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.

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.

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.

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.

Activation of the Ras/mitogen-activated protein kinase signaling pathway alone is not sufficient to induce glucose uptake in 3T3-L1 adipocytes.

The signal transduction pathway by which insulin stimulates glucose transport is largely unknown, but a role for tyrosine and serine/threonine kinases has been proposed. Since mitogen-activated protein (MAP) kinase is activated by insulin through phosphorylation on both tyrosine and threonine residues, we investigated whether MAP kinase and its upstream regulator, p21ras, are involved in insulin-mediated glucose transport. We did this by examining the time- and dose-dependent stimulation of glucose uptake in relation to the activation of Ras-GTP formation and MAP kinase by thrombin, epidermal growth factor (EGF), and insulin in 3T3-L1 adipocytes. Ras-GTP formation was stimulated transiently by all three agonists, with a peak at 5 to 10 min. Thrombin induced a second peak at approximately 30 min. The activation of p21ras was paralleled by both the phosphorylation and the activation of MAP kinase: transient for insulin and EGF and biphasic for thrombin. However, despite the strong activation of Ras-GTP formation and MAP kinase by EGF and thrombin, glucose uptake was not stimulated by these agonists, in contrast to the eightfold stimulation of 2-deoxy-D-[14C]glucose uptake by insulin. In addition, insulin-mediated glucose transport was not potentiated by thrombin or EGF. Although these results cannot exclude the possibility that p21ras and/or MAP kinase is needed in conjunction with other signaling molecules that are activated by insulin and not by thrombin or EGF, they show that the Ras/MAP kinase signaling pathway alone is not sufficient to induce insulin-mediated glucose transport.

Biological action of pancreatic amylin: relationship with glucose metabolism, diabetes, obesity and calcium metabolism.

Amylin, also called islet amyloid polypeptide (IAPP), or diabetes-associated peptide (DAP) is a recently discovered 37 amino acid polypeptide which has been shown to be co-secreted with insulin from the pancreatic beta-cell. The peptide turned out to be the major constituent of pancreatic amyloid deposits which are frequently found in the pancreas of type II diabetic patients. Therefore, a role for amylin in the aetiology of type II diabetes was hypothesized. To investigate this possibility, several studies have been performed to elucidate whether amylin is able to impair insulin secretion and action, two characteristic features of type II diabetes mellitus. These studies suggest that it is unlikely that amylin has a direct inhibitory effect on insulin secretion. Amyloid deposits, however, which are derived from the in situ polymerization and precipitation of amylin, may impair beta-cell function during type II diabetes by damaging and covering beta-cells. Furthermore, it has been shown that amylin has the potential to antagonize the action of insulin on glucose metabolism by increasing hepatic glucose production and by decreasing muscle, but not adipocyte glucose uptake. For these reasons, it has been suggested that amylin might be involved in the pathophysiology of type II diabetes and obesity, disease states which are characterized by abnormal beta-cell function and insulin resistance. In addition, amylin was shown to induce hypocalcaemia by inhibiting osteoclast-mediated bone resorption in a calcitonin-like manner. Therefore, amylin is likely to be involved in both the modulation of glucose and calcium metabolism.

Amylin-induced in vivo insulin resistance in conscious rats: the liver is more sensitive to amylin than peripheral tissues.

