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ORIGINAL RESEARCH |
From the University of Texas Southwestern Medical Center, Dallas, Texas; Portland CF Center and Kaiser Permanente, Portland, Oregon; Baylor College of Medicine, Houston, Texas; and National Jewish Medical and Research Center and University of Colorado Health Science Center, Denver, Colorado.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: We studied 8 CF women during pregnancy (CFPreg). Results were compared with those from 9 pregnant controls (PregCont) and 8 nonpregnant CF women (CFCont). The following metabolic studies were conducted: oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp, stable isotope infusion of [1-13C]leucine and [6,6-2H2]glucose for measurement of whole body protein turnover and hepatic glucose production (HGP), respectively. Indirect calorimetry was used to measure resting energy expenditure (REE), and food intake was measured by 3-day food journals. Fat-free mass was measured by total body potassium 40K scan.
Results: All but one CFPreg developed diabetes by the end of the second trimester and had significantly lower insulin secretion and more insulin resistance than PregCont. Hepatic glucose production was significantly higher and suppression by insulin was less in CF subjects, and protein breakdown was significantly higher. Insulin resistance and HGP increased during pregnancy similarly in CFPreg and PregCont groups.
Conclusion: Pregnancy in CF is associated with decreased insulin sensitivity and high HGP, in addition to inherent decreased insulin secretion. Pregnancy in CF is also associated with increased protein turnover and less response to insulin’s anticatabolic effect. These changes appear to predispose the pregnant CF women to early development of diabetes and poor weight gain.
Level of Evidence: II-2
During the first trimester, normal pregnancy is characterized by enhanced insulin secretion and normal-to-increased insulin sensitivity.8,9 These early metabolic changes augment maternal nutritional stores during later gestation. During the later stages of pregnancy, insulin resistance is present but is counter-balanced by augmented insulin secretion. Other changes include increased hepatic glucose production (HGP) and increased whole body protein turnover. In normal pregnancy there is no net protein catabolism because both synthesis and breakdown increase simultaneously.12
Multiple studies have described decreased insulin secretion in people with CF,13,14 but we are unaware of any studies of insulin secretion in CF pregnancy (CF Foundation database and PubMed, January 1980 through April 200, English and Italian languages; keywords: "cystic fibrosis," "pregnancy," "insulin secretion"). Studies by our group15,16 and others have documented both peripheral and hepatic insulin resistance, increased HGP, and increased protein catabolism in people with CF. The combination of decreased insulin secretion and the underlying changes in substrate metabolism have been implicated as the cause of CF-related diabetes.16 Given the data in nonpregnant CF patients, we hypothesized that pregnant CF women would be have less insulin secretion and worse peripheral and hepatic insulin resistance than pregnant women without CF, placing them at high risk for the development of gestational diabetes. We also hypothesized that pregnancy would cause worsened protein catabolism and poor weight gain in women with CF. We designed these studies to evaluate our hypothesis.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All CF subjects had been screened annually for the presence of CF-related diabetes according to the guidelines of the CF Foundation,13 and none had a previous diagnosis of CF-related diabetes before study participation. All subjects were studied when clinically stable, defined as no antibiotics for at least 6 weeks and no weight loss for at least 2 months. Exclusion criteria for CF subjects included previous diagnosis of diabetes, colonization with Burkholderia cepacia, and use of oral or intravenous corticosteroids within 4 weeks of study. Pregnant non-CF control (PregCont) volunteers were excluded if they had a prior history of diabetes, a first generation family history of diabetes, or any type of chronic illness. They were also excluded if they smoked cigarettes or engaged in rigorous exercise.
A 100-g carbohydrate load OGTT was conducted in the fasted state, and subjects were classified according to definitions derived by the National Diabetes Data Group21 using a 3-hour OGTT. They were also classified according to the new American Diabetes Association guidelines22 and the CF Foundation Consensus Conference Report.13 The classification of gestational diabetes mellitus (GDM) was made based on American Diabetes Association criteria.
