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A prospective evaluation of glycemic threshold for morbidity in pregnancy complicated by pre-existing diabetes mellitus
SPO
V o l u m e 176, N u m b e r 1, Part 2 A m J O b s t e t Gynecol 636
POLYMORPHISMS IN INSULIN RECEPTOR SUBSTRATE-1 GENE ARE N O T ASSOCIATED W I T H GESTATIONAL DIABETES. D. WiUiams~, D. Dizon-Townson, H. Major*, K. Ward. Depts. of O b / G y n and H u m a n Genetics, Univ. of Utah, Salt Lake City, UT. OBJECTIVE: Previous investigators have shown an association between polymorphisms at nucleotides 513 and 972 of the insulin receptor substrate-1 (IRS-1) and non-insulin-dependent diabetes mellitus. O u r objective was to determine the frequency of these two polymorphisms in a population with gestational diabetes mellitus (GDM). STUDY DESIGN: DNA was extracted from whole blood of 58 patients with gestational diabetes metlitus, diagnosed by 2 abnormal values on a 3 hour oral glucose tolerance test, and 71 gravid women without a diagnosis of gestational diabetes. Polymerase chain reaction (PCR) was used to amplify codons 513 and 972. Allele-specific restriction was used .tbr the polymorphism analysis. BstN1 for 972A and DRAIII for 513C. RESULTS:
638
Abstracts
S181
OBESITY AFFECTS INSULIN RESISTANCE IN GDM IN LATE PREGNANCY. M. Berkus, O. Langer, 72 Siley=Khodr~, Dept. Ob/Gyn, UTHSC, San Antonio, TX. OBJECTIVE: Although it has becmne axiomatic that obesity does not alter the enorntous insulin resistance of late normal or GDM pregnancy, studies evaluating this relationship suffer from small sample size. Therefbre, we sought to investigate the association between maternal size (obese vs non-obese) and insulin secretion/sensitivity (Si) in GDM gravidas using a large sample. Antepartum
GOML . . . . GOM Obese o
l~ ~ c =~ " \. n
==
=- 42o
9 "
+ ". +.. "..
* '..
b,.
vs S~
Insulin Secretion
".,.
~
Normal$.....
~
(M,,C,~I.~ ,gs~;c.l,)
II~g-1 Allele Frequencies
GDM n = 58 Controls n = 71 Published Controls n = 147
972G
972A
513G
513C
94% 89% 98%
6% 11% 2%
98% 98% 99%
2% 2% 1%
T- ~176 Insulin
ABNORMALITIES PERSIST POSTPARTUM IN GRAVIDAS W I T H LESSER DEGREES O F HYPERGLYCEMIA. M. Berkus, O. Langer, 72 Siler-Khodr~, Dept. Ob/Gyn, UTHSC, San Antonio, TX. OBJECTIVE: Recently it has been shown that gravidas having lesser degrees of hyperglycemia (GDM by lower threshold criteria of Coustan, Sacks, 1-abnormal GTT value), identify morbidity at an incidence and efficiency comparable to current ACOG standards. 60% of these gravidas also evidence both insulin secretion and sensitivity (Si) below normal during pregnancy. The hypothesis of this study" is that these patients would continue to have increased insulin resistance and decreased insulin response postpartum (PP). METHODS: 14 patients with lesser degrees of hyperglycemia during pregnancy were investigated PP using the insulin modified, Minimal Model (Bergman) to measure glucose, Si, and 1st phase insulin (0-19 rain). 20 normal, non-pregnant women matched tor age and obesity were studied as controls. Postpartum Insulin Secretion vs S+
'] iii '
"=- I
Ptov-Losser 9
i/~
0~
== |
\,~",
Non-GDM .....
