Intensive Insulin Therapy Research Articles

Important Decrease in Hospitalizations for Acute Diabetes Events Following FreeStyle Libre System Initiation in People with Type 2 Diabetes on Basal Insulin Therapy in France.

Aims/Hypothesis: Initiation of insulin therapy in people with type 2 diabetes (T2DM) may be necessary to achieve glycemic targets but is associated with acute diabetes events (ADEs), including severe hypoglycemia (SH) or diabetic ketoacidosis (DKA). We assessed the impact of initiating FreeStyle Libre® system (FSL) on hospitalizations for ADEs in people with T2DM on basal insulin only regimen±noninsulin antidiabetic drugs. Materials and Methods: A retrospective study of the French national Système National des Données de Santé reimbursement claims database (≈66 million French people) identified people with T2DM on basal insulin therapy receiving a first reimbursement of FSL between August 1, 2017 and December 31, 2018. Claims data for the 12 months before, and up to 24 months after FSL initiation, were analyzed. Hospitalizations for ADEs were identified, using ICD-10 codes as main or related diagnosis, for: SH events; DKA events; comas; and hyperglycemia-related admissions. Results: A total of 5933 people with T2DM on basal insulin therapy initiated FSL during the selection period. Of the patients, 78.9% were on basal insulin and other hypoglycemic agents. Among the 5933 patients identified, 2.01% had at least one hospitalization for any ADE in the year before FSL initiation, compared to 0.75% (1 year) and 0.60% (2 years). Reductions in ADEs were driven by 75% fewer DKA admissions, with a 44% reduction in SH admissions. These patterns of reduced ADEs persisted after 2 years, with a further 43% reduction in DKA rates. Conclusions/Interpretation: This study emphasizes the value of the FSL system in reducing ADEs in people with T2DM in France not on intensive insulin therapy and initially treated with basal-only insulin therapy.

Hypertriglyceridemic pancreatitis and cardiac tamponade in a26-year-old woman

A26-year-old woman with type2 diabetes mellitus and discontinued intensive conventional insulin therapy was admitted to the authors' hospital with acute upper abdominal pain. Severe hypertriglyceridemia and acute pancreatitis were diagnosed. Treatment included insulin administration and plasmapheresis. On day3, the patient developed sudden haemodynamic instability and in-hospital cardiopulmonary arrest. Focused echocardiography showed pericardial effusion with right ventricular collapse. Pericardiocentesis was performed, leading to areturn of spontaneous circulation.

Pilot Trial on the Effect of 5-Aminolevulinic Acid on Glucose Tolerance in Patients with Maternally Inherited Diabetes and Deafness.

The amino acid 5-aminolevulinic acid (5-ALA) is the first heme biosynthetic precursor. The combination of 5-ALA with sodium ferrous citrate (SFC) enhances heme production, leading to increased adenosine triphosphate (ATP) production in mitochondria. We investigated whether administering 5-ALA/SFC improves glucose tolerance with an increase in insulin secretion in patients with maternally inherited diabetes and deafness (MIDD), which is characterized by an insulin secretory disorder due to impaired mitochondrial ATP production. This was a single-arm, open-label, interventional study. We prospectively administered the oral glucose tolerance test (OGTT) twice in five patients with MIDD who had received intensive insulin therapy: before and 24weeks after an administration of 5-ALA/SFC (200/232mg per day). We measured the concentrations of glucose, insulin, C-peptide, and proinsulin at fasting, and 30, 60, and 120min after glucose load in each OGTT. The primary endpoint was the changes in the area under the curve (AUC) of serum insulin from 0 to 120min during OGTT from baseline to 24weeks. The serum insulin AUC (µU/mL) during the 120-min OGTT tended to increase from baseline to 24weeks but not significantly (17.1 ± 13.7 versus 22.3 ± 13.4, p = 0.077). The plasma glucose AUC (mg/dL) during the 120-min OGTT at 24weeks was not significantly decreased; the late phase of glucose excursion from 60 to 120min was significantly decreased compared with baseline (357 ± 42 versus 391 ± 50, p = 0.041). The mean level of glycated hemoglobin (HbA1c) decreased from 8.3 ± 1.2% at baseline to 7.9 ± 0.3% at 24weeks (p = 0.36) without increasing the daily dose of insulin injections. The 24-week administration of 5-ALA/SFC did not demonstrate a significant improvement in insulin secretion in patients with MIDD. Further investigations with a larger number of patients and a placebo control group are required to clarify the potential efficacy of 5-ALA/SFC for ameliorating mitochondrial dysfunctions in MIDD. UMIN-CTR000040581 and jRCT071200025.

