James D. Walker

Na+/H+ Antiport Activity and Cell Growth in Cultured Skin Fibroblasts of IDDM Patients With Nephropathy

IDDM patients with incipient and overt nephropathy have been found to exhibit an overactivity of RBC sodium-lithium countertransport. To explore the physiological relevance of this finding, we measured the activity of Na+/H+ antiport in serially passaged cultured skin fibroblasts from IDDM patients with and without nephropathy and from normal, nondiabetic control subjects. Na+/H+ antiport activity (measured as the rate of amiloride-sensitive Na+ influx at pH1 = 6.4, extracellular pH = 8.0, and [Na+] = 1 mM) was elevated significantly in IDDM patients with nephropathy compared with IDDM patients without nephropathy and nondiabetic control subjects (13.35 ± 3.8 vs. 8.54 ± 2.0 vs. 7.33 ± 2.3 nmol Na+ · mg protein−1 · min−1; P < 0.006 and P < 0.001, respectively). A kinetic analysis of Na+/H+ antiport activity showed that the raised activity in IDDM patients with nephropathy was caused by an increased Vmax for extracellular Na+. Km values were similar in the three groups. pH-stimulated amiloride-sensitive Na+ influx also was higher under baseline conditions and after serum stimulation in cells from IDDM patients with nephropathy. pHI values were significantly higher, both during active proliferation and after 10-min exposure to serum, in cells from IDDM patients with nephropathy, compared with IDDM patients without nephropathy and nondiabetic control subjects. Serum-stimulated incorporation of [3H]thymidine into DNA was greater in IDDM patients with nephropathy than in the other two groups (35.7 ± 18.9- vs. 17.4 ± 7.5- vs. 11.9 ± 8.7-fold stimulation above baseline; P < 0.01 for both). These data from cultured skin fibroblasts suggest that intrinsic abnormalities in cell function, independent of the metabolic disturbances of diabetes, are characteristic of IDDM patients who develop nephropathy.

Optimal Glycemic Control, Pre-eclampsia, and Gestational Hypertension in Women With Type 1 Diabetes in the Diabetes and Pre-eclampsia Intervention Trial

OBJECTIVE To assess the relationship between glycemic control, pre-eclampsia, and gestational hypertension in women with type 1 diabetes. RESEARCH DESIGN AND METHODS Pregnancy outcome (pre-eclampsia or gestational hypertension) was assessed prospectively in 749 women from the randomized controlled Diabetes and Pre-eclampsia Intervention Trial (DAPIT). HbA1c (A1C) values were available up to 6 months before pregnancy (n = 542), at the first antenatal visit (median 9 weeks) (n = 721), at 26 weeks’ gestation (n = 592), and at 34 weeks’ gestation (n = 519) and were categorized as optimal (<6.1%: referent), good (6.1–6.9%), moderate (7.0–7.9%), and poor (≥8.0%) glycemic control, respectively. RESULTS Pre-eclampsia and gestational hypertension developed in 17 and 11% of pregnancies, respectively. Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy compared with women who did not develop pre-eclampsia (P < 0.05, respectively). In early pregnancy, A1C ≥8.0% was associated with a significantly increased risk of pre-eclampsia (odds ratio 3.68 [95% CI 1.17–11.6]) compared with optimal control. At 26 weeks’ gestation, A1C values ≥6.1% (good: 2.09 [1.03–4.21]; moderate: 3.20 [1.47–7.00]; and poor: 3.81 [1.30–11.1]) and at 34 weeks’ gestation A1C values ≥7.0% (moderate: 3.27 [1.31–8.20] and poor: 8.01 [2.04–31.5]) significantly increased the risk of pre-eclampsia compared with optimal control. The adjusted odds ratios for pre-eclampsia for each 1% decrement in A1C before pregnancy, at the first antenatal visit, at 26 weeks’ gestation, and at 34 weeks’ gestation were 0.88 (0.75–1.03), 0.75 (0.64–0.88), 0.57 (0.42–0.78), and 0.47 (0.31–0.70), respectively. Glycemic control was not significantly associated with gestational hypertension. CONCLUSIONS Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy. These data suggest that optimal glycemic control both early and throughout pregnancy may reduce the risk of pre-eclampsia in women with type 1 diabetes.

