Plasma AGE and Oxidation Products, Renal Function, and Preeclampsia in Pregnant Women with Type 1 Diabetes: A Prospective Observational Study.

Aims: We aimed to determine whether plasma advanced glycation end products or oxidation products (AGE/oxidation-P) predict altered renal function and/or preeclampsia (PE) in pregnant women with type 1 diabetes. Methods: Prospectively, using a nested case-control design, we studied 47 pregnant women with type 1 diabetes, of whom 23 developed PE and 24 did not. Nineteen nondiabetic, normotensive pregnant women provided reference values. In plasma obtained at ~12, 22, and 32 weeks' gestation (visits 1, 2, and 3; V1-V3), we measured five AGE products (carboxymethyllysine (CML), carboxyethyl-lysine (CEL), methylglyoxal-hydroimidazolone (MGH1), 3-deoxyglucosone hydroimidazolone (3DGH), and glyoxal-hydroimidazolone (GH1)) and four oxidation products (methionine sulfoxide (MetSO), 2-aminoadipic acid (2-AAA), 3-nitrotyrosine (3NT), and dityrosine (DT)), by liquid chromatography/mass spectroscopy. Clinical outcomes were "estimated glomerular filtration rate" (eGFR) at each visit and onset of PE. Results: In diabetic women, associations between AGE/oxidation-P and eGFR were found only in those who developed PE. In this group, CEL, MGH1, and GH1 at V2 and CML, CEL, MGH1, and GH1 at V3 were inversely associated with contemporaneous eGFR, while CEL, MGH1, 3DGH, and GH1 at V2 were inversely associated with eGFR at V3 (all p < 0.05). There were no associations of plasma AGE or oxidation-P with pregnancy-related development of proteinuria or PE. Conclusions: Inverse associations of second and early third trimester plasma AGE with eGFR among type 1 diabetic women who developed PE suggest that these patients constitute a subset susceptible to AGE-mediated injury and thus to cardiorenal complications later in life. However, AGE/oxidation-P did not predict PE in type 1 diabetic women.

Prevalence of diabetic retinopathy in women with pregestational diabetes during pregnancy and the postpartum.

BACKGROUND: Diabetic retinopathy (DR) may be affected by pregnancy. The majority of prevalence data regarding DR in pregnancy predate the advent of contemporary guidelines for diabetes management during pregnancy. This study reports DR prevalence and associated risk factors in women with pregestational diabetes during pregnancy and the postpartum in Australia. METHODS: A total of 172 pregnant women with type 1 (T1DM) or type 2 diabetes diagnosed pre-pregnancy were prospectively recruited from two obstetrics hospitals in Melbourne (November 2017-March 2020). Eye examinations were scheduled in each trimester, at 3-, 6-, and 12-months postpartum. DR severity was graded from two-field fundus photographs by an independent grader utilising the Airlie House Classification. Sight-threatening DR (STDR) was defined as the presence of diabetic macular oedema or proliferative DR. RESULTS: Overall, 146 (84.9%) women had at least one eye examination during pregnancy. The mean age was 33.8 years (range 19-51), median diabetes duration was 7.0 years (IQR 3.0-17.0), 71 women (48.6%) had T1DM. DR and STDR prevalence during pregnancy per 100 eyes was 24.3 (95% CI 19.7-29.6) and 9.0 (95% CI 6.1-12.9); while prevalence in the postpartum was 22.2 (95% CI 16.5-29.3) and 10.0 (95% CI 5.4-17.9), respectively. T1DM, longer diabetes duration, higher HbA1c in early pregnancy, and pre-existing nephropathy were significant risk factors. CONCLUSIONS: The prevalence of DR in pregnant women was similar to the non-pregnant diabetic population in Australia. One in nine participants had STDR during pregnancy and the postpartum, highlighting the need to optimise DR management guidelines in pregnancy given the significant risk of vision loss.

Impact of preconception weight loss on fasting glucose and pregnancy outcomes in women with obesity: A randomized trial.

