Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling.

Adipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.

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.

Determinants of aspirin resistance in patients with type 2 diabetes.

BACKGROUND: Cardiovascular disease is a leading cause of mortality among patients with type 2 diabetes mellitus (T2DM). Numerous patients with T2DM show resistance to aspirin treatment, which may explain the higher rate of major adverse cardiovascular events observed compared with non-diabetes patients, and it has recently been shown that aspirin resistance is mainly related to accelerated platelet turnover with persistent high platelet reactivity (HPR) 24h after last aspirin intake. The mechanism behind HPR is unknown. The aim of this study was to investigate the precise rate and mechanisms associated with HPR in a population of T2DM patients treated with aspirin. METHODS: Included were 116 consecutive stable T2DM patients who had attended our hospital for their yearly check-up. HPR was assessed 24h after aspirin intake using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum thromboxane B2 (TXB2) measurement. Its relationship with diabetes status, insulin resistance, inflammatory markers and coronary artery disease (CAD) severity, using calcium scores, were investigated. RESULTS: Using LTA, HPR was found in 27 (23%) patients. There was no significant difference in mean age, gender ratio or cardiovascular risk factors in patients with or without HPR. HPR was significantly related to duration of diabetes and higher fasting glucose levels (but not consistently with HbA1c), and strongly related to all markers of insulin resistance, especially waist circumference, HOMA-IR, QUICKI and leptin. There was no association between HPR and thrombopoietin or inflammatory markers (IL-6, IL-10, indoleamine 2,3-dioxygenase activity, TNF-α, C-reactive protein), whereas HPR was associated with more severe CAD. Similar results were found with TXB2. CONCLUSION: Our results reveal that 'aspirin resistance' is frequently found in T2DM, and is strongly related to insulin resistance and severity of CAD, but weakly related to HbA1c and not at all to inflammatory parameters. This may help to identify those T2DM patients who might benefit from alternative antiplatelet treatments such as twice-daily aspirin and thienopyridines.

Oxidative and energetic stresses mediate beta-cell dysfunction induced by PGC-1α.

AIM: Alteration of functional beta-cell mass in adults can be programmed by adverse events during fetal life. Previously, it was demonstrated that high glucocorticoid (GC) levels during fetal life participate in this programming by inhibition of beta-cell development. More specifically, GC levels stimulate expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a transcriptional co-regulator of the GC receptor (GR), which per se impairs beta-cell mass and function when overexpressed. As PGC-1α is also a potent inducer of mitochondrial biogenesis, our study aimed to determine how PGC-1α modifies mitochondrial function in beta cells and how it might regulate insulin secretion. METHODS: Beta-cell function was studied in mice overexpressing PGC-1α specifically in beta cells and in MIN6 cells overexpressing PGC-1α in vitro. RESULTS: PGC-1α overexpression in beta cells in vivo leads to a reduced beta-cell mass early in fetal life, whereas PGC-1α overexpression in vitro stimulates mitochondrial biogenesis and respiratory activity without improving ATP production, while increasing oxidative stress and impairing insulin secretion in response to glucose. While oxidative stress with PGC-1α overexpression in beta cells activates AMPK, it has also been revealed that blocking such oxidative stress or AMPK activation restores insulin secretion. CONCLUSION: PGC-1α induces oxidative stress, which disrupts insulin secretion by AMPK activation. Thus, control of oxidative or energetic stress in beta cells may help to restore insulin secretion.

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.

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

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

Metabolic roles of PGC-1α and its implications for type 2 diabetes.

PGC-1α is a transcriptional coactivator expressed in brown adipose tissue, liver, pancreas, kidney, skeletal and cardiac muscles, and the brain. This review presents data illustrating how PGC-1α regulates metabolic adaptations and participates in the aetiology of type 2 diabetes (T2D). Studies in mice have shown that increased PGC-1α expression may be beneficial or deleterious, depending on the tissue: in adipose tissue, it promotes thermogenesis and thus protects against energy overload, such as seen in diabetes and obesity; in muscle, PGC-1α induces a change of phenotype towards oxidative metabolism. In contrast, its role is clearly deleterious in the liver and pancreas, where it induces hepatic glucose production and inhibits insulin secretion, changes that promote diabetes. Previous studies by our group have also demonstrated the role of PGC-1α in the fetal origins of T2D. Overexpression of PGC-1α in ß cells during fetal life in mice is sufficient to induce ß-cell dysfunction in adults, leading to glucose intolerance. PGC-1α also is associated with glucocorticoid receptors in repressing expression of Pdx1, a key ß-cell transcription factor. In conclusion, PGC-1α participates in the onset of diabetes through regulation of major metabolic tissues. Yet, it may not represent a useful target for therapeutic strategies against diabetes as it exerts both beneficial and deleterious actions on glucose homoeostasis, and because PGC-1α modulation is involved in neurodegenerative diseases. However, its role in cellular adaptation shows that greater comprehension of PGC-1α actions is needed.

