Anny H. Xiang

Gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of various degrees that is first detected during pregnancy. GDM is detected through the screening of pregnant women for clinical risk factors and, among at-risk women, testing for abnormal glucose tolerance that is usually, but not invariably, mild and asymptomatic. GDM appears to result from the same broad spectrum of physiological and genetic abnormalities that characterize diabetes outside of pregnancy. Indeed, women with GDM are at high risk for having or developing diabetes when they are not pregnant. Thus, GDM provides a unique opportunity to study the early pathogenesis of diabetes and to develop interventions to prevent the disease.

COMPLEX DISTRIBUTION, NOT ABSOLUTE AMOUNT OF ADIPONECTIN, CORRELATES WITH THIAZOLIDINEDIONE-MEDIATED IMPROVEMENT IN INSULIN SENSITIVITY

Adiponectin is an adipocyte-specific secretory protein that circulates in serum as a hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). Serum levels of the protein correlate with systemic insulin sensitivity. The full-length protein affects hepatic gluconeogenesis through improved insulin sensitivity, and a proteolytic fragment of adiponectin stimulates β oxidation in muscle. Here, we show that the ratio, and not the absolute amounts, between these two oligomeric forms (HMW to LMW) is critical in determining insulin sensitivity. We define a new index, SA, that can be calculated as the ratio of HMW/(HMW + LMW). db/db mice, despite similar total adiponectin levels, display decreased SA values compared with wild type littermates, as do type II diabetic patients compared with insulin-sensitive individuals. Furthermore, SA improves with peroxisome proliferator-activated receptor-γ agonist treatment (thiazolidinedione; TZD) in mice and humans. We demonstrate that changes in SA in a number of type 2 diabetic cohorts serve as a quantitative indicator of improvements in insulin sensitivity obtained during TZD treatment, whereas changes in total serum adiponectin levels do not correlate well at the individual level. Acute alterations in SA (ΔSA) are strongly correlated with improvements in hepatic insulin sensitivity and are less relevant as an indicator of improved muscle insulin sensitivity in response to TZD treatment, further underscoring the conclusions from previous clamp studies that suggested that the liver is the primary site of action for the full-length protein. These observations suggest that the HMW adiponectin complex is the active form of this protein, which we directly demonstrate in vivo by its ability to depress serum glucose levels in a dose-dependent manner.

A better index of body adiposity.

Obesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)1.5)–18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the “BetaGene” study, to develop the new index of body adiposity. %Body fat, as measured by the dual‐energy X‐ray absorptiometry (DXA), was used as a “gold standard” for validation. Hip circumference (R = 0.602) and height (R = −0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the “Triglyceride and Cardiovascular Risk in African‐Americans (TARA)” study of African Americans. Correlation between DXA‐derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly.

Predicting Future Diabetes in Latino Women With Gestational Diabetes: Utility of Early Postpartum Glucose Tolerance Testing

We tested 32 routine clinical parameters for their ability to discriminate between a high risk and a low risk of non-insulin-dependent diabetes mellitus (NIDDM) within 5–7 years after pregnancies complicated by gestational diabetes mellitus (GDM). Latino women (n = 671) with GDM who did not have diabetes 4–16 weeks after delivery returned for at least one 75-g oral glucose tolerance test (OGTT) within 7.5 years. Multivariate analysis was used to identify parameters ascertained during or immediately after the index pregnancy that were independently associated with the development of diabetes during follow-up. Life table analysis revealed a 47% cumulative incidence rate of NIDDM 5 years after delivery for this cohort of patients who did not have diabetes at the initial postpartum examination. Four variables were identified as independent predictors of NIDDM: the area under the OGTT glucose curve at 4–16 weeks postpartum, the gestational age at the time of diagnosis of GDM, the area under the OGTT glucose curve during pregnancy, and the highest fasting serum glucose concentration during pregnancy. Examination of relative risks (RRs) of NIDDM between the highest and lowest quartiles of the cohort for each variable, adjusted for the other three variables, revealed that the postpartum OGTT provided the best discrimination between high-risk and low-risk individuals (adjusted RR = 11.5 [95% confidence interval 4.5–29.1] compared with adjusted RRs of only 0.5–2.5 for the other three variables). Women who met World Health Organization criteria for impaired glucose tolerance at the early postpartum examination had a 5-year unadjusted 80% risk of diabetes, which was much higher than the risk of NIDDM that has been reported for Latino people with impaired glucose tolerance who were not selected for a history of GDM. Our findings indicate that postpartum glucose tolerance testing is superior to other routine clinical parameters in defining the risk of NIDDM within 5–7 years after pregnancies complicated by GDM. Furthermore, a history of GDM appears to impart a specific risk for NIDDM that cannot be explained by the degree of glucose tolerance observed when patients are not pregnant.