OBJECTIVE: This study examined the effectiveness of a nonsurgical, preconception weight loss intervention on pregnancy outcomes in women with obesity. METHODS: This was a two-arm, parallel-group randomized controlled trial. A total of 164 women with BMI 30 to 55 kg/m2 who were aged 18 to 38 years and planning pregnancy were randomized to a 12-week standard dietary intervention (SDI; n = 79) or a modified very low-energy diet (VLED; n = 85). Participants were observed for ≤48 weeks while trying for pregnancy and then during pregnancy. The primary outcome was maternal fasting plasma glucose at 26 to 28 weeks' gestation. Exploratory outcomes were individual and composite obesity-related adverse pregnancy outcomes. RESULTS: Weight loss was greater in the VLED group (SDI 3.2 [0.6] kg vs. VLED 13.0 [0.5] kg, p < 0.01). In completers who had a singleton live birth (SDI 22/79 vs. VLED 35/85, p = 0.10), there was no difference in fasting glucose at 26 to 28 weeks' gestation (SDI 4.8[0.2] mmol/L vs. VLED 4.6 [0.1] mmol/L, p = 0.42). However, the composite of adverse pregnancy outcomes was significantly lower in the VLED group (p < 0.001). CONCLUSIONS: Substantial prepregnancy weight loss in women with obesity does not alter fasting glucose at 26 to 28 weeks' gestation but does reduce a composite of adverse pregnancy outcomes. A better understanding of metabolic changes in pregnancy after preconception weight loss may assist in improving maternal and neonatal health outcomes.

Time to pregnancy after a prepregnancy very-low-energy diet program in women with obesity: substudy of a randomized controlled trial.

OBJECTIVE: To examine the impact of a prepregnancy very-low-energy diet (VLED) program on time to pregnancy in women with obesity. DESIGN: Substudy of a two-arm parallel group randomized controlled trial. SETTING: Multiple tertiary care centers. PATIENT(S): Women 18-38 years old with obesity (body mass index 30-55 kg/m2) and planning conception. INTERVENTION(S): One hundred sixty-four normoglycemic women with body mass index 30-55 kg/m2, aged 18-38 years, and planning pregnancy were recruited through a social media platform for a two-arm randomized controlled trial. Women were allocated to a 12-week standard dietary intervention (SDI) or modified VLED. Completers of the intervention were observed for up to 48 weeks, and time to pregnancy was recorded. MAIN OUTCOME MEASURE(S): The prespecified exploratory outcome for this substudy was time to pregnancy between the completion of the 12-week intervention and the date of conception. RESULT(S): Maternal weight loss at the end of the 12-week intervention was 3.1% in the SDI group and 11.9% in the VLED group. In completers of the 12-week intervention, time to pregnancy was significantly shorter in the women allocated to the VLED group than in the SDI group. Post hoc analysis showed that this difference in time to conception was particularly overt within 90 days of the intervention. CONCLUSION(S): A VLED program that achieves substantial weight loss before conception reduces time to pregnancy compared with an SDI in women with obesity. TRIAL REGISTRATION NUMBER: ACTRN12614001160628.

Vitamin D Metabolites and Binding Protein Predict Preeclampsia in Women with Type 1 Diabetes.