Incretin-based therapy and pancreatic beta cells.

Type 2 diabetes (T2D) is a complex, progressive disease with life-threatening complications and one of the most serious public-health problems worldwide. The two main mechanisms of T2D pathogenesis are pancreatic beta cell dysfunction and insulin resistance. It is now recognized that pancreatic beta cell dysfunction is a necessary factor for T2D development. Traditional therapies for controlling blood glucose are suboptimal as they fail to meet target goals for many patients. Glucagon-like peptide-1 receptor agonists (GLP1RA) and dipeptidyl peptidase-4 inhibitors (DPP4I) are an attractive class of therapy because they reduce blood glucose by targeting the incretin hormone system and, in particular, have the potential to positively affect pancreatic beta cell biology. This review outlines our current understanding of pancreatic beta cell incretin system dysfunction in T2D and summarizes recent evidence of the effect of incretin-based therapies on beta cell function and mass. Incretin-based therapies have shown strong evidence for beneficial effects on beta cell function and mass in animal studies. In humans, incretin-based therapies are effective glucose-lowering agents, but further study is still required to evaluate their long-term effects on beta cell function and safety as well as beta cell mass expansion.

Is continuous glucose monitoring (CGM) for everyone? To whom should CGM be prescribed and how?

Are all type 1 diabetes (T1DM) patients potential candidates for continuous glucose monitoring (CGM)? Clearly, some patients improve their metabolic control with this tool, such as adults with poor metabolic control, especially those treated with continuous subcutaneous insulin infusion (CSII), and compliant patients with HbA(1c) levels <7%. There are also less good candidates for CGM, such as patients aged 8-18 years because they are reluctant to wear the sensors or those with new-onset T1DM. Other patient groups have not yet been evaluated, such as patients aged <8 years, women during pregnancy, and those with HbA(1c) >10% and/or severe hypoglycaemia. Beyond the indications, the mode of use of CGM is crucial. An appropriate patient selection, in order to choose those able to run the tool and motivated to use it, is necessary. How to prescribe the sensors is also an important question. Two approaches have been compared: patient-led and physician-driven prescription. Both modes of using CGM provide similar long-term metabolic improvement. However, physician-driven prescription is probably more cost-effective. The last key question is the education of patients by an experienced team. It can help them to translate the large amount of data from the monitor into effective self-management for optimalizing the CGM experience. However, elaboration of a validated algorithm is necessary to take full advantage of this device.

Sexual activity in diabetic patients treated by continuous subcutaneous insulin infusion therapy.

BACKGROUND AND AIMS: As concerns over interference with sexual activity may be an obstacle to initiating pump therapy in diabetic patients, the aim of the study was to assess the impact of continuous subcutaneous insulin infusion (CSII) therapy on sexual activity. PATIENTS AND METHODS: Patients filled out a questionnaire on their demographic data, diabetes history, pump-treatment history, metabolic control, inconvenience/convenience of the pump and catheter, and information on sexual activity. RESULTS: A total of 271 diabetic patients (aged 44+/-17 years, 51% women, 22% single), treated with CSII for 4.2+/-5.9 years and with a diabetes duration of 19+/-11 years, filled out the questionnaire. Their HbA(1c) was 7.7+/-1.1%, with 2.4+/-2.1 mild hypoglycaemic episodes over the past week, and their frequency of sexual activity was: never 29.9%; <1/month 12.3%; >1/month and <1/week 18.2%; and >1/week 39.6%. Age and cohabitation were independently correlated with frequency of sexual activity (P<0.0001 and P<0.0003, respectively), but not diabetes duration or complications. To the question "Does the pump have an influence on your sexual activity?", The answer was "no" in 90% and "yes" in 10%. However, intercourse frequency was significantly decreased in the latter (P=0.04). On multivariate analyses, this negative influence of CSII was correlated with HbA(1c) (P<0.05), discomfort with the pump (P<0.05) and the number of mild hypoglycaemic episodes (P<0.01). CONCLUSION: Frequency of sexual activity appears to be unaffected by pump therapy or diabetes, but is decreased by the expected characteristics-namely, age and being single. Also, only 10% of patients believe that CSII is an obstacle during sexual activity and, in particular, because of the catheter.

