Exogenous Insulin Research Articles

A Changed Gut Microbiota Diversity Is Associated With Metabolic Improvements After Duodenal Mucosal Resurfacing With Glucagon-Like-Peptide-1 Receptor Agonist in Type 2 Diabetes in a Pilot Study.

The gut microbiota influences and interacts with the host metabolism through effects on nutrient metabolism and digestion. Duodenal Mucosal Resurfacing (DMR) is a novel endoscopic procedure involving duodenal mucosal ablation by the use of hydrothermal energy. DMR, when combined with a glucagon-like peptide-1 receptor agonist (GLP-1RA), resulted in discontinuation of exogenous insulin treatment in 69% of patients with insulin dependent type 2 diabetes mellitus (T2DM) in the INSPIRE study. These patients also experienced improved glycaemic control and metabolic health. We thus investigated if these clinical effects were associated with a change in gut microbiota alpha and beta diversity. Faecal samples from the 16 patients were obtained for Illumina shotgun sequencing at baseline and 3 months after DMR. We assessed alpha and beta diversity of the gut microbiota in these samples and analysed its correlations with changes in HbA1c, body weight, and liver MRI proton density fat fraction (PDFF). HbA1c correlated negatively with alpha diversity (p=0.011, rho: -0.62) whereas changes in PDFF correlated significantly with beta diversity (p=0.036, rho: 0.55) 3 months after initiation of the combined intervention. These correlations with metabolic parameters were observed despite finding no change in gut microbiota diversity at 3 months post DMR. The correlation between gut microbiota richness (alpha diversity) and HbA1c as well as the change in PDFF and changed microbiota composition (beta diversity) suggests that changed gut microbiota diversity is associated with metabolic improvements after DMR in combination with glucagon-like-peptide-1 receptor agonist in type 2 diabetes. Larger controlled studies are however needed to find causal links between DMR with GLP-1RA, the gut microbiota, and improvements in metabolic health.

Intraportal Islet Autotransplantation Independently Improves Quality of Life After Total Pancreatectomy in Patients With Chronic Refractory Pancreatitis.

To determine if islet autotransplantation (IAT) independently improves the quality of life (QoL) in patients after total pancreatectomy and islet autotransplantation (TP-IAT). TP-IAT is increasingly being used for intractable chronic pancreatitis. However, the impact of IAT on long-term islet function and QoL is unclear. TP-IAT patients at our center >1 year after TP-IAT with ≥1 Short Form-36 QoL measure were included. Patients were classified as insulin-independent or insulin-dependent, and as having islet graft function or failure by C-peptide. The associations of insulin use and islet graft function with QoL measures were analyzed by using a linear mixed model, accounting for time since transplant and within-person correlation. Among 817 islet autograft recipients, 564 patients [median (interquartile range) age: 34 (20, 45) years, 71% female] and 2161 total QoL surveys were included. QoL data were available for >5 years after TP-IAT for 42.7% and for >10 years for 17.3%. Insulin-independent patients exhibited higher QoL in 7 of 8 subscale domains and for Physical Component Summary and Mental Component Summary scores ( P <0.05 for all). Physical Component Summary was 2.91 (SE=0.57) higher in insulin-independent patients ( P <0.001). No differences in QoL were observed between those with and without graft function, but islet graft failure was rare (15% of patients). However, glycosylated hemoglobin was much higher with islet graft failure. QoL is significantly improved when insulin independence is present, and glycosylated hemoglobin is lower with a functioning islet graft. These data support offering IAT, rather than just performing total pancreatectomy and treating with exogenous insulin.

Ultrasound-Triggered On-Demand Insulin Release for Diabetes Mellitus Treatment.

