Pro-inflammatory effects of oestrogens during use of oral contraceptives and hormone replacement treatment.

The effects of two third-generation monophasic combined oral contraceptives (COC) and a postmenopausal hormone replacement therapy (HRT) consisting of 2 mg 17 beta-oestradiol on the plasma level of the acute-phase indicator C-reactive protein (CRP) and other acute-phase reactants were analysed. Two studies were conducted: (1) a randomised, open-label study with two different oral contraceptive preparations with an equal dose of ethinylestradiol (30 micrograms) and a different progestogen, either 75 micrograms gestodene (GSD-EE) or 150 micrograms desogestrel (DSG-EE); blood samples of 39 young women were analysed before and after 3, 6, 12 treatment cycles; (2) a randomised, blinded placebo-controlled study with 2 mg 17 beta-oestradiol in postmenopausal women with non-insulin-dependent diabetes mellitus without signs of cardiac involvement; blood samples of 38 women were analysed before and after 6 weeks of treatment. The plasma concentration of CRP increased strongly during oral contraceptive use for both preparations; the increase persisted over 12 cycles. The already elevated CRP in postmenopausal diabetic women showed a moderate increase after 6 weeks of treatment with 17 beta-oestradiol. CRP increases during oral contraceptive use were associated with changes in some other acute-phase proteins (fibrinogen, ceruloplasmin, von Willebrand factor [vWF]) originating from the liver and vessel wall, but not in others (interleukin-6 [IL-6], serum amyloid A [SAA]). The results demonstrate an increase in a specific set of acute-phase reactants caused by oestrogen-containing preparations. It is proposed that the pro-inflammatory effect of oestrogens should be checked for a relationship with the increased risk of thromboembolism for both oral contraceptive and HRT.

Management of type 2 diabetes: a challenge for patient and physician.

Type 2 diabetes mellitus is a chronic disease, associated with serious complications and co-morbidity and considerable costs. The number of people with diabetes mellitus is expected to increase with 40% in the next decade, due to prolonged life expectancy, the ageing of the population and developments in the health care sector, including more active screening strategies. The majority (40-60%) of type 2 diabetes patients in routine GP practice have a poor metabolic control (HbA1c > 8% or fasting blood glucose > 11 mmol/l). In this paper the obstacles in routine clinical practice for optimal type 2 diabetes care are discussed. Long-term complications are the major cause of morbidity and mortality in type 2 diabetes patients. Therefore, the primary aim of type 2 diabetes management is the prevention of complications, by lowering blood glucose levels and reducing the cardiovascular risk profile. An important component of type 2 diabetes management is an active role of the patient: diet, smoking habits, physical exercise and self-care behavior often need to change. In addition, the patient has to adhere to life long medical therapy. Motivating the patient for this active role is the challenge for health care providers. A complicating factor is that changes in lifestyle do not give immediate benefit for the patient, as the effects are seen in the reduction of the development of long-term complications. The cornerstones of health care to support active patient participation are: to guarantee the continuity of care, to integrate education in health care and to encourage the patient's attendance. It is the challenge for physicians to give type 2 diabetes patients the tools for active participation in the management of the disease.

The surgical approach to the adrenal gland: a comparison of the retroperitoneal and the transabdominal routes in 326 operations on 284 patients.

BACKGROUND: To compare the results of adrenalectomy using a retroperitoneal and a transabdominal approach, especially for adrenal carcinoma and pheochromocytoma. METHODS: A retrospective study was carried out at the Leiden University Medical Center. Charts of 284 patients who had undergone 326 adrenal operations between 1947 and 1995, including 44 patients with adrenal cancer and 60 patients with pheochromocytoma, were reviewed. The main outcome measures were operation time, blood loss, hospital stay and intra- and post-operative complications. RESULTS: In patients who underwent adrenalectomy (ADX) using a retroperitoneal (RP) approach, duration of operation, intra-operative blood loss, hospital stay and post-operative morbidity compared favourably with those undergoing a transabdominal approach (TA-ADX). However, most of these differences could be explained by the more frequently benign nature and smaller size of the lesions in patients undergoing RP-ADX. However, blood loss remained lower after correction for confounding in all patients undergoing RP-ADX. In patients with larger adrenal lesions, adrenal cancer and pheochromocytoma, that would nowadays be held unsuitable for laparoscopic adrenalectomy, RP-ADX was associated with shorter operation time, less blood loss and less intra-operative complications. CONCLUSION: Although laparoscopic adrenalectomy is the treatment of choice for small and benign adrenal lesions, larger lesions and/or adrenal malignancy require open adrenalectomy. In these cases the retroperitoneal approach is the preferred route.

