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Introduction/Background* Endometrial cancer is the second most common carcinoma of the female genital tract globally, and its incidence is still increasing. Optimal treatment of EC depends on early diagnostics and pre-operative stratification to appropriately select the extent of surgery and to plan further therapeutic approach. Current diagnosis and treatment of EC patients is guided by histopathological and surgical findings since there are no accurate non-invasive diagnostic or prognostic methods available. The lack of non-invasive diagnostic and prognostic biomarkers of EC is addressed in the current clinical study titled ‘Biomarkers for Diagnosis and Prognosis of Endometrial Carcinoma’ (NCT03553589). Methodology Patient recruitment takes place at six medical centers (University Medical Centre Ljubljana, Slovenia; University Medical Centre Maribor, Slovenia; Maastricht University Medical Centre, The Netherlands; Lublin Medical University, Poland; University Hospital Brno, Czech Republic, University of Genoa, Italy). Plasma samples from women with diagnosed EC and controls will be examined using non-targeted and targeted metabolomics and targeted proteomics approaches. Combined blood metabolome (>850 metabolites), proteome (>900 proteins), clinical and epidemiological data will be analyzed in order to construct diagnostic/prognostic algorithms for early diagnosis of EC and to identify patients with low/high risk for cancer progression and recurrence. BioEndoCar consortium has defined inclusion/exclusion criteria and a strict standard operating procedure for sample collection, processing and storage that is followed in all medical centers. Result(s)* Since the beginning of the project we recruited more than 440 patients. Discovery proteomics and discovery metabolomics phase have been concluded. Targeted proteomics and targeted metabolomics analysis are currently in progress and we are awaiting the results. Conclusion* Within the project we expect to find different metabolic and protein profiles in patients with early stages of EC as compared to controls and in patients with poor prognosis and high risk of disease progression and recurrence as compared to those with favorable prognosis. Great effort was put into informing the lay and expert public about the importance of the translational studies in EC. We have established an official website (https://bioendocar.eu/), Twitter profile and Facebook page (https://www.facebook.com/bioendocar) where we post all news concerning the project. Funded by ERA-NET Transcan2 and MIZS. Nothing to disclose.

The aim of this study was to determine whether permitting women in labour to eat a light diet would: (i) alter their metabolic profile, (ii) influence the outcome of labour, and (iii) increase residual gastric volume and consequent risk of pulmonary aspiration. Women were randomised to receive either a light diet (eating group, n = 48) or water only (starved group, n = 46) during labour. The light diet prevented the rise in plasma beta-hydroxybutyrate (p = 2.3 x 10(-5)) and nonesterified fatty acids (p = 9.3 x 10(-7)) seen in the starved group. Plasma glucose (p = 0.003) and insulin (p = 0.017) rose in the eating group but there was no difference in plasma lactate (p = 0.167) between the groups. There were no differences between the groups with respect to duration of first or second stage of labour, oxytocin requirements, mode of delivery, Apgar scores or umbilical artery and venous blood samples. Relative gastric volumes estimated by ultrasound measurement of gastric antral cross-sectional area were larger (p = 0.001) in the eating group. This was supported by the observation that those from this group who vomited, vomited significantly larger volumes than those in the starved group (p = 0.001). We conclude that eating in labour prevents the development of ketosis but significantly increases residual gastric volume.

AIMS—To determine whether patients with idiopathic retinal vasculitis have altered production of cortisol and dehydroepiandrosterone sulphate (DHEA-S), and whether differences in these variables occur between those who are sensitive (SS) and resistant (SR) to steroids. METHODS—20 patients with retinal vasculitis (off treatment) and 10 control subjects were prospectively recruited. Morning cortisol and DHEA-S levels were measured, and cortisol secretion rates and short synacthen tests (SST) carried out in patients before treatment, when on prednisolone 20 mg/day, and in controls. RESULTS—There were no differences in any variables between patients and controls. For retinal vasculitis patients pretreatment, the SST was lower in SR patients (p=0.02). More of the SR patients had ischaemic retinal vasculitis ( p

