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.

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.

My Little Smart Personal Assistant: A Co-Designed Solution to Ensure an Optimized Ageing-Well at Home in Rural European Settings.

My Little Smart Personal Assistant is a co-designed remote connected device with an interactive vocal assistant that provides a panel of social/medical services for the rural European elderly population. The aim is to create a new patient-centered solution to improve quality of life, self-autonomy, and integration within local community. This should improve aging-well at home in rural settings.

Modeling the variability of insulin sensitivity for people with Type 1 Diabetes based on clinical data from an artificial pancreas study.

Type 1 Diabetes is an autoimmune disease that eliminates endogenous insulin production. Without the crucial hormone insulin, which is necessary to equilibrate the blood glucose level, the patient must inject insulin subcutaneously. Treatment must be personalized (timing and size of insulin delivery) to achieve glycaemic equilibrium and avoid long-term comorbidities. Patients are educated on Functional Insulin Therapy (FIT) in order to independently adjust insulin delivery several times a day (at least prior to each meal and physical activity). Among personalized parameters, the Correction Factor is used to occasionally correct hyperglycemia via the injection of an insulin dose (bolus) and its value determines the bolus size. Although well-known in common diabetes practice for chronically poorly controlled patients, the phenomenon of "hyperglycemia induces insulin resistance" on a short term basis in patients with rather well controlled diabetes is presented here. Using a new database of evidence, we show that the insulin sensitivity factor, depends on the current level of glycaemia. This opens the door to refining dosing rules for patients and insulin delivery devices in artificial pancreas systems.

Indications for islet or pancreatic transplantation: Statement of the TREPID working group on behalf of the Société francophone du diabète (SFD), Société francaise d'endocrinologie (SFE), Société francophone de transplantation (SFT) and Société française de néphrologie - dialyse - transplantation (SFNDT).

While either pancreas or pancreatic islet transplantation can restore endogenous insulin secretion in patients with diabetes, no beta-cell replacement strategies are recommended in the literature. For this reason, the aim of this national expert panel statement is to provide information on the different kinds of beta-cell replacement, their benefit-risk ratios and indications for each type of transplantation, according to type of diabetes, its control and association with end-stage renal disease. Allotransplantation requires immunosuppression, a risk that should be weighed against the risks of poor glycaemic control, diabetic lability and severe hypoglycaemia, especially in cases of unawareness. Pancreas transplantation is associated with improvement in diabetic micro- and macro-angiopathy, but has the associated morbidity of major surgery. Islet transplantation is a minimally invasive radiological or mini-surgical procedure involving infusion of purified islets via the hepatic portal vein, but needs to be repeated two or three times to achieve insulin independence and long-term functionality. Simultaneous pancreas-kidney and pancreas after kidney transplantations should be proposed for kidney recipients with type 1 diabetes with no surgical, especially cardiovascular, contraindications. In cases of high surgical risk, islet after or simultaneously with kidney transplantation may be proposed. Pancreas, or more often islet, transplantation alone is appropriate for non-uraemic patients with labile diabetes. Various factors influencing the therapeutic strategy are also detailed in this report.

Obstructive sleep apnoea syndrome in patients living with diabetes: Which patients should be screened?

AIM: Because type 2 diabetes (T2D) is related to obesity, it is often associated with obstructive sleep apnoea syndrome (OSAS), although OSAS is also frequently diagnosed in patients with type 1 diabetes (T1D) and may promote gestational diabetes. Thus, this systematic review of the scientific evidence aimed to evaluate the epidemiological association between OSAS and all forms of diabetes, the current understanding of the pathophysiological mechanisms behind these associations, the expected benefits and limitations of OSAS treatment in patients with diabetes and, finally, to propose which patients require screening for OSAS. METHODS: A panel comprising French expert endocrinologists and pneumologists was convened. Two of these experts made a search of the relevant literature for each subpart of the present report; all panel experts then critically reviewed the entire report separately as well as collectively. RESULTS: There is little evidence to support the notion that OSAS treatment improves glycated haemoglobin, although it may improve nighttime blood glucose control and insulin sensitivity. However, there is robust evidence that OSAS treatment lowers 24-h blood pressure. CONCLUSION: The high prevalence of OSAS in patients with T1D and T2D justifies screening for the syndrome, which should be based on clinical symptoms, as the benefits of OSAS treatment are mainly improvement of symptoms related to sleep apnoea. There are also several clinical situations wherein screening for OSAS seems justified in patients with diabetes even when they have no symptoms, particularly to optimalize control of blood pressure in cases of resistant hypertension and microvascular complications.

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.

Anti-Donor HLA Antibody Response After Pancreatic Islet Grafting: Characteristics, Risk Factors, and Impact on Graft Function.

Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.

Sleep habits and diabetes.

Sleep duration has been constantly decreasing over the past 50 years. Short sleep duration, sleep quality and, recently, long sleep duration have all been linked to poor health outcomes, increasing the risk of developing metabolic diseases and cardiovascular events. Beyond the duration of sleep, the timing of sleep may also have consequences. Having a tendency to go early to bed (early chronotype) compared with the habit of going to bed later (late chronotype) can interfere considerably with social schedules (school, work). Eventually, a misalignment arises in sleep timing between work days and free days that has been described as 'social jet lag'. The present review looks at how different sleep habits can interfere with diabetes, excluding sleep breathing disorders, and successively looks at the effects of sleep duration, chronotype and social jet lag on the risk of developing diabetes as well as on the metabolic control of both type 1 and type 2 diabetes. Finally, this review addresses the current state of knowledge of physiological mechanisms that could be linking sleep habits and metabolic health.

Impact of flexible insulin therapy on blood glucose variability, oxidative stress and inflammation in type 1 diabetic patients: the VARIAFIT study.

AIMS: HbA1c only partially predicts vascular risk in patients with type 1 diabetes (T1D), and a role for blood glucose variability (BGV) is a matter of debate. For this reason, this study investigated the impact of an educational programme of flexible insulin therapy (FIT) on BGV and oxidative stress. METHODS: Tests were conducted on 30 adult T1D patients in a prospective, single-centre trial at baseline (M0), and at 3 and 6 months (M3 and M6, respectively) of the FIT programme to determine BGV, as reflected by mean amplitude of glycaemic excursions (MAGE), low blood glucose index (LBGI), lability index (LI), average daily risk range (ADRR), glycaemic lability (scored by two diabetologists), urinary leukotriene E4 (LTE4), 11-dehydro-thromboxane B2 (TXB2) and 8-iso-prostaglandin F2α (PGF2). RESULTS: HbA1c (7.7 ± 0.9%), ADRR, MAGE, LBGI and LI did not change from M0 to M3 and M6, although ADRR and LBGI significantly improved at M3 and M6 in patients with the highest baseline indices (≥ 40 and ≥ 5, respectively). TXB2 declined at M6 (832 ± 625 vs. 633 ± 972 pg/mg; P=0.048), whereas LTE4 and PGF2 remained stable. ADRR showed the strongest correlation with glycaemic lability scores at all visits (r≥0.84, P<0.0001). CONCLUSION: A FIT educational programme improved BGV only in patients with the highest baseline variability, and led to no changes in HbA1c, while ADRR closely correlated with glycaemic lability score. Our data do not support a relationship between BGV and oxidative stress in T1D patients, although the impact of variability on TXB2 deserves further investigation (ClinicalTrials.gov NCT00973492).

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.

Telemedicine and type 1 diabetes: is technology per se sufficient to improve glycaemic control?

AIM: In the TELEDIAB-1 study, the Diabeo system (a smartphone coupled to a website) improved HbA1c by 0.9% vs controls in patients with chronic, poorly controlled type 1 diabetes. The system provided two main functions: automated advice on the insulin doses required; and remote monitoring by teleconsultation. The question is: how much did each function contribute to the improvement in HbA1c? METHODS: Each patient received a smartphone with an insulin dose advisor (IDA) and with (G3 group) or without (G2 group) the telemonitoring/teleconsultation function. Patients were classified as "high users" if the proportion of "informed" meals using the IDA exceeded 67% (median) and as "low users" if not. Also analyzed was the respective impact of the IDA function and teleconsultations on the final HbA1c levels. RESULTS: Among the high users, the proportion of informed meals remained stable from baseline to the end of the study 6months later (from 78.1±21.5% to 73.8±25.1%; P=0.107), but decreased in the low users (from 36.6±29.4% to 26.7±28.4%; P=0.005). As expected, HbA1c improved in high users from 8.7% [range: 8.3-9.2%] to 8.2% [range: 7.8-8.7%] in patients with (n=26) vs without (n=30) the benefit of telemonitoring/teleconsultation (-0.49±0.60% vs -0.52±0.73%, respectively; P=0.879). However, although HbA1c also improved in low users from 9.0% [8.5-10.1] to 8.5% [7.9-9.6], those receiving support via teleconsultation tended to show greater improvement than the others (-0.93±0.97 vs -0.46±1.05, respectively; P=0.084). CONCLUSION: The Diabeo system improved glycaemic control in both high and low users who avidly used the IDA function, while the greatest improvement was seen in the low users who had the motivational support of teleconsultations.

Metabolic disturbances after acute vascular events: a comparative study of acute coronary syndrome and ischaemic atherothrombotic stroke.

