DEVELOPING twin-specific 75-g oral glucose tolerance test diagnostic thresholds for gestational diabetes based on the risk of future maternal diabetes: a population-based cohort study.

OBJECTIVE: To develop twin-specific outcome-based oral glucose tolerance test (OGTT) diagnostic thresholds for GDM based on the risk of future maternal type-2 diabetes. DESIGN: A population-based retrospective cohort study (2007-2017). SETTING: Ontario, Canada. METHODS: Nulliparous women with a live singleton (n = 55 361) or twin (n = 1308) birth who underwent testing for gestational diabetes mellitus (GDM) using a 75-g OGTT in Ontario, Canada (2007-2017). We identified the 75-g OGTT thresholds in twin pregnancies that were associated with similar incidence rates of future type-2 diabetes to those associated with the standard OGTT thresholds in singleton pregnancies. RESULTS: For any given 75-g OGTT value, the incidence rate of future maternal type-2 diabetes was lower for women with a twin than women with a singleton pregnancy. Using women with a negative OGTT as reference, the risk of future maternal type-2 diabetes in twin pregnancies with a positive OGTT based on the standard OGTT thresholds (9.86 per 1000 person years, adjusted hazard ratio (aHR) 4.79, 95% CI 2.69-8.51) was lower than for singleton pregnancies with a positive OGTT (18.74 per 1000 person years, aHR 8.22, 95% CI 7.38-9.16). The twin-specific OGTT fasting, 1-hour and 2-hour thresholds identified in the current study based on correlation with future maternal type-2 diabetes were 5.8 mmol/l (104 mg/dl), 11.8 mmol/l (213 mg/dl) and 10.4 mmol/l (187 mg/dl), respectively. CONCLUSIONS: We identified potential twin-specific OGTT thresholds for GDM that are associated with a similar risk of future type-2 diabetes to that observed in women diagnosed with GDM in singleton pregnancies based on standard OGTT thresholds. TWEETABLE ABSTRACT: Potential twin-specific OGTT thresholds for GDM were identified.

Effect of short-term intensive insulin therapy on the incretin response in early type 2 diabetes.

AIMS: Short-term intensive insulin therapy (IIT) and gastric bypass surgery are both interventions that can improve beta-cell function, reduce insulin resistance and induce remission of type 2 diabetes. Whereas gastric bypass yields an enhanced glucagon-like peptide-1 (GLP-1) response that may contribute to its metabolic benefits, the effect of short-term IIT on the incretin response is unclear. Thus, we sought to evaluate the impact of IIT on GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion in early type 2 diabetes. METHODS: In this study, 63 patients (age 59±8.3 years, baseline A1c 6.8±0.7%, diabetes duration 3.0±2.1 years) underwent 4 weeks of IIT (basal insulin detemir and pre-meal insulin aspart). GLP-1, GIP and glucagon responses were assessed by the area-under-the-curve (AUC) of these hormones on oral glucose tolerance tests at baseline and 1-day after the completion of therapy. Beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2), with insulin resistance measured by Homeostasis Model Assessment (HOMA-IR). RESULTS: As expected, comparing the post-therapy oral glucose tolerance test to that at baseline, IIT increased ISSI-2 (P=0.02), decreased HOMA-IR (P<0.001), and reduced AUCglucagon (P<0.001). Of note, however, IIT had no significant impact on AUCGLP-1 (P=0.24) and reduced AUCGIP (P=0.02). CONCLUSION: Despite improving beta-cell function, insulin resistance and glucagonemia, short-term IIT does not change GLP-1 secretion and decreases the GIP response to an oral glucose challenge in early type 2 diabetes. Thus, the beneficial impact of this therapy on glucose homeostasis is not attributable to its effects on incretin secretion.

Maternal pre-gravid cardiometabolic health and infant birthweight: A prospective pre-conception cohort study.

