ISPAD ANNUAL CONFERENCE HIGHLIGHTS 2023.

The 49th Annual Conference of the International Society of Pediatric and Adolescent Diabetes (ISPAD), held from October 18 to 21, 2023, in Rotterdam, Netherlands, showcased significant advancements and diversity in paediatric and adolescent diabetes research and clinical innovations. The conference, renowned for its global impact, brought together experts to discuss cutting-edge developments in the field. Highlights from the plenary sessions included ground-breaking research on immunotherapies and diabetes technologies and offering new insights into personalised treatment approaches. Keynote speakers emphasised the importance of early diagnosis, prevention and the potential of novel biomarkers in predicting disease progression. The symposia covered a broad spectrum of topics, from advancements in continuous glucose monitoring technologies to the latest in hybrid closed loop systems which promise to revolutionise diabetes management for young patients.

Skin Reactions in Children with Type 1 Diabetes Associated with the Use of New Diabetes Technologies-An Observational Study from a Regional Polish Pediatric Diabetes Center.

The study aimed to estimate the prevalence of skin problems in children and adolescents with type 1 diabetes (T1D) using insulin pumps (IPs) and/or continuous glucose monitoring (CGM) in our center and analyze their association with various factors. As part of the international ISPAD JENIOUS-initiated SKIN-PEDIC project, we interviewed and examined patients who visited the regional pediatric diabetes center in Opole (Poland) for four weeks regarding the use of IP and/or CGM and the presence of skin problems. Body mass index (BMI) and glycemic parameters were obtained retrospectively from medical records. Among 115 individuals (45.2% girls, 83.5% IP users, 96.5% CGM users), old scars were the most common skin problem (IP users 53.1%; CGM users 66.4%), while ≥2 types of skin problems co-occurred (IP users 40.6%; CGM users 27.3%). Longer IP use was associated with a higher prevalence of skin problems (50% for IP < 1 year, 98.1%-IP 1-3 years, 100% for IP > 3 years; p < 0.001), pointing out extra attention with IP use > 1 year. No significant associations were found between skin problems and gender, age, BMI centile and glycemic parameters. Dermatological complications were common among children using IP and CGM in our center, highlighting the need for vigilant monitoring and early intervention to manage these skin-related issues effectively.

Dabsylated Bradykinin Is Cleaved by Snake Venom Proteases from Echis ocellatus.

The vasoactive peptide bradykinin (BK) is an important member of the renin-angiotensin system. Its discovery is tightly interwoven with snake venom research, because it was first detected in plasma following the addition of viper venom. While the fact that venoms liberate BK from a serum globulin fraction is well described, its destruction by the venom has largely gone unnoticed. Here, BK was found to be cleaved by snake venom metalloproteinases in the venom of Echis ocellatus, one of the deadliest snakes, which degraded its dabsylated form (DBK) in a few minutes after Pro7 (RPPGFSP↓FR). This is a common cleavage site for several mammalian proteases such as ACE, but is not typical for matrix metalloproteinases. Residual protease activity < 5% after addition of EDTA indicated that DBK is also cleaved by serine proteases to a minor extent. Mass spectrometry-based protein analysis provided spectral proof for several peptides of zinc metalloproteinase-disintegrin-like Eoc1, disintegrin EO4A, and three serine proteases in the venom.

Pressure pain sensitivity: A new stress measure in children and adolescents with type 1 diabetes?

Type 1 diabetes (T1D) is associated with general- and diabetes-specific stress which has multiple adverse effects. Hence measuring stress is of great importance. An algometer measuring pressure pain sensitivity (PPS) has been shown to correlate to certain stress measures in adults. However, it has never been investigated in children and adolescents. The aim of our study was to examine associations between PPS and glycated hemoglobin (HbA1c), salivary cortisol and two questionnaires as well as to identify whether the algometer can be used as a clinical tool among children and adolescents with T1D. Eighty-three participants aged 6-18 years and diagnosed with T1D were included in this study with data from two study visits. Salivary cortisol, PPS and questionnaires were collected, measured, and answered on site. HbA1c was collected from medical files. We found correlations between PPS and HbA1c (rho = 0.35, P = 0.046), cortisol (rho = -0.25, P = 0.02) and Perceived Stress Scale (rho = -0.44, P = 0.02) in different subgroups based on age. Males scored higher in PPS than females (P < 0.001). We found PPS to be correlated to HbA1c but otherwise inconsistent in results. High PPS values indicated either measurement difficulties or hypersensibility towards pain.

