Glucose intolerance in pregnancy and future risk of pre-diabetes or diabetes

OBJECTIVE—The purpose of this study was to test the hypothesis that any degree of abnormal glucose homeostasis detected on antepartum screening for gestational diabetes mellitus (GDM) should be associated with an increased risk of postpartum pre-diabetes or diabetes.RESEARCH DESIGN AND METHODS—In this prospective cohort study, 487 women underwent 1) antepartum GDM screening by a glucose challenge test (GCT) and a diagnostic oral glucose tolerance test (OGTT) and 2) postpartum metabolic characterization by OGTT at 3 months after delivery. Four baseline glucose tolerance groups were defined on the basis of the antepartum GCT/OGTT: 1) GDM (n = 137); 2) gestational impaired glucose tolerance (GIGT) (n = 91); 3) abnormal GCT with normal glucose tolerance on an OGTT (abnormal GCT NGT) (n = 166); and 4) normal GCT with NGT on an OGTT (normal GCT NGT) (n = 93).RESULTS—The prevalence of postpartum glucose intolerance (pre-diabetes or diabetes) increased across the groups from normal GCT NGT (3.2%) to abnormal GCT NGT (10.2%) to GIGT (16.5%) to GDM (32.8%) (P_trend < 0.0001). On logistic regression analysis, all three categories of abnormal glucose homeostasis in pregnancy independently predicted postpartum glucose intolerance: abnormal GCT NGT odds ratio (OR) 3.6 (95% CI 1.01–12.9); GIGT OR 5.7 (1.6–21.1); and GDM OR 14.3 (4.2–49.1). Furthermore, both in pregnancy and at 3 months postpartum, insulin sensitivity (IS_OGTT) and pancreatic β-cell function (insulinogenic index/homeostasis model assessment of insulin resistance) progressively decreased across the groups from normal GCT NGT to abnormal GCT NGT to GIGT to GDM (all P_trend < 0.0001).CONCLUSIONS—Any degree of abnormal glucose homeostasis in pregnancy independently predicts an increased risk of glucose intolerance postpartum.The diagnosis of gestational diabetes mellitus (GDM) identifies a population of young women who have a very high risk of ultimately developing type 2 diabetes in the years after the index pregnancy (1,2). This relationship reflects the fact that both GDM and type 2 diabetes share a similar pathophysiology, characterized by two main metabolic defects: 1) target cell resistance to the activity of insulin (insulin resistance) and 2) insufficient secretion of insulin by the pancreatic β-cells to compensate for this peripheral tissue resistance (β-cell dysfunction) (1,3). Pregnancy is characterized by severe, acquired insulin resistance that has long been thought to provide a short-term challenge to the β-cells, with GDM arising in those women whose β-cells are unable to meet this challenge. It is now understood, however, that the defect in β-cell compensation that characterizes GDM is chronic (not acquired during pregnancy) and therefore may underlie the high risk of type 2 diabetes in women who have a history of previous GDM (1,4).Although controversy exists regarding the specific protocols to apply, screening for GDM by glucose tolerance testing in pregnancy has become a standard element of obstetrical care (5). With this testing, GDM is diagnosed on the basis of blood glucose levels that exceed specific glycemic thresholds. Affected women identified in this way are then treated with dietary therapy or insulin to reduce glucose levels in pregnancy and improve obstetrical outcome (6). These patients are also advised to undergo testing for type 2 diabetes postpartum (7). It is important to recognize, however, that glucose tolerance testing in pregnancy also identifies many women with glycemic responses that exceed the normal range but that do not meet the thresholds required for the diagnosis of GDM. These women are not typically treated in any way and are not subject to any postpartum surveillance. Indeed, little is known about their postpartum risk of glucose intolerance or diabetes. Given that pregnancy provides a physiologic test of the body''s glucoregulatory capacity, we hypothesized that any abnormality on glucose tolerance testing in pregnancy should reflect a degree of underlying β-cell dysfunction and hence should predict an increased risk of postpartum dysglycemia. In this context, our objective in this study was to systematically evaluate glucose tolerance and metabolic function at 3 months postpartum in a well-characterized cohort of women representing a broad spectrum of glucose homeostasis on GDM screening in pregnancy.     

Isolated hyperglycemia at 1 hour on oral glucose tolerance test in pregnancy resembles gestational diabetes mellitus in predicting postpartum metabolic dysfunction

OBJECTIVE—Gestational impaired glucose tolerance (GIGT), defined by a single abnormal value on antepartum 3-h oral glucose tolerance test (OGTT), is a metabolically heterogeneous disorder. Indeed, the antepartum metabolic phenotype of women with a single abnormal value at 1 h during the OGTT (1-h GIGT) resembles that of women with gestational diabetes mellitus (GDM), whereas GIGT at 2 or 3 h (2/3-h GIGT) is similar to normal glucose tolerance (NGT). Thus, we hypothesized that 1-h GIGT would be associated with the same adverse outcomes as GDM, i.e., increased infant birth weight and postpartum metabolic dysfunction.RESEARCH DESIGN AND METHODS—A total of 361 women underwent an antepartum glucose challenge test (GCT) and a 3-h OGTT, assessment of obstetrical outcome at delivery, and metabolic characterization by OGTT at 3 months postpartum. The antepartum GCT/OGTT identified five study groups: GDM (n = 97), 1-h GIGT (n = 28), 2/3-h GIGT (n = 34), abnormal GCT NGT (abnormal GCT with NGT on OGTT) (n = 128), and normal GCT NGT (normal GCT with NGT on OGTT) (n = 74).RESULTS—Caesarian section rate was higher in women with 1-h GIGT, but birth weight did not differ significantly between the non-GDM groups (P = 0.1978). At 3 months postpartum, glycemia (area under the glucose curve) progressively increased across the groups from normal GCT NGT to abnormal GCT NGT to 2/3-h GIGT to 1-h GIGT to GDM (P < 0.0001), while both insulin sensitivity (IS_OGTT) and β-cell function (insulinogenic index/homeostasis model assessment of insulin resistance [HOMA-IR]) progressively decreased (P = 0.002 and P < 0.0001, respectively). The strongest independent negative predictors of insulinogenic index/HOMA-IR were GDM (t = −4.1, P < 0.0001) and 1-h GIGT (t = −3.8, P = 0.0002).CONCLUSIONS—Like GDM, 1-h GIGT is associated with postpartum glycemia, insulin resistance, and β-cell dysfunction.Gestational diabetes mellitus (GDM) is associated with significant short- and long-term consequences (1,2). In the short term, the most pressing concern is an increased risk of adverse obstetrical outcomes related to fetal overgrowth and increased birth weight (1,3). The long-term concern is that women with a history of GDM have chronic insulin resistance and underlying β-cell dysfunction, leading to a substantially elevated risk of developing type 2 diabetes in the years following the index pregnancy (2,4). Thus, given these potential consequences, pregnant women are commonly screened for GDM by oral glucose tolerance test (OGTT) in late 2nd trimester, whereupon affected women are treated with glucose-lowering therapy (diet, insulin) to improve obstetrical outcome and advised to undergo testing for type 2 diabetes in the postpartum (3,5).Whereas GDM (diagnosed by two abnormal glucose values on 3-h OGTT in pregnancy) leads to these interventions, gestational impaired glucose tolerance (GIGT) (defined by a single abnormal glucose value on the OGTT) generally does not precipitate any specific treatment recommendations. Traditionally, it has been felt that GIGT represents an intermediate phenotype between normal glucose tolerance (NGT) and GDM (6,7). Interestingly, however, it has recently emerged that GIGT is actually a heterogeneous metabolic disorder, as defined by the glycemic response on the OGTT (8). Specifically, the metabolic phenotype in pregnancy of women with a single abnormal glucose value at 1 h during the OGTT (1-h GIGT) resembles that of GDM, as both conditions are characterized by increased severity of glycemia, insulin resistance, and decreased circulating adiponectin. In contrast, GIGT at 2 or 3 h during the OGTT (2/3-h GIGT) is more similar to NGT (8). In light of these data, we hypothesized that 1-h GIGT may be associated with the same adverse outcomes as GDM, namely, 1) increased infant birth weight and 2) postpartum hyperglycemia, insulin resistance, and β-cell dysfunction. Thus, our objective in the current study was to systematically evaluate obstetrical outcomes and postpartum metabolic function in a well-characterized cohort of women stratified by glucose tolerance status in pregnancy, ranging from NGT to 2/3-h GIGT to 1-h GIGT to GDM.     