BACKGROUND AND AIMS: Both low birthweight and high birthweight have been associated with the development of cardiometabolic disease in adulthood, possibly reflecting the effect of intrauterine fetal programming. As developmental programming can begin before conception, pre-gravid factors that predict birthweight may be relevant in this context. However, little is known about such factors. Thus, we established a pre-conception cohort to identify maternal pre-gravid cardiometabolic determinants of infant birthweight. METHODS AND RESULTS: In this prospective observational cohort study, 1484 newly-married women in Liuyang, China, underwent baseline (pre-gravid) evaluation and then were followed across a subsequent pregnancy. Pre-gravid cardiometabolic characterization consisted of clinical (anthropometry, blood pressure) and biochemical evaluation (total/LDL/HDL cholesterol, triglycerides, glucose) at median 20 weeks before a singleton pregnancy. Mean birthweight was 3294 ± 444 g, with 173 neonates large-for-gestational-age (LGA) and 110 small-for-gestational-age (SGA). On multiple linear regression analysis, positive determinants of birthweight were maternal age, pre-gravid body mass index (BMI), weight gain in pregnancy, length of gestation, and male infant (all p ≤ 0.0003). On logistic regression analysis, independent predictors of an LGA delivery were maternal age (OR = 1.10 per year, 95%CI 1.03-1.18), pre-gravid BMI (OR = 1.21 per kg/m2, 1.07-1.37), and gestational weight gain (OR = 1.10 per kg, 1.06-1.14). The only independent predictor of SGA was gestational weight gain (OR = 0.93 per kg, 0.89-0.97). CONCLUSION: Maternal weight before and during pregnancy is the predominant cardiometabolic determinant of infant birthweight, rather than pre-gravid blood pressure, glucose or lipid profile.

Fetal sex and maternal risk of pre-eclampsia/eclampsia: a systematic review and meta-analysis.

BACKGROUND: A preponderance of male fetuses in pregnancies complicated by pre-eclampsia was described over 40 years ago. Since then, however, there has been conflicting evidence in the literature, with some studies supporting a male preponderance, some demonstrating no relationship with fetal sex, and others reporting increased risk in pregnancies bearing females. OBJECTIVES: In this context, we sought to conduct a systematic review and meta-analysis to objectively evaluate the relationship between fetal sex and maternal risk of pre-eclampsia/eclampsia. SEARCH STRATEGY: Studies from January 1950 to April 2015 were identified from PUBMED and EMBASE. SELECTION CRITERIA: This systematic review and meta-analysis evaluated 22 articles reporting data on fetal sex and prevalence of pre-eclampsia/eclampsia. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers. Pooled estimates of the relative risk (RR) were calculated by random-effects model. MAIN RESULTS: Male fetus was considered the exposure and prevalence of maternal pre-eclampsia/eclampsia was the outcome of interest. We identified 534 studies through electronic searches and three studies through manual searches. Twenty-two studies fulfilled the inclusion criteria, yielding data on 3 163 735 women. Pooled analyses of these studies showed no association between male fetal sex and maternal risk of pre-eclampsia/eclampsia (RR 1.01; 95% confidence interval, 95% CI 0.97-1.05); however, a subgroup analysis including only studies that evaluated the non-Asian population (n = 2 931 771 women) demonstrated that male fetal sex was associated with increased maternal risk of pre-eclampsia/eclampsia (RR 1.05; 95% CI 1.03-1.06; I2 = 10%; P = 0.33). CONCLUSION: Male fetal sex is associated with maternal risk of pre-eclampsia/eclampsia in the non-Asian population. TWEETABLE ABSTRACT: Fetal sex is associated with maternal risk of pre-eclampsia/eclampsia in the non-Asian population.

Hepatic fat and abdominal adiposity in early pregnancy together predict impaired glucose homeostasis in mid-pregnancy.

Hepatic fat and abdominal adiposity individually reflect insulin resistance, but their combined effect on glucose homeostasis in mid-pregnancy is unknown. A cohort of 476 pregnant women prospectively underwent sonographic assessment of hepatic fat and visceral (VAT) and total (TAT) adipose tissue at 11-14 weeks' gestation. Logistic regression was used to assess the relation between the presence of maternal hepatic fat and/or the upper quartile (Q) of either VAT or TAT and the odds of developing the composite outcome of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or gestational diabetes mellitus at 24-28 weeks' gestation, based on a 75 g OGTT. Upon adjusting for maternal age, ethnicity, family history of DM and body mass index (BMI), the co-presence of hepatic fat and quartile 4 (Q4) of VAT (adjusted odds ratio (aOR) 6.5, 95% CI: 2.3-18.5) or hepatic fat and Q4 of TAT (aOR 7.8 95% CI 2.8-21.7) were each associated with the composite outcome, relative to women with neither sonographic feature. First-trimester sonographic evidence of maternal hepatic fat and abdominal adiposity may independently predict the development of impaired glucose homeostasis and GDM in mid-pregnancy.