Background: The red cell membrane fatty acid composition has frequently been used as an index of essential fatty acid (EFA) nutrition. After birth there is a decline in plasma arachidonic acid (AA and docosahexaenoic (DHA ) acids in babies fed on conventional formula which contains only the parent linoleic and α-linolenic acids. In human studies, the red cell phosphoglyceride composition appears to be more constant than that of plasma. In infants fed fish oil without AA, the AA proportions fall in the plasma but much less so in the red cells. This result might be considered to mean that there is no need for preformed AA. On the other hand, in a study where the levels of AA fell there was reduction of infant growth. Indeed, where cell membrane composition does change there is often an associated alteration in physiological functions of membranes. We therefore felt it worth investigating the balance between AA and DHA in a physiological situation where plasma levels are known to change, namely in pregnancy. Purpose: The aim of the study as to investigate a relationship between blood phosphoglyceride AA and DHA in pregnant women and neonates. Subjects: Health pregnant women from London, England (n = 193) and their term babies (n = 45); healthy pregnant women from Seoul, South Korea (n = 40) and their term babies (n = 40); and preterm neonates (n = 72) from London. Method: Blood samples were taken from British and Korean pregnant women during the third trimester, and from term and preterm babies at birth. These samples were taken for routine monitoring purposes in Korea and were a part of a study on pregnancy outcome for which ethical permission was granted from the East London and The City Health Authority and Lambeth, Southwark and Lewisham Health Authority. Approval was also obtained from the Ethical Committee of the Asan Medical Centre, Seoul, South Korea. Results: AA and DHA correlated in plasma choline phosphoglycerides (CPG) of the British mothers (r = 0.52 P < 0.0001). The correlation coefficients and significance were much stronger in the red cell CPG and even more so in the term and preterm infant red cell CPGs (r =0.75, 0.80 and 0.88, respectively Similarly, AA and DHA correlated in red cell CPGs of the Korean women and their term babies. There was also a significant relationship between the two fatty acids in red cell ethanolamine phosphoglycerides in the mothers and their babies. Both linoleic (LA) and α-linolenic acids (ALA) were inversely associated with AA and DHA in some of the phosphoglyceride fractions of the mothers and babies. Conclusions: Although AA and DHA have different primary dietary origins, there were significant relationships between AA and DHA in the phosphoglycerides of the red cell membrane. This finding seems surprising if the red cell composition is determined by diet. These results suggest a physiological mechanism which attempts to maintain an appropriate balance between AA and DHA. It is plausible that there is an optimum balance between AA and DHA for membrane stability, deformability, enzyme and receptor function. Sponsorship: The British Diabetic Association, March of Dimes Birth Defects Foundation and The Christopher H.R. Reeves Charitable Trust. Descriptors: linolcic; α-linolenic; arachidonic; docosahexaenoic; mothers; neonates.

The effect of a maternal diet high in fat, similar to Western foods, and of diabetes on liver essential fatty acid composition of the mother and the newborn and sucking pups was investigated. Female Sprague-Dawley rats were fed on either a low-fat (42 g/kg) or a high-fat (329 g/kg) diet for 10 d before mating, throughout pregnancy and post-partum. On the first day of pregnancy, diabetes was induced by intravenous administration of streptozotocin in half the animals from the two diet groups. Half the pups were killed at birth, and the remaining pups and mothers at days 15 and 16 respectively. At birth, there was a significant reduction in the proportions of docosahexaenoic acid (DHA) in the liver phosphoglycerols and neutral lipids of the pups of both high-fat control and diabetic mothers compared with those of low-fat control and diabetic mothers. Diabetes decreased arachidonic (AA) and linoleic acid values in both the low- and high-fat groups at birth. The sucking pups of both the high-fat control and diabetic mothers exhibited a significant reduction in DHA and a concomitant compensatory increase in AA and a lowering in DHA-AA balance. In the mothers, the high-fat diet significantly increased the proportions of DHA in ethanolamine phosphoglycerols but had no observable effect in choline phosphoglycerols and neutral lipids. In the fetus the DHA level (g/100 g total fatty acids) was disproportionately reduced by the maternal high-fat diet. The adverse effect of the high-fat diet on the level of DHA (g/100 g total fatty acids) was greater in the neonate (and by implication the fetus) than in the sucking pups or mothers. It is concluded that a distortion of the biochemistry is induced in the offspring through a maternal high-fat diet, without genetic predisposition.

The aim of this study was to determine whether permitting women in labour to eat a light diet would: (i) alter their metabolic profile, (ii) influence the outcome of labour, and (iii) increase residual gastric volume and consequent risk of pulmonary aspiration. Women were randomised to receive either a light diet (eating group, n = 48) or water only (starved group, n = 46) during labour. The light diet prevented the rise in plasma beta-hydroxybutyrate (p = 2.3 x 10(-5)) and nonesterified fatty acids (p = 9.3 x 10(-7)) seen in the starved group. Plasma glucose (p = 0.003) and insulin (p = 0.017) rose in the eating group but there was no difference in plasma lactate (p = 0.167) between the groups. There were no differences between the groups with respect to duration of first or second stage of labour, oxytocin requirements, mode of delivery, Apgar scores or umbilical artery and venous blood samples. Relative gastric volumes estimated by ultrasound measurement of gastric antral cross-sectional area were larger (p = 0.001) in the eating group. This was supported by the observation that those from this group who vomited, vomited significantly larger volumes than those in the starved group (p = 0.001). We conclude that eating in labour prevents the development of ketosis but significantly increases residual gastric volume.