Trends in postpartum diabetes screening and subsequent diabetes and impaired fasting glucose among women with histories of gestational diabetes mellitus: A report from the Translating Research Into Action for Diabetes (TRIAD) Study

OBJECTIVE—The purpose of this study was to examine trends in postpartum glucose screening for women with gestational diabetes mellitus (GDM), predictors of screening, trends in postpartum impaired fasting glucose (IFG) and diabetes, and diabetes and pre-diabetes detected by postpartum fasting plasma glucose (FPG) versus a 75-g oral glucose tolerance test (OGTT).RESEARCH DESIGN AND METHODS—This was a cohort study of 14,448 GDM pregnancies delivered between 1995 and 2006. Postpartum screening was defined as performance of either an FPG or OGTT at least 6 weeks after delivery and within 1 year of delivery.RESULTS—Between 1995 and 2006, the age- and race/ethnicity-adjusted proportion of women who were screened postpartum rose from 20.7% (95% CI 17.8–23.5) to 53.8% (51.3–56.3). Older age, Asian or Hispanic race/ethnicity, higher education, earlier GDM diagnosis, use of diabetes medications during pregnancy, and more provider contacts after delivery were independent predictors of postpartum screening. Obesity and higher parity were independently associated with lower screening performance. Among women who had postpartum screening, the age- and race/ethnicity-adjusted proportion of IFG did not change over time (24.2 [95% CI 20.0–27.8] in 1995–1997 to 24.3 [22.6–26.0] in 2004–2006), but the proportion of women with diabetes decreased from 6.1 (95% CI 4.2–8.1) in 1995–1997 to 3.3 (2.6–4.0) in 2004–2006. Among women who received an OGTT in 2006, 38% of the 204 women with either diabetes or pre-diabetes were identified only by the 2-h glucose measurements.CONCLUSIONS—Postpartum screening has increased over the last decade, but it is still suboptimal. Compared with FPGs alone, the 2-h values identify a higher proportion of women with diabetes or pre-diabetes amenable to intervention.Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance with onset of or first recognition during pregnancy. Postpartum diabetes screening may detect diabetes that preceded pregnancy and therefore enable early treatment of hyperglycemia, reducing the risk of adverse fetal outcomes in subsequent pregnancies (1) and maternal microvascular complications (2). Screening can also identify women who might benefit from diabetes prevention interventions (3,4).Performance rates of postpartum diabetes screening have been low (5–7), but screening performance may have changed recently. At present, only one population-based report has examined postpartum diabetes screening practices, and this report examined fasting plasma glucose (FPG) only (8). We used data from a GDM registry in a large prepaid group practice managed health care organization (the Kaiser Permanente Medical Care Program in Northern California [KPNC]) and examined 1) postpartum diabetes screening over time, 2) predictors of postpartum screening in a detailed electronic medical record, 3) trends in impaired fasting glucose (IFG) or diabetes detected with postpartum screening, and 4) the proportion of women with diabetes or pre-diabetes identified by the FPG screen versus the proportion of women with these abnormal glucose values identified by the 75-g oral glucose tolerance test (OGTT).     

Adipokines and incident type 2 diabetes in an Aboriginal Canadian [corrected] population: the Sandy Lake Health and Diabetes Project

OBJECTIVE—The aim of this study was to investigate associations of adiponectin, leptin, C-reactive protein (CRP), interleukin (IL)-6, and serum amyloid A (SAA), individually or in combinations, with risk of incident type 2 diabetes in a Canadian Aborigine population.RESEARCH DESIGN AND METHODS—Of the 606 Sandy Lake Health and Diabetes Project cohort subjects who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Concentrations of fasting adiponectin, leptin, CRP, IL-6, SAA, and covariates were measured at baseline. Fasting glucose and a 75-g oral glucose tolerance test were obtained at baseline and follow-up to determine incident type 2 diabetes, defined as clinically diagnosed type 2 diabetes or as fasting plasma glucose ≥7.0 mmol/l or 2-h postload plasma glucose ≥11.1 mmol/l at follow-up.RESULTS—Low adiponectin, high leptin, and low adiponectin-to-leptin ratio at baseline were associated with increased risk of incident type 2 diabetes after adjustment for age, sex, triglycerides, HDL cholesterol, hypertension, and impaired glucose tolerance (odds ratio 0.63 [95% CI 0.48–0.83], 1.50 [1.02–2.21], and 0.54 [0.37–0.77], respectively). When the models were additionally adjusted for waist circumference or BMI, however, only low adiponectin remained significantly associated with increased incident diabetes (0.68 [0.51–0.90]). Combinations of leptin, CRP, IL-6, and/or SAA with adiponectin, assessed using either the ratio or joint effects, did not improve diabetes prediction.CONCLUSIONS—Low baseline adiponectin is associated with increased risk of incident type 2 diabetes independent of leptin, CRP, IL-6, SAA, and metabolic syndrome variables including obesity.Obesity is a major risk factor for insulin resistance and type 2 diabetes (1). The recent focus on adipose tissue as an endocrine organ secreting signaling proteins, collectively termed adipokines, has prompted current interests in associations of adipokines with insulin resistance and diabetes (1–2). Although underlying mechanisms have not been completely explained, adipokines have been linked with obesity-induced inflammation and signaling pathways that contribute to type 2 diabetes (1). Prospectively, adiponectin, an anti-inflammatory, anti-atherogenic, and insulin-sensitizing adipokine (2,3), has been inversely associated with the development of type 2 diabetes (4–7). Several studies associated increased baseline levels of inflammatory markers, including interleukin (IL)-6 (8,9) and C-reactive protein (CRP) (9), with incident type 2 diabetes, while others reported no association of IL-6 (4) and CRP (4,8) with the development of type 2 diabetes after adjustment for adiposity measures. In another prospective study, the association between leptin and diabetes risk was attenuated after adjustment for intra-abdominal fat (10).Recent studies have suggested that adipokines may interact in regulating metabolic homeostasis (11–12). In a cross-sectional study, evidence was presented for CRP inhibiting the binding of leptin to its receptors and leptin stimulating expression of CRP (11). Others identified the adiponectin-to-leptin (A/L) ratio as a reliable marker of insulin resistance (12).Nonetheless, limited population-based data are available on how adipokines in combinations may contribute to the etiology of diabetes. In addition, previous prospective investigations on associations of adipokines with diabetes provide inconsistent findings (4–10). Among those, only a few have reported data from studies of North American Aboriginal people (4,5), while no studies have been conducted among Aboriginal Canadians in whom diabetes is increasingly prevalent (13). The objective of this study was to investigate associations of baseline adiponectin, leptin, CRP, IL-6, and serum amyloid A (SAA), individually and/or in combinations, with the development of type 2 diabetes in a Canadian Aborigine population undergoing rapid cultural transition.     

First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus

OBJECTIVE

To determine whether maternal levels of follistatin-like-3 (FSTL3), an inhibitor of activin and myostatin involved in glucose homeostasis, are altered in the first trimester of pregnancies complicated by subsequent gestational diabetes mellitus (GDM).

RESEARCH DESIGN AND METHODS

This was a nested case-control study of subjects enrolled in a prospective cohort of pregnant women with and without GDM (≥2 abnormal values on a 100-g glucose tolerance test at ∼28 weeks of gestation). We measured FSTL3 levels in serum collected during the first trimester of pregnancy. Logistic regression analyses were used to determine the risk of GDM.

RESULTS

Women who developed GDM (n = 37) had lower first-trimester serum levels of FSTL3 compared with women who did not (n = 127) (median 10,789 [interquartile range 7,013–18,939] vs. 30,670 [18,370–55,484] pg/ml, P < 0.001). When subjects were divided into tertiles based on FSTL3 levels, women with the lowest levels demonstrated a marked increase in risk for developing GDM in univariate (odds ratio 11.2 [95% CI 3.6–35.3]) and multivariate (14.0 [4.1–47.9]) analyses. There was a significant negative correlation between first-trimester FSTL3 levels and ∼28-week nonfasting glucose levels (r = −0.30, P < 0.001).

