A. Penfornis

The Diabeo Software Enabling Individualized Insulin Dose Adjustments Combined With Telemedicine Support Improves HbA1c in Poorly Controlled Type 1 Diabetic Patients A 6-month, randomized, open-label, parallel-group, multicenter trial (TeleDiab 1 Study)

OBJECTIVE To demonstrate that Diabeo software enabling individualized insulin dose adjustments combined with telemedicine support significantly improves HbA1c in poorly controlled type 1 diabetic patients. RESEARCH DESIGN AND METHODS In a six-month open-label parallel-group, multicenter study, adult patients (n = 180) with type 1 diabetes (>1 year), on a basal-bolus insulin regimen (>6 months), with HbA1c ≥8%, were randomized to usual quarterly follow-up (G1), home use of a smartphone recommending insulin doses with quarterly visits (G2), or use of the smartphone with short teleconsultations every 2 weeks but no visit until point end (G3). RESULTS Six-month mean HbA1c in G3 (8.41 ± 1.04%) was lower than in G1 (9.10 ± 1.16%; P = 0.0019). G2 displayed intermediate results (8.63 ± 1.07%). The Diabeo system gave a 0.91% (0.60; 1.21) improvement in HbA1c over controls and a 0.67% (0.35; 0.99) reduction when used without teleconsultation. There was no difference in the frequency of hypoglycemic episodes or in medical time spent for hospital or telephone consultations. However, patients in G1 and G2 spent nearly 5 h more than G3 patients attending hospital visits. CONCLUSIONS The Diabeo system gives a substantial improvement to metabolic control in chronic, poorly controlled type 1 diabetic patients without requiring more medical time and at a lower overall cost for the patient than usual care.

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 × 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 ≥10 mm and ≥ 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.

Medication adherence in type 2 diabetes: the ENTRED study 2007, a French Population-Based Study.

Background Adherence to prescribed medications is a key dimension of healthcare quality. The aim of this large population-based study was to evaluate self-reported medication adherence and to identify factors linked with poor adherence in patients with type 2 diabetes in France. Methodology The ENTRED study 2007, a French national survey of people treated for diabetes, was based on a representative sample of patients who claimed reimbursement for oral hypoglycaemic agents and/or insulin at least three times between August 2006 and July 2007, and who were randomly selected from the database of the two main National Health Insurance Systems. Medication adherence was determined using a six-item self-administered questionnaire. A multinomial polychotomous logistic regression model was used to identify factors associated with medication adherence in the 3,637 persons with type 2 diabetes. Principal Findings Thirty nine percent of patients reported good medication adherence, 49% medium adherence and 12% poor adherence. The factors significantly associated with poor adherence in multivariate analysis were socio-demographic factors: age <45 years, non-European geographical origin, financial difficulties and being professionally active; disease and therapy-related factors: HbA1c>8% and existing diabetes complications; and health care-related factors: difficulties for taking medication alone, decision making by the patient only, poor acceptability of medical recommendations, lack of family or social support, need for information on treatment, reporting no confidence in the future, need for medical support and follow-up by a specialist physician. Conclusions In a country with a high level of access to healthcare, our study demonstrated a substantial low level of medication adherence in type 2 diabetic patients. Better identification of those with poor adherence and individualised suitable recommendations remain essential for better healthcare management.

Human islet transplantation network for the treatment of Type I diabetes: first data from the Swiss-French GRAGIL consortium (1999–2000)

Aims/hypothesis. Improvements in islet transplantation require clinical series large enough to implement controlled new strategies. The goal of this study was to demonstrate the feasibility of a multicentre network for islet transplantation in Type I (insulin-dependent) diabetic patients. Methods. The five centres (Besançon, Geneva, Grenoble, Lyon, Strasbourg) of the GRAGIL network allow pancreas procurement, recipient recruitment, transplantation procedure and follow-up. Islet isolation is, however, performed in one single laboratory (Geneva). Pancreata were procured in each of the five centres and transported to Geneva with an ischaemia time of less than 8 hours. Islets were isolated using a standard automated method. If the islet number was too low for a graft ( < 6000 Islet-equivalent /kg), islets were cultured up to 12 days until another isolation was possible. Islets were transplanted by percutaneous transhepatic intraportal injection. Immunosuppression consisted of cyclosporine, mycophenolate mofetil, steroids and an anti-interleukin 2 receptor antibody. Results. From March 1999 to June 2000, 56 pancreata procurements were performed with an average yield of 234 500 islet-equivalent, with 32 preparations over 200 000 islet-equivalent. Ten C-peptide negative Type I diabetic patients (5 men and 5 women, median age 44 years, median diabetes duration 29 years) with an established kidney graft ( > 6 months) received 9030 ± 1090 islet-equivalent/kg with a median purity of 63 %. The number of pancreata required for each graft was 1 (n = 5) or 2 (n = 5). At the completion of a 12 month follow-up, we observed 0 % primary nonfunction, 50 % graft survival and 20 % insulin-independence. Conclusions/interpretation. This study demonstrates the interest and the feasibility of a multicentre collaboration in human islet transplantation. [Diabetologia (2001) 44: 859–864]

