Insulin-based strategies to prevent hypoglycaemia during and after exercise in adult patients with type 1 diabetes on pump therapy: the DIABRASPORT randomized study.

AIMS: To validate strategies to prevent exercise-induced hypoglycaemia via insulin-dose adjustment in adult patients with type 1 diabetes (T1D) on pump therapy. METHODS: A total of 20 patients randomly performed four 30-min late post-lunch (3 h after lunch) exercise sessions and a rest session: two moderate sessions [50% maximum oxygen consumption (VO2 max)] with 50 or 80% basal rate (BR) reduction during exercise + 2 h and two intense sessions (75% VO2 max) with 80% BR reduction or with their pump stopped. Two additional early post-lunch sessions (90 min after lunch) were analysed to compare hypoglycaemia incidence for BR reduction versus bolus reduction. RESULTS: In all, 100 late post-lunch sessions were analysed. Regardless of exercise type and BR reduction, no more hypoglycaemic events occurred in the period until the next morning than occurred after the rest sessions. In the afternoon, no more hypoglycaemic events occurred with 80% BR reduction/moderate exercise or with pump discontinuation/intense exercise than for the rest session, whereas more hypoglycaemic events occurred with 50% BR reduction/moderate exercise and 80% BR reduction/intense exercise. After early post-lunch exercise (n = 37), a trend towards fewer hypoglycaemic episodes was observed with bolus reduction versus BR reduction (p = 0.07). Mean blood glucose fell by ∼3.3 mmol/l after 30 min of exercise, irrespective of dose reduction, remaining stable until the next morning with no rebound hyperglycaemia. CONCLUSION: In adults with T1D, to limit the hypoglycaemic risk associated with 30 min of exercise 3 h after lunch, without carbohydrate supplements, the best options seem to be to reduce BR by 80% or to stop the pump for moderate or intense exercise, or for moderate exercise 90 min after lunch, to reduce the prandial bolus rather than the BR.

Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects.

OBJECTIVES: The aim of this study was to investigate whether the quadrivalent human papillomavirus (HPV) vaccine Gardasil is associated with a change in the risk of autoimmune disorders (ADs) in young female subjects. DESIGN: Systematic case-control study of incident ADs associated with quadrivalent HPV vaccination in young women across France. PARTICIPANTS AND SETTING: A total of 113 specialised centres recruited (from December 2007 to April 2011) females aged 14-26 years with incident cases of six types of ADs: idiopathic thrombocytopenic purpura (ITP), central demyelination/multiple sclerosis (MS), Guillain-Barré syndrome, connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus and autoimmune thyroiditis. Control subjects matched to cases were recruited from general practice. ANALYSIS: Multivariate conditional logistic regression analysis; factors included age, geographical origin, smoking, alcohol consumption, use of oral contraceptive(s) or vaccine(s) other than Gardasil received within 24 months before the index date and personal/family history of ADs. RESULTS: Overall, 211 definite cases of ADs were matched to 875 controls. The adjusted odds ratio (OR) for any quadrivalent HPV vaccine use was 0.9 [95% confidence interval (CI) 0.5-1.5]. The individual ORs were 1.0 (95% CI 0.4-2.6) for ITP, 0.3 (95% CI 0.1-0.9) for MS, 0.8 (95% CI 0.3-2.4) for connective disorders and 1.2 (95% CI 0.4-3.6) for type 1 diabetes. No exposure to HPV vaccine was observed in cases with either Guillain-Barré syndrome or thyroiditis. CONCLUSIONS: No evidence of an increase in the risk of the studied ADs was observable following vaccination with Gardasil within the time periods studied. There was insufficient statistical power to allow conclusions to be drawn regarding individual ADs.

A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up.

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

Effectiveness and tolerability of second-line therapy with vildagliptin vs. other oral agents in type 2 diabetes: a real-life worldwide observational study (EDGE).