We quantified fat-free mass by measuring total body potassium (40K scan). The whole body counters (either Houston or Denver) had 30 Nal(T1) detectors and a counting time of 15 minutes and were extensively calibrated for precision and accuracy. We used the conversion from total body potassium (TBK) to body cell mass (BCM): BCM = k x TBK, where the present constants are 0.0083. We used published correction factors to accommodate the growing fetus.
We measured peripheral insulin sensitivity using a "step-up" hyperinsulinemic euglycemic clamp, with insulin infusion rates of 10 and 40 mU · m–2 · min–1.26 Briefly, a catheter was placed into an antecubital vein for administration of glucose, insulin, potassium, and saline. A venous-arterial mix of blood was sampled with a retrograde indwelling catheter placed in a vein of the opposite hand and kept in a warming device. Blood samples were taken every 5 to 10 minutes for the immediate determination of plasma glucose using an automated glucose oxidase technique (glucose analyzer; Yellow Springs Instruments, Yellow Springs, OH) and were used to titrate the infusion rate of 20% glucose to maintain euglycemia (88–95 mg/dL). We obtained "steady state" glucose within 2.5–3 hours. Then the infusion rate was continued for an additional 30 minutes before increasing to the next infusion rate of insulin. Insulin sensitivity was calculated from the sum of the glucose infusion rate and endogenous glucose production during the final 30 minutes of the 40 mU · m–2 · min–1 clamp. Results are reported as maximal glucose disposal rate (mg · kg–1 · min–1).15
To measure basal HGP, subjects were given a 2.5 mg/kg bolus of [6,6-2H2]glucose, followed by a 2-hour and 30-minute constant infusion at a rate of 2.0 mg · kg–1 · h–1. After the equilibration period, blood was drawn in triplicate for baseline measures16 before the insulin infusion was started. Triplicate samples for measurement of HGP were drawn at steady-state glucose with each insulin "step." We added the stable isotope [6,6-2H2]glucose to the dextrose infusion used to maintain euglycemia,16 as previously validated in CF.16
We measured resting energy expenditure (REE), glucose oxidation, and fat oxidation by indirect calorimetry (Deltatrac; Sensormedics, Yorba Linda, CA) and Weir calculations.27 Calorimetry was measured at baseline and during 40 mU · m–2 · min–1 clamp for 30 minutes per measure. Calorimetry conducted during the clamp was used to calculate nonoxidative glucose metabolism (glycogen storage).28
Each subject kept a 3-day food journal before the study visit. Results were analyzed by a registered dietician using the Nutritionist IV software program (Hearst Corporation, San Bruno, CA).
We used the stable isotope of leucine and the same baseline and insulin clamp time points used for HGP to measure the effect of insulin on protein catabolism. Each subject received a 0.35 mg/kg bolus of [1-13C]leucine and 0.2 mg/kg NaH13CO3, followed by a 0.65 mg · kg–1 · h–1 infusion of [1-13C]leucine.19 Baseline serum and breath samples were drawn in triplicate before the insulin infusion was started. Serum samples were again collected during the last 5 minutes of each insulin infusion.
To measure pulmonary function (CF only), forced expiratory volume (FEV1) and forced vital capacity (FVC) were obtained using standard spirometry at the patient’s local CF center prepregnancy throughout the study and 6 weeks postpartum. Results were reported as absolute values, as well as percentage predicted, according to Knudson standards.29
Plasma [6,6-2H2]glucose and [1-13C]leucine enrichments were measured by using selected ion monitoring gas chromatography–mass spectrometry methods30 by Metabolic Solutions (Boston, MA). Isotopic enrichment of [6,6-2H2]glucose was calculated as previously described.16 Calculation of leucine flux (leucine Ra, a measure of protein breakdown) was based on mean values of [1-13C]leucine in plasma at baseline and during the last 15 minutes of each insulin infusion period. Leucine Ra was calculated by using the formula Ra = i(Ei/Ep – 1), where i is the infusion rate of tracer in micromoles per kilogram per hour, Ei is the isotopic abundance of tracer, and Ep is the isotopic abundance in plasma at isotopic plateau (each expressed as atom percentage excess). Leucine oxidation rates were calculated according to the formula LEUox = F(1/Ep – 1/Ei) x 100, where Ep is the plasma enrichment of [1-13C]leucine in atoms percentage excess and F is the production rate of 13CO2.