Treatment of pituitary-dependent Cushing's syndrome: long-term results of unilateral adrenalectomy followed by external pituitary irradiation compared to transsphenoidal pituitary surgery.

BACKGROUND: The preferred treatment of Cushing's disease (CD) nowadays is transsphenoidal pituitary surgery (TPS). Prior to TPS, patients at the Leiden University Medical Centre were treated by unilateral adrenalectomy followed by external pituitary irradiation (UAPI). We report on long-term results of both UAPI and TPS and compare remission, relapse rates, and complications. PATIENTS AND METHODS: A retrospective study was carried out on 130 patients with CD. Patients with pituitary macroadenoma were excluded. Eighty-six and 44 patients underwent UAPI and TPS, respectively. Of these patients, 85 and 41 were evaluable for long-term results. RESULTS: Remission following UAPI and TPS was identical at 64% (54/85 and 27/41). Cumulative relapse was also comparable - 17% (9/54) and 22% (6/27), respectively, - for UAPI and TPS, although the mean follow-up periods were different - 21.4 years and 8.5 years, respectively. Cumulative disease-free survival curves after UAPI and TPS are identical until 5 years of follow-up, but diverge thereafter indicating more sustained remissions following UAPI (P = 0.17, Wilcoxon statistic). Pituitary dysfunction following UAPI (36%) and pituitary surgery (55%) likewise did not differ significantly. However, pituitary dysfunction was an immediate event after TPS, whereas it developed after a mean interval of 17.8 years following UAPI.Low-dose dexamethasone testing during follow-up had no value in predicting therapeutic outcome. CONCLUSIONS: The results of unilateral adrenalectomy followed by external pituitary irradiation do not justify that this therapy is totally abandoned in favour of transsphenoidal pituitary surgery. Unilateral adrenalectomy followed by external pituitary irradiation is a valid therapeutic modality for the treatment of Cushing's disease, and could be considered as alternative to bilateral adrenalectomy and under some circumstances to transsphenoidal pituitary surgery.

[Elevated glucose levels in the elderly: is there a need for intensive treatment?]. / 'Een beetje suiker' bij ouderen; (intensief) behandelen?

Diabetes mellitus is a frequently occurring disease which is often found in combination with other diseases in older people. An interval of more than ten years is often seen between the first signs of diabetes and the diagnosis. The causes and consequences of insufficient production of insulin and the available diagnostic and therapeutic possibilities, with attention for hypoglycemia in older people, are discussed. In the early phase of diabetes glucose levels are only incidentally elevated and patients have no complaints. Elevated blood glucose values aggravate other diseases and decrease the effectivity of treatment for these diseases. Treatment can prevent or postpone secondary complications leading to improved quality of life. A plea is made for (regular) testing of blood glucose and adequate action when elevated values are found in older people.

Long-term results of total adrenalectomy for Cushing's disease.