Programming of Adiposity in Offspring of Mothers With Type 1 Diabetes at Age 7 Years

OBJECTIVE The goals of this study were to examine the influence of maternal type 1 diabetes during pregnancy on offspring adiposity and glucose tolerance at age 7 years and to assess whether metabolic factors at birth (neonatal leptin and insulin) predict adverse outcomes. RESEARCH DESIGN AND METHODS We examined 100 offspring of mothers with type 1 diabetes (OT1DM) and 45 offspring of control mothers. Mothers had previously been recruited during pregnancy, and, where possible, birth weight, umbilical cord insulin, and leptin were measured. Children were classed as overweight and obese using age-specific reference ranges. RESULTS OT1DM had similar height (control, 1.25 ± 0. 06 m; OT1DM, 1.24 ± 0.06 m; P = 0.81) but were heavier (control, 25.5 ± 3.8 kg; OT1DM, 27.1 ± 5.7 kg; P = 0.048) and had an increased BMI (control, 16.4 kg/m2; OT1DM, 17.4 ± 2.6 kg/m2, P = 0.005). Waist circumference (control, 56.0 ± 3.7 cm; OT1DM, 58 ± 6.8 cm; P = 0.02) and sum of skinfolds were increased (control, 37.5 ± 17.0 mm [n = 42]; OT1DM, 46.1 ± 24.2 mm [n = 91]; P = 0.02), and there was a marked increase in the prevalence of overweight and obese children (OT1DM, 22% overweight and 12% obese; control, 0% overweight and 7% obese; χ2 P = 0.001). Glucose tolerance was not different compared with that in control subjects. BMI at age 7 years correlated with cord leptin (OT1DM, r = 0.25; n = 61, P = 0.047), weakly with adjusted birth weight (r = 0.19; P = 0.06) and hematocrit (r = 0.25; n = 50, P = 0.07), but not cord insulin (OT1DM, r = −0.08; P = 0.54). CONCLUSIONS OT1DM are at increased risk of overweight and obesity in childhood. This risk appears to relate, in part, to fetal leptin and hematocrit but not insulin.

The relation of insulin, leptin and IGF-1 to birthweight in offspring of women with type 1 diabetes

objective  Maternal diabetes is associated with excess foetal growth. We have assessed the influence of maternal diabetes on hormones associated with foetal growth and the relationship of these hormones to birthweight.

The Diabetes and Pre-eclampsia Intervention Trial.

Rates of pre‐eclampsia in women with type 1 diabetes are two to four times higher than in normal pregnancies. Diabetes is associated with antioxidant depletion and increased free radical production, and an increasing body of evidence suggests that oxidative stress and endothelial cell activation may be relevant to disease pathogenesis in pre‐eclampsia. The Diabetes and Pre‐eclampsia Intervention Trial (DAPIT) aims to establish if pregnant women with type 1 diabetes supplemented with vitamins C and E have lower rates of pre‐eclampsia and endothelial activation compared with placebo treatment. Methods: DAPIT is a randomised multicentre double‐blind placebo‐controlled trial that will recruit 756 pregnant women with type 1 diabetes from 20 metabolic‐antenatal clinics in the UK over 4 years. Women are randomised to daily vitamin C (1000 mg) and vitamin E (400 IU) or placebo at 8–22 weeks of gestation until delivery. Maternal venous blood is obtained at randomisation, 26 and 34 weeks, for markers of endothelial activation and oxidative stress and to assess glycaemic control. The primary outcome of DAPIT is pre‐eclampsia. Secondary outcomes include endothelial activation (PAI‐1/PAI‐2) and birthweight centile.

The Role of Angiogenic and Antiangiogenic Factors in the Second Trimester in the Prediction of Preeclampsia in Pregnant Women With Type 1 Diabetes

OBJECTIVE To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes. RESEARCH DESIGN AND METHODS Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial. RESULTS Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120–423] vs. 365 pg/mL [237–582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108–3,393] vs. 1,193 pg/mL [844–1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9–7.9] vs. 5.1 ng/mL[(4.3–6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17–71] vs. 71 [44–114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4–15.7] vs. 3.1 [1.8–5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001). CONCLUSIONS These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes.