Preclinical exploration of combined glucagon inhibition and liver-preferential insulin for treatment of diabetes using in vitro assays and rat and mouse models

Aims/hypothesisNormalisation of blood glucose in individuals with diabetes is recommended to reduce development of diabetic complications. However, risk of severe hypoglycaemia with intensive insulin therapy is a major obstacle that prevents many individuals with diabetes from obtaining the recommended reduction in HbA1c. Inhibition of glucagon receptor signalling and liver-preferential insulin action have been shown individually to have beneficial effects in preclinical models and individuals with diabetes (i.e. improved glycaemic control), but also have effects that are potential safety risks (i.e. alpha cell hyperplasia in response to glucagon receptor antagonists and increased levels of liver triacylglycerols and plasma alanine aminotransferase activity in response to glucagon receptor antagonists and liver-preferential insulin). We hypothesised that a combination of glucagon inhibition and liver-preferential insulin action in a dual-acting molecule would widen the therapeutic window. By correcting two pathogenic mechanisms (dysregulated glucagon signalling and non-physiological distribution of conventional insulin administered s.c.), we hypothesised that lower doses of each component would be required to obtain sufficient reduction of hyperglycaemia, and that the undesirable effects that have previously been observed for monotreatment with glucagon antagonists and liver-preferential insulin could be avoided.MethodsA dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule was designed and tested in rodent models (normal rats, rats with streptozotocin-induced hyperglycaemia, db/db mice and mice with diet-induced obesity and streptozotocin-induced hyperglycaemia), allowing detailed characterisation of the pharmacokinetic and pharmacodynamic properties of the dual-acting molecule and relevant control compounds, as well as exploration of how the dual-acting molecule influenced glucagon-induced recovery and spontaneous recovery from acute hypoglycaemia.ResultsThis molecule normalised blood glucose in diabetic models, and was markedly less prone to induce hypoglycaemia than conventional insulin treatment (approximately 4.6-fold less potent under hypoglycaemic conditions than under normoglycaemic conditions). However, compared to treatment with conventional long-acting insulin, this dual-acting molecule also increased triacylglycerol levels in the liver (approximately 60%), plasma alanine aminotransferase levels (approximately twofold) and alpha cell mass (approximately twofold).Conclusions/interpretationWhile the dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule showed markedly improved regulation of blood glucose, effects that are potential safety concerns persisted in the pharmacologically relevant dose range.Graphical abstract

Efficacy and Safety of Emicizumab Prophylaxis in Patients with Acquired Hemophilia a Who Were Deemed Ineligible for Immunosuppressive Therapy: Additional Data from the Ageha Study

INTRODUCTION: Acquired hemophilia A (AHA) is a potentially fatal hemorrhagic disease caused by the appearance of autoantibodies against factor VIII (FVIII). Immunosuppressive therapy (IST) is started immediately after diagnosis to eradicate FVIII inhibitors. This leads to remission in most patients, but infections often occur as side effects, leading to death in many cases. Emicizumab is a bispecific antibody that mimics the cofactor function of activated FVIII and prevents bleeds in patients with congenital hemophilia A regardless of inhibitor status. Emicizumab prophylaxis is expected to reduce the risk of severe bleeds in patients with AHA (PwAHA), and also allow at-risk patients to consider reducing or postponing IST, which would minimize its side effects. To investigate the safety and efficacy of emicizumab in PwAHA, we are conducting an ongoing, prospective, multicenter, open-label, non-randomized, phase III study (AGEHA; JapicCTI-205151). Primary analysis results of AGEHA suggest that emicizumab prophylaxis with a new loading regimen and completion criteria has a favorable benefit-risk profile in PwAHA. However, all enrolled patients in that primary analysis (cutoff date: April 23, 2021) had received IST before starting emicizumab, and the influence of IST, especially on efficacy data, cannot be completely ruled out. Here, we present efficacy and safety data of emicizumab in PwAHA deemed ineligible for IST at enrollment, which were collected after cutoff date of the primary analysis. METHODS: AGEHA consisted of 2 cohorts: patients already undergoing or scheduled to immediately undergo IST at enrollment (Cohort 1), and patients deemed ineligible for IST at enrollment (Cohort 2). Emicizumab was administered subcutaneously at 6 mg/kg on Day 1 and 3 mg/kg on Day 2 followed by 1.5 mg/kg once weekly from Day 8. Predefined dosing completion criteria included FVIII activity >50 IU/dL. No restriction was set on IST use during the study. AGEHA was conducted in accordance with relevant ethical standards. Data from the 12 patients enrolled in Cohort 1 (Patients 1 to 12) is beyond the scope of this presentation. RESULTS: By the cutoff date for the presentation (September 10, 2021), 2 patients had been enrolled in Cohort 2, and 1 patient (Patient 13) had completed emicizumab treatment. Durations of emicizumab treatment were 7.1 weeks in Patient 13 and 16.3 weeks in Patient 14. Clinical courses of the 2 patients are shown in Figure 1. Patient 13 was an 82-year-old female who was diagnosed with AHA 6 days before enrollment. She was judged ineligible for IST because of her poor performance status and diabetes. After starting emicizumab, the bleeding symptoms immediately disappeared and her general condition dramatically improved. Following treatment with intensive insulin therapy for diabetes, the investigator judged that IST was applicable to her. IST with prednisolone and cyclophosphamide was started on Day 5 and Day 27, respectively, and then FVIII inhibitor titer decreased and FVIII activity gradually improved. Criteria for completion of emicizumab were met on Day 64. Patient 14 was a 59-year-old female with AHA of long disease duration (1009 days) who had been receiving a prophylactic regimen of activated prothrombin complex concentrate before enrollment. She was judged ineligible for IST because IST had not been effective for a long time in the past, and because IST was nearly contraindicated due to a complication of infections associated with osteonecrosis of the jaw. During the pre-treatment period, the 2 patients experienced a total of 3 treated bleeds, 1 of which was a treated major bleed in Patient 13. During the on-treatment period, no treated bleeds and no major bleeds occurred in either patient. The requirement for coagulation factor products or transfusions decreased between the pre- and on-treatment periods. Both patients experienced adverse events (AEs), all 9 of which were grade 1 or 2. One AE (rash) in Patient 13 was considered related to emicizumab, but no modification or discontinuation of emicizumab was required. No thrombotic events, serious AEs, AEs leading to study discontinuation, or anti-drug antibodies were reported. CONCLUSIONS: These results suggest that emicizumab prophylaxis with the new dosing regimen and completion criteria is safe and efficacious for PwAHA ineligible for IST. Further, efficacy under the non-influence of IST was also suggested. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Monitoring of continuous subcutaneous insulin infusion treatment in Portugal and its implications for diabetes management.