AIM: Real-life studies are needed to confirm the clinical relevance of findings from randomised controlled trials (RCTs). This study aimed to assess the effectiveness and tolerability of vildagliptin add-on vs. other oral antihyperglycaemic drugs (OADs) added to OAD monotherapy in a real-life setting, and to explore the advantages and limitations of large-scale 'pragmatic' trials. METHODS: EDGE was a prospective, 1-year, worldwide, real-life observational study in which 2957 physicians reported on the effects of second-line OADs in 45,868 patients with T2DM not reaching glycaemic targets with monotherapy. Physicians could add any OAD, and patients entered either vildagliptin or (pooled) comparator cohort. The primary effectiveness and tolerability end-point (PEP) evaluated proportions of patients decreasing HbA(1c) > 0.3%, without hypoglycaemia, weight gain, peripheral oedema or gastrointestinal side effects. The most clinically relevant secondary end-point (SEP 3) was attainment of end-point HbA(1c) < 7% without hypoglycaemia or ≥ 3% increase in body weight. RESULTS: In this large group of T2DM patients, a second OAD was added at mean HbA(1c) of 8.2 ± 1.3%, with no baseline HbA(1c) difference between cohorts. Second-line OAD therapy attained the PEP in the majority of patients, with higher attainment in those prescribed a vildagliptin-based regimen. The adjusted odds ratio was 1.49 (95% CI: 1.42, 1.55; p < 0.001). In patients with baseline HbA(1c) ≥ 7%, SEP 3 was achieved by 35% of patients on a vildagliptin-based combination and by 23% of those receiving comparator combinations. The adjusted odds ratio was 1.96 (95% CI: 1.85, 2.07; p < 0.001). Safety events were reported infrequently and safety profiles of vildagliptin and other OADs were consistent with previous data. CONCLUSION: EDGE demonstrates that in a 'real-life' setting, vildagliptin as second OAD can lower HbA(1c) to target without well-recognised OAD side effects, more frequently than comparator OADs. In addition, EDGE illustrates that conducting large-scale, prospective, real-life studies poses challenges but yields valuable clinical information complementary to RCTs.

The potential role of glucagon-like peptide-1 or its analogues in enhancing glycaemic control in critically ill adult patients.

Intravenous insulin therapy is the gold standard therapy for glycaemic control in hyperglycaemic critically ill adult patients. However, hypoglycaemia remains a major concern in critically ill patients, even in some populations who are not receiving infused insulin. Furthermore, the influence of factors such as glycaemic variability and nutritional support may conceal any benefit of strict glycaemic control on morbidity and mortality in these patients. The recently revised guidelines of the American Diabetic Association/American College of Clinical Endocrinologists no longer advocate very tight glycaemic control or normalization of glucose levels in all critically ill patients. In the light of various concerns over the optimal glucose level and means to achieve such control, the use of glucagon-like peptide-1 or its analogues administered intravenously may represent an interesting therapeutic option.

Practical implementation of automated closed-loop insulin delivery: A French position statement.

Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.

[Complete resolution of insulin-dependent diabetes mellitus in a patient with autoimmune pancreatitis following treatment with corticosteroids]. / Disparition totale d'un diabète insulinorequérant au décours d'une pancréatite auto-immune traitée par corticothérapie.

We report here the observation of a 60-year-old man who had an autoimmune pancreatitis revealed by a jaundice, in whom an insulin-treated diabetes mellitus, which was diagnosed one month before, completely resolved after the administration of prednisolone given to treat this symptomatic pancreatitis. Neither the symptoms, nor the diabetes have relapsed after a 3-year follow-up.

Quality of life after islet transplantation: data from the GRAGIL 1 and 2 trials.

BACKGROUND: Rigorous assessment of health-related quality of life (HRQL) is mandatory to establish the benefits of islet transplantation. METHODS: The 36-Item Short Form Health Survey (SF-36) and the Diabetes Quality of Life (DQOL) scales were completed by patients included in an Islet Transplantation Alone (ITA) trial (n = 10) and an Islet After Kidney (IAK) trial (n = 10). RESULTS: The two populations differed by HRQL scores at baseline, with poorer scores in ITA patients. SF-36 scores for physical limitations, bodily pain, general health perception, social functioning, and health transition improved significantly in ITA patients 6 and 12 months post transplantation. The DQOL global score was significantly improved at 6 months and remained so at 12 months, because of a significant improvement in the dimensions of satisfaction and impact of diabetes. No improvement was observed in the IAK patients. CONCLUSION: HRQL assessment may help in the selection of candidates with brittle diabetes for islet transplantation.

