Previous Gestational Diabetes Research Articles

Sequence Variation inPPARGMay Underlie Differential Response to Troglitazone

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-gamma (PPARG) agonists used to treat type 2 diabetes. TZDs can also be used to reduce rates of type 2 diabetes in at-risk individuals. However, a large fraction of TZD-treated patients (30-40%) do not respond to TZD treatment with an improvement in insulin sensitivity (Si). We hypothesized that variation within the gene encoding PPARG may underlie this differential response to TZD therapy. We screened approximately 40 kb of PPARG in 93 nondiabetic Hispanic women (63 responders and 30 nonresponders) with previous gestational diabetes who had participated in the Troglitazone In the Prevention Of Diabetes study. TZD nonresponse was defined as the lower tertile in change in Si after 3 months of treatment. Baseline demographic and clinical measures were not different between responders and nonresponders. We identified and genotyped 131 variants including 126 single nucleotide polymorphisms and 5 insertion-deletion polymorphisms. Linkage disequilibrium analysis identified five haplotype blocks. Eight variants were associated with TZD response (P < 0.05). Three variants were also associated with changes in Si as a continuous variable. Our results suggest that PPARG variation may underlie response to TZD therapy in women at risk for type 2 diabetes.

Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes

The insulinotropic effect of gastric inhibitory polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion. On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg(-1) min(-1); 30-90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA. Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration. These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.

Subclinical Inflammation and Vascular Dysfunction in Women with Previous Gestational Diabetes Mellitus

A history of gestational diabetes (GDM) significantly increases the risk of developing type 2 diabetes, an independent risk factor for cardiovascular disease (CVD). It is not known whether nondiabetic women with prior GDM are also at increased risk of CVD. The aim of this study was to compare biochemical and hemodynamic surrogate markers of CVD in nondiabetic women with and without a history of GDM who were at least 1 yr post delivery. This was a single center cross-sectional study. The study was performed in an academic referral center. Forty-eight premenopausal healthy women with a history of GDM (n = 25) or a history of normal pregnancy (n = 23) were studied in the follicular phase of the menstrual cycle. The main outcome measures were: 1) inflammatory markers associated with CVD including C-reactive protein, IL-6, and plasminogen activator inhibitor-1; 2) the adipokine adiponectin; and 3) conduit vessel stiffness. When compared to normal controls, women with prior GDM had higher mean levels of C-reactive protein (3.58 +/- 3.86 vs. 0.52 +/- 0.16 mg/liter; P < 0.001), IL-6 (1.81 +/- 1.04 vs. 0.99 +/- 0.52 pg/ml; P = 0.001), plasminogen activator inhibitor-1 (29.6 +/- 17.6 vs. 16.5 +/- 14.0 ng/ml; P = 0.001), and lower levels of adiponectin (8.9 +/- 3.9 vs. 15.9 +/- 7.3 microg/ml; P = 0.001). Women with prior GDM also had significantly (P </= 0.04) increased peripheral vascular resistance (1658 +/- 290 vs. 1462 +/- 340 dyne.sec/cm(5)), decreased stroke volume (65 +/- 13 vs. 75 +/- 14 ml/beat), and decreased cardiac output (70 +/- 12 vs. 74 +/- 13 ml/sec) when compared to controls, after adjusting for body mass index. Nondiabetic women with prior GDM have evidence of subclinical inflammation, hypoadiponectinemia, and early vascular dysfunction; this population may be at increased risk of developing CVD.

The Prevalence of the Metabolic Syndrome in a Danish Population of Women with Previous Gestational Diabetes Mellitus Is Three-Fold Higher than in the General Population