Intensive insulin therapy in the treatment of type 1 diabetes can, in place of multiple daily injections of subcutaneous insulin (MDI), be performed with continuous subcutaneous insulin infusion (CSII) systems. This method allows for better glycemic control and thus reduces the risk of complications of the disease. The aim of this study was to evaluate the results of treatment with CSII in Portugal. A retrospective analysis of the records on the national CSII platform was carried out between January 2010 and August 2021. All the registered patients are followed in certified CSII treatment centers in Portugal. Of the 7135 registered patients, 3807 were excluded due to absence of monitoring data. The reasons for treatment were analyzed and a comparison was made between patients with and without CSII. The statistical significance considered was α < 0.05. A total of 3328 patients were included in the study, 1136 under MDI and 2192 under CSII. The main reasons for CSII use were marked glycemic variability (25%) and HbA1c greater than 7% (23%). Patients under CSII had a lower HbA1c (7.7 ± 1.0% vs. 8.0 ± 1.5%, p < 0.001), as well as a lower frequency of episodes of severe hypoglycemia (1.4 vs. 3.3 per 100 patient-years, p < 0.001), and ketoacidosis (1 vs. 2.4 per 100 patient-years, p < 0.001). The present analysis validates the advantage of using CSII in metabolic control and reduction of acute complications of type 1 diabetes, both severe hypoglycemia and ketoacidosis, in the Portuguese population. CSII therapy is classically associated with an increased risk of ketoacidosis; however, in experienced centers and adequate patient education, the opposite is found.

Assessment of the spectrum of depression and bipolarity in patients with type 1 diabetes.

The aim of the study was to check the prevalence of unipolarity (depression), bipolarity, as well as the quality of sleep and temperament traits in patients with type 1 diabetes (T1DM) who are provided with optimal conditions of diabetes care and to identify possible risk factors connected with affective traits. Out of the 107 T1DM patients, 78 (54 females, 24 males) were included for the analysis (HbA1c [%] 7.11±1.0, BMI [kg/m2 ] 25.3±5.6; Years of disease duration [N] 13.7±8.3). The patients filled in a set of questionnaires during their regular visit to the outpatient clinic. Three patients from the whole group were on intensive insulin therapy with Multiple Daily Injections (MDI) and Self-Monitoring of Blood Glucose (SMBG), all the rest were on various types of personal insulin pumps (years on insulin pump [N] 9.1±4.5). All the patients were on regular diabetologist care, with regular visits in a Centre for Advanced Technologies in Diabetes (at least every 6months). In QIDS-S (full explanation and abbreviation26 patients (33.8%) were screened positive for depression, in PHQ (full explanation and ab 57.7% of the patients (45 patients) had symptoms of depression (age was negatively correlated with PHQ score [r=-0.26; p=0.023]). In CES-D 16 (20%) of the patients assessed their present affect as depressed. None of the analysed clinical variables correlated with depression scores. In the Mood Disorder Questionnaire (MDQ), 16 patients reported having symptoms of bipolarity (20.5% vs. 79.5%). Hypomania Checklist (HCL) analysis indicated 10 patients with bipolar traits (>14) (14.9% vs. 85.1%). None of the analysed clinical variables correlated with HCL results. 11.5% of patients were indicated to be of morning type. Morningness was more often seen in younger patients (r=0.39; p=0.001). As many as 46.6% declared that they had poor sleep quality. The temperament traits analysis correlated with clinical parameters: Cyclothymic temperament trait was negatively correlated with age (r=-0.30; p=0.007) and positively with HbA1c level (r=0.30; p=0.025). Hyperthymic temperament was positively correlated with (BMI r=0.28; p=0.016). Quality of sleep was highly correlated with depressive symptoms CESD (r=0.61, p=0.001), PHQ Score (r=0.62; p=0.001), QISD (r=0.68; p=0.001) and bipolarity MDQ (p=0.50, p=0.001) and HCL (r=0.42, p=0.001). In addition, QIDS was shown to be correlated with the following features of temperament: depressive factor (r=0.41; p=0.001), irritable factor (r=0.53; p=0.001), cyclothymic factor (r=0.59; p=0.001), anxious factor (r=0.58, p=0.001). The prevalence of affective disorders and poor sleep quality in the examined T1DM patients was much higher than in the general population. Even if the patients have in general good glycaemic control, their mental health condition should not be neglected. Well organised cooperation between patients, diabetologists, psychiatrists and psychotherapists is needed (Clinical Trials Identifier: NCT04616391).