Glycaemic dysregulation in nondiabetic patients after major lower limb prosthetic surgery.

AIM: Blood glucose (BG) dysregulation is common after cardiac surgery, but remains poorly described after major noncardiac surgery. The aim of this prospective observational study was to analyze perioperative changes in BG levels in nondiabetic patients undergoing major arthroplasty. METHODS: Nondiabetic consenting patients scheduled for hip or knee arthroplasty were eligible. BG levels were assessed from the preoperative period to the end of postoperative day 2. Oral feeding was resumed from the evening after surgery. Hyperglycaemia, defined as two sequential BG measurements that were either greater than 7.0 mmol/L during the fasting period or greater than 11.1 mmol/L 2 hours after a meal, was the primary outcome variable. Two groups of patients were identified, depending on the occurrence or not of hyperglycaemia (hyperglycaemic and normoglycaemic groups, respectively). Patients were followed-up for surgical wound infection for one year postoperatively. RESULTS: Thirty-eight patients, aged 65+/-14 years (mean+/-S.D.), were included. A significant increase in BG was observed during the fasting period (Anova, P<0.001), and 74% of patients met the primary outcome variable. In the hyperglycaemic group, the mean number of BG measurements per patient above the thresholds was 5.6+/-2.8, and 58% of the patients still had a postmeal BG level greater than 11.1 mmol/L at the end of the study period. No surgical wound infection was observed at follow-up. CONCLUSION: This study showed that nearly 75% of nondiabetic patients experience a moderate, but significant, increase in either fasting or postprandial BG levels in the first two days following major arthroplasty.

[Diabetes and second-generation (atypical) antipsychotics]. / Diabète et antipsychotiques de seconde génération.

Schizophrenia is a common psychiatric illness (1% of the general population), characterized by the association of positive and negative symptoms and cognitive disorders. Antipsychotics, typical or atypical, are known to induce in patients with schizophrenia weight gain and abnormalities in glucose and lipid metabolisms. These modifications, in addition to metabolic risk factors, intrinsic to the psychiatric illness (physical inactivity, smoking, diabetes), increase the risk of cardiovascular complications. Some antipsychotics are associated with a higher risk of metabolic disorders. Before starting such a medication, all risk factors must be taken into account. In case of even effectiveness, one should consider the risk of inducing metabolic disorders, as well as the intrinsic risk factors of the patient, in order to prescribe the medication associated with the lower metabolic risk. Regarding iatrogenic diabetes, the risk of occurrence seems different, depending on the molecules, being more marked for clozapine, olanzapine, risperidone, quietapine then amisulpride, aripiprazole and finally ziprasidone. The physiopathology seems to involve both an increase in insulin resistance and an alteration of insulin secretion. Nevertheless, the benefit/risk often remains largely in favour of treatment, the atypical antipsychotics are at least equally effective and better tolerated on the cognitive and neurological functions than conventional antipsychotics being. They have particularly far fewer extrapyramidal effects. The reversibility of pathologies induced by atypical antipsychotics led to the formulation of guidelines, leading to regular clinical and biological follow-up.

Specific phenotype associated with diabetes mellitus secondary to chronic hepatitis C infection.

AIM: A link between chronic hepatitis C virus (HCV) infection, Type 2 diabetes mellitus and insulin resistance has been suggested by several studies. However, HCV infection appears to be associated with insulin resistance but not with the metabolic syndrome. The aim of this study was to determine whether chronic HCV infection had an impact on the clinical characteristics of Type 2 diabetes. METHODS: We studied retrospectively a group of patients with diabetes mellitus associated with HCV infection (HCV-DM) and compared them with patients with conventional Type 2 diabetes (DM). RESULTS: The HCV-DM patients had a lower body mass index (P = 0.001) and systolic blood pressure (P = 0.04) compared with patients with DM diabetes. Ten patients (27.0%) in the HCV-DM group and 35 (47.3%) in the DM group had microalbuminuria (P = 0.04). DM patients had significantly higher serum creatinine levels than HCV-DM patients [87 (72-108) vs. 77 (64-86) micromol/l, P = 0.02; median (interquartile range)] but creatinine clearance (Cockroft Gault calculation) was similar. One HCV-DM patient (2.7%) and 44 DM patients (59.4%) were treated with hypolipidaemic therapy (P = 0.0001). Even although nearly two-thirds of the overall DM group were prescribed cholesterol-lowering drugs, DM patients had significantly higher total cholesterol, high-density lipoprotein cholesterol and triglyceride levels than HCV-DM patients. CONCLUSION: Our study provides further evidence that HCV-DM patients have specific clinical characteristics in comparison with classical DM patients. These data suggest an association between HCV virus infection and the development of insulin resistance or diabetes mellitus without the typical features of the metabolic syndrome.

