Pregnancy in Diabetes: challenges and opportunities for improving pregnancy outcomes.

Our aim was to review the data from the National Pregnancy in Diabetes (NPID) audit, and to identify the challenges and opportunities for improving pregnancy outcomes in women with diabetes. We reviewed three years of NPID data and relevant diabetes and obstetric literature, and found that there has been little change in pregnancy preparation or outcomes over the past 3 years, with substantial clinic-to clinic variations in care. Women with Type 2 diabetes remain less likely to take 5 mg preconception folic acid (22.8% vs. 41.8%; P < 0.05), and more likely to take potentially harmful medications (statin and/or ACE inhibitor 13.0% vs. 1.8%; P < 0.05) than women with Type 1 diabetes. However, women with Type 1 diabetes are less likely to achieve the recommended glucose control target of HbA1c < 48 mmol/mol (6.5%) (14.9% vs. 38.1%; P < 0.05). The following opportunities for improvement were identified. First, the need to integrate reproductive health into the diabetes care plans of all women with diabetes aged 15-50 years. Second, to develop more innovative approaches to improve uptake of pre-pregnancy care in women with Type 2 diabetes in primary care settings. Third, to integrate insulin pump, continuous glucose monitoring and automated insulin delivery technologies into the pre-pregnancy and antenatal care of women with Type 1 diabetes. Fourth, to improve postnatal care with personalized approaches targeting women with previous pregnancy loss, congenital anomaly and perinatal mortality. A nationwide commitment to delivering integrated reproductive and diabetes healthcare interventions is needed to improve the health outcomes of women with diabetes.

Plasma free fatty acids do not provide the link between obesity and insulin resistance or ß-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study.

AIMS: To investigate the relationship between adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and ß-cell function. METHODS: An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made between insulin sensitivity index, acute insulin response to glucose and disposition index and both adiposity measures (BMI, waist circumference and body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. RESULTS: After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: ß = -0.357; waist circumference: ß = -0.380; body fat mass: ß = -0.375) and disposition index (BMI: ß = -0.215; waist circumference: ß = -0.248; body fat mass: ß = -0.221) and positively associated with acute insulin response to glucose [BMI: ß = 0.200; waist circumference: ß = 0.195; body fat mass ß = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, but total plasma free fatty acid level was inversely associated with insulin sensitivity index (ß = -0.133), acute insulin response to glucose (ß = -0.148) and disposition index [ß = -0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. CONCLUSIONS: Plasma free fatty acid levels have a modest negative association with insulin sensitivity, ß-cell secretion and disposition index but no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or ß-cell dysfunction.

Development and evaluation of a standardized registry for diabetes in pregnancy using data from the Northern, North West and East Anglia regional audits.

OBJECTIVES: To develop and evaluate a standardized data set for measuring pregnancy outcomes in women with Type 1 and Type 2 diabetes and to compare recent outcomes with those of the 2002-2003 Confidential Enquiry into Maternal and Child Health. METHODS: Existing regional, national and international data sets were compared for content, consistency and validity to develop a standardized data set for diabetes in pregnancy of 46 key clinical items. The data set was tested retrospectively using data from 2007-2008 pregnancies included in three regional audits (Northern, North West and East Anglia). Obstetric and neonatal outcomes of pregnancies resulting in a stillbirth or live birth were compared with those from the same regions during 2002-2003. RESULTS: Details of 1381 pregnancies, 812 (58.9%) in women with Type 1 diabetes and 556 (40.3%) in women with Type 2 diabetes, were available to test the proposed standardized data set. Of the 46 data items proposed, only 16 (34.8%), predominantly the delivery and neonatal items, achieved ≥ 85% completeness. Ethnic group data were available for 746 (54.0%) pregnancies and BMI for 627 (46.5%) pregnancies. Glycaemic control data were most complete-available for 1217 pregnancies (88.1%), during the first trimester. Only 239 women (19.9%) had adequate pregnancy preparation, defined as pre-conception folic acid and first trimester HbA(1c) ≤ 7% (≤ 53 mmol/mol). Serious adverse outcome rates (major malformation and perinatal mortality) were 55/1000 and had not improved since 2002-2003. CONCLUSIONS: A standardized data set for diabetes in pregnancy may improve consistency of data collection and allow for more meaningful evaluation of pregnancy outcomes in women with pregestational diabetes.