=" 4
":>,
"
,. . . . . . . . .
nsulin S e n s i t i v i t y (lo4min- IpmollL)
I I
(Si)
RESULTS: The lesser degree subjects were compared to the mean normal curve (see figure). 71% of the study women had both Si and insulin response below the normal curve, i.e. values in the lower left corner of the graph. Additionally: (1) 80% of low responders in pregnancy remained abnormal PP; (2) 20% reverted to normal; (3) All gravidas above the non-GDM curve th~ring pregnancy remained above normaI PP. CONCLUSION: The decreased sensitivity and insulin secretion that persists PP in gravidas with lesser degrees of hyperglycemia, form the basis of their abnormal glycemic profile and adverse perinatal outcome, and strongly support their being considered at increased risk for fi+tture GDM and Type II diabetes.
i~i)
"~
METHOD: 106 gravidas were examined between 24-28 weeks gestation, prior to any diet or insulin treammnt, using the insulin-modified, frequently sampled IVGTT of Bergman (Minimal Model). Plasma glucose was nmasured with glucose oxide technique. Insulin was measured using double antibody methodology with a sensitivity of 0.625 u U / m l . The subjects were stratified into obese (body mass index -->29) and non-obese. 20 of these wmnen had normal glucose testing and were used as controls. RESULTS: 75% of obese and 64% of non-obese gravidas had both Si and insulin response below the curve fitted to non-GDM (Figure). Additionally, for obese vs non-obese GDM: (1) incremental area under glucose curve was greater (8473 vs 5976 m g / d L * m i n , p < .001); (2) insulin response was similar (2.7 vs 2.01 m U / m L * n t i n , p = .17); consistent with (3) Si being decreased (0.34 vs 0.49 1 0 - 4 m i n - t / p m o l / L , p < .03). CONCLUSION: The increase in glucose levels due to the effect of obesity on insulin resistance, may explain the abnormal, accelerated fetal growth in these pregnancies, the need for intensified therapy (insulin) for obese GDM and the increased rate of LGA in obese gravidas.
CONCLUSIONS: We did not find an association between these polymorphisms in IRS-1 and GDM. Furthermore, the allele frequency difference between our population and published controls from Denmark suggest ethnic variation in this gene which may confound association studies.
637
~'ensiilvity
(tO~mln"}retool/L)
639
A PROSPECTIVE EVALUATION O F GLYCEMIC T H R E S H O L D F O R MORBIDITY IN PREGNANCY COMPLICATED BY PRE-EXISTING DIABETES MELLITUS. O. Lango, M.B. Landon, M. Berkus, S.G. Gabbe, S. HissTich, Depts. Ob/Gyn, UTHSC, San Antonio, T X , OSU, Ohio. OBJECTIVE: To identi~ a glycemic threshold associated with increased maternal and fetal rnorbidity in pregnancies complicated by pre-existing diabetes mellitus. METHODS: 582 women with pre-existing diabetes mellitus (PEDM) were prospectively evaluated in two tertiary, care institutions for the relationship between ntaternal glycemia and pregnancy outcome by collecting ambulatol3/blood glucose measurements in the fasting, pre-prandial, and post prandial states using memory-based glucose reflectance meters. Glycemic characteristics were evaluated prior to and after 24~wks gestation. RESULTS: The fetal weight categories are displayed in tbe table below.
IVUz'ANSMBG Iow-94 95-104 105-114 115-124 125-higfi
LGA 12.8% 13.2% 16.8% 19.0% 24.0%
I I
MACROSOMIA 9.4% 11.2% 20.0% 17.0% 14.1%
Patients were further dichotomized in accordance with level of glycemic control (good, < 105). Poor control subjects (>104) had higher rates of morbidity when compared to good control subjects: polycytbemia (8.8% vs. 3.7% p < .05); hyperbilirubinemia (23.4% vs. 16.4%, ns); hypocalcemia (9.2% vs. 2.4%, p < .01); hypoglycemia (31.8% vs. 17.3%, p < .001). Cord blood pH was significantly lower in poor control subjects. Finally, shoulder dystocia rate was similar in both groups, 4.4% and 4.3%. CONCLUSION: Near physiologic maternal glycemia in PEDMs is associated with a frequency of neonatal morbidity comparable to a non~liabetic population. This data validates current clinical efforts aimed at achieving enoglycemia during gestation thus maximizing pregnancy outconm.