Therapeutic approach of type 2 diabetes mellitus with GLP-1 based therapies.

The goal of this review is to think about how to incorporate the GLP-1 based agents, represented by the dipeptidyl peptidase-4 (DPP-4) inhibitors or the glucagon-like peptide-1 (GLP-1) analogs, in the guidelines for the management of type 2 diabetes (T2DM). Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA(1c) (absolute values) by 0.5-1.1% (5 to 12%, relative values), with few adverse events and no weight gain. The sub-cutaneous injected GLP-1 analogs show larger reductions in HbA(1c) (0.8-1.7%, absolute values; 9.4-20.0%, relative values), associated with weight loss (1.75-3.8 kg); their most common adverse events are gastrointestinal symptoms which contribute to a substantial treatment interruption. If they do not challenge the use of metformin as the initial therapy of T2DM, several studies argue in favour of the use of DPP-4 inhibitors, either in combination with metformin as the initial treatment or, in add-on therapy to metformin. The advantages of this combination over others currently used are reviewed. In patients not tolerating metformin, DPP-4 inhibitors seem to be an excellent alternative as a monotherapy. As long as oral triple therapy is concerned, the choice for the association metformin + thiazolidinedione + incretin-based drug, has again several theoretical advantages against other triple therapy combinations. Finally, in patients with T2DM inadequately controlled with maximal tolerated oral multi-therapies, GLP-1 agonists are a good alternative to insulin therapy, allowing reaching a better glycaemic control together with a weight loss. However, for patients who do not tolerate GLP-1 agonist treatment, and for those not reaching the HbA(1c) target, insulin will remain necessary, allowing getting a better metabolic control, with few adverse events. The long-term effect of these new agents on glycaemic control has not yet been established, and their potential impact on beta-cell function in humans remains an area of active investigation. So, further studies are needed and will allow progressively refining the use of incretin-based agents in T2DM treatment strategy.

Practical implementation, education and interpretation guidelines for continuous glucose monitoring: A French position statement.

The use by diabetes patients of real-time continuous interstitial glucose monitoring (CGM) or the FreeStyle Libre® (FSL) flash glucose monitoring (FGM) system is becoming widespread and has changed diabetic practice. The working group bringing together a number of French experts has proposed the present practical consensus. Training of professionals and patient education are crucial for the success of CGM. Also, institutional recommendations must pay particular attention to the indications for and reimbursement of CGM devices in populations at risk of hypoglycaemia. The rules of good practice for CGM are the precursors of those that need to be enacted, given the oncoming emergence of artificial pancreas devices. It is necessary to have software combining user-friendliness, multiplatform usage and average glucose profile (AGP) presentation, while integrating glucose and insulin data as well as events. Expression of CGM data must strive for standardization that facilitates patient phenotyping and their follow-up, while integrating indicators of variability. The introduction of CGM involves a transformation of treatment support, rendering it longer and more complex as it also includes specific educational and technical dimensions. This complexity must be taken into account in discussions of organization of diabetes care.

Immunosuppressive drug-induced diabetes.