Cushing's syndrome is characterized by central obesity and muscle wasting. As GH is anabolic, it may be able to counteract the loss of body protein. To evaluate the potential therapeutic use of GH preoperatively, eight patients with Cushing's syndrome received sc injections of recombinant human GH (0.07 U/kg.day) for 7 days. Whole body leucine and glucose turnover were measured after an infusion of [1-13C]leucine and [6,6-2H2]glucose before (day 0) and after 2 and 7 days of GH treatment. Compared with the value on day 0, there was a significant increase on days 2 and 7 in insulin (P0.005 and P0.001), C peptide (P0.01 and P0.005), insulin-like growth factor I (P0.001), and glucose concentrations (P0.01 and P0.005) and a decrease in the leucine concentration (P0.005). There was no significant change in glucose production rate, glucose MCR, leucine production rate (a measure of protein degradation), or nonoxidative leucine disappearance rate (a measure of protein synthesis). The leucine MCR was increased after 7 days (P0.05), and the clearance of leucine into protein (nonoxidative leucine disappearance rate/leucine concentration) was increased (P0.05) after 2 and 7 days of GH treatment. This is consistent with GH stimulating the availability of amino acid transporters. GH may, therefore, have a therapeutic role in the preoperative treatment of Cushing's syndrome.

In order to establish the prevalence of gestational diabetes mellitus (GDM) among ethnic groups residing in the catchment area of one hospital in central London and to assess both the mode of delivery and the baby outcome, we studied retrospectively 703 women selected for screening for GDM during the years 1991 and 1992. While the prevalence of GDM was approximately 2% overall, within the ethnic groups a significant difference was found with Asians and Africans/Afrocaribbeans being four and two times more likely to have GDM, respectively, than Caucasians (P < 0.001). Both maternal obesity and the diagnosis of GDM influenced the time and the mode of delivery, but perinatal mortality and morbidity did not differ significantly between women with GDM and women with normal glucose tolerance. An association between the GTT glucose area and the gestational age and ethnicity adjusted birth weight was observed in women with normal glucose tolerance test, but was absent in the GDM pregnancies, providing indirect evidence that dietary treatment, with or without insulin treatment, altered the maternal milieu in the latter sufficiently to modify fetal growth.

The placental transfer of D- and L-glucose was investigated in anaesthetised non-diabetic and streptozotocin-induced diabetic rats. Maternal to fetal transfer was determined by perfusing the fetal side of one placenta in situ whilst infusing a mixture of D-[3-3H]glucose and L-[1-14C]glucose into the maternal circulation. Back-transfer from the fetal to maternal circulation was assessed by determining the uptake of the radiolabelled glucoses from the perfusion fluid during a single passage through the placenta on the fetal side. Maternal diabetes resulted in a reduced utero-placental blood flow but an increased bidirectional transfer of D-glucose. Non-specific maternal to fetal placental transfer of L-glucose was greater in diabetic rats than in controls, and the loss of L-glucose during placental perfusion on the fetal side was, again, greater in diabetic than in control rats. This increased bidirectional 'leak' of glucose possibly reflects a functionally compromised placenta, caused by its formation in a diabetic milieu, and may explain the greater fetal-maternal glucose ratios found in diabetic rats relative to controls.

As a clinical entity, growth hormone (GH) deficiency in adulthood has previously received little attention. This has been due in part to a traditional view that GH is only of physiological importance during childhood and adolescence, when its effects are most visible and dramatic, despite the fact that GH secretion normally continues throughout adult life. More importantly, the limited availability of pituitary-derived human GH in the past meant there was no possibility of exploring its effects in GH-deficient adults. This problem has been overcome with the introduction of recombinant human GH, in potentially unlimited quantities.

By perfusing two placentas concurrently in five animals we have found that linoleic acid is transferred across the guinea-pig placenta more readily than palmitic acid. In the in-situ perfusion this transfer is modulated by the type of albumin used in the perfusate. Removing the associated lipid from the perfusate albumin reduced the amount of non-esterified fatty acid (NEFA) transfer rather than enhanced it. Many researchers use fat free albumin as a protein carrier in in vivo and in-vitro systems, our results indicate that this may not be the most appropriate substance to use.

Studies were performed on the transfer of essential and non-essential non-esterified fatty acids across the in-situ perfused placenta in normal and diabetic rats in late gestation. Results indicated that increasing maternal glycaemia is associated with a decrease in the unidirectional transfer of both essential and non-essential fatty acids. This reduced transfer is dependent upon the uteroplacental blood flow, which is compromised in the diabetic animals. The transfer of essential fatty acid was always twofold that of non-essential fatty acids regardless of the total amount of lipid transferred, indicating a selective mechanism for the transfer of these moieties.

Centralisation of care leads to better outcome Editor—The finding of a persistently poor outcome of pregnancy in women with insu› lin dependent diabetes in two (northern) English regions is an important statement of the problem. 12 Both studies provide figures and show outcomes that are no different from those widely reported in the past. Unfortunately, neither give evidence of any degree of centralisation of obstetric or diabetic care, with on›site neonatal intensive care, although this is a proved means of improving the outcome of pregnancy for diabetic mothers. 3 The St Vincent declara›

Summary The gestational age and litter size in the guinea pig can be accurately assessed by taking an x-ray of the animal. From a measurement of the fetal head length on the x-ray plate a fetal weight can be calculated using previously accumulated data, included here. The gestational age can be assessed from this weight to within ± two days, using the fetal growth data of Draper (1920), Eckstein, McKeown and Record (1955) and Ibsen (1928). The litter size can be readily ascertained from the x-ray plate.