CONCLUSIONS

First-trimester FSTL3 levels are associated with glucose intolerance and GDM later in pregnancy.Gestational diabetes mellitus (GDM) afflicts 4% of pregnancies in the U.S. and is associated with unfavorable perinatal outcomes (1). Although GDM is characterized by glucose intolerance, β-cell dysfunction, and insulin resistance (1–3), the pathogenesis of GDM is not well understood. The association between GDM and insulin resistance postpartum and subsequent type 2 diabetes in up to 70% of mothers (1–4) has led to the theory that GDM is simply the unmasking of a chronic condition. However, GDM resolves, at least temporarily, with the delivery of the infant and placenta, occurs more often in twin pregnancy (5), and recurs only in 30–50% of subsequent pregnancies (6), suggesting that circulating factors released by the placenta may be involved, at least partially, in its pathogenesis.Pregnant women are typically screened for GDM at 24–28 weeks of gestation. Despite the fact that insulin sensitivity increases in the first trimester of pregnancy, a recent study showed that higher first-trimester levels of fasting blood glucose were linearly associated with increased risk of GDM, cesarean section, and macrosomia (7), suggesting that the pathophysiologic process that leads to GDM is underway weeks to months before its diagnosis. Thus, it is possible that factors linked with the pathogenesis of this condition may be present in blood samples well before the clinical diagnosis of GDM. Treatment of GDM in late pregnancy improves some adverse perinatal outcomes (8,9), but earlier detection of GDM through biomarker measurement in the first trimester of pregnancy may permit more time for intervention and lead to greater positive effects of treatment on maternal and fetal outcomes.Follistatin-like-3 (FSTL3, also referred to as FLRG), a follistatin homolog that inhibits circulating members of the transforming growth factor-β subfamily of proteins (10), is highly expressed by the placenta (11). FSTL3 expression is increased in placentas from pregnancies complicated by intrauterine growth restriction (12). Outside of pregnancy, FSTL3 may play a major role in glucose homeostasis, as FSTL3-null mice are characterized by pancreatic β-cell hyperplasia, elevated insulin levels, increased glucose tolerance, and upregulation of hepatic gluconeogenesis (13). Further evidence supporting a role for FSTL3 in glucose homeostasis includes the biological activities of activin A and myostatin, which are antagonized by FSTL3. Activin A promotes proliferation of β-cells and secretion of insulin (14,15); activin A levels were found to be elevated in pregnancies affected by GDM in previous studies (16,17). In mouse models, the absence of myostatin promotes insulin sensitivity and protects against weight gain (18,19). Although circulating levels of myostatin during pregnancy have not been described, myostatin is expressed by the human placenta and was shown to increase glucose uptake by placental explants (20).Based on the connection of FSTL3 to glucose homeostasis and the presence of insulin resistance and β-cell dysfunction in GDM, as well as the high expression levels of FSTL3 in the placentas of infants with small-for-gestational-age fetuses (12) and the occurrence of large-for-gestational-age infants in GDM, we hypothesized that circulating levels of FSTL3 would be altered in pregnancies complicated by GDM.     

Factors associated with intensification of oral diabetes medications in primary care provider-patient dyads: a cohort study

OBJECTIVE—Although suboptimal glycemic control is known to be common in diabetic adults, few studies have evaluated factors at the level of the physician-patient encounter. Our objective was to identify novel visit-based factors associated with intensification of oral diabetes medications in diabetic adults.RESEARCH DESIGN AND METHODS—We conducted a nonconcurrent prospective cohort study of 121 patients with type 2 diabetes and hyperglycemia (A1C ≥8%) enrolled in an academically affiliated managed-care program. Over a 24-month interval (1999–2001), we identified 574 hyperglycemic visits. We measured treatment intensification and factors associated with intensification at each visit.RESULTS—Provider-patient dyads intensified oral diabetes treatment in only 128 (22%) of 574 hyperglycemic visits. As expected, worse glycemia was an important predictor of intensification. Treatment was more likely to be intensified for patients with visits that were “routine” (odds ratio [OR] 2.55 [95% CI 1.49–4.38]), for patients taking two or more oral diabetes drugs (2.82 [1.74–4.56]), or for patients with longer intervals between visits (OR per 30 days 1.05 [1.00–1.10]). In contrast, patients with less recent A1C measurements (OR >30 days before the visit 0.53 [0.34–0.85]), patients with a higher number of prior visits (OR per prior visit 0.94 [0.88–1.00]), and African American patients (0.59 [0.35–1.00]) were less likely to have treatment intensified.CONCLUSIONS—Failure to intensify oral diabetes treatment is common in diabetes care. Quality improvement measures in type 2 diabetes should focus on overcoming inertia, improving continuity of care, and reducing racial disparities.Although glycemic control reduces microvascular complications and may reduce macrovascular complications (1–3), diabetic patients commonly have inadequately controlled blood glucose (4–8). Recent evidence suggests that lack of intensification of diabetes medications in a timely fashion is a powerful explanatory factor (4–6,9–11). This decision to intensify treatment may be affected by several factors, such as patient adherence (12) and preference, competing medical demands (13), or provider attitudes and knowledge (14).Identifying barriers and promoters of treatment intensification is a crucial first step toward developing strategies to improve blood glucose control in diabetic adults. Although many studies have documented lack of adequate glycemic control (4–8) and failures to intensify medications in subjects with diabetes (4–6,9–11), few studies have evaluated factors associated with treatment intensification besides glycemic control (13,15,16). Of these studies, two evaluated a variety of visit-based factors associated with intensification, but these had limited generalizability (13,15) and did not adjust for key confounders such as patient adherence (13). No study has focused in detail on a variety of visit-based factors in addition to patient and provider factors that might influence oral diabetes treatment intensification.Therefore, we conducted a nonconcurrent prospective cohort study to identify novel barriers and promoters of intensification of oral diabetes medications in type 2 diabetic adults. We felt these visit-based factors may be more modifiable than durable patient and physician factors such as age or sex.     

Improved Pregnancy Outcome in Type 1 Diabetic Women With Microalbuminuria or Diabetic Nephropathy: Effect of intensified antihypertensive therapy?

OBJECTIVE—To describe pregnancy outcome in type 1 diabetic women with normoalbuminuria, microalbuminuria, or diabetic nephropathy after implementation of an intensified antihypertensive therapeutic strategy.RESEARCH DESIGN AND METHODS—Prospective study of 117 pregnant women with type 1 diabetes. Antihypertensive therapy, mainly methyldopa, was given to obtain blood pressure <135/85 mmHg and urinary albumin excretion <300 mg/24 h. Blood pressure and A1C were recorded during pregnancy. The pregnancy outcome was compared with recently published studies of pregnant women with microalbuminuria or diabetic nephropathy.RESULTS—Antihypertensive therapy was given in 14 of 100 women with normoalbuminuria, 5 of 10 women with microalbuminuria, and all 7 women with diabetic nephropathy. Mean systolic blood pressure during pregnancy was 120 mmHg (range 101–147), 122 mmHg (116–135), and 135 mmHg (111–145) in women with normoalbuminuria, microalbuminuria, and diabetic nephropathy, respectively (P = 0.0095). No differences in mean diastolic blood pressure or A1C were detected between the groups. No women with microalbuminuria developed preeclampsia. The frequency of preterm delivery was 20% in women with normoalbuminuria and microalbuminuria in contrast to 71% in women with diabetic nephropathy (P < 0.01) where the median gestational age was 258 days (220–260). Compared with previous studies using less stringent antihypertensive therapeutic strategy and less strict metabolic control, gestational age was longer and birth weight was larger in our study.CONCLUSIONS—With intensified antihypertensive therapy and strict metabolic control, comparable pregnancy outcome was seen in type 1 diabetic women with microalbuminuria and normoalbuminuria. Although less severe than in previous studies, diabetic nephropathy was associated with more adverse pregnancy outcome.Type 1 diabetic women with microalbuminuria or diabetic nephropathy are at particular risk of poor pregnancy outcome (1–6). Diabetic nephropathy is associated with a high risk of gestational hypertension, preeclampsia, and preterm delivery (1–4,6). Likewise, preeclampsia and preterm delivery occur more frequently in type 1 diabetic women with microalbuminuria (3,5).Outside pregnancy, the importance of antihypertensive therapy with ACE inhibition to reduce the risk of renal complications is well documented in both type 1 diabetic patients with microalbuminuria (7) and diabetic nephropathy (8). To prevent development of hypertension and proteinuria, ACE inhibition has been documented to be effective even in normotensive diabetic women with microalbuminuria (7). However, ACE inhibition in early pregnancy has been associated with congenital malformations (9), while use late in pregnancy may cause fetal renal failure (10). ACE inhibition therefore should be discontinued before conception or as soon as pregnancy is confirmed (9). In diabetic women with microalbuminuria or diabetic nephropathy, the effect of antihypertensive therapy in relation to development and progression of hypertension and proteinuria during pregnancy seems promising when using antihypertensive drugs considered safe during pregnancy. However, this is only sparsely investigated (1,3,5).A retrospective study suggested that early intervention with antihypertensive therapy reduces the risk of preterm delivery in type 1 diabetic women with diabetic nephropathy (1).Previously, we found an association between early onset of antihypertensive therapy in pregnant type 1 diabetic women with microalbuminuria and a reduced prevalence of preterm delivery, probably due to a reduced prevalence of preeclampsia (5). Methyldopa was first-choice therapy based on reports of stable utero-placental blood flow, fetal hemodynamics (11,12), and long-term follow-up (13). Given that the prevalence of preterm delivery and preeclampsia was still high (5), we speculated that pregnant type 1 diabetic women with microalbuminuria or diabetic nephropathy would benefit from further intensified antihypertensive therapy in early pregnancy. Therefore, in 2004, we intensified our treatment strategy in early pregnancy in type 1 diabetic women with microalbuminuria or diabetic nephropathy.In this study, we describe the pregnancy outcome in type 1 diabetic women according to their degree of albuminuria after the implementation of an intensified antihypertensive therapeutic strategy.     