Long-term diabetogenic effect of single pregnancy in women with previous gestational diabetes mellitus

BACKGROUND Pregnancy is associated with marked insulin resistance that seems to have little, if any, impact on the long-term risk of non-insulin-dependent diabetes mellitus (NIDDM) in the general population. The aim of this study was to test whether pregnancy would alter the risk of NIDDM among women with a high prevalence of pancreatic beta-cell dysfunction, as indicated by a history of gestational diabetes mellitus. METHODS The cohort consisted of 666 Latino women with gestational diabetes attending a high-risk family planning clinic. They were followed up for up to 7.5 years, during which time they were weighed and underwent an oral glucose-tolerance test annually. The effect of an additional pregnancy, and of other risk factors for diabetes, was examined. FINDINGS 87 (13%) of the women completed an additional pregnancy. 80 of those women did not have NIDDM immediately after the additional pregnancy and their subsequent annual incidence rate of NIDDM was 30.9% (95% CI 12.7-49.1), more than 2.5 times the annual incidence rate of NIDDM in the cohort overall (11.9%; 95% CI 10.0-13.8). Proportional hazards regression analysis using the presence or absence of an additional pregnancy as a time-dependent variable confirmed that an additional pregnancy increased the rate ratio of NIDDM to 3.34 (95% CI 1.80-6.19), compared with women without an additional pregnancy after adjustment for other potential diabetes risk factors during the index pregnancy (antepartum oral glucose tolerance, highest fasting glucose, gestational age at diagnosis of gestational diabetes) and during follow-up (postpartum body mass index [BMI], and glucose tolerance, weight change, breast feeding, and months of contraceptive use). Weight gain also was independently associated with an increased risk of NIDDM; the rate ratio was 1.95 (95% CI 1.63-2.33) for each 10 lb (4.5 kg) gained during follow-up after adjustment for the additional pregnancy and the other potential risk factors. INTERPRETATION The study showed that a single pregnancy, independent of the well-known effect of weight gain, accelerated the development of NIDDM in a group of women with a high prevalence of pancreatic beta-cell dysfunction. This finding implies that episodes of insulin resistance may contribute to the decline in beta-cell function that leads to NIDDM in many high-risk individuals.

Congenital Malformations in Pregnancies Complicated by NIDDM: Increased risk from poor maternal metabolic control but not from exposure to sulfonylurea drugs

OBJECTIVE To determine whether the use of oral hypoglycemic agents during early pregnancy is associated with a risk of congenital malformations in infants of mothers with non-insulin-dependent diabetes mellitus (NIDDM) independent of maternal metabolic control. RESEARCH DESIGN AND METHODS From a prospectively collected data-base of pregnancies complicated by diabetes at a large urban medical center, we identified 332 consecutive infants born to women with NIDDM who did not participate in a preconceptional diabetes care program. Stepwise logistical regression was used to identify maternal characteristics that were independently associated with risks of major and minor congenital malformations in infants. RESULTS Overall, 56 (16.9%) of the 332 infants were born with congenital anomalies (11.7% major anomalies and 5.1% minor anomalies). Analysis of data from subgroups of women who were treated with diet therapy, exogenous insulin, or sulfonylurea compounds during the first 8 weeks of gestation did not reveal statistically significant differences in major or minor malformation rates among the three groups. Stepwise logistic regression analysis revealed two maternal characteristics that were independently associated with major malformations in infants: maternal HbA1c at initial presentation for care (direct relationship; P = 0.0007) and the maternal age at onset of diabetes (inverse relationship; P = 0.009). The risk of major malformations was unrelated to the mode of antidiabetic therapy during early pregnancy. No relationship was found between maternal glycemia or treatment modality and rates of minor congenital anomalies. CONCLUSIONS These data indicate that, in the absence of special preconceptional care, NIDDM is associated with a risk for major congenital anomalies that is in the range reported for pregnancies complicated by insulin-dependent diabetes mellitus. Moreover, the risk in individual patients appears to be related to maternal glycemic control rather than to the mode of antidiabetic therapy during early pregnancy.

