Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes Thomas A. Buchanan, MD,. Boyd E. Metzger, MD: Norbert Freinkel, MD,b. t and Richard N. Bergman, PhDc Chicago, Illinois, and Los Angeles, California We used the minimal model technique to obtain concurrent measurements of whole-body insulin sensitivity and pancreatic 8-cell responsiveness to glucose during the third trimester of pregnancy. Insulin sensitivity in normal pregnant women (n = 8) was reduced to only one third that of a group of nonpregnant women (n = 7) .of similar age and relative weight. This marked insulin resistance was compensated by reciprocal enhancement of the first- and second-phase insulin responses to intravenous glucose, which were increased threefold as compared with the nonpregnant women. Women with gestational diabetes mellitus (n = 16) had mean insulin sensitivity that was similar to that of the normal pregnant group, which indicates that insulin action was appropriate for the late phase of pregnancy in the gestational diabetic group. 8y contrast, the mean first-phase insulin response was significantly reduced in women with gestational diabetes mellitus, as compared with that of normal pregnant women (p < 0.001). However, approximately one fifth of the group with gestational diabetes mellitus had first-phase responses that did not fall below the 95% confidence interval for the mean in normal pregnant women. The mean second-phase response was also lower in the group with gestational diabetes, although the difference was of borderline statistical significance (p < 0.09). Our findings reveal the quantitative nature of the reciprocal changes in insulin sensitivity and 8-cell function that normally accompany late pregnancy. They further indicate that during the third trimester, mild gestational diabetes is characterized by an impairment of pancreatic 8-cell fUnction rather than an exaggeration of the normal insulin resistance of late pregnancy. (AM J OSSTET GVNECOL 1990;162:1008-14.)
Key words: Insulin sensitivity, insulin secretion, gestational diabetes mellitus
It is well known that insulin's ability to lower circulating glucose is impaired,I.4 whereas pancreatic B-cell responses to glucose are enhanced 5. 7 during the latter half of pregnancy. However, it has not been possible to quantify these changes precisely and simultaneously. Thus the magnitude of the insulin resistance of late pregnancy and that of the attendant B-cell responses to this resistance are not known. Likewise, the degree to which abnormalities of insulin sensitivityS and
From the Center for Endocrinology, Metabolism and Nutrition, and the Departments of Medicine and Molecular Biology, Northwestern University Medical School,' and the Departments of Medicine" and Physiology and Biophysics,' University of Southern California School of Medicine. Supported by Research Grant Nos. AM10699, MRP-HDI1021, HD-19070 and DK-29867; General Clinical Research Center Grant No. RR-48, and Training Grant No. AM07169 from the National Institutes of Health. Dr. Buchanan was supported by a Clinical Research Fellowship from the Chicago Community Trust and an Individual National Research Service Award from the National Institutes of Health (AM-07008-02). Received for publication July 17, 1989; accepted December 4, 1989. Reprint requests: Thomas A. Buchanan, MD, OCD 252,2025 Zonal Ave., Los Angeles, CA 90033. tDeceased. 611118572
secretion 4. 9·15 contribute to the genesis of gestational diabetes mellitus (GDM) remains to be identified. A method has become available with which to address these issues. Computer analysis of glucose and insulin data from a frequently sampled intravenous glucose tolerance test provides quantitative measures of insulin sensitivity and B-cell responsiveness to glucose at the same time. 16.1S This method is relatively noninvasive and thus can be applied safely during pregnancy. We have used computer modeling of frequently sampled intravenous glucose tolerance test data to obtain what we believe to be the first quantitative and simultaneous measures of insulin sensitivity and B-cell function during late pregnancy in normal women and women with GDM.
Material and methods Subjects. Nonpregnant control women (four lean, three obese*) were recruited from the staff of the Northwestern University McGaw Medical Center. Nor*Obesity denotes nonpregnant weight 2:120% of ideal or pregnancy weight gain 2: 18 kg by the time of the frequently sampled intravenous glucose tolerance test.
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1009
Table I. Clinical characteristics of the three study groups* Study group
Age (yr)
Nonpregnant weight (% ideal)
Pregnancy weight gain
Nonpregnant (n = 7) Normal pregnant (n = 8) GDM (n = 16)
29 ± 2
112 ± 8
29 ±
III ± I
12.3 ± 0.9
33.8 ± 0.8
30 ±
117 ± 4
11.6 ± 1.2
32.2 ± 0.5
(kg)
Gestational age (wk)
*Pregnancy weight gain was calculated as the difference between prepregnancy weight and weight at the time of intravenous GTT. Gestational age refers to the time of intravenous GTT, as determined by menstrual history and, where indicated, ultrasonography. Numbers in parentheses denote the number of subjects in each group. None of the intergroup differences in mean values was significant at the 0.05 level.
mal pregnant women (five lean, three obese) and women with GDM (eight lean, eight obese) were recruited from the obstetric clinics of Prentice Women's Pavilion of Northwestern Memorial Hospital. None of the nonpregnant or normal pregnant women had a family history of diabetes mellitus. Glucose tolerance was documented in all subjects according to National Diabetes Data Group criteria. '9 To minimize the phenotypic heterogeneity of our study population, II. 12 we excluded women with fasting plasma glucose levels ~130 mg/dl because we consider them to have overt diabetes during pregnancy. We also excluded women with medical or obstetric problems other than GDM and those ingesting medications other than vitamin or iron supplements. All subjects gave written, informed consent for participation in the study, which was approved by the Northwestern University Institutional Review Board. Protocol. Nonpregnant women were studied during the latter half of the menstrual cycle. Pregnant women were studied between 29 and 36 weeks' gestation. All studies were performed on the Clinical Research Center of Northwestern University Medical School, McGaw Medical Center. Subjects ingested a diet that contained ~ 150 gm of carbohydrate per day for 3 days, then underwent a single frequently sampled intravenous glucose tolerance test after a 12-hour overnight fast. Frequently sampled intravenous glucose tolerance tests were performed as follows: dextrose (300 mg/kg body weight as a 50% solution in water) was injected over 60 seconds into an indwelling antecubital venous catheter. Heparinized blood samples (0.3 ml each) were collected from a contralateral antecubital venous catheter 13, 8, and 3 minutes before and 2, 3, 4,5,6,7,8,9, 10, 12, 14, 16, 18, 20, 22, 27, 32, 42, 52, 62, 72,82,92, 102, 122, 142, 162, and 182 minutes after the beginning of the dextrose injection. Plasma was immediately separated and stored at - 20° C for subsequent glucose and insulin measurements. Analytical methods Assays. Glucose was measured by a glucose oxidase method (Glucose Analyzer II, Beckman Instruments,
Fullerton, Calif.). Insulin was measured by a double antibody radioimmunoassay with human insulin standard (Eli Lilly Co., Indianapolis, Ind.). Computer analysis of frequently sampled intravenous glucose tolerance test data. Glucose and insulin data from each frequently sampled intravenous glucose tolerance test were analyzed with the MINMOD computer program,20 which has been used widely to measure insulin sensitivity in humans. 21 . 25 Insulin sensitivity is measured by the MINMOD computer program as the fractional rate of glucose disappearance that can be attributed to the effects of insulin. This measurement takes into account the fact that glucose levels decline by insulin-independent mechanisms immediately after the glucose i~ection.'6. 26. 27 Insulin then acts to increase the glucose disappearance rate. Computer analysis measures this rate increase and relates it to the magnitude of the insulin response to determine insulin sensitivity (units: minutes-I per jLU/ml). In people who are very resistant to insulin, a large insulin response may effect only a small change in the glucose disappearance rate. In some patients this change is so small that it is obscured by imprecisions in plasma glucose measurements. These patients have insulin sensitivity that is below the detection limit of the model. We have determined this limit to be 0.31 x 10- 4 for the glucose model used in these studies. The first-phase insulin response is represented as a bolus of insulin released into the circulation. The change in plasma insulin that results from this bolus, expressed relative to the rise in glucose that stimulated the insulin response, is first-phase B-cell responsiveness '7 (units: [jLUnits per milliliter x minute] per milligram / dl). The second-phase insulin response occurs because B-cells continue to release insulin as long as plasma glucose is elevated above a threshold level!" The rate of insulin release is proportional to the glucose level, although the proportionality constant varies among persons. Second-phase B-cell responsiveness is the proportionality constant that relates the rise in plasma insulin to the degree of glucose elevation '7 (units, [mi-