Differential impact of maternal and paternal ethnicity on the pattern of fat distribution in infants at age 3 months.

BACKGROUND: As ethnicity is typically recorded as a single demographic variable in clinical studies, little is known about the relative impact of maternal vs. paternal ethnicity on fat distribution. OBJECTIVES: The objective of this study was to determine whether there is a differential impact of maternal and paternal ethnicity on infant adiposity. METHODS: Three hundred fifty-five infants underwent anthropometric assessment at age 3 months, including skin-fold thickness (SFT) measurement at subscapular, suprailiac and triceps. Maternal (M) and paternal (P) ethnicity were classified as white (M = 241, P = 252), Asian (M = 50, P = 42) or other (M = 64, P = 61). RESULTS: Infants with either Asian mother (compared with white) or Asian father (compared with white) had increased subscapular, suprailiac and triceps SFT (all P < 0.05). On logistic regression analysis, however, only maternal Asian ethnicity (compared with white) independently predicted the likelihood of an infant being in the highest tertile for SFT at subscapular (odds ratio [OR] = 2.72, 95% confidence interval 1.17-6.34, P = 0.02), suprailiac (OR = 3.56, 1.51-8.42, P = 0.004) and triceps (OR = 3.26, 1.40-7.55, P = 0.005). In contrast, paternal Asian ethnicity was independently associated with sum of SFT only (OR = 2.46, 1.02-5.97, P = 0.04). CONCLUSION: Maternal and paternal Asian ethnicity have differential effects on infant fat distribution. Future clinical studies on obesity and fat composition should consider the distinct contributions of both parents to the ethnic classification of participants.

Sex of the baby and future maternal risk of Type 2 diabetes in women who had gestational diabetes.

AIMS: Women who develop gestational diabetes mellitus have a chronic defect in the secretion of insulin by the pancreatic ß cells that underlies both their diagnostic hyperglycaemia in pregnancy and their elevated lifetime risk of developing Type 2 diabetes in the future. It has recently emerged that carrying a male fetus is associated with poorer maternal ß-cell function and an increased risk of gestational diabetes, whereas the development of gestational diabetes when carrying a girl (as compared with a boy) predicts a comparatively higher risk of early progression to Type 2 diabetes before any subsequent pregnancy. In this context, we sought to determine the impact of fetal sex on the long-term risk of Type 2 diabetes in women with gestational diabetes. METHODS: Using population-based administrative databases, we identified all women in Ontario, Canada, with a singleton live-birth first pregnancy complicated by gestational diabetes between April 2000 and March 2010 (n = 23 363). We compared the risk of subsequent Type 2 diabetes after pregnancy in those who carried a girl (n = 11 229) vs. those who carried a boy (n = 12 134). RESULTS: Over median 5.5 years follow-up, 5483 women (23.5%) were diagnosed with diabetes. Compared with those who carried a boy, women who had a girl had an elevated risk of subsequently developing diabetes (adjusted hazard ratio = 1.06, 95% CI 1.01-1.12). CONCLUSIONS: Among women with gestational diabetes, those who are carrying a girl have a slightly higher overall future risk of Type 2 diabetes.

Maternal folate status and obesity/insulin resistance in the offspring: a systematic review.

OBJECTIVE: Prenatal folic acid supplementation or maternal folate sufficiency may protect the offspring from obesity and insulin resistance. This study aims to summarize the findings of association between prenatal folic acid supplementation/maternal folate sufficiency and obesity/insulin resistance in the offspring. METHODS: Twelve databases were searched for both published and unpublished work of prenatal folic acid supplementation/maternal folate status up to 1 July 2014. Experimental and observational studies on animals and human beings were included based on the eligibility criteria. There were no limits to the time period and language of publication. The study quality was assessed with a 10-Point Scale for Scientific Methodology. RESULTS: The search identified 2548 records. Nine animal studies and five human studies satisfied search criteria were included. Five of these nine animal studies showed a protective effect of folic acid. Of the five human studies, one showed a protective effect of folic acid, two showed a harmful effect and two showed uncertain results. CONCLUSIONS: Data from both animal studies and human studies are inconsistent. Future researches with sophisticated designs are needed to demonstrate the potential protective effect of maternal folate on obesity/insulin resistance in the offspring in animal models and human pregnancies.