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.Abbreviations: CNS - central nervous system, CT scan - computed tomography, EPT - endocrine pancreatic tumors, EUS - endoscopic ultrasonography, SRS - somatostatin receptor scintigraphy, VHL - von Hippel-Lindau disease

Expectations and strategies regarding islet transplantation: metabolic data from the GRAGIL 2 trial

Background. Whether islet transplantation should be aimed at restoring insulin independence or providing adequate metabolic control is still debated. The GRAGIL2 trial was designed as a phase 1–2 study where primary outcome was the rate of insulin independence, and secondary outcome was the success rate defined by a composite score based upon basal C-peptide, HbA1c, hypoglycemic events, and exogenous insulin needs. Methods. C-peptide negative type 1 brittle diabetic patients experiencing severe hypoglycemia were eligible to receive a maximum of two islet preparations totalizing 10,000 IE/kg or more, with a threshold of 5,000 IE/kg for the first infusion, according to the Edmonton protocol, within the Swiss-French GRAGIL multicentric network. A sequential analysis with a triangular test was performed in every five patients after 6- and 12-month follow-up. Maximal inefficiency was set at 40% and minimal efficiency at 66%. Results. From September 2003 to October 2005, 10 patients were included. Median waiting time was 6.7 months (first injection) and 9 weeks (second injection). All but one patient received 11,089±505 IE/kg: one received a single graft of 5398 IE/kg. At 6 months, insulin independence and composite success rates were 6 of 10 and 6 of 10, respectively. At 12 months, insulin independence was observed in 3 of 10 patients and success in 5 of 10 patients. Conclusion. Based upon our sequential analysis settings, islet transplantation failed to achieve the primary goal, insulin independence, but tended to succeed in reaching the secondary goal, successful metabolic control. Currently it appears to be a successful biological closed-loop glucose control method for brittle diabetes.

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

BackgroundMost 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.MethodsDYNAMIT 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.ResultsThe 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.ConclusionsThese 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 registrationClinicalTrials.gov: NCT00627783

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.

Assessment of Patient-Led or Physician-Driven Continuous Glucose Monitoring in Patients With Poorly Controlled Type 1 Diabetes Using Basal-Bolus Insulin Regimens A 1-year multicenter study

OBJECTIVE The benefits of real-time continuous glucose monitoring (CGM) have been demonstrated in patients with type 1 diabetes. Our aim was to compare the effect of two modes of use of CGM, patient led or physician driven, for 1 year in subjects with poorly controlled type 1 diabetes. RESEARCH DESIGN AND METHODS Patients with type 1 diabetes aged 8–60 years with HbA1c ≥8% were randomly assigned to three groups (1:1:1). Outcomes for glucose control were assessed at 1 year for two modes of CGM (group 1: patient led; group 2: physician driven) versus conventional self-monitoring of blood glucose (group 3: control). RESULTS A total of 257 subjects with type 1 diabetes underwent screening. Of these, 197 were randomized, with 178 patients completing the study (age: 36 ± 14 years; HbA1c: 8.9 ± 0.9%). HbA1c improved similarly in both CGM groups and was reduced compared with the control group (group 1 vs. group 3: −0.52%, P = 0.0006; group 2 vs. group 3: −0.47%, P = 0.0008; groups 1 + 2 vs. group 3: −0.50%, P < 0.0001). The incidence of hypoglycemia was similar in the three groups. Patient SF-36 questionnaire physical health score improved in both experimental CGM groups (P = 0.004). Sensor consumption was 34% lower in group 2 than in group 1 (median [Q1–Q3] consumption: group 1: 3.42/month [2.20–3.91] vs. group 2: 2.25/month [1.27–2.99], P = 0.001). CONCLUSIONS Both patient-led and physician-driven CGM provide similar long-term improvement in glucose control in patients with poorly controlled type 1 diabetes, but the physician-driven CGM mode used fewer sensors.

Expression of Major Histocompatibility Complex Class I Chain–Related Molecule A, NKG2D, and Transforming Growth Factor–β 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 hosts immunity.