Hypoglycaemia after gastric bypass: mechanisms and treatment.

Hypoglycaemia after gastric bypass can be severe, but is uncommon, and is sometimes only revealed through monitoring glucose concentrations. The published literature is limited by the heterogeneity of the criteria used for diagnosis, arguing in favour of the Whipple triad with a glycaemia threshold of 55 mg/dl as the diagnostic reference. Women who lost most of their excess weight after gastric bypass, long after the surgery was performed, and who did not have diabetes before surgery are at the greatest risk. In this context, hypoglycaemia results from hyperinsulinism, which is either generated by pancreas anomalies (nesidioblastosis) and/or caused by an overstimulation of ß cells by incretins, mainly glucagon-like peptide-1 (GLP-1). Glucose absorption is both accelerated and increased because of the direct communication between the gastric pouch and the jejunum. This is a post-surgical exaggeration of a natural adaptation that is seen in patients who have not undergone surgery in whom glucose is infused directly into the jejunum. There is not always a correspondence between symptoms and biological traits; however, hyperinsulinism is constant if hypoglycaemia is severe and there are neuroglucopenic symptoms. The treatment relies firstly on changes in eating habits, splitting food intake into five to six daily meals, slowing gastric emptying, reducing the glycaemic load and glycaemic index of foods, using fructose and avoiding stress at meals. Pharmacological treatment with acarbose is efficient, but other drugs still need to be validated in a greater number of subjects (insulin, glucagon, calcium channel blockers, somatostatin analogues and GLP-1 analogues). Lastly, if the surgical option has to be used, the benefits (efficient symptom relief) and the risks (weight regain, diabetes) should be weighed carefully.

Diabetes mellitus as a modulator of functional impairment and decline in Alzheimer's disease. The Real.FR cohort.

AIMS: To determine whether diabetes mellitus influences functional status in patients with Alzheimer's disease. METHODS: We studied 608 community-dwelling patients with Alzheimer's disease from a prospective multicenter cohort. Diabetes was assessed at baseline. Functional status was assessed twice yearly with the Activities of Daily Living scale. Each patient had a baseline functional disability if their Activities of Daily Living score was < 6. Progression of functional disability was defined by a decreased Activities of Daily Living score over 4 years of follow-up visits. RESULTS: At baseline, diabetes was present in 63 participants (10.4%) and, compared with those without diabetes, was associated with functional impairment [age- and sex-adjusted OR = 2.73 (95% CI 1.41-5.28)]. After controlling for confounders, the association remained significant [OR = 2.04 (95% CI 1.02-4.11)]. Follow-up demonstrated a significant interaction between duration of Alzheimer's disease and diabetes, which was associated with progression of functional impairment in patients who had been diagnosed with Alzheimer's disease for less than 1 year [age- and sex-adjusted hazard ratio = 1.52 (95% CI 1.01-2.30), P = 0.048], but not in those who had been diagnosed with Alzheimer's disease for more than 1 year [age- and sex-adjusted hazard ratio = 0.78 (95% CI 0.47-1.28), P = 0.32]. Abnormal one-leg balance, polymedication and obesity seem to be important factors explaining the association between diabetes and functional status. CONCLUSIONS: At baseline, the presence of diabetes significantly increases the risk of functional disability in patients with Alzheimer's disease; our longitudinal data confirm that in patients with a recent diagnosis of Alzheimer's disease (but not in those who have had Alzheimer's disease for longer than 1 year), diabetes continues to worsen functional status.

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.

Glucose Abnormalities and Inappropriate Weight Gain Predict Negative Pregnancy Outcomes After Gastric Bypass Surgery.

PURPOSE: Pregnancy after gastric bypass (RYGB) surgery remains at high risk for gestational diabetes mellitus, prematurity, and small for gestational age infants (SGA). Our objective was to describe the interstitial glucose (IG) profiles and weight changes during such pregnancies, and the association of these factors with adverse pregnancy outcomes. MATERIAL AND METHODS: One hundred twenty two pregnancies were analyzed in a monocentric retrospective study. IG profiles were evaluated by continuous glucose monitoring for 4 days. Maternal (hypertension, hospitalizations, and caesarean section) and neonatal outcomes (prematurity, weight for gestational age, hospitalizations, and malformations) were recorded. A logistic stepwise regression model assessed the influence of weight gain and impaired IG on pregnancy outcomes. RESULTS: Pregnancies occurred 33 (SD 21 months) after surgery. 73% of the women had IG abnormalities (55% with an increased % of time >140 mg/dl and 69% with an increased % of time <60 mg/dl). Five (4%) children were large for gestational age (LGA), 24 (20%) were SGA and 16 (13%) were born prematurely. There were 3 malformations but no stillbirth. LGA was associated with a high % of time >140 mg/dl and an excessive maternal weight gain. Prematurity was associated with a high % of time <60 mg/dl and an insufficient maternal weight gain. In the multivariate analysis, inappropriate weight gain explained LGA and prematurity independently. SGA was associated with a shorter % of time <60 mg/dl. CONCLUSION: The relationship between IG abnormalities and/or maternal weight gain and neonatal outcomes in pregnancies after RYGB, suggests a careful monitoring of these parameters.

