Assessing diabetic foot osteomyelitis remission with white blood cell SPECT/CT imaging.

AIMS: Diabetic foot osteomyelitis is an important risk factor of lower limb amputation. Antibiotic therapy is often effective in preventing surgery. However, the duration of antibiotic therapy is difficult to define in the absence of a marker to diagnose osteomyelitis remission at the end of the treatment. In this study, we assessed the diagnostic performance of white blood cell SPECT/CT imaging for evaluating osteomyelitis remission. PATIENTS AND METHODS: Twenty-nine out of 42 episodes of diabetic foot osteomyelitis seen between December 2009 and April 2012 had radiographs, a three-phase bone scintigraphy and a white blood cell SPECT/CT at the end of antibiotic therapy. They were treated with antibiotics alone and considered in clinical remission. White blood cell SPECT/CT results were considered positive when abnormal uptake in the osteomyelitis location was identified. Osteomyelitis remission was defined by the absence of an osteomyelitis relapse after 12 months' follow-up. RESULTS: A negative white blood cell SPECT/CT was seen for 22 episodes of osteomyelitis. All of them were in remission. A positive white blood cell SPECT/CT was observed for seven episodes. A relapse occurred in five episodes (71.5%) after a median duration of 4 months (2-7 months). Sensitivity, specificity, positive predictive value and predictive negative value in predicting osteomyelitis relapse after the discontinuation of antibiotic treatment were, respectively, for radiographs 80%, 33%, 20% and 89%; for three-phase bone scintigraphy 100%, 12.5%, 15.5% and 100%; and for the white blood cell SPECT/CT 100%, 91.5%, 71.5% and 100%. CONCLUSION: Negative uptake on white blood cell SPECT/CT is a good marker for diagnosis of diabetic foot osteomyelitis remission and might be very useful in guiding antibiotic therapy.

Oesophageal function assessed by high-resolution manometry in patients with diabetes and inadequate glycaemic control.

AIMS: To describe oesophageal function in people with diabetes and poor glycaemic control using oesophageal high-resolution manometry and to compare the result between control subjects and patients with gastro-oesophageal reflux disease. METHODS: The results of oesophageal high-resolution manometry and a gastric emptying test were reviewed in 20 patients with diabetes. The high-resolution manometry protocol consisted of 5-ml swallows of water and multiple swallows of water. Oesophageal motility disorders were classified according to the Chicago classification system. The occurence of multiphasic contractions and intragastric and intrabolus pressures were measured. High-resolution manometry results were compared between 10 control subjects and 20 patients with gastro-oesophageal reflux disease. Data were expressed as medians and compared using Mann-Whitney and chi-squared tests. RESULTS: Oesophageal motility disorders were similarly distributed between the groups. Multiphasic contractions occurred more frequently in patients with diabetes than in those with gastro-oesophageal reflux disease (60 vs 20% per patient; P<0.01) and were not observed in control subjects. Gastric emptying was delayed in six patients with diabetes and did not correlate with symptoms or oesophageal motility disorders. Intrabolus pressure was higher in patients with diabetes and gastroparesis than in those without (17 vs 10 mmHg; P=0.02) and correlated with intragastric pressure (r=0.46, P<0.01). During multiple swallows of water, oesophageal contractile activity was incompletely inhibited in 83% of patients with diabetes and gastroparesis vs 9% without (P<0.01). Oesophageal function and gastric emptying were not influenced by fasting glycaemia. CONCLUSIONS: Patients with gastroparesis might present with impaired inhibition of contractile activity during multiple swallows of water. Increased intrabolus pressure is suggestive of delayed oesophageal clearance as a consequence of gastroparesis.

The first simultaneous kidney-adrenal gland-pancreas transplantation: outcome at 1 year.