No associations between type 1 diabetes and atopic dermatitis, allergic rhinitis, or asthma in childhood: a nationwide Danish case-cohort study.

Studies examining the association between type 1 diabetes (T1D) and atopic diseases, i.e., atopic dermatitis, allergic rhinitis and asthma have yielded conflicting results due to different algorithms for classification, sample size issues and risk of referral bias of exposed cohorts with frequent contact to health care professionals. Using Danish national registries and well-established disease algorithms, we examined the bidirectional association between T1D and atopic diseases in childhood and adolescence using Cox Proportional Hazard regression compared to two different unexposed cohorts from a population of 1.5 million Danish children born from 1997 to 2018. We found no associations between T1D and atopic dermatitis, allergic rhinitis, or asthma (defined after age five). However, in multivariable analysis we found an increased risk of persistent wheezing (defined as asthma medication before age five) after T1D with an adjusted hazard ratio (aHR) of 1.70 [1.17-2.45]. We also identified an increased risk of developing T1D after persistent wheezing with aHR of 1.24 [1.13-1.36]. This study highlights similar risks of atopic diseases in children with T1D and of T1D in children with atopic disease after age of five years versus healthy controls. However, more research is needed to understand the possible early immunological effects of the link between persistent wheezing and T1D.

First International Survey on Diabetes Providers' Assessment of Skin Reactions in Youth With Type 1 Diabetes Using Technological Devices.

BACKGROUND: Advances in diabetes technological devices led to optimization of diabetes care; however, long-lasting skin exposure to devices may be accompanied by an increasing occurrence of cutaneous reactions. METHODS: We used an open-link web-based survey to evaluate diabetes-care providers' viewpoint on prevalence, management practices, and knowledge related to skin reactions with the use of diabetes technological devices. A post hoc analysis was applied to investigate differences in the level of awareness on this topic in relation to the experience in diabetes technology. RESULTS: One hundred twenty-five responses from 39 different countries were collected. Most respondents (69%) routinely examine patients' skin at each visit. All the preventive measures are not clear and, mainly, homogenously put into clinical practice. Contact dermatitis was the most frequently reported cutaneous complication due to diabetes devices, and its most common provocative causes are not yet fully known by diabetes-care providers. Almost half of the respondents (42%) had discussed the presence of harmful allergens contained in adhesives with device manufacturers. There is general agreement on the need to strengthen knowledge on dermatological complications. CONCLUSIONS: Although diabetes-care providers are quite aware of the chance to develop skin reactions in people with diabetes using technological devices, there are still some unmet needs. Large follow-up studies and further dissemination tools are awaited to address the gaps revealed by our survey.

A Skin Care Program to Prevent Skin Problems due to Diabetes Devices in Children and Adolescents: A Cluster-Controlled Intervention Study.

OBJECTIVE: Diabetes devices that deliver insulin and measure blood glucose levels are cornerstones in modern treatment of type 1 diabetes. However, their use is frequently associated with the development of skin problems, particularly eczema and wounds. Proper skin care may prevent skin problems, yet evidence-based information from interventional studies is missing. Providing this information is the aim of this study. RESEARCH DESIGN AND METHODS: This cluster-controlled intervention study tested the efficacy of a basic skin care program (including use of lipid cream, removal, and avoidance of disinfection). A total of 170 children and adolescents with type 1 diabetes were included and assigned either to the intervention group (n = 112) or the control group (n = 58). Participants were seen quarterly the first year after device initiation, with clinical assessment and interview in an unblinded setting. RESULTS: Eczema or wounds were observed in 33.6% of the intervention group compared with 46.6% of control participants (absolute difference, 12.9% [95% CI -28.7%, 2.9%]; P = 0.10). The adjusted odds of wound development were decreased by 71% in the intervention compared with control group (for wounds, odds ratio 0.29 [95% CI 0.12, 0.68]; P = 0.005). In total, only eight infections were seen, without a higher frequency in the intervention group, despite advice to omit disinfection. CONCLUSIONS: These data indicate our basic skin care program partially prevented diabetes device-induced skin reactions. However, more preventive strategies with other adhesives, patches, and/or types of lotions are needed for optimized prevention.