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.

Diabetes Remission and Relapse After Bariatric Surgery: a Nationwide Population-Based Study.

PURPOSE: The long-term impact of bariatric surgery on the remission of type 2 diabetes (T2DM) remains to be clarified through large nationally representative cohorts. The objectives were to determine the incidence of T2DM remission and relapse after bariatric surgery, to determine the factors associated with remission and to establish a profile for patients at risk for relapse. MATERIALS AND METHODS: We conducted a population-based cohort study using data from the French national health insurance database (Systeme national des données de santé [SNDS]). We had access to exhaustive regional data between 2013 and 2017 and to a national representative sample of the French population (EGB) from 2008 to 2018. Patients were included if they were adults and diabetics with incidental bariatric surgery. RESULTS: This study shows that 50% of patients are in remission from diabetes after bariatric surgery within a median of 2 to 4 months. Diabetes relapse was observed in 13-20% within 10 years. The factors favouring remission already described were noted (non-insulin-dependent diabetes) and original factors were also identified, in particular the advantage of bypass surgery over sleeve gastrectomy, with more remissions and fewer relapses. CONCLUSION: This study highlights a 50% prevalence of remission and a low prevalence of relapse. There are non-modifiable risk factors for remission and relapse (characteristics of diabetes, age, lipid-lowering therapy) and modifiable factors (type of surgery). Identifying these factors is essential for optimal management of patients. Additional data are essential to confirm the results of our analysis of the factors associated with relapse.

Efficacy and adherence of glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes mellitus in real-life settings.

Despite the availability of a large number of therapeutic options throughout the world, rates of optimal glycaemic control in adult patients with type 2 diabetes mellitus remain low. Delays in treatment intensification to insulin and low adherence to insulin regimes, which are well-documented contributors to poor glycaemic control, are in many cases driven by fear of hypoglycaemic events, weight gain and injections. Over the last 10 years, injectable glucagon-like peptide-1 receptor agonists (GLP1-RAs) have emerged as alternatives to basal insulin for treatment intensification in patients inadequately controlled with oral antidiabetic drugs. As a class, GLP1-RAs are associated with weight loss and fewer hypoglycaemic events than insulin. In addition, some of them are available in once-a-week formulations and therefore require fewer injections. However, as randomized controlled trials are not representative of everyday practice, physicians should consider the results of real-life studies to guide their treatment decisions. In this review, while significant variations in efficacy, tolerability and adherence data were noted from one study to another, rates of glycaemic control overall were low. Indeed, our present analysis has suggested that regular re-evaluations of treatment, including response, tolerability, adherence, cost and quality of life, are necessary.

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.

Treatment of diabetes mellitus using an external insulin pump: the state of the art.

The aim of diabetes treatment is to achieve tight glucose control to avoid the development of chronic diabetic complications while reducing the frequency of hypoglycaemic episodes. Continuous subcutaneous insulin infusion (CSII) using an external pump is an intensive diabetes therapy recognized to improve metabolic control and glycaemic instability, and to reduce the frequency of severe hypoglycaemia. For years, the theoretical advantages of the insulin pump (constancy of basal delivery, adjustable basal rates, and low insulin depots allowing the reduction of glycaemic variability) have contributed to its reported superiority compared with multiple daily injections (MDI). However, insulin pump therapy is now challenged by new MDI regimens based on long-acting insulin analogues that could replace the use of CSII. As a consequence, health professionals now have to determine which patients are likely to benefit the most from CSII. Recently, several studies reported that children and adolescents, and patients whose blood glucose imbalance was initially the most pronounced with basal-bolus regimens, would particularly benefit from CSII. Other indications were also proposed in marginal clinical situations with highly selected patients in whom a significant improvement of blood glucose was demonstrated. Finally, the use of CSII in type 2 diabetic patients now appears to be a good alternative to the ineffective MDI regimens observed in some of these patients. However, past experience with CSII indicates that candidates for insulin pump therapy must be carefully selected and strongly motivated to improve their glucose control. Use of CSII also requires strict medical supervision by physicians and a regular programme of patient education by paramedical teams, to ensure optimal responsible use of this technique by healthcare professionals.

