Comparison of Iron Dosing Strategies in Patients Undergoing Long-Term Hemodialysis: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Whether iron supplementation in patients on hemodialysis could be delivered by less frequent but higher single doses compared with the currently more common higher-frequency schedules of lower single iron doses is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We carried out an open-label, randomized, controlled noninferiority trial over 40 weeks in patients on prevalent hemodialysis (n=142). We administered in total 2 g iron as 100 mg iron sucrose biweekly in a continuous (20 × 100 mg) fashion or 500 mg ferric carboxymaltose every 10 weeks in a periodic (4 × 500 mg) fashion. The primary end point was the change in hemoglobin at week 40 from baseline with a noninferiority margin of -0.8 g/dl. Secondary end points were changes in ferritin, transferrin, transferrin saturation, and erythropoiesis-stimulating agent use. RESULTS: In total, 108 patients completed the study. At 40 weeks, hemoglobin changed by -0.27 g/dl (95% confidence interval, -0.64 to 0.09) in the iron sucrose arm and by -0.74 g/dl (95% confidence interval, -1.1 to -0.39) in the ferric carboxymaltose arm compared with baseline. Noninferiority was not established in the per-protocol population as hemoglobin changes compared with baseline differed by -0.47 g/dl (95% confidence interval, -0.95 to 0.01) in the ferric carboxymaltose arm compared with the iron sucrose arm. Proportional changes from baseline to week 40 differed by -31% (98.3% confidence interval, -52 to -0.1) for ferritin, by 1% (98.3% confidence interval, -7 to 10) for transferrin, and by -27% (98.3% confidence interval, -39 to -13) for transferrin saturation in the ferric carboxymaltose arm compared with the iron sucrose arm. Erythropoiesis-stimulating agent dosing did not differ between groups. The overall number of adverse events was similar; however, more infections were observed in the iron sucrose arm. CONCLUSIONS: An equal cumulative dose of ferric carboxymaltose administered less frequently did not meet noninferiority for maintaining hemoglobin levels compared with iron sucrose administered more frequently. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Comparison Study of Two Iron Compounds for Treatment of Anemia in Hemodialysis Patients (COPEFER), NCT02198495.

Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis.

[Figure: see text].

Extracorporeal IgE Immunoadsorption in Allergic Asthma: Safety and Efficacy.

BACKGROUND: Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody fragment and can be used for the specific extracorporeal desorption of IgE. OBJECTIVE: To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes. METHODS: Fifteen subjects were enrolled and randomly assigned to the treatment group (n=10) or to the control group (n=5). Immunoadsorption was done by veno-venous approach, processing the twofold calculated plasma volume during each treatment. A minimum average IgE-depletion of 50% after the last cycle in the intention-to-treat population was defined as primary endpoint. Safety of the treatment was studied as secondary endpoint. In addition, possible changes in allergen-specific sensitivity were investigated, as well as clinical effects by peak flow measurement and symptom-recording. The depletion of IgE-Omalizumab immune complexes was studied in vitro. The study was registered at clinicaltrials.gov (NCT02096237) and conducted from December 2013 to July 2014. RESULTS: IgE immunoadsorption with IgEnio selectively depleted 86.2% (±5.1% SD) of IgE until the end of the last cycle (p<0.0001). Removal of pollen allergen-specific IgE was associated with a reduction of allergen-specific basophil-sensitivity and prevented increases of allergen-specific skin-sensitivity and clinical symptoms during pollen seasons. IgEnio also depleted IgE-Omalizumab immune complexes in vitro. The therapy under investigation was safe and well-tolerated. During a total of 81 aphereses, 2 severe adverse events (SAE) were recorded, one of which, an episode of acute dyspnea, possibly was related to the treatment and resolved after administration of antihistamines and corticosteroids. CONCLUSIONS: This pilot study indicates that IgE immunoadsorption with IgEnio may be used to treat patients with pollen-induced allergic asthma. Furthermore, the treatment could render allergic patients with highly elevated IgE-levels eligible for the administration of Omalizumab and facilitate the desorption of IgE-Omalizumab complexes. This study was funded by Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.

Hidden metabolic disturbances in women with normal glucose tolerance five years after gestational diabetes.