V o l u m e 176, N u m b e r 1, Part 2 A m J O b s t e t Gynecol 636
POLYMORPHISMS IN INSULIN RECEPTOR SUBSTRATE-1 GENE ARE N O T ASSOCIATED W I T H GESTATIONAL DIABETES. D. WiUiams~, D. Dizon-Townson, H. Major*, K. Ward. Depts. of O b / G y n and H u m a n Genetics, Univ. of Utah, Salt Lake City, UT. OBJECTIVE: Previous investigators have shown an association between polymorphisms at nucleotides 513 and 972 of the insulin receptor substrate-1 (IRS-1) and non-insulin-dependent diabetes mellitus. O u r objective was to determine the frequency of these two polymorphisms in a population with gestational diabetes mellitus (GDM). STUDY DESIGN: DNA was extracted from whole blood of 58 patients with gestational diabetes metlitus, diagnosed by 2 abnormal values on a 3 hour oral glucose tolerance test, and 71 gravid women without a diagnosis of gestational diabetes. Polymerase chain reaction (PCR) was used to amplify codons 513 and 972. Allele-specific restriction was used .tbr the polymorphism analysis. BstN1 for 972A and DRAIII for 513C. RESULTS:
638
Abstracts
S181
OBESITY AFFECTS INSULIN RESISTANCE IN GDM IN LATE PREGNANCY. M. Berkus, O. Langer, 72 Siley=Khodr~, Dept. Ob/Gyn, UTHSC, San Antonio, TX. OBJECTIVE: Although it has becmne axiomatic that obesity does not alter the enorntous insulin resistance of late normal or GDM pregnancy, studies evaluating this relationship suffer from small sample size. Therefbre, we sought to investigate the association between maternal size (obese vs non-obese) and insulin secretion/sensitivity (Si) in GDM gravidas using a large sample. Antepartum
GOML . . . . GOM Obese o
l~ ~ c =~ " \. n
==
=- 42o
9 "
+ ". +.. "..
* '..
b,.
vs S~
Insulin Secretion
".,.
~
Normal$.....
~
(M,,C,~I.~ ,gs~;c.l,)
II~g-1 Allele Frequencies
GDM n = 58 Controls n = 71 Published Controls n = 147
972G
972A
513G
513C
94% 89% 98%
6% 11% 2%
98% 98% 99%
2% 2% 1%
T- ~176 Insulin
ABNORMALITIES PERSIST POSTPARTUM IN GRAVIDAS W I T H LESSER DEGREES O F HYPERGLYCEMIA. M. Berkus, O. Langer, 72 Siler-Khodr~, Dept. Ob/Gyn, UTHSC, San Antonio, TX. OBJECTIVE: Recently it has been shown that gravidas having lesser degrees of hyperglycemia (GDM by lower threshold criteria of Coustan, Sacks, 1-abnormal GTT value), identify morbidity at an incidence and efficiency comparable to current ACOG standards. 60% of these gravidas also evidence both insulin secretion and sensitivity (Si) below normal during pregnancy. The hypothesis of this study" is that these patients would continue to have increased insulin resistance and decreased insulin response postpartum (PP). METHODS: 14 patients with lesser degrees of hyperglycemia during pregnancy were investigated PP using the insulin modified, Minimal Model (Bergman) to measure glucose, Si, and 1st phase insulin (0-19 rain). 20 normal, non-pregnant women matched tor age and obesity were studied as controls. Postpartum Insulin Secretion vs S+
'] iii '
"=- I
Ptov-Losser 9
i/~
0~
== |
\,~",
Non-GDM .....
