Perspective of Continuous Glucose Monitoring-Based Interventions at the Various Stages of Type 2 Diabetes.

Continuous glucose monitoring (CGM) is now advocated for the clinical management of individuals with type 1 diabetes (T1D). However, this glucose monitoring strategy is not routinely used in type 2 diabetes (T2D), given the large population, significant cost implications and relatively limited supporting evidence. T2D is a more heterogenous condition compared with T1D with various glucose lowering therapies that do not necessarily require CGM to ensure within target glucose levels. While all individuals with T2D may benefit from CGM at certain time points, the whole T2D population does not necessarily require this technology continuously, which should be prioritized based on patient benefit and cost effectiveness. In this pragmatic opinion piece, we describe the rationale and evidence for CGM use in different subgroups of individuals with T2d, divided according to the stage of the condition, glycemic therapies, presence of diabetes complications, or associated co-morbidities. We discuss a total of 16 T2D subgroups and provide a clinical view on CGM use in each, based on current evidence while also highlighting areas of knowledge gaps. This work provides health care professionals with a simple guide to CGM use in different T2D groups and gives suggestion for future studies to justify expansion of this technology.

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.

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.

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.

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.

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.

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.

How should postprandial glycemia be treated?

In an attempt to prevent the complications of type 2 diabetes, particular attention should be paid to controlling postprandial glycemia (PPG): on the one hand, it contributes substantially to the HbAlc level in moderately controlled patients, on the other hand, the postprandial glucose peak induces oxidative stress and endothelial dysfunction, the first step toward accelerated atherogenesis. Metformin, glitazones, and insulin secretagogues have an additive effect on fasting blood glucose (FBG), and a significant impact on PPG. Alpha-glucosidase inhibitors can reduce PPG by a mean 0.50 g/l, no matter what the insulin resistance or insulinopenia status or the other diabetes treatments already in use. After evolving for several years and the failure of oral antidiabetics to normalize fasting blood glucose, long-acting (slow-acting) insulin analogues, well titrated, can reach this goal. They will have no effect on PPG other than a simple level effect. At this stage, rather than overtreating high fasting blood glucose concentrations, systematic PPG exploration should be the rule so as to better define PPG treatment: the advantages of alpha-glucosidase inhibitors and the role of GLP-1 analogs should be defined, the use of a rapid-acting insulin analog before the meal causing the highest postprandial blood glucose excursions, even systematically at all three meals, should be considered, or inhaled insulin. As natural life expectancy is on the rise, these active strategies designed to normalize the daily glycemic profile, necessary in a strict strategy to prevent the complications of diabetes, will need to be discussed for an increasing number of patients with type 2 diabetes.

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.

Subcutaneous insulin resistance successfully circumvented on long term by peritoneal insulin delivery from an implantable pump in four diabetic patients.

UNLABELLED: Extreme subcutaneous insulin resistance is a rare syndrome characterized by a severe resistance to subcutaneous (S/C) insulin together with persistence of normal or near normal intravenous (IV) insulin sensitivity. Its pathophysiology is unknown, although increased insulin degrading activity has been reported in the S/C adipose tissue fraction in some cases. Until now, proposed treatments have been disappointing. We report 4 cases who were successfully treated by intraperitoneal (IP) route. METHODS: The diagnosis of subcutaneous insulin resistance was based upon following combined conditions: resistance to hypoglycaemic action of subcutaneous insulin but normal or near normal sensitivity to IV or IP insulin. RESULTS: 4 patients among those followed by EVADIAC group met these criteria: 3 with type 1 diabetes (C peptide=0), the last one with unexplained non insulin-deficient diabetes (no anti-GAD antibodies, C peptide=5 ng/ml). All of them had been treated with subcutaneous insulin therapy without success despite huge doses (up to 4000 IU/day in two patients). The 3 type 1 diabetic patients presented with a history of repeated ketoacidosis episodes. A treatment of insulin mixed with aprotinin had been proposed to 2 patients without success. The IV insulin sensitivity was proved to be normal in two patients by euglycaemic clamp data. A skin biopsy was performed in 1 patient. An accumulation of insulin in the derma was revealed with no increase of degradation products of insulin. In these 4 patients, a dramatic improvement of diabetes control was obtained by IP insulin delivery from an implantable pump (HbA1c decrease by at least 3%). CONCLUSION: Although pathophysiology of the subcutaneous insulin resistance syndrome remains unexplained, our data show that intra-peritoneal insulin therapy from an implantable pump allows diabetes control in patients affected by this uncommon but severely disabling condition.