Background. The study aimed to assess whether women with prior gestational diabetes (pGDM), despite maintenance of normal glucose tolerance (NGT) five years after delivery, display metabolic disturbances compared to healthy controls. Methods. 45 pGDM with NGT were compared to 18 women without a history of GDM (CON), matched for age (37.0 ± 4.1 versus 35.2 ± 5.3, P = ns) and BMI (24.3 ± 3.1 versus 23.3 ± 3.3, P = ns). Metabolic parameters were derived from oral and intravenous glucose tolerance tests; furthermore lipid profile, C-reactive protein (CRP), adiponectin, leptin, and glucagon were assessed. Results. Five years postpartum, pGDM had increased glucose concentrations during the OGTT (AUC: 1.12 ± 0.15 versus 1.0 ± 0.12 mol/L ∗ min, P = 0.003) and insulin sensitivity was decreased compared to CON (OGIS: 467.2 ± 64.1 versus 510.6 ± 53.1 mL/min ∗ m(2), P = 0.01). pGDM had lower adiponectin (8.1 ± 2.6 versus 12.6 ± 5.3, P < 0.008) but increased waist circumference and CRP compared to CON. Conclusions. Despite diagnosis of normal glucose tolerance, pGDM are characterized by hyperglycemia and insulin resistance compared to healthy controls, accompanied by decreased adiponectin and increased CRP concentrations, thus linking metabolic disturbances to an increased cardiovascular risk in pGDM.

Biomarkers of endothelial dysfunction in relation to impaired carbohydrate metabolism following pregnancy with gestational diabetes mellitus.

BACKGROUND: History of gestational diabetes mellitus (GDM) identifies a very young population of females predisposed for type 2 diabetes and cardiovascular disease. Endothelial dysfunction might represent a shared precursor of both disorders. Hence, this study aimed to characterize endothelial biomarkers in relation to impaired insulin sensitivity and progression to overt diabetes early after index pregnancy. METHODS: 108 women with previous GDM and 40 controls were included three to six months after delivery and underwent specific metabolic assessments including a frequently sampled intravenous glucose tolerance test and an oral glucose tolerance test. Diabetes progression was assessed in females with pGDM over 10 years of follow-up. Circulating sICAM-1 (intracellular-adhesion-molecule-1), sVCAM-1 (vascular-cell-adhesion-molecule-1) and sE-selectin, representing biomarkers of endothelial dysfunction were assessed at baseline and annually over five years. RESULTS: Endothelial biomarkers were significantly associated with insulin sensitivity (sICAM-1: r = -0.23, p = 0.009; sVCAM-1: r = -0.22, p = 0.011; sE-selectin: r = -0.21, p = 0.018) as well as with GDM status and parameters of subtle inflammation. Analysis of long-term trajectories revealed constantly elevated sICAM-1 (p = 0.033) and sE-selectin (p = 0.007) in 25 subjects with diabetes progression. Accordingly, sE-selectin levels at the early post partum visit predicted a later development of the disease (HR =1.02 95%CI 1.01 to 1.04, p = 0.013), however, this was attenuated after adjustment for BMI. CONCLUSIONS: Elevated circulating markers of endothelial dysfunction in young females with GDM history might reflect an early stage on the pathway to the manifestation of future cardiometabolic disorders. Timely identification of women at high risk and optimization of follow-up management might provide an opportunity to prevent disease progression.

Lower fasting muscle mitochondrial activity relates to hepatic steatosis in humans.

OBJECTIVE: Muscle insulin resistance has been implicated in the development of steatosis and dyslipidemia by changing the partitioning of postprandial substrate fluxes. Also, insulin resistance may be due to reduced mitochondrial function. We examined the association between mitochondrial activity, insulin sensitivity, and steatosis in a larger human population. RESEARCH DESIGN AND METHODS: We analyzed muscle mitochondrial activity from ATP synthase flux (fATP) and ectopic lipids by multinuclei magnetic resonance spectroscopy from 113 volunteers with and without diabetes. Insulin sensitivity was assessed from M values using euglycemic-hyperinsulinemic clamps and/or from oral glucose insulin sensitivity (OGIS) using oral glucose tolerance tests. RESULTS: Muscle fATP correlated negatively with hepatic lipid content and HbA1c. After model adjustment for study effects and other confounders, fATP showed a strong negative correlation with hepatic lipid content and a positive correlation with insulin sensitivity and fasting C-peptide. The negative correlation of muscle fATP with age, HbA1c, and plasma free fatty acids was weakened after adjustment. Body mass, muscle lipid contents, plasma lipoproteins, and triglycerides did not associate with fATP. CONCLUSIONS: The association of impaired muscle mitochondrial activity with hepatic steatosis supports the concept of a close link between altered muscle and liver energy metabolism as early abnormalities promoting insulin resistance.

