Régis Radermecker

Continuous subcutaneous insulin infusion with short-acting insulin analogues or human regular insulin: efficacy, safety, quality of life, and cost-effectiveness.

Portable insulin infusion devices are effective and safe insulin delivery systems for managing diabetes mellitus, especially type 1 diabetes. Rapidly absorbed insulin analogues, such as insulin lispro or insulin aspart, may offer an advantage over regular human insulin for insulin pumps. Several open‐label randomised crossover trials demonstrated that continuous subcutaneous insulin infusion (CSII) with insulin lispro provided a better control of postprandial hyperglycaemia and a slightly but significantly lower glycated haemoglobin level, with lower daily insulin requirement and similar or even less hypoglycaemic episodes. A CSII study comparing insulin lispro and insulin aspart demonstrated similar results with the two analogues, and better results than those with regular insulin. Because these analogues have a quicker onset and a shorter duration of action than regular insulin, one might expect an earlier and greater metabolic deterioration in case of CSII interruption, but a more rapid correction of metabolic abnormalities after insulin boluses when reactivating the pump. These expectations were confirmed in randomised protocols comparing the metabolic changes occurring during and after CSII interruption of various durations when the pump infused either insulin lispro or regular insulin. The extra cost resulting from the use of CSII and insulin analogues in diabetes management should be compensated for by better metabolic control and quality of life. In conclusion, CSII delivering fast‐acting insulin analogues may be considered as one of the best methods to replace insulin in a physiological manner by mimicking meal and basal insulin requirements, without higher risk of hypoglycaemia or ketoacidosis in well‐educated diabetic patients. Copyright

Lipodystrophy reactions to insulin: effects of continuous insulin infusion and new insulin analogs.

Management of diabetes mellitus can be responsible for cutaneous adverse events. For example, lipoatrophy or lipohypertrophy can develop at the site of insulin injections. Lipohypertrophy remains a frequent complication of insulin therapy irrespective of the insulin source and mode of administration. Lipoatrophy at insulin injection sites is considered to be an immune complex-mediated inflammatory lesion; however, it has become a rare event since the advent of human insulin. Nowadays, continuous subcutaneous insulin infusion (CSII) using a portable pump and/or injections of insulin analogs with an altered amino acid sequence compared with native insulin may cause lipodystrophy in diabetic patients. Some case reports describe the recovery of lipoatrophy following the use of CSII and/or short-acting insulin analogs. Conversely, exceptional cases of lipoatrophy have occurred in patients receiving lispro insulin analog via CSII. Lipodystrophy reactions remain a potential problem when managing diabetic patients with new insulin therapy technologies.

Allergy reactions to insulin: effects of continuous subcutaneous insulin infusion and insulin analogues.

The purification of animal insulin preparations and the use of human recombinant insulin have markedly reduced the incidence but not completely suppressed the occurrence of insulin allergy manifestations. Advances in technologies concerning the mode of delivery of insulin, i.e. continuous subcutaneous insulin infusion (CSII), and the use of insulin analogues, resulting from the alteration in the amino acid sequence of the native insulin molecule, may influence the immunogenicity and antigenicity of native insulin. Instead of increasing allergy reactions, CSII has been reported to represent a successful alternative treatment in diabetic patients presenting local or generalized allergy to insulin or other components (zinc, protamine) of conventional treatment. Most recent reports concern CSII‐treated patients using short‐acting insulin analogues (essentially insulin lispro), although the precise role of these insulin analogues remains unclear as allergy to them has also been described. Finally, data on antigenicity and immunogenicity of long‐acting insulin analogues (glargine, detemir), which may mimic the basal insulin delivery with CSII, remain scarce at present. Copyright

Assessment of Patient-Led or Physician-Driven Continuous Glucose Monitoring in Patients With Poorly Controlled Type 1 Diabetes Using Basal-Bolus Insulin Regimens A 1-year multicenter study

OBJECTIVE The benefits of real-time continuous glucose monitoring (CGM) have been demonstrated in patients with type 1 diabetes. Our aim was to compare the effect of two modes of use of CGM, patient led or physician driven, for 1 year in subjects with poorly controlled type 1 diabetes. RESEARCH DESIGN AND METHODS Patients with type 1 diabetes aged 8–60 years with HbA1c ≥8% were randomly assigned to three groups (1:1:1). Outcomes for glucose control were assessed at 1 year for two modes of CGM (group 1: patient led; group 2: physician driven) versus conventional self-monitoring of blood glucose (group 3: control). RESULTS A total of 257 subjects with type 1 diabetes underwent screening. Of these, 197 were randomized, with 178 patients completing the study (age: 36 ± 14 years; HbA1c: 8.9 ± 0.9%). HbA1c improved similarly in both CGM groups and was reduced compared with the control group (group 1 vs. group 3: −0.52%, P = 0.0006; group 2 vs. group 3: −0.47%, P = 0.0008; groups 1 + 2 vs. group 3: −0.50%, P < 0.0001). The incidence of hypoglycemia was similar in the three groups. Patient SF-36 questionnaire physical health score improved in both experimental CGM groups (P = 0.004). Sensor consumption was 34% lower in group 2 than in group 1 (median [Q1–Q3] consumption: group 1: 3.42/month [2.20–3.91] vs. group 2: 2.25/month [1.27–2.99], P = 0.001). CONCLUSIONS Both patient-led and physician-driven CGM provide similar long-term improvement in glucose control in patients with poorly controlled type 1 diabetes, but the physician-driven CGM mode used fewer sensors.