In a study of risk factors for cardiovascular disease in 2388 school children aged 9--12 years carried out in Westland, Holland, serum insulin levels at one hour after an oral challenge of 50 g glucose were measured in a systematically selected subsample of 715 children. The distribution and associations of serum insulin in these children are described. The mean insulin values were 24.6 muU/ml for boys and 32.0 muU/ml for girls. The difference between these means was statistically significant and remained so even taking measures of adiposity into account. Insulin values were positively related to levels of plasma sugar and systolic blood pressure in both sexes.

Serum samples from a patient with a presumed islet-cell adenoma with a 20-year history of hypoglycaemic attacks were chromatographed on a 'Sephadex G50' column. Besides the peaks eluting in the position of insulin and proinsulin, a third immunoassayable and bioassayable peak was present in serum taken fasting and after oral glucose. This peak ("peak A") eluted before proinsulin but well behind albumin. The estimated molecular weight was 24,000. The quantity of peak A detected in the patient's serum varied from 32% of total immunoreactive insulin to nil. Peak A was not identified in samples from a patient with islet-cell hyperplasia (accompanied by spontaneous hypoglycaemia) nor in a patient with acromegaly. It was not detected when varying amounts of human insulin and labelled insulin were added to the column in buffer or in insulin-free human serum. In contrast to proinsulin, peak A had between 50% and 100% the biological activity of the material eluting in the position of insulin. Significant quantities of peak A were isolated only when the sera contained a considerable quantity of proinsulin.

In 1979-80 a national survey of the incidence of congenital malformations in babies born to diabetic mothers in the United Kingdom was carried out by questionnaire. Of the 1034 mothers reported, 773 were known to have diabetes before the index pregnancy. The incidence of congenital malformations ws 7.1% which is significantly higher than the 2.1% in the offspring reported to the Office of Population, Censuses and Surveys (OPCS) for England and Wales in 1979-80. The increase was most pronounced for malformations of the heart, spine, lungs, and brain. In 40% of the diabetic mothers blood glucose was not recorded during the first trimester of pregnancy, and in this group the malformation rate was twice that in babies born of mothers who had had at least one reported blood glucose estimation during this time. We conclude that there is an urgent need to improve health education and supervision before and during pregnancy in all diabetic women if the prevalence of malformations amongst their offspring is to be reduced.

Serum-lipid concentrations and their relationship to blood-glucose and serum-insulin were examined in non-insulin-requiring diabetics, 62 with and 45 without retinopathy. The age, sex, body-weight, and duration of known diabetes was comparable in the two groups. All were treated by diet only or diet and oral hypoglycaemic agents. Patients with retinopathy had higher fasting serum- triglyceride and serum-cholesterol levels than those without. Compared with a non-diabetic population, significantly more diabetics with retinopathy had raised serum-lipids. The lipid concentrations did not correlate with body-weight, serum-thyroid-stimulating-hormone levels, renal involvement, or fasting blood-sugar. While the blood-sugar concentrations were similar in the two groups the absolute insulin increment and the relative insulin response to a 50 g oral glucose load were significantly lower in those with retinopathy than in those without. The impairment of insulin response correlated significantly with the frequency of hyperlipidaemia. It is suggested that insulin deficiency with secondary hyperlipidaemia is characteristic of diabetic patients with retinopathy.

In 2388 schoolchildren aged 9-12 years who took part in a study of cardiovascular risk factors in Westland, Holland, plasma sugar concentrations were found to be positively correlated with systolic and diastolic blood pressure, independently of weight. Serum cholesterol levels were also related to systolic blood pressure in boys, but much less strongly than plasma sugar levels. The relation between serum insulin and blood pressure, independent of plasma sugar, was weak. The relation between plasma sugar and systolic pressure existed for both sexes and regardless of whether measurements were made in the morning or afternoon; its association with diastolic pressure was weaker, and was not so consistent over all groups. These findings suggest that the relations between risk factors for coronary heart disease that exist in adults are already evident in childhood.

Twenty diabetic patients, whose hyperglycaemia had been shown to fail to respond to at least one month's dietary treatment, completed a crossover study in order to: 1) compare the effectiveness of two sulphonylureas, chlorpropamide and glibenclamide, and 2) study the effects of sulphonylureas on insulin secretion and on biochemical indices of glucose intolerance. Fasting blood glucose fell on active treatment from 10.7±0.6 (mean ± SEM) to 6.6+0.7 mmol/l and rose again to 10.6±0.7 after 4 months placebo. A second period of 4 months sulphonylurea therapy resulted in a comparable fall in blood glucose (to 6.9±0.7 mmol/l) and a similar relapse was seen after the second placebo period (to 10.5±0.9 mmol/l). Glucose tolerance and associated insulin secretion improved markedly on active treatment, with ketone bodies, non-esterified fatty acids, and glycerol falling to within the reference range. Sulphonylurea therapy was associated with a small but significant increase in the fasting insulin level. These effects were nearly all reversed 4 months after withdrawal of the sulphonylureas. No marked changes were found in growth hormone, lactate, pyruvate, lactate/pyruvate ratio or fasting cholesterol, triglycerides and lipoproteins. On a weight basis, glibenclamide was 26 times more potent than chlorpropamide and, in the doses used in this study, their biochemical effects were indistinguishable. The effects of these two sulphonylureas seem most likely to be mediated by a direct stimulation of insulin secretion by the B-cell.