Estimating the risk after gestational diabetes mellitus: can we improve the information from the postpartum OGTT?

Risk stratification after pregnancy with gestational diabetes mellitus (GDM) is based on screening with the 2-h oral glucose tolerance test (OGTT). Actually, prediabetes and diabetes are diagnosed by impaired fasting [fasting plasma glucose (FPG)] and 120 min-postload glucose levels (120'-PLG). We hypothesized that the clinical information could be improved by including measurements at different time points from the OGTT in the medical decision-making process. One hundred ten women with previous gestational diabetes (pGDM) and 41 controls were included 3-6 mo after delivery and underwent specific metabolic assessments: 3-h OGTT, frequently sampled intravenous glucose tolerance test (FSIGT) with markers of inflammation and endothelial function. pGDMs were annually invited for reexaminations for a maximum of 10 yr. Multiple linear regression suggested that postload glucose levels at 60 min (60'-PLG) were a better predictor for insulin sensitivity [ß: -0.10, 95% confidence interval (CI) -0.14 to -0.05, P < 0.001] and disposition index (DI) (ß: -0.07, 95% CI -0.12 to -0.02, P = 0.004) estimated from the FSIGT compared with other time points during the OGTT. The association between 60'-PLG and insulin secretion was of particular importance in women after GDM. We further identified associations of 60'-PLG with ultrasensitive C-reactive protein, plasminogen activator inhibitor 1, tissue plasminogen activator, endothelial-leukocyte adhesion molecule 1, and intercellular adhesion molecule (ICAM)-1. There appeared to be no interactions between females with pGDM and controls, suggesting comparable effects. We observed that 60'-PLG levels were closely related to the later onset of diabetes independent from the routinely measured FPG and 120'-PLG levels. Our data suggest that the sole interpretation of FPG and 120'-PLG of the OGTT leads to significant loss of information. Particularly 60'-PLG was shown to distinguish women at low or high metabolic and cardiovascular risk.

The impact of recurrent gestational diabetes on maternal metabolic and cardiovascular risk factors.

OBJECTIVE: The development of overt diabetes in women with prior gestational diabetes mellitus (priorGDM) has been linked to several risk factors including age, obesity and insulin therapy during pregnancy; the role of recurrent GDM as a further risk factor remains unclear. As studies examining detailed metabolic consequences of recurrent GDM are missing and the role of recurrent GDM on cardiovascular risk is unknown, our aim was to investigate the impact of recurrent GDM (within 5 years after an index pregnancy) on metabolic and cardiovascular parameters. METHODS: Oral and intravenous glucose tolerance tests as well as assessment of cardiovascular risk factors were performed at baseline (6 months after index pregnancy) and 5 years thereafter in 21 prior GDM with recurrent GDM (recGDM), 41 prior GDM with no additional pregnancy (nonrecGDM) and 10 healthy controls [CON]. RESULTS: Despite weight gain in recGDM (2·3 ± 5·1 vs. -1·3 ± 6·7 kg, P < 0·04), glucose tolerance, insulin sensitivity and secretion did not differ compared with nonrecGDM at baseline and follow-up. Furthermore, recGDM did not exhibit increased cardiovascular risk factors. Metabolic deterioration in (19% of) the total priorGDM group was associated with decreased insulin sensitivity (OGIS:367·4 ± 89·6 vs. 436·4 ± 75·5 mL/min*m², P = 0·01), hyperinsulinaemia (TIS:37·9 ± 9·7 vs. 28·0 ± 10·2 nM, P < 0·006) and postchallenge hyperglycaemia at 5 years postpartum. CONCLUSIONS: Recurrence of gestational diabetes was not associated with deterioration of glucose metabolism, insulin sensitivity and secretion nor with increased cardiovascular risk. Consequently, priorGDM should not be recommended to refrain from subsequent pregnancies, but be encouraged to regain and maintain normal body weight after delivery and regularly undergo OGTTs to early detect metabolic deterioration.