1010 Buchanan et al.
April 1990 Am J Obstet Gynecol
Table II. Fasting plasma glucose and insulin, insulin sensitivity, and first- and second-phase B-cell responsiveness to glucose in the three study groups* B -cell responsiveness Study group
I
Fasting glucose
Fasting insulin
Insulin sensitivity
First phase
Nonpregnant
90 ± 1
12 ± 1
3.0 ± 0.6
3.8 ± 1.1
39 ± 10
Normal pregnant (n = 8) GDM (n = 16)
80 ± It
12 ± 2
0.9 ± 0.3t
11.0 ± 2.6:j:
129 ± 32:j:
94 ± 4§
24 ± 4§
1.1 ± 0.2t
2.4 ± 0.4§
69 ± 9:j:
(n = 7)
Second phase
*Glucose and insulin are given in mg/dl and ~U/ml, respectively. Units for insulin sensitivity: min- l per ~U/ml X 10- 4 ; for first-phase B-cell responsiveness: (~U/ml x min) per mg/dl; for second-phase B-cell responsiveness: (~U/ml x min- 2 ) per mg/dl. The statistical significance of differences between group mean values is denoted: tp < 0.01 versus nonpregnant; :j:p < 0.05 versus nonpregnant; §p < 0.01 versus normal pregnant.
crounits per milliliter x minute- 2 ] per milligram per deciliter) . Data analysis. Results are expressed as mean ± SE. Kg values were calculated as the slope (X 100) of the line that relates the natural logarithm of the glucose concentration to time between 10 and 40 minutes after the glucose injection. Mean values for Kg, age, nonpregnant relative weight, fasting glucose level, fasting insulin level, first- and second-phase B-cell responsiveness to glucose and insulin sensitivity were compared among nonpregnant, normal pregnant, and gestational diabetic groups by analysis of variance. Mean values for gestational age and weight gain during pregnancy were compared between the normal pregnant group and the group with GDM by unpaired Student t tests. Results
Patient characteristics. The nonpregnant, normal pregnant, and gestational diabetic groups were of similar mean age and nonpregnant relative weight (Table I). Likewise, the mean gestational age and pregnancy weight gain at the time of testing were similar in the normal pregnant group and the group with GDM (Table I). Plasma glucose and insulin patterns. In the normal pregnant group, the plasma glucose level after a 12hour overnight fast (Table II) was lower than that of the nonpregnant group (80 ± 1 versus 90 ± 1 mgl dl; p < 0.01). The mean fasting glucose level of the group with GDM was significantly higher than that of the normal pregnant women (94 ± 4 mg/dl; range, 77 to 121 mg/dl). After the glucose injection, plasma glucose rose to similar levels in the three groups (Fig. 1). The subsequent glucose patterns during the first hour of testing were similar in the nonpregnant and normal pregnant groups. Glucose patterns in these groups then diverged as the normal pregnant women returned to a basal glucose level lower than that ofthe nonpregnant controls. Glucose levels appeared to decline more slowly in women with gestational diabetes than in either of the other two groups (Fig. 1). This impression was
confirmed by a comparison of Kg values among the three groups. As we have observed in earlier studies,6 Kg did not differ significantly between the nonpregnant and normal pregnant groups (1.83 ± 0.08 versus 1.61 ± 0.09, respectively; p > 0.05). However, Kg was lower in the group with gestational diabetes (1.05 ± 0.07) than in each of the other two groups (p < 0.001). The mean of fasting insulin levels in the gestational diabetic group (24 ± 4 ""V I ml; Table II) was elevated, as compared with the nonpregnant and normal pregnant groups (12 ± 1 and 12 ± 2 ""Vlml, respectively). Nonetheless, the greatest insulin response to glucose was observed in the normal pregnant woman. The peak insulin level in that group (274 ± 50 ""Vlml) was more than twofold greater than the peak response in either the nonpregnant women (104 ± 15 ""V Iml) or the women with GDM (l18 ± 18 ""V Iml). Insulin returned to a level not greater than basal within 70 minutes in the nonpregnant women and within 100 minutes in the normal pregnant group. In contrast, insulin levels remained elevated until 160 minutes in the group with GDM, presumably because of the persistently elevated glucose levels in that group. Insulin sensitivity and B-cell responsiveness Nonpregnant group. We were able to identify an insulin-dependent increase in fractional glucose disappearance (i.e., insulin sensitivity) in all of the nonpregnant women. The mean insulin sensitivity in that group was 3.0 ± 0.6 x 10- 4 min- l per ""Vlml (Table II), similar to insulin sensitivity measures that have been reported for lean and moderately obese normal subjects. lB, 21·25 First- and second-phase B-cell responses in the nonpregnant group were 3.8 ± 1.1 [""Vlml x min] per mgldl and 39 ± 10 [""U/ml x min- 2 ] per mgldl, respectively (Table II). Normal pregnant group. Pregnancy was associated with a marked reduction in insulin sensitivity. In fact, we were unable to measure an insulin-dependent increase in glucose disappearance in three (38%) of the eight normal pregnant women. We assigned a value of
Insulin sensitivity and secretion in gestational diabetes
Volume 162 Number 4
Normal
NonPregnant A
Pregnant 0
GDM
1011
+
300
Glucose (mg/dll
o 300
60
120
180
60
120
180
I
200 Insulin (uUlmll 100
o
o
Minutes Fig. 1. Mean plasma glucose and insulin concentrations during intravenous GTTs in the three study groups. Glucose (300 mg/kg body weight) was injected into an antecubital vein at t '" 0 (arrow).