Extract: Blood glucose levels and rates of excretion of insulin in urine were measured in 31 infants with erythroblastosis. Twenty-two of these infants had determinations of insulin excretion in urine performed during the first 24 h of life. These infants can be divided into two groups. Group 1 were infants of greater than 36 weeks gestation. When using hemoglobin as the index of severity of the disease, they can be subdivided into two groups. Group 1A (six infants with a cord hemoglobin value of greater than 13 g/100 ml) had a mean excretion ratio of insulin/creatinine in urine of 6.9 μU/mg compared with a mean of 5.4 μU/mg for the control group (P = 0.5). Group 1 B (six infants with a cord hemoglobin value of less than 13 g/100 ml) had a mean value for insulin in the urine of 47.0 μU/mg, compared with a mean value of 5.4 μU/mg for the control group. Group 2, composed of 10 infants of less than 36 weeks gestation, had a mean value for insulin in urine of 129.7 μU/mg, compared with a mean of 21.9 μU/mg for the control group (P < 0.01). Excretion of insulin was inversely related to blood glucose. Seven infants were hypoglycemic (blood glucose levels of less than 20 mg/100 ml) and all had elevated insulin levels in urine. Speculation: In erythroblastotic infants, simultaneous occurrence of islet cell hyperplasia, hypoglycemia, and hyperinsulinuria is indicative of increased insulin production. The cause of the islet cell hyperplasia is not apparent. The placenta is commonly hyperplastic, and hence, its ability to destroy insulin may be enhanced, thus causing islet cell hyperplasia. At birth, separation of the infant from the placenta leads to an abrupt decrease in the infant's rate of insulin destruction, and thus, to temporary over-production of insulin. This hypothesis is in keeping with the observed early hypoglycemia and the normal birth weight for gestational age.

SUMMARY Results of a collaborative study in which the insulin concentrations of a number of plasma samples were estimated in several laboratories are reported. They indicate that: (1) laboratories agreed on the ranking of plasma samples according to insulin content; (2) the reproducibility of replicate estimates obtained in the same assay usually overestimated the reproducibility of estimates made on different occasions; (3) values reported for the insulin concentration of the same plasma examined in each of a number of laboratories were likely to range from about one half to twice the inter-laboratory mean estimate. Possible reasons for the variability of estimates are discussed.

Glucose-tolerance tests were done in 137 hypertensive patients before and after a year of therapy with one of four diuretics (clorexolone, ethacrynic acid, hydrochlorothiazide, or frusemide). The mean blood-sugar, serum-insulin, and serum-free-fatty-acid levels did not alter significantly during the year in the group as a whole or in the individual drug groups, except the frusemide group, where blood-sugar and serum-insulin both fell. Serum-potassium fell significantly during the year but was not related to changes in blood-sugar. 3 patients developed clinical diabetes. In 2 of these, diuretic therapy may have been of aetiological significance.

Immunochemical insulin is measurable in urine by the double-antibody assay procedure. Its excretion per hour correlates with the mean serum level and its “clearance” does not vary with changes in serum insulin concentrations. In 28 normal subjects the “insulin clearance”, measured during an oral GTT, was low (mean 0.42 ml./min.; range 0.23–0.87 ml./min.) and varied with the “creatinine clearance” and less with urinary albumin. This low “clearance” suggests that either serum insulin is bound to a larger protein or polymerized, or that it is avidly reabsorbed by the renal tubules after glomerular filtration. The log-mean basal (overnight) urine insulin level in 28 normal subjects was 215 μU/hr. (range 89–499). During the 2 hr. following 50 Gm. oral dextrose the level rose to a log-mean of 834 μU/hr. (range 330–2370).

The metabolic response to two weeks' fasting and the influence of starvation on glucose tolerance have been studied in obese diabetic and obese nondiabetic subjects. After an overnight fast, mean concentrations of both blood glucose and plasma triglyceride were significantly greater in the diabetics than in the nondiabetics. In neither group, however, were correlations found in any combination between circulating levels of triglyceride, glucose, insulin, free fatty acids, or the degree of obesity. During the fast, concentrations of plasma triglyceride and blood glucose fell slightly in the nondiabetics, but strikingly in the diabetics, and in the latter these reductions were highly correlated. Glucose tolerance was impaired by starvation in the nondiabetics but considerably improved in the diabetics. In the former, the rise in both serum insulin and plasma lactate concentrations was delayed following starvation. In the latter, the most striking change was a reduction in the basal glucose concentration after fasting; a rise in lactate levels was observed prior to starvation but no elevation was detected during the post-fast glucose tolerance test, while serum insulin responses remained unchanged. It is suggested that in some obese diabetics the development of endogenous hypertriglyceridemia is dependent on increased hepatic gluconeogenesis, and that a reduction in gluconeogenesis is the principal mechanism by which both plasma triglyceride levels are decreased, and glucose tolerance improved, in such patients following starvation. It is further suggested that both diminished β-cell responsiveness and decreased muscle glycolysis contribute to the genesis of starvation diabetes.