Exogenous insulin (INS) is successfully used for controlling glucose in diabetic patients. Although frequent INS injections can overcome hyperglycemia, they are both painful and inconvenient. Herein, we report an ultrasound-regulated INS release platform (INS-PPIX@ER hydrogel) that allows for remotely regulated on-demand INS release and minimizes pain. In this system, protoporphyrin IX (PPIX)-containing erythrocytes (ERs) served as an INS reservoir, an injectable peptide hydrogel provided strong protection for the ERs, and INS release was regulated using ultrasound. This particular INS release behavior was triggered by increased production of reactive oxygen species (ROS) by PPIX from the PPIX-loaded ERs under ultrasound irradiation. The ROS then interacted with the phospholipid bilayer of the ERs, thereby opening the stomata of the INS-PPIX@ER and releasing INS. INS-PPIX@ER hydrogels could control hyperglycemia within 2 h and maintained normal blood glucose levels for up to 3 days. This effective remote approach allowed closed-loop drug release spatiotemporally without causing any pain and injury. Our findings could serve as a powerful tool for constructing a precisely controlled release system.

The impact of Rhodiola rosea on biomarkers of diabetes, inflammation, and microbiota in a leptin receptor-knockout mouse model

Type 2 diabetes is the most prevalent endocrine disease in the world, and recently the gut microbiota have become a potential target for its management. Recent studies have illustrated that this disease may predispose individuals to certain microbiome compositions, and treatments like metformin have been shown to change gut microbiota and their associated metabolic pathways. However, given the limitations and side effects associated with pharmaceuticals currently being used for therapy of diabetes, there is a significant need for alternative treatments. In this study, we investigated the effects of a root extract from Rhodiola rosea in a Leptin receptor knockout (db/db) mouse model of type 2 diabetes. Our previous work showed that Rhodiola rosea had anti-inflammatory and gut microbiome-modulating properties, while extending lifespan in several animal models. In this study, treatment with Rhodiola rosea improved fasting blood glucose levels, altered the response to exogenous insulin, and decreased circulating lipopolysaccharide and hepatic C-reactive protein transcript levels. We hypothesize that these changes may in part reflect the modulation of the microbiota, resulting in improved gut barrier integrity and decreasing the translocation of inflammatory biomolecules into the bloodstream. These findings indicate that Rhodiola rosea is an attractive candidate for further research in the management of type 2 diabetes.

Gender Difference in Type 1 Diabetes: An Underevaluated Dimension of the Disease

Gender difference in all fields of medicine and biology has recently become a topic of great interest. At present, most studies report gender differences in their secondary analysis; however, this information receives scant attention from clinicians, and is often overwhelmed by press trumpeting the overall main positive results. Furthermore, and more importantly, any statistical evaluation of results obtained without specific and careful planning in the study for the topic of research is probably worthless. There are few studies in animals, but these are not typically useful because of the different biology, pharmacodynamics and pharmacokinetics compared to humans. Type 1 diabetes is a disease where gender difference can be easily evaluated. Irrespective of the cause of the loss of pancreatic beta-cell function, the common denominators of all forms of type 1 diabetes are the absence of circulating insulin and a reduction in peripheral insulin sensitivity leading to exogenous injections being required. Consequently, exogenous insulin infusion, with any of the widely used research tools, such as the insulin–glucose clamp, can be easily used to evaluate gender difference. Female patients with type 1 diabetes have many factors that impact glucose level. For example, the hormones that drive the ovulatory/menstrual cycle and the connected change at the time of the menopause have a role on insulin action; thus, one should expect great research emphasis on this. On the contrary, there is a dearth of data available on this topic, and no pump producer has created a gender-specific insulin infusion profile. Patients are usually approached on the basis of their diagnosis. This review is intended to focus on personalized treatment, more specifically on gender, according to the modern way of thinking.

Influence of Insulin Receptor Single Nucleotide Polymorphisms on Glycaemic Control and Formation of Anti-Insulin Antibodies in Diabetes Mellitus.