0.31 X 10- 4 to insulin sensitivity in these women because that was the lower limit of insulin sensitivity that our computer analysis could detect. The resultant mean insulin sensitivity of the normal pregnant group (0.9 ± 0.3 x 10- 4 min- 1 per f.LU/ml) was reduced 70% below that of the nonpregnant women (p < 0.01). We observed a trend toward greater insulin resistance in the obese, as compared with the lean normal pregnant women (0.47 ± 0.29 10- 4 versus 1.04 ± 0.45 10- 4 min- 1 per f.LU/ml, respectively), although this difference was not statistically significant. In association with this marked insulin resistance, normal pregnant women had mean first-phase Bcell responsiveness (11.0 ± 2.6 [f.LU Iml X min] per mg/dl) that was increased nearly threefold as compared with the nonpregnant group (p < 0.05; Ta-
ble II). Second-phase B-cell responsiveness (129 ± 32 [f.LU/ml X min- 2] per mg/dl) was likewise increased approximately threefold above that in nonpregnant women (p < 0.05; Table II). Gestational diabetic [ffoup. Women with GDM had insulin resistance that was similar in magnitude to that of the normal pregnant women. We were unable to identify an insulin-mediated increase in glucose disappearance in seven (44%) of the women with GDM (P > 0.4 compared with normal pregnancy). After assignment of a value of 0.31 x 10- 4 to insulin sensitivity in those women, we found that mean insulin sensitivity for the entire group with GDM (1.1 ± 0.2 x 10- 4 min- 1 per f.LU/ml) was not lower than that of normal pregnant women (0.9 ± 0.3 X 10- 4 ; Table II). We were concerned that the seven women with GDM and
1012 Buchanan et al.
insulin sensitivity below the detection limit might actually have had lower insulin sensitivity than that of the three normal pregnant women with an undetectable insulin effect. Therefore we repeated the insulin sensitivity comparisons after assignment of a value of zero in the gestational diabetic women with values below the detection limit. Even in this "worst case" comparison, the mean of insulin sensitivity in the women with GDM (0.9 ± 0.2 X 10- 4 ) was not lower than that of normal pregnant women (p> 0.9). Thus we found no exaggeration of the normal insulin resistance of late pregnancy in women with mild GDM. In contrast to insulin sensitivity, B-cell function was different between the normal pregnant group and the group with gestational diabetes (Table II). The mean of first-phase B-cell responsiveness in the women with GD M was less than one fourth that of the normal pregnant group (2.4 ± 0.4 versus 11 ± 2.6 [fLU /ml] x min per mg/dl; p < 0.01). The mean of second-phase responsiveness was also lower in the women with GDM (69 ± 9 versus 129 ± 32 [fLU/ml x min- 2] per mg/ dl), although this difference was of borderline statistical significance (p < 0.09). Despite these differences in mean values, some of the women with GDM appeared to have well-preserved B-cell responses. Three had first-phase insulin responses that fell within the 95% confidence interval of the mean for normal pregnant women. Ten had second-phase B-cell responses that were within the 95% confidence interval for the normal pregnant group. However, only one woman with GDM had both first- and second-phase B-cell responses that were within the 95% confidence intervals for the normal pregnant means. Lean and obese women. The sizes of the nonpregnant and normal pregnant groups (seven and eight subjects, respectively) precluded meaningful statistical comparisons of insulin sensitivity and B-cell responsiveness between lean and obese women within each of these groups. Comparison of lean and obese women with GDM revealed similar first-phase (2.03 ± 0.61 versus 2.73 ± 0.63 [fLU/ml] x min per mg/dl, respectively) and second-phase (65 ± 14 versus 74 ± 13 [fLU/ml x min- 2] per mg/dl) B-cell responsiveness in these subgroups. Mean insulin sensitivity was somewhat lower in the lean than in the obese women with GDM (0.66 ± 0.25 versus 1.53 ± 0.28 min -I per fLU / ml). However, none of these intergroup differences reached statistical significance at the 0.05 level. Comment
Minimal model analysis allowed us to obtain simultaneous and quantitative measures of insulin sensitivity and pancreatic B-cell function in vivo during the late phase of human pregnancy. This approach revealed that lean and moderately obese women during the third
April 1990 Am] Obstet Gynecol
trimester had insulin sensitivity that was reduced by approximately two thirds as compared with a group of nonpregnant women of similar age and relative weight. This represents a remarkable reduction in insulin's action on glucose disposition. In fact, of a variety of clinical situations in which insulin sensitivity has been measured with the minimal model, only noninsulindependent diabetes mellitus has been associated with lower insulin sensitivity than we found in normal pregnant women!I-25, 29 Thus pregnancy represents the most extreme example of physiologic insulin resistance that we have encountered to date. In the face of this marked insulin resistance, firstand second-phase pancreatic B-cell responses to glucose were increased approximately threefold in the normal pregnant women as compared with the nonpregnant women. The fact that insulin sensitivity in the pregnant group was reduced to one third that of nonpregnant controls, whereas insulin responses were increased threefold, indicates that the alterations in insulin action and B-cell function, which are known to accompany late pregnancy,I-7 are not simply qualitatively reciprocal, but are quantitatively reciprocal in nature. Our present data do not reveal whether these reciprocal alterations represent primary reductions in insulin sensitivity that are compensated by enhanced Bcell function or vice versa. However, the increasing exogenous insulin requirements of women with type I diabetes during pregnancy30-32 suggest that reduced insulin sensitivity is a primary event during gestation. 33 In that context our findings show the great capacity of normal human B cells to compensate for reductions in insulin sensitivity. Results from our patients with gestational diabetes suggested an abnormality in this compensatory capacity of B cells. As was true for normal pregnant women, insulin sensitivity in the gestational diabetic group was reduced to approximately one third that of nonpregnant women. Thus during the late phase of pregnancy GDM was not accompanied by insulin resistance beyond that accounted for by the effects of gestation per se. By contrast, the B-cell adaptation to this insulin resistance was impaired in the women with GDM. In keeping with the report of Yen et al.,I3 we found the impairment to be most marked for the first-phase insulin response to glucose, which was less than one fourth that of the normal pregnant women. Fully 80% of the gestational diabetic group had first-phase responses that were below the 95% confidence interval for the mean of normal pregnant women. The mean of second-phase insulin responses in the GDM group also was lower than that of the normal pregnant group. However, this difference was of borderline statistical
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Insulin sensitivity and secretion in gestational diabetes
significance and only 38% of the women with GDM had second-phase responses that were below the 95% confidence interval for the mean in normal pregnant women. These findings indicate that there is clearly heterogeneity of B-cell function in women with GDM, as we have reported previously'" 9-12 Nonetheless, because only one woman with GDM had both first- and second-phase insulin responses that were within 95% confidence intervals for mean values in the normal pregnant group, our findings suggest a defect in B-cell function, rather than an exaggeration of the normal insulin resistance oflate pregnancy, as the predominant abnormality in women with mild GDM during the third trimester. The elevated fasting insulin levels in the GDM group are not inconsistent with such a B-cell defect because they occurred under the combined influences of pregnancy-related insulin resistance and mild hyperglycemia.
