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Hepatic lipase has a putative role in the catabolism of HDL particles and, while its activity is dependent upon insulin in the rat, no such insulin responsiveness has been demonstrated in man. We studied 21 patients with type 2 diabetes to examine whether hepatic lipase activity was influenced by hyperinsulinaemia during a 2-4 h isoglycaemic clamp study. Acute changes in lipids, lipoproteins and apolipoproteins were also documented in pre- and post-clamp serum. Hepatic lipase activity during hyperinsulinaemia was compared with activity measured after an equivalent period without insulin. For comparison, nine non-diabetic subjects (matched for age and body mass index) underwent similar clamp studies. In the control experiment without insulin, hepatic lipase activity did not change significantly (mean 9.7 (range 2.3-22.3) in the morning and 9.9 (3.0-22.5) mmol h-1 l-1 in the afternoon, NS). In contrast, after the hyperinsulinaemic clamp, hepatic lipase activity fell significantly in diabetic subjects from 12.8 (4.4-30.6) to 10.4 (3.3-31.3) mmol h-1 l-1, P less than 0.0002 along with serum triglycerides and total and LDL cholesterol. The change in hepatic lipase activity was positively related to the fasting apoprotein B concentration (Spearman r = 0.54, P = 0.016). In the normal subjects, a similar decline in hepatic lipase activity was observed during hyperinsulinaemia (from 15.1 (9.8-32.7) to 12.6 (6.3-28.3) mmol h-1 l-1, P less than 0.01) along with decreases in total, HDL and LDL cholesterol, triglycerides and apoproteins A1 and B.(ABSTRACT TRUNCATED AT 250 WORDS)

The plasma glucose and insulin responses to oral glucose were studied in 44 women who had previously had gestational diabetes, but had reverted to normal glucose tolerance. Twenty were White, 14 Black, and 10 Asian. A group of race-, age- and weight-matched controls was also studied. Fasting values of glucose and insulin did not differ significantly between the study group and controls. During the 2 h 75-g OGTT the White and Black previously gestational-diabetic women had similar plasma glucose values to their controls, while the Asian previously gestational-diabetic women had significantly higher glucose values at 30 min (9.2 +/- 0.6 (+/- SE) vs 7.1 +/- 0.3 mmol l-1, p less than 0.02) and at 60 min (8.6 +/- 0.8 vs 6.2 +/- 0.4 mmol l-1, p less than 0.02). Compared with their race-matched controls, the White previously gestational-diabetic women had significantly lower insulin values at 60 min (median 41 range 2-91) vs 56 (15-118) mU l-1, p less than 0.05), and the Black previously gestational-diabetic women had lower values at both 30 min (17 (4-116) vs 53 (22-197) mU l-1) and 60 min (36 (4-148) vs 99 (12-169) mU l-1, p less than 0.05). The insulin values were similar during the OGTT in the Asian previously gestational-diabetic women and their controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: The aim of this study was to compare intermediary metabolism in glucose tolerant women with previous gestational diabetes and control women without a history of gestational diabetes., Subjects: Fifteen women with previous gestational diabetes and 15 controls individually matched for race, age and body mass index were included. Only subjects with normal glucose tolerance were included in this study., Methods: Plasma glycerol, 3-OH butyrate, non-esterified fatty acids (NEFA), glucose and insulin were measured fasting and following a 75 g oral glucose load., Results: The women with previous gestational diabetes and their matched controls were of similar racial origin, age and body mass index. There was no difference between those with previous gestational diabetes and controls in fasting glycerol, 3-OH butyrate, NEFA, glucose or insulin concentrations. Following the oral glucose load, glycerol, 3-OH butyrate and NEFA concentrations fell in both groups. However, compared with controls at 120 minutes, those with previous gestational diabetes had significantly higher concentrations of glycerol (median 57, range 24-216 vs 27, range 8-89 mumols/l, P less than 0.005) and 3-OH butyrate (9, range 1-18 vs 5, range 2-11 mumols/l, P less than 0.01). NEFA concentrations were similar in the two groups. Despite similar glucose concentrations during the oral glucose tolerance test the insulin response during the first 60 minutes following oral glucose was significantly reduced in the subjects with previous gestational diabetes when compared with controls (insulin area, 0-60 minutes; 2172, range 788-4767 vs 2830, range 996-4784 pmol min/l, P less than 0.05)., Conclusions: Women with a previous history of gestational diabetes, despite having normal glucose tolerance, have defective insulin release with resultant abnormalities of intermediary metabolism.

1. Sialic acid moieties of erythrocyte membrane glycoproteins are the principal determinants of the negative charge on the cell surface. The resultant electrostatic repulsion between the cells reduces erythrocyte aggregation and hence the low shear rate viscosity and yield stress of blood. 2. Using g.c.-m.s., a decrease in sialic acid content has been observed in the major erythrocyte membrane glycoprotein, glycophorin A, obtained from nine diabetic patients compared with that from seven normal control subjects [median (range): 3.30 (0.01-11.90) versus 18.60 (3.20-32.60) micrograms/100 micrograms of protein, P less than 0.02]. 3. Erythrocyte aggregation, measured by viscometry as the ratio of suspension viscosity to supernatant viscosity (LS/S) in fibrinogen solution, was increased in ten diabetic patients compared with ten normal control subjects (mean +/- SEM, 37.6 +/- 1.3 versus 33.8 +/- 0.6, P less than 0.02). 4. In the patients in whom both viscometry and carbohydrate analysis were performed, the decrease in erythrocyte glycophorin sialylation and the increase in erythrocyte aggregation in fibrinogen solution were related statistically (LS/S correlated negatively with glycophorin sialic acid content, r = 0.73, P less than 0.05). 5. Decreased glycophorin sialylation provides an explanation at the molecular level for increased erythrocyte aggregation and it may be important in the pathogenesis of vascular disease in diabetes.

Objective: To assess cardiac structure and function in patients with treated hypopituitarism and to determine their relation to the degree of growth hormone deficiency and body composition pattern., Design: 26 patients with treated hypopituitarism were studied by cross sectional and Doppler echocardiography and by exercise testing. The results were analysed and their relation to the degree of growth hormone deficiency and body composition determined., Setting: All tests were performed in the department of cardiology and the unit of metabolic medicine at a tertiary referral centre., Patients: Patients with hypopituitarism referred for endocrine assessment., Main Outcome Measures: Left ventricular mass, left ventricular diastolic function, and exercise capacity in patients with hypopituitarism and their relation to growth hormone deficiency., Results: Mean (SD) serum concentration of insulin-like growth factor 1 (IGE-1), a measure of growth hormone deficiency, was 82.4 (45) micrograms/l. Lean body mass calculated by measuring total body potassium was 50 (9) kg. All patients had a normal left ventricular mass index and a normal left ventricular ejection fraction. Eight patients had abnormal left ventricular diastolic function. There was a significant correlation between IGF-1 and left ventricular mass (r = 0.45, p less than 0.02). Lean body mass was also significantly correlated with left ventricular mass (r = 0.78, p less than 0.0001) and left ventricular diastolic function (r = -0.63, p less than 0.01). The mean exercise duration was 8.6 (3.6) minutes. There was a significant correlation between serum IGF-1 and the rate-pressure product on exercise (r = 0.47, p less than 0.01). Seven patients had planar ST segment depression greater than 0.1 mV during exercise testing. In five of these patients there was rapid resolution of ST segment depression immediately after exercise. Two patients developed considerable ST segment depression, and subsequent coronary angiography showed normal coronary arteries. Exercise-induced ST segment depression was not related to the severity or duration of growth hormone deficiency or serum cholesterol concentration., Conclusions: This study suggests that left ventricular mass and the rate-pressure product are related to the degree of growth hormone deficiency, that left ventricular diastolic dysfunction is frequently seen in hypopituitarism, and that these patients may have ischaemic-like ST segment changes during exercise testing. These findings may explain the increased cardiovascular mortality in patients with hypopituitarism and may also have implications for growth hormone replacement therapy in adults.