Prevention of progression to dementia in the elderly: rationale and proposal for a health-promoting memory consultation (an IANA Task Force).

Alzheimer's disease (AD) is the most frequent form of dementia and according to the most recent estimation it affects nearly 27 million people in the world. The onset of the disease is generally insidious. It is becoming increasingly evident that the underlying pathophysiological mechanisms are active long before the appearance of the clinical symptoms of the disease. In the current context, it is important to develop strategies to delay the onset of cognitive decline. Delaying the onset by 5 years would reduce the prevalence by half at term, and a delay of 10 years would reduce it by three-quarters. The effectiveness of currently suggested preventive approaches remains to be confirmed, but certain strategies could be applied straight away to at-risk subjects. We propose that a health-promoting memory consultation should be set up for elderly persons who have attended a specialized memory consultation and in whom the diagnosis of dementia and of AD in particular, has not been established by standardized tools. Through this consultation, they would be offered full multidimensional investigation of all aspects of their health status, follow-up could be organized, general practitioners in private practice could be made more conscious of this population and the elderly could be made more aware of the risk factors to which they are exposed. The development of an information policy for the elderly would meet a present need. In our reflection, we must take into account the question of how to give this preventive consultation its due place in the healthcare pathway of the elderly person in order to ensure coordinated follow-up with all the other health professionals involved. The principle of the health-promoting memory consultation is undergoing validation in a large French multicentre preventive trial in 1200 frail elderly persons aged 70 years followed for three years, the Multidomain Alzheimer Preventive Trial (MAPT).

Predictors of Cardiovascular Autonomic Neuropathy Onset and Progression in a Cohort of Type 1 Diabetic Patients.

AIM: The prevalence of cardiovascular autonomic neuropathy (CAN) in diabetes mellitus is well documented. However, the rate and predictors of both the development and progression of CAN have been less studied. Hereby, we assessed the rate and the major risk factors for CAN initiation and progression in a cohort of type 1 diabetic patients followed over a three-year period. METHODS: 175 type 1 diabetic patients (mean age: 50 ± 11 years; female/male: 76/99) with positive bedside screening for CAN were included and underwent 2 standardized autonomic testings using 4 standardized tests (deep breathing, Valsalva maneuver, 30/15 ratio, and changes in blood pressure during standing), separated by 3 ± 1 years. CAN staging was achieved according to the Toronto Consensus Panel on Diabetic Autonomic Neuropathy into 4 categories: absent, possible, confirmed, or severe CAN. RESULTS: Out of the 175 patients included, 31.4% were free of CAN, 34.2% had possible CAN, 24.6% had confirmed CAN, and 9.7% exhibited severe CAN at the first assessment. Among the 103 patients with nonsevere CAN at inclusion, forty-one (39.8%) had an increase of at least one category when reassessed and 62 (60.2%) remained stable. A bivariate analysis indicated that only BMI and exposure to selective serotonin reuptake inhibitors (SSRIs) were significantly different in both groups. A multivariate analysis indicated that lower BMI (OR: 0.15, CI 95%: 0.05-0.48, p = 0.003) and SSRI exposure (OR: 4.18, CI 95%: 1.03-16.97, p = 0.04) were the sole predictors of CAN deterioration. In the 55 patients negative for CAN at the first laboratory assessment, 12 became positive at the second assessment. CONCLUSION: No clear predictive factor for CAN onset was identified. However, once present, CAN progression was related to low BMI and SSRI exposure.

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.

Long-term treatment combining continuous subcutaneous insulin infusion with oral hypoglycaemic agents is effective in type 2 diabetes.

