David R. McCance

Hyperglycemia and adverse pregnancy outcomes

BACKGROUND It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. METHODS A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. RESULTS For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker. CONCLUSIONS Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels.

Birth weight and non-insulin dependent diabetes : Thrifty genotype, thrifty phenotype, or surviving small baby genotype?

Abstract Objective : To determine the prevalence of diabetes in relation to birth weight in Pima Indians. Design : Follow up study of infants born during 1940-72 who had undergone a glucose tolerance test at ages 20-39 years. Setting : Gila River Indian community, Arizona. Subjects : 1179 American Indians. Main outcome measure: Prevalence of non-insulin dependent diabetes mellitus (plasma glucose concentration >=11.1 mmol/l two hours after ingestion of carbohydrate). Results : The prevalence was greatest in those with the lowest and highest birth weights. The age adjusted prevalences for birth weights <2500 g, 2500-4499 g, and >=4500 g were 30%, 17%, and 32%, respectively. When age, sex, body mass index, maternal diabetes during pregnancy, and birth year were controlled for, subjects with birth weights <2500 g had a higher rate than those with weights 2500-4499 g (odds ratio 3.81; 95% confidence interval 1.70 to 8.52). The risk for subsequent diabetes among higher birthweight infants (>=4500 g) was associated with maternal diabetes during pregnancy. Most diabetes, however, occurred in subjects with intermediate birth weights (2500-4500 g). Conclusions : The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes. Low birth weight is associated with non-insulin dependent diabetes. Given the high mortality of low birthweight infants selective survival in infancy of those genetically predisposed to insulin resistance and diabetes provides an explanation for the observed relation between low birth weight and diabetes and the high prevalence of diabetes in many populations.

The Hyperglycemia and Adverse Pregnancy Outcome Study: Associations of GDM and obesity with pregnancy outcomes

OBJECTIVE To determine associations of gestational diabetes mellitus (GDM) and obesity with adverse pregnancy outcomes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. RESEARCH DESIGN AND METHODS Participants underwent a 75-g oral glucose tolerance test (OGTT) between 24 and 32 weeks. GDM was diagnosed post hoc using International Association of Diabetes and Pregnancy Study Groups criteria. Neonatal anthropometrics and cord serum C-peptide were measured. Adverse pregnancy outcomes included birth weight, newborn percent body fat, and cord C-peptide >90th percentiles, primary cesarean delivery, preeclampsia, and shoulder dystocia/birth injury. BMI was determined at the OGTT. Multiple logistic regression was used to examine associations of GDM and obesity with outcomes. RESULTS Mean maternal BMI was 27.7, 13.7% were obese (BMI ≥33.0 kg/m2), and GDM was diagnosed in 16.1%. Relative to non-GDM and nonobese women, odds ratio for birth weight >90th percentile for GDM alone was 2.19 (1.93–2.47), for obesity alone 1.73 (1.50–2.00), and for both GDM and obesity 3.62 (3.04–4.32). Results for primary cesarean delivery and preeclampsia and for cord C-peptide and newborn percent body fat >90th percentiles were similar. Odds for birth weight >90th percentile were progressively greater with both higher OGTT glucose and higher maternal BMI. There was a 339-g difference in birth weight for babies of obese GDM women, compared with babies of normal/underweight women (64.2% of all women) with normal glucose based on a composite OGTT measure of fasting plasma glucose and 1- and 2-h plasma glucose values (61.8% of all women). CONCLUSIONS Both maternal GDM and obesity are independently associated with adverse pregnancy outcomes. Their combination has a greater impact than either one alone.

Beta‐cell deterioration determines the onset and rate of progression of secondary dietary failure in Type 2 diabetes mellitus: the 10‐year follow‐up of the Belfast Diet Study

Secondary failure of plasma glucose control following initial successful response to diet therapy may be due to dietary indiscretion, or to progression of the intrinsic diabetic condition. We report a 10‐year prospective natural history study of 432 newly diagnosed diabetic patients aged 40–69 years undertaken to assess the effect of intensive dietary management, where patients were transferred to insulin, or oral hypoglycaemic therapy (tolbutamide, metformin) by predetermined criteria of weight and plasma glucose. Secondary failure to diet therapy occurred in 41 patients in years 2–4, 67 patients in years 5–7, and 51 patients in years 8–10; 173 patients remained on diet alone until death or the end of the study. Continuation on diet alone was associated with a lower ongoing fasting plasma glucose, greater beta‐cell function assessed by an oral glucose tolerance test at 6 months, and increasing age. The rate of rise of fasting plasma glucose was inversely related to the duration of successful dietary therapy, but mean weight remained constant in all groups while on diet alone. The ongoing fall in beta‐cell function assessed by HOMA modelling closely mirrored the progressive rise in fasting plasma glucose: there was no change in mean insulin sensitivity in any of the groups.