Real-life application and validation of flexible intensive insulin-therapy algorithms in type 1 diabetes patients.

AIMS: Flexible intensive insulin therapy (FIT) has become the reference standard in type 1 diabetes. Besides carbohydrate counting (CHO), it requires the use of algorithms to adjust prandial insulin doses to the number of CHO portions. As recourse to standard algorithms is usual when initiating FIT, the use of personalized algorithms would also allow more precise adjustments to be made. The aim of the present study was to validate personalized prandial algorithms for FIT as proposed by Howorka et al. in 1990. METHODS: We conducted a 4-month observational study of 35 patients with type 1 diabetes, treated with FIT for at least 6 months, who were already using Howorka's prandial algorithms (meal-related and correctional insulin doses for blood glucose increases induced by CHO). These patients were asked to use a personal digital assistant (PDA) phone with an electronic diary (instead of a paper one) to take advantage of the computerized data-collection system to assess the quality of postprandial metabolic control. RESULTS: Whatever the number of CHO portions, mean postprandial blood glucose values remained close to the target of 7.8mmol/L, and the compensatory algorithm allowed precise correction of preprandial hyperglycaemia. In fact, the algorithms for meal-related and correctional insulin doses at the end of the study did not differ significantly from those initially calculated, but they generally differed from one patient to another. CONCLUSION: In type 1 diabetic patients treated with FIT, the use of individualized parameters permits fast and accurate adjustment of mealtime insulin doses, leading to good control of the postprandial state.

The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes.

CONTEXT: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. OBJECTIVE: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. PARTICIPANTS: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. RESULTS: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA(1c) was also found and remained significant after adjustment for age at molecular sampling and gender. CONCLUSIONS: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

Treatment of diabetes mellitus using an external insulin pump in clinical practice.

Before the initiation of insulin pump therapy, patients must be aware of the different aspects of this form of intensive insulin therapy. Most healthcare professionals recommend a sequential approach to inform patients about CSII. Factors that need to be considered in choosing an insulin pump include its safety features, durability of the device, tolerability and comfort of the catheter, user-friendliness, technical features and appearance. The initial insulin requirements need to be individualized for the given patient, using different methods to determine the appropriate dosages for the basal rate and prandial boluses. Glycaemic targets and algorithms for insulin dose adaptation need to be learned by the patients to enable them to avoid and/or correct hypo- and hyperglycaemia/ketosis episodes. Patients are also advised on how to carry out frequent self-monitoring of blood glucose-and of ketone bodies, if necessary. Insulin pumps are now able to deliver a range of basal rates and boluses that increase the flexibility of CSII. One specific issue is the approach to meal-planning, based on carbohydrate-counting or the equivalent: this method of so-called 'flexible insulin therapy' can improve metabolic control (for instance, by diminishing postprandial excursions) as well as the quality of life of patients. Evaluation of the knowledge and practices of the patient can be made through a continuous educational programme carried out by experienced nurses and physicians at the start of therapy and during follow-up. In addition, it may be necessary to identify the reasons for lack of improvement in metabolic control after several months of therapy, which include pump malfunction, cannula problems, miscalculated insulin dosages and insufficient metabolic control in specific clinical situations with a high risk of metabolic deterioration (illness, exercise, concomitant drugs). Annual assessment of the patient using an itemized checklist is required to verify the continued efficacy and safety of insulin pump therapy, two main factors of success with CSII treatment.

Insulin-pump use in everyday practice: data from an exhaustive regional registry in France.