AIM: To compare over 3 years the efficacy of two treatment regimens combining continuous subcutaneous insulin infusion (CSII) and oral hypoglycaemic agents (OHA) in type 2 diabetic patients with HbA(1c) levels>8% despite OHA+/-insulin. METHODS: Fifty-nine patients were randomized to two groups. In both groups metformin was continued; CSII (velosulin) was used with minimal manipulation. Group A: the optimization of insulin doses was exerted on boluses to achieve postprandial glycaemia<9.99 mmol/l. Sulfonylurea, administered as a single dose at bedtime, was adjusted to attain fasting glycaemia<6.66 mmol/l. Group B: the optimization of insulin doses was exerted on night time basal rate to attain fasting glycaemia<6.66 mmol/l. Sulfonylurea, given before each meal, was adjusted to obtain postprandial glycaemia<9.99 mmol/l. RESULTS: During the 3 years follow-up, overall mean HbA(1c) values decreased similarly for both groups from baseline (9.45+/-0.83%) to 1, 2, 3 years (7.76+/-0.85%; 8.06+/-1.10%; 8.27+/-1.06% P<0.0001). The mean frequency of minor hypoglycaemia was 1.3+/-2.3 events per month per patient and 14 severe hypoglycaemic events occurred with no difference between the two groups. In both groups we observed a significant and similar weight gain and improvement in quality of life. CONCLUSION: Long-term combination therapy with OHA and CSII with only basic manipulation and optimization of insulin doses exerted on basal rate or on boluses is feasible, effective and well accepted in type 2 diabetes.

One-year efficacy and safety of Web-based follow-up using cellular phone in type 1 diabetic patients under insulin pump therapy: the PumpNet study.

AIM: Conventional follow-up of type 1 diabetic patients treated with continuous subcutaneous insulin infusion (CSII) was compared with intensive coaching using the Web and the cellular phone network for retrospective data transmission and short message service (SMS). METHODS: Thirty poorly controlled patients (HbA1c 7.5-10%) were enrolled in a bicenter, open-label, randomized, 12-month, two-period, crossover study. After a 1-month run-in period, 15 patients were randomly assigned to receive weekly medical support through SMS based upon weekly review of glucose values, while 15 patients continued to download self-monitored blood glucose (SMBG) values on a weekly basis without receiving SMS. After 6 months, patients crossed over to the alternate sequence for 6 additional months. Visits at the clinic were maintained every 3 months. RESULTS: Patients with long-standing inadequately controlled diabetes (24 +/- 13 years) were included. A non-significant trend to reduction in HbA(1c) (-0.25+/-0.94%, P<0.10) and mean glucose values (-9.2+/-25 mg/dl, P=0.06) during the 6-month SMS sequence was observed as compared with the no-SMS period. No safety issue (hypoglycemia, glucose variability) was reported. Adherence to SMBG was not affected by the trial. Quality of life analysis suggests a significant improvement in DQOL global score, as well as the DQOL satisfaction with life subscale, during the SMS sequence. CONCLUSIONS: Long-term telemedical follow-up of insulin pump-treated patients using a cellular phone-, SMS- and Web-based platform is feasible, safe, does not alter quality of life and associated with a trend toward improved metabolic control.

[Sub-cutaneous closed-loop: continuous glucose measurement and external insulin pump: hope in treatment of type 1 diabetes]. / La boucle fermée sous-cutanée: mesure continue du glucose et pompe à insuline externe: un espoir de traitement du diabète de type 1.

The development of an artificial pancreas allowing a continuous insulin infusion according to glucose measurement is closed to be an ideal device for type 1 diabetic patients and for the diabetologits. The development of miniaturized external pumps infusing short acting analogues with pharmacokinetic profile closer to physiology, and the availability of accurate continuous glucose sensors has led to the development of closed-loop subcutaneous system. The feasibility of this solution as been proven at a small scale but remains to be confirmed in a home setting. Intermediate solutions, such as semi-automatic systems might be immediately valuable.

Continuous glucose monitoring and external insulin pump: towards a subcutaneous closed loop.

The development of an artificial pancreas for the treatment of type 1 diabetes is a highly desired endeavour for type 1 diabetic patients, physicians, scientists and engineers. The development of the first miniaturized external pumps in the 70s and the pharmacokinetic properties of short acting insulin analogues, closer to physiology, have raised hopes for the elaboration of such a device. Recent technological progress in the development of continuous glucose sensors, have improved the reliability and accuracy of these devices. This has led to the development of prototypes of closed-loop system based on the combination of a continuous monitor, a control algorithm, and an insulin pump. This review focuses on the SC-SC approach, employing subcutaneous glucose monitoring and subcutaneous insulin delivery. The feasibility of this solution has been proven at a small scale, but remains to be confirmed in the home setting. Intermediate solutions, such as semi-automatic systems, might be immediately valuable.

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.

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.