OBJECTIVE: This pilot study aimed to compare metabolic disturbances, particularly insulin resistance (IR) and cardiovascular risk factors (CRFs), following two types of acute vascular atherothrombotic disease events: ischaemic atherothrombotic stroke (AS); and acute coronary syndrome (ACS). DESIGN AND METHODS: A total of 110 non-diabetic patients presenting with either AS (n=55) or ACS (n=55) were included in our prospective comparative study, and matched for age and gender. IR was determined using the homoeostasis model assessment of insulin resistance (HOMA-IR) method, and each patient's personal and family history were also recorded. RESULTS: IR was significantly higher in the ACS vs AS group (HOMA-IR index 2.17±1.90 vs 1.50±0.81, respectively; P=0.03). The AS group had a significantly higher prevalence of personal history of hypertension (51% vs 31%; P=0.03), while current smoking was more prevalent in the ACS group (30% vs 18%; P=0.04). There were no significant differences between the two groups as regards any other CRFs. CONCLUSION: The distribution of CRFs varied depending on the vascular event, and metabolic disturbances differed according to the atherothrombotic disease. IR was greater after ACS than AS.

Studies of circulating microparticle release in peripheral blood after pancreatic islet transplantation.

The loss of graft function after intraportal islet transplantation is likely multifactorial involving allogeneic rejection, recurrent autoimmunity, graft exhaustion due to a marginally implanted islet mass, immunosuppressant toxicity, and impaired ß-cell regeneration. Because early markers of the loss of ß-cell mass or function are lacking, monitoring of islet function remains a challenging issue. We have reported herein monitoring of membrane procoagulant microparticles (MPs) as markers of cell stress in the plasma of three recipients with various clinical histories. Early kinetics of C-peptide and MPs followed identical patterns during the first weeks after transplantation; a major increase probably reflected processes related to cell infusion and islet engraftment. Importantly in the case of rejection, MPs and C-peptide showed opposite patterns. A fall in C-peptide was associated with enhanced insulin needs. Our results suggested that a peak in MP levels might indicate rejection with prognotic value. Treatment of the loss of islet function by a new islet infusion or steroid therapy returned MP and C-peptide levels to their baselines with concomitant restoration of islet function. In the patient with suspected acute cellular rejection, MPs also appeared to be sensors of immunosuppressive steroid therapy.

Protection of pancreatic INS-1 ß-cells from glucose- and fructose-induced cell death by inhibiting mitochondrial permeability transition with cyclosporin A or metformin.

Hyperglycemia is detrimental to ß-cell viability, playing a major role in the progression of ß-cell loss in diabetes mellitus. The permeability transition pore (PTP) is a mitochondrial channel involved in cell death. Recent evidence suggests that PTP inhibitors prevent hyperglycemia-induced cell death in human endothelial cells. In this work, we have examined the involvement of PTP opening in INS-1 cell death induced by high levels of glucose or fructose. PTP regulation was studied by measuring the calcium retention capacity in permeabilized INS-1 cells and by confocal microscopy in intact INS-1 cells. Cell death was analyzed by flow cytometry. We first reported that metformin and cyclosporin A (CsA) prevented Ca²+-induced PTP opening in permeabilized and intact INS-1 cells. We then showed that incubation of INS-1 cells in the presence of 30 mM glucose or 2.5 mM fructose induced PTP opening and led to cell death. As both metformin and CsA prevented glucose- and fructose- induced PTP opening, and hampered glucose- and fructose- induced cell death, we conclude that PTP opening is involved in high glucose- and high fructose- induced INS-1 cell death. We therefore suggest that preventing PTP opening might be a new approach to preserve ß-cell viability.

Impact of diabetes mellitus on clinical presentation and prognosis of pancreatic cancer.

INTRODUCTION: The aim of this study was to investigate possible effects of diabetes mellitus on clinical manifestations and prognosis of pancreatic cancer (PC). PATIENTS AND METHODS: We retrospectively reviewed the clinical files of 122 patients with PC, and divided them into two groups: those with diabetes (56 patients) and those without diabetes (66 patients). The two groups were then compared for demographic profiles, clinical manifestations of PC, features of the tumor and fatal outcomes. RESULTS: Mean age, sex distribution, body mass index at cancer diagnosis, prevalence of hypertension, dyslipidemia, weight loss, abdominal pain, lumbar pain, signs of dyspepsia, and size, and histological features of the tumor were similar between the two groups. The cancer was located in the head of the pancreas in 50% of those with diabetes, and 80% of those without diabetes (P=0.04). The median survival time was similar. CONCLUSIONS: Clinical features, tumor size and prognosis of PC are similar in people with and without diabetes. Having diabetes does not seem to contribute to earlier diagnosis of PC.