Adults with hypopituitarism die prematurely, and the excess mortality is from vascular disease. On echocardiography we have demonstrated abnormalities of myocardial diastolic function in hypopituitary adults, indicating possible early ischaemic change. Peripheral arterial disease is evident on ultrasonography. Vascular risk factors have also been examined. Impaired glucose tolerance and unrecognized diabetes are common in hypopituitary adults. Total cholesterol levels are elevated, particularly in hypopituitary women. The role of growth hormone (GH) deficiency in the vascular disease and in the vascular-risk-factor abnormalities is unknown at present. Prolonged GH therapy causes a decrease in the levels of fasting total cholesterol, without any adverse effects on glucose homeostasis. GH therapy trials in adults will clarify the role of GH in the excess vascular risk of hypopituitarism. Prolonged GH therapy will be necessary for the vascular effects to be defined.

Dopamine plays an important role in the hypothalamic-pituitary axis where its major effects are to inhibit pituitary hormone secretion and cell division. Chronic dopamine deficiency has been postulated as a cause of pituitary tumour formation and several lines of evidence exist to suggest that a functional deficiency may develop as a result of defective dopamine receptor action. The available data suggest that a number of sites in the dopamine-D2 receptor-second messenger pathways may be implicated. These abnormalities are reflected in the variety of responses to dopamine and its agonists which have been observed in pituitary tumours both in the clinical situation and in cultured cells in vitro. Whilst it seems likely that the primary defect in pituitary tumour formation lies within the pituitary itself, the role of hypothalamic factors in facilitating tumour growth remains to be explored. Further studies of the dopamine receptor and its function will be of value not only in pathophysiological studies of human pituitary adenomas, but also in the development of new pharmacological agents to treat patients with these tumours.

Objectives: To investigate whether growth hormone (GH) absorption is site dependent., Design and Measurements: Human growth hormone (hGH, Norditropin) 4 IU, was injected subcutaneously on two separate occasions: into the thigh on one occasion and into the abdomen on a second occasion. Blood was sampled for GH, insulin, glucose, non-esterified fatty acids and glycerol at baseline and hourly for 12 hours. Serum insulin-like growth factor I was measured at baseline, and after 12 and 24 hours., Subjects: Eleven healthy young adults (8 M, 3 F)., Results: Following the injection serum GH had risen by 1 hour and peaked by 3-6 hours. The peak GH and growth hormone area under the curve were significantly higher after injection in the abdomen compared with the thigh (GH peak (mean +/- SEM) 103 +/- 20 vs 41 +/- 8 mU/l, P = 0.002 and GH area 528 +/- 86 vs 239 +/- 34 mU/l h, P = 0.003 respectively). Serum insulin-like growth factor I at 12 and at 24 hours showed a significant rise from the baseline level, but no significant difference was observed between the two injection sites. No significant difference in plasma insulin, glucose, non-esterified fatty acids or glycerol was observed between the two methods of injection., Conclusion: Subcutaneously injected GH is better absorbed from the abdominal site than from the thigh.

1. The purpose of the present study was to examine the ability of insulin to inhibit its own secretion in type 2 diabetes independently of the prevailing plasma glucose concentration. 2. The responses of the plasma C-peptide concentration to sustained hyperinsulinaemia were assessed during a 200 min isoglycaemic clamp study in 14 patients with type 2 diabetes and seven age- and weight-matched control subjects. The arterialized venous plasma glucose concentration was clamped at approximately 0.3 mmol/l below each subject's own basal level and was not permitted to rise above the basal level. 3. In the fasting state, the plasma C-peptide concentration was slightly, but not significantly, higher in the diabetic patients than in the control subjects (667 versus 413 pmol/l, respectively, P = 0.07), but it remained significantly higher in the diabetic patients during the clamp studies in absolute terms (minimum plasma C-peptide concentration 400 pmol/l in diabetic patients versus 151 pmol/l in control subjects, P less than 0.05) and was suppressed to a lesser extent when expressed as a percentage change from basal (35.8% in diabetic patients versus 59.4% in control subjects, P less than 0.01). 4. In order to investigate whether a high plasma glucose concentration was maintaining the plasma C-peptide concentration in the diabetic patients, six of these patients underwent a second clamp study at euglycaemia (plasma glucose concentration 5.2 mmol/l). Under these conditions, the plasma C-peptide concentration was suppressed to the same extent as in the control subjects (from 623 to 195 pmol/l, a change of 62.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Some pituitary tumours respond to dopamine by decreasing the release of prolactin and/or GH and by inhibition of tumour growth. Certain tumours are unresponsive. Dopamine D2 receptor high-affinity binding is impaired in these tumours, and the rat GH3 cell line behaves in a similar way. The hypothesis that the dopamine-binding defect results from impaired D2 receptor gene expression has been tested in the present study. On Northern blots, D2 receptor mRNA was present in both normal rat pituitary cells and in GH3 cells. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis identified a putative D2 receptor protein in normal and GH3 cell membranes. The lack of effect of dopamine in GH3 cells does not reflect the absence of D2 receptor gene expression.