Adrenal insufficiency is a rare but life-threatening disease. Replacement therapy sometimes fails to prevent an acute adrenal crisis and most often does not lead to restoration of well-being. We report here the 1-year outcome of the first simultaneous kidney-adrenal gland-pancreas transplantation in a 33-year-old patient with type 1 diabetes and concomitant autoimmune adrenal insufficiency. En bloc left adrenal gland and kidney grafts were anastomosed on the left iliac vessels in normal vascular conditions and the pancreas graft was anastomosed on the right iliac vessels. The immunosuppressive regimen was not modified by the addition of the adrenal gland. We observed no additional morbidity due to the adrenal gland transplantation, as there were no surgical complications. One-year kidney and pancreas graft functions were satisfactory (estimated glomerular filtration rate: 55 mL/min/1.73 m(2) and HbA1c: 4.8%). The adrenal graft functioned well at 12 months with a normalization of cortisol and aldosterone baseline levels. Functional imaging at 3 months showed good uptake of [(123) I]-metaiodobenzylguanidine by the adrenal graft. Transplantation of the adrenal gland en bloc with the left kidney appears to be a good therapeutic option in patients with adrenal insufficiency awaiting kidney or kidney-pancreas transplantation.

Hybrid closed Loop improved glucose control compared to sensor-augmented pumps in outpatients with type 1 diabetes in real-life conditions with telehealth monitoring.

OBJECTIVES: The study aims at evaluating glucose metrics and HbA1C values after pump initiation in outpatient settings. RESEARCH DESIGN AND METHODS: This single center observational study enrolled 121 subjects with type 1 diabetes between September 2020 and May 2021 initiating sensor-augmented pump therapy with stand-alone CGM (n = 26) or pump users who only changed their device (n = 51), with predictive low glucose management (n = 8) or with Hybrid Closed Loop using Medtronic 780G (n = 36) systems. Changes in HbA1C levels and glucose metrics were analyzed after 3 months. All subjects received diabetes and carbohydrate-counting education if needed at time of initiation and were proposed a telehealth monitoring by a diabetic nurse educator. RESULTS: There was no episodes of severe hypoglycemia or diabetic ketoacidosis nor serious pump-related adverse events despite outpatient model of care. While only 18/121 (14.8%) participants reached initially the recommended HbA1C levels, 23/85 (27%) in the conventional group and 33/36 (91%) subjects in the Hybrid Closed Loop group reached target levels after 3 months of follow-up. Time in target range 3.9-10 mmol/L (70-180 mg/dl) also improved and was optimal with closed loop with 30/36 (83%) subjects with time in range above 70%. CONCLUSIONS: Initiation of insulin pump therapy for outpatients is safe with a dedicated facility. Telehealth monitoring after outpatient initiation provides tools for improvement in glucose control with an insulin pump. Outpatient pump initiation is compatible with Hybrid Closed Loop systems which provide the largest improvements in glucose control.

Design of a prospective, longitudinal cohort of people living with type 1 diabetes exploring factors associated with the residual cardiovascular risk and other diabetes-related complications: The SFDT1 study.

Type 1 diabetes mellitus (T1DM) is associated with a high risk of cardiovascular (CV) complications, even after controlling for traditional CV risk factors. Therefore, determinants of the residual increased CV morbidity and mortality remain to be discovered. This prospective cohort of people living with T1DM in France (SFDT1) will include adults and children aged over six years living with T1DM, recruited throughout metropolitan France and overseas French departments and territories. The primary objective is to better understand the parameters associated with CV complications in T1DM. Clinical data and biobank samples will be collected during routine visits every three years. Data from connected tools, including continuous glucose monitoring, will be available during the 10-year active follow-up. Patient-reported outcomes, psychological and socioeconomic information will also be collected either at visits or through web questionnaires accessible via the internet. Additionally, access to the national health data system (Health Data Hub) will provide information on healthcare and a passive 20-year medico-administrative follow-up. Using Health Data Hub, SFDT1 participants will be compared to non-diabetic individuals matched on age, gender, and residency area. The cohort is sponsored by the French-speaking Foundation for Diabetes Research (FFRD) and aims to include 15,000 participants.

Pumps that predict and manage low blood glucose are superior to pumps with stand-alone CGM for reducing hypoglycaemia in type 1 diabetes patients in a real-world setting.