Increasing the proportion of plasma MUFA, as a result of dietary intervention, is associated with a modest improvement in insulin sensitivity.

The effect of modifying dietary fatty acid (FA) composition on insulin sensitivity remains unclear. We aimed to investigate whether changes in plasma phospholipid (PL) FA composition, as a result of dietary intervention, correspond with changes in insulin sensitivity. The RISCK study was a 6-month randomised controlled dietary intervention study, which assessed the effect of modifying dietary fat and the glycaemic index (GI) of carbohydrates on insulin sensitivity. Total NEFA levels, fasting plasma PL FA profiles and an insulin sensitivity index (Si), derived from intravenous glucose tolerance minimal-model analysis, were available from 533 participants, all at elevated risk of type 2 diabetes. Bivariate correlations between changes in saturated PL FA (SFA), MUFA (as a percentage of total plasma NEFA) and changes in Si were assessed according to treatment group. Age, sex, ethnicity, percentage change in body mass and change in dietary GI were controlled for. Increasing total NEFA concentration was associated with worsening Si (r -0·152; P = 0·001). In the high-MUFA/low-GI diet group, change in PL-MUFA was positively and independently associated with change in Si (r 0·297; P = 0·002). Among MUFA, change in oleic acid (18 : 1) was most strongly correlated with change in Si (r 0·266; P = 0·005), as was change in minor FA 24 : 1 (r 0·244; P = 0·011) and 17 : 1 (r 0·196; P = 0·042). In the high-SFA/high-GI group, change in SFA concentration was not significantly associated with change in Si. In conclusion, increases in the proportion of plasma PL-MUFA following a high-MUFA dietary intervention were associated with improvements in insulin sensitivity.

Transferring to insulin detemir from NPH insulin or insulin glargine in type 2 diabetes patients on basal-only therapy with oral antidiabetic drugs improves glycaemic control and reduces weight gain and risk of hypoglycaemia: 14-week follow-up data from PREDICTIVE.

AIM: The aim of this study was to evaluate the safety and efficacy of insulin detemir in type 2 diabetes patients previously receiving NPH insulin (NPH group, n = 175) or insulin glargine (glargine group, n = 118) in combination with oral antidiabetic drugs (OADs). METHODS: Patients were transferred to insulin detemir, while the OAD regimen and number of injections remained the same. The incidence of serious adverse drug reactions, including major hypoglycaemia, and haemoglobin A(1c) (HbA(1c)), fasting glucose, within-patient fasting glucose variability and body weight change were measured at 14 weeks. RESULTS: Glycaemic control improved in both NPH (HbA(1c) = -0.2%, p < 0.05; fasting glucose -1.0 mmol/l, p < 0.0001) and glargine (HbA(1c) = -0.6%, p < 0.0001; fasting glucose -1.4 mmol/l, p < 0.0001) groups, including a reduction in fasting glucose variability (p < 0.01 for both). The incidence of total and nocturnal hypoglycaemia was reduced in both NPH and glargine groups. The incidence of major hypoglycaemia was low and did not change significantly during the follow-up period. Mean body weight was significantly reduced in the NPH (-0.7 kg, p < 0.01) and glargine (-0.5 kg, p < 0.05) groups. CONCLUSIONS: These results indicate that in type 2 diabetes, transferring from other basal insulins to insulin detemir in combination with OADs was associated with improvements in glycaemic control, which were accompanied by a reduced risk of hypoglycaemia and a reduction in body weight.

The effect of a 12-week low glycaemic index diet on heart disease risk factors and 24 h glycaemic response in healthy middle-aged volunteers at risk of heart disease: a pilot study.