An Occlusive Hydrocolloid-Based Patch Is Effective, Feasible, and Safe As a Treatment of Irritant Contact Dermatitis Due to Diabetes Devices in Children and Adolescents with Type 1 Diabetes.

Irritant contact dermatitis (ICD) occurs frequently with the use of diabetes devices, but no guidelines for treatment exist. Since subsequent devices need intact skin for intended use, quick healing is crucial. Normal wound healing is expected to be 7-10 days. This was a single-center cross-over study that investigated the effectiveness of an occlusive hydrocolloid-based patch versus nonocclusive treatment of ICD. Participants were aged 6-20 years with active ICD caused by using diabetes device. First study period was patch treatment for 3 days. A control arm was initiated if a new ICD occurred within 30 days. ICD healed completely in 21% of the patch group but none in the controls. Itching was reported as an adverse event (AE) in both arms, but only one additional AE was noted in the patch arm: an infection at a different site from investigated. The hydrocolloid-based patch showed signs of faster healing of ICD with no additional AEs, but larger studies are needed.

Ultrasound Detected Subcutaneous Changes in a Pediatric Cohort After Initiation of a New Insulin Pump or Glucose Sensor.

Objective: This study examined subcutaneous tissue changes at sites used by continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM), and tested whether these changes, if any, were associated with glycated hemoglobin (HbA1c). Research Design and Methods: This prospective study investigated recently used CSII or CGM sites in 161 children and adolescents during the first year after initiation of a new diabetes device. Subcutaneous changes such as echogenicity, vascularization, and the distance from the skin surface to the muscle at CSII and CGM sites were assessed by ultrasound. Results: The distance from skin surface to muscle fascia at both the upper arm and abdomen was influenced by age, body mass index z-score, and sex. Especially in boys and the youngest, the depth of many devices outreached the mean distance. The mean distance for boys at the abdomen and upper arm ranged from 4.5-6.5 mm and 5-6.9 mm for all ages, respectively. Hyperechogenicity at CGM sites was 4.3% after 12 months. The frequency of subcutaneous hyperechogenicity and vascularization at CSII sites increased significantly over time (41.2% to 69.3% and 2% to 16% respectively, P < 0.001 and P = 0.009). Hyperechogenicity in the subcutis was not a predictor of elevated HbA1c (P = 0.11). Conclusion: There is large variation in the distance from the skin surface to the muscle fascia and many diabetes devices reach even deeper. Hyperechogenicity and vascularization increased significantly over time at CSII sites, but not CGM sites. The importance of hyperechogenicity for insulin absorption is unclear and further investigations are needed. Clinical Trial Registration number: NCT04258904.

Similar Skin Barrier Function in Persons with Type 1 Diabetes Compared with Healthy Controls.

Contact dermatitis because of use of diabetes devices is frequent in individuals with type 1 diabetes (TD1), especially in the pediatric age group, but the putative role of a constitutional impaired skin barrier in persons with TD1 is unclear. This study examined the skin barrier function by the measurement of natural moisturizing factor and free cytokines collected through skin tape strips, as well as biophysical markers and the skin microbiome, in persons with TD1 than to age- and sex-matched healthy controls. All measurements were done in nonlesional skin. We found that the skin barrier function was similar in children and adolescents with TD1 than to controls but found that the beta-diversity of skin microbiome at the buttock differed between the two groups. We conclude that individuals with TD1 have normal skin barrier function, and that the increased occurrence of contact dermatitis following pump and sensor use is explained by exogenous factors.

Liquid AbobotulinumtoxinA: Pooled Data From Two Double-Blind, Randomized, Placebo-Controlled Phase III Studies of Glabellar Line Treatment.