Clinical predictors and time course of the improvement in ß-cell function with short-term intensive insulin therapy in patients with Type 2 diabetes.

AIMS: In patients with Type 2 diabetes, a short course of intensive insulin therapy can improve ß-cell function and even induce transient remission of diabetes. However, not all patients respond to this therapy. Although the achievement of fasting glucose  < 7.0 mmol/l one day after stopping intensive insulin therapy can identify patients in whom ß-cell function has improved, we sought to determine clinical predictors for the early identification of such responders and the time course of response. METHODS: We pooled data from two studies in which 97 patients with Type 2 diabetes mellitus (median 3 years duration) and HbA1c 51 ± 8.7 mmol/mol (6.8 ± 0.8%) underwent 4-8 weeks of intensive insulin therapy, consisting of basal detemir and pre-meal insulin aspart. They were classified as responders (n = 74) or non-responders (n = 23), defined by the achievement of fasting glucose  < 7.0 mmol/l after stopping intensive insulin therapy. RESULTS: On logistic regression analyses, duration of diabetes (odds ratio [OR] = 0.72, 95% confidence interval [CI] 0.56-0.92, P = 0.009) and baseline fasting glucose (OR = 0.40, 95% CI 0.24-0.68, P = 0.001) emerged as predictors of the likelihood of responding. Ninety per cent of patients with duration ≤ 4 years and fasting glucose ≤ 8.0 mmol/l responded to intensive insulin therapy. Despite having lower glucose levels during intensive insulin therapy, responders had less hypoglycaemia than non-responders (median 0.3 vs. 1.6 episodes/week, P < 0.0001), with rates of hypoglycaemia diverging sharply from the third week onwards. CONCLUSION: At baseline, shorter duration of diabetes and lower fasting glucose can identify patients most likely to benefit from short-term intensive insulin therapy. Most importantly, during therapy, responders had less hypoglycaemia from the third week onwards, despite lower glycaemia, suggesting that 2 weeks of intensive insulin therapy may be needed to improve endogenous islet function.

Concordance of retinopathy and nephropathy over time in Type 1 diabetes: an analysis of data from the Diabetes Control and Complications Trial.

AIMS: Little is known about the dynamic relationship over time between diabetic retinopathy and nephropathy. Thus, we sought to evaluate the concordance over time of retinopathy and nephropathy in patients with Type 1 diabetes during the Diabetes Control and Complications Trial. METHODS: This analysis was conducted in patients with Type 1 diabetes participating in the Diabetes Control and Complications Trial. Only participants with urinary albumin excretion rate < 40 mg/24 h were included in the analysis (n = 1365). We evaluated the relationship between the progression of retinopathy and the development of nephropathy over a mean 6.5 years of follow-up. Progression of retinopathy was defined by 3-step change in Early Treatment Diabetic Retinopathy Study score on consecutive annual evaluations. Development of nephropathy was defined as incidence of urinary albumin excretion rate ≥ 40 mg/24 h on annual evaluation. RESULTS: Over a mean 6.5 years of follow-up, the incidence of progression of retinopathy was higher in those who developed nephropathy than in those who did not (36.2 vs. 13.4%; P < 0.001). The development of nephropathy independently increased the risk for progression of retinopathy (hazard ratio 1.62, 95% CI 1.23-2.13, P = 0.001), after adjustment for age, gender, diabetes duration, treatment, HbA1c , BMI, HDL cholesterol and blood pressure. Similarly, the incidence of nephropathy was higher in participants who had progression of retinopathy than in those who did not (40.7 vs. 15.7%; P < 0.001). Furthermore, progression of retinopathy independently increased the risk for development of nephropathy (hazard ratio 1.72, 95% CI 1.30-2.27, P < 0.001). CONCLUSIONS: Progression of retinopathy and development of nephropathy each increase the risk for incidence of the other, independent of established risk factors for microvascular complications, supporting the notion of a shared aetiologic basis.

Effect of maternal gestational diabetes on the cardiovascular risk factor profile of infants at 1 year of age.