OBJECTIVE: To compare the effects of two energy-restricted healthy diets, one with a low GI and one with a high GI, on heart disease risk factors and weight loss in subjects at risk of heart disease. DESIGN: A 12-week randomized parallel study of low and high GI, healthy eating diets was carried out. SETTING: The study was carried out at the Hammersmith Hospital. SUBJECTS: Eighteen subjects were recruited by advertisement and randomized to one of the two diets. Fourteen completed the study but one was excluded from the final analysis. METHODS: At randomization, subjects were advised to follow the intervention diet for 12 weeks. Before randomization and on completion of the study, anthropometrics, fasting cholesterol and glucose blood tests and 24-h glucose measurements were taken using a continuous glucose monitoring system (CGMS). Statistical analysis was carried out using non-parametric tests. Median (IQR) are presented. RESULTS: A significantly different dietary GI was achieved in the low GI (median: 51.3 (IQR: 51.0-52.0) compared to the high GI (59.3 (59.2-64.0) (P=0.032) group. By week 12, both groups reduced their energy intake by: low GI group: (-)167 ((-)312-(-)123) kcal/day (P=0018) vs high GI group: (-)596 ((-)625-(-)516) (P=0.018) kcal/day, the difference between the groups being significant (P=0.010). However, only the low GI group lost weight ((-)4.0 ((-)4.4-(-)2.4) kg (P=0.018) whereas the high GI group did not significantly change in weight ((-)1.5 ((-)3.6-0.8) kg (P=0.463). By week 12, the low GI group also had a significantly lower 24-h area under the curve (AUC) (7556 (7315-8434) vs 8841 (8424-8846) mmol-h/l (P=0.045) and overnight AUC (2429 (2423-2714) vs 3000 (2805-3072) mmol-h/l (P=0.006) glucose as measured by CGMS. There were no differences in the other heart disease risk factors assessed. CONCLUSIONS: This pilot study provides some evidence that consuming a low GI diet in addition to weight loss and healthy eating may reduce cardiovascular risk. Other potential benefits of GI might have been masked by weight loss in the low GI group. Larger-scale studies need to follow.

Insulin detemir improves glycaemic control without weight gain in insulin-naïve patients with type 2 diabetes: subgroup analysis from the PREDICTIVE study.

OBJECTIVE: Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation (PREDICTIVE) is a multi-national, open-label, prospective, observational study assessing the safety and efficacy of insulin detemir in clinical practice. This post hoc subanalysis evaluates insulin-naïve patients on oral antidiabetic drugs (OADs) who were initiated on insulin detemir as basal therapy (+/- OADs). METHODS: The European cohort of the PREDICTIVE study currently includes 20,531 patients (12,981 with type 2 diabetes) who were prescribed insulin detemir and followed up for 12, 26 or 52 weeks. Here, we report data from a subgroup of 2377 OAD-treated, insulin-naïve type 2 diabetes patients for a mean follow-up of 14.4 weeks. Patients were prescribed insulin detemir as basal therapy (+/- OADs) by their physician, as part of routine clinical care. Results were reported in comparison with baseline observations. RESULTS: One serious adverse drug reaction was reported, which was a major hypoglycaemic episode. Treatment with insulin detemir (+/- OADs) significantly reduced mean haemoglobin A(1c) (HbA(1c)) (-1.3%; p < 0.0001), fasting glucose (-3.7 mmol/l; p < 0.0001), and within-patient fasting glucose variability (-0.5 mmol/l; p < 0.0001). In the majority of patients (82%), these improvements in glycaemic control were achieved with once daily administration of insulin detemir. There was a small reduction in mean body weight (-0.7 kg; p < 0.0001), which was most apparent in patients with a higher body mass index (BMI) at baseline. A significant negative relationship between weight change and baseline BMI was observed (greater the BMI, greater the weight reduction). Multiple regression analysis showed that BMI and HbA(1c) at baseline, and change in HbA(1c), were all predictors for weight change (p < 0.0001 for all), with BMI being the strongest predictor. CONCLUSIONS: Patients with type 2 diabetes naïve to insulin can be effectively treated with once-daily insulin detemir (+/- OADs) to achieve improved glycaemic control with no adverse effect on weight and a low risk of hypoglycaemia. These short-term results are consistent with the findings of clinical trials.

Calorie restriction for treatment of gestational diabetes.

Birth weights of infants of 35 gestational diabetic mothers treated with calorie restriction alone (1200-1800 kcal) were compared with those of infants of 2337 nondiabetic women, including two control groups (A and B) matched for race, body mass index, age, and parity. All women were screened for gestational diabetes with the O'Sullivan screening method, and a 3-h oral glucose tolerance test was performed on all abnormal results. Control group A mothers had a normal screen, and control group B mothers had an abnormal screen with a normal glucose tolerance test. Pregnancy weight gain was significantly less for the gestational diabetic mothers (mean +/- SD 4.6 +/- 4.9 kg) than for the general prenatal population (9.3 +/- 5.3 kg), group A control subjects (9.7 +/- 5.3 kg), and group B control subjects (9.7 +/- 5.4 kg; P less than 0.0005). No infant of a gestational diabetic mother was below the 10th percentile for weight, and birth weights were similar to those of the control groups even though weight gain after the 28th wk of gestation was only 1.7 +/- 1.6 kg. The frequency of macrosomia (birth weight greater than or equal to 4000 g) was similar among the gestational diabetic mothers (9.3%), the general prenatal population (7.4%), and group A mothers (11.6%) but significantly higher for the group B control subjects (20.9%; chi 2 = 8.57, P less than 0.005). This study demonstrated that gestational diabetic mothers who are calorie restricted have infants with normal birth weights and a frequency of macrosomia less than that of screen-positive nondiabetic women with similar macrosomic risk factors.