Diabetes, glycemic control, and risk of hospitalization with pneumonia: a population-based case-control study

OBJECTIVE—To examine whether diabetes is a risk factor for hospitalization with pneumonia and to assess the impact of A1C level on such risk.RESEARCH DESIGN AND METHODS—In this population-based, case-control study we identified patients with a first-time pneumonia-related hospitalization between 1997 and 2005, using health care databases in northern Denmark. For each case, 10 sex- and age-matched population control subjects were selected from Denmark''s Civil Registration System. We used conditional logistic regression to compute relative risk (RR) for pneumonia-related hospitalization among subjects with and without diabetes, controlling for potential confounding factors.RESULTS—The study included 34,239 patients with a pneumonia-related hospitalization and 342,390 population control subjects. The adjusted RR for pneumonia-related hospitalization among subjects with diabetes was 1.26 (95% CI 1.21–1.31) compared with nondiabetic individuals. The adjusted RR was 4.43 (3.40–5.77) for subjects with type 1 diabetes and 1.23 (1.19–1.28) for subjects with type 2 diabetes. Diabetes duration ≥10 years increased the risk of a pneumonia-related hospitalization (1.37 [1.28–1.47]). Compared with subjects without diabetes, the adjusted RR was 1.22 (1.14–1.30) for diabetic subjects whose A1C level was <7% and 1.60 (1.44–1.76) for diabetic subjects whose A1C level was ≥9%.CONCLUSIONS—Type 1 and type 2 diabetes are risk factors for a pneumonia-related hospitalization. Poor long-term glycemic control among patients with diabetes clearly increases the risk of hospitalization with pneumonia.Hospitalizations with pneumonia have increased by 20–50% in Western populations during the past 10 years (1,2). Combined with influenza, pneumonia is the seventh leading cause of death in the U.S. (3).Diabetes is thought to be a risk factor for pneumonia, but available data are few and inconclusive (4–11). Diabetic subjects may have increased susceptibility to pneumonia for several reasons. They are at increased risk of aspiration, hyperglycemia, decreased immunity, impaired lung function, pulmonary microangiopathy, and coexisting morbidity (12). Five cohort studies (4,6,8–10) found that diabetes is a risk factor for pneumonia, with relative risks (RRs) ranging from 1.30 to 1.75, while three studies (5,7,11) failed to find an association. Existing studies have limitations: some included only patients aged >60 years (8,10,11), one did not adjust for comorbidity (9), and few were population-based (9,11). Only one study (6) of respiratory tract infections distinguished between type 1 and type 2 diabetes.Immunologic abnormalities in diabetic subjects are related in part to the harmful effects of hyperglycemia (12). Recently, a cohort study (4) encompassing 10,063 subjects followed for 7 years found that each 1 mmol/l increase in baseline plasma glucose was associated with a 6% increase in the RR of pneumonia. However, this result was based on a single nonfasting glucose measurement. The impact of poor long-term glycemic control on risk of pneumonia-related hospitalization still remains uncertain.Given the rising incidence of pneumonia-related hospitalizations (1,2) and the increasing prevalence of diabetes (13), it is important to clarify whether diabetes and poor long-term glycemic control is a risk factor for pneumonia. We examined whether diabetes is associated with an increased risk of pneumonia-related hospitalization and whether this risk is modulated by A1C level.     

Sociodemographic correlates of the increasing trend in prevalence of gestational diabetes mellitus in a large population of women between 1995 and 2005

OBJECTIVE—Gestational diabetes mellitus (GDM) is an increasingly prevalent risk factor for the development of type 2 diabetes in the mother and is responsible for morbidity in the child. To better identify women at risk of developing GDM we examined sociodemographic correlates and changes in the prevalence of GDM among all births between 1995 and 2005 in Australia''s largest state.RESEARCH DESIGN AND METHODS—A computerized database of all births (n = 956,738) between 1995 and 2005 in New South Wales, Australia, was used in a multivariate logistic regression that examined the association between sociodemographic characteristics and the occurrence of GDM.RESULTS—Between 1995 and 2005, the prevalence of GDM increased by 45%, from 3.0 to 4.4%. Women born in South Asia had the highest adjusted odds ratio (OR) of any region (4.33 [95% CI 4.12–4.55]) relative to women born in Australia. Women living in the three lowest socioeconomic quartiles had higher adjusted ORs for GDM relative to women in the highest quartile (1.54 [1.50–1.59], 1.74 [1.69–1.8], and 1.65 [1.60–1.70] for decreasing socioeconomic status quartiles). Increasing age was strongly associated with GDM, with women aged >40 years having an adjusted OR of 6.13 (95% CI 5.79–6.49) relative to women in their early 20s. Parity was associated with a small reduced risk. There was no association between smoking and GDM.CONCLUSIONS—Maternal age, socioeconomic position, and ethnicity are important correlates of GDM. Future culturally specific interventions should target prevention of GDM in these high-risk groups.Type 2 diabetes affects an estimated 246 million individuals worldwide—a figure that is predicted to increase to 380 million by 2025, with a disproportionate number of affected individuals living in lower- and middle-income countries of the Asia-Pacific region (1). Diabetes is a major cardiovascular risk factor, more than doubling the risk of having a stroke or heart attack. Moreover, diabetes appears to be particularly hazardous in women, as there is a 50% greater risk of dying from coronary heart disease compared with that of men with the same condition (2).Gestational diabetes mellitus (GDM), defined as glucose intolerance first detected during pregnancy, is a strong predictor of type 2 diabetes. Women with GDM are up to six times more likely to develop type 2 diabetes than women with normal glucose tolerance in pregnancy (3). The incidence of GDM varies among populations, similar to the variation of type 2 diabetes, with recent prevalence estimates ranging from 2.8% of pregnant women in Washington, DC, to 18.9% in India and 22% in Sardinia, Italy (4). The risk for GDM increases with age, and incidence rates vary by ethnicity within a population, again similar to the risk for type 2 diabetes (4,5). There is also evidence that obesity, parity, smoking, and family history are risk factors for GDM (5). However, less is known regarding the sociodemographic distribution of GDM. Given the strong link between GDM and the subsequent risk of diabetes for the mother and the perinatal morbidity for mother and child—an association recently updated with findings of a continuous association of maternal glucose levels and adverse perinatal outcomes by the Hyperglycemia and Adverse Pregnancy Outcomes Study Cooperative Research Group (6)—a better understanding of the sociodemographic determinants of GDM may provide novel opportunities to reduce the incidence and to prevent the onset of type 2 diabetes in later life.Most studies that have examined the etiology of GDM have been hospital based or have been based on samples of births in a particular region (4,5). There are currently no large, comprehensive population-wide urban and rural datasets that have been collected in an attempt to examine multiple risk factors for GDM over a number of years and no population-based studies outside the U.S. The New South Wales (NSW) Midwives Dataset has information on nearly 1 million births in the state of NSW during the period from 1995 to 2005 in a health system in which there is almost universal screening for GDM. This dataset was used to study the current and changing population rates of GDM and its associated sociodemographic risk factors in a large, ethnically diverse population of women.     