BACKGROUND AND AIM: Offspring of women with gestational diabetes (GDM) exhibit an adverse cardiovascular risk factor profile by as early as age 5 years. Recently, maternal glycemia has been associated with epigenetic modification of genes on the fetal side of the placenta, including those encoding emerging risk factors (adiponectin, leptin), suggesting that vascular differences may emerge even earlier in life. Thus, we sought to evaluate cardiovascular risk factors and determinants thereof in 1-year-old infants of women with and without GDM. METHODS AND RESULTS: Traditional (glucose, lipids) and emerging (C-reactive protein (CRP), adiponectin, leptin) risk factors were assessed in pregnancy in 104 women with (n = 36) and without GDM (n = 68), and at age 1-year in their offspring. In pregnancy, women with GDM had higher triglycerides (2.49 vs 2.10 mmol/L, p = 0.04) and CRP (5.3 vs 3.6 mg/L, p = 0.03), and lower adiponectin (7.3 vs 8.5 µg/mL, p = 0.04) than did their peers. At age 1-year, however, there were no differences in cardiovascular risk factors (including adiponectin) between the infants of women with and without GDM. Of note, maternal and infant adiponectin levels were associated in the non-GDM group (r = 0.39, p = 0.001) but not in the GDM group (r = 0.07, p = 0.67). Furthermore, on multiple linear regression analyses, maternal adiponectin emerged as an independent predictor of infant adiponectin in the non-GDM group only (beta = 776.1, p = 0.0065). CONCLUSION: Infants of women with and without GDM have a similar cardiovascular risk factor profile at age 1-year. However, there are differences in their early-life determinants of adiponectin that may be relevant to the subsequent vascular risk of GDM offspring.

Area-under-the-HbA1c-curve above the normal range and the prediction of microvascular outcomes: an analysis of data from the Diabetes Control and Complications Trial.

AIMS: In the Diabetes Control and Complications Trial, mean updated HbA(1c) accounted for most of the differential risk of microvascular complications between intensive and conventional insulin therapy. We hypothesized, however, that a more precise measure of chronic hyperglycaemic exposure may be the incremental area-under-the-HbA(1c)-curve above the Diabetes Control and Complications Trial-standardized normal range for HbA(1c) (iAUC(HbA1c>norm)). METHODS: Using the Principal Diabetes Control and Complications Trial data set, we compared the following three measures of chronic glycaemic exposure for their capacity to predict retinopathy, nephropathy and neuropathy during the Diabetes Control and Complications Trial: mean updated HbA(1c), iAUC(HbA1c>norm), and total area-under-the-HbA(1c)-curve (tAUC(HbA1c)). For each outcome, models using each of these three glycaemic measures were compared in the following three ways: hazard or odds ratio, χ(2) statistic, and Akaike information criterion. RESULTS: The three glycaemic measures did not differ in their prediction of neuropathy. iAUC(HbA1c>norm) was modestly superior to mean updated HbA(1c) for predicting nephropathy (χ(2) P = 0.017, Akaike P = 0.032). In contrast, for predicting retinopathy, both iAUC(HbA1c>norm) (χ(2) P = 0.0005, Akaike P = 0.0005) and tAUC(HbA1c) (χ(2) P = 0.004, Akaike P = 0.004) were significantly better than mean updated HbA(1c). Varying its HbA(1c) threshold incrementally between 37 and 53 mmol/mol (5.5-7.0%), inclusive, did not improve the prediction of retinopathy by iAUC(HbA1c>threshold) beyond that of tAUC(HbA1c,) consistent with the concept of a continuous relationship between glycaemia and retinopathy, with no glycaemic threshold. CONCLUSIONS: Both iAUC(HbA1c>norm) and tAUC(HbA1c) were superior to mean updated HbA(1c) for predicting retinopathy. Optimal assessment of chronic glycaemic exposure as a determinant of retinopathic risk may require consideration of both the degree of hyperglycaemia and its duration.

Maternal pregravid weight is the primary determinant of serum leptin and its metabolic associations in pregnancy, irrespective of gestational glucose tolerance status.