Objective: Polycystic ovary syndrome (PCOS) is said to be associated with hyperinsulinaemia. Insulin stimulates androgen production by ovarian tissue in vitro and previous studies have identified a positive correlation of insulin with androstenedione. The aim of the present study was to discover whether insulin levels correlate with clinical presentation and with markers of androgen transport and metabolism in women with PCOS., Design: Within-group analysis of clinical and biochemical characteristics of a consecutive series of women with PCOS, focusing on correlations of plasma insulin with clinical presentation and androgens. Insulin levels were also compared with a control group of normal women., Patients: Forty-seven women who presented with hirsutism, cycle abnormalities or both, with ultrasound proven PCOS, were recruited. Mean age was 26.6 +/- 0.7 years (mean +/- SEM), BMI 27.3 +/- 1.2 kg/m2., Measurements: Plasma insulin levels were measured at 30-minute intervals for 3 hours following a 75 g glucose load. Blood was also taken for measurement of testosterone (T), androstenedione (A), free testosterone (fT), sex hormone binding globulin (SHBG) and insulin-like growth factor-I (IGF-I). Androsterone glucoronide (AG), a marker of peripheral androgen metabolism, was also measured., Results: Neither basal insulin nor the sum of insulin measurements during the glucose tolerance test (sumINS) in women with PCOS were significantly different from a control group with normal ovaries. Within the PCOS group, basal insulin was greater in women with irregular cycles or amenorrhoea than in those with regular ovulatory menses (8.0 +/- 1.1 vs 3.1 +/- 1.5 mU/l, P less than 0.01) despite similarly raised androgen levels. Both basal insulin and sumINS correlated with BMI in women with PCO (r = 0.37, P less than 0.05 and r = 0.64, P less than 0.01 respectively) but not in controls. There was no significant correlation between insulin or IGF-I levels and T, A or AG despite a positive correlation of AG (but no other androgen) with BMI. SHBG showed an inverse correlation and fT correlated positively with sumINS (r = -0.51, P less than 0.01; r = 0.39, P less than 0.05). Regression analysis of each of the androgens on the other variables demonstrated no significant relationship between insulin and androgens., Conclusions: These data suggest that, in vivo, the major effect of insulin on androgen secretion is mediated by changes in SHBG rather than by direct stimulation of ovarian androgen production. Higher insulin concentrations in anovulatory compared with ovulatory women with hyperandrogenaemia may indicate that insulin resistance in the ovary contributes to the mechanism of anovulation in PCOS.

1. A study on seven Caucasian glucose-tolerant women with previous gestational diabetes and seven matched control subjects is presented. The insulin response to oral glucose, insulin sensitivity and fasting glucose production rates were measured by using a 75 g oral glucose tolerance test, an insulin tolerance test and a non-radioactive tracer, [6,6-2H]glucose, respectively. 2. Fasting plasma glucose levels were similar between the women with previous gestational diabetes and the control subjects (4.8 +/- 0.3 versus 4.7 +/- 0.2 mmol/l), as were fasting plasma insulin levels (median 4 m-units/l, range 1-13 m-units/l versus median 4 m-units/l, range 1-24 m-units/l). After oral glucose the 60 min plasma glucose levels in the women with previous gestational diabetes were significantly higher (8.5 +/- 0.6 versus 6.7 +/- 0.8 mmol/l, P less than 0.05), whereas the plasma insulin level was significantly lower at both 30 min (median 23 m-units/l, range 4-47 m-units/l versus median 55 m-units/l, range 23-100 m-units/l, P less than 0.02) and at 60 min (median 23 m-units/l, range 4-43 m-units/l versus median 60 m-units/l, range 16-126 m-units/l, P less than 0.02). 3. Insulin sensitivity, expressed as the slope of the regression line of plasma glucose level against time after intravenous infusion of insulin (0.05 unit/kg), was similar in the women with previous gestational diabetes and the control subjects (mean slope, -0.17 +/- 0.01 versus -0.17 +/- 0.01). 4. Fasting glucose production rates were similar in the women with previous gestational diabetes and the control subjects (2.2 +/- 0.3 versus 1.9 +/- 0.1 mg min-1 kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Fourteen male patients with Type 2 diabetes were studied to identify relationships between insulin-mediated glucose disposal, basal and glucose-stimulated insulin secretion, fasting lipoproteins and apolipoproteins, and the activities of lipoprotein lipase and hepatic lipase. Sensitivity of glucose disposal to exogenous insulin correlated positively with HDL-cholesterol (r = 0.65, p less than 0.05), HDL2-cholesterol (r = 0.59, p less than 0.05), and apolipoprotein A1 (r = 0.57, p less than 0.05) and negatively with apolipoprotein B (r = -0.53, p less than 0.05) and total: HDL-cholesterol ratio (r = -0.68, p less than 0.01). Fasting C-peptide correlated negatively with HDL-cholesterol (r = -0.76, p less than 0.01), HDL2-cholesterol (r = -0.80, p less than 0.001) and apoprotein A1 (r = -0.56, p less than 0.05) and positively with total: HDL-cholesterol ratio (r = 0.64, p less than 0.05). Neither fasting plasma glucose nor the indices of stimulated insulin secretion (glucose-stimulated plasma insulin and C-peptide) were related to any of the lipoprotein measures. Insulin insensitivity and hyperinsulinaemia were both associated with higher levels of hepatic lipase activity but did not influence lipoprotein lipase activity. In multiple linear regression analysis, hepatic lipase activity was related to HDL-cholesterol independent of insulin insensitivity. In addition, fasting C-peptide alone accounted for 70% of the variance in hepatic lipase activity and this was independent of insulin sensitivity and body mass index. We propose that the abnormalities of HDL-cholesterol in Type 2 diabetes are closely related to enhanced hepatic lipase activity brought about by increased insulin secretion which, in turn, is secondary to the defect in insulin action.

To determine firstly whether body fat distribution could predict the presence of atherogenic risk factors better than overall adiposity in Type 2 diabetes, and secondly whether sex differences in these risk factors could be explained by sex differences in fat distribution, waist-to-hip girth ratio (WHR), serum lipids, lipoproteins, apolipoproteins, plasma lipolytic activity, and blood pressure were assessed in 47 patients with Type 2 diabetes, 21 women matched for age, body mass index (BMI) and blood glucose control with 26 men. The men had higher WHR (0.95 (range 0.83-1.07) vs 0.82 (0.74-0.94), p less than 0.001), lower HDL-cholesterol (1.03 +/- 0.05 vs 1.38 +/- 0.06 mmol l-1, p less than 0.001) and apolipoprotein A1 (1.40 +/- 0.06 vs 1.76 +/- 0.06 gl-1, p less than 0.001) concentrations, and higher hepatic lipase activities (16.2 (6.4-38.0) vs 8.6 (2.3-23.1) mmol h-1 l-1, p less than 0.01). In both men and women, BMI and WHR were positively related to serum triglyceride, insulin and C-peptide concentrations. In women, HDL-cholesterol was negatively related to BMI (r = -0.45, p less than 0.05) but only possibly related to WHR (r = -0.33, NS). In men, by contrast, WHR was related negatively to HDL-cholesterol (r = -0.60, p less than 0.005), HDL2-cholesterol (r = -0.43, p less than 0.05), and apolipoprotein A1 (r = -0.70, p less than 0.001) and positively to hepatic lipase activity (r = 0.65, p less than 0.001), whereas the same relationships with BMI were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors contributing to fasting hypertriglyceridaemia were studied in 20 patients with non-insulin-dependent diabetes--nine with normal triglyceride concentrations [fasting triglyceride 0.94 (range 0.58-1.23) mmol l-1] and eleven with mild fasting hypertriglyceridaemia [fasting triglyceride 2.4 (1.82-4.0) mmol l-1]. The patients with hypertriglyceridaemia were more obese [body mass index 29.0 (24.6-33.8) vs. 25.7 (21.9-30.1) kg m-2, P less than 0.05] and demonstrated impaired glucose disposal in response to exogenous insulin at isoglycaemia [insulin sensitivity index, SIp 0.7 (0.27-2.5) vs. 2.4 (0.62-5.1) ml m-2 min per mU l-1, P less than 0.001]. Basal non-esterified fatty acid (NEFA) and glycerol concentrations were higher and were suppressed to a lesser extent during isoglycaemic hyperinsulinaemia. Fasting glucose and apolipoprotein B concentrations were higher in the hypertriglyceridaemic patients, but lipoprotein lipase activities were similar in the two groups. When the effect of obesity was removed (by weight-matching six normotriglyceridaemic with seven hypertriglyceridaemic patients) basal NEFA and glycerol concentrations and the suppression of NEFA in response to insulin remained significantly different between the two groups. We propose that defects in both the glucoregulatory and antilipolytic actions of insulin contribute to mild fasting hypertriglyceridaemia in NIDDM, and that these defects cannot be attributed solely to obesity. These disorders of insulin action may also have important implications for the postprandial metabolism of triglyceride-rich lipoproteins and hence atherogenesis.