The objective of this study was to present the long-term results of total adrenalectomy for Cushing's disease. Forty-four patients undergoing total adrenalectomy for Cushing's disease between 1953 and 1989 at Leiden University Medical Center, The Netherlands, were studied retrospectively. Remission was achieved in 42 patients (95%), with a mean duration of 19 years. Adrenal remnants were observed in 12 patients (27%), and were without clinical consequence in the majority of patients, but caused early recurrent disease in 2 patients. Nine patients (20%) experienced Addisonian crises up to 30 years following treatment. Nelson's syndrome developed in 10 patients (23%) 7-24 years following total adrenalectomy. Prior pituitary irradiation was a protective factor against Nelson's syndrome as it delayed its onset (p = 0.025). On the other hand, subnormal dose or noncontinuous glucocorticoid replacement therapy was associated with increased risk of development of Nelson's syndrome (p = 0.047). The incidence of Nelson's syndrome increased with prolonged follow-up, and female patients seemed to be at increased risk. Quality-of-life assessment showed less favorable scores on mental health and health perception scales, for which no explanation can be found except the long-lasting metabolic effects of Cushing's disease, even when successfully treated. In conclusion, total adrenalectomy remains the final treatment for Cushing's disease. The presence of adrenal remnants which can cause recurrent disease and the development of Nelson's syndrome during prolonged follow-up enhance the need for continued regular follow-up. Pituitary irradiation prior to total adrenalectomy delays the onset of Nelson's syndrome.

Associations of fat and cholesterol intake with serum lipid levels and cardiovascular disease: the EURODIAB IDDM Complications Study.

The EURODIAB IDDM Complications Study, a cross-sectional, clinic-based study examined the fat and cholesterol intakes of European individuals with type 1 diabetes for possible relations to serum lipid levels (total cholesterol, HDL- and LDL-cholesterol, fasting triglycerides) and to the prevalence of cardiovascular disease (past history or electrocardiogram abnormalities). Fat intake (total fat, saturated fat, cholesterol) from 2,868 subjects with type 1 diabetes (mean age 32.9 +/- 10.2 years (range: 14-61 years), mean diabetes duration 14.7 +/- 9.4 years (range: 1-56 years)) was assessed by a standardized 3-day dietary record at the Nutrition Co-Ordinating Centre (Düsseldorf). Serum lipid levels were determined in the central laboratory (London) by standard enzymatic methods. Energy-adjusted total and LDL-cholesterol levels increased significantly with higher intakes of total fat, saturated fat and cholesterol. However, these relations were largely explained by concomitant decreases in dietary fibre intake. For levels of HDL-cholesterol and triglycerides no independent associations were observed with fat or cholesterol intake. Increased intakes of total fat, saturated fat and cholesterol were also related to higher prevalences of cardiovascular disease. These associations were, however, no longer significant after adjustment for dietary fibre intake for which we previously demonstrated independent associations with the serum cholesterol pattern and CVD. Since higher fat intakes are commonly accompanied by lower carbohydrate and fibre intakes we conclude that restricted intakes of cholesterol, saturated fat and total fat combined with higher fibre intakes beneficially affect both the levels of total and LDL-cholesterol and the risk for cardiovascular disease in European individuals with type 1 diabetes.

[Diabetes mellitus: current classification based on cause and sharpened blood glucose limits for diagnosis]. / Diabetes mellitus: nieuwe classificatie naar oorzaak en aangescherpte bloedglucosegrenzen voor diagnostiek.

Recently new definitions were agreed for the glucose tolerance test (GTT), for impaired glucose tolerance and for the classification of diabetes mellitus. The World Health Organization and the American Diabetes Association have been active on this point. The fasting glucose value has been lowered and been brought into line with the two hour value of the GTT. Fasting glucose values can now be used for the diagnosis of diabetes mellitus and of impaired glucose tolerance. The new classification is based on differences in cause of the diabetes. The classification includes diabetes mellitus types 1 and 2, pregnancy diabetes and 'other forms of diabetes'.

Short-term oestrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM.