Veganism and its relationship with insulin resistance and intramyocellular lipid.

OBJECTIVE: To test the hypothesis that dietary factors in the vegan diet lead to improved insulin sensitivity and lower intramyocellular lipid (IMCL) storage. DESIGN: Case-control study. SETTING: Imperial College School of Medicine, Hammersmith Hospital Campus, London, UK. SUBJECTS: A total of 24 vegans and 25 omnivores participated in this study; three vegan subjects could not be matched therefore the matched results are shown for 21 vegans and 25 omnivores. The subjects were matched for gender, age and body mass index (BMI). INTERVENTIONS: Full anthropometry, 7-day dietary assessment and physical activity levels were obtained. Insulin sensitivity (%S) and beta-cell function (%B) were determined using the homeostatic model assessment (HOMA). IMCL levels were determined using in vivo proton magnetic resonance spectroscopy; total body fat content was assessed by bioelectrical impedance. RESULTS: There was no difference between the groups in sex, age, BMI, waist measurement, percentage body fat, activity levels and energy intake. Vegans had a significantly lower systolic blood pressure (-11.0 mmHg, CI -20.6 to -1.3, P=0.027) and higher dietary intake of carbohydrate (10.7%, CI 6.8-14.5, P<0.001), nonstarch polysaccharides (20.7 g, CI 15.8-25.6, P<0.001) and polyunsaturated fat (2.8%, CI 1.0-4.6, P=0.003), with a significantly lower glycaemic index (-3.7, CI -6.7 to -0.7, P=0.01). Also, vegans had lower fasting plasma triacylglycerol (-0.7 mmol/l, CI -0.9 to -0.4, P<0.001) and glucose (-0.4 mmol/l, CI -0.7 to -0.09, P=0.05) concentrations. There was no significant difference in HOMA %S but there was with HOMA %B (32.1%, CI 10.3-53.9, P=0.005), while IMCL levels were significantly lower in the soleus muscle (-9.7, CI -16.2 to -3.3, P=0.01). CONCLUSION: Vegans have a food intake and a biochemical profile that will be expected to be cardioprotective, with lower IMCL accumulation and beta-cell protective.

Risk and prevention of type 2 diabetes in women with gestational diabetes.

Women with a history of gestational diabetes mellitus (GDM) are at increased risk of future diabetes, predominantly type 2 diabetes, as are their children. The extent of this risk depends both on the diagnostic criteria used to identify GDM and on maternal risk factors, some of which are potentially modifiable whereas others are not. The unmodifiable risk factors are ethnicity, pre-pregnancy weight, age, parity, family history of diabetes, and degree of hyperglycemia in pregnancy and immediately postpartum. The modifiable risk factors are persistent obesity, future weight gain, and subsequent pregnancies. Additional modifiable risk factors in these women are likely to be levels of physical activity, dietary fat, and avoidance of other lifestyle factors that adversely influence insulin resistance, such as smoking and certain drugs. Diabetic prevention strategies need to address the potentially modifiable risk factors using the unmodifiable risk factors to identify women most at risk.

Implications of new diagnostic criteria for abnormal glucose homeostasis in women with previous gestational diabetes.