Diabetes and obesity, components of the metabolic syndrome, are common characteristics of women with prior gestational diabetes mellitus (GDM). Due to increasing incidence of diabetes and obesity, the metabolic syndrome might comprise a major health problem among these women. The objective was to estimate the prevalence of the metabolic syndrome by three different criteria [World Health Organization 1999 (WHO), The National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults 2001, and European Group for the Study of Insulin Resistance 2002] among women with previous GDM. We conducted a follow-up study of a Danish cohort of women admitted in 1978-1996 to the Diabetes and Pregnancy Center, Rigshospitalet, Copenhagen University Hospital, with diet-treated GDM. The follow-up took place in 2000-2002 at median 9.8 yr (interquartile range 6.4-17.2) after pregnancy. Results were compared with a control group of 1000 age-matched women from a population-based sample (Inter99). Four hundred eighty-one women at median age 43 yr (interquartile range 38-48) participated. The main outcome measures were body mass index (BMI), glucose tolerance, blood pressure, lipid profile, and insulin resistance. Independent of the criteria, the prevalence of the metabolic syndrome was three times higher in the prior GDM group, compared with the control group (e.g. WHO: 38.4 vs. 13.4%, P < 0.0005). Age- and BMI-adjusted odds ratio for having the WHO-defined metabolic syndrome was 3.4 (95% confidence interval 2.5-4.8) for the prior GDM group vs. the control group. Obese women (BMI > 30 kg/m(2)) with previous GDM had a more than 7-fold increased prevalence of the metabolic syndrome (WHO), compared with normal-weight prior GDM women (BMI < 25 kg/m(2)). In glucose-tolerant women, the prevalence was doubled in the prior GDM group, compared with control group. The prevalence of the metabolic syndrome was three times as high in women with prior diet-treated GDM, compared with age-matched control subjects.

Can type 2 diabetes mellitus be considered preventable?

The primary prevention of type 2 diabetes mellitus (T2DM) is of great importance. There is now substantial evidence that T2DM can be prevented or delayed by lifestyle modification. A statistically significant reduction of relative risk of newly diagnosed T2DM was observed in large clinical trials with metformin, acarbose or orlistat in subjects with impaired glucose tolerance as well as with troglitazone in women with previous gestational diabetes. A relative risk reduction of newly diagnosed diabetes was observed in prospective, double blind clinical studies evaluating the effect of different antihypertensive drugs (ACE-inhibitors, angiotensin repector blockers, calcium channel blockers) or that of lipid-lowering agents (pravastatin) on the cardiovascular morbidity and mortality in high risk patients. In studies with postmenopausal hormone replacement therapy a relative risk reduction of newly developed T2DM was also observed. Thus, T2DM should be considered as a preventable disease. Nevertheless, it is noteworthy that oral antidiabetic drugs with an indication of preventing T2DM are not registered in several countries at present, so that drug therapy should not be used as a routine for preventing diabetes. On the other hand, patients with pre-diabetes (impaired fasting glycaemia, impaired glucose tolerance) should be given counseling on weight loss as well as instruction for increasing physical activity in order to prevent T2DM.

Lack of suppression of plasma glucagon levels in late pregnancy persists postpartum only in women with previous gestational diabetes mellitus

The aim of the present study was to examine fasting (0') and postglucose glucagon levels in normal and gestational diabetes mellitus (GDM) pregnancy, as available data are somewhat conflicting. To this end we studied 18 women with GDM at 26-32 weeks of pregnancy and compared these with 26 normal pregnant women matched for age and BMI. We also examined glucagon suppressibility postpartum (2-4 months) in the same ex-GDM women, in whom normal glucose tolerance was confirmed (WHO criteria) and compared these with 17 controls matched for age and BMI. Glucose, insulin and glucagon levels were measured during a 100 or 75 g oral glucose tolerance test (OGTT) respectively. In pregnant women, baseline and 3 h after glucose ingestion, plasma glucagon levels were significantly higher (p < 0.05) in women with GDM compared to normal women. Interestingly, in normal pregnancy a significant increase (p < 0.01) of postglucose plasma glucagon levels at 1 and 2 h compared to baseline levels was observed, while there was no change in GDM pregnancy. In postpartum euglycaemic women, there was no difference in basal glucagon levels between the two groups. A differential glucagon response during OGTT was observed: in control women there was a significant glucagon suppression (p < 0.01) at 2 h, while there was a significant glucagon increase (p < 0.01) 1 h after glucose ingestion, in ex-GDM women. We conclude that (a) absence of the suppressibility of glucagon in ex-GDM women with normal OGTT may indicate insulin resistance and might be involved in the natural history towards glucose intolerance; and (b) nonsuppression of glucagon in normal late pregnancy as well as in pregnancy complicated by GDM may be due to "physiological" insulin resistance of the alpha cells during this period.