Fasting plasma proinsulin, insulin and glucose concentrations were measured in ten women with mild gestational diabetes and ten controls matched for race, age (32 +/- 6 vs 31 +/- 6 years), body mass index (28 +/- 8 vs 27 +/- 6) and gestational week (24 +/- 4 vs 25 +/- 4 weeks). There was no significant difference in fasting plasma glucose between these gestational diabetics and their controls (median 4.7, range 3.7-6.0 mmol/l vs 4.5, range 3.4-5.3 mmol/l). The fasting proinsulin levels were significantly higher in the gestational diabetics compared with the controls (median 12.2, range less than 4-14.8 pmol/l vs 5.8, range less than 4-12.8 pmol/l, P less than or equal to 0.02, Wilcoxon Summed Rank Test), while the calculated intact insulin levels (immunoreactive insulin minus proinsulin) were significantly lower (median 14.5, range 6.3-81.8 pmol/l vs 51.6, range 11.7-312 pmol/l, P less than or equal to 0.01). The ratio of proinsulin to calculated intact insulin was significantly higher in the gestational diabetics than the controls (median 0.66, range 0.16-2.04 vs 0.12, range 0.03-0.62), P less than or equal to 0.01). These results demonstrate that gestational diabetics, with normal fasting plasma glucose values, have abnormalities in pancreatic beta-cell secretion, which are likely to be important both in the aetiology of gestational diabetes and non-insulin dependent diabetes.

Twelve-hour hormonal and metabolic profiles were performed in a 68-year-old woman with a benign adrenal phaeochromocytoma (a) prior to adrenergic blockade, (b) after the establishment of pharmacological alpha-blockade with phenoxybenzamine, (c) after combined alpha and beta-blockade with phenoxybenzamine and propranolol, and (d) after successful surgery and withdrawal of medication. Pretreatment, (a) vs (d), significant elevations (12-h mean +/- SD) were observed in the concentrations of noradrenaline (44.9 +/- 14.4 vs 2.3 +/- 0.7 nmol/l, P less than 0.01), glucose (6.9 +/- 1.9 vs 5.0 +/- 1.0 mmol/l, P less than 0.05), glycerol (0.22 +/- 0.02 vs 0.07 +/- 0.01 mmol/l, P less than 0.01), non-esterified fatty acids (0.71 +/- 0.28 vs 0.34 +/- 0.08 mmol/l, P less than 0.01), and total ketone bodies (0.08 +/- 0.03 vs 0.03 +/- 0.02 mmol/l, P less than 0.01). Alpha-blockade, (b) vs (a), was associated with an increase in noradrenaline levels (P less than 0.01) but not with any significant alterations in intermediary metabolite concentrations. Following the establishment of combined alpha and beta-blockade, (c) vs (b), plasma noradrenaline returned to its pretreatment level while the concentrations of glycerol, fatty acids and ketone bodies were normalized. A completely physiological 12-h blood glucose profile, however, was observed only post-operatively. No significant differences were observed in mean plasma insulin levels between the four studies. These results indicate impaired regulation of multiple aspects of carbohydrate, lipid and ketone body metabolism in our patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose tolerance and insulin secretion were studied in 56 women 6-12 years following a pregnancy complicated by gestational diabetes, and in 23 matched controls. At recall 14 women were known to have diabetes and five were again pregnant with recurrent gestational diabetes. The early development of diabetes was associated with a fasting plasma glucose greater than 6 mmol/l during pregnancy and with a high plasma glucose response to oral glucose which persisted after delivery. Obesity was predictive of non-insulin-dependent diabetes whereas those that later required insulin were not obese. At recall, seven of the remaining 37 women were found to have unrecognized diabetes, 13 had impaired glucose tolerance (IGT) and 17 were normal by WHO criteria using a 75 g oral glucose tolerance test. In these 37 women, fasting plasma glucose and the glucose response to oral glucose in pregnancy were not predictive of subsequent diabetes or impaired glucose tolerance. Obesity in pregnancy and subsequent weight gain were associated with non-insulin-dependent diabetes and impaired glucose tolerance at recall. Insulin deficiency was observed during the oral glucose tolerance test in the diabetics (the mean +/- SEM ratio insulin area:glucose area 4.1 +/- 1.3 diabetics, 10.7 +/- 1.8 controls, p less than 0.05), whereas in the group with impaired glucose tolerance insulin levels were high and in proportion to their hyperglycaemia (insulin area:glucose area 10.9 +/- 1.4 IGT, 9.4 +/- 1.4 controls). Women with normal glucose tolerance and previous gestational diabetes had significantly lower insulin responses than their controls, despite mild hyperglycaemia (insulin area:glucose area 4.0 +/- 0.7 normal glucose tolerance, 7.6 +/- 1.1 controls, p less than 0.02). Abnormalities of glucose tolerance and insulin secretion are present following a gestational diabetic pregnancy. Gestational diabetes identifies women at risk for developing diabetes and impaired glucose tolerance, both of which are risk factors for premature vascular disease.

Objective: Glycaemic control in a young woman with "brittle" diabetes., Design: Use of a preprogrammable fully implanted pump (Infusaid) to deliver insulin intraperitoneally at variable rates, giving a total dose of about 60 units/24 h., Setting: Endocrinology department in a teaching hospital., Patient: Thirty year old woman with 15 years' history of "brittle" diabetes., Main Outcome Measures: Glycated haemoglobin concentration; plasma glucose concentration., Results: After implantation of the pump there was an immediate and sustained improvement in diabetic control. The patient's glycated haemoglobin concentration decreased from 15.2% to 9.2% over seven months. Her daily glucose concentrations were in the range 3.5-12 mmol/l. She has not been admitted to hospital since implantation of the pump, which was eight months before the time of writing., Conclusion: The implanted programmable intraperitoneal insulin pump may be of value in the management of patients with "brittle" diabetes in whom other attempts at glycaemic control have failed.

The basis for the hypothesis that growth hormone is a permissive factor in the pathogenesis of diabetic microvascular complications is a weak one. The best way forward in this research will be to devise a pharmacological method of suppressing growth hormone secretion in diabetic subjects.