selection may be responsible for the different insulin sensitivity results between the two studies. A full comparison of these studies is precluded because Ryan et al. did not characterize B-cell function in their patients. In summary, we report the first application of minimal model analysis to obtain simultaneous quantification of insulin sensitivity and pancreatic B-cell function during pregnancy. We found that late normal pregnancy in lean and moderately. obese women was associated with a two thirds reduction in insulin sensitivity, as compared with the non gravid state. This insulin resistance was compensated by threefold increases in first- and second-phase insulin responses to intravenous glucose. Women with mild GDM had insulin sensitivity that was similar to that of normal pregnant women. However, insulin responses to glucose, especially first-phase responses, were impaired in GDM. Our findings suggest that failure of pancreatic B-cell compensation for the normal insulin resistance of late pregnancy represents a predominant defect in women with mild GDM during the third trimester. Careful follow-up studies will be required to determine whether this B-cell defect, a defect in insulin action that becomes apparent after the insulin resistance of pregnancy subsides, or both can be used to predict the development of diabetes in later life.
Our data are cross-sectional. Therefore it is not possible to determine the extent to which our results reflect events that lead to the development of GDM. With regard to insulin sensitivity, Ward et al. have reported insulin resistance in former gestational diabetic women soon after their index pregnancy!4.25 It is possible that similar defects were present in our patients before or during the early phase of gestation but were small compared with the marked insulin resistance of the third trimester. Only longitudinal studies can address that possibility. Nonetheless, our findings do not implicate an exaggeration of the normal insulin resistance of pregnancy as the cause of glucose intolerance in our patients duriilg the third trimester. With regard to Bcell function, hyperglycemia per se may impair insulin responses to a glucose challenge. This defect may be partially reversed by normalization of circulating glucose levels with insulin.'4-36 In our own hands, this approach caused less than a twofold increase in the firstphase insulin response to intravenous glucose after 2 weeks of pre meal normoglycemia in a separate group of women with mild GDM (Buchanan TA, Metzger BE, and Freinkel N. Unpublished observations). Because we found first-phase responsiveness to be less than one fourth that of normal pregnant women in the present study, it is unlikely that the B-cell defects in our patients with GDM resulted wholly from the effects of hyperglycemia on B-cell function. Our results in women with GDM differ from those of Ryan et al.," who found that insulin sensitivity measured by the euglycemic clamp technique was lower in three of five gestational diabetic women than in five normal pregnant women. Fasting blood glucose levels in three of their patients was> 130 mg/dl, whereas the fasting plasma glucose level was ::;121 mg/dl in all of our patients. Because insulin resistance is a well-known characteristic of overt diabetes, differences in patient
1013
We thank the nurses of the Clinical Research Center of Northwestern University for their help in performing these studies and Joyce Schemmer, Terry Agajanian, and Richard Watanabe for their excellent technical assistance. REFERENCES 1. Burt RL. Peripheral utilization of glucose in pregnancy. III. Insulin tolerance. Obstet Gynecol 1956;7:658-64. 2. Burt RL. Reactivity to tolbutamide in normal pregnancy. Obstet Gynecol 1958;12:447-58. 3. Knopp RH, Ruder HJ, Herrera E, Freinkel N. Carbohydrate metabolism in pregnancy. VII. Insulin tolerance during late pregnancy in the fed and fasted rat. Acta Endocrinol 1970;65:352-9. 4. Metzger BE, Freinkel N. Effects of diabetes mellitus on endocrinologic and metabolic adaptations of gestation. Semin Perinatol 1978;2:309-24. 5. Spellacy WN, Goetz FC. Plasma insulin in normal late pregnancy. N Engl J Med 1963;268:988-91. 6. Bleicher SJ, O'SullivanJB, Freinkel N. Carbohydrate metabolism in pregnancy. V. The interaction of glucose, insulin and free fatty acids in late pregnancy and postpartum. N EnglJ Med 1961;271:866-72. 7. Kalkhoff R, Schalch DS, Walker JL, Beck P, Kipnis DM, Daughaday WHo Diabetogenic factors associated with pregnancy. Trans Assoc Am Physicians 1964;77:270-9. 8. Ryan EA, O'Suliian MJ, Skyler JS. Insulin action during pregnancy. Diabetes 1985;34:380-9. 9. Metzger BE, Freinkel N. Inquiries into the pathogenesis of gestational diabetes. In: Camerini-Davalos RA, Hanover B, eds. Treatment of Early Diabetes. New York: Plenum Press, 1979:201-8. 10. Freinkel N, Metzger BE. Gestational diabetes in Chicago.
