Impact of the Rapid Normalization of Chronic Hyperglycemia on the Receptor Activator of Nuclear Factor-Kappa B Ligand and the Osteoprotegerin System in Patients Living with Type 2 Diabetes: RANKL-GLYC Study.

The RANKL-GLYC study aims to explore the impact of the rapid correction of chronic hyperglycemia on the receptor activator of nuclear factor-kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG). RANKL and OPG are considered the main factors in the pathophysiology of Charcot neuroarthropathy, a devastating complication of the joints that remains poorly understood. The study began recruiting patients in September 2021 and ends in June 2022; the final study results are scheduled for January 2023.

Impact of a Remote Monitoring Programme Including Lifestyle Education Software in Type 2 Diabetes: Results of the Educ@dom Randomised Multicentre Study.

INTRODUCTION: Telemonitoring in type 2 diabetes (T2D) is mainly based on glucose monitoring. A new type of connected device which routinely gathers data on weight, physical activity and food intake could improve patients' diabetes control. The main aim of this study was to assess the efficacy of an at-home interventional programme incorporating such devices and lifestyle education software on diabetes control, i.e., change in HbA1c, compared to standard care. METHODS: This multicentre study randomly assigned 282 people with T2D to either a telemonitoring group (TMG) or a control group (CG) for a 1-year intervention period. While routine follow-up was maintained in the CG, TMG subjects were provided with interactive lifestyle educational software (with artificial intelligence algorithms) and connected objects (blood glucose meters, scales and actimeters) for use in their own homes and were remotely monitored by their diabetologists. Changes in HbA1c were compared between groups using a mixed linear model. RESULTS: The mean HbA1c dropped from 7.8 ± 0.8% (62 mmol/mol) to 7.4 ± 1.0% (57 mmol/mol) in the TMG and from 7.8 ± 0.8% (62 mmol/mol) to 7.6 ± 1.0% (60 mmol/mol) in the CG, resulting in an intergroup difference of - 0.16 (p = 0.06) in favour of TMG, after adjustment for confounding factors. Within TMG, the decrease in HbA1c was greater in frequent users: - 0.23% (p = 0.03) in the case of connections to telemonitoring synthesis above the median and - 0.21% (p = 0.05) in the case of connections to tele-education software above the median compared to the CG. Significant weight loss was observed in the TMG but only in women (p = 0.01). FINDINGS: The EDUC@DOM telemonitoring and tele-education device did not highlight a significant decrease in HbA1c levels compared to routine management although a slight, albeit significant improvement in glycaemic control was observed in the frequent user subgroup as well as significant weight loss but only in women. A high level of satisfaction with the connected device was recorded amongst all participants. TRIAL REGISTRATION: This trial was registered in the Clinical Trials Database on September 27, 2013, under no. NCT01955031 and bears ID-RCB number 2013-A00391-44.

Chronic hyperinsulinemia does not increase the production rate of high-density lipoprotein apolipoprotein AI: evidence from a kinetic study in patients with insulinoma.

OBJECTIVE: In vitro studies showed that insulin stimulates the production of apolipoprotein AI (apoAI). Thus, we hypothesized that chronic hyperinsulinemia could contribute to the increase in the production of high-density lipoprotein apoAI that is observed in metabolic syndrome. APPROACH AND RESULTS: We performed an in vivo kinetic study with stable isotope in 7 patients with insulinoma who showed hyperinsulinemia but no insulin resistance, 8 patients with insulin resistance, and 16 controls. Insulinemia was 3.1× (P<0.01) higher in patients with insulinoma or insulin resistance than in controls in the fasting state and, respectively, 3.5× and 2.6× (P<0.05) higher in the fed state. The high-density lipoprotein apoAI pool size was smaller in patients with insulin resistance than in controls (49.3 ± 5.4 versus 59.6 ± 7.7 mg · kg(-1); P<0.01), whereas both the high-density lipoprotein apoAI fractional catabolic rate and the high-density lipoprotein apoAI production rate were higher (0.30 ± 0.07 versus 0.20 ± 0.04 pool · d(-1); P<0.0001 and 14.6 ± 1.5 versus 11.5 ± 1.9 mg · kg(-1) · d(-1); P<0.01, respectively). In contrast, no significant difference was observed for these parameters between patients with insulinoma and controls. In patients with insulinoma, the apoAI pool size tended to be greater than in patients with insulin resistance (56.3 ± 8.6 versus 49.3 ± 5.4 mg · kg(-1); P=0.078), whereas both the apoAI fractional catabolic rate and the production rate were lower (0.20 ± 0.06 versus 0.30 ± 0.07 pool · d(-1); P<0.01 and 11.1 ± 1.6 versus 14.6 ± 1.5 mg·kg(-1) · d(-1); P<0.01, respectively). The apoAI fractional catabolic rate was the only variable associated with the apoAI production rate in multivariate analysis and explained 80% of its variance. CONCLUSIONS: Chronic endogenous hyperinsulinemia does not induce any increase in the apoAI production rate, which seems to be more dependent on the apoAI fractional catabolic rate.

Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study.

Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.

Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds.

Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

Magnetic resonance imaging versus endoscopic ultrasonography for the detection of pancreatic tumours in multiple endocrine neoplasia type 1.

OBJECTIVE: In multiple endocrine neoplasia type 1, the main risk factor for metastases is pancreatic tumour size. We and others recommend limiting surgery to non-functioning pancreatic tumors ≥20 mm or growing, based on their size measured with endoscopic ultrasonography. Because endoscopic ultrasonography is invasive, we compared endoscopic ultrasonography (EUS) to non-invasive magnetic resonance imaging (MRI) for the detection of pancreatic tumours ≥10 mm in multiple endocrine neoplasia type 1 patients. METHODS: A prospective study was performed in nine participating centres; 90 patients with multiple endocrine neoplasia type 1 underwent EUS and MRI with gadolinium infusion. Gastroenterologists and radiologists were blinded to the results, magnetic resonance images were reviewed centrally. RESULTS: EUS detected 86 tumours ≥10 mm, and 48 (53.3%) patients had at least one tumour ≥10 mm. MRI detected 67 tumours ≥10 mm, and 46 (51.1%) patients had at least one tumour ≥10 mm. EUS and MRI agreement was moderate for detection of tumours ≥10 mm (Kappa coefficient=0.49), and for selection of patients with tumours ≥10 mm (Kappa coefficient=0.55). EUS and MRI missed 11/24 and 4/24 lesions ≥20 mm, respectively. EUS failed to identify 9/57 (15.7%) patients with pancreatic tumours ≥10 mm, and MRI failed to identify 11/57 (19.3%) patients with pancreatic tumours ≥10 mm. CONCLUSIONS: EUS and MRI are complementary and should be performed at initial evaluation in multiple endocrine neoplasia type 1 patients. Whether follow-up should be based on either technique or both, requires further evaluation.

Impact of the number of infusions on 2-year results of islet-after-kidney transplantation in the GRAGIL network.

BACKGROUND: Insulin independence after islet transplantation is generally achieved after multiple infusions. However, single infusion would increase the number of recipients. Our aim was to evaluate the results of islet-after-kidney transplantation according to the number of infusions. METHODS: Islets were isolated at the Geneva University, shipped, and transplanted into French patients from the Swiss-French GRAGIL network, on the "Edmonton" immunosuppression protocol between 2004 and 2010. RESULTS: Nineteen patients were transplanted with 33 preparations. Fifteen patients reached 24 months follow-up; eight subjects were single-graft recipients and seven were double-graft recipients. Finally, single-graft recipients received a median of 5312 islet equivalents/kg (5186-6388) vs. 10,564 (10,054-11,375) for double-graft recipients (P=0.0003) with similar islet mass at first infusion. Insulin independence was achieved in five of eight single-graft subjects (62.5%) versus five of seven in double-graft subjects (71.4%), not significant. Median insulin independence duration was 4.7 (3.1-15.2) months after one infusion vs. 19 (9.6-20.8) months after two infusions (not significant). At 24 months posttransplant, comparing single- with double-graft patients, insulin doses were 0.23 (0.11-0.34) U/kg vs. 0.02 (0.0-0.23) U/kg, P=0.11; HbA1c was 6.5% (5.9%-6.8%) vs. 6.2% (5.9%-6.3%), P=0.16; and basal C-peptide was 302 (143-480) pmol/L vs. 599 (393-806) pmol/L, P=0.05. Only 37.5% of single-graft patients had a ß-score ≥4 compared with 100% of double-graft patients (P=0.03). Two recipients experienced postinfusion bleeding, and two patients (13%) showed renal dysfunction in the absence of biopsy-proven rejection. CONCLUSIONS: One infusion achieves good glycemic control and sometimes insulin independence. However, double-graft patients remain insulin-free longer, tend to have lower HbA1c, and show better graft function 24 months after transplant.