Long-term remission rates after pituitary surgery for Cushing's disease: the need for long-term surveillance

Objective  There have been a few reports on long‐term remission rates after apparent early remission following pituitary surgery in the management of Cushings disease. An undetectable postoperative serum cortisol has been regarded as the result most likely to predict long‐term remission. Our objective was to assess the relapse rates in patients who underwent transsphenoidal surgery in order to determine whether undetectable cortisol following surgery was predictive of long‐term remission and whether it was possible to have long‐term remission when early morning cortisol was measurable but not grossly elevated. Endocrinological factors associated with late relapse were also studied.

Ascorbic Acid Reduces Blood Pressure and Arterial Stiffness in Type 2 Diabetes

Abstract—Experimental evidence suggests that acute parenteral administration of high-dose ascorbic acid has beneficial vascular effects in type 2 diabetes. We studied the hemodynamic effects of chronic oral supplementation in this condition. Thirty patients, 45 to 70 years of age, with type 2 diabetes, were randomly assigned in a double-blind manner to receive 500 mg ascorbic acid daily by mouth or placebo. Patients were studied at baseline and after 4 weeks of assigned treatment. The central aortic augmentation index (AgIx) and the time to wave reflection (Tr) were derived from radial artery pulse wave analysis data. AgIx and Tr were used as measures of systemic arterial stiffness and aortic stiffness, respectively. Ascorbic acid decreased brachial systolic blood pressure from 142.1±12.6 (SD) to 132.3±12.1 mm Hg (difference [95% CI] 9.9 [4.7, 15.0];P <0.01), brachial diastolic pressure from 83.9±4.8 to 79.5±6.0 mm Hg (4.4 [1.8, 7.0];P <0.01), and AgIx from 26.8±5.5% to 22.5±6.8% (4.3 [1.5, 7.1];P <0.01). Tr increased from 137.1±12.6 to 143.4±9.2 ms (−6.3 [−10.1, −2.5];P <0.01). Placebo had no hemodynamic effects, and this difference between treatments was significant (P <0.01 for blood pressure and Tr, P =0.03 for AgIx). We have therefore shown that after 1 month, oral ascorbic acid lowered arterial blood pressure and improved arterial stiffness in patients with type 2 diabetes. As strict control of blood pressure reduces cardiovascular risk in diabetes, ascorbic acid supplementation may potentially be a useful and inexpensive adjunctive therapy. Larger and longer studies now need to be performed.

Maternal Glycemic Control and Hypoglycemia in Type 1 Diabetic Pregnancy: A randomized trial of insulin aspart versus human insulin in 322 pregnant women

OBJECTIVE—To assess the safety and efficacy of insulin aspart (IAsp) versus regular human insulin (HI) in basal-bolus therapy with NPH insulin in pregnant women with type 1 diabetes. RESEARCH DESIGN AND METHODS—Subjects (n = 322) who were pregnant or planning pregnancy were randomized to IAsp or HI as meal-time insulin in an open-label, parallel-group, multicenter study. Subjects had A1C ≤8% at confirmation of pregnancy. Insulin doses were titrated toward predefined glucose targets and A1C <6.5%. Outcomes assessed included risk of major maternal hypoglycemia, A1C, plasma glucose profiles, and maternal safety outcomes. RESULTS—Major hypoglycemia occurred at a rate of 1.4 vs. 2.1 episodes/year exposure with IAsp and HI, respectively (relative risk 0.720 [95% CI 0.36–1.46]). Risk of major/major nocturnal hypoglycemia was 52% (RR 0.48 [0.20–1.143]; P = NS) lower with IAsp compared with HI. A1C was comparable with human insulin in second (IAsp-HI −0.04 [−0.18 to 0.11]) and third (−0.08 [−0.23 to 0.06]) trimesters. A total of 80% of subjects achieved an A1C ≤6.5%. At the end of first and third trimesters, average postprandial plasma glucose increments were significantly lower with IAsp than HI (P = 0.003 and P = 0.044, respectively), as were mean plasma glucose levels 90 min after breakfast (P = 0.044 and P = 0.001, respectively). Maternal safety profiles and pregnancy outcomes were similar between treatments. CONCLUSIONS—IAsp is at least as safe and effective as HI when used in basal-bolus therapy with NPH insulin in pregnant women with type 1 diabetes and may potentially offer some benefits in terms of postprandial glucose control and preventing severe hypoglycemia.

Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: Associations of maternal A1C and glucose with pregnancy outcomes

OBJECTIVE To compare associations of maternal glucose and A1C with adverse outcomes in the multinational Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and determine, based on those comparisons, if A1C measurement can provide an alternative to an oral glucose tolerance test (OGTT) in pregnant women. RESEARCH DESIGN AND METHODS Eligible pregnant women underwent a 75-g OGTT at 24–32 weeks’ gestation. A sample for A1C was also collected. Neonatal anthropometrics and cord serum C-peptide were measured. Associations with outcomes were assessed using multiple logistic regression with adjustment for potential confounders. RESULTS Among 23,316 HAPO Study participants with glucose levels blinded to caregivers, 21,064 had a nonvariant A1C result. The mean ± SD A1C was 4.79 ± 0.40%. Associations were significantly stronger with glucose measures than with A1C for birth weight, sum of skinfolds, and percent body fat >90th percentile and for fasting and 1-h glucose for cord C-peptide (all P < 0.01). For example, in fully adjusted models, odds ratios (ORs) for birth weight >90th percentile for each measure higher by 1 SD were 1.39, 1.45, and 1.38, respectively, for fasting, 1-, and 2-h plasma glucose and 1.15 for A1C. ORs for cord C-peptide >90th percentile were 1.56, 1.45, and 1.35 for glucose, respectively, and 1.32 for A1C. ORs were similar for glucose and A1C for primary cesarean section, preeclampsia, and preterm delivery. CONCLUSIONS On the basis of associations with adverse outcomes, these findings suggest that A1C measurement is not a useful alternative to an OGTT in pregnant women.

Age-dependent increase in ortho-tyrosine and methionine sulfoxide in human skin collagen is not accelerated in diabetes. Evidence against a generalized increase in oxidative stress in diabetes

The glycoxidation products Nepsilon-(carboxymethyl)lysine and pentosidine increase in skin collagen with age and at an accelerated rate in diabetes. Their age-adjusted concentrations in skin collagen are correlated with the severity of diabetic complications. To determine the relative roles of increased glycation and/or oxidation in the accelerated formation of glycoxidation products in diabetes, we measured levels of amino acid oxidation products, distinct from glycoxidative modifications of amino acids, as independent indicators of oxidative stress and damage to collagen in aging and diabetes. We show that ortho-tyrosine and methionine sulfoxide are formed in concert with Nepsilon-(carboxymethyl)lysine and pentosidine during glycoxidation of collagen in vitro, and that they also increase with age in human skin collagen. The age-adjusted levels of these oxidized amino acids in collagen was the same in diabetic and nondiabetic subjects, arguing that diabetes per se does not cause an increase in oxidative stress or damage to extracellular matrix proteins. These results provide evidence for an age-dependent increase in oxidative damage to collagen and support previous conclusions that the increase in glycoxidation products in skin collagen in diabetes can be explained by the increase in glycemia alone, without invoking a generalized, diabetes-dependent increase in oxidative stress.

Dietary Intake of Fruits and Vegetables Improves Microvascular Function in Hypertensive Subjects in a Dose-Dependent Manner

Background— Observational evidence has consistently linked increased fruit and vegetable consumption with reduced cardiovascular morbidity; however, there is little direct trial evidence to support the concept that fruit and vegetable consumption improves vascular function. This study assessed the dose-dependent effects of a fruit and vegetable intervention on arterial health in subjects with hypertension. Methods and Results— After a 4-week run-in period during which fruit and vegetable intake was limited to 1 portion per day, participants were randomized to consume either 1, 3, or 6 portions daily for the next 8 weeks. Endothelium-dependent and -independent arterial vasodilator responses were assessed by venous occlusion plethysmography in the brachial circulation before and after intervention. Compliance was monitored with serial contemporaneous 4-day food records and by measuring concentrations of circulating dietary biomarkers. A total of 117 volunteers completed the 12-week study. Participants in the 1-, 3-, and 6-portions/d groups reported consuming on average 1.1, 3.2, and 5.6 portions of fruit and vegetables, respectively, and serum concentrations of lutein and &bgr;-cryptoxanthin increased across the groups in a dose-dependent manner. For each 1-portion increase in reported fruit and vegetable consumption, there was a 6.2% improvement in forearm blood flow responses to intra-arterial administration of the endothelium-dependent vasodilator acetylcholine (P=0.03). There was no association between increased fruit and vegetable consumption and vasodilator responses to sodium nitroprusside, an endothelium-independent vasodilator. Conclusions— The present study illustrates that among hypertensive volunteers, increased fruit and vegetable consumption produces significant improvements in an established marker of endothelial function and cardiovascular prognosis.