Oestrogen replacement therapy is associated with a decreased risk of cardiovascular disease in postmenopausal women. Patients with non-insulin-dependent diabetes mellitus (NIDDM) have an increased cardiovascular risk. However, oestrogen replacement therapy is only reluctantly prescribed for patients with NIDDM. In a double blind randomized placebo controlled trial we assessed the effect of oral 17 beta-estradiol during 6 weeks in 40 postmenopausal women with NIDDM. Glycated haemoglobin (HbA1c), insulin sensitivity, suppressibility of hepatic glucose production, lipoprotein profile and parameters of fibrinolysis were determined. The oestrogen treated group demonstrated a significant decrease of HbA1c and in the normotriglyceridaemic group a significantly increased suppression of hepatic glucose production by insulin. Whole body glucose uptake and concentrations of non-esterified fatty acids did not change. LDL-cholesterol- and apolipoprotein B levels decreased, and HDL-cholesterol, its subfraction HDL2-cholesterol and apolipotrotein A1 increased. The plasma triglyceride level remained similar in both groups. Both the concentration of plasminogen activator inhibitor-1 antigen and its active subfraction decreased. Tissue type plasminogen activator activity increased significantly only in the normotriglyceridaemic group. Oestrogen replacement therapy improves insulin sensitivity in liver, glycaemic control, lipoprotein profile and fibrinolysis in postmenopausal women with NIDDM. For a definite answer as to whether oestrogens can be more liberally used in NIDDM patients, long term studies including the effect of progestogens are necessary.

Effect of 17 beta-estradiol on plasma lipids and LDL oxidation in postmenopausal women with type II diabetes mellitus.

In type II diabetes mellitus the altered hormonal state after menopause may represent an additional cardiovascular risk factor. Estrogen replacement therapy (ERT) is associated with a decreased cardiovascular risk, at least in nondiabetic postmenopausal women. We studied the effect of ERT on plasma lipids and lipoproteins and on LDL oxidation in 40 postmenopausal women with type II diabetes but with minimal vascular complications in a randomized placebo-controlled trial. Twenty patients were treated orally with 2 mg/d micronized 17 beta-estradiol and 20 patients with placebo for 6 weeks. Plasma total cholesterol (-6%, P = .04), LDL cholesterol (-16%, P = .0001), and apoB (-11%, P = .001) levels decreased and HDL cholesterol (20%, P = .0001) and apoA-I (14%, P = .0001) levels increased after ERT compared with placebo. Glycated hemoglobin (HbA1c) decreased significantly after ERT (-3%, P = .03), the cholesterol content of the LDL particles decreased (-5%, P = .006), triglyceride content increased (16%, P = .01), and LDL particle size did not change significantly. ERT had no effect on parameters of LDL oxidation. We conclude that plasma levels of HDL cholesterol, apoA-I, LDL cholesterol, apoB, and glycated hemoglobin are improved in postmenopausal women with type II diabetes mellitus after treatment with 17 beta-estradiol, indicative of a better metabolic control, and that ERT has no effect on LDL oxidizability.

Clostridium botulinum C3 exoenzyme stimulates GLUT4-mediated glucose transport, but not glycogen synthesis, in 3T3-L1 adipocytes--a potential role of rho?

The signal transduction pathway by which insulin stimulates glucose transport is largely unknown, but a role of PI-3-kinase and small GTP-binding proteins has been proposed. In previous studies we, among many others, excluded a role for the ras/MAP kinase pathway in insulin-mediated glucose transport. In this study we examined a possible role of the small GTP-binding protein rho in this process. Pretreatment of 3T3-L1 adipocytes with botulinum C3 exoenzyme (C3), which is known to ADP-ribosylate and inactivate rho, potently stimulated glucose uptake to a level similar to insulin. Interestingly, glycogen synthesis was not affected by C3 treatment. Insulin stimulates glucose uptake by triggering the translocation of GLUT4, the insulin-sensitive glucose transporter isotype, from an intracellular compartment to the plasma membrane. Similarly, C3-induced glucose uptake was paralleled by GLUT4 translocation. These data point to an important and novel role of the target of C3 (likely rho) in the regulation of GLUT4-mediated glucose transport. Our data suggest that insulin might stimulate glucose uptake through inactivation of rho.

Diabetes monitoring system in The Netherlands.