GLP-1 receptor agonists today.

Type 2 diabetes mellitus (T2DM) is a complex, progressive disease affecting an estimated 257 million people worldwide. A number of unmet needs exist with traditional T2DM therapies, which can lead to insufficient glycaemic control and increased risk of diabetes-associated complications. An emerging class of diabetes therapeutics, the glucagon-like peptide-1 (GLP-1) receptor agonists, appear to address many of the unmet needs of patients with T2DM. This review summarises the recent findings and current clinical guidelines of the currently approved GLP-1 receptor agonists and explores the new GLP-1 receptor agonists in development. It also concentrates on the physiological basis for early use of GLP-1 receptor agonists, their use as an alternative to insulin therapy, the rationale for combining them with insulin and their cost-effectiveness.

Endogenous chronic hyperinsulinemia does not increase the production rate of VLDL apolipoprotein B: proof from a kinetic study in patients with insulinoma.

OBJECTIVE: It is currently suggested that chronic hyperinsulinemia is a causal factor for the increased production rate of very-low-density lipoproteins (VLDL) associated with metabolic syndrome. However, the involvement of hyperinsulinemia independently of the other abnormalities also observed in metabolic syndrome has never been proven in humans. DESIGN: We used patients with insulinoma showing hyperinsulinemia but no insulin resistance as a model and conducted an apolipoprotein B (apoB) kinetic study in seven patients with insulinoma, seven insulin-resistant (IR) obese patients, and 12 controls. RESULTS: Insulinemia was higher in patients with insulinoma or IR than in controls both in the fasting state [2.4-fold (P = 0.039) and 3.1-fold (P = 0.003), respectively] and in the fed state [3.5-fold (P = 0.006) and 2.6-fold (P = 0.05), respectively]. Patients with insulinoma were not IR (steady state plasma glucose = 80 ± 46 mg/dl, a value lower than in IR subjects (231 ± 75, P = 0.0013). In the fed state, triglyceridemia and VLDL apoB pool size were higher in IR subjects compared with controls and patients with insulinoma [208 ± 56 vs. 89 ± 30 mg/dl (P < 0.0001) and 96 ± 42 mg/dl (P < 0.0001), respectively, for triglyceridemia and 3.56 ± 0.60 vs. 1.85 ± 0.88 mg/kg (P = 0.004) and 2.32 ± 1.79 (P = 0.052) mg/kg for VLDL apoB pool size]. The production rate of VLDL apoB in subjects with insulinoma was not significantly different from that in controls (14.56 ± 7.43 vs. 16.40 ± 7.70 mg/kg · d) but was higher in IR subjects compared with these two groups [25.66 ± 12.84 mg/kg · d (P = 0.046 and 0.035, respectively)]. CONCLUSION: Chronic endogenous hyperinsulinemia is not directly responsible for any increase in the production rate of VLDL apoB in humans.

Detection of silent myocardial ischemia in asymptomatic patients with diabetes: results of a randomized trial and meta-analysis assessing the effectiveness of systematic screening.