Serum insulin and C-peptide concentrations were measured by radioimmunoassay with a double antibody technique31 (Diagnostic Products Corporation, Los Angeles, CA). Estradiol and 24-hour urinary free cortisol were measured by Esoterix Laboratory (Calabasas Hills, CA)
The data are expressed as mean ± standard deviation. Data from the CFCont and PregCont groups were compared with published data11,12,15,16 and found to be similar for each subgroup. Thus we proceeded with our analysis using analysis of variance. Multiple comparisons were used to compare data between the second and third trimesters in a given subgroup. Statistical analysis was performed using SPSS software (SPSS Inc, Chicago, IL).
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RESULTS |
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Weight gain in the CFPreg subjects was less than that in the PregCont group during the second trimester, but was not statistically different during the third trimester (change in weight [kg]: second trimester: CFPreg 3.1 ± 1.6, PregCont 7.9 ± 3.2, P = .03; third trimester: CFPreg 5.8 ± 1.7, PregCont 5.4 ± 1.5, P = not significant). Total weight gain during pregnancy was also less in CFPreg subjects than in controls (CFPreg 9.4 ± 2.9, PregCont 14.6 ± 1.6, P = .03). Fat-free mass was not measured before study enrollment. In the second trimester, fat-free mass was slightly less in CFPreg than PregCont subjects (CFPreg 36.7 ± 3.9, PregCont 38.8 ± 4.3, P = .05). The CF controls were well matched to the other pregnant groups for fat-free mass (38.8 ± 4.3, P = .06). Fat-free mass increased more in the PregCont than the CFPreg group in the third trimester (
fat-free mass [kg]: CFPreg 2.9 ± 1.8, PregCont 8.2 ± 2.1; P = .02). The follow-up 12-week study of CFCont was not different from baseline (38.2 ± 3.0, 38.6 + 2.9, P = .1).
During the second trimester measure (mean 23 weeks of gestation), all CFPreg subjects but the youngest, age 17, had GDM by American Diabetes Association criterion.23 According to the CF Consensus guidelines, these subjects had CF-related diabetes without fasting hyperglycemia.22 These results are presented in Table 2. At week 36, all CFPreg subjects had GDM, but only 3 had CF-related diabetes with fasting hyperglycemia. All were receiving insulin: Ultralente insulin (0.4 U · kg–1 · d–1) plus Lys-pro 1 U per 15 g carbohydrate with meals. Long-acting insulin was withheld for 24 hours before study participation, but euglycemia was maintained with short-acting insulin administered every 3 hours, with the last dose given at 4 am (clamp started 3 hours later). All PregCont and CFCont subjects were normally glucose tolerant throughout the study (Table 2).
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The mean change from baseline glucose to steady-state glucose was similar between the pregnant females at each trimester (delta glucose mg/dL: second trimester: CFPreg 17 ± 10, CFCont 11 ± 5; third trimester: CFPreg 4 ± 8, CFCont 6 ± 7). As measured by the glucose disposal rate, insulin sensitivity was lower in the CFPreg than in PregCont during both the first and second trimesters. However, the decrease in insulin sensitivity between the trimesters was similar in the pregnant subgroups (mean decrease 3.2 mg · kg–1 · min–1). There was no change in glucose disposal rate between the first and second measures conducted in the CFCont group, but glucose disposal rate was lower in this group than in the second-trimester measure of the PregCont subjects (Fig. 1). The insulin levels at steady state during the hyperinsulinemic euglycemic clamp were similar between the groups (mean serum insulin level for the 40 mU · m–2 · min–1 clamp = 87 ± µU/mL ± 15).