RF28 | PSUN184 New American Diabetes Association Definition of Diabetes Remission Does not Correlate with Time in Remission in Ketosis-Prone Diabetes

Abstract Introduction Approximately 50% of obese Black patients presenting with diabetic ketoacidosis (DKA) at new-onset of diabetes have immunologic and metabolic features of type 2 diabetes, also called ketosis-prone diabetes (KPDM). With intensive insulin treatment, ∼70% have improvements in beta-cell function and insulin sensitivity and achieve diabetes remission. The definition of remission in KPDM has been heterogeneous with our group defining remission as HbA1c &amp;lt; 7%, fasting blood glucose (BG) &amp;lt; 130 mg/dl and random BG &amp;lt; 180 mg/dl while off insulin injections for at least 1 week. In 2021, the American Diabetes Association (ADA) consensus recommended that the definition of diabetes remission as HbA1c &amp;lt; 6.5% or a fasting BG &amp;lt; 126 mg/dl while off medications for &amp;gt; 3 months. We hypothesized that patients who achieved the more intensive ADA definition of remission (HbA1c &amp;lt; 6.5%) will have longer time in remission compared to our previous non-intensive definition of remission (HbA1c 6.5-7%). Methods Forty obese Black patients (BMI ≥ 28 kg/m2) with newly diagnosed diabetes and unprovoked DKA had intensive insulin therapy until HbA1c &amp;lt; 7% without insulin therapy for at least one week. Patients were followed until hyperglycemia relapse (HbA1c &amp;gt; 6.5% or fasting BG &amp;gt; 126 mg/dl and/or requiring antidiabetic medications). Baseline characteristics and clinical time to hyperglycemia relapse-free survival were compared between patients with HbA1c &amp;lt; 6.5 (n= 24) and HbA1c 6.5-7% (n=16). Results Age, sex, family history of type 2 diabetes, BMI, HbA1C, weight change and insulin doses received between the two groups (HbA1c &amp;lt; 6.5 vs 6.5-7%) did not differ significantly. Median follow-up overall was 404 days with a range of 7-1099 days. In patients that experienced a hyperglycemia relapse, bivariate analysis shows that median days to hyperglycemia relapse was longer in HbA1c &amp;lt; 6.5% (411 days, range (17-804) vs HbA1c 6.5-7% (126 days, range (7-391), p= 0.05) but without a statistical difference. Survival analysis showed that time in remission did not statistically differ between the two groups (log rank, p=0.6853). Conclusion In obese Black patients with KPDM, HbA1c &amp;lt; 6.5% at time of insulin discontinuation does not prolong diabetes compared to patients that achieved HbA1c 6.5-7%, suggesting that predictors of prolonged remission may differ among diverse populations with diabetes. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:44 p.m. - 12:49 p.m.

PSUN92 Type 1 Diabetes and Obesity: The Overlooked Epidemic

Abstract Introduction The type 1 diabetes (T1D) cohort in the DCCT study (1983-1989) began with a 1.3% prevalence of obesity that climbed to 18.6% with intensive insulin therapy, and subsequently increased further to a prevalence of 31% in the EDIC observational study (2005).1, 2 The aim of this report was determine the prevalence of overweight and obesity in T1D patients seen at our institution. Methods The electronic health record system was used to create a cross-sectional summary of patients with T1D seen on or before the index date (8/12/2021). Patients were included if they were ≥18 years of age, with at least two outpatient encounters with primary care provider or endocrinologist within the past 18 months, along with an active diagnosis of T1D (ICD-9 or -10 code) on their problem list, or at least 2 encounter diagnosis for T1D in the past 18 months, or documentation of a positive glutamic acid decarboxylase (GAD)-65 antibody titer. Categorical and continuous variables were summarized using N (%) and median (IQR), respectively. Results A total of 2,165 patients were identified. The population was 51% female and 86% Caucasian, with median age of 44 years (33, 55). The median A1C (%) was 7.9% (6.9, 9.4), median income $63,381 ($49,611, $78,367), and insurance coverage was 50% commercial, 11% Medicaid, 23% Medicare, and 16% other. While the median BMI (kg/m2) was 26.7 (23.6, 30.5), the % with a BMI 25-29.9 or ≥30 were 37% and 28%, respectively. Conclusion There is a high prevalence of overweight and obesity in patients with T1D. While the prevalence of these comorbidities is less than what is observed in the general population, 31.1 and 42.4%, respectively (2017–2018)3, it signifies that the T1D population still has a heavy burden of these comorbidities that is contradictive to the stereotype T1D patients are lean. These results stand in stark comparison with the starting 1.3% prevalence of obesity in the DCCT study. Studies directed at the burden of overweight and obesity in T1D patients are necessary to optimize the treatment and prevention of these comorbidities. Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): 977–986. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005 Dec 22;353(25): 2643-53. doi: 10.1056/NEJMoa052187. PMID: 16371630; PMCID: PMC2637991. Centers for Disease Control and Prevention. Obesity and Overweight. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm. Last visited 1/12/2022. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Cost-Effectiveness Analysis of Flash Glucose Monitoring System for People with Type 2 Diabetes Receiving Intensive Insulin Treatment.