BACKGROUND: Most guidelines recommend a systematic screening of asymptomatic high risk patients with diabetes for silent ischemia, but the clinical benefit of this strategy has not been demonstrated compared with the simple control of cardiovascular risk factors. We sought to determine whether referring asymptomatic diabetic patients for screening of silent ischemia decreases the risk of cardiovascular events compared with usual care. METHODS: DYNAMIT was a prospective, randomized, open, blinded end-point multicenter trial run between 2000 and 2005, with a 3.5 year mean follow-up in ambulatory care in 45 French hospitals. The study included 631 male and female with diabetes aged 63.9 ± 5.1 years, with no evidence of coronary artery disease and at least 2 additional cardiovascular risk factors, receiving appropriate medical treatment. The patients were randomized centrally to either screening for silent ischemia using a bicycle exercise test or Dipyridamole Single Photon Emission Computed Tomography (N = 316), or follow-up without screening (N = 315). The main study end point was time to death from all causes, non-fatal myocardial infarction, non-fatal stroke, or heart failure requiring hospitalization or emergency service intervention. The results of a meta-analysis of DYNAMIT and DIAD, a similar study, are also presented. RESULTS: The study was discontinued prematurely because of difficulties in recruitment and a lower-than expected event rate. Follow-up was complete for 98.9% patients regarding mortality and for 97.5% regarding the main study end point. Silent ischemia detection procedure was positive or uncertain in 68 (21.5%) patients of the screening group. There was no significant difference between the screening and the usual care group for the main outcome (hazard ratio = 1.00 95%CI 0.59 to 1.71). The meta-analysis of these and DIAD results gave similar results, with narrower confidence intervals for each endpoint. CONCLUSIONS: These results suggest that the systematic detection of silent ischemia in high-risk asymptomatic patients with diabetes is unlikely to provide any major benefit on hard outcomes in patients whose cardiovascular risk is controlled by an optimal medical treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00627783.

Results of cryopreserved parathyroid autografts: a retrospective multicenter study.

BACKGROUND: The functionality of cryopreserved parathyroid autotransplantation (CPAT) has been evaluated in few studies, mostly conducted by experienced single-institution centers that have reported different success rates ranging from 17% to 83%. In France, CPAT are rare and their functionality has never been evaluated. Moreover, French tissue banks are facing an accumulation of ungrafted samples. The aim of our work was to evaluate the implantation rate of cryopreserved parathyroid samples and the functionality of CPAT in a multicenter study. METHODS: Data from 9 French tissue banks were analyzed. CPAT functionality was defined as fully functional (normal parathyroid hormone [PTH] and calcium levels without treatment), partially functional (normal PTH levels but need for treatment to maintain normocalcemia), and nonfunctional (low PTH levels and need for treatment). For dialyzed patients, CPAT was considered nonfunctional if the PTH level in the nongrafted arm was less than 20 pg/mL, partially functional if the PTH level was between 20 and 50 pg/mL, and fully functional if the PTH level was between 50 and 300 pg/mL. RESULTS: The 9 centers had cryopreserved 1376 samples of parathyroid tissue and only 22 (1.6%) had been autografted in 20 patients (65% renal hyperparathyroidism, 20% multiple endocrine neoplasia type 1, 15% "other") by 12 different surgical teams. The median duration of storage was 11.1 months (range, 0.4-28.5). Only 2 autografts (10%) were fully functional, 2 (10%) were partially functional, and 17 (80%) were nonfunctional at 26 months median follow-up. CONCLUSION: The reimplantation rate is low, and the functionality of CPAT is less than those published by experienced centers. Logistical and technical problems occurring in less experienced centers are probably the main reasons for nonfunctioning implants. Considering the results of this study, we suggest that cryopreservation of parathyroid glands should be abandoned when not performed in very large experimented centers, that CPAT should be used only for patients with hyperplasic parathyroid tissue, and that tissue samples should be systematically destroyed when patients do not have hypoparathyroidism or after 1 year of storage.

Endocrine pancreatic tumors in von Hippel-Lindau disease: clinical, histological, and genetic features.