BACKGROUND: This study aimed to assess the efficacy of insulin pumps with automated predictive low-glucose insulin suspension in a real-world setting compared with stand-alone flash glucose monitoring (FGM). METHODS: The data analyzed were uploaded by patients with type 1 diabetes (n=195) treated with external insulin pumps [either a MiniMed 640G system (Medtronic) including SmartGuard technology that predicts and manages low glucose (n=61) or an Omnipod patch pump accompanied by a FreeStyle Libre sensor (Abbott) for FGM (n=134)]. RESULT: The median (25th-75th percentile) time spent with sensor glucose values≤3.9mmol/L was 0.9% (0.4-1.55) vs. 5.6% (3.05-9.55) in the predictive low-glucose suspend group vs. FGM users, respectively (P<0.0001), with similar results obtained for median time spent with sensor glucose values≤3mmol/L (P<0.0001). The group using sensor-integrated pumps had lower % coefficient of variation (CV) values and lower mean amplitude glycaemic excursions (P<0.0001). Mean glucose values as well as measured HbA1c levels were also lower. CONCLUSION: These real-world data show that predictive low-glucose insulin suspension is more effective than pumps with stand-alone FGM for reducing hypoglycaemic events, and could be of benefit to patients at risk of hypoglycaemia as well as those lacking in hypoglycaemic awareness.

Effects of remote care of patients with poorly controlled type 1 diabetes included in an experimental telemonitoring programme.

AIM: To assess, in a real-life setting, the effectiveness of telemonitoring adults with type 1 diabetes (T1D) using continuous glucose monitoring in a telemedicine experiment. METHODS: Experimentation in Telemedicine for the Improvement of Healthcare Pathways (ETAPES), an experimental telehealth programme for five chronic diseases, is supported by the French national healthcare system to promote telemedical care. Using data from a single university hospital centre, 72 adults were studied, including 42 subjects (58%) receiving insulin pump therapy and 30 (42%) receiving multiple daily injections, with a median age of 35.5 years [28.0; 45.0] and poorly controlled type 1 diabetes (T1D) with a mean ± standard error of mean (SEM) HbA1c value of 8.69 ± 0.13%. The primary study outcome was the difference in HbA1c values between baseline and the end of a 6-month follow-up. Other end points of interest were mean blood glucose, glucose management indicator (GMI) level and % time in range (3.9-10 mmol/L) or below or above range. RESULTS: At month 6, mean HbA1c levels were significantly reduced by -0.5% (P < 0.001) as were also mean blood glucose levels (P = 0.015), with a significant increase of 6.75 ± 1.36% of time in range at month 3 and of 4.98 ± 1.4% at month 6. Such improvements did not depend on age, gender or type of insulin therapy, but were inversely correlated to initial HbA1c values on multivariate analysis (P < 0.001). CONCLUSION: Although the use of telehealth monitoring offers efficacy and safety in the metabolic control of patients with T1D, it does not fulfil all of these patients' clinical needs. As such, this new healthcare pathway cannot replace, but is a useful complement to, face-to-face in-person clinical visits.

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.

Specific gene expression signature associated with development of autoimmune type-I diabetes using whole-blood microarray analysis.

Understanding the pathogenesis of type-I diabetes (T1D) is hindered in humans by the long autoimmune process occurring before clinical onset and by the difficulty to study the pancreas directly. Alternatively, exploring body fluids and particularly peripheral blood can provide some insights. Indeed, circulating cells can function as 'sentinels', with subtle changes in gene expression occurring in association with disease. Therefore, we investigated the gene expression profiles of circulating blood cells using Affymetrix microarrays. Whole-blood samples from 20 first-degree relatives of T1D children with autoimmune diabetes-related antibodies, 19 children immediately after the onset of clinical T1D and 20 age- and sex-matched healthy controls were collected in PAXgene tubes. A global gene expression analysis with MDS approach allowed the discrimination of pre-diabetic subjects, diabetic patients and healthy controls. Univariate statistical analysis highlighted 107 distinct genes differently expressed between these three groups. Two major gene expression profiles were characterized, including type-I IFN-regulated genes and genes associated with biosynthesis and oxidative phosphorylation. Our results showed the presence of early functional modifications associated with T1D, which could help to understand the disease and suggest possible avenues for therapeutic interventions.

Prognostic factors in patients with diabetes hospitalized for COVID-19: Findings from the CORONADO study and other recent reports.