BACKGROUND: AbobotulinumtoxinA (aboBoNT-A) solution is a new ready-to-use formulation developed to reduce preparation time and improve reproducibility of injections. OBJECTIVE: To further evaluate treatment of moderate-to-severe glabellar lines (GLs) using pooled data from 2 Phase III studies. METHODS: Following double-blind treatment with 50 U aboBoNT-A solution (n = 251) or placebo (n = 123), GL severity was assessed by investigators (ILA) and subjects (SSA). Other assessments included subject-reported time to onset, subject satisfaction, FACE-Q, and adverse events. RESULTS: One month after aboBoNT-A solution treatment, 88% had none-or-mild GLs at maximum frown and 93% had ≥1-grade improvement in ILA (similar for SSA), 24% to 27% remaining improved at Month 6. Glabellar lines responder rates remained higher than placebo throughout Month 6 ( p < .001). Almost two-thirds of subjects reported onset within 3 days, nearly a quarter reporting effect by Day 1. Subject satisfaction with GL appearance, and FACE-Q satisfaction with facial appearance overall and psychological well-being were also improved over placebo throughout Month 6, p < .05. Treatment-related adverse events were nonserious and mild or moderate. CONCLUSION: Pooled analysis confirmed a duration of effect on GLs of up to 6 months for aboBoNT-A solution, with onset starting within 24 hours, high subject satisfaction, and improved psychological well-being. The treatment was well tolerated.

Exclusive inhibition of IL-6 trans-signaling by soluble gp130FlyRFc.

gp130 is the signal-transducing receptor for the Interleukin (IL)-6 type cytokines IL-6 and IL-11. To induce signaling, IL-6 forms a complex with IL-6 receptor (IL-6R) and IL-11 with IL-11 receptor (IL-11R). Membrane-bound IL-6R and IL-11R in complex with gp130 and the cytokine mediate classic-signaling, whereas trans-signaling needs soluble IL-6R and IL-11R variants. Interleukin (IL)-6 trans-signaling is of particular importance because it drives the development of autoimmune diseases, including rheumatoid arthritis and chronic inflammatory bowel diseases, whereas a role for IL-11 trans-signaling remains elusive. Soluble gp130 selectively inhibits trans-signaling of IL-6 whereas both, classic- and trans-signaling are abrogated by IL-6- and IL-6R-antibodies. Recently, we described an optimized sgp130 variant, which carries three amino acid substitutions T102Y/Q113F/N114L (sgp130FlyFc) resulting in reduced inhibition of IL-11 trans-signaling by increasing the affinity of sgp130 for the site I of IL-6. Moreover, we described that the patient mutation R281Q in gp130 results in reduced IL-11 signaling. Here, we show that the combination of T102Y/Q113F/N114L and R281Q in the new variant sgp130FlyRFc results in complete preservation of IL-11 mediated trans-signaling, whereas inhibition of IL-6 trans-signaling is maintained. Since sgp130Fc (olamkicept) has successfully completed a phase IIa trial in Crohn's disease (CD) and ulcerative colitis, sgp130FlyRFc might serve as second-generation therapeutic to diminish IL-11 trans-signaling cross-reactivity.

AbobotulinumtoxinA for the Treatment of Moderate-to-Severe Glabellar Lines: A Randomized, Dose-Escalating, Double-Blind Study.

OBJECTIVE: To evaluate the efficacy and safety of AbobotulinumtoxinA (ABO) dose escalation in the correction of moderate-to-severe glabellar lines. DESIGN: Phase 2, 36-week, multicenter, randomized, dose-ranging, double-blind, placebo-controlled study. METHODS: Adults with moderate-to-severe glabellar lines received a single ABO treatment, dosed at 50, 75, 100, or 125 U, or placebo. Primary endpoint was week 4 composite ≥2-grade responder rate among those achieving a severity score of 0 (none) or 1 (mild) at maximum frown, evaluated using concurrent investigator and subject assessments. Secondary endpoints included ≥1-grade severity improvement, duration of effect, and reporting of treatment-emergent adverse events (TEAEs). RESULTS: Overall, 399 subjects were included (88.2% were female). Week 4 composite ≥2-grade ABO responder rate was 80.0% (50 U), 88.8% (75 U), 90.0% (100 U) and 95.1% (125 U), versus 2.6% with placebo (P<0.001). Responder rate (≥1-grade) ranged between 53% (50 U) and 69% (125 U) at week 24 and between 18% (50 U) and 31% (125 U) at week 36. Median time (weeks) to return to baseline severity/worse, among those scoring 0 (none) or 1 (mild), was 32.3 (50 U), 34.3 (75 U), 36.0 (100 U) and 36.6 (125 U), versus 23.7 (placebo). ABO-related TEAEs were reported in 4% of subjects (80% were mild). No seroconversion to ABO neutralizing antibodies was seen. CONCLUSION: A single ABO treatment provided rapid and effective improvements in glabellar line severity at all doses. Higher doses tended to demonstrate elevated response rates and longer duration of effect. All ABO doses were well-tolerated with low TEAE incidence. J Drugs Dermatol. 2021;20(9):980-987. doi:10.36849/JDD.6263.