The risk for preeclampsia (PE) is enhanced ~4-fold by the presence of maternal type 1 diabetes (T1DM). Vitamin D is essential for healthy pregnancy. We assessed the total, bioavailable, and free concentrations of plasma 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and vitamin D binding protein (VDBP) at ~12, ~22, and ~32 weeks' gestation ("Visits" (V) 1, 2, and 3, respectively) in 23 T1DM women who developed PE, 24 who remained normotensive, and 19 non-diabetic, normotensive women (reference controls). 25(OH)D deficiency was more frequent in diabetic than non-diabetic women (69% vs. 22%, p < 0.05), but no measure of 25(OH)D predicted PE. By contrast, higher 1,25(OH)2D concentrations at V2 (total, bioavailable, and free: p < 0.01) and V3 (bioavailable: p < 0.05; free: p < 0.01), lower concentrations of VDBP at V3 (p < 0.05), and elevated ratios of 1,25(OH)2D/VDBP (V2, V3: p < 0.01) and 1,25(OH)2D/25(OH)D (V3, p < 0.05) were all associated with PE, and significance persisted in multivariate analyses. In summary, in women with T1DM, concentrations of 1,25(OH)2D were higher, and VDBP lower, in the second and third trimesters in women who later developed PE than in those who did not. 1,25(OH)2D may serve as a new marker for PE risk and could be implicated in pathogenesis.

Haptoglobin Phenotype Modulates Lipoprotein-Associated Risk for Preeclampsia in Women With Type 1 Diabetes.

CONTEXT: The incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the general population), and first trimester lipoprotein profiles are predictive. Haptoglobin (Hp), a protein with functional genetic polymorphisms, has antioxidant, anti-inflammatory, and angiogenic effects. Among people with diabetes, the Hp 2-2 phenotype is associated with cardiorenal disease. OBJECTIVE: To investigate whether Hp phenotype is associated with PE in type 1 diabetes mellitus (T1DM) and/or modulates lipoprotein-associated risks. DESIGN AND SETTING: Multicenter prospective study of T1DM pregnancy. PATIENTS: Pregnant women with T1DM (normal albuminuria, normotensive at enrolment, n = 47) studied at three visits, all preceding PE onset: 12.3 ± 1.9, 21.8 ± 1.5, and 31.5 ± 1.6 weeks' gestation (mean ± SD). MAIN OUTCOME MEASURES: Hp phenotype and lipoprotein profiles in women with (n = 23) vs without (n = 24) subsequent PE. RESULTS: Hp phenotype did not predict PE, but lipoprotein associations with subsequent PE were confined to women with Hp 2-2, in whom the following associations with PE were observed: increased low-density lipoprotein (LDL) cholesterol, LDL particle concentration, apolipoprotein B (APOB), triacylglycerol/high-density lipoprotein (HDL) cholesterol ratio, and APOB/apolipoprotein AI (APOA1) ratio; decreased HDL cholesterol, APOA1, large HDL particle concentration, and peripheral lipoprotein lipolysis (all P < 0.05). In women with one or two Hp-1 alleles, no such associations were observed. CONCLUSIONS: In women with T1DM, although Hp phenotype did not predict PE risk, lipoprotein-related risks for PE were limited to those with the Hp 2-2 phenotype. Hp phenotype may modulate PE risk in diabetes.

Early Intervention for Diabetes in Medical and Surgical Inpatients Decreases Hyperglycemia and Hospital-Acquired Infections: A Cluster Randomized Trial.

OBJECTIVE: To investigate if early electronic identification and bedside management of inpatients with diabetes improves glycemic control in noncritical care. RESEARCH DESIGN AND METHODS: We investigated a proactive or early intervention model of care (whereby an inpatient diabetes team electronically identified individuals with diabetes and aimed to provide bedside management within 24 h of admission) compared with usual care (a referral-based consultation service). We conducted a cluster randomized trial on eight wards, consisting of a 10-week baseline period (all clusters received usual care) followed by a 12-week active period (clusters randomized to early intervention or usual care). Outcomes were adverse glycemic days (AGDs) (patient-days with glucose <4 or >15 mmol/L [<72 or >270 mg/dL]) and adverse patient outcomes. RESULTS: We included 1,002 consecutive adult inpatients with diabetes or new hyperglycemia. More patients received specialist diabetes management (92% vs. 15%, P < 0.001) and new insulin treatment (57% vs. 34%, P = 0.001) with early intervention. At the cluster level, incidence of AGDs decreased by 24% from 243 to 186 per 1,000 patient-days in the intervention arm (P < 0.001), with no change in the control arm. At the individual level, adjusted number of AGDs per person decreased from a mean 1.4 (SD 1.6) to 1.0 (0.9) days (-28% change [95% CI -45 to -11], P = 0.001) in the intervention arm but did not change in the control arm (1.8 [2.0] to 1.5 [1.8], -9% change [-25 to 6], P = 0.23). Early intervention reduced overt hyperglycemia (55% decrease in patient-days with mean glucose >15 mmol/L, P < 0.001) and hospital-acquired infections (odds ratio 0.20 [95% CI 0.07-0.58], P = 0.003). CONCLUSIONS: Early identification and management of inpatients with diabetes decreased hyperglycemia and hospital-acquired infections.