UNLABELLED: Amylin is a polypeptide of 37 amino acids, predominantly synthesized in pancreatic Beta cells. The peptide was suggested to be dysregulated in Type 2 (non-insulin-dependent) diabetes mellitus and it antagonized certain actions of insulin in vitro in rat muscle. This led to speculation that amylin is involved in the pathogenesis of Type 2 diabetes. We have examined the in vivo effects of rat amylin, amidated at the carboxy-terminus, on insulin-mediated carbohydrate metabolism in conscious rats, using the hyperinsulinaemic (+/- 1 nmol/l) euglycaemic (6 mmol/l) clamp technique combined with [3-3H]-glucose infusion. Basal plasma amylin levels were less than or equal to 75 pmol/l. Applied amylin levels of 220 +/- 75 pmol/l (infusion rate of 12.5 pmol/min) antagonized only the insulin action on liver, resulting in a 100% increase of hepatic glucose output. Amylin levels of 4750 +/- 750 pmol/l (infusion rate of 125 pmol/min) induced a 250% increase of insulin-inhibited hepatic glucose output and, in addition, a 30% decrease of insulin-stimulated peripheral glucose up-take. Amylin did not affect: 1) the metabolic clearance rate of insulin, 2) the levels of plasma glucagon, epinephrine, norepinephrine, and corticosterone, 3) in vitro insulin binding and insulin-stimulated receptor autophosphorylation. This suggests that amylin antagonizes insulin action via binding to a yet unknown receptor. IN CONCLUSION: amylin causes in vivo insulin resistance and the liver seems the predominant organ regulated by this hormone. The in vivo effects of amylin mimic the pathophysiological abnormalities of insulin action in Type 2 diabetes.

Antilipolytic action of insulin in adipocytes from starved and diabetic rats during adenosine-controlled incubations.

Insulin action on adipocytes induces two major metabolic effects: stimulation of glucose transport and inhibition of lipolysis. Previously, we have shown that incubated isolated adipocytes from starved (S), and streptozotocin-treated diabetic (D) rats show insulin resistance on glucose transport. It is not known whether insulin resistance is also present on antilipolysis. In this study the antilipolytic action of insulin was investigated. Since basal lipolysis was low, lipolysis was first stimulated by isoproterenol (ISO). This showed that differences existed in sensitivity for ISO among control (C), S, and D adipocytes. We investigated whether changes in adenosine accumulation could attribute to the differences in ISO action and thereby influence insulin action. When endogenous accumulating adenosine was removed by adenosine deaminase and replaced by a fixed concentration (200 nM) of the nonhydrolyzable adenosine analog phenylisopropyladenosine, the differences in ISO action disappeared. This indicates that the sensitivity of C, S, and D adipocytes for ISO is strongly influenced by endogenous adenosine release. The dose-response relationship between insulin and inhibition of ISO-stimulated lipolysis showed that insulin sensitivity was increased and responsiveness unaltered in S and D compared to C adipocytes for incubations with both uncontrolled and controlled adenosine concentrations. This indicates that during S and D states, endogenous adenosine release has no major effect on insulin action. The increased sensitivity for insulin of S and D adipocytes was paralleled by an increased binding of [125I]iodoinsulin. The unaltered responsiveness for insulin indicates that there is no insulin resistance at the postbinding level for antilipolysis, i.e. intracellular processes for antilipolysis are intact. This is in contrast to glucose transport, where insulin resistance exists at the postbinding level during S and D. Thus, insulin resistance is no general phenomenon, but is confined to specific effector systems.

Transport-associated phosphorylation of 2-deoxyglucose in rat adipocytes.

The relationship between ATP levels and 2-deoxyglucose uptake was investigated. When the concentration in the medium lies between 1 and 10 mM 2-deoxyglucose uptake causes a marked decrease in ATP level. This could partly be explained by an inhibiting effect of 2-deoxyglucose and 2-deoxyglucose 6-phosphate on ATP synthesis in the mitochondria. A good correlation between the various ATP levels induced by 2,4-dinitrophenol and the rate of uptake of 5 microM and 0.5 mM (but not 5 mM) 2-deoxyglucose was observed. The addition of glucose and 2-deoxyglucose to cells incubated in the presence of trace amounts of 2-deoxy-[1-14C]glucose induced marked changes in the uptake of the tracer that were associated with a rapid decline in ATP level. It appeared that the phosphorylation of 2-deoxyglucose is an important step in the uptake of the sugar. It is hypothesized that the processes of transport and phosphorylation of 2-deoxyglucose are coupled in rat adipocytes.

Corticosteroids as long-term regulators of the insulin effectiveness in mouse 3T3 adipocytes.