Diabetes mellitus is challenging in the context of the COVID-19 pandemic. The prevalence of diabetes patients hospitalized in intensive care units for COVID-19 is two- to threefold higher, and the mortality rate at least double, than that of non-diabetes patients. As the population with diabetes is highly heterogeneous, it is of major interest to determine the risk factors of progression to a more serious life-threatening COVID-19 infection. This brief review discusses the main findings of CORONADO, a prospective observational study in France that specifically addressed this issue as well as related observations from other countries, mainly China and the US. Some prognostic factors beyond old age have been identified: for example, an increased body mass index is a major risk factor for requiring respiratory assistance. Indeed, obesity combines several risk factors, including impaired respiratory mechanics, the presence of other comorbidities and inappropriate inflammatory responses, partly due to ectopic fat deposits. While previous diabetic microvascular (renal) and macrovascular complications also increase risk of death, the quality of past glucose control had no independent influence on hospitalized diabetes patient outcomes, but whether the quality of glucose control might modulate risk of COVID-19 in non-hospitalized diabetes patients is still unknown. In addition, no negative signs regarding the use of RAAS blockers and DPP-4 inhibitors and outcomes of COVID-19 could be identified. Hyperglycaemia at the time of hospital admission is associated with poor outcomes, but it may simply be considered a marker of severity of the infection. Thus, the impact of glucose control during hospitalization on outcomes related to COVID-19, which was not investigated in the CORONADO study, is certainly deserving of specific investigation.

Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells.

AIMS/HYPOTHESIS: Displaying immunomodulatory capacities, mesenchymal stem cells (MSCs) are considered as beneficial agents for autoimmune diseases. The aim of this study was to examine the ability of MSCs to prevent autoimmune diabetes in the NOD mouse model. METHODS: Prevention of spontaneous insulitis or of diabetes was evaluated after a single i.v. injection of MSCs in 4-week-old female NOD mice, or following the co-injection of MSCs and diabetogenic T cells in irradiated male NOD recipients, respectively. The frequency of CD4(+)FOXP3(+) cells and Foxp3 mRNA levels in the spleen of male NOD recipients were also quantified. In vivo cell homing was assessed by monitoring 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE)-labelled T cells or MSCs. In vitro, cell proliferation and cytokine production were assessed by adding graded doses of irradiated MSCs to insulin B9-23 peptide-specific T cell lines in the presence of irradiated splenocytes pulsed with the peptide. RESULTS: MSCs reduced the capacity of diabetogenic T cells to infiltrate pancreatic islets and to transfer diabetes. This protective effect was not associated with the modification of diabetogenic T cell homing, but correlated with a preferential migration of MSCs to pancreatic lymph nodes. While injection of diabetogenic T cells resulted in a decrease in levels of FOXP3(+) regulatory T cells, this decrease was inhibited by MSC co-transfer. Moreover, MSCs were able to suppress both allogeneic and insulin-specific proliferative responses in vitro. This suppressive effect was associated with the induction of IL10-secreting FOXP3(+) T cells. CONCLUSIONS/INTERPRETATION: MSCs prevent autoimmune beta cell destruction and subsequent diabetes by inducing regulatory T cells. MSCs may thus offer a novel cell-based approach for the prevention of autoimmune diabetes and for islet cell transplantation.

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.

Screening of diabetic retinopathy: effect of field number and mydriasis on sensitivity and specificity of digital fundus photography.