Post-transplant diabetes mellitus (PTDM) has emerged as a major adverse effect of immunosuppressive drugs (ISD). As recipients of organ transplants survive longer, the complications of diabetes mellitus have assumed greater importance. The predominant factor for causing PTDM by corticosteroids seems to be the aggravation of insulin resistance, however several studies have displayed deleterious effects on insulin secretion and beta-cells. Calcineurin inhibitors induce PTDM by a number of mechanisms, including decreased insulin secretion and a direct toxic effect on the pancreatic beta-cells. Recent in vitro studies stress on the increased apoptosis of beta-cells when exposed to these drugs. Studies involving other immunosuppressive agents (mycophenolate mofetil [MMF], sirolimus) are scarcer and lead to conflicting results, while daclizumab seems to have a neutral effect. Clinical studies have consistently shown a greater potential of tacrolimus to induce PTDM compared with cyclosporine. Reducing PTDM incidence is a feasible goal while using corticosteroid-sparing regimens and/or lower tacrolimus trough levels. In patients developing PTDM, conversion from tacrolimus to cyclosporine could improve or reverse glucose tolerance abnormalities. In the absence of well-designed studies in this specific indication, treatment of PTDM is based on the same principles as type 2 diabetes mellitus. Thiazolidinediones do not display any pharmacological interaction with calcineurin inhibitors, but their safety and efficacy in PTDM need to be confirmed in large-scale randomized trials. Use of sulfonylureas has to be cautious regarding the suspected interaction of some of them with calcineurin inhibitors. If needed, insulin regimens have to be adapted in patients who display the particular glycaemic profile of corticosteroid-induced diabetes. Incretin-based therapies, due to their specific action on beta-cell apoptosis and proliferation, raise promises that have to be confirmed in clinical studies. Until methods for inducing specific graft tolerance become available, immunosuppressive regimens should be tailored to the individual patient on the basis of predictive criteria for the development of PTDM.

Bayesian analysis of case control polygenic etiology studies with missing data.

Many genetic studies are based on analysing multiple DNA regions of cases and controls. Usually each is tested separately for association with disease. However, some diseases may require interacting polymorphisms at several regions, and most disease susceptibility is polygenic. In this paper, we develop new methods for determining combinations of polymorphisms that affect the risk of disease. For example, two different genes might produce normal proteins, but these proteins improperly function when they occur together. We consider a Bayesian approach to analyse studies where DNA data from cases and controls have been analysed for polymorphisms at multiple regions and a polygenic etiology is suspected. The method of Gibbs sampling is used to incorporate data from individuals who have not had every region analysed at the DNA sequence or amino acid level. The Gibbs sampling algorithm alternatively generates a sample from the posterior distribution of the sequence of combinations of polymorphisms in cases and controls and then uses this sample to impute the data that are missing. After convergence the algorithm is used to generate a sample from the posterior distribution for the probability of each combination in order to identify groups of polymorphisms that best discriminate cases from controls. We apply the methods to a genetic study of type I diabetes. The protein encoded by the TAP2 gene is important in T cell function, and thus may affect the development of autoimmune diseases such as insulin dependent diabetes mellitus (IDDM). We determine pairs of polymorphisms of genetic fragments in the coding regions of linked HLA genes that may impact the risk of IDDM.

Indication, organization, practical implementation and interpretation guidelines for retrospective CGM recording: A French position statement.

AIM: The benefits of retrospective continuous glucose monitoring (retroCGM) recording have been widely explored in clinical studies, and many diabetes physicians routinely use this examination. However, the method of interpretation of CGM recordings has never been precisely described. METHOD: An expert French panel of physicians met for two days to discuss several aspects of retroCGM use and to produce a position statement. RESULTS: The guidelines cover the indications for retroCGM, the general organization and practical implementation of CGM recordings, a description of the different devices available and guidelines for the interpretation of retroCGM recordings. CONCLUSION: This consensus document should help clinicians in the proper use of retroCGM.

Sequential occurrence of thyroid autoantibodies and Graves' disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients.