The mean additional energy requirement for pregnancy has been calculated at 285 kcal daily and it reflects the energy needs for production of the fetoplacental unit and for the maternal physiological adaptations to pregnancy. In practice there is considerable variation in energy requirement due to alterations in maternal energy expenditure. Optimal energy intakes are dictated also by the pre-pregnancy maternal weight. The outcome of pregnancy is improved in the underweight mother by an intake which produces a weight gain in pregnancy of approximately 14 kg, whereas a rise of only 7 kg may be optimal for the obese mother. Obesity with or without diabetes is associated with macrosomia and other problems and it is sensible to attempt to limit weight gain in pregnancy at a time when maternal motivation is high. Diabetes in pregnancy may arise in patients with pre-existing NIDDM or IDDM, but more commonly it is diagnosed for the first time during pregnancy and it usually disappears after delivery (gestational diabetes). Recent evidence suggests that gestational diabetes has a strong genetic component and is usually NIDDM precipitated early in life by the pregnancy. Both gestational diabetes and NIDDM are characterized by insulin deficiency and by insulin resistance. Long-term follow-up studies have demonstrated that NIDDM or impaired glucose tolerance develop in later life in 50-70% of women with previous gestational diabetes. The adverse effects of pregnancy on the mother with pre-existing diabetes may be minimized by good diabetic control as may be adverse effects on the fetus and neonate of diabetes in the mother. An increased incidence of fetal malformations persists in pregnancies with pre-existing maternal diabetes. Diabetes of any form may be associated with neonatal hypoglycaemia. The aim of therapy is to produce maternal normoglycaemia throughout pregnancy by dietary measures and insulin treatment if required. Women with pre-existing diabetes should tighten their blood glucose control from before conception. Optimization of insulin therapy and diet are required for IDDM and most NIDDM women will require insulin treatment in pregnancy. Gestational diabetics require diet and possibly insulin. Most pregnancies now proceed to term.

We have previously reported that glucose production assessed using radioisotopic methods is 50% increased in hyperthyroidism but 30% decreased in hypothyroidism. These studies, however, do not distinguish between glycogenolysis and gluconeogenesis. In fasting man more than 80% of circulating glycerol is cleared by the liver and enters the gluconeogenic pathway. We have therefore measured glycerol clearance following bolus intravenous glycerol administration as an indirect assessment of gluconeogenic capacity. Hyperthyroid and hypothyroid subjects were compared with separate matched controls after an overnight fast. In hyperthyroid subjects blood glucose and blood glycerol were increased but lactate, pyruvate, and alanine concentrations were normal. Glycerol clearance was increased in hyperthyroidism and followed a double exponential decay with a shortened second component half-time. Endogenous glycerol production was increased three-fold. In hypothyroidism fasting circulating levels of glucose, lactate, pyruvate, alanine, and glycerol were normal but glycerol clearance was diminished. Both first and second component half-times were prolonged in hypothyroidism and endogenous glycerol production was decreased by 50%. Thus in hyperthyroidism glycerol clearance is greatly enhanced whilst in hypothyroidism glycerol clearance is diminished. The magnitude of the changes suggests that alterations in gluconeogenesis are probably the major factors concerned in the reported increase and decrease in glucose production in hyperthyroidism and hypothyroidism respectively.

Blood glucose test strips provide a convenient and rapid method for estimation of blood glucose. They can be read either by eye against a color scale or in a reflectance meter. This study compares the performance characteristics of the principal test strips available. When read visually, the BM Glycemie 20-800 (Chemstrip bG) strip was shown to be more accurate than the Dextrostix strip. Comparison of the meter systems showed Reflotest-Glucose to be more accurate and precise than Dextrostix. This was because the Reflotest system was read closer to the endpoint of color development and because there was less subsequent color fade than with the Dextrostix system. Reflotest-Glucose and Reflotest-Hypoglycemie developed colors that were stable for at least 2 days after completion of the test. However, when using a reflectance meter the Reflotest system required two strips to cover the important range of blood glucose.

Circulating hormone and metabolite profiles have been studied in ten patients with alcoholic cirrhosis, five patients with alcoholic hepatitis and/or fatty liver, and nine normal controls over a 12-h period of meals and activity. Blood glucose was elevated throughout the day in both cirrhotic and non-cirrhotic alcoholics (mean 12-h glucose; controls 5.38 +/- 0.16 (SEM) mmol/l; cirrhotics 6.98 +/- 0.30 mmol/l, P less than 0.001; non-cirrhotics 7.18 +/- 0.26 mmol/l, P less than 0.001). Non-cirrhotic alcoholics had an exaggerated insulin response to meals, whereas cirrhotic patients had hyperinsulinaemia throughout the day (mean 12-h insulin; controls 16.3 +/- 2.3 mU/l; cirrhotics 35.8 +/- 6.6 mU/l, P less than 0.02). Growth hormone levels were elevated only in patients with cirrhosis (mean 12-h growth hormone, 7.06 +/- 1.35 v. 0.85 +/- 0.17 micrograms/l, P less than 0.001). Serum cortisol was persistently elevated in cirrhotics but only in the evening in non-cirrhotic alcoholics. Lactate and pyruvate responses to meals were exaggerated in non-cirrhotic patients whereas in cirrhotics, levels were persistently raised. Blood glycerol was elevated in all alcoholic patients whereas ketone body levels were normal. Hypertriglyceridaemia was observed only in non-cirrhotic patients. No relationship between the endocrine and metabolic state was observed in either cirrhotic or non-cirrhotic patients.

The effects of dopamine blockade on the endocrine and metabolic response to starvation have been investigated by administration of metoclopramide, 30 mg daily, or placebo to five normal subjects fasted for sixty hours on two occasions. Blood glucose and alanine concentrations fell with starvation and metoclopramide had no further effect. Concentrations of the other gluconeogenic precursors, lactate and pyruvate, were also unaffected by metoclopramide. The rise in circulating ketone body concentrations with fasting was impaired by metoclopramide, significantly from 44 h onwards (blood total ketone body concentration at 60 h, 3.42 +/- 0.94 mmol/l with placebo; 2.08 +/- 0.67 mmol/l with metoclopramide, P less than 0.05). Blood glycerol and plasma non-esterified fatty acids (NEFA) levels rose with starvation, and metoclopramide had no further effect. Serum insulin concentrations remained low with fasting, while circulating glucagon and growth hormone levels rose. Similar changes were noted with both metoclopramide and placebo. Serum prolactin concentrations during starvation were elevated two to four fold by metoclopramide. The inhibitory effect of dopamine blockade on ketosis thus occurred despite hyperprolactinaemia, and did not result from measurable alterations in insulin, glucagon or growth hormone secretion. The data suggest a stimulatory role for endogenous dopamine on starvation ketonaemia in man.