Oral glucose-tolerance tests were done in 43 patients with acromegaly (38 with normal glucose tolerance and 5 with diabetes). Insulin levels were compared with 45 healthy London controls and levels found in a population survey in Western Australia from which a sixty-minute insulin-response index was derived. Although the mean serum-insulin levels were higher during the oral glucose-tolerance tests in non-diabetic acromegalics than in controls, only 10 out of 38 showed levels clearly outside the normal range. Only 9 were outside two standard deviations from the mean in the population survey. The insulin levels for the diabetics lay in the lower range for the rest of the group and they were less responsive to glucose. Apart from a possible correlation between mean serum-insulin and mean growth-hormone levels during the glucose-tolerance test no correlation was found between serum-insulin and indicators of disease activity. After treatment there was an appreciable fall in insulin levels only in those who initially had high insulin levels. The fall in serum-growth-hormone after treatment did not relate to the fall in insulin levels.

1.Details are given of a double antibody immunoassay method suitable for measuring insulin in urine. — 2. The method proved specific and reproducible. Human insulin added to urine was quantitatively recovered and dilution and concentration resulted in proportional changes in measured insulin. — 3.Urines kept at 4°C for 24 hours showed no loss of assayable insulin, while decreases of 4–23 % were observed after standing at room temperature for 24 hours; samples of urine adjusted to pH 7.4–8.4 and centrifuged were kept at −20°C for 9 months without loss. Addition of albumin to urine to prevent adsorption of insulin on the container was found to be unnecessary. — 4. Tests of the first antibody reaction showed that non-specific co-precipitation of radioactive insulin was less than 3.5 % and that addition of sodium chloride did not alter the standard insulin curve. Monitor tubes containing131I-guinea-pig gamma-globulin showed optimal second antibody precipitation in all the urine assays surveyed. — 5. In normal subjects, the renal clearance of insulin was relatively constant over a wide range of serum insulin levels, but varied with body size. However, preliminary studies suggested that the clearance was reduced in pregnancy, hypertension and peripheral vascular disease, all of which are characterized by high serum insulin values. In contrast, the clearance in acromegaly was normal as both serum and urine insulin levels were raised. In chronic renal disease the urinary excretion of insulin was very high. — 6. Direct measurement of urinary insulin was feasible in insulin-treated diabetics provided that renal function was normal; insulin-binding antibodies were found in the urine of these diabetics only in association with proteinuria.

This study was planned to investigate the pathogenesis of diabetes in acromegaly. Standard intravenous glucose tolerance tests were done with measurements of blood sugar, plasma insulin, growth hormone and free fatty acids. Sixteen patients were studied, and 10 had more than one glucose tolerance test. Seven of the patients had impaired carbohydrate tolerance, including 2 with symptomatic diabetes. In 6 patients serial tests showed the change that may occur as carbohydrate tolerance deteriorates, and in 5 the response to surgical hypophysectomy was observed. Fasting hyperinsulinism was present in 6, and insulin response to intravenous glucose was increased in 10. The pattern of this response varied—in 10 there was a peak in the first 15 min, in 4 the pattern resembled that of maturity onset diabetes, with a gradual rise of plasma insulin concentration toward a peak at 60 min. In the 2 patients with symptomatic diabetes, there was no response to intravenous glucose although the fasting plasma insu...

Fifty g oral glucose tolerance tests were performed on 25 subjects with chronic renal failure, 8 with the nephrotic syndrome and 6 recovering from acute renal failure. Urine was collected during a basal overnight period and during the glucose tolerance test and immunoreactive growth hormone (GH) and insulin were determined in serum and urine. Sixteen acromegalic subjects with normal renal function were also studied since unlike insulin, GH could not be measured in unconcentrated urine in healthy control subjects. Insulin and GH clearances were markedly elevated in chronic renal failure and in patients recovering from acute renal failure, but raised in 3 subjects only with the nephrotic syndrome. In spite of this marked elevation of clearance in chronic renal failure patients, in any one subject insulin and GH clearance remained relatively constant. There was a correlation between insulin clearance and GH clearance during the glucose tolerance test, indicating that the patients with the higher insulin clearances also had the raised GH clearances. Since a common path of degradation of GH and insulin has not been demonstrated the results suggest that changes in tubular cell transport are responsible. GH clearance in uncomplicated acromegalic subjects was about 1/50 of the insulin clearance in healthy controls. This ratio fell to unity in patients with very severe chronic renal failure with creatinine clearances of 2 ml/min. In 2 patients with creatinine clearances of less than 2 ml/min the insulin and GH clearance approached the creatinine clearance, suggesting that GH and insulin in the glomerular filtrate were not reabsorbed by the proximal tubule. Since normal renal clearances of insulin and GH are so low and clearance changes so dramatically in renal failure, measurement of these hormones may provide a useful and simple assessment of proximal tubular function.