AimsFor people with type 2 diabetes (T2D) on intensive insulin therapy, the use of flash continuous glucose monitoring (“flash monitoring”) is associated with improved average glucose control and/or reduced hypoglycemic exposure. This study assessed the cost-effectiveness of flash monitoring versus traditional blood glucose monitoring (BGM) in people with T2D using intensive insulin in the United Kingdom (UK).MethodsThe IQVIA CORE Diabetes Model (IQVIA CDM; v9.0) was used to analyze the impact of flash monitoring versus BGM over a 40-year time horizon from the UK payer perspective. Model inputs included baseline characteristics, intervention effects, resource utilization, costs, and utilities, based on recently published literature and national databases. UK National Health Service reimbursed costs of flash monitoring and BGM were used. An intervention-related health utility was obtained from a time trade-off study. Alternative scenarios were explored to assess the impact of key assumptions on base case results.ResultsIn base-case analysis, flash monitoring compared with BGM resulted in an incremental cost of £5781 and an additional 0.47 quality-adjusted life years (QALYs). This provides an incremental cost-effectiveness ratio (ICER) of £12,309/QALY. HbA1c and the intervention-related health utility were the key drivers of differentiation. All scenario analyses, including different discount rates, time horizons, effects on HbA1c and on the intervention-related health utility, as well as glycemic emergencies, generated ICERs of less than £20,000 per QALY.ConclusionsThe consistent results across base case and a range of scenario analyses indicate that long-term flash glucose monitoring use is cost-effective compared with BGM in a UK population of T2D on intensive insulin therapy based on updated clinical effects and a cost-effectiveness threshold of £20,000–30,000 per QALY. Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01325-w.

ВОЗМОЖНОСТИ ПРИМЕНЕНИЯ ТЕЛЕМЕДИЦИНСКИХ ТЕХНОЛОГИЙ ПРИ НАБЛЮДЕНИИ ДЕТЕЙ С ВПЕРВЫЕ ВЫЯВЛЕННЫМ САХАРНЫМ ДИАБЕТОМ 1-го ТИПА

Effective control of type 1 diabetes mellitus (DM1) is a difficult and burdensome task for the patient and/or his/her parents/caretakers as well as healthcare professionals. Another approach to improve glycemic control could be the use of telemedicine. The purpose of this study was to evaluate the possibility and effectiveness of remote monitoring and education of children with newly diagnosed DM1. Materials and methods of the research: a multicenter prospective open uncontrolled experimental clinical study was conducted between Oct. 2020 and Feb. 2022. The study was conducted in the two clinical centers as follows: Endocrinology Research Centre of the Ministry of Healthcare of Russia; and M.F. Vladimirsky Moscow Oblast Regional Scientific and Research Clinical Institute (MONIKI), both located in Moscow, Russia. Children aged 1 to 18 years old diagnosed with DM1 within 12 weeks prior to inclusion in the study and receiving intensified insulin therapy were invited to participate in the study. Results: the study included 220 children with DM1 living overall the Moscow Oblast region aged 1 to 18 years old (median age 8.1 (5.1–10.9) years old), of which 48% were male and 52% female. During the period of remote monitoring 1062 remote consultations were concluded as follows: 12% via videoconferencing, 64% via audio, and 34% via specialized mobile app. The duration of consultations averaged as follows: 14.9, 20.7 and 14.8 minutes for consultations via videoconferencing, audio and mobile app, respectively. Glycated hemoglobin (HbA1c) level was one of the main indicators for evaluating the effectiveness of participation of children with DM1 in the program of remote observation and education. HbA1c values decreased statistically significantly by the end of the study by –5.0% (p&lt;0.001). As a result, there was a statistically significant (p&lt;0.001) (+55%) increase in the number of children with HbA1c level of less than 7%, thus, most of the children reached the target indicators of glycemic control. In addition to indicators of glycemic control, indicators of the quality of life and the level of distress in parents of children with DM1 were analyzed using specialized questionnaires as supplemental criteria reflecting the clinical effectiveness of remote monitoring. After the first month of participation parents/caretakers showed a statistically significant decrease in the level of stress associated with DM1 in their children (p=0.033), while at the same time the level returned to baseline values (p=0.201) by the end of the project. Conclusion: the outpatient monitoring of children with newly diagnosed DM1 using telemedicine and specialized mobile products (“niche apps”) is an effective (in terms of glycemic control) addition to traditional dispensary monitoring which increases the accessibility of medical care and its convenience to the patients and the quality of life for pediatric patients and their parents/caretakers.