Under the aegis of the European Regional Offices of the World Health Organization (WHO) and the International Diabetes Federation (IDF) a joint action programme to contest the growing burden of diabetes has been drawn up. The St. Vincent Declaration (1980) specifies targets for diabetes care, the reduction of complications, the integration into society and the education of the diabetic individual. The WHO/IDF have drawn up a data set to monitor progress in reaching the targets of the St. Vincent Declaration. The objective of the project Diabetes Monitoring System is to examine the possibilities for implementing a longitudinal-based and standardised diabetes monitoring system in the Netherlands. Although computerised recording systems for diabetes are seldom used and the agreement with the WHO/IDF data set varies substantially, the willingness of physicians to participate is clearly sufficient. This principally explorative project will hopefully lead to the implementation of a monitoring system in which a widely accepted data set is recorded to establish improvements in quality of care and to perform epidemiological research.

Pulsatile intravenous insulin replacement in streptozotocin diabetic rats is more efficient than continuous delivery: effects on glycaemic control, insulin-mediated glucose metabolism and lipolysis.

Short-term exposure of tissues to pulses of insulin generally leads to an enhancement of insulin action. We have investigated the possible beneficial effects of long-term near-physiological continuous vs pulsatile intravenous insulin treatment of insulin-deficient streptozotocin (70 mg/kg) diabetic rats on blood glucose control, in vivo insulin action and in vitro insulin action in isolated adipocytes. First, we determined the 24-h peripheral plasma insulin profiles in normal rats under precisely controlled mealfeeding conditions. Basal plasma insulin levels (40 +/- 9 microU/ml) oscillate with a periodicity of 11.9 +/- 0.9 min (p < 0.05), and an amplitude of 60 +/- 10%. Subsequently, the 24-h insulin profile was mimicked in diabetic (D) rats by a continuous (c) or pulsatile (p) (6-min double, 6-min off) insulin infusion rate for 2 weeks, using a programmable pumpswivel unit. Control (C) rats received vehicle treatment. In Cc, Dc, Cp and Dp daily urinary glucose loss and average plasma glucose levels were 0 +/- 0, 7.5 +/- 4.4, 0 +/- 0, 0.8 +/- 0.4 mmol and 6.7 +/- 0.2, 11.5 +/- 2.7, 6.6 +/- 0.1, 5.9 +/- 1.4 mmol/l, respectively. Hypoglycaemia (< 3 mmol/l) was observed in 10 and 20% of the blood samples collected from Dc and Dp rats, respectively. After 2 weeks of treatment, in vivo peripheral and hepatic insulin action was measured by the hyperinsulinaemic euglycaemic (6 mmol/l) clamp with [3-3H]-glucose infusion. Pre-clamp counter-regulatory hormone levels were similar among rats. Compared to Cc and Cp, Dc showed a reduction in insulin sensitivity and responsiveness for peripheral glucose uptake whereas Dp only showed a reduction in insulin sensitivity. Suppression of hepatic glucose production by insulin was similar among rats. After 2.5 weeks of treatment, epididymal adipocytes were isolated. Specific [125I]-insulin binding, basal and insulin-stimulated [U-14C]-glucose uptake and isoproterenol-stimulated glycerol output were comparable among rat adipocytes. The inhibition of glycerol output by insulin was identical in Cp and Dp (V(max) = 48.6 +/- 6.1 and 42.3 +/- 4.6%) but blunted in Dc vs Cc (V(max) = 8.2 +/- 4.6 vs 44.0 +/- 7.2%, p < 0.01) adipocytes, suggesting a post-binding defect in the antilipolytic action of insulin in Dc rats. In conclusion, long-term near-physiological pulsatile intravenous insulin replacement in insulin-deficient diabetic rats is more efficient than continuous delivery in reducing blood glucose, lowering glucosuria, increasing insulin sensitivity and inhibiting lipolysis.

Tissue-related changes in insulin receptor number and autophosphorylation induced by starvation and diabetes in rats.