OBJECTIVE: To determine the consequences of applying revised American Diabetes Association (ADA) (1997) and World Health Organization (WHO) (1998) recommendations for the classification of glucose intolerance in women with previous gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: There were 192 women with previous GDM who took an oral glucose tolerance test (OGTT) 1-86 months after delivery and were classified by WHO (1985), ADA (1997, fasting glucose), and revised WHO (1998) guidelines. RESULTS: Among the 165 women without a preexisting diagnosis of diabetes, WHO-1985 and ADA-1997 provided similar estimates of diabetes prevalence (13.3% vs. 11.5%) but widely differing estimates of impaired glucose homeostasis (31.5% impaired glucose tolerance [IGT] by WHO-1985 vs. 10.9% impaired fasting glucose by ADA-1997 criteria). Overall, 56 women (34%) showed a classification discrepancy between WHO-1985 and ADA-1997 criteria, including 44 with normal fasting glucose by ADA-1997 criteria, but abnormal 2-h glucose by WHO-1985 criteria (40 IGT, 4 diabetes). The cardiovascular risk profile of these women was more favorable than that of 18 women with impaired fasting glucose. WHO-1998 recommendations reproduced ADA-1997 findings when used as a fasting screen, but behaved similarly to WHO-1985 criteria when 2-h glucose values were also analyzed. CONCLUSIONS: All criteria produced similar estimates of diabetes prevalence. However, analyses based on a single fasting glucose screen (and a threshold of 6.1 mmol/l) failed to identify 60% of women with abnormal 2-h glucose levels. Screening women with previous GDM (and by analogy, other groups at high risk of diabetes) with a single fasting glucose has low sensitivity for the detection of abnormal glucose tolerance. Recent guidelines recommending this approach require reevaluation.

Organization of the lateral hypothalamus for control of adrenocorticotropin release in the cat.

Regions in the ventral midbrain that project to the lateral hypothalamus have been implicated in the control of ACTH release. To define further those areas in the lateral hypothalamus through which afferent signals might pass, we electrically stimulated 188 sites in the lateral hypothalamus of 20 cats anesthetized with chloralose-urethane. Stimulations were monophasic pulses of DC (200 microA; 0.2 msec; 100 Hz; 20 sec). Venous samples were drawn over 30 sec 0.5 min before and 1.5 min after stimulation. Equal volumes of warmed isoncotic dextran were infused during sampling to prevent hypovolemia. ACTH was assayed by RIA. Areas were defined in which stimulation led to increased, decreased,, or unchanged ACTH. Mean changes in ACTH were tested by analysis of variance. The present data indicate that the ACTH-active areas defined previously in the midbrain may join the medial forebrain bundle in the subthalamic area and nucleus to traverse the lateral hypothalamus. At the level of the mammillary bodies, a facilitatory area occupied the ventral portion of the medial forebrain bundle. This area extended rostrally and medially to join the medial aspect of the medial forebrain bundle. Continuity with the mediobasal hypothalamus was seen only anteriorly in the area of the supraoptic decussations. An inhibitory area occupied the dorsal extent of the medial forebrain bundle at the level of the mammillary bodies. It extended rostrally and laterally around the caudal pole of the supraoptic nucleus and then medially at the level of the optic chiasm. There appear to be no other medial projections of the lateral lying ACTH-active areas to the mediobasal hypothalamus. The lateral hypothalamus may serve as a site of passage and/or of processing of information that ascends from the midbrain and descends from the limbic system.

Vasopressin-dependent and -independent control of the release of adrenocorticotropin.

We tested the possibility that vasopressin mediates the responses of adrenocorticotropin (ACTH) to electrical stimulation of various areas of the hypothalamus. Thirty-three cats were anesthetized with chloralose-urethane, immobilized with gallamine, and respired artificially. Plasma ACTH was measured by RIA. Intraventricular administration of antiserum to vasopressin blocked the release of ACTH induced by electrical stimulation of the paraventricular nucleus (PVN), suggesting a role for the vasopressinergic projection from PVN to the external zone of the median eminence. In contrast, the release of ACTH induced by stimulation of areas ventral to PVN was unaffected by the antiserum. Thus, there is at least one corticotropin releasing factor released from nuclei other than PVN that is distinct from vasopressin.

Control of release of adrenocorticotropin and vasopressin by the supraoptic and paraventricular nuclei.