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Hepatic glucose production was higher in the CFPreg than in the PregCont group at both the second and third trimesters. However, the change in HGP between the second and third trimesters was similar between the groups (mean increase 1.1 ± 0.8 mg · kg–1 · min–1). The baseline measure of HGP was higher in CFCont subjects than the second-trimester value in PregCont subjects. There was no change in HGP between the baseline and 12-week measure in the CFCont group (Fig. 2).
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The CFPreg subjects did not suppress HGP in response to insulin to the same degree as those in the PregCont group in either trimester (percentage suppression of HGP during steady-state 40 mU · m–2 · min–1 clamp: CFPreg 80% ± 10%, ContPreg 98% ± 5%, P = .03). This suggests hepatic insensitivity to insulin (hepatic insulin resistance). The CFCont group also demonstrated hepatic insulin resistance (percentage suppression 85% ± 8%), which did not change between baseline and the 12-week measure.
We measured both protein catabolism (leucine Ra) and leucine oxidation at baseline (before any insulin was started). Pregnancy increased leucine oxidation in both controls and CF but was not enough to offset the increase in leucine Ra. Our results indicate that protein catabolism was higher in CF subjects than in controls and significantly higher in the CFPreg group than in both other groups. This imbalance improved during the third trimester, likely secondary to insulin treatment. As demonstrated by the clamp results, the CF subjects exhibited resistance to insulin’s anticatabolic effect on whole body protein turnover (Table 3).
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As measured by indirect calorimetry, glucose oxidation was similar in all 3 groups (glucose oxidation, mg · kg–1 · min–1: CFPreg 2.8 ± 1.2, PregCont 2.4 ± 1.3, CFCont 2.7 ± 1.1, P = not significant), and there was no significant change at the third-trimester evaluation (data not shown). Nonoxidative glucose metabolism was lower in the CF subjects than in PregCont subjects (nonoxidative glucose metabolism, mg · kg–1 · min–1: CFPreg 0.32 ± 0.41, CFCont 0.35 ± 1.2, PregCont 0.51 ± 0.3, P = .04) and did not significantly change during the third trimester.
At the time of first measure (second trimester in the pregnant patients), the CFPreg subjects had higher (P = .04) REE than CFPreg subjects. Resting energy expenditure in the CFCont group did not differ significantly from that in the CFPreg group (P = .07), but was significantly higher than in the PregCont group (REE kcal/24h: CFPreg 1,847 ± 235, PregCont 1,375 ± 127, CFCont 1,489 ± 138). Resting energy expenditure significantly increased (P = .04) in both pregnant groups at the third-trimester study, but did not change in CFCont subjects (CFPreg 2,199 ± 301, PregCont 1,880 ± 268, CFCont 1,501 ± 233). These differences in REE remained when corrected for fat-free mass.
Total caloric intake was similar in both the CF groups and the PregCont group during the first study (kcal/24h: PregCont 1,983 ± 423, CFPreg 2,075 ± 768, CFCont 2,024 ± 554). Calorie intake increased similarly in both pregnant groups in the third trimester, and there was no change in the CFCont group (kcal/24h: CFPreg 2,585 ± 299, PregCont 2,136 ± 301, CFCont 2,192 ± 210).
Complete spirometry data were obtained in 6 CFPreg women. Several subjects did not return for postpregnancy follow-up pulmonary function testing, and thus results are not included. Pulmonary function decreased in the CFPreg group with each trimester of pregnancy. In all but one patient (the youngest), FEV1 remained lower than baseline at 6 weeks postpartum (Fig. 3). The CFCont subjects had similar pulmonary function at each visit: mean FEV1 1.87 (58%), FVC 3.08 (81%).
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Fasting insulin concentrations were lower in both CF groups than in the PregCont group at the first evaluation (insulin, µU/mL: CFPreg 3.8 ± 1.0, CFCont 3.2 ± 0.8, PregCont 6.2 ± 1.4, P = .02). C-peptide was also lower in CF subjects (Table 2). There was no difference between the C-peptide values measured at the second an third trimesters in the CF subjects, but third-trimester values were higher at the third trimester than the second trimester. C-peptide levels were lower in the CFPreg and CFCont groups at all time points.