Effect of intensive insulin therapy on inflammatory response after cardiac surgery using bedside artificial pancreas: A propensity score-matched analysis.

Perioperative hyperglycemia leads to poor postoperative clinical outcomes, including compromised immune function, cardiovascular events, and mortality. The optimal perioperative blood glucose levels during cardiac surgery remain unclear. A closed-loop glycemic control system (artificial pancreas, target blood glucose range:120-150 mg/dl) prevents postoperative inflammatory response more effectively than conventional insulin therapy (<200 mg/dl). However, the clinical effects of intensive insulin therapy with strict glycemic control (80-110 mg/dl) are controversial. This study aimed to determine whether intensive insulin therapy would further suppress postoperative inflammatory reactions. This study analyzed 262 patients who underwent cardiovascular surgery with cardiopulmonary bypass. The patients were divided into two groups according to their target blood glucose range: 80-110 mg/dl and 120-150 mg/dl. The primary outcome was the difference in the C-reactive protein levels between the two groups. Propensity score matching resulted in 95 patients in each group based on their covariates. There was no difference in the postoperative maximum C-reactive protein levels between the two groups (14.81 ± 5.93 mg/dl vs. 14.34 ± 5.52 mg/dl; p =0.571) following propensity score matching. Hypoglycemia did not occur during intensive insulin therapy. Intensive insulin therapy following cardiac surgery with cardiopulmonary bypass did not demonstrate significant advantages in the suppression of postoperative inflammatory reactions compared to that with mild glycemic control. However, intensive insulin therapy using an artificial pancreas was found to be safe, with no hypoglycemic events.

Automated insulin delivery: benefits, challenges, and recommendations. A Consensus Report of the Joint Diabetes Technology Working Group of the European Association for the Study of Diabetes and the American Diabetes Association.

A technological solution for the management of diabetes in people who require intensive insulin therapy has been sought for decades. The last 10 years have seen substantial growth in devices that can be integrated into clinical care. Driven by the availability of reliable systems for continuous glucose monitoring, we have entered an era in which insulin delivery through insulin pumps can be modulated based on sensor glucose data. Over the past few years, regulatory approval of the first automated insulin delivery (AID) systems has been granted, and these systems have been adopted into clinical care. Additionally, a community of people living with type 1 diabetes has created its own systems using a do-it-yourself approach by using products commercialised for independent use. With several AID systems in development, some of which are anticipated to be granted regulatory approval in the near future, the joint Diabetes Technology Working Group of the European Association for the Study of Diabetes and the American Diabetes Association has created this consensus report. We provide a review of the current landscape of AID systems, with a particular focus on their safety. We conclude with a series of recommended targeted actions. This is the fourth in a series of reports issued by this working group. The working group was jointly commissioned by the executives of both organisations to write the first statement on insulin pumps, which was published in 2015. The original authoring group was comprised by three nominated members of the American Diabetes Association and three nominated members of the European Association for the Study of Diabetes. Additional authors have been added to the group to increase diversity and range of expertise. Each organisation has provided a similar internal review process for each manuscript prior to submission for editorial review by the two journals. Harmonisation of editorial and substantial modifications has occurred at both levels. The members of the group have selected the subject of each statement and submitted the selection to both organisations for confirmation.

Insulin edema after initiation of hybrid closed-loop insulin pump therapy with continuous glucose monitoring: a case report

BackgroundInsulin edema is a rare complication which can present after initiation or intensification of insulin therapy in people with diabetes. Initiation of closed-loop hybrid insulin pump therapy can result in rapid improvement in glycemic control for people with diabetes. We present a case in which transition to a closed-loop hybrid insulin pump system, followed by significant improvement in glycemic control, led to development of insulin edema in a person with type 1 diabetes.Case presentationWe present a 51-year-old woman with type 1 diabetes of 16 years duration, on insulin pump therapy for more than 10 years, who presented for follow-up 7 weeks after transitioning to a hybrid closed-loop insulin pump system with continuous glucose monitoring (CGM). She complained of weight gain and bilateral lower extremity edema which had started two weeks after the change in pump modality. Laboratory studies and echocardiogram did not reveal any etiology of the acute edema. HbA1c was 3.3% lower than the previous measurement 15 weeks earlier, and there was a significant increase in the daily total insulin dose. With exclusion of other causes of acute edema, the patient was diagnosed with insulin edema and started on hydrochlorothiazide. On follow up, her lower extremity edema significantly improved although her weight did not return to baseline.ConclusionTo our knowledge, this is the first case of insulin edema reported in a person with type 1 diabetes using CGM and a hybrid closed-loop insulin pump system. The increase in total daily insulin dose, rapid improvement of glycemic control, and lack of hypoglycemic episodes were important factors to consider in evaluation of this case. Use of hybrid closed-loop systems can help achieve rapid improvement in glycemic control in people with diabetes. This case suggests that consideration should be given to adjusting initial blood glucose targets when starting these remarkable new technologies in people with baseline poor glycemic control.