Selective inhibition of IL-6 trans-signaling by a miniaturized, optimized chimeric soluble gp130 inhibits TH17 cell expansion.

The cytokine interleukin-6 (IL-6) signals through three mechanisms called classic signaling, trans-signaling, and trans-presentation. IL-6 trans-signaling is distinctly mediated through a soluble form of its transmembrane receptor IL-6R (sIL-6R) and the coreceptor gp130 and is implicated in multiple autoimmune diseases. Although a soluble form of gp130 (sgp130) inhibits only IL-6 trans-signaling, it also blocks an analogous trans-signaling mechanism of IL-11 and its soluble receptor sIL-11R. Here, we report miniaturized chimeric soluble gp130 variants that efficiently trap IL-6:sIL-6R but not IL-11:sIL-11R complexes. We designed a novel IL-6 trans-signaling trap by fusing a miniaturized sgp130 variant to an IL-6:sIL-6R complex-binding nanobody and the Fc portion of immunoglobulin G (IgG). This trap, called cs-130Fc, exhibited improved inhibition of as well as increased selectivity for IL-6 trans-signaling compared to the conventional fusion protein sgp130Fc. We introduced affinity-enhancing mutations in cs-130Fc and sgp130Fc that further improved selectivity toward IL-6 trans-signaling. Moreover, cs-130Fc efficiently inhibited the expansion of T helper 17 (TH17) cells in cultures of mouse CD4+ T cells treated with IL-6:sIL-6R. Thus, these variants may provide or lead to the development of more precisely targeted therapeutics for inflammatory disorders associated with IL-6 trans-signaling.

Current status and relevance of single nucleotide polymorphisms in IL-6-/IL-12-type cytokine receptors.

Cytokines control immune related events and are critically involved in a plethora of patho-physiological processes including autoimmunity and cancer development. In rare cases, single nucleotide polymorphisms (SNPs) or single nucleotide variations (SNVs) in cytokine receptors eventually cause detrimental ligand-independent, constitutive activation of signal transduction. Most SNPs have, however, no or only marginal influences on gene expression, protein stability, localization and function and thereby only slightly affecting pathogenesis probability. The SNP database (dbSNP) is an archive for a broad collection of polymorphisms in which SNPs are categorized and marked with a locus accession number "reference SNP" (rs). Here, we engineered an algorithm to directly align dbSNP information to DNA and protein sequence information to clearly illustrate a genetic SNP landscape exemplified for all tall cytokine receptors of the IL-6/IL-12 family, including IL-23R, IL-12Rß1, IL-12Rß2, gp130, LIFR, OSMR and WSX-1. This information was complemented by a comprehensive literature summary and structural insights of relevant disease-causing SNPs in cytokine/cytokine receptor interfaces. In summary, we present a general strategy with potential to apply to other cytokine receptor networks.

Five-Month Follow-up Shows No Improvement in Dermatological Complications in Children With Type 1 Diabetes Using Continuous Glucose Monitoring Systems and Insulin Pumps.

BACKGROUND: A Danish study showed that 90% of the pediatric patients who participated had some time experienced dermatological complications due to treatment with continuous subcutaneous insulin infusion (CSII). This follow-up study describes dermatological complications due to CSII and/or continuous glucose monitoring (CGM) between the two study periods and includes health-related quality of life (HrQoL) measurements. METHODS: A total of 138 patients (95%) out of 145 patients from the initial study answered an online questionnaire regarding dermatological complications related to CSII and/or CGM, five months later. A second questionnaire (DISABKIDS) regarding HrQoL was sent out to those 138 of which 111 patients completed it. The patients were aged from 2 to 20 years. Descriptive statistics, χ2 tests, and univariate and multivariate analyses were used to analyze the data. RESULTS: In total, 81% of the 138 patients continued to have dermatological complications at follow-up. Itching was the most frequently reported complication. Patients using Enlite reported more dermatological complications than those using Libre. In total, 79% of the patients who used barrier cream in the initial study still had dermatological complications five months later. Age, gender, Body Mass Index (BMI), or HbA1c levels showed no significant association with dermatological complications. Patients who perceived dermatological complications as a greater problem had lower HrQoL scores. CONCLUSION: Once dermatological complications start to appear, they become chronic, indicating that the treatments currently available are inadequate. Patients perceiving dermatological complications as a greater problem were associated with lower HrQoL. These findings highlight the need for additional preventive studies.

