, but increases with advancing age (24, 28, 29). Twenty-four-hour ambulatory systolic blood pressure measurements are higher in women with PCOS compared with controls and may predict the development of sustained hypertension later in life (29, 30, 31).
There is a normal circadian rhythm in blood pressure, with a fall in blood pressure readings during the night and an increase during the daytime (12). The absence of this nocturnal dipping in some children is regarded as an early expression of a population-related CVD evident later in adult life (13, 31, 32). Neither of the PCOS groups showed dipping in diastolic blood pressure. In addition, however, the group with IGT exhibited no dipping in systolic blood pressure. This blunted decrease in nocturnal blood pressure in PCOS adolescents may signal an early expression of the risk for future development of sustained hypertension. In epidemiological data, diabetes confers a markedly increased risk of CVD after adjusting for other markers of macrovascular disease (33). Therefore, the absence of systolic blood pressure dipping in the group with IGT may be a further expression of the added burden of diabetes on CVD risk in this high risk obese adolescent population. Unlike adult women with PCOS and obesity who are hyperlipidemic (24, 25), adolescents in the present study did not have major derangements in lipid levels, and the two groups did not differ in lipid profile. However, lipid abnormalities may evolve over time in the presence of severe insulin resistance and abnormal glucose metabolism. Because CVD is the number one cause of death in older women, early intervention in adolescent girls with PCOS, both to prevent diabetes and to preserve cardiovascular function, may be warranted.
In summary, the present study demonstrates that obese adolescents with PCOS have important impairments in insulin secretion and sensitivity that are metabolic precursors of type 2 diabetes. Moreover, the increased risk of CVD in this population may be manifested initially by abnormalities in diurnal blood pressure regulation. These metabolic and cardiovascular risk markers are present early in the course of PCOS in obese adolescents. Further studies are needed 1) to investigate whether similar findings are present in lean adolescents with PCOS, and 2) to devise intervention strategies to lessen the burden of type 2 diabetes and CVD in this high risk population of obese adolescent girls with PCOS.
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Acknowledgments |
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Footnotes |
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Received May 12, 2000.
Revised August 15, 2000.
Revised September 25, 2000.
Accepted October 3, 2000.
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M. I. Goran, R. N. Bergman, Q. Avila, M. Watkins, G. D. C. Ball, G. Q. Shaibi, M. J. Weigensberg, and M. L. Cruz Impaired Glucose Tolerance and Reduced {beta}-Cell Function in Overweight Latino Children with a Positive Family History for Type 2 Diabetes J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 207 - 212. [Abstract] [Full Text] [PDF]
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M. E. Silfen, M. R. Denburg, A. M. Manibo, R. A. Lobo, R. Jaffe, M. Ferin, L. S. Levine, and S. E. Oberfield Early Endocrine, Metabolic, and Sonographic Characteristics of Polycystic Ovary Syndrome (PCOS): Comparison between Nonobese and Obese Adolescents J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4682 - 4688. [Abstract] [Full Text] [PDF]
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F. Bacha, R. Saad, N. Gungor, J. Janosky, and S. A. Arslanian Obesity, Regional Fat Distribution, and Syndrome X in Obese Black Versus White Adolescents: Race Differential in Diabetogenic and Atherogenic Risk Factors J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2534 - 2540. [Abstract] [Full Text] [PDF]
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D. Dereli, G. Ozgen, F. Buyukkececi, E. Guney, and C. Yilmaz Platelet Dysfunction in Lean Women with Polycystic Ovary Syndrome and Association with Insulin Sensitivity J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2263 - 2268. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC Diabetes Care, April 1, 2003; 26(4): 1297 - 1303. [Full Text] [PDF]
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D. Cibula, J. Skrha, M. Hill, M. Fanta, L. Haakova, J. VrbIkova, and J. Zivny Prediction of Insulin Sensitivity in Nonobese Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5821 - 5825. [Abstract] [Full Text] [PDF]
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E. Charmandari, M. Weise, S. R. Bornstein, G. Eisenhofer, M. F. Keil, G. P. Chrousos, and D. P. Merke Children with Classic Congenital Adrenal Hyperplasia Have Elevated Serum Leptin Concentrations and Insulin Resistance: Potential Clinical Implications J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2114 - 2120. [Abstract] [Full Text] [PDF]
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S. A. Arslanian, V. Lewy, K. Danadian, and R. Saad Metformin Therapy in Obese Adolescents with Polycystic Ovary Syndrome and Impaired Glucose Tolerance: Amelioration of Exaggerated Adrenal Response to Adrenocorticotropin with Reduction of Insulinemia/Insulin Resistance J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1555 - 1559. [Abstract] [Full Text] [PDF]
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 E Charmandari, C G D Brook, and P C Hindmarsh Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty? Arch. Dis. Child., April 1, 2002; 86(4): 266 - 269. [Abstract] [Full Text] [PDF]
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 R. Sinha, G. Fisch, B. Teague, W. V. Tamborlane, B. Banyas, K. Allen, M. Savoye, V. Rieger, S. Taksali, G. Barbetta, et al. Prevalence of Impaired Glucose Tolerance among Children and Adolescents with Marked Obesity N. Engl. J. Med., March 14, 2002; 346(11): 802 - 810. [Abstract] [Full Text] [PDF]
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M. R. Palmert, C. M. Gordon, A. I. Kartashov, R. S. Legro, S. J. Emans, and A. Dunaif Screening for Abnormal Glucose Tolerance in Adolescents with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1017 - 1023. [Abstract] [Full Text] [PDF]
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