Use of Fetal Ultrasound to Select Metabolic Therapy for Pregnancies Complicated by Mild Gestational Diabetes

OBJECTIVE To determine whether fetal ultrasound early in the third trimester can identify Latina with mild gestational diabetes mellitus (GDM) whose fetuses are at risk for macrosomia and, if so, whether maternal insulin therapy can reduce that risk. RESEARCH DESIGN AND METHODS Study subjects included 303 consecutive women with GDM and a fasting serum glucose level <5.8 mM on diet therapy who had a fetal ultrasound between 29 and 33 weeks gestation. Of the women, 98 (32%) had a fetal AC ≥ 75th percentile for gestational age, and 59 women completed a randomized trial of diet therapy (n = 29) or diet plus twice daily insulin (n = 30). Maternal nutrient levels were assessed by meal tolerance testing (MTT) before and during therapy and by capillary glucose monitoring four to seven times a day. Birth weights corrected for gestational age and neonatal glycemia and skin folds were the primary outcome variables compared between treatment groups. RESULTS Diet and diet-plus-insulin groups were well matched for maternal age, prepregnancy relative weight, weight gain during pregnancy, and glycemia at entry. Insulin therapy reduced maternal capillary (P < 0.005) and MTT (P < 0.001) glucose levels and prevented a diet-associated rise in MTT triglyceride levels (P < 0.002). Gestational age at delivery was similar in insulin- and diet-treated groups (39.6 ± 0.2 vs. 39.5 ± 0.2 weeks). Birth weights (3,647 ± 67 vs. 3,878 ± 84 g; P < 0.02), the prevalence of large-for-gestational age infants (13 vs. 45%, P < 0.02), and neonatal skin-fold measurements at three sites (P < 0.005) were reduced in the insulin-treated group. Rates of transient neonatal hypoglycemia were low in both treatment groups (14 and 18%, respectively) and didnot differ significantly between groups. CONCLUSIONS Fetal ultrasound early in the third trimester identified women with mild GDM whose infants were at high risk for fetal macrosomia in the absence of standard glycemic criteria for insulin therapy. Insulin treatment reduced the macrosomia, indicating that fetal ultrasound can be used to guide metabolic therapy in pregnancies complicated by mild GDM.

Gestational Diabetes Mellitus: Risks and Management during and after Pregnancy

Gestational diabetes mellitus (GDM) carries a small but potentially important risk of adverse perinatal outcomes and a long-term risk of obesity and glucose intolerance in offspring. Mothers with GDM have an excess of hypertensive disorders during pregnancy and a high risk of developing diabetes mellitus thereafter. Diagnosing and treating GDM can reduce perinatal complications, but only a small fraction of pregnancies benefit. Nutritional management is the cornerstone of treatment; insulin, glyburide and metformin can be used to intensify treatment. Fetal measurements complement maternal glucose monitoring in the identification of pregnancies that require such intensification. Glucose testing shortly after delivery can stratify the short-term diabetes risk in mothers. Thereafter, annual glucose and HbA1c testing can detect deteriorating glycaemic control, a harbinger of future diabetes mellitus, usually type 2 diabetes mellitus. Interventions that mitigate obesity or its metabolic effects are most potent in preventing or delaying diabetes mellitus. Lifestyle modification is the primary approach; use of medications for diabetes prevention after GDM remains controversial. Family planning enables optimization of health in subsequent pregnancies. Breastfeeding may reduce obesity in children and is recommended. Families should be encouraged to help children adopt lifestyles that reduce the risk of obesity.