C-Reactive Protein Levels in Non-Obese Pregnant Women with Gestational Diabetes

A low-grade systemic inflammation is concomitant in diabetes. There is a pathophysiological relation between gestational diabetes mellitus and type 2 diabetes mellitus, which was further supported by significantly elevated risk of type 2 diabetes in women with a history of previous gestational diabetes mellitus. We investigated the relation between low-grade systemic inflammation expressed as C-reactive protein and gestational diabetes in non-obese pregnant women. This study included 20 non-obese pregnant women with gestational diabetes mellitus and 30 non-obese pregnant women without gestational diabetes mellitus as a control group. The body mass index of all the subjects were < 25 kg/m2. During 26-28 gestational weeks 100-g oral glucose tolerance test was performed and simultaneously fasting C-reactive protein levels were measured. Serum median C-reactive protein level was higher in patients with gestational diabetes mellitus (p = 0.0001). C-reactive protein was strongly associated with glycemic parameters and weight gain during pregnancy. A model consisting of glucose intolerance, age, parity, and weight gain during pregnancy accounted for 61% of the variance in log C-reactive protein. We demonstrated that serum C-reactive protein level was related with gestational diabetes mellitus and weight gain during pregnancy in late second and early third trimesters.

Impaired circulating glucagon‐like peptide‐1 response to oral glucose in women with previous gestational diabetes

Women with previous gestational diabetes (pGDM) are at risk of developing Type 2 diabetes. Glucagon-like peptide-1 (GLP-1) potentiates the insulin response to oral glucose, and its secretion is diminished in Type 2 diabetes. The aim of the study was to see if decreased GLP-1 secretion might be an early abnormality in the progression to Type 2 diabetes and would therefore be diminished in women with pGDM. Eleven women with pGDM and previously documented normal glucose tolerance and 11 control women underwent a 75 g oral glucose tolerance test (OGTT). Circulating plasma glucose, insulin, nonesterified fatty acids (NEFA) and GLP-1 concentrations were sampled. One of the women with pGDM had impaired glucose tolerance and was excluded from the study. All other women had normal glucose tolerance. The women with pGDM had higher fasting glucose concentrations than controls (5.1; 4.9-5.3 vs. 4.8; 4.4-5.1 mmol/l, median; interquartile range, P = 0.04) and greater circulating glucose area under the curve (AUC) following the oral glucose load (930; 818-1015 vs. 668; 584-737 min x mmol/l, P = 0.0007). Fasting insulin concentrations and total insulin AUC were similar. The initial (0-30 min) insulin response was decreased in the pGDM women (AUC 3981; 2783-4795 vs. 6167; 5009-8145 min x pmol/l, P = 0.05). The initial (0-30 min) GLP-1 response was reduced in the pGDM women (AUC 816; 663-984 vs. 1163; 872-2024 min x pmol/l, P = 0.02). A reduced initial GLP-1 response to oral glucose may therefore be an early abnormality in the progression to Type 2 diabetes.

Estudo do encurtamento global do átrio esquerdo em fetos de mães diabéticas

To test the hypothesis that left atrial shortening fraction is lower in fetuses of diabetic mothers than in fetuses of mothers with no systemic disease. Forty-two fetuses of mothers with previous diabetes or gestational diabetes and 39 healthy fetuses of mothers with no systemic disease (controls) underwent echocardiographic examination. Their gestational ages ranged from 25 weeks to term. The left atrial shortening fraction was obtained with the following formula: (left atrial maximum diameter - left atrial minimum diameter)/left atrial maximum diameter. Data were compared using the Student t test, with an alpha level of 0.05. Mean left atrial shortening fractions in fetuses of diabetic mothers and in those in the control group were 0.39 +/- 0.15 and 0.51 +/- 0.11, respectively. This difference was significant with P < 0.001. Left atrial dynamics, with a reduction in global left atrial shortening, is increased in fetuses of diabetic mothers. We speculate that this parameter may be useful in assessing fetal left ventricular diastolic function.