��-Cell Function Declines Within the First Year Postpartum in Women With Recent Glucose Intolerance in Pregnancy

OBJECTIVE

Both gestational diabetes mellitus (GDM) and mild glucose intolerance in pregnancy identify women at increased risk of future type 2 diabetes. In this context, we queried whether metabolic changes that occur in the 1st year postpartum vary in relation to gestational glucose tolerance status.

RESEARCH DESIGN AND METHODS

Three-hundred-and-ninety-two women underwent glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy followed by repeat OGTT at both 3 months'' postpartum and 12 months'' postpartum. The antepartum testing defined four gestational glucose tolerance groups: GDM (n = 107); gestational impaired glucose tolerance (GIGT) (n = 75); abnormal GCT with normal glucose tolerance (NGT) on OGTT (abnormal GCT NGT) (n = 137); and normal GCT with NGT on OGTT (normal GCT NGT) (n = 73).

RESULTS

The prevalence of dysglycemia progressively increased across the groups from normal GCT NGT to abnormal GCT NGT to GIGT to GDM at both 3 months'' postpartum (2.7% to 10.2% to 18.7% to 34.6%, P < 0.0001) and 12 months'' postpartum (2.7% to 11.7% to 17.3% to 32.7%, P < 0.0001). Between 3 and 12 months'' postpartum, the groups did not differ with respect to changes in waist circumference, weight, or insulin sensitivity. Importantly, however, they exhibited markedly different changes in β-cell function (Insulin Secretion-Sensitivity Index-2 [ISSI-2]) (P = 0.0036), with ISSI-2 declining in both the GDM and GIGT groups. Furthermore, on multiple linear regression analysis, both GDM (t = −3.06, P = 0.0024) and GIGT (t = −2.18, P = 0.03) emerged as independent negative predictors of the change in ISSI-2 between 3 and 12 months'' postpartum.

CONCLUSIONS

Women with GDM and GIGT exhibit declining β-cell function in the 1st year postpartum that likely contributes to their future diabetic risk.The diagnosis of gestational diabetes mellitus (GDM) identifies a population of young women who are at high risk of developing type 2 diabetes on the order of 20–60% in the first 5 years following an index pregnancy (1–3). A systematic review of studies evaluating the risk of progression to type 2 diabetes following GDM has demonstrated that the cumulative incidence of diabetes increases markedly in the first 5 years'' postpartum and appears to plateau after 10 years (3). Thus, events in the early postpartum years are likely to be important in determining diabetic risk in this patient population. At present, however, little is known about the pathophysiologic changes that take place in these early years following a pregnancy complicated by GDM.A recent series of reports have demonstrated that even women with mild glucose intolerance in pregnancy (i.e., less severe than GDM) have an increased risk of ultimately developing pre-diabetes and diabetes (4–9). The magnitude of this risk is proportional to the degree of gestational dysglycemia, with the highest risk in women with GDM and proportionately lower risk in women with milder abnormalities of gestational glucose tolerance (4). It thus emerges that the spectrum of abnormal glucose homeostasis in pregnancy identifies a continuum of risk for future diabetes and, based on the temporal findings pertaining to GDM, pathophysiologic changes that occur in the early postpartum years may be relevant to the manifestation of this risk potential. Therefore, in the current study, our objective was to perform a longitudinal evaluation of the metabolic changes that take place in the 1st year postpartum in a well-characterized cohort of women representing the full spectrum of glucose tolerance in pregnancy and hence a broad range of future diabetic risk.     

Pharmacokinetic Properties of Azithromycin in Pregnancy

Azithromycin (AZI) is an azalide antibiotic with antimalarial activity that is considered safe in pregnancy. To assess its pharmacokinetic properties when administered as intermittent preventive treatment in pregnancy (IPTp), two 2-g doses were given 24 h apart to 31 pregnant and 29 age-matched nonpregnant Papua New Guinean women. All subjects also received single-dose sulfadoxine-pyrimethamine (SP) (1,500 mg or 75 mg) or chloroquine (450-mg base daily for 3 days). Blood samples were taken at 0, 1, 2, 3, 6, 12, 24, 32, 40, 48, and 72 h and on days 4, 5, 7, 10, and 14 for AZI assay by ultra-high-performance liquid chromatography-tandem mass spectrometry. The treatments were well tolerated. Using population pharmacokinetic modeling, a three-compartment model with zero-order followed by first-order absorption and no lag time provided the best fit. The areas under the plasma concentration-time curve (AUC_0-∞) (28.7 and 31.8 mg·h liter⁻¹ for pregnant and nonpregnant subjects, respectively) were consistent with the results of previous studies, but the estimated terminal elimination half-lives (78 and 77 h, respectively) were generally longer. The only significant relationship for a range of potential covariates, including malarial parasitemia, was with pregnancy, which accounted for an 86% increase in the volume of distribution of the central compartment relative to bioavailability without a significant change in the AUC_0-∞. These data suggest that AZI can be combined with compounds with longer half-lives, such as SP, in combination IPTp without the need for dose adjustment.Azithromycin (AZI) is a semisynthetic azalide antibiotic that is structurally related to erythromycin but has a broader spectrum of antibacterial activity and a more favorable pharmacokinetic profile (13, 22). It is widely used in the treatment of respiratory and sexually transmitted infections, including those in HIV-infected patients (32, 34). AZI also inhibits protein synthesis in the plasmodial apicoplast (39, 40) and thus has activity against both Plasmodium falciparum and Plasmodium vivax (5, 12, 16, 27-30, 41). It acts mainly against the progeny of parasites that inherit a nonfunctioning apicoplast after exposure, with the result that its antimalarial effect has a slow onset and is relatively weak. Therefore, AZI is best used in combination with other antimalarial compounds as both treatment (20, 27, 29) and chemoprophylaxis (5, 19), with likely additive or synergistic effects (28, 30, 31).Malaria in pregnancy can result in adverse outcomes for both mother and fetus (14). Intermittent preventive treatment in pregnancy (IPTp) aims to reduce the burden of malaria by administering treatment doses of antimalarial drugs at predetermined intervals as part of routine antenatal care in areas of endemicity (44). Because AZI is considered safe in pregnancy and could have activity against other clinically significant pathogens (8, 38), it has been suggested as a candidate for IPTp. Although the pharmacokinetics of AZI have been investigated (2, 6, 7, 11, 13, 23-26, 35-37, 45), only one study included pregnant women (36), and most focused on its antibacterial properties. In addition, AZI is likely to be partnered with conventional antimalarial drugs if given as IPTp, and there is evidence that such combinations are safe and well tolerated in studies with chloroquine (CQ) in healthy volunteers (11) and with sulfadoxine-pyrimethamine (SP) in pregnant women (20). Although there does not appear to be a clinically significant pharmacokinetic interaction with CQ (11), AZI interactions with other conventional IPTp treatments are unknown. Therefore, we investigated the pharmacokinetic properties of AZI in combination with CQ or SP in pregnant and nonpregnant women from an area of Papua New Guinea (PNG) with intense transmission of both P. falciparum and P. vivax malaria.     