Single nucleotide polymorphisms (SNPs) in insulin and insulin receptor genes may influence the interaction between the two molecules, as may anti-insulin antibodies (IAs), commonly found in patients with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) treated with exogenous insulin. We examined the impact of two SNPs in the human insulin gene (INS), rs3842752 and rs689, and two in the insulin receptor gene (INSR) rs2245649 and rs2229429, on disease susceptibility, glycaemic control, and IAs formation in 100 T1D patients and 101 T2D patients treated with insulin. 79 individuals without diabetes were typed as healthy controls. The minor alleles of rs3842752 and rs689 in INS protected against T1D (OR: 0.50, p = 0.01 and OR: 0.44; p = 0.002, respectively). The minor alleles of both rs2245649 and rs2229429 in INSR were risk factors for poor glycaemic control (HbA1c ≥ 80 mmol/mol) in T1D (OR: 5.35, p = 0.009 and OR: 3.10, p = 0.01, respectively). Surprisingly, the minor alleles of rs2245649 and rs2229429 in INSR associated strongly with the absence of IAs in T1D (OR = 0.28, p = 0.008 and OR = 0.30, p = 0.002, respectively). In conclusion, the minor alleles of the investigated INS SNPs protect against T1D, and the minor alleles of the investigated INSR SNPs are associated with poor glycaemic control and the absence of IAs in T1D.

112-OR: Metabolic Outcomes One Year after Total Pancreatectomy with Islet Autotransplantation after Early Pump Initiation

Background: We previously published that insulin pump initiation immediately after IV insulin therapy was associated with improved post-surgical glycemic outcomes compared to multiple daily injections (MDI) in pediatric patients following total pancreatectomy with islet autotransplantation (TPIAT) . We investigated metabolic outcomes of this population at 1 year post-TPIAT to assess if the improved outcomes in the early pump group were sustained over time. Methods: We retrospectively reviewed 40 patients post-TPIAT previously studied at days post-surgery (14 used MDI and 26 used pump therapy immediately post-ICU, all discharged on pump therapy) . Data analyzed included: demographics, islet equivalents per kilogram (IEQ/kg) transplanted, exogenous insulin use, and baseline vs. 1 year (via mixed meal testing) HgA1C, fasting glucose, insulinogenic index and area under the curve (AUC) for insulin and c-peptide. Results: More patients were off insulin at 1 year in the early pump group compared to the MDI group (43% vs. 14%, p=0.08) . Of all patients off insulin, 100% of the early pump users weaned off by 6 months post-TPIAT compared to 30% of the MDI users. Two known variables associated with favorable insulin outcomes, lower age and higher IEQ/kg were not significantly different between groups. Fasting glucose was lower in the early pump group compared to the MDI group (median 97.5 vs. 122 mg/dL, p=0.01) while AUC c-peptide was greater in early pump users at 1 year post-TPIAT but did not reach significance (median 65.3 vs. 49.5 ng/mL x minutes, p=0.07) . Other metabolic outcomes did not differ between groups. Conclusion: Despite lower median age and higher IEQ/kg in the MDI group, the early pump group had a lower fasting glucose. Though not significant, the early pump group had a higher proportion off insulin and greater AUC c-peptide secretion. This study was limited by sample size. Early pump use may have long term benefits in post-TPIAT endogenous insulin secretion. Disclosure S.E.Tellez: None. L.Hornung: None. J.D.Courter: None. M.Abu-el-haija: None. J.D.Nathan: None. S.Lawson: None. D.A.Elder: None.

159-OR: Endocrine and Metabolic Counterregulation to Standardized Postprandial Hypoglycemia after Bariatric Surgery