Albumin has been found to be more effective than gelatine in preventing insulin loss from insulin containing solutions. It is probable that this has led to falsely elevated levels of insulin-like activity (ILA) reported with bio-assays. Preparations of crystalline human albumin have been found to be free from ILA and from insulin measured by the radio-immuno-assay. Other human albumin prepared by acid-ethanol extraction (that has been shown previously to contain insulin antagonistic properties on the isolated rat hemidiaphragm) has contained significant ILA on the isolated rat fat pad and also contained insulin demonstrable by radio-immuno-assay.

To learn more about insulin excretion in the neonatal period, 24-hour urine samples from unfed, breast-fed, and bottle-fed male infants in the first day of life were analysed for insulin content. Urine was also collected from breast-fed and bottle-fed babies on the fifth day of life. The results were expressed as a ratio of creatinine excretion. Insulin excretion was not affected by feeding on the first day of life: by day 5 there was a sixfold increase. Excretion was independent of renal function. The findings support the view that improvement in glucose tolerance in the first week of life is due to increased insulin secretion.

The epidemiological evidence for an association between diabetes mellitus and ischaemic heart disease is reviewed briefly. The relationship between blood sugar after challenge and blood pressure is described, with particular reference to studies in populations of U.S. and Jamaican adults and Dutch children.

To study the importance of the residual insulin secretion for the degree of diabetic control and for the development of microangiopathy 55 patients with non-insulin-dependent diabetes mellitus (NIDDM) were studied. A 1 hr oral glucose tolerance test was performed at diagnosis and 5-10 yr later. At diagnosis all patients were free of microangiopathy, at reassessment 24 patients had evidence of microangiopathy, i.e. retinopathy, neuropathy or nephropathy, alone or in combination. The glucose induced increments of insulin levels (delta IRI) at reassessment correlated inversely with the degree of diabetic control, measured by Haemoglobin A1 (r = -0.466, p less than 0.01), and with the mean fasting blood glucose throughout the follow up period (r = -0.491, p less than 0.01). delta IRI at diagnosis was similar in patients with and without microangiopathy, and at reassessment, although lower in the microangiopathy group (11.2 +/- 2.1 vs. 16.4 +/- 2.1 microunits/ml, p less than 0.1). The difference between the 2 groups did not reach statistical significance. When patients were separated into those treated with diet alone and those treated with oral antidiabetic agents, delta IRI at reassessment was significantly lower in patients on oral agents (10.5 +/- 1.9 vs. 17.2 +/- 2.2 microunits ml, p less than 0.01), but the prevalence of microangiopathy was not different between 2 groups (37% and 52%, respectively). These findings show that in patients with NIDDM the residual beta cell function is important for the degree of diabetic control, but a direct relationship between the degree of insulin deficiency and the presence of diabetic microangiopathy is not established.

Using an in situ perfusion of the fetal side of the guinea-pig placenta the modification of a non-esterified fatty acid during transfer across the placenta was investigated. Simultaneous constant infusions of [9,10(3)H] palmitic acid and [1-14C] palmitic acid (3 animals) or [9,10(3)H] and [6-14C] palmitic acids (3 animals) or [9,10(3)H] and universal [14C] palmitic acids (3 animals) were given to the mothers and blood samples and perfusion fluid collected over 90 min in each experiment. When expressed as a ratio of perfusion fluid/maternal plasma radioactive counts, no difference between [3H] isotopes results were found for the 3 triplets of experiments. However significant differences were found between the [14C] isotope ratios. More radioactive lipid was found in the perfusion fluid when the label was positioned away from the C1 terminal of the fatty acid chain, i.e. the ratios were [1-14C] less than [6-14C] less than [9,10(3)H] less than universal [14C] palmitic acid. It was concluded that this indicates release of partially oxidised fatty acid products from the fetal side of the placenta, and it was speculated that this partial oxidation takes place in placental peroxisomes.

Thirty-five freshly presenting, diabetic patients received 5 hour, 100 g oral glucose tolerance tests when first seen and after a period of carbohydrate and energy restriction. After treatment, the significant improvement in glucose tolerance was accompanied by increased insulin secretion and lower concentrations of blood ketone bodies, lactate, glycerol, FFA, triglycerides, cholesterol and pre-beta lipoprotein. There were no significant changes in serum growth hormone or blood pyruvate concentrations. Improvement in glucose tolerance was greater in patients who were obese (greater than 115% of desirable body weight for height) on presentation and was related to the improvement in insulin secretion and the diminished lipolysis. An hypothesis to explain the changes in insulin secretion is prosposed. Eleven out of the 35 patients showed sufficient improvement in glucose tolerance to require no treatment other than diet.