Twelve insulin deficient Type 1 (insulin-dependent) diabetic subjects were studied over an 11 1/2 h period during both subcutaneous insulin therapy and closed loop insulin delivery, using a glucose controlled insulin system (Biostator) programmed to maintain normoglycaemia. Results were compared with those from 21 age and weight-matched normal subjects. Using the Biostator, normoglycaemia was achieved in all diabetic subjects within 3.5 h and normal profiles maintained thereafter. Blood metabolite and hormone values were evaluated during the subsequent 8 h normoglycaemic period. Subcutaneous therapy resulted in abnormal glucose levels throughout the study period (mean 8 h value 8.3 +/- 0.7 compared with 5.6 +/- 0.3 mmol/l on feedback control and 5.5 +/- 0.1 mmol/l in normal subjects). The mean value of lactate and pyruvate over the final 8 h period was 25% higher in diabetic patients than in normal subjects with no difference between the two insulin treatments (blood lactate: 0.94 +/- 0.04 on subcutaneous insulin, 0.91 +/- 0.04 on feedback control and 0.74 +/- 0.03 mmol/l in control subjects). The pre-prandial peaks of blood glycerol and plasma non-esterified fatty acids were significantly decreased or absent during both feedback control and subcutaneous therapy in comparison with the normal subjects, whereas after the midday and evening meals, total ketone body levels were significantly higher in the diabetic patients. Peripheral serum free insulin levels were two-to fourfold greater in the diabetic than in the normal subjects. There were no significant differences between levels in diabetic patients receiving subcutaneous insulin or on the Biostator. Glucose turnover (1600-1800 h) was normal on feedback control (1.41 +/- 0.20 versus 1.55 +/- 0.18 mg X kg-1 X min-1 in the normal subjects) but was significantly decreased during subcutaneous insulin (1.04 +/- 0.09 mg X kg-1 X min-1). There was, in addition, a decrease in glucose recycling during both subcutaneous insulin therapy and feedback control in the diabetic subjects. These data suggest that although fine control of glucose metabolism both in terms of circulating concentrations and rates of production can be achieved by feedback-control, insulin infusion by the peripheral route is associated with significant metabolic abnormalities, at least in the short term. Longer term studies and examination of portal insulin delivery seem warranted.

Certain hyperprolactinemic patients have an obvious pituitary tumor while others with normal pituitary radiology may or may not harbor a pituitary microadenoma. A variety of biochemical tests have been proposed to distinguish between those with and those without pituitary tumors. The aims of this study were: firstly to examine these tests to assess their efficacy in differentiating between patients with radiologically-demonstrated pituitary tumors and normal controls; and secondly to establish if those hyperprolactinemic patients with normal radiology formed two distinct groups biochemically as might be expected if some did and some did not have tumors. The prolactin (PRL) and thyroid stimulating hormone (TSH) response to domperidone and the PRL response to TRH and insulin-induced hypoglycemia have thus been examined in hyperprolactinemic subjects with and without radiological evidence of an adenoma and in normal controls. The basal serum PRL was similar in patients with and without radiological evidence of a pituitary adenoma. The serum PRL response to all stimuli studied, expressed as a percentage of initial values, was blunted in patients with known pituitary tumors with total separation from values in control subjects. Results for patients with normal pituitary radiology were similar to those for patients with tumors with minimal overlap with controls. The peak TSH increment after domperidone was exaggerated in patients with known tumors, but overlap with control values was observed in 25%. In patients with normal radiology the peak TSH increment after domperidone was similarly increased but again overlap with control values occurred in 28%. Cluster analysis showed no evidence of two subgroups of response with in the hyperprolactinemic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of dopamine in starvation ketonaemia was investigated in male Wistar rats by administration of a specific dopamine receptor antagonist, metoclopramide (4 mg . kg-1 . 24h-1), or placebo, intragastrically during a 48-h fast. Starvation alone caused a fall in blood glucose and gluconeogenic precursor concentrations, which was unaffected by metoclopramide administration. Circulating 3-hydroxybutyrate and acetoacetate levels rose with fasting alone but metoclopramide impaired this ketonaemic response. After 48-h starvation, total ketone body concentrations (mean +/- SEM) were 2.28 +/- 0.19 mmol/l with metoclopramide therapy, 3.49 +/- 0.21 mmol/l with placebo, P less than 0.001. Plasma non-esterified fatty acid levels were similar in metoclopramide- and placebo-treated animals, as were circulating concentrations of insulin, glucagon and growth hormone. Metoclopramide thus decreased the ketonaemic response to starvation without an apparent change in lipolysis or circulating hormone levels, suggesting a direct role for dopamine in production of starvation ketonaemia.

The metabolic and hormonal responses to oral glucose were studied in a patient with a pheochromocytoma before treatment, after alpha-blockade, after combined alpha- and beta-blockade, and after surgical removal of the tumor. Before treatment, fasting blood glucose was elevated [6.5 mmol/liter (117 mg/dl); normal range, 4.2--5.5 mmol/liter (75--100 mg/dl)], as was the fasting plasma nonesterified fatty acid level (1.19 mmol/liter; normal range, 0.06--0.7 mmol/liter), the blood total ketone body concentration (0.50 mmol/liter; normal range, 0.02--0.44 mmol/liter) and the lactate ot pyruvate ratio (16.2; normal range, 5.9--15.01. These abnormalities were corrected by alpha-adrenergic blockade alone and together with beta-blockade. Oral glucose tolerance (50 g) was mildly impaired in the untreated state, and the insulin response was decreased. Both alpha- and alpha- plus beta-blockade restored the insulin response to glucose but failed to correct the glucose intolerance. Three months after removal of the tumor, all metabolic findings were normal. The correction of the fasting metabolite concentrations and serum insulin levels by alpha-adrenergic blockade suggests that an alpha-adenergic effect causes the original metabolic abnormalities. The residual glucose intolerance after adrenergic blockade may result from incomplete blockade or factors other than alpha- and beta-adrenergic activity.

The metabolic responses to 4-h infusions of adrenaline (3 micrograms kg-1 h-1) and cortisol (10 mg m-2 h-1 for 2 h followed by 5 mg m-2 h-1 for 2 h), separately and in combination, have been studied in six healthy subjects with concurrent somatostatin infusion (250 micrograms h-1). A combined infusion of adrenaline, cortisol, glucagon (180 ng kg-1 h-1) and somatostatin has also been studied. Somatostatin plus adrenaline and somatostatin plus cortisol resulted in hyperglycaemia (at 240 min, somatostatin plus adrenaline 11.4 +/- 0.4 mmol l-1, P less than 0.001; somatostatin plus cortisol 6.7 +/- 0.3 mmol l-1, P less than 0.05; somatostatin alone 4.9 +/- 0.4 mmol l-1). No synergistic effect on blood glucose was seen with adrenaline and cortisol together. When glucagon was added, blood glucose rose more rapidly than without glucagon (9.3 +/- 0.4 mmol l-1 v. 7.2 +/- 0.5 mmol l-1 at 45 min, P less than 0.001), but plateau values were similar. Plasma NEFA levels were raised by somatostatin plus adrenaline (0.55 +/- 0.04-1.82 +/- 0.11 mmol l-1 at 60 min). Somatostatin plus cortisol had no more effect on plasma NEFA than somatostatin alone. During the combined infusion of somatostatin plus adrenaline plus cortisol, a synergistic effect on plasma NEFA was observed (2.30 +/- 0.11 mmol l-1 at 60 min, P less than 0.01 v. somatostatin plus adrenaline). This occurred despite a small escape of insulin secretion. The lipolytic actions of adrenaline are potentiated by elevated circulating cortisol levels in insulin-deficient man.(ABSTRACT TRUNCATED AT 250 WORDS)

Phobia and panic are defined by the measures used. Rating scales, diaries, global measures, physiological measures, behavioural assessment. Three fear systems: physiological, cognitive and behavioral. Concordance and discordance. Synchrony and desynchrony. The Behavioural Approach Test at the Calgary General Hospital.