To determine the relative roles of the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei in the control of the release of vasopressin and of ACTH, we have examined the hormonal responses to electrical stimulation (200 microA, 0.2 msec, 100 Hz, 20 sec) of these regions. Cats were anesthetized with chloralose-urethane. Blood samples were taken 30 sec before stimulation and 1.5 min poststimulation. ACTH and vasopressin were measured by RIA. Electrical stimulation of the caudal pole of the SON increased vasopressin in plasma (1.82 +/- 0.41 microU/ml, n = 17, P less than 0.01) and decreased ACTH (-26 +/- 4 pg/ml, n = 13, P less than 0.01). In contrast, stimulation of the PVN increased vasopressin (2.01 +/- 0.60 microU/ml, n = 7, P less than 0.001) and increased ACTH (107 +/- 20 pg/ml, n = 32, P less than 0.01). Previous work has shown that vasopressinergic neurons of PVN, but not of SON, project to the zona externa of the median eminence. Other have suggested that the retrograde flow of blood from the neural lobe to the median eminence and thence to the anterior lobe would allow vasopressin to influence the release of ACTH. The present results indicate that both SON and PVN facilitate the release of vasopressin. However, PVN facilitates, but SON inhibits the release of ACTH. These findings suggest that the projection from PVN to the zona externa of the median eminence mediates the release of ACTH and that retrograde flow from the neural lobe is not important in the control of ACTH release during modest and transient increases in the release of vasopressin.

The evaluation of sodium valproate in the treatment of Nelson's syndrome.

It has previously been reported that sodium valproate (Epilim) lowers plasma ACTH levels in Nelson's syndrome. This report describes further experience with its use. Ten patients with Nelson's syndrome were treated with sodium valproate (600-1200 mg/day) for 5-32 weeks. Plasma ACTH was measured by cytochemical methods and RIA. Initial treatment for 5-12 weeks significantly (P less than 0.005) lowered plasma ACTH from a pretreatment mean of 2460 +/- 1870 ng/liter to 480 +/- 330 ng/liter, and the ACTH circadian rhythm was restored in two patients. On discontinuing treatment, plasma ACTH levels remained suppressed for 3 weeks and rose to pretreatment values in 5-12 weeks. Two patients' plasma ACTH levels failed to show a second response to treatment, while a third patient had a favorable second response to treatment over 32 weeks. In six patients, skin pigmentation lightened with treatment, and in one patient, a reduction in size of a pituitary microadenoma, demonstrated radiographically, occurred with treatment. gamma-Aminobutyric acid and sodium valproate were shown to be ineffective in inhibiting ACTH secretion from cultured pituitary tumor cells from a patient with Nelson's syndrome. The results show that sodium valproate is effective in some cases of Nelson's syndrome. We suggest that it reduces the hypersecretion of ACTH by enhancing gamma-aminobutyric acid function in the hypothalamus, thereby inhibiting the release of corticotropin-releasing factor.

Immunoperoxidase stains cortisol in adrenal and pituitary.

The unlabeled peroxidase-anti-peroxidase (PAP) method of Sternberger was used to localize cortisol within paraffin embedded sections of cat adrenal and pituitary tissue. Incubation of the cortisol antiserum used in this method with increasing concentrations of cortisol led to progressive extinction of cortisol staining of the adrenal fasciculata cells, (as measured with a scanning integrating microdensitometer). This result suggests strongly that the staining achieved with this method was specific for cortisol. Cortisol staining was demonstrated not only within cells that synthesize cortisol (the adrenal fasciculata) but also in cells of the adrenal medulla and of the anterior pituitary, two target sites for cortisol action.

Insulin sensitivity in women at risk of coronary heart disease and the effect of a low glycemic diet.

The risk of coronary heart disease (CHD) is influenced by family history, insulin sensitivity (IS), and diet. Adiposity affects CHD and IS. The cellular mechanism of IS is thought to involve the adipocyte cytokine tumor necrosis factor-alpha (TNF-alpha). Insulin-stimulated glucose uptake in isolated subcutaneous and omental adipocytes obtained during elective surgery was measured in 61 premenopausal women, 24 with a parental history (PH) of CHD. In vivo IS was measured using the short insulin tolerance test (SITT) in 28 women, 16 with PH-CHD, before and 3 weeks after randomization to a low glycemic index (LGI) or high glycemic index (HGI) diet. In vitro adipocyte IS and TNF-alpha production was measured following dietary modification. On the habitual diet, in vitro insulin-stimulated glucose uptake in adipocytes as a percentage increase over basal was less in women with PH-CHD than in those without it (presented as the median with 95% confidence limits: subcutaneous, 28% (17% to 39%) v 96% (70% to 120%), P < .01); omental, 40% (28% to 52%) v 113% (83% to 143%), P < .01). In vivo IS in 16 PH-CHD subjects and 12 controls before dietary randomization was similar, and increased in both groups consuming a LGI versus HGI diet (PH-CHD, 0.31 (0.26 to 0.37) v 0.14 (0.10 to 0.24) mmol/L/min, P < .01; controls, 0.31 (0.1 to 0.53) v 0.15 (0.06 to 0.23) mmol/L/min, P < .05). Adipocyte IS was greater in PH-CHD women on a LGI versus HGI diet (subcutaneous, 50% (20% to 98%) v 13% (1% to 29%); omental, 97% (47% to 184%) v 29% (4% to 84%), P < .05). Adipocyte TNF-alpha production was higher in women with versus without PH-CHD (subcutaneous, 0.3 (0.18 to 0.42) v 0.93 (0.39 to 1.30) ng/mL/min; visceral, 0.22 (0.15 to 1.30) v 0.64 (0.24 to 1.1) ng/mL/min, P < .04, respectively), but was uninfluenced by the dietary glycemic index. We conclude that in vitro adipocyte IS is reduced and adipocyte TNF-alpha production is increased in premenopausal women with PH-CHD. A LGI diet improves both adipocyte IS in women with PH-CHD and in vivo IS in women with and without PH-CHD.