=" 4
":>,
"
,. . . . . . . . .
nsulin S e n s i t i v i t y (lo4min- IpmollL)
I I
(Si)
RESULTS: The lesser degree subjects were compared to the mean normal curve (see figure). 71% of the study women had both Si and insulin response below the normal curve, i.e. values in the lower left corner of the graph. Additionally: (1) 80% of low responders in pregnancy remained abnormal PP; (2) 20% reverted to normal; (3) All gravidas above the non-GDM curve th~ring pregnancy remained above normaI PP. CONCLUSION: The decreased sensitivity and insulin secretion that persists PP in gravidas with lesser degrees of hyperglycemia, form the basis of their abnormal glycemic profile and adverse perinatal outcome, and strongly support their being considered at increased risk for fi+tture GDM and Type II diabetes.
i~i)
"~
METHOD: 106 gravidas were examined between 24-28 weeks gestation, prior to any diet or insulin treammnt, using the insulin-modified, frequently sampled IVGTT of Bergman (Minimal Model). Plasma glucose was nmasured with glucose oxide technique. Insulin was measured using double antibody methodology with a sensitivity of 0.625 u U / m l . The subjects were stratified into obese (body mass index -->29) and non-obese. 20 of these wmnen had normal glucose testing and were used as controls. RESULTS: 75% of obese and 64% of non-obese gravidas had both Si and insulin response below the curve fitted to non-GDM (Figure). Additionally, for obese vs non-obese GDM: (1) incremental area under glucose curve was greater (8473 vs 5976 m g / d L * m i n , p < .001); (2) insulin response was similar (2.7 vs 2.01 m U / m L * n t i n , p = .17); consistent with (3) Si being decreased (0.34 vs 0.49 1 0 - 4 m i n - t / p m o l / L , p < .03). CONCLUSION: The increase in glucose levels due to the effect of obesity on insulin resistance, may explain the abnormal, accelerated fetal growth in these pregnancies, the need for intensified therapy (insulin) for obese GDM and the increased rate of LGA in obese gravidas.
CONCLUSIONS: We did not find an association between these polymorphisms in IRS-1 and GDM. Furthermore, the allele frequency difference between our population and published controls from Denmark suggest ethnic variation in this gene which may confound association studies.
637
~'ensiilvity
(tO~mln"}retool/L)
639
A PROSPECTIVE EVALUATION O F GLYCEMIC T H R E S H O L D F O R MORBIDITY IN PREGNANCY COMPLICATED BY PRE-EXISTING DIABETES MELLITUS. O. Lango, M.B. Landon, M. Berkus, S.G. Gabbe, S. HissTich, Depts. Ob/Gyn, UTHSC, San Antonio, T X , OSU, Ohio. OBJECTIVE: To identi~ a glycemic threshold associated with increased maternal and fetal rnorbidity in pregnancies complicated by pre-existing diabetes mellitus. METHODS: 582 women with pre-existing diabetes mellitus (PEDM) were prospectively evaluated in two tertiary, care institutions for the relationship between ntaternal glycemia and pregnancy outcome by collecting ambulatol3/blood glucose measurements in the fasting, pre-prandial, and post prandial states using memory-based glucose reflectance meters. Glycemic characteristics were evaluated prior to and after 24~wks gestation. RESULTS: The fetal weight categories are displayed in tbe table below.
IVUz'ANSMBG Iow-94 95-104 105-114 115-124 125-higfi
LGA 12.8% 13.2% 16.8% 19.0% 24.0%
I I
MACROSOMIA 9.4% 11.2% 20.0% 17.0% 14.1%
Patients were further dichotomized in accordance with level of glycemic control (good, < 105). Poor control subjects (>104) had higher rates of morbidity when compared to good control subjects: polycytbemia (8.8% vs. 3.7% p < .05); hyperbilirubinemia (23.4% vs. 16.4%, ns); hypocalcemia (9.2% vs. 2.4%, p < .01); hypoglycemia (31.8% vs. 17.3%, p < .001). Cord blood pH was significantly lower in poor control subjects. Finally, shoulder dystocia rate was similar in both groups, 4.4% and 4.3%. CONCLUSION: Near physiologic maternal glycemia in PEDMs is associated with a frequency of neonatal morbidity comparable to a non~liabetic population. This data validates current clinical efforts aimed at achieving enoglycemia during gestation thus maximizing pregnancy outconm.