Subclinical First Trimester Renal Abnormalities Are Associated With Preeclampsia in Normoalbuminuric Women With Type 1 Diabetes.

OBJECTIVE: This study was conducted to determine the utility of tubular (urinary/plasma neutrophil gelatinase-associated lipocalin [NGAL] and urinary kidney injury molecule 1 [KIM-1]) and glomerular (estimated glomerular filtration rate [eGFR]) biomarkers in predicting preeclampsia (PE) in pregnant women with type 1 diabetes mellitus (T1DM) who were free of microalbuminuria and hypertension at the first trimester. RESEARCH DESIGN AND METHODS: This was a prospective study of T1DM pregnancy. Maternal urinary and plasma NGAL, urinary KIM-1 (ELISA of frozen samples), and eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) were determined at three study visits (V1: 12.4 ± 1.8; V2: 21.7 ± 1.4; V3: 31.4 ± 1.5 weeks' gestation [mean ± SD]) in 23 women with T1DM with subsequent PE (DM+PE+), 24 who remained normotensive (DM+PE-), and, for reference, in 19 normotensive pregnant women without diabetes (DM-). The groups with diabetes were matched for age, diabetes duration, and parity. All subjects were normotensive and free of microalbuminuria or albuminuria at V1. All study visits preceded the onset of PE. RESULTS: Urinary creatinine-corrected NGAL (uNGALcc, ng/mg) was significantly elevated at V1 in DM+PE+ vs. DM+PE- women (P = 0.01); this remained significant after exclusion of leukocyte-positive samples (5 DM+PE+ and 2 DM+PE-) (P = 0.02). Accounting for BMI, HbA1c, and total daily insulin dose, a doubling of uNGALcc at V1 conferred a sevenfold increase in risk for PE (P = 0.026). In contrast, neither plasma NGAL nor urinary KIM-1 predicted PE. Also at V1, eGFR was elevated in DM+PE+ vs. DM+PE- (P = 0.04). CONCLUSIONS: Early tubular and glomerular dysfunction may predict PE in first trimester women with T1DM, even if free of microalbuminuria. These data suggest that subclinical renal tubular and glomerular injury, if present early in pregnancy, may predispose women with T1DM to PE.

Recent advances in type 1 diabetes.

Type 1 diabetes (T1D) is caused by an autoimmune attack on pancreatic beta cells that leads to insulin deficiency. The incidence of T1D in Australia has doubled over the past 20 years. T1D treatment focuses on physiological insulin replacement, aiming for near-normal blood glucose levels. Hypoglycaemia is a significant cause of morbidity and mortality in T1D. Optimal T1D management is complex, and is enhanced by empowering individuals in all aspects of managing diabetes. New technologies, including insulin pumps, continuous glucose monitors and sensor-augmented pumps, can assist people achieve better glycaemic control and reduce the risk of severe hypoglycaemia. Women with T1D can achieve significantly better outcomes during pregnancy and for their infants by planning for their pregnancy and by intensive glycaemic control. Several trials are underway that seek to identify the determinants of autoimmunity and to develop therapies that prevent T1D in at-risk individuals. Pancreatic and islet cell transplants are proven therapies, but are only offered to individuals with diabetes and renal failure (pancreas) or severe hypoglycaemia unawareness (islet cell transplants). Although T1D is still associated with considerable premature mortality, recent findings show that a significant improvement in life expectancy has occurred.