PURPOSE: To evaluate the sensitivity and specificity of one- and three-field, nonmydriatic and mydriatic, and 45 degrees digital colour photography compared with mydriatic indirect ophthalmoscopy for diabetic retinopathy (DR) screening. METHODS: A group of 79 patients (158 eyes) were included in this prospective study. Colour fundus photographs were taken with a Topcon TRC-NW6S digital camera, using four different techniques--single-field nonmydriatic; three-field nonmydriatic; single-field mydriatic; and three-field mydriatic--followed by dilated ophthalmoscopy. Two independent ophthalmologists classified blinded photographs according to the presence or absence of specific diabetic retinal findings. The sensitivity, specificity and agreement (kappa analyses) of the four methods were calculated for the presence or absence of DR and for all diabetic retinal findings. RESULTS: The sensitivity and specificity of digital photography compared with ophthalmoscopy for detection of DR were, respectively: 77 and 99% using single-field nonmydriatic; 92 and 97% using three-field nonmydriatic; 90 and 98% using single-field mydriatic; 97 and 98% using three-field mydriatic. The degrees of agreement for the four methods were 0.82, 0.90, 0.90 and 0.95, respectively. For specific retinal findings, sensitivity was greater for detection of hard exudates, nerve fibre layer haemorrhage and venous beading, and lower for detection of microaneurysms, dot-blot haemorrhage, cotton wool spots and intraretinal microvascular anomalies. CONCLUSION: The three-field strategy without pupil dilation represents a good compromise, with reasonable sensitivity and good comfort (short examination duration, able to drive after photography) favouring patient compliance with the screening programme.

Distinction between epidermal antigens binding pemphigus vulgaris and pemphigus foliaceus autoantibodies.

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune blistering diseases in which antibodies develop to the cell surface of epidermal cells. In this study we sought to determine the antigenic specificity of antibodies in the sera of patients with PV and PF. Sera from 12 patients with PV were used to immunoprecipitate extracts of cultured human epidermal cells that were radiolabeled with 14C-amino acids. Immunoprecipitates were identified by SDS polyacrylamide gel electrophoresis (PAGE) and fluorography. All 12 PV sera precipitated a protein which, when reduced, displayed chains of 130,000 and 80,000 mol wt on SDS-PAGE. Electrophoresis under nonreducing conditions identified a 210,000-mol wt molecule, which was presumably formed by disulfide crosslinking of the 130,000 and 80,000-mol wt chains. Immunoprecipitates of epidermal cell extracts that were labeled with 14C-glucosamine indicated that the 130,000-mol wt chain. Seven of eight PF sera, which were run concurrently with the PV sera in this immunoprecipitation assay, did not precipitate this glycoprotein, nor did they specifically precipitate any protein. To determine if a specific molecule which reacted with antibodies in PF sera could be identified, we used immunoblot analysis of extracts of normal human epidermis. The proteins in these extracts were reduced, separated by SDS-PAGE, and electrophoretically transferred to nitrocellulose sheets or to 2-aminophenylthioether paper. Immunoperoxidase staining of the transferred proteins with PF sera indicated that four of eight PF sera contained antibodies that stained a protein band of 160,000 mol wt. Indirect immunofluorescence, using normal human skin as the substrate, indicated that IgG that was eluted from this protein band stained the epidermis in a cell surface pattern. PV sera did not specifically recognize any bands by immunoblot analysis. Immunoblots performed with PV antigen that was immunoprecipitated from cell culture extracts suggested that, once denatured for SDS-PAGE, PV antigen is no longer immunoreactive. Taken together, these data indicate that: autoantibodies contained in PV sera from various patients have a unique molecular specificity; autoantibodies from most PF sera have a specificity different from that of PV autoantibodies; and autoantibodies from various PF patients may not have identical antigenic specificities. These differences in antigenic specificity between PV and PF sera may account for the clinical and histologic differences between these diseases.

Familial aggregation of LADA and juvenile type 1 diabetes in a French Caucasian family.

We describe here the unusual aggregation of diabetes cases in a family of 10 subjects. Among them, three adult siblings presented with LADA and one child presented with juvenile type 1 diabetes. Although the exact pathogenesis of LADA is unknown and questions the role of autoimmunity in beta cell failure, the familial aggregation of these two forms of diabetes underlines the existence of common roots, i.e. immune mechanisms and genetic susceptibility. This report clearly illustrates the differences in terms of autoimmunity (prevalence and titer of GAD and IA2 antibodies) and HLA class II genotype between patients with LADA and those with juvenile type 1 diabetes.

Immunology of pancreatic islet transplantation.