Partial reversal of protan and tritan colour defects with inhaled oxygen in insulin dependent diabetic subjects.

AIMS: Abnormalities in colour perception occur early in the development of diabetic retinopathy. Whether these changes can be influenced by increasing circulating oxygen saturation was studied in comparison with non-diabetic controls. METHODS: Protan and tritan colour thresholds were measured using a computer graphics system in 37 insulin dependent diabetic subjects, with no or minimal background retinopathy, and 27 matched controls. Colour thresholds were performed after subjects inhaled either gaseous air or 100% oxygen for a minimum of 5 minutes. RESULTS: Diabetic subjects had higher colour vision thresholds when inhaling air when compared with controls (protan (mean 3.93 (SEM 0.39), v 2.36 (0.16), p < 0.0002) and tritan (8.15 (0.62) v 5.42 (0.31), p < 0.002)). The colour vision thresholds observed in diabetic subjects inhaling air fell when they inhaled oxygen (protan (3.93 (0.39) v 3.57 (0.33), p < 0.025) and tritan (8.15 (0.62) v 7.35 (0.59), p < 0.005)). No fall in colour thresholds was seen in non-diabetic controls who inhaled oxygen. CONCLUSION: A small improvement in the colour vision thresholds was observed using computer graphics in diabetic subjects, with minimal or no retinopathy, who inhaled oxygen. This study supports a hypothesis that reduced retinal oxygenation contributes to the colour vision defects in diabetes.

Glycaemic control and plasma lipoproteins in menopausal women with Type 2 diabetes treated with oral and transdermal combined hormone replacement therapy.

AIMS: To compare the effect of a fixed combination of an oestrogen (17-beta oestradiol) with a cyclical progestagen (norethisterone) on glycaemic control, plasma lipoproteins and haemostatic factors in women with Type 2 diabetes. METHODS: Oral and transdermal hormone replacement therapy (HRT) were compared to no HRT treatment in 33 postmenopausal women with Type 2 diabetes, in a 12-week randomised prospective open parallel group study. RESULTS: In the 11 women who received 12 weeks of oral HRT, there was a significant fall in total cholesterol (5.9+/-1.0 (S.D.) to 4.7+/-1.0 mmol l(-1), P=0.005), low density lipoprotein cholesterol (3.44+/-0.89 to 2.77+/-0.92 mmol l(-1), P=0.005) and triglyceride values (median (range)), (2.46 (0.96-5.52) to 2.29 (1.00-3.87) mmol l(-1), P<0.05). Oral HRT improved glycated haemoglobin (HbA(1c)) (7.4+/-1.4 to 6.8+/-1.2%, P< or =0.005). Oral HRT additionally reduced the cell adhesion factor E-selectin (82+/-33 to 60+/-20 microg l(-1), P<0.01) and factor VII (143+/-25 to 109+/-24% pooled plasma activity, P<0.01). No improvement in any of these parameters, except E-selectin (65+/-19 to 58+/-18 microg l(-1), P<0.01), occurred in the nine women receiving transdermal HRT, and no improvement occurred in the 13 controls randomised to no treatment. CONCLUSION: In women with Type 2 diabetes, cyclical oestrogen and progestagen taken orally for 12 weeks significantly improved glycaemic control and lipoprotein concentrations. These metabolic benefits were not apparent when a similar HRT preparation was administered transdermally.