Trace elements as predictors of preeclampsia in type 1 diabetic pregnancy.

Preeclampsia (PE) affects approximately 5% of all pregnancies, but is increased several-fold in women with pre-gestational type 1 diabetes mellitus (T1DM). Increased oxidative stress and altered maternal plasma trace elements that modulate the antioxidant system have been implicated in PE. In non-diabetic women, increased plasma copper and iron and decreased manganese, selenium, and zinc have been associated with PE in cross-sectional studies. In a longitudinal study, we hypothesized that plasma levels of trace elements differ between T1DM women with vs. without subsequent PE. Samples were collected during the first (gestation 12.2 ± 1.9 weeks, [mean ± SD]), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy, all before the onset of PE. We compared 23 T1DM women who subsequently developed PE with 24 T1DM women who remained normotensive; and we included 19 non-diabetic (non-DM) normotensive pregnant women as reference controls. Trace elements were measured using inductively coupled plasma mass spectroscopy. In T1DM women with subsequent PE vs normotensive, only plasma zinc was significantly higher at the first trimester, while copper:zinc and copper:high-density lipoprotein cholesterol ratios were higher throughout gestation (all P < .05). These findings persisted after adjustment for covariates. Higher copper:zinc ratios may contribute to oxidative stress in T1DM women who develop PE. Ratios of pro- to anti-oxidant factors may predict risk for PE in diabetic pregnancies more effectively than individual trace element levels.

Plasma lipoproteins and preeclampsia in women with type 1 diabetes: a prospective study.

CONTEXT: In nondiabetic pregnancy, cross-sectional studies have shown associations between maternal dyslipidemia and preeclampsia (PE). In type 1 diabetes mellitus (T1DM), the prevalence of PE is increased 4-fold, but prospective associations with plasma lipoproteins are unknown. OBJECTIVES: The aim of this study was to define lipoprotein-related markers and potential mechanisms for PE in T1DM. DESIGN AND SETTINGS: We conducted a multicenter prospective study in T1DM pregnancy. PATIENTS: We studied 118 T1DM women (26 developed PE, 92 remained normotensive). Subjects were studied at three visits before PE onset [12.2 ± 1.9, 21.6 ± 1.5, and 31.5 ± 1.7 wk gestation (means ± SD)] and at term (37.6 ± 2.0 wk). Nondiabetic normotensive pregnant women (n = 21) were included for reference. MAIN OUTCOME MEASURES: Conventional lipid profiles, lipoprotein subclasses [defined by size (nuclear magnetic resonance) and by apolipoprotein content], serum apolipoproteins (ApoAI, ApoB, and ApoCIII), and lipolysis (ApoCIII ratio) were measured in T1DM women with and without subsequent PE. RESULTS: In women with vs. without subsequent PE, at the first and/or second study visits: low-density lipoprotein (LDL)-cholesterol, particle concentrations of total LDL and large (but not small) LDL, serum ApoB, and ApoB:ApoAI ratio were all increased (P < 0.05); peripheral lipoprotein lipolysis was decreased (P < 0.01). These early differences remained significant in covariate analysis (glycated hemoglobin, actual prandial status, gravidity, body mass index, and diabetes duration) but were not present at the third study visit. High-density lipoprotein and very low-density lipoprotein subclasses did not differ between groups before PE onset. CONCLUSIONS: Early in pregnancy, increased cholesterol-rich lipoproteins and an index suggesting decreased peripheral lipolysis were associated with subsequent PE in T1DM women. Background maternal lipoprotein characteristics, perhaps masked by effects of late pregnancy, may influence PE risk.

Serum carotenoids and fat-soluble vitamins in women with type 1 diabetes and preeclampsia: a longitudinal study.