Since corticosteroid treatment is often accompanied by insulin resistance, we explored the role of corticosteroids in the regulation of the insulin effectiveness in cultured 3T3 (mouse) adipocytes. Exposure of the fat cells to dexamethasone or corticosterone (0-5 days) induced a time-, concentration-, and protein synthesis-dependent and reversible decrease in insulin binding and in basal and insulin-stimulated 2-deoxyglucose uptake. The decrease in binding (50%) was primarily due to a decrease in receptor affinity i.e. to an increase in the rate of dissociation of insulin from its receptors, and was independent from the effects of pH and temperature on the affinity. The reduction in the 2-deoxyglucose uptake (30-50%) was due to a decrease in the hexose transport capacity rather than to a decrease in the phosphorylation component of the 2-deoxyglucose uptake process. Lineweaver-Burk analysis revealed the dexamethasone induced a decrease in the apparent Vmax of the transport system i.e. in the number or activity of the hexose transporters. The effect of dexamethasone seemed to be superimposed on that of long-term insulin treatment, suggesting a different mechanism. It is concluded that corticosteroids act as long-term regulators of the insulin effectiveness by influencing the rate at which insulin dissociates from its receptors and by altering the number or activity of the hexose transporters by a common mechanism, which differs from that of the long-term regulatory effect of insulin.

Long-term regulation of hexose uptake by isoproterenol in cultured 3T3 adipocytes.

Catecholamines are known to have short-term regulatory effects on fat cell hexose uptake. We examined the long-term effects of catecholamines on the insulin-sensitive 2-deoxyglucose (dGlc) uptake in cultured 3T3-L1 adipocytes. Prolonged exposure (48 h) to isoproterenol (beta-adrenergic agonist) stimulated the basal dGlc uptake up to 90%. The effect was specific, time, concentration, and protein synthesis dependent and reversible. The effect of insulin was unaltered and superimposed on the increase in basal dGlc uptake. The long-term effect of isoproterenol was mimicked by epinephrine, dibutyryl cAMP (DBcAMP), and 1-methyl-3-isobutylxanthine (IBMX). By contrast, short-term exposure to isoproterenol (and epinephrine) induced a protein synthesis-independent increase in basal dGlc uptake (30%) not accompanied by an increase in insulin responsiveness. Moreover, on short-term basis, DBcAMP and IBMX suppressed both the basal and insulin-stimulated uptake up to 50%. Determination of the intracellular nonphosphorylated dGlc during the uptake and of the hexokinase activity revealed that the long-term effect of isoproterenol was most likely due to alterations low in dGlc transport. In conclusion, long-term regulators of hexose uptake are in cultured 3T3-L1 adipocytes, isoproterenol, and other cAMP stimulators. The long-term effect is independent from the short-term regulatory effect of the agents and from the effect of insulin.

Stimulatory and inhibitory effects of adrenaline and 8-bromo-cAMP on insulin-sensitive 2-deoxyglucose transport in rat adipocytes.

The effects of adrenaline and 8-bromo-cAMP on 2-deoxyglucose uptake in isolated rat adipocytes were investigated under conditions of unidirectional flux, in which the transport process is rate limiting. Adrenaline showed a dualistic effect in the absence of insulin. At concentrations below 1 microM adrenaline stimulated 2-deoxyglucose uptake; at higher concentrations adrenaline inhibited the uptake. In the presence of insulin at the maximum effective concentration, addition of adrenaline further increased the 2-deoxyglucose uptake by about 50%. In the presence of insulin 8-bromo-cAMP had the same effect as adrenaline. In the absence of insulin, 8-bromo-cAMP only inhibited 2-deoxyglucose uptake.

The effects of 1-methyl-3-isobutylxanthine on insulin-sensitive 2-deoxyglucose transport.

The effect of 1-methyl-3-isobutylxanthine on insulin-sensitive 2-deoxyglucose uptake in rat adipocytes was studied. 1-Methyl-3-isobutylxanthine inhibited 2-deoxyglucose uptake rate substantially in both the absence and presence of insulin. The lag-time for the effect of insulin on 2-deoxyglucose uptake was prolonged. At the same time 1-methyl-3-isobutylxanthine caused a decrease in ATP levels. From experiments with isolated rat liver mitochondria it appeared that 1-methyl-3-isobutylxanthine inhibits glutamate plus malate oxidation in State 3.