SUMMARY The treatment of hypogonadotrophic hypogonadism with gonadotrophin releasing hormone (LHRH) has proved difficult in the past because of a progressive decline in the pituitary gonadotrophin response. These early studies generally used large relatively infrequent doses of natural LHRH (Davies et al., 1977) or analogues with a prolonged action (Smith et al., 1979). Recently, several reports have indicated that the lack of gonadotrophin response to LHRH can be overcome by frequent administration of low doses of natural LHRH in a pulsatile fashion (Belchetz et al., 1978; Crowley et al., 1980; Jacobson et al., 1979; Schoemaker et al., 1981; Valk et al., 1980). However, it is not known whether those patients with hypogonadotrophic hypogonadism who fail to respond to human chorionic gonadotrophin (hCG) (Bardin et al., 1969) are capable of responding to LHRH. In this case report of a patient with hypogonadotrophic hypogonadism who was resistant to prolonged hCG therapy, normal pituitary gonadotrophin and testosterone responses were obtained following pulsatile LHRH administration. The sperm count rose to 11 ± 106/ml. His wife became pregnant and was delivered of a normal healthy female infant after an uneventful pregnancy.

In situ perfusion of the fetal side of the placenta of five normal and eight diabetic anaesthetized rabbits was performed. The does were infused with a mixture of 14C palmitic acid and 3H glucose whilst simultaneous maternal blood and placental perfusate samples were taken for 90 min. Radiolabelled palmitate and glucose levels in the perfusate closely followed levels in the maternal plasma in both normal and diabetic animals. Total placental non-esterified fatty acid transfer was 0.96 mumol/min in the diabetic animals, although due to the considerable variation within the groups this was not statistically significantly more than the 0.58 mumol/min transferred in the normal rabbits. This transfer was significantly affected by maternal uteroplacental blood flow. Total placental glucose transfer was significantly raised in the diabetic (5.0 mumols/min) compared with the normal (1.8 mumols/min) animals, reflecting maternal hyperglycaemia in the diabetic rabbits. Placental glucose transfer was also significantly correlated with maternal uteroplacental blood flow. Maternal diabetes thus increases the placental flux of nutrients to the fetus in the rabbit.

Thirty-eight non-insulin-dependent diabetic patients within 130% of desirable body weight were given a 100-g oral glucose tolerance test (OGTT) at diagnosis and after at least 1 mo of dietary treatment with energy and carbohydrate restriction. Thirteen "responders" showed an improvement in fasting blood glucose, glucose tolerance, and insulin secretion, with near-normalization of plasma, lactate, pyruvate, free fatty acids, glycerol, and ketone bodies. There were no significant changes in the 25 "non-responders." The responders were, at diagnosis, heavier than the non-responders (75.5 versus 64.3 kg, P less than 0.01). Twenty non-responders subsequently completed a prospective controlled study of glibenclamide, chlorpropamide, and placebo lasting for 16 mo with OGTTs at the end of each 4-mo treatment phase. The results showed that there were no significant differences between the metabolic effects of glibenclamide and chlorpropamide. On active treatment, insulin levels rose coincident with a fall in fasting blood glucose and an improvement in glucose tolerance and near-normalization of plasma lactate, pyruvate, free fatty acids, glycerol, and ketone bodies, all of which relapsed to initial values after placebo. Ten years after the initial study, 29 of the original patients were traced and reviewed and the outcome related to their earlier tests. Twenty-two percent of the responders and 70% of the non-responders were now on insulin (P less than 0.02); the initial insulin response to OGTT at the end of the diet treatment was significantly lower in those subsequently treated with insulin (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Using a constant infusion of [1-14C] palmitic acid into 7 late pregnant guinea-pigs the contribution of circulating maternal lipid to the fetuses was assessed. Within the mother plasma radioactivity was found mainly in free fatty acid with only a small amount circulating as triacylglycerol. In contrast in the fetal plasma [14C] was distributed as one-quarter free fatty acid and three-quarters triacylglycerol, with total [14C] levels being four-fold higher than in the maternal plasma after 160 min of infusion. [14C] Triacylglycerol was found in the fetal liver within 10 min of commencing infusion and levels rose to 12 times the levels of [14C] triacylglycerol in the fetal plasma (per/g or ml) by 100-160 min. [14C] Distribution into the lipid moieties of fetal tissues was found to change with time. By 100-160 min the distribution was: liver, triacylglycerol 83%, phospholipid 7%, free fatty acid 4%; fat, triacylglycerol 80%; heart, triacylglycerol 38%, phospholipid 33%, free fatty acid 9%; kidney, triacylglycerol 15%, phospholipid 58%, free fatty acid 10%; muscle, triacylglycerol 70%, phospholipid 10%, free fatty acid 10%; lung, phospholipid 75%; brain, phospholipid 80%. It was concluded that free fatty acid transferred from the mother contributes substantially to fetal lipids in late gestation in this species.