Author Correction: MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

[Allergic contact dermatitis caused by insulin pumps and glucose monitors in children with diabetes].

Insulin pump therapy and the use of flash or continuous glucose monitoring in children is increasing. The diabetes devices are attached to the skin for several days to weeks with a strong adhesive, and recently, several cases of allergic contact dermatitis in children caused by components of the adhesive have been reported. In this review, we discuss such problems. The most frequent cause of allergic contact dermatitis is acrylates in the adhesive material, and the problem is serious and calls for rapid development of devices used in the treatment and monitoring of Type 1 diabetes without allergenic agents.

Pecan (Carya illinoinensis (Wagenh.) K. Koch) Nut Shell as an Accessible Polyphenol Source for Active Packaging and Food Colorant Stabilization.

Herein, the antioxidant and food stabilizing properties of a pecan nut shell (PNS) hydroalcoholic extract (PNSE) are reported. Chemical degradation of PNSE demonstrated the presence of condensed tannins as the main phenolic components. PNSE showed remarkable antioxidant properties in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay (EC50 = 0.004 mg/mL). PNSE was initially tested as an inhibitor of mushroom tyrosinase, exhibiting a quite low IC50 value (0.055 mg/mL) against the enzyme diphenolase activity, suggesting its use in enzymatic browning inhibition. The anthocyanin stabilization properties were evaluated under accelerated aging conditions of both pure pigments and commercial fruit juices, and PNSE was found to be effective at concentrations (0.05 mg/mL) at which well-known stabilizers such as chlorogenic and ferulic acids proved to fail. PNSE also performed well in the stabilization of spray-dried anthocyanins for use as a food colorant, increasing the half-life of blackberry anthocyanins up to 20%. In order to explore the possibility of using PNSE as a functional additive for active packaging, polylactic acid (PLA) films containing PNSE were prepared by solvent casting, and no substantial alteration of the mechanical properties was found on addition of the extract up to 10% w/w. The films showed remarkable antioxidant properties (DDPH reduction >60% with a 3% w/w loading, at a dose of 1 mg/mL in the DPPH solution) and delayed the onset of browning of apple smoothies (ca. 30% inhibition with a 10% w/w loading). These results highlight the exploitation of PNS as a low-cost polyphenol source for food industry applications.

Cost of Treating Skin Problems in Patients with Diabetes Who Use Insulin Pumps and/or Glucose Sensors.

Background: The use of insulin pump and glucose sensor is advantageous, but unfortunately many experience skin problems. To reduce or overcome skin problems, patients use additional products or change their sets preterm. Therefore, the aim was to investigate costs related to skin problems. Materials and Methods: Two hundred sixty-three patients from four different hospitals in Denmark participated in a cross-sectional survey about skin problems related to insulin pump and/or glucose sensor use. Additional costs aside technology and diabetes treatment were calculated based on adhesives, patches, lotion, and preterm shifts of infusion or sensor sets due to skin problems. Descriptive statistics and linear regression were used. Results: The total costs for all these expenses were 11493.9 U.S. dollars (USD) in 145 pediatric patients and 4843 USD in 118 adult patients. The costs were higher in patients with, than without, skin problems and for skin problems due to the glucose sensor compared with insulin pump. Pediatric patients with eczema and/or wound due to the glucose sensor did cost 154.3 USD more, than patients without these skin problems (P < 0.01). We found a clear dose/response relationship between costs and severity of skin problems, especially in pediatric patients. Conclusions: Our data show that skin problems due to use of insulin pump and/or glucose sensor have significant costs on the Danish welfare system. This leaves an economic incentive for developing more skin-sensitive adhesive for the infusion set and sensors, at least for a certain subgroup of patients.