OBJECTIVE: Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy are therefore of interest. RESEARCH DESIGN AND METHODS: Maternal serum carotenoids (α- and ß-carotene, lycopene, and lutein) and vitamins A, D, and E (α- and γ-tocopherols) were measured at first (12.2 ± 1.9 weeks [mean ± SD], visit 1), second (21.6 ± 1.5 weeks, visit 2), and third (31.5 ± 1.7 weeks, visit 3) trimesters of pregnancy in 23 women with type 1 diabetes who subsequently developed PE (DM PE+) and 24 women with type 1 diabetes, matched for age, diabetes duration, HbA(1c), and parity, who did not develop PE (DM PE-). Data were analyzed without and with adjustment for baseline differences in BMI, HDL cholesterol, and prandial status. RESULTS: In unadjusted analysis, in DM PE+ versus DM PE-, α-carotene and ß-carotene were 45 and 53% lower, respectively, at visit 3 (P < 0.05), before PE onset. In adjusted analyses, the difference in ß-carotene at visit 3 remained significant. Most participants were vitamin D deficient (<20 ng/mL), and vitamin D levels were lower in DM PE+ versus DM PE- throughout the pregnancy, although this did not reach statistical significance. CONCLUSIONS: In pregnant women with type 1 diabetes, low serum α- and ß-carotene were associated with subsequent development of PE, and vitamin D deficiency may also be implicated.

Neonatal hyperinsulinaemic hypoglycaemia and monogenic diabetes due to a heterozygous mutation of the HNF4A gene.

Recent research has demonstrated that mutations of the hepatocyte nuclear factor 4-alpha (HNF4A) gene are associated with neonatal hyperinsulinaemic hypoglycaemia. Mutations of this gene also cause one of the subtypes of monogenic diabetes, a form of diabetes formerly known as maturity-onset diabetes of the young. This article describes a family discovered to have a novel frame-shift mutation of the HNF4A gene in the setting of early-onset maternal diabetes and severe neonatal hyperinsulinaemic hypoglycaemia. The implications of a diagnosis of HNF4A gene mutation for obstetric and paediatric practice are discussed.

Effectiveness and side effects of thiazolidinediones for type 2 diabetes: real-life experience from a tertiary hospital.

OBJECTIVE: To assess effectiveness and side effects of thiazolidinediones (TZDs) as adjunctive therapy in suboptimally controlled patients with type 2 diabetes. DESIGN AND SETTING: Review of a prospectively recorded database at the Royal Melbourne Hospital diabetes clinic. PARTICIPANTS: 203 patients with type 2 diabetes who received pioglitazone or rosiglitazone between 1 May 2000 and 31 October 2002. OUTCOME MEASURES: Response in glycohaemoglobin (HbA(1c)) level, lipid profile changes and side effects, including hypoglycaemia, weight gain, oedema and precipitation of cardiac failure. RESULTS: Both pioglitazone and rosiglitazone improved glycaemic control, with a reduction in the HbA(1c) level of 1.02% (range, 0.85%-1.19%) and 0.96% (range, 0.81%-1.11%), respectively, in the first 6 months of therapy. Rosiglitazone was associated with a 0.45 mmol (range, 0.31-0.59 mmol) increase in cholesterol level and 0.99 mmol (range, 0.60-1.38 mmol) increase in triglyceride level, while pioglitazone was associated with insignificant declines in cholesterol and triglyceride levels. There was reduced requirement for insulin, but not for oral hypoglycaemic agent (OHA), in most patients who used these agents. Pioglitazone and rosiglitazone were associated with increased rates of hypoglycaemia (17% and 11% of patients, respectively), significant weight gain (48% and 58%) and oedema (33% and 21%). There were four cases of acute left ventricular failure and two cases of reversible liver dysfunction in patients treated with TZDs. CONCLUSIONS: Adding pioglitazone or rosiglitazone therapy to OHA or insulin in patients with type 2 diabetes significantly improved glycaemic control. However, the use of these drugs in routine clinical practice was associated with more frequent adverse events than previously reported in clinical trials.