Aim: To compare endocrine and metabolic counterregulation to postprandial hypoglycemia in patients with postbariatric hypoglycemia (PBH) after gastric bypass (GB) vs. surgical and non-surgical controls. Methods: Thirty-two adults (age 42.9±12.8 years, 13% male, BMI 28.2±4.3kg/m2) of 4 matched groups (PBH patients, GB, sleeve gastrectomy [SG] and non-surgical controls [CON]) ingested 15g glucose with subsequent induction of hypoglycemia (target 2.5mM) at t150-170 min using a constant insulin infusion with controller-guided iv dextrose adjustment. Primary outcome was mean glucagon during hypoglycemia (t150-170) . Further outcomes were responses of catecholamines, cortisol, growth hormone, pancreatic polypeptide (PP) , glucagon-like peptide 1, endogenous glucose production (EGP) and exogenous insulin. Values are shown as mean±SD. Results: Plasma glucose and insulin at t150-170 were 2.6±0.2mM and 891±382pM across all groups. Glucagon was significantly lower in all surgical groups (PBH: 12.0±8.2pM, GB: 13.4±5.7pM and SG: 11.0±6.8pM vs. CON: 23.0±6.2pM, p=0.005) . PP was significantly lower in PBH vs. CON (28.1±49.6pM vs. 146.0±93.5pM, p=0.01) . EGP did not differ significantly between groups, nor did any other hormones. Conclusion: Our results suggest diminished glucagon response to postprandial hypoglycemia after GB and SG compared to CON, with additionally lower PP values in PBH. Disclosure A.Tripyla: None. J.Zehetner: None. D.Giachino: None. S.Del favero: Research Support; Dexcom, Inc. A.Thomas: None. M.Thevis: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. L.Bally: None. D.Herzig: None. G.Reverter branchat: Employee; Fresenius Medical Care. J.Pavan: None. M.Schiavon: None. P.J.Eugster: None. E.Grouzmann: None. C.T.Nakas: None. S.Valérie: None. Funding Swiss National Science Foundation (PCEGP3_186978)

1300-P: Novel Insulin Modified Oral Glucose Tolerance Test Improves the Estimation of Insulin Sensitivity and Glucose Effectiveness

Estimating insulin resistance from the oral glucose tolerance test (OGTT) has long been a challenge in diabetes research and practice. Because the time courses of glucose and insulin during the OGTT are similar in shape, the estimates of insulin sensitivity per se may be corrupted by other metabolic responses such as insulin release or glucose absorption. We have previously shown insulin injection during the intravenous test yields accurate values of insulin sensitivity (SI) and glucose effectiveness (SG) . Here we examine an analogous approach during the OGTT - in which exogenous insulin is administered during the test. Methods: For 100 simulated subjects (NGT: n=25, IGT: n=25, T2D: n=25, T1D: n=25) , glucose and insulin data were calculated using Dalla Man Mixed Meal Simulator. For each simulated subject, several protocols were examined by varying the time of insulin bolus (30, 60, or 90 min) and the dose of the bolus (0, 0.01, 0.02, or 0.03 IU/kg) . The resulting 3600 simulated datasets were analyzed with Dalla Man’s OGTT model to estimate SI. Results: When adjusted for the dose of insulin, the time of the dose did not significantly impact the estimation of SI. The 0.IU/kg insulin dose resulted in significantly (P&amp;lt;0.001) better estimates of SI when compared to the three other doses. Unique estimates of SG were obtained only without and with insulin dose of 0.IU/kg. There was no difference (P=NS) between the quality of SG estimates with these two doses. Conclusions: An intravenous insulin bolus of 0.IU/kg given at 60 min during the OGTT will enable accurate and precise estimations of both SI and SG. Disclosure D.Stefanovski: None. F.Piccinini: Employee; Medtronic. M.Ader: None. M.Kabir: None. R.N.Bergman: Consultant; Fractyl Health, Inc., Novo Nordisk, Research Support; AstraZeneca, Janssen Research &amp; Development, LLC.