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In: Bibergill H, Huhlke H, Poser U, eds. Proceedings of the Satellite Symposium to the 10th IDF Congress of Vienna. Karlsburg, East Germany (Sept. 4-6, 1979). Karlsburg: Central Institute for Diabetes, "Gerhard Katsch," 1980:438-42. Freinkel N, Metzger BE, Phelps RL, et al. Gestational diabetes mellitus: heterogeneity of maternal age, weight, insulin secretion, HLA antigens, and islet cell antibodies and the impact of maternal metabolism on pancreatic Bcell function and somatic growth in the offspring. Diabetes 1985;34(suppI2):1-7. Freinkel N, Metzger BE, Phelps RL, et al. Gestational diabetes mellitus: a syndrome with phenotypic and genotypic heterogeneity. Horm Metab Res 1986;18:427-33. Yen SCC, Tsai CC, Vela P. Gestational diabetogenesis: quantitative analysis of glucose-insulin interrelationship between normal pregnancy and pregnancy with gestational diabetes. AMJ OBSTET GYNECOL 1971;111 :792-800. Kuhl C, Holst JJ. Plasma glucagon and the insulin/glucagon ratio in gestational diabetes. Diabetes 1976;25:1623. Fisher PM, Sutherland HW, Bewsher PD. The insulin response to glucose infusion in gestational diabetes. Diabetologia 1980;19:10-20. Bergman RN, Ider YZ, Bowden CR, Cobelli C. Quantitative estimation of insulin sensitivity. Am J Physiol 1979;236:E667-77. Tofollo GR, Bergman RN, Finegood DT, Bowden DR, Cobelli C. Quantitative estimation of B-cell sensitivity to glucose in the intact organism: a minimal model of insulin kinetics in the dog. Diabetes 1980;29:979-90. Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose disposition in man. J Clin Invest 1981;68:1456-67. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;29: 1039-57. Pacini G, Bergman RN. MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Com put Methods Programs Biomed 1986; 23: 113-22. Chen M, Bergman RN, Pacini G, Porte D, Jr. Pathogenesis of age-related glucose intolerance in man: insulin resistance and decreased B-cell function. J Clin Endocrinol Metab 1985;60: 13-20. Beard JC, Bergman RN, Ward WK, Porte D Jr. The in-
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sulin sensItivity index in nondiabetic man. Diabetes 1986;35:362-9. Bergman RN, Prager R, Volund A, Olefsky JM. Equivalence of the insulin sensitivity index in man derived by the minimal model and the euglycemic glucose clamp. J Clin Invest 1987;79:790-800. Ward WK, Johnston CLW, Beard JC, Benedetti TJ, Porte D. Abnormalities of islet B-cell function, insulin action and fat distribution in women with a history of gestational diabetes: relation to obesity.J Clin Endocrinol Metab 1985;61:1039-45. Ward WK,Johnston CLW, BeardJC, Benedetti TJ, Halter JB, Porte D. Insulin resistance and impaired insulin secretion in subjects with a history of gestational diabetes mellitus. Diabetes 1985;34:861-9. Sherwin RS, Kramer KJ, Tobin JD, et al. A model of insulin kinetics in man.J Clin Invest 1974;53:1481-92. Insel PA, Liljenquist JE, Tobin J, et al. Insulin control of glucose metabolism in man.J Clin Invest 1975;55:105766. Bergman RN, Urquhart J. The pilot gland approach to the study of insulin secretory dynamics. Recent Prog Horm Res 1971;27:583-90. Bergman RN. Towards physiological understanding of glucose tolerance: minimal model approach. Diabetes 1989;38:1512-27. Pedersen J. Course of diabetes during pregnancy. Acta Endocrinol 1952;9:342-64. Jovanovic L, Druzin M, Peterson CM. Effect of euglycemia on the outcome of pregnancy in insulin-dependent diabetic women as compared with normal control subjects. AmJ Med 1981;71:921-7. Rudolf MC, Coustan DR, Sherwin RS, et al. Efficacy of the insulin pump in home treatment of pregnant diabetics. Diabetes 1981;30:891-5. Freinkel N. The effect of pregnancy on insulin homeostasis. Diabetes 1964;13:260-7. Turner RC, McCarthy ST, Holman RR, Harris E. Betacell function improved by supplementing basal insulin secretion in mild diabetes. Br Med J 1976; 1: 1252-4. Vague P, Moulin J-P. Defective glucose sensitivity of the B-cell in noninsulin-dependent diabetes. Metabolism 1982;31:139-42. Hideki H, Nagulesparan M, Klimes I, eta!' Improvement of insulin secretion but not insulin resistance after shortterm control of plasma glucose in obese Type II diabetics. J Clin Endocrinol Metab 1982;54:217-22.
Key words: Insulin sensitivity, insulin secretion, gestational diabetes mellitus
It is well known that insulin's ability to lower circulating glucose is impaired,I.4 whereas pancreatic B-cell responses to glucose are enhanced 5. 7 during the latter half of pregnancy. However, it has not been possible to quantify these changes precisely and simultaneously. Thus the magnitude of the insulin resistance of late pregnancy and that of the attendant B-cell responses to this resistance are not known. Likewise, the degree to which abnormalities of insulin sensitivityS and
From the Center for Endocrinology, Metabolism and Nutrition, and the Departments of Medicine and Molecular Biology, Northwestern University Medical School,' and the Departments of Medicine" and Physiology and Biophysics,' University of Southern California School of Medicine. Supported by Research Grant Nos. AM10699, MRP-HDI1021, HD-19070 and DK-29867; General Clinical Research Center Grant No. RR-48, and Training Grant No. AM07169 from the National Institutes of Health. Dr. Buchanan was supported by a Clinical Research Fellowship from the Chicago Community Trust and an Individual National Research Service Award from the National Institutes of Health (AM-07008-02). Received for publication July 17, 1989; accepted December 4, 1989. Reprint requests: Thomas A. Buchanan, MD, OCD 252,2025 Zonal Ave., Los Angeles, CA 90033. tDeceased. 611118572
secretion 4. 9·15 contribute to the genesis of gestational diabetes mellitus (GDM) remains to be identified. A method has become available with which to address these issues. Computer analysis of glucose and insulin data from a frequently sampled intravenous glucose tolerance test provides quantitative measures of insulin sensitivity and B-cell responsiveness to glucose at the same time. 16.1S This method is relatively noninvasive and thus can be applied safely during pregnancy. We have used computer modeling of frequently sampled intravenous glucose tolerance test data to obtain what we believe to be the first quantitative and simultaneous measures of insulin sensitivity and B-cell function during late pregnancy in normal women and women with GDM.
Material and methods Subjects. Nonpregnant control women (four lean, three obese*) were recruited from the staff of the Northwestern University McGaw Medical Center. Nor*Obesity denotes nonpregnant weight 2:120% of ideal or pregnancy weight gain 2: 18 kg by the time of the frequently sampled intravenous glucose tolerance test.
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1009
Table I. Clinical characteristics of the three study groups* Study group
Age (yr)
Nonpregnant weight (% ideal)
Pregnancy weight gain
Nonpregnant (n = 7) Normal pregnant (n = 8) GDM (n = 16)
29 ± 2
112 ± 8
29 ±
III ± I
12.3 ± 0.9
33.8 ± 0.8
30 ±
117 ± 4
11.6 ± 1.2
32.2 ± 0.5
(kg)
Gestational age (wk)
*Pregnancy weight gain was calculated as the difference between prepregnancy weight and weight at the time of intravenous GTT. Gestational age refers to the time of intravenous GTT, as determined by menstrual history and, where indicated, ultrasonography. Numbers in parentheses denote the number of subjects in each group. None of the intergroup differences in mean values was significant at the 0.05 level.