Men with hyperprolactinaemia present with large tumours. Conventional therapy with surgery and/or irradiation is unsatisfactory, with up to 100% of patients remaining hyperprolactinaemic (or subsequently developing pituitary insufficiency). In view of reports of bromocriptine-induced regression of prolactinomas, eight consecutive male hyperprolactinaemic patients with impotence and/or symptoms related to local tumour effects were treated with bromocriptine 20 mg daily as sole therapy for 3-11 months. Symptoms were relieved partly or completely in seven patients and serum prolactin was restored to normal or near normal in all men. Serum thyroxine and plasma cortisol response to hypoglycaemia became normal in two men who had subnormal values before therapy. Mean serum growth hormone response to hypoglycaemia rose significantly as did plasma testosterone concentrations. Evidence of tumour regression, sometimes massive, was seen in the six patients who underwent repeat radiology. The symptomatic relief and biochemical and radiological improvement in these patients indicate that bromocriptine therapy may now be the treatment of choice for hyperprolactinaemic men with large tumours.

Pancreatic beta-cell function was evaluated in uraemic patients by measuring beta-cell peptides in the peripheral blood after intravenous glucagon (1 mg) stimulation. Patients in chronic renal failure, patients on haemodialysis, and both new and established subjects on continuous ambulatory peritoneal dialysis (CAPD) (10 in each group) were studied and compared to 8 healthy controls. Fasting glucose (3.6-4.4 mmol/l) and insulin concentrations (9.5-11.7 mU/l) were normal and did not differ between the uraemic groups, but c-peptide concentrations were markedly increased in uremia (1.84-2.38 nmol/l) compared to controls (0.48 nmol/l). Following glucagon stimulation an exaggerated blood glucose response with delayed glucose peak was observed, while the peak insulin response to glucagon was normal; however, the return to basal concentrations was delayed in uraemia. The c-peptide response was also exaggerated and peak concentrations in uraemic subjects (3.0-4.3 nmol/l) were significantly greater than controls (1.5 nmol/l). The response of CAPD patients was similar to those on haemodialysis and non-dialysed uraemic patients. The abnormalities seen were due to uraemia, and CAPD treatment had no specific adverse effect on beta-cell function. Thus, from this data there was no evidence that CAPD per se is detrimental to beta-cell integrity.

Transfusion of whole blood and some blood components may result in serious or fatal complications, among which hepatitis is most frequent (20,000 to 30,000 cases and 3,000 deaths a year). Although hepatitis B virus (HB Ag) sometimes is implicated in posttransfusion hepatitis, non-A non-B. virus(es) (hepatitis "C" virus) probably accounts for most posttransfusion hepatitis. Half of all blood transfusions may be unnecessary.Responsible transfusion practice requires use of appropriate blood components for which there is adequate justification. Transfusion of red blood cells should be given as packed cells in most instances and whole blood should seldom be used.

Bromocriptine therapy may cause regression of prolactinomas, but its effect on nonsecretory pituitary tumors is uncertain. Conventional treatment for such "functionless" tumors is surgery and/or radiotherapy, but recurrences pose a therapeutic dilemma. We describe a patient with such a tumor treated by surgery and radiotherapy who presented with recurrent disease 14 days later. On treatment with bromocriptine, 20 mg daily for 25 months, the intrasellar tumor recurrence had diminished in size and a suprasellar extension had almost disappeared. Bromocriptine therapy may therefore benefit some patients with nonsecretory pituitary tumors considered unsuitable for surgery or radiotherapy.

The effect of pergolide mesylate was studied in two previously untreated men with large prolactinomas and exceptionally high prolactin concentrations. The study was designed to determine whether pergolide would be effective in alleviating symptoms, correcting hormonal abnormalities and shrinking the tumour. Starting with 50 micrograms daily the dose of pergolide was slowly increased over 10 weeks to 1 mg once daily, when repeat assessment was performed. Both patients reported complete relief of symptoms, with no side effects. Serum prolactin concentration was suppressed to normal in both subjects, and evidence to suggest tumour shrinkage was observed. Pergolide appears to be effective treatment for men with large prolactinomas.

The interaction between the stimulatory effects of hpGRF 1-44 and the inhibitory effects of somatostatin on GH release have been investigated in six normal male subjects receiving continuous 4 h infusions of these peptides alone and in combination. hpGRF 1-44 0.3 microgram/kg/h alone produced a peak GH response of 27.0 +/- 7.6 mU/l (mean +/- SEM). Somatostatin 1.0 microgram/kg/h markedly inhibited the GH response to hpGRF 1-44 with mean levels less than 4.0 mU/l during the infusion, though a rebound rise in GH levels to 26.1 +/- 9.0 mU/l was observed at the end of the infusion period. Somatostatin 0.2 microgram/kg/h inhibited the GH response to hpGRF 1-44 to a lesser degree (peak GH during the infusion 11.7 +/- 2.5 mU/l) and the rebound rise in GH levels (maximum 13.2 +/- 4.3 mU/l) was less than that observed with high dose somatostatin. During somatostatin 1.0 microgram/kg/h alone GH levels were suppressed less than 1.0 mU/l followed by a rebound at the end of the infusion in only two subjects. These data demonstrate a dose-dependent inhibition of hpGRF 1-44 by somatostatin in vivo in man.

Patients with hyperprolactinemia may be managed by pituitary surgery or irradiation, bromocriptine treatment, or a combination of these methods, and some patients remain untreated. Little is known of the long-term consequences of some of these therapeutic regimens. Forty-six hyperprolactinemic patients (40 female and six male) managed solely with bromocriptine or no treatment over a period of 12 months to six years were therefore evaluated in this study. Nine patients with radiologically normal pituitary fossae were untreated and 10 received bromocriptine, 7.5 to 10 mg daily, while 20 patients with radiologic evidence of a pituitary tumor were treated with bromocriptine, generally 10 to 20 mg daily. Patients were assessed clinically, biochemically, and radiologically before treatment and at least six weeks after discontinuation of therapy. A further seven patients were similarly assessed before and after eight bromocriptine-induced pregnancies. Symptoms persisted in the untreated group of nine patients, although menstruation returned in four of the females with previous amenorrhea; serum prolactin levels remained elevated, other pituitary function did not change, and pituitary fossae remained normal radiologically. In all patients treated with bromocriptine, symptoms improved irrespective of radiologic findings on the pituitary, and were abolished in 67 percent during treatment associated with a decrease in serum prolactin levels in all, and a return of levels to within normal limits in 80 percent of patients. Persistent side effects were usually dose-related, but remained troublesome in 13 percent. Bromocriptine-induced tumor regression was evident radiologically in all patients with suprasellar tumor tissue and in some with purely intrasellar adenomas. This effect occurred rapidly and persisted or increased throughout follow-up. On discontinuation of treatment, prolactin levels remained significantly lower than before therapy (mean 2,934 versus 5,052 mU/liter, p less than 0.05) but were within the normal range in only two patients. Other pituitary function was unaltered, or improved in some patients with definite tumors. Bromocriptine-induced pregnancy produced no permanent change in clinical, biochemical, or radiologic status. Long-term bromocriptine treatment for hyperprolactinemia is thus highly effective in alleviating symptoms and suppressing prolactin secretion, and induces persistent tumor regression on treatment without deterioration of other pituitary function in patients with macroadenomas. On discontinuation of therapy, however, hyperprolactinemia usually recurs, and treatment may therefore need to be continued for years.