149-LB: Pediatric Exogenous Insulin Antibody Syndrome—Successful Treatment with Mycophenolate Mofetil

Case Description: A lean, 17-year-old Caucasian male with type 1 diabetes diagnosed at age 9 experienced an abrupt increase in his insulin requirements. He was managed on mixed daily injections. Daily insulin requirements increased from 1.7 units/kg/day to 3.3 units/kg/day over 6 months. His total insulin level was 7 mcIU/mL with a free insulin level of 4.8 mcIU/mL, indicating exogenous insulin antibodies. Switching from insulin aspart to glulisine, due to presumed antibodies against insulin aspart was unsuccessful, and his insulin requirements continued to increase to 4.4 units/kg/day. Immunosuppressive therapy was commenced with mycophenolate mofetil, decreasing his insulin requirements to 1.1 units/kg/day after 7 months of treatment. Repeat testing revealed an improvement in the discrepancy between total and free insulin levels, with a total insulin level of 5.2 mcIU/mL and free insulin level of 4.6 mcIU/mL. Discussion: Exogenous insulin antibody syndrome should be considered in patients with poorly controlled diabetes and requiring greater than 2 units/kg/day of insulin without obesity. Classically, antibodies against exogenous insulin were found in patients receiving insulin derived from animal sources; however, recombinant human insulin can very rarely trigger an antibody response in select patients. Immunosuppression using mycophenolate mofetil greatly reduced insulin requirements and this case highlights its novel use in children with diabetes who develop insulin antibody syndrome. Disclosure L. Saba: None. A. B. Orandi: None. S. Pittock: None. A. Creo: None.

259-OR: Stem Cell–Derived, Fully Differentiated Islet Cells for Type 1 Diabetes

Cadaveric islet transplantation can achieve glycemic control in T1D, but cadaveric islet quantity and quality are limiting. We report the first patient-administered VX-880, an investigational allogeneic stem cell–derived, fully differentiated, pancreatic islet cell replacement therapy. A 64-year-old male with a 40-year history of T1D complicated by impaired awareness of hypoglycemia with 5 severe hypoglycemic events (SHEs) the year before VX-880 was receiving 34U insulin/day at baseline (HbA1c 8.6%; undetectable fasting and stimulated C-peptide) . After a single VX-880 infusion at half target dose, fasting C-peptide was detected by Day 29 and increased rapidly; HbA1c and daily insulin decreased in parallel. At Day 90, robust increases in fasting and stimulated C-peptide, improved glycemic control, and a substantial reduction in exogenous insulin administration were observed and continued to improve through last time point assessed (Table) . VX-880 was generally safe and well tolerated; most AEs were mild or moderate and consistent with immunosuppression. The most common AEs were SHEs (not serious or related to VX-880) , which occurred in the perioperative period. There was 1 serious AE of rash (mild, unrelated to VX-880) , which resolved. These unprecedented results are the first evidence that stem cell–derived islets can restore insulin production and glucose control in T1D. The study continues to enroll and dose patients. Disclosure J.F.Markmann: Consultant; Vertex Pharmaceuticals Incorporated. L.S.Kean: Advisory Panel; HiFiBio, Mammoth Biosciences, Other Relationship; Bristol-Myers Squibb Company, Research Support; Bluebird Bio, Gilead Sciences, Inc., Magenta Therapeutics, Merck &amp; Co., Inc., Novartis AG, Regeneron Therapeutics. A.L.Peters: Advisory Panel; Abbott Diabetes, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Shouti, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Other Relationship; Omada Health, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Leona M. and Harry B. Helmsley Charitable Trust, Stock/Shareholder; Teladoc Health. P.Witkowski: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated. C.Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. A.Naji: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. M.Alba: None. G.Marigowda: None. L.Ross: Employee; Vertex Pharmaceuticals Incorporated. C.Wang: Employee; Vertex Pharmaceuticals Incorporated. F.Pagliuca: Employee; Vertex Pharmaceuticals Incorporated, Other Relationship; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. B.Sanna: Employee; Vertex Pharmaceuticals Incorporated.