mal pregnant women (five lean, three obese) and women with GDM (eight lean, eight obese) were recruited from the obstetric clinics of Prentice Women's Pavilion of Northwestern Memorial Hospital. None of the nonpregnant or normal pregnant women had a family history of diabetes mellitus. Glucose tolerance was documented in all subjects according to National Diabetes Data Group criteria. '9 To minimize the phenotypic heterogeneity of our study population, II. 12 we excluded women with fasting plasma glucose levels ~130 mg/dl because we consider them to have overt diabetes during pregnancy. We also excluded women with medical or obstetric problems other than GDM and those ingesting medications other than vitamin or iron supplements. All subjects gave written, informed consent for participation in the study, which was approved by the Northwestern University Institutional Review Board. Protocol. Nonpregnant women were studied during the latter half of the menstrual cycle. Pregnant women were studied between 29 and 36 weeks' gestation. All studies were performed on the Clinical Research Center of Northwestern University Medical School, McGaw Medical Center. Subjects ingested a diet that contained ~ 150 gm of carbohydrate per day for 3 days, then underwent a single frequently sampled intravenous glucose tolerance test after a 12-hour overnight fast. Frequently sampled intravenous glucose tolerance tests were performed as follows: dextrose (300 mg/kg body weight as a 50% solution in water) was injected over 60 seconds into an indwelling antecubital venous catheter. Heparinized blood samples (0.3 ml each) were collected from a contralateral antecubital venous catheter 13, 8, and 3 minutes before and 2, 3, 4,5,6,7,8,9, 10, 12, 14, 16, 18, 20, 22, 27, 32, 42, 52, 62, 72,82,92, 102, 122, 142, 162, and 182 minutes after the beginning of the dextrose injection. Plasma was immediately separated and stored at - 20° C for subsequent glucose and insulin measurements. Analytical methods Assays. Glucose was measured by a glucose oxidase method (Glucose Analyzer II, Beckman Instruments,
Fullerton, Calif.). Insulin was measured by a double antibody radioimmunoassay with human insulin standard (Eli Lilly Co., Indianapolis, Ind.). Computer analysis of frequently sampled intravenous glucose tolerance test data. Glucose and insulin data from each frequently sampled intravenous glucose tolerance test were analyzed with the MINMOD computer program,20 which has been used widely to measure insulin sensitivity in humans. 21 . 25 Insulin sensitivity is measured by the MINMOD computer program as the fractional rate of glucose disappearance that can be attributed to the effects of insulin. This measurement takes into account the fact that glucose levels decline by insulin-independent mechanisms immediately after the glucose i~ection.'6. 26. 27 Insulin then acts to increase the glucose disappearance rate. Computer analysis measures this rate increase and relates it to the magnitude of the insulin response to determine insulin sensitivity (units: minutes-I per jLU/ml). In people who are very resistant to insulin, a large insulin response may effect only a small change in the glucose disappearance rate. In some patients this change is so small that it is obscured by imprecisions in plasma glucose measurements. These patients have insulin sensitivity that is below the detection limit of the model. We have determined this limit to be 0.31 x 10- 4 for the glucose model used in these studies. The first-phase insulin response is represented as a bolus of insulin released into the circulation. The change in plasma insulin that results from this bolus, expressed relative to the rise in glucose that stimulated the insulin response, is first-phase B-cell responsiveness '7 (units: [jLUnits per milliliter x minute] per milligram / dl). The second-phase insulin response occurs because B-cells continue to release insulin as long as plasma glucose is elevated above a threshold level!" The rate of insulin release is proportional to the glucose level, although the proportionality constant varies among persons. Second-phase B-cell responsiveness is the proportionality constant that relates the rise in plasma insulin to the degree of glucose elevation '7 (units, [mi-
1010 Buchanan et al.
April 1990 Am J Obstet Gynecol
Table II. Fasting plasma glucose and insulin, insulin sensitivity, and first- and second-phase B-cell responsiveness to glucose in the three study groups* B -cell responsiveness Study group
I
Fasting glucose
Fasting insulin
Insulin sensitivity
First phase
Nonpregnant
90 ± 1
12 ± 1
3.0 ± 0.6
3.8 ± 1.1
39 ± 10
Normal pregnant (n = 8) GDM (n = 16)
80 ± It
12 ± 2
0.9 ± 0.3t
11.0 ± 2.6:j:
129 ± 32:j:
94 ± 4§
24 ± 4§
1.1 ± 0.2t
2.4 ± 0.4§
69 ± 9:j:
(n = 7)
Second phase
*Glucose and insulin are given in mg/dl and ~U/ml, respectively. Units for insulin sensitivity: min- l per ~U/ml X 10- 4 ; for first-phase B-cell responsiveness: (~U/ml x min) per mg/dl; for second-phase B-cell responsiveness: (~U/ml x min- 2 ) per mg/dl. The statistical significance of differences between group mean values is denoted: tp < 0.01 versus nonpregnant; :j:p < 0.05 versus nonpregnant; §p < 0.01 versus normal pregnant.
crounits per milliliter x minute- 2 ] per milligram per deciliter) . Data analysis. Results are expressed as mean ± SE. Kg values were calculated as the slope (X 100) of the line that relates the natural logarithm of the glucose concentration to time between 10 and 40 minutes after the glucose injection. Mean values for Kg, age, nonpregnant relative weight, fasting glucose level, fasting insulin level, first- and second-phase B-cell responsiveness to glucose and insulin sensitivity were compared among nonpregnant, normal pregnant, and gestational diabetic groups by analysis of variance. Mean values for gestational age and weight gain during pregnancy were compared between the normal pregnant group and the group with GDM by unpaired Student t tests. Results
Patient characteristics. The nonpregnant, normal pregnant, and gestational diabetic groups were of similar mean age and nonpregnant relative weight (Table I). Likewise, the mean gestational age and pregnancy weight gain at the time of testing were similar in the normal pregnant group and the group with GDM (Table I). Plasma glucose and insulin patterns. In the normal pregnant group, the plasma glucose level after a 12hour overnight fast (Table II) was lower than that of the nonpregnant group (80 ± 1 versus 90 ± 1 mgl dl; p < 0.01). The mean fasting glucose level of the group with GDM was significantly higher than that of the normal pregnant women (94 ± 4 mg/dl; range, 77 to 121 mg/dl). After the glucose injection, plasma glucose rose to similar levels in the three groups (Fig. 1). The subsequent glucose patterns during the first hour of testing were similar in the nonpregnant and normal pregnant groups. Glucose patterns in these groups then diverged as the normal pregnant women returned to a basal glucose level lower than that ofthe nonpregnant controls. Glucose levels appeared to decline more slowly in women with gestational diabetes than in either of the other two groups (Fig. 1). This impression was
confirmed by a comparison of Kg values among the three groups. As we have observed in earlier studies,6 Kg did not differ significantly between the nonpregnant and normal pregnant groups (1.83 ± 0.08 versus 1.61 ± 0.09, respectively; p > 0.05). However, Kg was lower in the group with gestational diabetes (1.05 ± 0.07) than in each of the other two groups (p < 0.001). The mean of fasting insulin levels in the gestational diabetic group (24 ± 4 ""V I ml; Table II) was elevated, as compared with the nonpregnant and normal pregnant groups (12 ± 1 and 12 ± 2 ""Vlml, respectively). Nonetheless, the greatest insulin response to glucose was observed in the normal pregnant woman. The peak insulin level in that group (274 ± 50 ""Vlml) was more than twofold greater than the peak response in either the nonpregnant women (104 ± 15 ""V Iml) or the women with GDM (l18 ± 18 ""V Iml). Insulin returned to a level not greater than basal within 70 minutes in the nonpregnant women and within 100 minutes in the normal pregnant group. In contrast, insulin levels remained elevated until 160 minutes in the group with GDM, presumably because of the persistently elevated glucose levels in that group. Insulin sensitivity and B-cell responsiveness Nonpregnant group. We were able to identify an insulin-dependent increase in fractional glucose disappearance (i.e., insulin sensitivity) in all of the nonpregnant women. The mean insulin sensitivity in that group was 3.0 ± 0.6 x 10- 4 min- l per ""Vlml (Table II), similar to insulin sensitivity measures that have been reported for lean and moderately obese normal subjects. lB, 21·25 First- and second-phase B-cell responses in the nonpregnant group were 3.8 ± 1.1 [""Vlml x min] per mgldl and 39 ± 10 [""U/ml x min- 2 ] per mgldl, respectively (Table II). Normal pregnant group. Pregnancy was associated with a marked reduction in insulin sensitivity. In fact, we were unable to measure an insulin-dependent increase in glucose disappearance in three (38%) of the eight normal pregnant women. We assigned a value of
Insulin sensitivity and secretion in gestational diabetes
Volume 162 Number 4
Normal
NonPregnant A
Pregnant 0
GDM
1011
+
300
Glucose (mg/dll
o 300
60
120
180
60
120
180
I
200 Insulin (uUlmll 100
o
o
Minutes Fig. 1. Mean plasma glucose and insulin concentrations during intravenous GTTs in the three study groups. Glucose (300 mg/kg body weight) was injected into an antecubital vein at t '" 0 (arrow).