The estradiol levels (ng/mL) were similar between the pregnant groups at both trimesters of pregnancy (second-trimester estradiol: CFPreg 15.6 ± 4.2, PregCont 14.8 ± 4.9, P = NS; third-trimester estradiol CFPreg 1,522 ± 260, PregCont 1,363 ± 152, P = not significant). Urine 24-hour cortisol levels were similar in all groups (cortisol µg/24h: CFPreg 22 ± 10, PregCont 21 ± 11, CFCont 26 ± 11, P = not significant).
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DISCUSSION |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Gestational diabetes mellitus most frequently develops during the third trimester of pregnancy, and currently the American Diabetes Association23 recommends a screening glucose tolerance test (glucose load 50 g) between the 24th and 28th week of gestation. The 1998 CF Foundation consortium on diabetes in CF13 recommended that all pregnant CF patients have an OGTT to screen for diabetes prepregnancy and an OGTT at the end of each trimester until diabetes develops. Our current results strongly support this recommendation. First-trimester screening and treatment for diabetes would likely have improved the poor weight gain and protein catabolism present at the second trimester.
In normal women, the insulin resistance associated with pregnancy is counterbalanced by augmented insulin secretion. The increase in insulin secretion, combined with increased nutritional intake, allows the pregnant woman to preserve vitally important protein and fat stores, which are needed to support the growing fetus. It is currently believed that GDM develops in women who have underlying defects in either insulin secretion8,10 or insulin action.9 Because of the time commitment of the clamp studies, we did not perform an intravenous glucose tolerance test. Such a study would have been helpful for the study of insulin secretion. However, the low C-peptide levels measured in the CF women are suggestive of decreased insulin levels, and certainly previous studies in CF support our belief that insulin secretion is lower than normal in these patients. Therefore, this study suggests that underlying defects of both insulin secretion and insulin action predispose pregnant CF women to develop GDM presenting early in pregnancy.
We used insulin doses for the clamp previously used safely during pregnancy.9,11 Studies by our group15,16 and others have demonstrated that CF patients have decreased insulin sensitivity when compared with controls. Our current study confirms our previous finding and suggests that the pre-existing state of insulin resistance worsens during pregnancy. However, insulin sensitivity does not appear to worsen more than is found in pregnancy per se.9,11 The insulin-resistant state of pregnancy is a response to increased levels of circulating diabetogenic hormones, including human placental lactogen (HPL) and estradiol.8 Estradiol levels were similar in our pregnant CF women and in the pregnant controls; we did not measure HPL levels. Elevation of cortisol could also cause increased insulin resistance.32 Therefore, we measured 24-hour urine-free cortisol. The similarity among the 3 groups suggests cortisol is not responsible for the underlying insulin resistance in the CF subjects. Human placental lactogen is another important hormone mediating insulin resistance in pregnancy. Although we did not measure this hormone, results would have been interesting. Studies have documented the role of tumor necrosis factor-
in insulin resistance, although studies specific to pregnancy have not been conducted. We did not measure cytokines, but all of our subjects were studied when clinically well.
Elevated HGP and hepatic insulin resistance contribute to type 2 diabetes.26 Normal pregnancy causes elevation of HGP by 16–30%.11,33 Catalano and coworkers demonstrated11 greater hepatic insulin resistance in women who later developed GDM. Previous studies of CF patients have described increased basal HGP.16,17 Additionally, our group16 and others17,18 have noted the presence of hepatic insulin resistance in adults with CF. Our current study confirms the presence of high HGP and hepatic insulin resistance in CF. We also have found that these metabolic alterations increase during pregnancy, but no more than with normal pregnancy. Consistent with our previous findings in CF,16 we have found similar glucose oxidation, but lower nonoxidative glucose metabolism. We hypothesize that high rates of HGP may preclude storage of glucose, despite pregnancy. However, the increase in HGP may be secondary to increased fetal and placental needs for glucose.