We analyzed the kinetics of CD4 cells, human immunodeficiency virus (HIV) viral load, and autoantibodies in acquired immune deficiency syndrome patients with Graves' disease (GD) after immune restoration on highly active antiretroviral therapy (HAART; retrospective study). Five patients (median age, 41 yr) were diagnosed with GD after 20 (range, 14-22) months on HAART on the basis of clinical and biological hyperthyroidism, diffuse hyperfixation of thyroid scan, and the presence of anti-TSH receptor (anti-TSHR) antibodies (Ab). GD was diagnosed several months after the plasma HIV ribonucleic acid load became undetectable, when the CD4+ cell count had risen from 14 (range, 0-62) to 340 (range, 163-460) x 10(6) cells/L. Antithyroid peroxidase (anti-TPO) and anti-TSHRAb appeared 14 (range, 9-18) and 14 (range, 11-20) months after starting HAART and 12 (range, 6-15) and 11 (range, 9-17) months after the increase in CD4+ cells. In 3 patients, TPOAb preceded TSHRAb by 3-10 months. No other autoantibodies were detected. Thyroid antibodies were absent in a group of 55 HIV-1-positive patients with comparable response to HAART and no symptoms of hyperthyroidism (cross-sectional study). Thyroid-specific autoimmunity can occur upon immune restoration with HAART. Our observations suggest a relationship between thymus-dependent immune reconstitution after immunosuppression and autoimmunity and may provide insight into the pathophysiology of GD.

Evaluation of TAP1 polymorphisms with insulin dependent diabetes mellitus in Finnish diabetic patients. The Childhood Diabetes in Finland (DiMe) Study Group.

Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease with a strong association between disease and the HLA class II region. Because abnormal antigen processing, in part characterized by altered class I processing, has been identified in patients with IDDM, the TAP (transporter associated with antigen processing) genes located in the HLA class II region make attractive candidate genes for IDDM. Five coding region variants of TAP1 were typed in a cohort of well characterized Finnish patients with diabetes (n = 119) and compared to racially marched control subjects (n = 92). We found that although no single TAP1 polymorphism was associated with IDDM, a genotypic combination of Ile/Val at codon 333 with Asp/Asp at codon 637 was found more frequently in subjects with IDDM (9.4%) compared to controls (1.2%; p = 0.025). This could not be accounted for by an association with any particular haplotype defined by class I or class II serology.

Evaluation of plasma insulin-like growth factor binding protein-2 as a marker for adrenocortical tumors.

OBJECTIVE: Recent studies have pointed to the role of the IGF system in the pathogenesis of adrenocortical tumors, and it was shown recently that malignant adrenocortical tumors exhibit a high insulin-like growth factor binding protein (IGFBP)-2 content. Circulating markers specific for adrenocortical carcinoma are needed and the aim of this study was to evaluate plasma IGFBP-2 as a marker for these malignant tumors. METHODS: Plasma IGFBP-2 was determined in 51 patients referred to our institutions for adrenocortical tumors. Fifteen patients were in complete remission (group 1), eight patients had preoperative localized tumors (group 2) and 28 patients had metastatic tumors (group 3). Thirty-six healthy volunteers constituted a control group. RESULTS: There was no significant difference in plasma IGFBP-2 concentration between healthy controls and patients with complete remission or localized tumors. In contrast, patients with metastatic disease had significantly higher IGFBP-2 plasma levels than the control group (P<0.001). IGFBP-2 levels in patients with metastatic disease were inversely correlated with survival (R2=0.308; P=0.0026). In patients with localized tumors, there was no correlation between plasma IGFBP-2 concentration and tumor size or histological features. Analysis of individual IGFBP-2 concentrations showed that five patients (17.8%) with metastatic tumors had normal IGFBP-2 levels and two patients (13.3%) in complete remission had high plasma IGFBP-2 levels. The influence of nutrition, hormone secretion and treatment on IGFBP-2 levels was examined. Nutritional status was evaluated by determining IGF-I levels and was found to be normal in 16 patients (61.5%) with high IGFBP-2 levels, suggesting that malnutrition was not responsible for the high IGFBP-2 concentrations in these patients. IGFBP-2 levels did not differ significantly according to tumor secretion or mitotane treatment. In a follow-up study, plasma IGFBP-2 concentration remained stable in patients with complete remission or stabilized disease and was a late marker of tumor progression in patients with progressive metastatic disease. CONCLUSIONS: These results indicate that plasma IGFBP-2 is elevated in patients with malignant adrenocortical tumors and that the major factor affecting IGFBP-2 levels in these patients is tumor stage. However, plasma IGFBP-2 was less sensitive than expected for a tumor marker, which may limit its value in the diagnosis and follow-up of adrenocortical carcinoma.