Studies of the Ala/Val98 polymorphism of the hepatocyte nuclear factor‐1α gene and the relationship to β‐cell function during an OGTT in glucose‐tolerant women with and without previous gestational diabetes mellitus

In pregnancies complicated by gestational diabetes mellitus (GDM) an increased demand for insulin is not met due to beta-cell dysfunction. An Ala/Val polymorphism at codon 98 of the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene has been associated with decreased serum insulin and C-peptide responses during an oral glucose tolerance test (OGTT) in glucose-tolerant subjects. The aims of the present study were to evaluate the influence of the polymorphism on the serum insulin and C-peptide responses to an OGTT in glucose-tolerant women with and without previous GDM and to investigate if this polymorphism is associated with GDM. The Ala/Val98 polymorphism was measured in 376 women of Danish origin with previous GDM, and in 724 age-matched and 310 middle-aged glucose tolerant women using polymerase chain reaction-restriction fragment length polymorphism. The allelic frequency of the Ala/Val98 polymorphism was 0.043 [95% confidence interval (CI) 0.028, 0.057] in women with previous GDM vs. 0.037 (95% CI 0.028, 0.047) in age-matched and 0.039 (95% CI 0.024, 0.054) in middle-age women. Among 117 glucose-tolerant women with previous GDM, 10 carriers of the Ala/Val98 polymorphism had a non-significant 27% and 22% reduction in serum C-peptide and insulin levels, respectively, at 30 min during an OGTT. Seventy-eight control subjects carrying the Ala/Val98 polymorphism had a 10% (P = 0.001) and 16% (P = 0.004) reduction in serum C-peptide and insulin levels, respectively, compared with 956 Ala/Ala control subjects. The Ala/Val polymorphism at codon98 of HNF-1alpha is not associated with GDM in Danish women. However, the codon 98 variant is associated with a significant impairment of serum insulin and C-peptide responses during an OGTT in glucose-tolerant women without previous GDM.

Endothelial dysfunction, inflammation, and insulin resistance: a focus on subjects at risk for type 2 diabetes.

Subjects with obesity, family history of type 2 diabetes, polycystic ovary syndrome, previous gestational diabetes, dyslipidemia, hypertension, impaired glucose tolerance or impaired fasting glucose, and those with metabolic syndrome are at risk for the development of type 2 diabetes. Some of them are also at risk for cardiovascular disease. Some underlying abnormalities such as insulin resistance, endothelial dysfunction, and low-grade chronic inflammation are frequently present and closely associated in all these groups. The flow of substrates, hormones, and cytokines from visceral fat to skeletal muscle and to the endothelial cells, along with some genetic abnormalities that lead to impaired insulin action in the peripheral tissues and to impaired insulin-stimulated nitric oxide production in endothelial cells, may play a role in establishing these shared metabolic and vascular derangements. Weight loss, thiazolidinediones, and metformin improve vascular function in subjects at risk for type 2 diabetes and may prove to reduce cardiovascular events in these individuals.

Increasing incidence of diabetes after gestational diabetes: a long-term follow-up in a Danish population.

To study the incidence of diabetes among women with previous diet-treated gestational diabetes mellitus (GDM) in the light of the general increasing incidence of overweight and diabetes and to identify risk factors for the development of diabetes. Women with diet-treated GDM during 1978-1985 (old cohort, n = 241, also followed up around 1990) or 1987-1996 (new cohort, n = 512) were examined in 2000-2002. Women were classified by a 2-h, 75-g oral glucose tolerance test according to the World Health Organization criteria or an intravenous glucagon test supplemented by measurement of GAD antibodies. Historical data from index-pregnancy and anthropometrical measurements were collected. A total of 481 (63.9%) women were examined (median 9.8 years [interquartile range 6.4-17.2]) after index pregnancy. Diabetes and impaired glucose tolerance (IGT)/impaired fasting glucose were present in 40.0 and 27.0% of women, respectively. In the new cohort, 40.9% had diabetes compared with 18.3% in the old cohort at the 1990 follow-up (P < 0.0005). Prepregnancy BMI was significantly higher in the new compared with the old cohort (26.0 [22.5-30.8] vs. 22.9 kg/m2 [20.2-28.0], P < 0.0005). Among others, new-cohort membership, prepregnancy overweight (BMI > or = 25 kg/m2), and IGT postpartum were identified as independent predictors of diabetes by multiple logistic regression analyses. The incidence of diabetes among Danish women with previous diet-treated GDM was very high and had more than doubled over a 10-year period. This seems to be due to a substantial increase in BMI in women with GDM.

Reproducibility of diabetes mellitus diagnosis (WHO 1999 criteria) in women.