1324-P: Short-Term Effects of Glycemia-Lowering Medications on ß-Cell Function in the GRADE Study

Therapies that preserve β-cell function and enhance glycemic control in type 2 diabetes are of great value. We examined β-cell function in GRADE participants after one year of intervention with insulin glargine U-100, glimepiride, liraglutide or sitagliptin. Participants who remained on originally assigned medication and had complete OGTT data at baseline and Year 1 were analyzed (n=3342 of 5047 initially randomized) . OGTT derived β-cell responses were measured as the ratio of the increment of C-peptide to glucose in the first 30 minutes (CPI) and over 120 minutes (CP/G AUC) . At baseline, age (57.7±9.7 y) , sex (63.5% male) , race (66.8% White) , BMI (34.2±6.7 kg/m2) , fasting C-peptide (1.3±0.5 nmol/L) , HOMA-B (87±35.2 %) , CPI (0.08±0.nmol/mg) and CP/G AUC (1.1±0.6 nmol/mg) did not differ by treatment group. At Year 1, measures of β-cell function were different by treatment groups (Table) . After pairwise analysis, glargine had the lowest fasting C-peptide while CP/G AUC was highest in the liraglutide group. When tested for treatment heterogeneity across subgroups, participants with longer duration of diabetes had smaller increases in CPI and CP/G AUC. Decreased fasting C-peptide by glargine is likely due to lower endogenous insulin secretion in the setting of exogenous insulin. Improved β-cell responses with liraglutide may indicate better β-cell function during the first year of treatment. Disclosure N. Rasouli: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi. Research Support; Allergan, Eli Lilly and Company, Novo Nordisk. J. Albu: None. R.M. Cohen: Research Support; Dexcom, Inc. R.A. DeFronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk. Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck &amp; Co., Inc. Speaker’s Bureau; AstraZeneca. E. Diaz: None. A. Ghosh: None. J.A. Luchsinger: None. J.B. McGill: Advisory Panel; Gilead Sciences, Inc., Lilly Diabetes, MannKind Corporation, Novo Nordisk A/S, Provention Bio, Inc., Salix Pharmaceuticals. Consultant; Bayer AG, Boehringer Ingelheim International GmbH. Research Support; Dexcom, Inc., Novo Nordisk. L. Sayyed Kassem: None. W.V. Tamborlane: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Medtronic, Novo Nordisk, Sanofi, Takeda Pharmaceutical Company Limited. K. Utzschneider: Consultant; Nevro Corp. N. Younes: None. S.E. Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK098246, U34-DK-088043)

364-OR: Apolipoprotein A-I and Clinical Remission in Adults with Type 1 Diabetes-InLipoDiab1 Study

Introduction: Apolipoprotein A-I (Apo A-I) , the main protein in high-density lipoproteins, improves beta-cell function and insulin sensitivity in experimental models and in people with type 2 diabetes. In those with type 1 diabetes (DM1) , clinical remission (CR) is a key factor for improved prognosis. However, predictors of CR in DM1 are not well described. Whether Apo A-I predicts CR in patients with DM1 remains unknown. Aim To assess the relationship between baseline Apo A-I at the time of diagnosis of DM1 with the presence of CR after 12 months of the disease. Methods: The participants of Insulin Therapy and Lipoproteins' Profile in Type 1 Diabetes Study (InLipoDiab1; NCT02306005) were prospectively observed from the onset of the disease (the blood collection was performed before exogenous insulin administration) through 12 months. The final observation included 53 adults (62% men, age at onset 27±6 years) . DM1 was confirmed with guideline-based criteria on the presence of specific autoantibodies. The endpoint was the presence of pCR at the end of observation, which was defined as IDAA1C ≤ 9, according to the definition by Mortensen et al.: A1C (%) + [4 × insulin dose (U/kg/day) ]. Apo A-I was measured in serum with an ELISA kit. The group was divided into two according to the presence and absence of pCR. Results: At 12 months, pCR was present in 43 participants (81%) . Baseline serum Apo A-I was significantly lower in participants without pCR versus those with the presence of pCR [0.79 (0.39-1.58) vs. 4.51 (0.95-5.93) mg/dl, p=0.002, respectively]. In multiple logistic regression, higher baseline Apo A-I was associated with the presence of pCR after 12 months, adjusted for sex, age, weight and the presence of diabetic ketoacidosis at onset (OR 1.74 (CI 95% 1.02-2.96) , p=0.03) . Conclusion: The higher Apo A-I serum concentration at onset of DM1 the higher chance is for pCR in adults with DM1, after 12 months of observation. Higher serum Apo A-I levels seem to be a good prognostic factor for pCR of DM1. Disclosure A.Uruska: Other Relationship; Lilly, Novo Nordisk. A.Rohatgi: Speaker's Bureau; CSL Behring. A.Cieluch: None. A.Grzelka-wozniak: Other Relationship; Novo Nordisk, Roche Diabetes Care. J.Flotynska: None. A.Pypec: None. D.Zozulinska-ziolkiewicz: Advisory Panel; Dexcom, Inc., Medtronic, Speaker's Bureau; Abbott Diabetes, Ascensia Diabetes Care, AstraZeneca, BIOTON S.A., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Sanofi. Funding Kosciuszko Foundation and Poznan University of Medical Sciences