Fatty liver index predicts further metabolic deteriorations in women with previous gestational diabetes.

BACKGROUND AND AIMS: Determinants of fatty liver (FL) might be predictive for further deterioration in insulin resistance (IR) in women with previous gestational diabetes (pGDM). The aim was to evaluate the association between pGDM, FL and future manifestation of type 2 diabetes (T2DM) by a detailed pathophysiological characterization early after pregnancy. METHODS: 68 pGDM and 29 healthy controls were included 3-6 months after delivery and underwent specific metabolic assessments: status of IR was determined via oral- and intravenous-glucose-tolerance-tests with analysis of proinflammatory factors and kinetics of free-fatty-acids (FFA). According to the fatty-liver-index (FLI), pGDMs were categorized into three groups with low (FLI≤20), intermediate (20

Skeletal muscle phosphodiester content relates to body mass and glycemic control.

BACKGROUND: Aging and insulin resistance have been related to reduced mitochondrial function and oxidative stress. Muscular phosphodiesters (PDE) are comprised of metabolites of phospholipid breakdown and may reflect membrane damage. We aimed to test the hypothesis that myocellular PDE are increased in patients with type 2 diabetes (T2D) and correlate inversely with mitochondrial ATP turnover. METHODS: A Cross-sectional study in the Clinical Research Facility of an University hospital was performed. 10 nonobese middle-aged patients with T2D, 10 healthy humans matched for sex, age and physical activity index (CONm) and 18 young healthy humans (CONy) were included. Myocellular PDE and unidirectional flux through ATP synthase (fATP) were measured with (31)P magnetic resonance spectroscopy (MRS). Intramyocellular (IMCL) and hepatocellular lipid deposition (HCL) were quantified with (1)H MRS. Insulin sensitivity (Rd) was assessed from hyperinsulinemic-euglycemic clamp tests in 10 T2D, 10 CONm and 11 CONy. RESULTS: During fasting, T2D and CONm had 1.5 fold greater PDE than CONy (2.8±0.2, 2.5±0.2, 1.7±0.1 mmol/l, P = 0.004). Stimulation by insulin did not affect PDE in any group. PDE correlated negatively with Rd (r = -0.552, p<0.005) and fATP (r = -0.396, p<0.05) and positively with age (r = 0.656, p<0.001) and body mass (r = 0.597, p<0.001). PDE also related positively to HbA1c (r = 0.674, p<0.001) and fasting plasma glucose (r = 0.629, p<0.001) within T2D and across all participants. CONCLUSIONS: Muscular PDE concentrations associate with age, lower resting mitochondrial activity and insulin resistance, which is determined mainly by body mass and glycemia.

Early possible risk factors for overt diabetes after gestational diabetes mellitus.

OBJECTIVE: To assess a cluster of risk factors, including parameters of the metabolic syndrome, in women with gestational diabetes mellitus (GDM) early after delivery, that features the best prediction for developing diabetes. METHODS: Women with GDM 3-6 months after delivery received a complete metabolic characterization at baseline as well as annually for up to 10 years of follow-up (N=110). We used parameters characterizing the metabolic syndrome as well as demographic variables at baseline to predict diabetes manifestation. RESULTS: Metabolic disturbances and insulin treatment during pregnancy were significantly associated with overt diabetes. Waist circumference of 80 cm or higher failed to show a significant effect on later development of the disease; however, it was significant when 88 cm or more was used as a cutoff value. We identified impaired glucose tolerance (13 [56.5%]; hazard ratio 6.77, confidence interval [CI] 2.96-15.45, P<.001) as well as high-density lipoprotein (HDL) cholesterol less than 50 mg/dL (14 [60.9%]; hazard ratio 2.88, CI 1.24-6.67, P=.010) and age older than 35 years (12 [52.2%]; hazard ratio 3.06, CI 1.32-7.12, P=.006) as the best predictors with additive effects. Women with at least two risk factors had a higher risk to develop the disease as compared with those women who showed only one risk factor (hazard ratio 3.2, CI 1.4-7.7, P=.008). CONCLUSION: Impaired glucose tolerance, HDL cholesterol less than 50 mg/dL, and age older than 35 years were identified as the best predictors of developing diabetes after GDM.