Effect of a low-resource-intensive lifestyle modification program incorporating gymnasium-based and home-based resistance training on type 2 diabetes risk in Australian adults

OBJECTIVE—The purpose of this study was to assess the effectiveness of a low–resource-intensive lifestyle modification program incorporating resistance training and to compare a gymnasium-based with a home-based resistance training program on diabetes diagnosis status and risk.RESEARCH DESIGN AND METHODS—A quasi-experimental two-group study was undertaken with 122 participants with diabetes risk factors; 36.9% had impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) at baseline. The intervention included a 6-week group self-management education program, a gymnasium-based or home-based 12-week resistance training program, and a 34-week maintenance program. Fasting plasma glucose (FPG) and 2-h plasma glucose, blood lipids, blood pressure, body composition, physical activity, and diet were assessed at baseline and week 52.RESULTS—Mean 2-h plasma glucose and FPG fell by 0.34 mmol/l (95% CI −0.60 to −0.08) and 0.15 mmol/l (−0.23 to −0.07), respectively. The proportion of participants with IFG or IGT decreased from 36.9 to 23.0% (P = 0.006). Mean weight loss was 4.07 kg (−4.99 to −3.15). The only significant difference between resistance training groups was a greater reduction in systolic blood pressure for the gymnasium-based group (P = 0.008).CONCLUSIONS—This intervention significantly improved diabetes diagnostic status and reduced diabetes risk to a degree comparable to that of other low–resource-intensive lifestyle modification programs and more intensive interventions applied to individuals with IGT. The effects of home-based and gymnasium-based resistance training did not differ significantly.Reductions in diabetes incidence of 42–58% in lifestyle modification groups compared with control groups have been reported in randomized controlled studies of individuals with impaired glucose tolerance (IGT) (1–3). All subjects in these studies had IGT, but those with other recognized risk factors such as elevated BMI, elevated waist circumference, a history of high plasma glucose, physical inactivity, and poor diet (4,5) but without IGT were excluded. These studies involved considerable intervention efforts including individualized counseling, tailored physical activity guidance, individual case manager meetings, supervised group exercise, home visits, additional group classes, loans of exercise equipment, exercise club membership, and intersession support (1–3,6), which may not be sustainable in clinical practice (6).The applicability of these findings needs testing in “real-world” clinical settings using less resource-intensive interventions (6,7). Recent studies of the effectiveness of low–resource-intensive lifestyle modification interventions (8,9) have yielded inconsistent findings. The Good Ageing in Lahti Region (GOAL) study (8) with individuals at risk of type 2 diabetes but not necessarily with IGT reported reductions in many diabetes risk factors at 12 months but no beneficial effect on fasting plasma glucose (FPG) or postload glucose (2-h plasma glucose) levels. In the Greater Green Triangle Study (GGTS) significant reductions were reported (for program completers only) in FPG, 2-h plasma glucose, weight, and waist circumference (9). Also, in contrast to the landmark Finnish Diabetes Prevention Study (FDPS), which provided gym memberships for regular resistance training, neither the GOAL study nor the GGTS included structured resistance training. This difference is important because resistance training has been shown to reduce plasma glucose levels in individuals with IGT (10) and type 2 diabetes (11).Previously effective interventions (1–3,8,9) were based in clinical settings, which may reduce access for socioeconomically disadvantaged or geographically isolated groups, both of whom have a relatively high risk of diabetes (12). Home-based interventions with appropriate professional support could address these barriers (13).The primary goal of the Ballarat Diabetes Prevention Pilot Initiative (BDPPI) was to assess the effectiveness of a low–resource-intensive lifestyle modification program incorporating resistance training on diabetes diagnosis status and risk in individuals at elevated risk of diabetes (but not necessarily with IGT). The secondary goal was to compare the effectiveness of gymnasium-based and home-based resistance training programs.     

Increased risk of cardiovascular disease in young women following gestational diabetes mellitus

OBJECTIVE—To determine whether women with gestational diabetes mellitus (GDM) have an increased risk of cardiovascular disease (CVD) following pregnancy.RESEARCH DESIGN AND METHODS—All women aged 20–49 years with live births between April 1994 and March 1997 in Ontario, Canada, were identified. Women with GDM were matched with 10 women without GDM and were followed for CVD.RESULTS—The matched cohorts included 8,191 women with GDM and 81,262 women without GDM. Mean age at entry was 31 years, and median follow-up was 11.5 years. The hazard ratio for CVD events was 1.71 (95% CI 1.08–2.69). After adjustment for subsequent type 2 diabetes, the hazard ratio was attenuated (1.13 [95% CI 0.67–1.89]).CONCLUSIONS—Young women with GDM had a substantially increased risk for CVD compared with women without GDM. Much of this increased risk was attributable to subsequent development of type 2 diabetes.Gestational diabetes mellitus (GDM) is a common condition affecting 2–4% of pregnant women (1) and is associated with adverse outcomes for both the fetus and the mother. Previous GDM is a major risk factor for type 2 diabetes, which occurs in 20–60% of affected women within 5 years of the pregnancy (2). Women with a history of GDM are also at increased risk of other cardiovascular risk factors, such as obesity, hypertension, dyslipidemia, and the metabolic syndrome (3–5), as well as subclinical atherosclerosis (6). Taken together, these findings suggest that GDM identifies a population of young women at increased risk for cardiovascular disease (CVD). We used population-based administrative data to determine whether women with GDM have a heightened risk for CVD compared with women without GDM and whether any increase in risk is independent of subsequent type 2 diabetes.     

Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women

To determine the pharmacokinetic disposition of sulfadoxine (SDOX) and pyrimethamine (PYR) when administered as intermittent presumptive treatment during pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were given a single dose of 1,500 mg of SDOX plus 75 mg of pyrimethamine PYR. Blood was taken at baseline and 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h and at 7, 10, 14, 28, and 42 days posttreatment in all women. Plasma samples were assayed for SDOX, N-acetylsulfadoxine (NASDOX), and PYR by high-performance liquid chromatography. Population pharmacokinetic modeling was performed using NONMEM v6.2.0. Separate user-defined mamillary models were fitted to SDOX/NASDOX and PYR. When the covariate pregnancy was applied to clearance, there was a significant improvement in the base model for both treatments. Pregnancy was associated with a significantly lower area under the concentration-time curve from 0 to ∞ for SDOX (22,315 versus 33,284 mg·h/liter), NASDOX (801 versus 1,590 mg·h/liter), and PYR (72,115 versus 106,065 μg·h/liter; P < 0.001 in each case). Because lower plasma concentrations of SDOX and PYR could compromise both curative efficacy and posttreatment prophylaxis in pregnant patients, IPTp regimens incorporating higher mg/kg doses than those recommended for nonpregnant patients should be considered.Treatment strategies for malaria during pregnancy include drug administration for symptomatic episodes and, because asymptomatic infections in areas of malaria endemicity can also be associated with adverse maternal and fetal outcomes, giving antimalarial therapy at prespecified intervals during pregnancy. This latter approach, known as intermittent preventive treatment in pregnancy (IPTp), clears maternal parasitemia and prevents or suppresses subsequent infections (37). Although conventional adult antimalarial treatment doses are recommended, the physiologic changes that take place during pregnancy may significantly alter drug disposition through a variety of mechanisms, including increases in plasma volume, increased clearance, and altered protein binding (2, 16). Despite these considerations, <150 pregnant women have been enrolled in published studies of antimalarial pharmacokinetics (14, 18, 33), and such data have been identified as an urgent priority for optimization of IPTp strategies (33).The treatment with the best evidence for use as IPTp is sulfadoxine (SDOX) plus pyrimethamine (PYR) (SP) (22, 26, 31), but its effectiveness appears paradoxical given the component drugs have a relatively short elimination half-life (t_1/2β), specifically 6 to 11 days for SDOX (12, 19, 21, 24, 25, 32, 34, 35) and 3 to 5 days for PYR (3, 5, 9, 11, 12, 14, 19, 21, 25, 30, 32, 34, 35, 38). SDOX is acetylated by the enzyme N-acetyltransferase 2. Polymorphisms in the N-acetyltransferase 2 gene are associated with rapid or slow acetylation (20), and there is some evidence that the extent of acetylation is linked to treatment failure in malaria (24). In Papua New Guinea (PNG), the national treatment policy is to give SP with chloroquine (CQ) as presumptive treatment at the first antenatal visit. We have investigated the pharmacokinetic properties of SDOX and PYR in pregnant PNG women and in nonpregnant female controls. Since PNG populations comprise predominantly rapid acetylators (8, 23), we measured N-acetylsulfadoxine (NASDOX), the primary metabolite of SDOX, to assess its potential clinical importance.     