Reproducibility of diabetes mellitus (DM) diagnosis has been recognized as non-optimal and a few studies have analyzed its reproducibility using new diagnostic criteria. Our aim was to evaluate the reproducibility of WHO 1999 criteria for DM diagnosis in women. A total of 696 caucasian women with previous gestational diabetes mellitus (GDM) underwent an OGTT at a median of 6.2 years (interquartile range, 0.5-7.3) after delivery. When OGTT was diagnostic of DM, a second test was scheduled and performed after a median of 3 months (interquartile range, 1.6-10.6). At the second test, 35 women were diagnosed with DM (12 by fasting plasma glucose (FPG) alone, 10 by isolated post-challenge hyperglycemia (IPH), 10 by fasting and 2-h plasma glucose, 3 by symptoms of hyperglycemia plus measurement of plasma glucose). DM was confirmed in 56.3% of women diagnosed without symptoms. In this subgroup, reproducibility according to the abnormality at the first test was: 33.3% in those diagnosed by FPG alone, 40% in those diagnosed by IPH, and 100% in those diagnosed by both fasting and 2-h plasma glucose ( p<0.05 vs. the two previous groups). In women with former GDM, the reproducibility of DM diagnosis by FPG alone or IPH is similar and lower than the diagnosis made by abnormality in both values.

The impact of an insulin sensitizer, troglitazone, on glucose metabolism in African Americans at risk for type 2 diabetes mellitus: a placebo-controlled, 24-month randomized study

African Americans (AA) have greater prevalence of type 2 diabetes mellitus (DM), and nondiabetic AA have demonstrated increased insulin resistance when compared with Caucasian Americans (CA). The objective of this study was to examine the impact of chronic use of an insulin sensitizer on glucose metabolism in normal glucose tolerant AA at risk for DM (previous gestational diabetes mellitus [GDM] or first-degree relative with DM). Forty-nine high-risk AA received 200 mg/d troglitazone (TRO) versus 81 age-, weight-, and body mass index (BMI)-matched high-risk AA who received placebo (PLA) for 24 months. Yearly anthropometric measurements, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Biochemical parameters were monitored quarterly. There was no significant change in anthropometric measurements over 24 months in TRO versus PLA. There were no significant differences in serum glucose, insulin, or C-peptide incremental area under the curve (AUC) in TRO versus PLA at baseline or 24 months for OGTT and FSIVGTT. The insulin sensitivity (SI) for TRO and PLA increased from baseline to 24 months by 17% and 16%, respectively. The TRO demonstrated a 26% increase in insulin/glucose ratio versus 1% increase in the PLA at 24 months. The disposition index (DI) increased 33% from baseline in TRO versus 21% increase in PLA. Modest improvement in glucose metabolism was seen in TRO when compared with PLA. TRO was well tolerated without significant reported adverse events. Based on our current data, the treatment of normal glucose tolerant high-risk AA with thiazolidinedione (TZD) may be beneficial to “reset” and protect glucose metabolism by improving insulin responses. Because of the potential drug-related risks associated with use of TZD and the proven positive impact of diet and exercise in prevention of DM, studies of longer duration with examination of other potentially beneficial parameters, such as cardiovascular indices and inflammatory markers will be necessary to justify the cost in the nondiabetic population.

Insulin resistance and beta-cell dysfunction in normoglycaemic European women with a history of gestational diabetes.

Women with previous gestational diabetes (GDM) are at increased risk of subsequent type 2 diabetes. To characterize early metabolic abnormalities associated with this increased risk, we studied normoglycaemic women with a history of GDM. We performed an insulin-modified, frequently sampled intravenous glucose tolerance test (FSIVGTT) in 34 normoglycaemic European women with previous GDM and 44 European control women, deriving measures of insulin sensitivity, glucose effectiveness, glucose disappearance rate and acute insulin response to glucose. Post-GDM women were more obese than controls [body mass index (BMI), geometric mean (95% confidence interval); 25.3 kg/m2 (23.8-27.1 kg/m2) vs. 23.1 kg/m2 (21.9-24.3 kg/m2), P = 0.03]. Evidence of insulin resistance was provided by their lower insulin sensitivity as measured by FSIVGTT [0.6 x 10-4/min/pmol/l (0.3-1.2 x 10-4/min/pmol/l) vs. 1.5 x 10-4/min/pmol/l (1.2-1.8 x 10-4/min/pmol/l), P = 0.01] and by homeostatic model assessment [72% (49-107%) vs. 153% (113-206%), P = 0.004]; and by their higher fasting triglycerides [1.0 mmol/l (0.7-1.5 mmol/l) vs. 0.7 mmol/l (0.6-0.8 mmol/l), P = 0.001]. Though there was no difference between groups in fasting NEFA levels, acute NEFA suppression was diminished in the post-GDM group (P = 0.01). Concomitant beta-cell dysfunction in the post-GDM women was revealed by their lower disposition index [0.05/min (0.02-0.10/min) vs. 0.11/min (0.09-0.14/min), P = 0.02] compared to controls. The differences in insulin sensitivity, but not those of beta-cell function, were partly, though not completely, attributable to differences in regional and total adiposity. European normoglycaemic women with previous GDM display both glucoregulatory and antilipolytic insulin resistance, reduced beta-cell function and dyslipidaemia. These metabolic abnormalities are likely to contribute to their increased risk of future type 2 diabetes.