Body and liver fat mass rather than muscle mitochondrial function determine glucose metabolism in women with a history of gestational diabetes mellitus.

OBJECTIVE: Ectopic lipid storage in muscle (intramyocellular lipids [IMCL]) and liver (hepatocellular lipids [HCL]) coexists with impaired myocellular flux through ATP synthase (fATPase) in certain cohorts with increased risk of type 2 diabetes. Because women with a history of gestational diabetes mellitus (pGDM) have elevated ectopic lipids and diabetes risk, we tested whether deteriorated energy metabolism contributes to these abnormalities. RESEARCH DESIGN AND METHODS: A total of 23 glucose-tolerant nonobese pGDM and eight women with normal glucose metabolism during pregnancy with similar age, body mass, and physical activity underwent oral glucose tolerance tests (OGTT) and intravenous glucose tolerance tests at 4-5 years after delivery. OGTT values <463 mL ⋅ min(-1) ⋅ m(-2) were considered to indicate insulin resistance. pGDM were further stratified into insulin-resistant (pGDM-IR) and insulin-sensitive (pGDM-IS) groups. IMCL, HCL, and fATPase were measured with (1)H/(31)P magnetic resonance spectroscopy. RESULTS: pGDM had 36% higher fat mass and 12% lower insulin sensitivity. Log-transformed fATPase was lower in pGDM (10.6 ± 3.8 µmol ⋅ mL muscle(-1) ⋅ min(-1) vs. 12.1 ± 1.4 µmol ⋅ mL muscle(-1) ⋅ min(-1), P < 0.03) and related to plasma adiponectin after adjustment for body fat (r = 0.44, P < 0.04). IMCL were 61% and 69% higher in pGDM-IR (P < 0.05 vs. pGDM-IS) and insulin resistant women (P < 0.003 vs. insulin sensitive), respectively. HCL were doubled (P < 0.05) in pGDM and insulin resistant women, and correlated positively with body fat mass (r = 0.50, P < 0.01) and inversely with insulin sensitivity (r = -0.46, P < 0.05). CONCLUSIONS: Glucose-tolerant pGDM show increased liver fat but only slightly lower muscular insulin sensitivity and ATP synthesis. This suggests that alteration of hepatic lipid storage represents an early and predominant abnormality in this cohort.

Effect of the proteasome inhibitor bortezomib on humoral immunity in two presensitized renal transplant candidates.

BACKGROUND: Recipient presensitization represents a major hurdle to successful renal transplantation. Previous case series have suggested that the proteasome inhibitor bortezomib directly affects the alloantibody-secreting plasma cells in rejecting allograft recipients. However, the ability of this agent to desensitize nonimmunosuppressed transplant candidates before transplantation is currently unknown. METHODS: In this analysis, two sensitized hemodialysis patients were selected to receive two subsequent bortezomib cycles. Bortezomib was given at 1.3 mg/m(2) on days 1, 4, 8, and 11. Dexamethasone was added to the second cycle to enhance treatment efficiency. Serial immune monitoring included cytotoxic panel reactive antibody testing, Luminex single antigen testing for anti-human leukocyte antigen (HLA) IgG with or without C4d-fixing capability, and ABO antibody detection. RESULTS: During a half-year follow-up period, cytotoxic panel reactive antibody decreased from 87% to 80% (patient 1) and 37% to 13% (patient 2). Patient 1 showed a 40% reduction in binding intensities of identified Luminex HLA single antigen reactivities and, in parallel, slight reductions in ABO blood group antibody and total immunoglobulin levels. In patient 2, bortezomib did not affect circulating antibody levels in a meaningful way. Both patients showed a more than 50% reduction in the levels of anti-HLA antibody-triggered C4d deposition to Luminex beads. CONCLUSION: Our initial experience suggests that, without additional immunosuppressive measures, bortezomib has modest effects on circulating antibodies against HLA or blood group antigens. The reduced levels of antibody-triggered complement fixation, however, imply potential clinical relevance of proteasome inhibition for recipient desensitization.

Serum vaspin concentrations in relation to insulin sensitivity following RYGB-induced weight loss.