Urinary Angiotensinogen in Patients With Type 1 Diabetes With Microalbuminuria: Gender Differences and Effect of Intensive Insulin Therapy

Angiotensinogen (AOG) is the precursor of peptides of the renin angiotensin system (RAS). Because insulin up-regulates transcriptional factors that normally repress kidney AOG synthesis, we evaluated urinary AOG (uAOG) in patients with type 1 diabetes (T1D) and microalbuminuria who are receiving either intensive or conventional insulin therapy. Urine samples from participants of the Diabetes Control and Complications Trial (DCCT) were used for the following: (i) uAOG/creatinine measurements in 103 patients with microalbuminuria and 103 patients with normoalbuminuria, matched for age, gender, disease duration, and allocation to insulin therapy; and (ii) uAOG/creatinine measurements from patients with microalbuminuria allocated to intensive insulin therapy (n= 58) or conventional insulin therapy (n= 41) after 3 years on each modality. uAOG was higher in patients who started with microalbuminuria than in those with normoalbuminuria (6.65 vs. 4.0 ng/mg creatinine, P< 0.01). uAOG was higher in females than in males with microalbuminuria (11.7 vs. 5.4 ng/mg creatinine, P= 0.015). uAOG was lower in patients with microalbuminuria allocated to intensive insulin therapy than in conventional insulin therapy (3.98 vs. 7.42 ng/mg creatinine, P< 0.01). These differences in uAOG were observed though albumin excretion rate (AER) was not significantly different. In patients with T1D and microalbuminuria, uAOG is increased and varies with gender and the type of insulin therapy independently of AER. This suggests that AOG production is increased in females and it is decreased by intensive insulin therapy. The reduction in uAOG with intensive insulin therapy, by kidney RAS downregulation, may contribute to the known renoprotective action associated with intensive insulin and improved glycemic control.

Clinical relevance of glucose metrics during the early brain injury period after aneurysmal subarachnoid hemorrhage: An opportunity for continuous glucose monitoring.

Hyperglycaemia, hypoglycaemia and higher glucose variability during the Early Brain Injury (EBI) period of aneurysmal subarachnoid hemorrhage (aSAH) have been associated with poor clinical outcome. However, it is unclear whether these associations are due to direct glucose-driven injury or if hyperglycaemia simply acts as a marker of initial severity. Actually, strict glucose control with intensive insulin therapy has not been demonstrated as an effective strategy for improving clinical outcomes after aSAH. Currently published studies describing an association between hyperglycaemia and prognosis in aSAH patients have been based on isolated glucose measurements and did not incorporate comprehensive dynamic evaluations, such as those derived from subcutaneous continuous glucose monitoring devices (CMG). Arguably, a more accurate knowledge on glycaemic patterns during the acute phase of aSAH could increase our understanding of the relevance of glycaemia as a prognostic factor in this disease as well as to underpin its contribution to secondary focal and diffuse brain injury. Herein, we have summarized the available evidence on the diagnostic and prognostic relevance of glucose metrics during the acute phase of cerebrovascular diseases, focusing in the EBI period after aSAH. Overall, obtaining a more precise scope of acute longitudinal glucose profiles could eventually be useful for improving glucose management protocols in the setting of acute aSAH and to advance toward a more personalized management of aSAH patients during the EBI phase.

Omnipod® Insulin Management System - "patch-pump", as a breakthrough in the treatment of type 1 diabetes

Introduction: There are 425 million adults with diabetes worldwide, 10% of whom have type 1 diabetes. The treatment of choice in this group of patients is insulin delivery. In order to avoid disease-related metabolic disorders, insulin therapy should be planned so that their risk is minimized. This often involves multiple subcutaneous deliveries throughout the day. In order to improve patient satisfaction and comfort, , "smart pumps" have been developed. OmniPod® is the first commercially available pump of this type. Aim of the study: The purpose of our work was to present an innovative form of treatment for type 1 diabetes, to demonstrate the advantages, disadvantages and results of treatment using it. Methods and materials: A literature review was conducted in the PubMed database, using the key words: "diabetes type 1"; "diabetes mellitus"; "OmniPod®"; "insulin"; Results: OmniPod® improves glycemic control and glycated hemoglobin (HbA1c) values over traditional therapies. The algorithm used in the pump ensures normal glycemic ranges throughout the day, without the risk of prolonged episodes of hypo- and hyperglycemia. It improves the quality of life (QOL) index thanks to, among other things, water resistance, lack of difficulties during sleep in contrast to conventional insulin pumps. Conclusion: OmniPod® significantly improves users' glycemic and HbA1c control. It allows users to forgo conventional insulin pumps or intensive insulin therapy by raising QOL and increasing patients' sense of proper disease control. Further research should be inclined to evaluate the utility of OmniPod® in other types of diabetes, as well as on the application of the technology in other disease entities.

Insidious enemy - phaeochromocytoma. Can diabetes be cured?

We present the case of a 54-year-old patient with long-term type 2 diabetes, treated with intensive insulin therapy, who was considered to be ordinary diabetes. In a random imaging examination it turned out to be a phaeochromocytoma. The patient underwent surgical treatment. It turned out that after the surgery, the diabetes resolved. It is a casuistic curiosity that the patient was "cured" of the disease after diagnosis and treatment for pheochromocytoma, and on the second day after the surgery. It is also a valuable guide when looking for all possible causes of "secondary" diabetes.