0.31 X 10- 4 to insulin sensitivity in these women because that was the lower limit of insulin sensitivity that our computer analysis could detect. The resultant mean insulin sensitivity of the normal pregnant group (0.9 ± 0.3 x 10- 4 min- 1 per f.LU/ml) was reduced 70% below that of the nonpregnant women (p < 0.01). We observed a trend toward greater insulin resistance in the obese, as compared with the lean normal pregnant women (0.47 ± 0.29 10- 4 versus 1.04 ± 0.45 10- 4 min- 1 per f.LU/ml, respectively), although this difference was not statistically significant. In association with this marked insulin resistance, normal pregnant women had mean first-phase Bcell responsiveness (11.0 ± 2.6 [f.LU Iml X min] per mg/dl) that was increased nearly threefold as compared with the nonpregnant group (p < 0.05; Ta-
ble II). Second-phase B-cell responsiveness (129 ± 32 [f.LU/ml X min- 2] per mg/dl) was likewise increased approximately threefold above that in nonpregnant women (p < 0.05; Table II). Gestational diabetic [ffoup. Women with GDM had insulin resistance that was similar in magnitude to that of the normal pregnant women. We were unable to identify an insulin-mediated increase in glucose disappearance in seven (44%) of the women with GDM (P > 0.4 compared with normal pregnancy). After assignment of a value of 0.31 x 10- 4 to insulin sensitivity in those women, we found that mean insulin sensitivity for the entire group with GDM (1.1 ± 0.2 x 10- 4 min- 1 per f.LU/ml) was not lower than that of normal pregnant women (0.9 ± 0.3 X 10- 4 ; Table II). We were concerned that the seven women with GDM and
1012 Buchanan et al.
insulin sensitivity below the detection limit might actually have had lower insulin sensitivity than that of the three normal pregnant women with an undetectable insulin effect. Therefore we repeated the insulin sensitivity comparisons after assignment of a value of zero in the gestational diabetic women with values below the detection limit. Even in this "worst case" comparison, the mean of insulin sensitivity in the women with GDM (0.9 ± 0.2 X 10- 4 ) was not lower than that of normal pregnant women (p> 0.9). Thus we found no exaggeration of the normal insulin resistance of late pregnancy in women with mild GDM. In contrast to insulin sensitivity, B-cell function was different between the normal pregnant group and the group with gestational diabetes (Table II). The mean of first-phase B-cell responsiveness in the women with GD M was less than one fourth that of the normal pregnant group (2.4 ± 0.4 versus 11 ± 2.6 [fLU /ml] x min per mg/dl; p < 0.01). The mean of second-phase responsiveness was also lower in the women with GDM (69 ± 9 versus 129 ± 32 [fLU/ml x min- 2] per mg/ dl), although this difference was of borderline statistical significance (p < 0.09). Despite these differences in mean values, some of the women with GDM appeared to have well-preserved B-cell responses. Three had first-phase insulin responses that fell within the 95% confidence interval of the mean for normal pregnant women. Ten had second-phase B-cell responses that were within the 95% confidence interval for the normal pregnant group. However, only one woman with GDM had both first- and second-phase B-cell responses that were within the 95% confidence intervals for the normal pregnant means. Lean and obese women. The sizes of the nonpregnant and normal pregnant groups (seven and eight subjects, respectively) precluded meaningful statistical comparisons of insulin sensitivity and B-cell responsiveness between lean and obese women within each of these groups. Comparison of lean and obese women with GDM revealed similar first-phase (2.03 ± 0.61 versus 2.73 ± 0.63 [fLU/ml] x min per mg/dl, respectively) and second-phase (65 ± 14 versus 74 ± 13 [fLU/ml x min- 2] per mg/dl) B-cell responsiveness in these subgroups. Mean insulin sensitivity was somewhat lower in the lean than in the obese women with GDM (0.66 ± 0.25 versus 1.53 ± 0.28 min -I per fLU / ml). However, none of these intergroup differences reached statistical significance at the 0.05 level. Comment
Minimal model analysis allowed us to obtain simultaneous and quantitative measures of insulin sensitivity and pancreatic B-cell function in vivo during the late phase of human pregnancy. This approach revealed that lean and moderately obese women during the third
April 1990 Am] Obstet Gynecol
trimester had insulin sensitivity that was reduced by approximately two thirds as compared with a group of nonpregnant women of similar age and relative weight. This represents a remarkable reduction in insulin's action on glucose disposition. In fact, of a variety of clinical situations in which insulin sensitivity has been measured with the minimal model, only noninsulindependent diabetes mellitus has been associated with lower insulin sensitivity than we found in normal pregnant women!I-25, 29 Thus pregnancy represents the most extreme example of physiologic insulin resistance that we have encountered to date. In the face of this marked insulin resistance, firstand second-phase pancreatic B-cell responses to glucose were increased approximately threefold in the normal pregnant women as compared with the nonpregnant women. The fact that insulin sensitivity in the pregnant group was reduced to one third that of nonpregnant controls, whereas insulin responses were increased threefold, indicates that the alterations in insulin action and B-cell function, which are known to accompany late pregnancy,I-7 are not simply qualitatively reciprocal, but are quantitatively reciprocal in nature. Our present data do not reveal whether these reciprocal alterations represent primary reductions in insulin sensitivity that are compensated by enhanced Bcell function or vice versa. However, the increasing exogenous insulin requirements of women with type I diabetes during pregnancy30-32 suggest that reduced insulin sensitivity is a primary event during gestation. 33 In that context our findings show the great capacity of normal human B cells to compensate for reductions in insulin sensitivity. Results from our patients with gestational diabetes suggested an abnormality in this compensatory capacity of B cells. As was true for normal pregnant women, insulin sensitivity in the gestational diabetic group was reduced to approximately one third that of nonpregnant women. Thus during the late phase of pregnancy GDM was not accompanied by insulin resistance beyond that accounted for by the effects of gestation per se. By contrast, the B-cell adaptation to this insulin resistance was impaired in the women with GDM. In keeping with the report of Yen et al.,I3 we found the impairment to be most marked for the first-phase insulin response to glucose, which was less than one fourth that of the normal pregnant women. Fully 80% of the gestational diabetic group had first-phase responses that were below the 95% confidence interval for the mean of normal pregnant women. The mean of second-phase insulin responses in the GDM group also was lower than that of the normal pregnant group. However, this difference was of borderline statistical