Transient Improvement in Glycemic Control: The impact of pregnancy in women with IDDM

OBJECTIVE Good glycemic control throughout pregnancy in patients with diabetes is of paramount importance but often appears to deteriorate in the postpartum period. The aim of this study was to ascertain the timing of the improvement in glycemic control associated with pregnancy in women with IDDM and to examine changes in glycemic control after delivery. RESEARCH DESIGN AND METHODS Peripartum glycemic control was assessed in a retrospective study of 30 women with IDDM whose age was 28 ± 6 years (means ± SD) and whose diabetes duration was 14 ± 6 years. RESULTS Mean total HbA1 fell incrementally from a peak at 2–3 years preconception to a nadir between 24 weeks and term, only to return to preconception levels within a year after delivery. Of the 30 women, 15 (50%) attained an HbA1 in the nondiabetic range for pregnancy at some point during their pregnancy, and 7 (23%) women achieved this by 24 weeks gestation. Women with an HbA1 > 9% at booking had a significantly higher HbA1 at 0–6 and 6–12 months preconception, and throughout pregnancy their HbA1 was significantly higher. After delivery, attendance rates at routine diabetes review clinics were low, with 11% of women not attending for longer than 24 months. CONCLUSIONS Nearly all women with IDDM can achieve near normoglycemia during pregnancy, irrespective of previous glycemic control, although those with high HbA1 levels at booking are less likely to achieve this. After delivery, glycemic control deteriorates. Efforts to improve glycemic control should be intensified in the preconception period and maintained after delivery. The poor postpartum attendance at diabetes clinics requires specific action.

Severe hypercalcaemia secondary to isolated adrenocorticotrophic hormone deficiency and subacute thyroiditis

Severe hypercalcaemia is usually due to either neoplastic disease or primary hyperparathyroidism. Rarer causes do exist, and exceptionally these may occur concomitantly. We describe the case of a 45-year-old man who presented in a debilitated state with severe hypercalcaemia (total serum calcium 3·56 mmol/L, albumin 35 g/L) and suppressed serum parathyroid hormone concentration. It was initially suspected that he had neoplastic disease, but routine thyroid function tests demonstrated evidence of thyrotoxicosis [thyroid-stimulating hormone <0·05 mU/L (0·15-3·5); free thyroxine 75 pmol/L (8-27); total tri-iodothyronine 7·0 nmol/L (1·0-2·6)], which was probably secondary to a silent or subacute thyroiditis. After extensive investigation, it was established that the patient also had isolated adrenocorticotrophic hormone deficiency, presumably secondary to lymphocytic hypophysitis. Glucocorticoid therapy resulted in a dramatic improvement in the patients clinical state and 1 year later he remained euthyroid and normocalcaemic.

Serum Fatty Acid Binding Protein 4 (FABP4) Predicts Pre-eclampsia in Women With Type 1 Diabetes

OBJECTIVE To examine the association between fatty acid binding protein 4 (FABP4) and pre-eclampsia risk in women with type 1 diabetes. RESEARCH DESIGN AND METHODS Serum FABP4 was measured in 710 women from the Diabetes and Pre-eclampsia Intervention Trial (DAPIT) in early pregnancy and in the second trimester (median 14 and 26 weeks’ gestation, respectively). RESULTS FABP4 was significantly elevated in early pregnancy (geometric mean 15.8 ng/mL [interquartile range 11.6–21.4] vs. 12.7 ng/mL [interquartile range 9.6–17]; P < 0.001) and the second trimester (18.8 ng/mL [interquartile range 13.6–25.8] vs. 14.6 ng/mL [interquartile range 10.8–19.7]; P < 0.001) in women in whom pre-eclampsia later developed. Elevated second-trimester FABP4 level was independently associated with pre-eclampsia (odds ratio 2.87 [95% CI 1.24–6.68], P = 0.03). The addition of FABP4 to established risk factors significantly improved net reclassification improvement at both time points and integrated discrimination improvement in the second trimester. CONCLUSIONS Increased second-trimester FABP4 independently predicted pre-eclampsia and significantly improved reclassification and discrimination. FABP4 shows potential as a novel biomarker for pre-eclampsia prediction in women with type 1 diabetes.

Lipoatrophy With Human Insulin

We describe a case of lipoatrophy that was secondary to human insulin. The patient had only ever been treated with human insulin, and the lipoatrophy appeared to partially resolve with continued use of the same insulin preparations. Possible underlying pathogenic mechanisms are discussed.