Vitamin D and type 2 diabetes mellitus: Where do we stand?

AIMS In-vitro and observational studies have established a link between vitamin D deficiency and different type 2 diabetes outcomes (insulin resistance, insulin secretion, glucose intolerance). Although the number of randomized controlled trials vs placebo is small, vitamin D (VTD) has been shown to prevent increases in glucose concentration and insulin resistance, enhance insulin sensitivity and reduce systolic blood pressure in type 2 diabetic patients. METHODS In this review, we have focused on the potential mechanisms that might explain the association between VTD and type 2 diabetes mellitus (T2DM). We have also evaluated the different epidemiological and observational studies on the topic, as well as the various interventional studies. RESULTS Although the in vitro studies appear to be promising in explaining the link between VTD metabolism and T2DM, the results of in vivo studies are conflicting. This could be related to differences in their methodological approaches. CONCLUSION Although more studies are needed to confirm the role of VTD in the treatment of T2DM, there is nevertheless enough evidence at this time to suggest a need to maintain 25-OH vitamin D levels in T2DM patients around 30 ng/mL over the course of a year.

What makes tight glycemic control tight? The impact of variability and nutrition in two clinical studies.

Introduction: Tight glycemic control (TGC) remains controversial while successful, consistent, and effective protocols remain elusive. This research analyzes data from two TGC trials for root causes of the differences achieved in control and thus potentially in glycemic and other outcomes. The goal is to uncover aspects of successful TGC and delineate the impact of differences in cohorts. Methods: A retrospective analysis was conducted using records from a 211-patient subset of the GluControl trial taken in Liege, Belgium, and 393 patients from Specialized Relative Insulin Nutrition Titration (SPRINT) in New Zealand. Specialized Relative Insulin Nutrition Titration targeted 4.0–6.0 mmol/liter, similar to the GluControl A (N = 142) target of 4.4–6.1 mmol/liter. The GluControl B (N = 69) target was 7.8–10.0 mmol/liter. Cohorts were matched by Acute Physiology and Chronic Health Evaluation II score and percentage males (p > .35); however, the GluControl cohort was slightly older (p = .011). Overall cohort and per-patient comparisons (median, interquartile range) are shown for (a) glycemic levels achieved, (b) nutrition from carbohydrate (all sources), and (c) insulin dosing for this analysis. Intra- and interpatient variability were examined using clinically validated model-based insulin sensitivity metric and its hour-to-hour variation. Results: Cohort blood glucose were as follows: SPRINT, 5.7 (5.0–6.6) mmol/liter; GluControl A, 6.3 (5.3–7.6) mmol/liter; and GluControl B, 8.2 (6.9–9.4) mmol/liter. Insulin dosing was 3.0 (1.0–3.0), 1.5 (0.5–3), and 0.7 (0.0–1.7) U/h, respectively. Nutrition from carbohydrate (all sources) was 435.5 (259.2–539.1), 311.0 (0.0–933.1), and 622.1 (103.7–1036.8) kcal/day, respectively. Median per-patient results for blood glucose were 5.8 (5.3–6.4), 6.4 (5.9–6.9), and 8.3 (7.6–8.8) mmol/liter. Insulin doses were 3.0 (2.0–3.0), 1.5 (0.8–2.0), and 0.5 (0.0–1.0) U/h. Carbohydrate administration was 383.6 (207.4–497.7), 103.7 (0.0–829.4), and 207.4 (0.0–725.8) kcal/day. Overall, SPRINT gave ∼2x more insulin with a 3–4x narrower, but generally non-zero, range of nutritional input to achieve equally TGC with less hypoglycemia. Specialized Relative Insulin Nutrition Titration had much less hypoglycemia (<2.2 mmol/liter), with 2% of patients, compared to GluControl A (7.7%) and GluControl B (2.9%), indicating much lower variability, with similar results for glucose levels <3.0 mmol/liter. Specialized Relative Insulin Nutrition Titration also had less hyperglycemia (>8.0 mmol/liter) than groups A and B. GluControl patients (A+B) had a ∼2x wider range of insulin sensitivity than SPRINT. Hour-to-hour variation was similar. Hence GluControl had greater interpatient variability but similar intrapatient variability. Conclusion: Protocols that dose insulin blind to carbohydrate administration can suffer greater outcome glycemic variability, even if average cohort glycemic targets are met. While the cohorts varied significantly in model-assessed insulin resistance, their variability was similar. Such significant intra- and interpatient variability is a further significant cause and marker of glycemic variability in TGC. The results strongly recommended that TGC protocols be explicitly designed to account for significant intra- and interpatient variability in insulin resistance, as well as specifying or having knowledge of carbohydrate administration to minimize variability in glycemic outcomes across diverse cohorts and/or centers.