Intermediate metabolism in normal pregnancy and in gestational diabetes.

Complex though integrated hormonal and metabolic changes characterize pregnancy. In the face of progressive decline in insulin action, glucose homeostasis is maintained through a compensatory increase in insulin secretion. This switches energy production from carbohydrates to lipids, making glucose readily available to the fetus. This precise and entangled hormonal and metabolic condition can, however, be disrupted and diabetic hyperglycemia can develop (gestational diabetes). The increase in plasma glucose level is believed to confer significant risk of complications to both the mother and the fetus and the newborn. Moreover, exposition of fetal tissues to the diabetic maternal environment can translate into an increased risk for development of diabetes and/or the metabolic syndrome in the adult life. In women with previous gestational diabetes, the risk of developing type 2 diabetes is greatly enhanced, to the point that GDM represents an early stage in the natural history of type 2 diabetes. In these women, accurate follow-up and prevention strategies are needed to reduce the subsequent development of overt diabetes. This paper will review current knowledge on the modifications occurring in normal pregnancy, while outlining the mechanisms. In this paper, we will review the changes of intermediary metabolism occurring during pregnancy. In particular, we will outline the mechanisms responsible for gestational diabetes; the link between these alterations and associated maternal and neonatal morbidity will be examined.

Irregular menses: An independent risk factor for gestational diabetes mellitus

Objective: Our purpose was to determine whether a history of irregular menses predicts gestational diabetes mellitus independently of traditional risk factors. Study Design: We analyzed demographic characteristics, body mass index, and menstrual history of 85 pregnant women with gestational diabetes mellitus and compared them with 85 systematically selected control subjects who were matched for age, race, and delivery year. Subjects with pregestational diabetes mellitus, previous gestational diabetes mellitus, family history of diabetes mellitus, weight >200 pounds, previous macrosomic infants, or previous stillbirth were excluded. Results: Demographic characteristics between case and control groups were similar. Mean body mass index was higher among cases (26.5 kg/m2) versus control subjects (24.5 kg/m2, P =.004). Irregular cycles were more prevalent in the cases (24% vs 7%, P =.006). With the use of body mass index as a stratification factor, menstrual irregularity maintained a strong association with gestational diabetes mellitus (P =.014). Conclusion: A history of irregular menstrual cycles was a significant independent predictor of gestational diabetes mellitus. If selective screening is implemented for gestational diabetes mellitus, such history should be considered in the decision of whom to test. (Am J Obstet Gynecol 2003;188:1189-91.)

Diabetes and abnormal glucose tolerance in women with previous gestational diabetes.

In Spanish women with gestational diabetes mellitus (GDM), we aimed to study the progression to diabetes and abnormal glucose tolerance (AGT) and identify predictive factors. In 696 women with GDM and 70 control women, glucose tolerance was evaluated postpartum and at 5-year intervals. In the GDM group, the cumulative risk for diabetes and AGT was 13.8 and 42.4% after 11 years compared with 0 and 2.8% in control women, respectively (P < 0.05). Independent predictive factors for diabetes were previous hyperglycemia, four abnormal glucose values on the diagnostic oral glucose tolerance test (OGTT) or overt diabetes during pregnancy, 2-h blood glucose on the diagnostic OGTT >/=11.7 mmol/l, gestational age at diagnosis <24 weeks, and prepregnancy BMI >/=26.4 kg/m(2). All of these factors (some with different cutoff points) in addition to fasting glycemia were predictors of AGT also. The risk was nonlinear. Four abnormal glucose values on the diagnostic OGTT or overt diabetes during pregnancy was the strongest predictive factor for diabetes (relative risk 3.92), and prepregnancy BMI was the predictive factor with the highest attributable fraction in the whole group (13.3%). When first postpartum OGTT data were included in the analysis, predictors changed, but the overall prediction was similar. Spanish women with GDM have an increased risk of diabetes and AGT. Predictive factors display a nonlinear relationship. The strongest predictive factor for diabetes was four abnormal glucose values on the diagnostic OGTT or overt diabetes during pregnancy; the factor with the highest attributable fraction in the whole group was prepregnancy BMI.

Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content.

Our objective was to determine how 8% weight loss influences subcutaneous, intra-abdominal, and liver fat (LFAT), as well as features of insulin resistance, in obese women with high versus low LFAT. A total of 23 women with previous gestational diabetes were divided into groups of high (9.4 +/- 1.4%) and low (3.3 +/- 0.4%) LFAT based on their median LFAT (5%) measured with proton spectroscopy. Both groups were similar with respect to age, BMI, and intra-abdominal and subcutaneous fat. Before weight loss, women with high LFAT had higher fasting serum insulin and triglyceride concentrations than women with low LFAT. At baseline, LFAT correlated with the percent of fat (r = 0.44, P < 0.05) and saturated fat (r = 0.45, P < 0.05) of total caloric intake but not intra-abdominal or subcutaneous fat or fasting serum free fatty acids. Weight loss was similar between the groups (high LFAT -7.4 +/- 0.2 vs. low LFAT -7.7 +/- 0.3 kg). LFAT decreased from 9.4 +/- 1.4 to 4.8 +/- 0.7% (P < 0.001) in women with high LFAT and from 3.3 +/- 0.4 to 2.0 +/- 0.2% (P < 0.001) in women with low LFAT. The absolute decrease in LFAT was significantly higher in women with high than low LFAT (-4.6 +/- 1.0 vs. -1.3 +/- 0.3%, P < 0.005). The decrease in LFAT was closely correlated with baseline LFAT (r = -0.85, P < 0.001) but not with changes in the volumes of intra-abdominal or subcutaneous fat depots, which decreased similarly in both groups. LFAT appears to be related to the amount of fat in the diet rather than the size of endogenous fat depots in obese women. Women with initially high LFAT lost more LFAT by similar weight loss than those with low LFAT, although both groups lost similar amounts of subcutaneous and intra-abdominal fat. These data suggest that LFAT is regulated by factors other than intra-abdominal and subcutaneous fat. Therefore, LFAT does not appear to simply reflect the size of endogenous fat stores.

Increased intramyocellular lipid concentration identifies impaired glucose metabolism in women with previous gestational diabetes.

Women with previous gestational diabetes (pGDM) are frequently insulin-resistant, which could relate to intramyocellular lipid content (IMCL). IMCL were measured with (1)H nuclear magnetic resonance spectroscopy in soleus (IMCL-S) and tibialis-anterior muscles (IMCL-T) of 39 pGDM (32 +/- 2 years, waist-to-hip ratio 0.81 +/- 0.01) and 22 women with normal glucose tolerance (NGT; 31 +/- 1 years, 0.76 +/- 0.02) at 4-6 months after delivery. Body fat mass (BFM) was assessed from bioimpedance analysis, insulin sensitivity index (S(I)), and glucose effectiveness (S(G)) from insulin-modified frequently sampled glucose tolerance tests. pGDM exhibited 45% increased BFM, 35% reduced S(I) and S(G) (P < 0.05), and 40% (P < 0.05) and 55% (P < 0.005) higher IMCL-S and IMCL-T, respectively. IMCL related to body fat (BFM P < 0.005, leptin P < 0.03), but only IMCL-T correlated (P < 0.03) with S(I) and glucose tolerance index independent of BMI. Insulin-resistant pGDM (n = 17) had higher IMCL-S (+66%) and IMCL-T (+86%) than NGT and insulin-sensitive pGDM (+28%). IMCL were also higher (P < 0.005, P = 0.05) in insulin-sensitive pGDM requiring insulin treatment during pregnancy and inversely related to the gestational week of GDM diagnosis. Thus, IMCL-T reflects insulin sensitivity, whereas IMCL-S relates to obesity. IMCL could serve as an additional parameter of increased diabetes risk because it identifies insulin-resistant pGDM and those who were diagnosed earlier and/or required insulin during pregnancy.