Volume 162 Number 4
Insulin sensitivity and secretion in gestational diabetes
significance and only 38% of the women with GDM had second-phase responses that were below the 95% confidence interval for the mean in normal pregnant women. These findings indicate that there is clearly heterogeneity of B-cell function in women with GDM, as we have reported previously'" 9-12 Nonetheless, because only one woman with GDM had both first- and second-phase insulin responses that were within 95% confidence intervals for mean values in the normal pregnant group, our findings suggest a defect in B-cell function, rather than an exaggeration of the normal insulin resistance oflate pregnancy, as the predominant abnormality in women with mild GDM during the third trimester. The elevated fasting insulin levels in the GDM group are not inconsistent with such a B-cell defect because they occurred under the combined influences of pregnancy-related insulin resistance and mild hyperglycemia.
selection may be responsible for the different insulin sensitivity results between the two studies. A full comparison of these studies is precluded because Ryan et al. did not characterize B-cell function in their patients. In summary, we report the first application of minimal model analysis to obtain simultaneous quantification of insulin sensitivity and pancreatic B-cell function during pregnancy. We found that late normal pregnancy in lean and moderately. obese women was associated with a two thirds reduction in insulin sensitivity, as compared with the non gravid state. This insulin resistance was compensated by threefold increases in first- and second-phase insulin responses to intravenous glucose. Women with mild GDM had insulin sensitivity that was similar to that of normal pregnant women. However, insulin responses to glucose, especially first-phase responses, were impaired in GDM. Our findings suggest that failure of pancreatic B-cell compensation for the normal insulin resistance of late pregnancy represents a predominant defect in women with mild GDM during the third trimester. Careful follow-up studies will be required to determine whether this B-cell defect, a defect in insulin action that becomes apparent after the insulin resistance of pregnancy subsides, or both can be used to predict the development of diabetes in later life.
Our data are cross-sectional. Therefore it is not possible to determine the extent to which our results reflect events that lead to the development of GDM. With regard to insulin sensitivity, Ward et al. have reported insulin resistance in former gestational diabetic women soon after their index pregnancy!4.25 It is possible that similar defects were present in our patients before or during the early phase of gestation but were small compared with the marked insulin resistance of the third trimester. Only longitudinal studies can address that possibility. Nonetheless, our findings do not implicate an exaggeration of the normal insulin resistance of pregnancy as the cause of glucose intolerance in our patients duriilg the third trimester. With regard to Bcell function, hyperglycemia per se may impair insulin responses to a glucose challenge. This defect may be partially reversed by normalization of circulating glucose levels with insulin.'4-36 In our own hands, this approach caused less than a twofold increase in the firstphase insulin response to intravenous glucose after 2 weeks of pre meal normoglycemia in a separate group of women with mild GDM (Buchanan TA, Metzger BE, and Freinkel N. Unpublished observations). Because we found first-phase responsiveness to be less than one fourth that of normal pregnant women in the present study, it is unlikely that the B-cell defects in our patients with GDM resulted wholly from the effects of hyperglycemia on B-cell function. Our results in women with GDM differ from those of Ryan et al.," who found that insulin sensitivity measured by the euglycemic clamp technique was lower in three of five gestational diabetic women than in five normal pregnant women. Fasting blood glucose levels in three of their patients was> 130 mg/dl, whereas the fasting plasma glucose level was ::;121 mg/dl in all of our patients. Because insulin resistance is a well-known characteristic of overt diabetes, differences in patient
1013
We thank the nurses of the Clinical Research Center of Northwestern University for their help in performing these studies and Joyce Schemmer, Terry Agajanian, and Richard Watanabe for their excellent technical assistance. REFERENCES 1. Burt RL. Peripheral utilization of glucose in pregnancy. III. Insulin tolerance. Obstet Gynecol 1956;7:658-64. 2. Burt RL. Reactivity to tolbutamide in normal pregnancy. Obstet Gynecol 1958;12:447-58. 3. Knopp RH, Ruder HJ, Herrera E, Freinkel N. Carbohydrate metabolism in pregnancy. VII. Insulin tolerance during late pregnancy in the fed and fasted rat. Acta Endocrinol 1970;65:352-9. 4. Metzger BE, Freinkel N. Effects of diabetes mellitus on endocrinologic and metabolic adaptations of gestation. Semin Perinatol 1978;2:309-24. 5. Spellacy WN, Goetz FC. Plasma insulin in normal late pregnancy. N Engl J Med 1963;268:988-91. 6. Bleicher SJ, O'SullivanJB, Freinkel N. Carbohydrate metabolism in pregnancy. V. The interaction of glucose, insulin and free fatty acids in late pregnancy and postpartum. N EnglJ Med 1961;271:866-72. 7. Kalkhoff R, Schalch DS, Walker JL, Beck P, Kipnis DM, Daughaday WHo Diabetogenic factors associated with pregnancy. Trans Assoc Am Physicians 1964;77:270-9. 8. Ryan EA, O'Suliian MJ, Skyler JS. Insulin action during pregnancy. Diabetes 1985;34:380-9. 9. Metzger BE, Freinkel N. Inquiries into the pathogenesis of gestational diabetes. In: Camerini-Davalos RA, Hanover B, eds. Treatment of Early Diabetes. New York: Plenum Press, 1979:201-8. 10. Freinkel N, Metzger BE. Gestational diabetes in Chicago.
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