Circulating insulin antibodies: influence of continuous subcutaneous or intraperitoneal insulin infusion, and impact on glucose control.

The purification of animal insulin preparations and the use of human recombinant insulin have markedly reduced the incidence, but not completely suppressed, the development of anti‐insulin antibodies (IAs). Advances in technologies concerning the mode of delivery of insulin, i.e. continuous subcutaneous insulin infusion (CSII), continuous peritoneal insulin infusion (CPII) and more recently inhaled insulin administration, appear to significantly increase circulating levels of immunoglobulin G (IgG) anti‐IAs in diabetic patients. However, the increase is usually moderate and mostly transient as compared to previous observations with poorly purified animal insulin preparations. The clinical impact of these circulating anti‐IAs remains unclear. Nevertheless, several studies have suggested that antibodies could retard insulin action, leading to a worsening of postprandial hyperglycaemia and/or serve as a carrier, thus leading to unexpected hypoglycaemia. CPII may be associated with more marked and sustained increase in IAs levels, possibly related to the use of an unstable insulin and the formation of immunogenic aggregates of insulin. The possible clinical consequences of these high levels of IAs remain to be evaluated because a low‐glucose morning syndrome or severe insulin resistance with ketone bodies production have been reported in some cases. In conclusion, even if CSII and CPII may promote the development of circulating IAs, this increase does not lead to immunological insulin resistance, compared to that previously described with animal non‐purified insulin preparations, and seems to have only marginal influence on blood glucose control or complications in most diabetic patients. Copyright

Cystatin C or Creatinine for Detection of Stage 3 Chronic Kidney Disease in Anorexia Nervosa

Background: Patients with anorexia nervosa (AN) are at a high risk of renal failure. Chronic kidney disease (CKD) is often missed in these patients because the serum creatinine is a poor marker of kidney function. We studied the utility of cystatin C to detect renal failure in this population. Method: Twenty-seven AN patients were studied. Glomerular filtration rates (GFR) were measured with the chromium-51- ethylenediaminetetraacetate (51Cr-EDTA) method. We compared the ability of creatinine and cystatin C to detect stage 3 CKD (GFR below 60 ml/min) by ROC curve analysis. Results: In this cohort, there is no correlation between GFR and serum creatinine, but there is a significant correlation between cystatin C and GFR. By ROC analysis, the cystatin C concentration is better than the serum creatinine concentration for the detection of stage 3 CKD (area under the curve of 0.86 vs. 0.61, p = 0.05). Conclusion: Plasma cystatin C is better than serum creatinine in detecting stage 3 CKD in patients with AN.

Real-time continuous glucose monitoring (CGM) integrated into the treatment of type 1 diabetes: Consensus of experts from SFD, EVADIAC and SFE

P.-Y. Benhamou, B. Catargi, B. Delenne, B. Guerci, H. Hanaire, N. Jeandidier, R. Leroy, L. Meyer, A. Penfornis, R.-P. Radermecker, E. Renard, S. Baillot-Rudoni, J.-P. Riveline, P. Schaepelynck, A. Sola-Gazagnes, V. Sulmont, N. Tubiana-Rufi, D. Durain, I. Mantovani Coordination: A. Sola-Gazagnes, J.-P. Riveline Societe Francophone du Diabete (SFD), Societe Francaise d’Endocrinologie (SFE) and EVADIAC group (EVAluation dans le Diabete des Implants ACtifs)

Continuous glucose monitoring reduces both hypoglycaemia and HbA1c in hypoglycaemia-prone type 1 diabetic patients treated with a portable pump.

AIM This study aimed to assess the effectiveness of continuous glucose monitoring (CGM) for glucose control in type 1 diabetic patients treated by continuous subcutaneous insulin infusion (CSII) and presenting with frequent hypoglycaemic episodes. METHODS Thirteen patients with type 1 diabetes (diabetes duration: 25±15 years; CSII duration: 5.5±7.0 years), with more than six recorded capillary blood glucose (CBG) values <60 mg/dL, according to their metres for the past 14 days, were offered the permanent use of a CGM device (Guardian RT(®), Medtronic) plus ongoing self-monitoring of blood glucose (SMBG) for 12 weeks, followed by a 12-week crossover period of SMBG only, or vice versa. Glucose control, determined by recorded 14-day CBG values <60 mg/dL and HbA(1c) levels, and quality of life according to the Diabetes Quality of Life (DQOL) questionnaire, were assessed at baseline, and after 12- and 24-week follow-ups. RESULTS Four patients withdrew from the study during the first period (of whom three were using CGM). In the nine study completers, the number of low CBG values decreased significantly from 13.9±9.2 to 7.6±6.8 (P=0.011) when patients used CGM, in either the initial or final trial period, while a decrease in HbA(1c) from 8.3±0.7 to 7.7±0.6% (P=0.049) was also observed, in contrast to the absence of any significant differences during the SMBG-only period. DQOL scores were also essentially unaffected. CONCLUSION This pilot observational study supports the hypothesis that CGM use can significantly improve overall glucose control while reducing hypoglycaemic episodes in hypoglycaemia-prone type 1 diabetic patients treated by CSII.