BACKGROUND: Recently, vaspin was identified as a novel adipokine with insulin-sensitizing effects that might be implicated in endogenous glucose regulation. Our objective was to evaluate the impact of acute weight loss and metabolic changes on serum vaspin concentrations in morbidly obese subjects following laparoscopic Roux-en-Y gastric bypass (RYGB) surgery. METHODS: Longitudinal, clinical intervention study in 33 morbidly obese subjects before and 12 months after RYGB was conducted. Fasting serum concentrations of vaspin were measured by a commercially available ELISA and correlated with BMI, parameters of insulin sensitivity, and other biochemical measurements. Fasting insulin sensitivity was estimated using the homeostasis model assessment (HOMA) of insulin resistance. RESULTS: RYGB-induced weight loss resulted in a reduction of circulating vaspin, leptin, insulin, and C-peptide levels as well as of BMI, HbA1c, and HOMA (p < 0.0001, respectively). Changes in serum vaspin concentrations correlated positively with those in HOMA, insulin, C-peptide, HbA1c, and leptin (p < 0.05, respectively) levels. The association between percent change of vaspin and HOMA remained significant even after the adjustment for RYGB-induced changes in BMI. CONCLUSIONS: Following RYGB surgery, changes in serum vaspin concentrations correlate significantly with the reduction of circulating leptin, insulin, and C-peptide levels and with the amelioration of insulin sensitivity. However, further studies have to elucidate whether vaspin is only a biomarker for body-weight-related changes of insulin sensitivity or whether it is implicated in the regulation of human glucose homeostasis.

CXCL12/SDF-1 over-expression in human insulinomas and its biological relevance.

This study was performed on the basis of previously obtained investigative gene array data concerning the over-expression of CXCL12/SDF-1 in human insulinomas versus human pancreatic islet preparations. The presence of CXCL12/SDF-1 was studied by RT-qPCR in human insulinomas (n=8) versus pancreatic islets (n=3), and was found to be significantly up-regulated in the former (p<0.012). The mRNA data were confirmed by immunostaining and confocal microscopy of human normal pancreatic islets, which showed the absence of CXCL12 protein and high expression in insulinoma tissue. Individual human insulinoma cells at cytospins stained positive for CXCL12 in the paranuclear region. These morphological data were extended by consecutive immunoblotting for cell-compartment-specific marker proteins of fractions obtained by sucrose gradient fractionation using Rin-5F insulinoma cells. CXCL12-containing fractions were positive for the membrane marker NSF but negative for SNAP-25 and appeared at a lighter density in the gradient than heavy insulin granules, suggesting packaging in specific granules different from insulin. In order to determine the biological relevance of the protein in insulinomas, we investigated the colony-forming potential of human CXCL12 stable-transfected rat Rin-5F insulinoma cells. These clones secreted human CXCL12 and contained 50-1000-fold higher copy numbers compared to its endogenous rat homologue. In colony-forming assays, these transfectant clones developed greater colony numbers, which were larger than wild-type and sham transfectants. To elucidate the mechanism of action, we identified a CXCL12 transfectant-specific increase in the pro-survival factor Mn-SOD, which is considered important for the inactivation of reactive oxygen species, thereby prolonging cell survival. These data demonstrate the importance of CXCL12 in the tumor biology of insulinoma.

Haptoglobin phenotype and gestational diabetes.

OBJECTIVE: Haptoglobin (Hp), an Hb-binding plasma protein, exists in two major allelic variants. Hp1 has higher Hb binding and antioxidant capacity compared with Hp2. Individuals with Hp1 exhibit a lower incidence of angiopathies. Gestational diabetes mellitus (GDM) is an early manifestation of type 2 diabetes in pregnant women. It is usually confined to the time of gestation, but carries an increased risk to develop type 2 diabetes later in life. RESEARCH DESIGN AND METHODS: From consecutive Caucasian pregnant women (n = 250) referred for oral glucose tolerance testing, the Hp phenotype was determined. Significance of distribution and odds ratios (ORs) associated with Hp phenotype were calculated for women with GDM (n = 110) and women with normal glucose tolerance (n = 140). RESULTS: -Frequency of GDM in Hp phenotype classes increased with the number of Hp2 alleles (P < 0.001). ORs for GDM in women heterozygous and homozygous for Hp2 were 2.7 (95% CI 1.06-6.84) and 4.2 (1.67-10.55), respectively. CONCLUSIONS: Hp phenotype is an apparent risk factor for the development of GDM in our study population. This might be due to the low antioxidative potential of Hp2 compared with Hp1.