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.

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.

High serum luteinizing hormone levels induce ovarian delta4 cytochrome P450c17alpha down-regulation in hirsute women: complete effect on 17-hydroxylase and partial effect on 17,20-lyase.

It is well known that normal and mildly elevated luteinizing hormone (LH) levels induce increased activity of ovarian 17-hydroxylase and 17,20-lyase, the cytochrome P450cl7alpha (P450) enzymes. This leads to increased ovarian 17alpha-hydroxyprogesterone (17-OHP) and androstenedione production. In contrast, it has been shown in both in vitro and in vivo studies in animals and in in vitro studies in women that high LH concentrations have opposite effects on these enzymes. These LH down-regulating effects appear to be more marked on 17,20-lyase than on 17-hydroxylase. Finally, these LH effects have not been reported in vivo in women. Therefore, we investigated the relationships between serum LH levels and serum 17-OHP and androstenedione concentrations in 263 consecutive hirsute women (HW) with normal serum 17-OHP responses to acute adrenocorticotropin (ACTH) stimulation. The patterns of basal serum steroid concentrations differed according to the basal serum LH levels. Indeed, for relationships between LH and 17-OHP concentrations, a positive correlation (P < 0.001) was found between the levels of these parameters when LH levels ranged from 0.2 to 9.0 IU/l. Conversely, for LH levels greater than 9.0 to 21.0 IU/l, LH values were negatively correlated (P<0.001) with 17-OHP concentrations. Similar results were observed for relationships between LH and androstenedione levels but the LH peak level related to decreasing androstenedione concentrations was 12.0 IU/l. Finally, the mean 17-OHP level in patients with LH levels which induced marked P450 down-regulation (i.e. more than 12 IU/l) was similar to that in patients with LH levels within the normal range (i.e. less than 6 IU/l). In contrast, the mean androstenedione level in the former patients was markedly higher (P<0.001) than that in the latter patients. In conclusion, as previously reported in in vitro studies, this in vivo study indicates that LH induces stimulating and down-regulating effects on both ovarian delta(4)17-hydroxylase and delta(4)17,20-lyase activities as serum LH levels gradually increase. However, in contrast to in vitro studies, LH levels which induce P450 down-regulation appear to be less effective on delta(4)17,20-lyase than on delta(4)17-hydroxylase in HW. This strongly suggests that serum factors induce, in most HW, a marked increase in delta(4)17,20-lyase, but not in delta(4)17-hydroxylase, activity leading to both partial impairment of LH-induced delta(4)17,20-lyase down-regulation and complete LH-induced delta(4)17-hydroxylase down-regulation in these patients.

Management of drugs affecting blood glucose in diabetic patients with renal failure.

Prevention of the onset or worsening of microalbuminuria by good blood glucose control has been confirmed in Type 2 diabetes, though not at the stage of chronic renal failure (CRF). Thus, it would seem desirable to maintain strict blood glucose control whenever circumstances allow. If prescribed sulphonylureas (SU) are effective, they can be continued at adjusted doses until an advanced stage of CRF, subject to strict monitoring. SU are eliminated by the liver, but their metabolites (often active) are eliminated to varying degrees by the kidney. Non-SU insulin secretagogues and thiazolidinediones metabolised by the liver might also be used. The fate of their metabolites (some active) remains to be defined in CRF, and further clinical trials are required. Acarbose and its metabolites, as well as miglitol, very probably accumulate in CRF, causing ill-defined (but especially hepatic) iatrogenic risks. Although the danger of metformin in diabetic patients with renal failure is currently uncertain, CRF remains a regulatory contraindication. Insulin, which is necessary in most Type 2 diabetic patients with CRF, decreases as CRF progresses and when dialysis is started. The kinetics of insulin analogs are modified in CRF. Regardless of the choice of treatment, specialist and regular monitoring is required.

Sulfonylureas and cardiovascular effects: from experimental data to clinical use. Available data in humans and clinical applications.