Population-based study on the prevalence and risk factors of orthostatic hypotension in subjects with pre-diabetes and diabetes

OBJECTIVE—The aim of this study was to investigate the relationship between pre-diabetes and orthostatic hypotension and to examine the prevalence and correlates of orthostatic hypotension in community dwellers with normal glucose tolerance (NGT), pre-diabetes, and diabetes.RESEARCH DESIGN AND METHODS—All participants were classified as having NGT (n = 1,069), pre-diabetes (n = 412), or diabetes (n = 157). Orthostatic hypotension was defined as a decline in systolic/diastolic blood pressure of ≥20/10 mmHg when an individual changed from a supine to a standing position. The cardiovagal response to standing was the ratio between the longest RR interval around beat 30 and the shortest RR interval around beat 15 after standing (30 max–to–15 min ratio).RESULTS—The prevalences of orthostatic hypotension were 13.8, 17.7, and 25.5% in subjects with NGT, pre-diabetes, and diabetes, respectively. For all subjects, age, diabetes, hypertension, and a decreased 30 max–to–15 min ratio, but not pre-diabetes, were independently associated with orthostatic hypotension. Age, hypertension, and 30 max–to–15 min ratio were the correlates of orthostatic hypotension in NGT subjects. Age and hypertension were related to orthostatic hypotension in pre-diabetic subjects. A1C and hypertension were the determinants of orthostatic hypotension in diabetic subjects. Supine blood pressure was related to orthostatic hypotension in all subjects and subgroups.CONCLUSIONS—Pre-diabetic subjects do not have a higher risk of orthostatic hypotension than subjects with NGT, although the risk of orthostatic hypotension is higher in diabetic subjects. Hypertension and supine blood pressure were risk factors for orthostatic hypotension in both pre-diabetic and diabetic subjects. Age and A1C were the correlates of orthostatic hypotension in pre-diabetic and diabetic subjects, respectively. The cardiovagal response to standing is an important determinant of orthostatic hypotension in subjects with NGT but not in pre-diabetic and diabetic subjects.Diabetic autonomic neuropathy with abnormal cardiovascular reflex has been associated with increased mortality from unexpected sudden death and renal failure (1). Orthostatic hypotension is one clinical manifestation of diabetic autonomic neuropathy (1) and is also a significant risk factor for fall, syncope, cardiovascular disease, and all-cause morality (1–4). Recently, pre-diabetes has been suggested to produce a significant increase in all-cause mortality and combined diabetes and cardiovascular disease mortality risks (5). However, the relationship between pre-diabetes and orthostatic hypotension is not clear, although there have been reports about orthostatic hypotension in subjects with diabetes (3,6–11).When a normal individual stands up from a lying position, the baroregulatory reflex produces vagal inhibition and sympathetic stimulation, resulting in an increase in heart rate and vasoconstriction to maintain the systemic blood pressure. Any impairment in the reflex arc, such as an efferent lesion with an inability to increase heart rate and vasoconstriction, may result in orthostatic hypotension (2,12). The initial heart rate response to standing consists of a maximal tachycardia around beat 15, followed by a relative bradycardia around beat 30 (12). It is generally recommended that the 30 max–to–15 min ratio (calculated by dividing the longest RR interval around beat 30 and the shortest RR interval around beat 15 after standing) be used as a cardiovagal response to standing (12). Although diabetic subjects exhibited impaired cardiac autonomic function (1,13), the cardiovagal response to active standing in subjects with diabetes and even pre-diabetes is not clear.The prevalence of orthostatic hypotension in diabetic subjects varied extremely from 8.2 to 43%, depending on the diagnostic criterion and study subject selection (3,6–10). Aging and some pathological changes, such as hypertension and cardiovascular disease, have been shown to be risk factors for orthostatic hypotension (2,6,9,11). However, some of the risk factors are interrelated, which may confound the effect of diabetes and even pre-diabetes on orthostatic hypotension. Most of the studies on orthostatic hypotension in diabetic subjects were hospital based, not population based (3,6–8,10), and adopted only the postural change in systolic blood pressure as the criteria (3,6–8). There is a lack of epidemiological study on orthostatic hypotension in subjects across the different blood glucose levels, including normal glucose tolerance (NGT), pre-diabetes, and diabetes. Research on whether the cardiovagal response to standing is different among these three groups is also lacking. Thus, the aim of this study was to investigate the relationship between pre-diabetes and orthostatic hypotension and also to examine the prevalence and risk factors for orthostatic hypotension in subjects with NGT, pre-diabetes, and diabetes from population-based data in Tainan, Taiwan.     

A1C but not serum glycated albumin is elevated in late pregnancy owing to iron deficiency

OBJECTIVE—A1C levels have been shown to be elevated in relation to glycemia in late pregnancy, although the precise mechanisms remain undetermined. We hypothesized that iron deficiency is involved in the A1C increase in late pregnancy.RESEARCH DESIGN AND METHODS—In study 1, A1C, serum glycated albumin, erythrocyte indexes, and iron metabolism indexes were determined in 47 nondiabetic pregnant women not receiving iron supplementation who were divided into four groups according to gestational period (group I, 21–24 weeks; group II, 25–28 weeks; group III, 29–32 weeks; and group IV, 33–36 weeks). In study 2, these determinants were obtained at two gestational periods (20–23 weeks and 32–33 weeks) in 17 nondiabetic pregnant women.RESULTS—In study 1, A1C levels were higher in groups III and IV than those in groups I and II, whereas serum glycated albumin levels were not different among these four groups. Hemoglobin, mean corpuscular hemoglobin (MCH), serum transferrin saturation, and serum ferritin were lower in groups III and IV. A1C levels were negatively correlated with MCH, serum transferrin saturation, and serum ferritin. In study 2, A1C levels were significantly increased at gestational weeks 32–33 from those at weeks 20–23, whereas serum glycated albumin levels did not differ between the two gestational periods. MCH, serum transferrin saturation, and serum ferritin were decreased at gestational weeks 32–33. A1C levels showed a negative correlation with MCH, serum transferrin saturation, and serum ferritin.CONCLUSIONS—A1C levels were elevated in late pregnancy owing to iron deficiency. Serum glycated albumin may offer a better index for monitoring glycemic control in pregnancy.In pregnant women displaying diabetes and women with gestational diabetes mellitus, intensive glycemic control during pregnancy is needed to lower the risk of intrauterine fetal death, fetal growth disorders, and maternal complications (1,2). The extent of nonenzymatic glycation of proteins increases in diabetic patients. Of these glycated proteins, A1C is widely used as the current standard marker for monitoring chronic glycemic control (3,4) and represents an important target for treatment of diabetic patients (5). Phelps et al. (6) showed biphasic changes in A1C levels during pregnancy, with A1C levels being lowest at gestational week 24. A longitudinal study also demonstrated similar biphasic changes in A1C levels (7).A1C measurements are known to be profoundly affected by erythrocyte turnover, as are plasma glucose levels (8,9). Blood dilution–related anemia is known to be frequently observed in pregnancy. In late pregnancy, iron deficiency anemia is also often observed, caused by the increased demands for iron (10). A1C levels have been shown to be higher in relation to glycemia in patients with iron deficiency anemia (11–13). We have recently shown that A1C levels are higher in premenopausal women with an iron-deficient state, even in the absence of anemia (14). We therefore hypothesized that A1C levels are set higher in relation to glycemia in late pregnancy, during which most women are iron deficient. To confirm this possibility, we studied the relationship between A1C and iron metabolism in nondiabetic pregnant women. For clinical issues, a study performed in pregnant diabetic women is important. However, in diabetic women fluctuations of plasma glucose may directly influence A1C levels beyond the effect of iron metabolism, making it difficult to analyze the direct effects of gestational course on A1C levels. Thus, in this study, we aimed to examine the relationship between A1C and iron metabolism in nondiabetic pregnant women, in whom the influence of plasma glucose levels is minimal. Serum glycated albumin, a different indicator for chronic glycemia, was also studied in these subjects.     