673-P: Successful Use of Dexcom G6 in Neonate with SGA and Chromosome 6q24-Related Transient Neonatal Diabetes Mellitus

Blood glucose in neonates with diabetes is variable due to frequent feeding, inexact exogenous insulin dosing and dynamic physiology. Rapid glucose fluctuation makes continuous glucose monitoring (CGM) ideal. We describe the successful use of CGM in an infant with small for gestational age (SGA) and chromosome 6q24-related transient neonatal diabetes mellitus, diagnosed by methylation study. A term male weighing 2650g (5th%) was born following uncomplicated pregnancy and delivery. Glucose checked per SGA-protocol revealed rising glucoses from initial 78 to &amp;gt;300 mg/dL over 24 hours. Hyperglycemia managed with insulin drip until transitioned to subcutaneous dilute regular insulin (U-concentration) administered q6 hours (every other feed) . Trial of sulfonylurea titrated to maximum dose was ineffective.Initially glucoses checked hourly while on insulin drip and transitioned to every 3 hours once on subcutaneous insulin. Dexcom G6 placed in lateral thigh without incident on DOL and impermeable dressing applied to prevent soiling.CGM values were generally within 10% of heelstick POC values though specific MARD was not calculated. In the 7 days prior to CGM placement, there were POC glucoses &amp;lt;80 mg/dL; in the 7 days after placement, there were none. Anecdotally, numerous times the CGM trend provided advanced notice of impending hypoglycemia and was able to be treated proactively (treatment decisions based on confirmatory heelstick) . The subject was discharged home on DOL 20.In followup, insulin degledec 0.5 unit/day was added and total prandial insulin requirements varied from 0-1 unit per day (total daily insulin dose approx. 0.1-0.3 units/kg/day) . By age 2.5 months weight was 6.1 kg (38th%) . CGM ambulatory glucose profile demonstrated mean glucose 185 mg/dL, &amp;lt;70 mg/dL &amp;lt;1%, 71-250 88%, &amp;gt;250 11%. In summary, Dexcom G6 CGM was successfully used in an infant with SGA and neonatal diabetes to optimize glucose control while minimizing hypoglycemia risk. Disclosure E.A. Los: Advisory Panel; Medtronic. K. Wise: None. J. Welsh: Employee; Dexcom, Inc.

Effect of type 2 diabetes on A disintegrin and metalloprotease 10.