AIM: The aim of this study is to evaluate the effectiveness and safety of continuous subcutaneous insulin infusion (CSII) under real-life conditions among all patients treated with CSII in the south of Paris. METHODS: The 42 diabetologists practising in the region enrolled all patients treated with CSII or admitted for CSII initiation. During the study visit, the data for pump use and clinical results were recorded. RESULTS: Data were obtained for 424 patients, mean age 44.2+/-15.6 years, disease duration 18.7+/-10.6 years, including 339 treated with CSII for longer than three months (mean duration: 3.5+/-3.5 years; range: 3-258 months). Most of the patients (N=285, 84.8%) had type 1 diabetes; 44 (13.1%) had type 2 diabetes. In patients treated for more than three months, HbA1c decreased significantly between CSII initiation (9.1+/-1.9%) and the study visit (7.8+/-1.4%; P<0.0001). Patients with HbA1c >9%, using the pump, experienced a significant 0.9% improvement in their HbA1c levels with CSII versus multiple daily injections (P=0.001). The number of episodes of moderate hypoglycaemia was 2.7+/-2.5 per patient per week; of severe hypoglycaemia, 0.34 per patient per year and of ketoacidosis, 0.11 per patient per year. Factors significantly associated with HbA1c levels included amount of physical activity, pregnancy, HbA1c at CSII initiation and number of glucose self-determinations. Those associated with the number of moderate hypoglycaemia episodes were basal rate number, female gender and HbA1c level. HbA1c was negatively correlated with moderate hypoglycaemia (P<0.001), but not with severe hypoglycaemia. CONCLUSION: This 'pump' registry establishes the effectiveness of CSII in everyday practice, yet underscores the risks of severe hypoglycaemia and ketosis episodes. It could help diabetologists to improve patient training programmes and follow-up.

Real-time continuous glucose monitoring using GuardianRT: from research to clinical practice.

The limited number of self-monitoring blood glucose measurements is an obstacle for good metabolic control in patients with type 1 diabetes. However, continuous glucose measurement with real-time data and alarms is a recent technology that promises to improve the efficacy of treatment in diabetic patients. GuardianRT uses a continuous telemetry display of real-time glucose values, and automatic alerts at preset hypo- and hyperglycaemic levels. Three calibrations a day are required, and the sensor must be changed every three days. The GuardControl study showed that, within three months, real-time continuous glucose monitoring with the GuardianRT led to significantly improved HbA1c values in 162 poorly controlled patients (children and adults) with type 1 diabetes despite intensive insulin therapy. The continuous availability of glucose measurements permitted the patients to adjust their own insulin doses, food intake and physical activity and, thus, improve their glycaemic control. This report summarizes the available data on this tool and details how best to use this state-of-the-art modality in diabetic patients in clinical practice.

Continuous intraperitoneal insulin infusion does not increase the risk of organ-specific autoimmune disease in type 1 diabetic patients: results of a multicentric, comparative study.

AIM: The purpose of this national multicenter prospective study by the French EVADIAC group was to investigate the possibility that continuous intraperitoneal insulin infusion using an implanted pump (CIpii) increases the risk of autoimmune disease in type 1 diabetic patients as it increased anti-insulin immunogenicity. METHODS: Prevalence of clinical (Hashimoto's disease, hyperthyroidism, gastric atrophic disease and vitiligo) and subclinical (presence of anti-thyroperoxidase antibodies, anti-intrinsic factor antibodies, abnormal TSH levels) autoimmune diseases was estimated by comparing two groups of patients already treated by either CIpii (n=154) or external pump (CSII) (n=121) for an average of 6 years. Incidence of autoimmune disease was determined by comparing the same measurements one year after inclusion. RESULTS: No significant difference was observed for the total prevalence of clinical and subclinical auto-immune thyroid and gastric di-seases (35.6% and 3.2% respectively in the CIpii group versus 40.4% and 2.6% in the CSII group). No significant difference for the incidence of clinical and subclinical auto-immune diseases was observed: 7.2% and 0% in CIpii and 7.3% and 1.7% in CSII. CONCLUSION: As previously shown AIA (anti-insulin antibodies) levels were higher in CIpii than in CSII (32.9% vs 20.2%, P<0.0001) but no correlation was observed with either clinical or subclinical autoimmune disease. This large-scale study eliminates the possibility that CIpii increases the risk of autoimmune disease.