OBJECTIVES: Endocrine pancreatic tumors (EPTs) in von Hippel-Lindau (VHL) disease pose difficult management problems. We aimed to assess (1) the accuracy of somatostatin receptor scintigraphy, (2) histological features with focus on malignancy and genotype-phenotype correlations, and (3) prognosis of VHL-EPT. METHODS: Thirty-five patients with EPT-VHL (20 women; median age, 37 years) from 29 families were studied. Histological diagnosis was available in 29 patients. Endocrine pancreatic tumor patients were treated surgically (n = 22), medically (n = 8), or followed (n = 5). Somatostatin receptor scintigraphy was performed in 27 patients. Germinal alterations of the VHL gene were determined. RESULTS: Tumors were malignant in 58% of patients. Somatostatin receptor scintigraphy was positive in 60% of cases, and weak expression of the somatostatin receptor type 2A was found in 47% of tumors. In operated patients, there was no mortality or tumor relapse (median follow-up, 5 [1-10] years). Mortality rate due to EPT was 6%. Germinal mutations were mainly located in exons 3 and 1, and a specific mutation (P86S) was identified. CONCLUSIONS: Most EPTs in VHL patients are somatostatin receptor scintigraphy-positive and malignant, without correlation with the VHL genotype. Surgical resection is often required, but prognosis of these EPTs seems to be fairly good.

Expression of major histocompatibility complex class I chain-related molecule A, NKG2D, and transforming growth factor-beta in the liver of humans with alveolar echinococcosis: new actors in the tolerance to parasites?

BACKGROUND: Echinococcus multilocularis growth and persistent granuloma, which lead to the development of the severe parasitic disease alveolar echinococcosis (AE), might be caused by abnormal expression of stress-induced proteins, with subsequent abnormalities in T cell activation. Similar to its involvement in tumors, the NKG2D-major histocompatability complex class I chain-related molecules A and B (MICA/B) signaling system could be involved in host-parasite interactions; however, its involvement in helminthic diseases has never been studied. METHODS: We studied MICA/B, NKG2D, and transforming growth factor-beta (TGF-beta) expression on liver sections and measured levels of soluble MICA in serum samples obtained from patients with progressive AE. Livers from healthy and cirrhotic subjects were studied as controls. RESULTS: Expression of MICA/B proteins was strongly enhanced in the hepatocytes and endothelial and bile duct cells; in the CD68+ cells of the periparasitic infiltrate, especially epithelioid and giant cells; and, also, in the metacestode germinal layer. Strong expression of MICA/B in the liver contrasted with low numbers of NK cells and lack of expression of NKG2D on the numerous CD8+ T lymphocytes of the periparasitic infiltrate, as well as with the absence of soluble MICA in serum. TGF-beta was strongly expressed by most of the infiltrating lymphocytes. CONCLUSIONS: Sustained expression of MICA/B molecules and TGF-beta might lead to modulation of NKG2D with subsequent inhibition of NKG2D-dependent cytotoxicity. Abnormalities of this signaling system could contribute to parasitic evasion of the host's immunity.

Two types of circulating endothelial progenitor cells in patients receiving long term therapy by HMG-CoA reductase inhibitors.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used to decrease cholesterol synthesis and are well established to reduce vascular diseases. Recently, it has been proposed that statins mobilize endothelial progenitor cells from bone marrow during the first four weeks, which could help to prevent vascular diseases. However, in humans there are few data concerning the long term effects of statin treatment on these endothelial progenitor cells. We investigated whether endothelial progenitor cells can be detected and characterized in patients receiving long term statin therapy. Mononuclear cells from patients receiving or not receiving statin therapy were assessed for progenitor cell content by flow cytometry and were cultured in specific conditions to determine the number and the type of progenitors. Our results showed there were significantly more CD34(+), CD34(+)/CD144(+) circulating progenitor cells in the statin(pos) group than in the statin(neg) group. In culture two types of endothelial progenitor cells were detected. Early endothelial progenitor cells gave colonies at day 5 comprising elongated cells whereas late endothelial progenitor cells generated cobblestone-like colonies with strong proliferation capacities. The number of circulating early endothelial progenitor cells was significantly higher in the statin(neg) group, while only late endothelial progenitor cells were detected in the statin(pos) group. Moreover, cells from cobblestones clearly had an endothelial phenotype CD31(+), VEGF-R2(+), CD34(+), CD146(+) in contrast to cells from colonies from early endothelial progenitor cells, which were VEGF-R2(low), CD34(-). These results strongly suggest that long term statin treatment specifically maintains late endothelial progenitor cells in circulation with a CD34(+)/CD144(+) phenotype.

Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

IL-6 promoter polymorphism -174 is associated with new-onset diabetes after transplantation.

New-onset diabetes after transplantation (NODAT) is a serious complication of transplantation. This study tested whether IL-6 production capacity may influence the development of NODAT in two different groups of patients. The occurrence of NODAT was analyzed with respect to IL-6 gene promoter polymorphism at position -174 (G-->C) and other relevant risk factors retrospectively in 217 renal transplant recipients and prospectively in 132. A linear increase in both circulating IL-6 (P = 0.09) and C-reactive protein (an indicator of basal IL-6 secretion; P = 0.03) concentrations from the CC genotype to the GG genotype was observed. In the multivariate model, the CC genotype was associated with a decreased risk for NODAT compared with the GG genotype in the two cohorts. Homeostasis Model Assessment for Insulin Resistance also revealed lesser insulin sensitivity in the GG carriers than in the CC carriers (2.15 +/- 2 versus 1.32 +/- 1.03; P = 0.03). Subgroup analysis showed that the influence of IL-6 gene promoter polymorphism on the development of NODAT was restricted mostly to overweight patients. These results highly suggest that IL-6 production capacity influences the development of NODAT and that diabetes-inducing drug administration should be limited in overweight patients who carry the GG genotype.

Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1.

BACKGROUND: The frequency of pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1 (MEN1) remains unknown. AIM: To evaluate prospectively with endoscopic ultrasonography (EUS) the frequency of nonfunctioning (asymptomatic) pancreaticoduodenal tumors. PATIENTS AND METHODS: MEN1 patients without functioning pancreatic involvement underwent systematic pancreaticoduodenal EUS in nine GTE (Groupe des Tumeurs Endocrines) centers. Demographic and clinical factors predictive of pancreatic involvement were sought, and standardized biochemical measurements obtained. RESULTS: Between November 1997 and July 2004, 51 patients (median age: 39 [range: 16-71] yr) were studied. MEN1 had been diagnosed 3 [0-20] yr earlier, notably by genetic screening for 26 (51%) with asymptomatic disease. Twenty-five patients had minor biochemical anomalies (<2 x normal (N)) and serum somatostatin was 10.8 N in 1; EUS detected pancreatic lesions in 28 patients (54.9%; 95% CI: 41.3-68.7%). A median of three [1-9] tumors with a median diameter of 6 [2-60] mm was found per patient; for 19 (37.3%) patients a tumor measured > or =10 mm and > or = 20 mm in 7 (13.7%) patients. Only one duodenal lesion was found and three patients had peripancreatic adenopathies. Pancreatic tumors were not associated with any of the studied parameters, notably age, family history, biochemical anomalies. Sixteen of twenty-six patients underwent EUS monitoring over 50 [12-70] months; six (37.5%) had more and/or larger pancreatic lesions. CONCLUSION: The frequency of nonfunctioning pancreatic endocrine tumors is higher (54.9%) than previously thought. The size and number of these tumors can increase over time. Pancreatic EUS should be performed once MEN1 is diagnosed to monitor disease progression.

Impaired processing and presentation by MHC class II proteins in human diabetic cells.

The biochemical processing of and Ag presentation by MHC class II molecules were examined in B cell lines derived from pairs of identical twins discordant for type 1 diabetes. MHC class II defects detected exclusively in cells derived from the twins with autoimmunity included increased rates of transport to and subsequent turnover at the cell surface, inadequate glycosylation, and a reduced display at the cell surface of antigenic peptides. These defects appeared to be secondary to a decreased abundance of the p35 isoform of the invariant chain (Ii), a human-specific chaperone protein for MHC class II normally generated by use of an alternative translation start site. Stable transfection of diabetic B cell lines with an Ii p35 expression vector corrected the defects in MHC class II processing and peptide presentation. A defect in the expression of Ii p35 may thus result in impairment of Ag presentation by MHC class II molecules and thereby contribute to the development of type 1 diabetes in at-risk genotypes.