CONTEXT: Several previous studies have investigated circulating levels of the adipokine leptin in relation to gestational diabetes mellitus (GDM). However, these studies have yielded markedly conflicting results, including increased, decreased, and unchanged leptin levels in women with GDM as compared with their peers. OBJECTIVE: We sought to evaluate the metabolic determinants of serum leptin in a well-characterized cohort reflecting the full spectrum of glucose intolerance in pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Metabolic characterization, including oral glucose tolerance test (OGTT) and measurement of serum leptin, insulin, lipids, adiponectin, and C-reactive protein, was performed in 817 pregnant women. The OGTT identified 198 women with GDM, 142 with gestational impaired glucose tolerance, and 477 with normal glucose tolerance. RESULTS: Median leptin (ng/ml) did not differ between the normal glucose tolerance (33.7), gestational impaired glucose tolerance (36.3), and GDM (36.4) groups (P = 0.085). On univariate correlation analysis, leptin was most strongly associated with prepregnancy body mass index (BMI) (r = 0.54, P < 0.0001), fasting insulin (r = 0.60, P < 0.0001), and C-reactive protein (r = 0.38, P < 0.0001) but only weakly associated with area under the glucose curve (AUC(glucose)) on the OGTT (r = 0.10, P = 0.0066). On multiple linear regression analysis, the strongest independent determinant of leptin was prepregnancy BMI (t = 11.55, P < 0.0001), whereas AUC(glucose) was not a significant predictor (t = -0.95, P = 0.34). Furthermore, although its respective associations with fasting insulin, triglycerides, and adiponectin varied across tertiles of prepregnancy BMI, leptin was not significantly associated with AUC(glucose) in any BMI tertile. CONCLUSIONS: Pregravid BMI, rather than gestational glucose tolerance, is the primary determinant of serum leptin concentration in pregnancy.

Short-term intensified insulin treatment in type 2 diabetes: long-term effects on ß-cell function.

The natural history of type 2 diabetes (T2DM) is characterized by progressive deterioration of pancreatic ß-cell function, leading to worsening glycemia over time. As current antidiabetic therapies have not yet been shown to profoundly alter this natural history, many patients ultimately will require exogenous insulin therapy to obtain adequate glycemic control. Interestingly, the temporary use of short-term intensive insulin therapy early in the course of T2DM has recently emerged as a therapeutic option that may offer favourable long-term effects on ß-cell function. Indeed, after receiving this treatment, many patients will experience sustained euglycemia without requiring any antidiabetic therapy. This apparent 'remission' of diabetes is likely secondary to improved ß-cell function and can last for more than a year, although it is not sustained and hyperglycemia eventually will return. Nevertheless, owing to its effects on ß-cell function, short-term intensive insulin therapy holds promise as a means for modifying the natural history of T2DM and warrants further study in this context. In this report, we will review the rationale and evidence underlying this interesting therapeutic option, and its implications for both clinical research and the management of patients with T2DM.

Adiponectin in pregnancy: implications for health and disease.

Pregnancy is a unique physiologic state that is associated with profound alterations in maternal metabolic, endocrine, and vascular function, designed to ensure the delivery of appropriate energy and nutrition to the developing fetus. In this context, the role of the fat-derived hormone adiponectin is of interest, particularly in light of emerging recognition of the broad array of physiologic processes upon which this adipokine impacts. Indeed, adiponectin has pleiotropic effects on the regulation of energy homeostasis, systemic inflammation, vascular function, cell growth, and even bone metabolism. Thus, in this review, we consider existing evidence for the physiologic role of adiponectin in human gestation and how this protein may be relevant to two major medical disorders of pregnancy: gestational diabetes mellitus and preeclampsia. While studies to date have yielded many conflicting findings pertaining to adiponectin in pregnancy, further investigation in this area is essential. Ultimately, elucidation of adiponectin physiology in the setting of both normal pregnancy and its pathologic conditions may provide unique insight into fundamental processes that are relevant to health and disease in mother and child.

Preeclampsia and gestational diabetes mellitus: pre-conception origins?