Congenital malformations in offspring of women with hyperglycemia first detected during pregnancy

OBJECTIVES Our aim was to determine risk factors for congenital malformations in offspring of women with hyperglycemia first detected during pregnancy (i.e., women with gestational diabetes). STUDY DESIGN A total of 3743 pregnancies complicated by gestational diabetes mellitus delivered at > 20 weeks of gestation were reviewed for the presence of congenital malformations diagnosed before hospital discharge. Anomalies were categorized as major, minor, or absent. Pregnancies with genetic syndromes and aneuploidies were excluded. In addition to maternal clinical and historic parameters, diagnostic glycemic parameters (fasting and post-glucose-challenge levels from the diagnostic glucose tolerance test, highest fasting serum glucose level, and hemoglobin A1c level before insulin therapy) were examined by logistic regression for predictive risk of major anomalies. RESULTS One or more major congenital anomalies were present in 108 (2.9%) of the newborns; an additional 91 (2.4%) had only minor anomalies. None of the maternal variables were associated with the risk of minor anomalies. By contrast, parity, a history of gestational diabetes mellitus, and several glycemic parameters were associated with the risk of major anomalies. The highest fasting serum glucose level was the best independent predictor (odds ratio 1.13/10 mg/dl, 95% confidence interval 1.09 to 1.34). The fasting serum glucose level at diagnosis, a parameter that is almost uniformly available to clinicians, gave similar predictive information about the risk of major anomalies (odds ratio 1.13, 95% confidence interval 1.08 to 1.14). Stratification of women into subgroups of fasting serum glucose level at diagnosis revealed the incidence of major anomalies to be as follows: 2.1% with a fasting serum glucose level < 120 mg/dl (2973 pregnancies), 5.2% with a fasting serum glucose level of 121 to 260 mg/dl (747 pregnancies), and 30.4% with a fasting serum glucose level > 260 mg/dl (23 pregnancies). CONCLUSION In a large population of women without a diagnosis of diabetes before pregnancy, the maternal fasting serum glucose concentration at diagnosis was a useful predictor of the risk of major but not minor anomalies. The rate of major anomalies doubled with a fasting glucose level > 120 mg/dl. Thus a fasting glucose level below that of overt diabetes outside of pregnancy carries an important risk of major anomalies that must be considered in the counseling and management of these patients.

TRIPOD (TRoglitazone In the Prevention Of Diabetes): a randomized, placebo-controlled trial of troglitazone in women with prior gestational diabetes mellitus.

The TRoglitazone In the Prevention Of Diabetes (TRIPOD) trial is a single-center, randomized, placebo-controlled, double-masked study. The primary aim of the TRIPOD trial is to test the hypothesis that chronic administration of troglitazone to nondiabetic women with prior gestational diabetes mellitus (GDM) will improve whole-body insulin sensitivity and reduce the incidence of non-insulin-dependent diabetes (NIDDM). Because troglitazone is already known to lower blood glucose concentrations in persons who have developed NIDDM, an additional aim of the project will be to determine whether early intervention with troglitazone will achieve better final glycemic control than can be achieved by later intervention. In addition, since troglitazone treatment is expected to improve insulin sensitivity and may prevent or delay a decline in glucose tolerance, we also plan to determine whether long-term troglitazone treatment alters the development or progression of atherosclerosis. In this article we describe the experiments design, the studys endpoints and methods for determining those endpoints, methods for assessing quality of life, and proposed methods for statistical analyses. The unique two-phase study design of the TRIPOD trial will permit testing not only of the biological question about reversal of insulin resistance and prevention of diabetes, but also of the clinical question about whether early intervention is superior to late intervention. Results from this trial will have an important impact on the monitoring and treatment of patients at high risk for NIDDM.