OBJECTIVES: 33 years after the UGDP study, the question of deleterious effects of the sulfoylurea (SU) is still raised. We have made a systematic review of the literature from experimental studies to clinical and epidemiological studies. RESULTS: The main molecule studied is glibenclamide (GB). In vitro and in animal studies, GB is both deleterious for ischemic preconditionning (IPC) and protective for arrhythmia during acute ischemia. Glimepiride (GM) and gliclazide (GCZ) do not seem to have effect on IPC. These effects have been few studied in diabetic animals. In human, according to the investigations used, the GB seems nil or suppressing for IPC, it seems elsewhere decreases ventricular arrhythmias during periods of acute ischemia. It is possible that these two actions account for the non-appearance of concordant deleterious effects between short and long-term studies. With regards to other drugs, only the GM has been specifically studied in human and appears to be nil on IPC. The only prospective clinical study available, although not having for objective to answer to this question, is the UKPDS study. This trial demonstrates the absence of deleterious cardiac effects of GB compared to chlorpropamide and particularly compared to insulin. CONCLUSION: In conclusion, in experimental studies the cardiac effects of SU differ: both deleterious and protective for GB, nil for GM and GCZ on IPC. In all cases the clinical consequences seems to be nil.

Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience.

OBJECTIVE: To report a long-term multicentre experience with implantable insulin pumps in type 1 diabetic patients, and to test safety and accuracy of the systems following improvements in infused insulin solutions and peritoneal catheter. RESEARCH DESIGN AND METHODS: Forty MiniMed Implantable Pumps model 2001 were consecutively implanted over a two-month period in type 1 diabetic volunteers. The systems were equipped by a new compliant sideport catheter and were refilled at 45-day intervals with HOE 21 PH ETP insulin batches showing enhanced physical stability in vitro. Safety was assessed from the incidence of acute adverse events and effectiveness from quarterly HbA(1c) assays. Accuracy of delivery was measured at each pump refill by comparing residual insulin in the pump reservoir with expected amount according to programmed infusion. The study lasted until pump battery depletion or premature pump explantation. RESULTS: Cumulated experience was 106 patient-years. Premature explantations occurred in 3 cases, due to one electronic pump failure and two "pump-pocket" infections. Near-normal insulin delivery was sustained until expected battery depletion in 13 cases. Forty underdelivery events occurred in 24 pumps, but 36 among them were related to pump slowdowns due to insulin aggregation in pumps that were promptly solved by an outpatient NaOH rinse procedure. Only 4 underdeliveries were caused by catheter obstructions that required laparoscopy to remove peritoneal tissue overgrowth around the catheter. Over pump lifetime, HbA(1c) was 7.2 +/- 0.2% in the 13 patients with no underdelivery and 7.7 +/- 0.5% in the other ones. Only one severe hypoglycemia and one ketoacidosis occurred during the whole study. CONCLUSION: Our current experience with improved implantable pumps and insulin solutions shows both long-term safety and effectiveness of this treatment in type 1 diabetic patients following improvement in infused insulin solutions and catheter. This therapy may be a good alternative for patients that experience frequent severe hypoglycemia with intensive subcutaneous insulin therapy.

[Optimising the equilibrium of diabetes and atheromatous progression: myth or reality?]. / Optimisation de l'équilibre du diabète et progression athéromateuse: mythes ou réalités?

Is chronic hyperglycaemia, which defines diabetes of whatever type, a simple marker of cardiovascular risk, with no effect on atheroma independent of the other factors with which it is associated such as dyslipidaelia or hypertension? Whatever the case, its treatment, although fundamental for preventing the progression of microangiopathy and neuropathy, has another significance regarding the progression of atheromatous disease. Chronic hyperglycaemia acts as an independent factor for the genesis and progression of atheromatous disease and the beneficial effect of treating it aggressively could add to that obtained by treatment of the classic atherogenic factors such as hypercholesterolaemia or hypertension. This controversy, renewed by the interpretation of the UKPDS results, still remains. There is also a 2nd question: how does chronic hyperglycaemia, which is generally well evaluated in the medium term by HbA1c, overlap with other physiological situations? In particular, does post-prandial hyperglycaemia have greater atherogenic effects than the same level of fasting hyperglycaemia? Whatever the case, greater attention must be paid to post-prandial glycaemic control, which has been rather neglected up to now in favour of fasting glycaemic control, taken to mean overall glycaemic control.