Multitissue insulin resistance despite near-normoglycemic remission in Africans with ketosis-prone diabetes

OBJECTIVE—To characterize insulin action in Africans with ketosis-prone diabetes (KPD) during remission.RESEARCH DESIGN AND METHODS—At Saint-Louis Hospital, Paris, France, 15 African patients with KPD with an average 10.5-month insulin-free near-normoglycemic remission period (mean A1C 6.2%) were compared with 17 control subjects matched for age, sex, BMI, and geographical origin. Insulin stimulation of glucose disposal, and insulin suppression of endogenous glucose production (EGP) and nonesterified fatty acids (NEFAs), was studied using a 200-min two-step (10 mU · m⁻² body surface · min⁻¹ and 80 mU · m⁻² · min ⁻¹ insulin infusion rates) euglycemic clamp with [6,6-²H₂]glucose as the tracer. Early-phase insulin secretion was determined during an oral glucose tolerance test.RESULTS—The total glucose disposal was reduced in patients compared with control subjects (7.5 ± 0.8 [mean ± SE] vs. 10.5 ± 0.9 mg · kg⁻¹ · min⁻¹; P = 0.018). EGP rate was higher in patients than control subjects at baseline (4.0 ± 0.3 vs. 3.0 ± 0.1 mg · kg⁻¹ · min⁻¹; P = 0.001) and after 200-min insulin infusion (10 mU · m⁻² · min⁻¹: 1.6 ± 0.2 vs. 0.6 ± 0.1, P = 0.004; 80 mU · m⁻² · min⁻¹: 0.3 ± 0.1 vs. 0 mg · kg⁻¹ · min⁻¹, P = 0.007). Basal plasma NEFA concentrations were also higher in patients (1,936.7 ± 161.4 vs. 1,230.0 ± 174.1 μmol/l; P = 0.002) and remained higher after 100-min 10 mU · m⁻² · min⁻¹ insulin infusion (706.6 ± 96.5 vs. 381.6 ± 55.9 μmol/l; P = 0.015).CONCLUSIONS—The triad hepatic, adipose tissue, and skeletal muscle insulin resistance is observed in patients with KPD during near-normoglycemic remission, suggesting that KPD is a form of type 2 diabetes.Impairment of insulin sensitivity is considered the background defect that interplays with the add-on progressive β-cell dysfunction to underlie the development of type 2 diabetes (1,2). An atypical form of diabetes, ketosis-prone diabetes (KPD), has been described over the past 2 decades and may represent a significant proportion of diabetes cases in people of sub-Saharan African origin (3,4). Patients with KPD present at onset with acute hyperglycemia, usually >30 mmol/l, and ketosis or ketoacidosis as type 1 diabetes but do not have autoimmune markers against the islet β-cell (3,5–7). The correction of those insulin-requiring acute-phase disorders is followed in >50% of cases by an insulin-free near-normoglycemic remission weeks to months later (8–10), thus resembling the course of type 2 diabetes. The pathogenesis and, consequently, the classification of KPD are still debated. It was classified under idiopathic type 1 diabetes or type 1B diabetes (11). However, growing evidence based on clinical and metabolic studies suggests its high phenotypical likeness to type 2 diabetes, and “ketosis-prone type 2 diabetes” has been proposed as a provisional name and is being used elsewhere (4,8,12). Metabolic studies have evidenced insulin secretion deficiency as the major determinant of the ketotic onset (8–10). This deficit is marked by a loss of acute-phase insulin secretion in response to intravenous glucose (10) or a decrease in C-peptide response to glucagon (9,10). The subsequent remission process is due to a restoration, at least partial, of the β-cell insulin secretory capacity after achievement of good metabolic control (8,10). Insulin action was assessed in three reports, but only toward glucose metabolism, and was found to be normal or decreased while patients were in good metabolic control (6,8,10). Moreover, most studies on KPD have been reported in African-Americans who are more overweight than native Africans and may be metabolically different from them, as suggested earlier (13).In this study, we aimed at characterizing all aspects of insulin action in Africans with KPD when in the near-normoglycemic state without insulin treatment compared with control subjects of the same geographic origin.     

Effects of an Intravenous Lipid Challenge and Free Fatty Acid Elevation on In Vivo Insulin Sensitivity in African American Versus Caucasian Adolescents

OBJECTIVE—African American youth have lower insulin sensitivity than their Caucasian peers, but the metabolic pathways responsible for this difference remain unknown. Free fatty acids (FFAs) are associated with insulin resistance through the Randle cycle. The present investigation determined whether elevating FFA is more deleterious to insulin sensitivity in African American than in Caucasian adolescents.RESEARCH DESIGN AND METHODS—Insulin sensitivity (3-h hyperinsulinemic-euglycemic clamp) was evaluated in 22 African American and 21 Caucasian adolescents on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid.RESULTS—During intralipid infusion, fasting insulin and C-peptide concentrations increased while fasting glucose and basal glucose turnover did not change in either group. Insulin sensitivity decreased similarly in African American (normal saline 7.65 ± 0.61 vs. intralipid 5.15 ± 0.52 μmol · kg⁻¹ · min⁻¹ per pmol/l) and Caucasian subjects (normal saline 8.97 ± 0.85 vs. intralipid 5.96 ± 0.56 μmol · kg⁻¹ · min⁻¹ per pmol/l) (P < 0.001).CONCLUSIONS—African American and Caucasian adolescents respond to FFA elevation similarly through increased fasting insulin secretion to maintain fasting glucose homeostasis and reduced peripheral glucose uptake and insulin resistance. Thus, African American adolescents are not more susceptible to FFA-induced insulin resistance than Caucasian youth.Free fatty acids (FFAs) are implicated in insulin resistance development through the Randle cycle (1,2). In adults, elevating plasma FFA by infusing lipid emulsion inhibits glucose disposal and oxidation in normal-weight, obese, and type 2 diabetic patients (3–5). The only pediatric study was performed in Caucasian children and demonstrated that intralipid infusion decreased insulin sensitivity in pubertal adolescents, with no such effect in prepubertal children (6). Such data support that pubertal insulin resistance is driven by the Randle cycle/substrate competition (7,8).Insulin sensitivity is lower in African American children than in their Caucasian peers (9,10), but the metabolic pathways responsible for this contrast remain unknown. Lower insulin sensitivity correlates inversely with an increased fat-to-carbohydrate ratio in the diet of African American children (10,11). Thus, FFAs may be detrimental to insulin sensitivity in African American children. If race-related differences in the susceptibility to FFA-induced insulin resistance exist, then this is of increased importance during puberty when increased FFAs decrease glucose disposal (6). The present investigation, therefore, aimed to compare the effects of FFA elevation on fasting and insulin-stimulated glucose metabolism in African American and Caucasian adolescents. We hypothesized that increased concentrations of circulating FFAs result in a greater decrement in insulin sensitivity in African American than in Caucasian adolescents.     

Adult metabolic syndrome and impaired glucose tolerance are associated with different patterns of BMI gain during infancy: Data from the New Delhi Birth Cohort

OBJECTIVE—The purpose of this study was to describe patterns of infant, childhood, and adolescent BMI and weight associated with adult metabolic risk factors for cardiovascular disease.RESEARCH DESIGN AND METHODS—We measured waist circumference, blood pressure, glucose, insulin and lipid concentrations, and the prevalence of metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III definition) in 1,492 men and women aged 26–32 years in Delhi, India, whose weight and height were recorded every 6 months throughout infancy (0–2 years), childhood (2–11 years), and adolescence (11 years–adult).RESULTS—Men and women with metabolic syndrome (29% overall), any of its component features, or higher (greater than upper quartile) insulin resistance (homeostasis model assessment) had more rapid BMI or weight gain than the rest of the cohort throughout infancy, childhood, and adolescence. Glucose intolerance (impaired glucose tolerance or diabetes) was, like metabolic syndrome, associated with rapid BMI gain in childhood and adolescence but with lower BMI in infancy.CONCLUSIONS—In this Indian population, patterns of infant BMI and weight gain differed for individuals who developed metabolic syndrome (rapid gain) compared with those who developed glucose intolerance (low infant BMI). Rapid BMI gain during childhood and adolescence was a risk factor for both disorders.Approximately 10% of urban Indian men and women aged 40–49 years have type 2 diabetes, and a rising prevalence is predicted to produce 80 million diabetic patients in India by 2030 (1–3). Cardiovascular disease is also rising (4). Similar trends, thought to reflect increasing obesity, are occurring in other developing countries undergoing economic transition, and interventions to prevent disease are urgently needed.Research in high-income countries has shown that factors linked to weight gain in early life contribute to the risk of developing diabetes and cardiovascular disease. Low birth weight (5,6) and accelerated gain in BMI during childhood and adolescence predict increased risk (7,8). The optimal pattern of infant weight gain (the first 1–2 postnatal years) is unclear; studies of adults suggest that low infant weight gain is a risk factor for later disease (7–9), whereas studies of children suggest the opposite (10,11). There are few data from developing countries.In the New Delhi birth cohort (12,13), children were measured at birth and every 6 months throughout infancy, childhood, and adolescence. We reported earlier that low BMI in infancy and rapid childhood BMI gain were associated with an increased risk of adult diabetes or impaired glucose tolerance (IGT) (12). We have now examined other cardiovascular risk factors and the cluster of risk factors known as the metabolic syndrome.