Clinical protocols in type 1 diabetic patients to optimize islet survival and function post-transplantation improved dramatically in the last decade, but it is clear that this approach still has potential limitations to provide long term insulin independency. Islet allografts administered in the liver via the portal vein are exposed to several factors contributing to a rapid loss of function that may reach 50% of the initial beta cell mass. Allo- and auto-immune reactions - an unique situation in clinical transplantation - are partially overcome with immunosuppressive regimen. Serological markers and T cell reactivities may correlate with graft failure. Most of the drugs that are used, including rapamycin (sirolimus) or the calcineurin inhibitor tacrolimus (FK506), have deleterious effects on beta function and/or insulin sensitivity. Immediate factors that limit initial islet engraftment have been elucidated, including instant blood mediated inflammatory reaction and angiogenesis. Newer interventions designed to promote islet survival, to prevent apoptosis, to promote islet growth and to protect islets in the long run from immunological injury are rapidly approaching clinical trials.

Protection of Human Pancreatic Islets from Lipotoxicity by Modulation of the Translocon.

Type 2 diabetes is characterized by peripheral insulin resistance and pancreatic beta cell dysfunction. Elevated free fatty acids (FFAs) may impair beta cell function and mass (lipotoxicity). Altered calcium homeostasis may be involved in defective insulin release. The endoplasmic reticulum (ER) is the major intracellular calcium store. Lipotoxicity induces ER stress and in parallel an ER calcium depletion through unknown ER calcium leak channels. The main purposes of this study is first to identify one of these channels and secondly, to check the opportunity to restore beta cells function (i.e., insulin secretion) after pharmacological inhibition of ER calcium store depletion. We investigated the functionality of translocon, an ER calcium leak channel and its involvement on FFAs-induced alterations in MIN6B1 cells and in human pancreatic islets. We evidenced that translocon acts as a functional ER calcium leak channel in human beta cells using anisomycin and puromycin (antibiotics), respectively blocker and opener of this channel. Puromycin induced a significant ER calcium release, inhibited by anisomycin pretreatment. Palmitate treatment was used as FFA model to induce a mild lipotoxic effect: ER calcium content was reduced, ER stress but not apoptosis were induced and glucose induced insulin secretion was decreased in our beta cells. Interestingly, translocon inhibition by chronic anisomycin treatment prevented dysfunctions induced by palmitate, avoiding reticular calcium depletion, ER stress and restoring insulin secretion. Our results provide for the first time compelling evidence that translocon actively participates to the palmitate-induced ER calcium leak and insulin secretion decrease in beta cells. Its inhibition reduces these lipotoxic effects. Taken together, our data indicate that TLC may be a new potential target for the treatment of type 2 diabetes.

Lymphocyte function associated antigen-1, integrin alpha 4, and L-selectin mediate T-cell homing to the pancreas in the model of adoptive transfer of diabetes in NOD mice.

The involvement of adhesion molecule in the process of T-cell homing to the pancreas was investigated in the model of the T-cell transfer of type I diabetes in NOD mice. Treatment of mice using monoclonal anti-lymphocyte function associated antigen (LFA)-1, anti-integrin alpha 4, anti-intercellular adhesion molecule (ICAM)-1, and anti-L-selectin antibodies (monoclonal antibodies [mAbs]) gave rise to a partial or complete prevention of diabetes via different mechanisms of protection. On day 20 posttransfer, diabetes was only observed in control mice (26 of 32) and in few mice treated with the anti-L-selectin mAbs (3 of 24). On day 60, the best protection was observed using the anti-LFA-1 or the anti-integrin alpha 4 mAbs with 3 of 11 and 2 of 5 diabetic mice, respectively. On day 20, no insulitis was observed in the pancreases of mice treated with these mAbs compared with the pancreases of controls, suggesting that such treatment blocked the penetration of T-cells into the islets. In vitro adhesion assays confirmed that adhesion of T-cells to the pancreatic endothelium was blocked, except when using the anti-L-selectin mAb, which induced a modification of the traffic of the transferred T-cells; the ability of T-cells to migrate into the pancreatic lymph nodes was significantly reduced (10.4 vs. 22%). Anti-LFA-1 mAbs did not modify such T-cell trafficking. The present study, therefore, elucidates the role of LFA-1, integrin alpha 4, and L-selectin in T-cell homing to the pancreas, first step of the cascade of events leading to type I diabetes.