Recurrent hypoglycemia increases hepatic gluconeogenesis without affecting glycogen metabolism or systemic lipolysis in rat

IntroductionRecurrent hypoglycemia (RH) impairs secretion of counterregulatory hormones. Whether and how RH affects responses within metabolically important peripheral organs to counterregulatory hormones are poorly understood. ObjectiveTo study the effects of RH on metabolic pathways associated with glucose counterregulation within liver, white adipose tissue and skeletal muscle. MethodsUsing a widely adopted rodent model of 3-day recurrent hypoglycemia, we first checked expression of counterregulatory hormone G-protein coupled receptors (GPCRs), their inhibitory regulators and downstream enzymes catalyzing glycogen metabolism, gluconeogenesis and lipolysis by qPCR and western blot. Then, we examined epinephrine-induced phosphorylation of PKA substrates to validate adrenergic sensitivity in each organ. Next, we measured hepatic and skeletal glycogen content, degree of breakdown by epinephrine and abundance of phosphorylated glycogen phosphorylase under hypoglycemia and that of phosphorylated glycogen synthase during recovery to evaluate glycogen turnover. Further, we performed pyruvate and lactate tolerance tests to assess gluconeogenesis. Additionally, we measured circulating FFA and glycerol to check lipolysis. The abovementioned studies were repeated in streptozotocin-induced diabetic rat model. Finally, we conducted epinephrine tolerance test to investigate systemic glycemic excursions to counterregulatory hormones. Saline-injected rats served as controls. ResultsRH increased counterregulatory hormone GPCR signaling in liver and epidydimal white adipose tissue (eWAT), but not in skeletal muscle. For glycogen metabolism, RH did not affect total content or epinephrine-stimulated breakdown in liver and skeletal muscle. Although RH decreased expression of phosphorylated glycogen synthase 2, it did not affect hepatic glycogen biosynthesis during recovery from hypoglycemia or after fasting-refeeding. For gluconeogenesis, RH upregulated fructose 1,6-bisphosphatase 1 and monocarboxylic acid transporter 1 that imports lactate as precursor, resulting in a lower blood lactate profile during hypoglycemia. In agreement, RH elevated fasting blood glucose and caused higher glycemic excursions during pyruvate tolerance test. For lipolysis, RH did not affect circulating levels of FFA and glycerol after overnight fasting or upon epinephrine stimulation. Interestingly, RH upregulated the trophic fatty acid transporter FATP1 and glucose transporter GLUT4 to increase lipogenesis in eWAT. These aforementioned changes of gluconeogenesis, lipolysis and lipogenesis were validated in streptozotocin-diabetic rats. Finally, RH increased insulin sensitivity to accelerate glucose disposal, which was attributable to upregulated visceral adipose GLUT4. ConclusionsRH caused metabolic adaptations related to counterregulation within peripheral organs. Specifically, adrenergic signaling was enhanced in liver and visceral fat, but not in skeletal muscle. Glycogen metabolism remained unchanged. Hepatic gluconeogenesis was augmented. Systemic lipolysis was unaffected, but visceral lipogenesis was enhanced. Insulin sensitivity was increased. These findings provided insights into mechanisms underlying clinical problems associated with intensive insulin therapy, such as high gluconeogenic flux and body weight gain.

국내 인슐린 주입기기 요양비 지원 정책 현황 및 개선 방안

Intensive insulin therapy is the primary treatment option for patients with type 1 and uncontrolled type 2 diabetes. Insulin pump therapy and multiple daily insulin injections (MDI) are the principal methods of intensive insulin therapy. The clinical utility of an insulin pump is generally greater than an MDI regimen. An artificial pancreas, which is an insulin pump with an integrated continuous glucose monitor (CGM), has recently been introduced on the market with emerging clinical evidence. Although it may offer clinical benefits and reduce the self-management burden among patients with diabetes, its potential for inappropriate use and unaffordability are the major barriers to its universal utilization. Despite the medical assistance program offered by the Korean National Healthcare System, which provides coverage for consumables and devices for diabetes treatment, some patients cannot afford to use an advanced insulin delivery system (i.e., the artificial pancreas). Under the current reimbursement policy, the healthcare system considers an insulin pump and a CGM as separate items for regulatory and reimbursement purposes. In other words, the artificial pancreas is categorized as an insulin pump and reimbursed at the same amount as a traditional insulin pump. The fundamental operating function may be the same between the artificial pancreas and a traditional insulin pump; however, there should be a different reimbursement pathway to make a novel category for the artificial pancreas instead of categorizing it under insulin pumps and to differentiate pricing based on the comparative (cost-) effectiveness among insulin delivery devices. Other countries such as the United States, the United Kingdom, Germany, and France are moving toward rapid and universal adoption of the artificial pancreas supported by their clinical governance and regulatory affairs. In this review, we highlight the need to improve the accessibility and affordability of advanced diabetes technology by discussing the current issues in the reimbursement policy that limit the universal use of advanced insulin delivery devices in Korea.