1. Glucose kinetics were assessed in seven normal adult male subjects by an intravenous bolus technique with the use of a non-radioactive isotopically labelled preparation, [6,6-2H]glucose, as tracer. Tracer enrichment in plasma was assessed by gas chromatography-mass spectrometry. For comparison five subjects also received a simultaneous intravenous bolus of [6-3H]glucose and kinetics were assessed by conventional means. 2. Administration of [6,6-2H]glucose did not alter circulating glucose or insulin concentrations. 3. Glucose turnover, assessed by the use of [6,6-2H]glucose, was 11.4 (+/- 0.9) micromol min-1 kg-1 and 11.6 (+/- 0.5) micromol min-1 kg-1 with rate of glucose was 2.3 (+/- 0.3) ml min-1 kg-1 with both isotopically labelled tracers. Estimates of mean residence time, glucose pool and glucose space were also similar by each technique. 4. [6,6-2H]Glucose is therefore an effective tracer and allows investigation of glucose kinetics without administration of a radioactive label.

Circulating intermediary metabolite and hormone concentrations were measured at intervals over 24 h in five uraemic patients before starting dialysis and after 3 months' treatment with continuous ambulatory peritoneal dialysis (CAPD) and in 13 non-uraemic normal controls. Fasting and postprandial glucose concentrations were significantly raised in uraemic patients undialysed and on CAPD but 24 h mean (+/- SEM) levels fell from 6.63 +/- 0.40 to 6.00 +/- 0.26 mmol/l (P less than 0.02) after 3 months' dialysis despite peritoneal glucose absorption. Insulin levels were raised in uraemic patients but were unchanged by CAPD. Uraemia was associated with raised levels of the gluconeogenic precursors lactate and alanine and a further rise in fasting and 24 h mean alanine concentrations occurred with CAPD. Fasting total ketone body concentrations were raised in undialysed uraemic patients but concentrations were suppressed throughout the 24 h in CAPD subjects. Fasting triglyceride concentrations were increased in uraemic subjects and mean 24 h levels rose by 30% from 1.55 +/- 0.42 mmol/l before dialysis to 2.02 +/- 0.59 mmol/l during CAPD. Non-esterified fatty acid concentrations were low in uraemic patients and remained low during CAPD. Undialysed and dialysed uraemic patients displayed raised plasma glucagon concentrations throughout the 24 h, suppression of the normal nocturnal secretion of growth hormone and raised mean cortisol levels, which were 23% (CAPD) to 57% (undialysed) higher than in normal controls. The endocrine and metabolic abnormalities of uraemia are not fully corrected by CAPD. Many of the additional changes observed during CAPD reflect an adaptation to the constant absorption of peritoneal glucose.

Growth hormone (GH) is important in diabetes in view of its anti-insulin actions and its relation to the long-term complications of the disease. The suppression of GH secretion in diabetics has theoretical and possible therapeutic interest. Native somatostatin has multiple actions, including inhibition of the secretion of insulin, glucagon, thyroid-stimulating hormone (TSH), and various gut hormones. It also has inhibitory effects on gastrointestinal motility, exocrine secretion, nutrient absorption, and splanchnic blood flow. Its therapeutic use is limited by a duration of effect of several minutes only. SMS 201-995 holds more potential than native somatostatin in view of its longer duration of action. Preliminary data suggest that 50 micrograms SMS 201-995 subcutaneously at night inhibits the nocturnal rise in GH secretion in normal man, but no effect on 24-h GH secretion is observed when SMS 201-995 is injected twice daily before meals. SMS 201-995 inhibits secretion of insulin, glucagon, and TSH in addition to growth hormone and induces carbohydrate intolerance when administered before food in normal subjects. Gastrointestinal side effects suggest additional effects on nutrient disposal, which are important when it is administered before food. Further studies are required to elucidate these effects of SMS 201-995 on endocrine and gastro-intestinal function in normal and diabetic man.

Growth hormone (GH) has long been considered to have importance in diabetes. With poor control in Type 1 diabetes GH levels are high and may aggravate poor metabolic control. Pharmacological suppression of GH release at this stage might reverse the metabolic changes, with the possible added benefit of lower plasma insulin concentrations. Diabetic patients with life-long GH deficiency rarely develop retinopathy, while pituitary ablation in patients with retinopathy often leads to improvement. Growth hormone release inhibiting factor, somatostatin, has a short plasma half-life, and multiple effects on the endocrine system and on the gastrointestinal tract, making it unsuitable for clinical use as a GH suppressant. Long-acting analogues have a long half-life, but remain non-specific in their effects. In Type 2 diabetes the analogue Octreotide suppresses insulin and glucagon release, leaving glucose levels either unchanged or somewhat elevated. Gastrointestinal side-effects have been common, but may diminish with long-term treatment. In Type 1 diabetes insulin requirement is decreased by Octreotide, but as in Type 2 diabetes GH suppression has been observed consistently only when the drug was given at bed-time. The decrease in insulin requirement may reflect suppression of glucagon release and/or gut effects. Amelioration of the 'dawn phenomenon' has not proved possible, and hypoglycaemia has proved a particular problem with Octreotide given subcutaneously at night. The lack of effective GH suppression (particularly in patients with proliferative retinopathy), lack of specificity, and the gut and hypoglycaemic side-effects, argue strongly against a clinical role for the current somatostatin analogues in diabetes mellitus.

Long-acting somatostatin analogues may be of benefit in certain hypersecretory endocrine and gastrointestinal disorders. The 24 h hormonal and metabolic profiles of six normal male subjects receiving a twice daily subcutaneous injection of one such analogue SMS 201-995, 50 micrograms, has been compared to that obtained following placebo injection. Spontaneous daytime peaks of GH secretion were delayed until 1400 h following SMS 201-995 but nocturnal and total 24 h GH secretion were unaffected. The nocturnal rise in thyrotrophin was abolished by SMS 201-995 but thyroid function was unaffected. Insulin levels were suppressed following SMS 201-995 and the response to meals was inhibited. Glucose intolerance followed main meals. Glucagon levels were suppressed for up to 6 h. Circulating alanine levels were raised between 1200 h and 0600 h and there were intermittent elevations in lactate, pyruvate, glycerol and 3-hydroxybutyrate. Amino acid levels, including branched chain amino acids, were also increased. All six subjects suffered gastrointestinal side-effects. SMS 201-995, 50 micrograms, given twice daily shortly before meals does not suppress 24 h GH secretion, but demonstrates significant effects on metabolism and causes side effects in normal subjects.