Insulin action is subject to regulation at the level of the insulin receptor and at postreceptor levels. Starvation and diabetes are often associated with insulin resistance for glucose metabolism in various tissues. In muscle, fat, and liver, we examined whether changes in the functionality of the insulin receptor correlated with changes in insulin action in the starved and diabetic state. Insulin-stimulated receptor autophosphorylation reflects an early physiologic step in transmission of the insulin signal, and for that reason, changes in autophosphorylation activity of the insulin receptor were used as a marker to determine the functionality of the insulin receptor. Glycoprotein fractions prepared from skeletal muscle, diaphragm, epididymal fat, and liver of control, 3-day starved, short-term 3-day (S) diabetic (streptozotocin, 70 mg/kg intravenously), and long-term 6-month (L) diabetic (neonatal streptozotocin 100 micrograms/g intraperitoneally) rats were used in this study. Receptor activity was monitored by measuring insulin-stimulated [gamma-32P]adenosine triphosphate (ATP) receptor autophosphorylation. In addition, to obtain information about whether changes in receptor autophosphorylation are related to changes in receptor number, relative numbers of high-affinity insulin receptors were determined by affinity cross-linking of [125I]insulin to the receptor alpha-chain and quantitation of the yield of labeled receptor alpha-chain. Control, starved, S diabetic, and L diabetic rats had plasma insulin and glucose levels of 294 +/- 42, 90 +/- 24, 48 +/- 12, and 216 +/- 30 pmol/L and 6.7 +/- 0.2, 4.1 +/- 0.2, 23.3 +/- 0.7, and 21.6 +/- 2.9 mmol/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients.

Mitotane is considered to be the drug of choice for patients with inoperable, recurrent and metastatic adrenocortical carcinoma, although a favourable effect of this drug on survival has never been documented. We evaluated the efficacy of mitotane treatment of 96 patients with adrenocortical carcinoma followed up in our department between 1959 and 1992. Complete tumour resection was the goal of the initial treatment. Mitotane treatment was classified according to serum trough concentrations on maintenance therapy: low (< 14 mg l-1) or high (> or = 14 mg l-1). Total tumour resection was feasible in 47 patients (49%), and subtotal resection was performed in 37 patients (39%). Patients who underwent total tumour resection survived significantly longer than those who did not (P < 0.001). Adjuvant mitotane therapy (n = 11) did not influence survival after total resection. Sixty-two patients were given mitotane treatment at some time during their illness, only 30 of whom reached high maintenance serum levels. Mitotane treatment with high serum levels had an independently favourable influence on patient survival, using univariate (P < 0.01) and multivariate analysis (P = 0.01). Mitotane treatment resulting in low serum levels was tantamount to not giving mitotane at all. We conclude that mitotane treatment in adrenocortical carcinoma is effective only when high serum levels can be achieved.

A mutation in the insulin receptor that impairs proreceptor processing but not insulin binding.

Here we report the identification of a new mutation in the alpha-chain of the insulin receptor, changing Trp412 into Ser using DNA from consanguineous parents who gave birth to a child with leprechaunism. The mutant receptor was expressed stably in CHO and transiently in COS-1 cells. It was found that the Ser412 mutant is not cleaved into alpha- and beta-subunits and remains as a 210-kDa proreceptor at an intracellular site. This property of the mutant receptor is in line with the observed decreased insulin binding to the parental fibroblasts. Cross-linking experiments show that the Ser412 proreceptor is able to bind insulin with an affinity comparable to that of the wild-type alpha-chain. Despite its capacity to bind insulin, the mutant receptor is not autophosphorylated. We postulate that the patient was homozygous for the Trp412-->Ser mutation and that the mutation was responsible for the leprechaun phenotype. This is the first description of a transport-defective receptor with the mutation outside the tetrabasic processing site and a functional insulin binding domain. The ability of the Ser412 mutant to bind insulin in cross-linking experiments suggests that the impaired transport of the proreceptor to the cell surface is the primary cause for the binding defect to intact cells.