Measurement of HGP by the traditional Steele equation 34 can overestimate insulin’s effect on HGP.29 Thus, we used a method specifically designed for measurement of HGP during non–steady-state conditions,35 modified by using stable isotopes (the "stable-GINF" method). We previously have validated the use of this technique in CF.16
Our group19 and others36 have demonstrated that CF subjects have increased catabolism and require higher insulin levels to suppress protein breakdown. Studies in normal pregnant women suggest protein catabolism increases 15–30%12,33 by the third trimester, and our findings are consistent with these reports. However, normal pregnancy also results in increased protein synthesis;12,37 thus, no net loss of protein occurs. Our findings suggest that in CF pregnancy, protein synthesis does not increase to the same degree as breakdown. This results in net protein catabolism. Our findings are consistent with a previous report of 18 malnourished pregnant Gambian women.38 However, our pregnant CF women were not necessarily malnourished; therefore, underlying changes in insulin secretion and sensitivity likely account for these findings. Resistance to insulin’s anticatabolic effect on protein turnover also appears to be part of normal pregnancy because even our pregnant controls had an increase in whole body protein turnover.
Studies have documented approximately 25% higher REE in CF patients.39 Pregnancy also increases REE.8,12 We have found higher REE in the CFPreg than in the PregCont group. Because REE is already high in CF, further increase in REE with pregnancy results in very high caloric requirements to achieve appropriate weight gain. Adequate weight gain is necessary for the health of both the fetus and the mother.40 Our study suggests adequate weight gain during pregnancy is difficult for the CF woman. Additionally, underweight women (body mass index < 19.8) are advised to gain at least 5 pounds more than normal-weight mothers (body mass index 19.9–26).40 This clearly was not accomplished by the pregnant CF women in our study.
Pregnancy causes measurable decrease in pulmonary function, even in women with normal health.41 Most previous studies of pregnancy in CF have focused primarily on pulmonary function. In a 1995 retrospective review,3 Edinborough supported the use of prepregnancy FEV1 as the most accurate predictor of outcome in pregnant women with CF. Fitz-Simmons et al42 reviewed data from the National CF Patient Registry and reported decline in percentage predicted FEV1, measured over 2 years postpregnancy. In a separate report, this group2 noted an even greater decline in 2-year postpartum FEV1 in CF women known to be diabetic at the time of pregnancy. All but one of our subjects (the youngest) demonstrated lower absolute and percentage predicted measures during pregnancy. Values had not returned to normal by 6 weeks postpartum. Our subject number is too small to evaluate the relationship between hyperglycemia and pulmonary function testing results, but there is little doubt that decreased pulmonary function, poor weight gain, and protein catabolism could have negative consequences postpartum. Our subjects were of similar age as those in the CFCont group, but a recent report by Boyd et al43 demonstrated that pregnancy generally occurs in older women with CF. There is a natural decline in clinical status with advanced age, which must be taken into account when these data are considered.
In conclusion, this study demonstrates that pregnant women with CF are at high risk for gestational diabetes and should be screened throughout pregnancy. We also strongly recommend the use of an OGTT for screening any woman seeking pregnancy. We have demonstrated that insulin resistance and abnormal substrate metabolism are present in CF women and likely account for increased risk of GDM. Finally, protein catabolism is present in CF women and worsens with pregnancy. Based on these findings, we recommend careful nutritional follow-up for pregnant CF women and, likewise, even greater calorie and protein intake than that recommended in normal pregnancy.
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Footnotes |
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Corresponding author: Dana S. Hardin, MD, Associate Professor of Pediatrics, University of Texas Southwestern Medical Center–Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75093-9063; e-mail: dana.hardin{at}utsouthwestern.edu.
doi:10.1097/01.AOG.0000172421.04007.74
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  I. D. Wexler, M. Johannesson, F. P. Edenborough, B. S. Sufian, and E. Kerem Pregnancy and Chronic Progressive Pulmonary Disease Am. J. Respir. Crit. Care Med., February 15, 2007; 175(4): 300 - 305. [Abstract] [Full Text] [PDF]
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Significantly lower than second trimester. # Significantly lower than pregnant controls.