Preeclampsia (PE) and gestational diabetes mellitus (GDM) are two of the most common medical complications of pregnancy, with risks for both mother and child. Like many other antepartum complications, PE and GDM occur only in pregnancy. However, it is not clear if pregnancy itself is the cause of these complications or it these conditions are caused by factors that existed prior to gestation. In this paper, we hypothesize that although the clinical findings of PE and GDM are first noted during pregnancy, the origins of both conditions may actually precede pregnancy. We further hypothesize that pathophysiologic changes underlying PE and GDM are present prior to pregnancy, but remain undetected in the non-gravid state either because pregnancy is the trigger that makes these pathologies become clinically detectable or because there has been limited prospective longitudinal data comparing the pre-gravid and antepartum status of women that go on to develop these conditions. Rigorous prospective cohort studies in which women undergo serial systematic evaluation in the pre-conception period, throughout pregnancy and into the postpartum are ideally needed to test this hypothesis of pre-conception origins of PE and GDM. In this context, we are creating a pre-conception cohort, involving about 5000 couples who plan to have a baby within six months in Liuyang county in the Chinese province of Hunan. Results from this pre-conception cohort program should be able to provide definitive answer to the question of whether the underpinnings of PE and GDM originate prior to pregnancy. Ultimately, the significance of addressing this hypothesis is underscored by its potential implications for targeted interventions that could be designed to (i) prevent the deleterious effects of PE/GDM and (ii) thereby interrupt the vicious cycle of disease that links affected women and their offspring.

Discordant effects on central obesity, hepatic insulin resistance, and alanine aminotransferase of low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance.

Alanine aminotransferase (ALT) predicts incident type 2 diabetes (T2DM), possibly reflecting early fatty liver and hepatic insulin resistance. Thiazolidinediones and metformin can improve fatty liver and hepatic insulin resistance, respectively. In the Canadian Normoglycemia Outcome Evaluation trial, rosiglitazone/metformin (Rosi/Met, 4/1000 mg) reduced incident T2DM by 66% in subjects with impaired glucose tolerance. For insight on the hepatic effects of this therapy in relation to T2DM, we evaluated the temporal changes in waist, hepatic insulin sensitivity (1/Homeostasis Model Assessment of Insulin Resistance) and ALT in the Rosi/Met (n = 103) and placebo (n = 104) arms over median of 3.9 years. Waist did not differ between the arms. Hepatic insulin sensitivity improved in the Rosi/Met arm in year 1, but deteriorated thereafter as in the placebo arm. In contrast, Rosi/Met lowered ALT in year 1 and maintained this effect throughout the trial. Thus, low-dose Rosi/Met had no effect on central obesity, a transient effect on hepatic insulin sensitivity, and a sustained effect on ALT.

The postpartum cardiovascular risk factor profile of women with isolated hyperglycemia at 1-hour on the oral glucose tolerance test in pregnancy.

BACKGROUND AND AIMS: Women with gestational diabetes mellitus (GDM) have an enhanced cardiovascular risk factor profile at 3-months postpartum and an elevated risk of future cardiovascular disease, as compared to their peers. Recently, it has emerged that even mild dysglycemia on antepartum oral glucose tolerance test (OGTT) predicts an increased risk of future cardiovascular disease, although it is not known whether there exists an identifiable high-risk subgroup within this patient population. Since gestational impaired glucose tolerance (GIGT) due to isolated hyperglycemia at 1-h during the OGTT (1-h GIGT) bears metabolic similarity to GDM, we hypothesized that, like GDM, 1-h GIGT may predict a high-risk postpartum cardiovascular phenotype. METHODS AND RESULTS: In this prospective cohort study, 485 women underwent antepartum OGTT, followed by cardiovascular risk factor assessment at 3-months postpartum. The antepartum OGTT identified 4 gestational glucose tolerance groups: GDM (n = 137); 1-h GIGT (n = 39); GIGT at 2- or 3-h (2/3-h GIGT)(n = 50); and normal glucose tolerance (NGT)(n = 259). After adjustment for age, ethnicity, breastfeeding and waist circumference, mean levels of the following cardiovascular risk factors progressively increased from NGT to 2/3-h GIGT to 1-h GIGT to GDM: LDL cholesterol (p = 0.0026); total cholesterol:HDL (p = 0.0030); apolipoprotein B (p = 0.004); apolipoprotein B:apolipoprotein A1 (p = 0.026); leptin (p = 0.018); and C-reactive protein (p = 0.011). CONCLUSIONS: Amongst women without GDM, 1-h GIGT predicts an enhanced postpartum cardiovascular risk factor profile. It thus emerges, that amongst young women with mild dysglycemia in pregnancy, those with 1-h GIGT may comprise an unrecognized patient population at risk for future cardiovascular disease.