BackgroundAs a type 1 transmembrane protein, a disintegrin and metalloprotease 10 (ADAM10) is responsible for the cleavage of a variety of cell surface molecules and has been implicated in the pathogenesis of Alzheimer disease, atherosclerosis, and inflammatory and neoplastic disorders. It has been suggested that systemic ADAM10 concentration may potentially be used as a prognostic biomarker. Since high glucose can upregulate ADAM10 expression in vitro, we investigated whether serum levels of ADAM10 and its substrate, the lectin‐like oxidized low‐density lipoprotein receptor 1 (LOX‐1), can be influenced by type 2 diabetes.MethodsA total of 1091 individuals with type 2 diabetes and 358 age‐matched healthy control subjects were recruited. Serum concentrations of ADAM10 and the soluble form of LOX‐1 (sLOX‐1) released by cleavage of LOX‐1 by ADAM were measured by enzyme‐linked immunosorbent assay kits (ELISA).ResultsSerum ADAM10 was increased in subjects with diabetes compared with control (40.5 ng/mL [22.3‐65.7] vs 10.3 ng/mL [7.0‐17.9], respectively; P < .01); the highest levels were seen in insulin‐treated subjects. On multiple linear regression analysis, glycosylated hemoglobin, age, body mass index, and insulin use were independent determinants of ADAM10 level. The increase in serum ADAM10 levels in diabetes was accompanied by changes in serum sLOX‐1. Subjects with diabetes had higher serum sLOX‐1 than the control (110 pg/mL [89‐153] vs 104 pg/mL [85‐138], respectively; P < .01), and there was a significant correlation between serum ADAM10 and sLOX‐1 (r = 0.26, P < .01).ConclusionsSerum concentration of ADAM10 is increased in type 2 diabetes and is associated with glycemia and insulin therapy, which may potentially affect the specificity of systemic ADAM10 level as a biomarker.

1449-P: Reducing Ghrelin Levels as a Novel Method to Increase Pancreatic Beta-Cell Mass

Objective: Exogenous insulin remains the leading therapy for type 1 diabetes mellitus, T1D. However, current insulin formulations and delivery methods do not match the precision of functioning beta-cells, and even intensive monitoring of blood glucose and use of insulin pumps are not enough to halt frequent hypoglycemia, hyperglycemia and morbidity. Thus, regenerating beta-cells has become a major target of diabetes research to treat T1D. While the hormone ghrelin is well known to increase blood glucose, at least in part by inhibiting insulin secretion, ghrelin’s action on beta-cell mass and proliferation has heretofore not been explored in detail. Here, we sought to test the hypothesis that reducing ghrelin levels increases beta-cell mass. Methods: Using histologic methods, we compared islet anatomy in ghrelin-knockout (ghrelin-KO) mice vs. wildtype littermates at three different ages: newborns (P0-P2) , juveniles (4-week-old) , and adults (10-12-week-old) . We also compared islet anatomy in adult wildtype mice, 4 weeks following conditional ghrelin-cell ablation vs. wildtype mice with intact ghrelin-cells. n= 4-8 mice per group and 33-433 islets per mouse. Results: Ghrelin gene deletion or ghrelin-cell ablation increased mean islet area and mean islet insulin-immunoreactive (insulin-IR) area by 52-82 % and by 45-51 %, respectively, in juveniles and adults. Increased islet size was driven by an increased % of large islets. Increased insulin-IR area was associated with increased beta-cell number per islet. An increased % of large islets was also observed in newborn ghrelin-KO mice. Conclusions: In mice, ghrelin plays an important role in controlling beta-cell mass. Reducing ghrelin levels for even short periods can increase islet size by increasing beta-cell numbers. Disclosure D.Gupta: None. C.P.Richard: None. J.M.Zigman: Research Support; Novo Nordisk Research Center Indianapolis, Novo Nordisk Research Center Indianapolis, Stock/Shareholder; Medtronic, Medtronic. A.W.Burstein: None. K.Shankar: None. S.Varshney: None. O.Singh: None. S.Paul: None. S.B.Ogden: None. S.Osborne-lawrence: None. N.Metzger: None.

Smart Technique of Insulin Dose Prediction for Type-1 Diabetic Patients

A type-1 diabetic patient needs an exogenous insulin dose based on the blood glucose level to avoid hyper/hypoglycemia. In this paper, we propose a control system for maintaining the blood glucose level of type −1 diabetic patients within the normal range. The proposed protocol consists of a Wireless Body Area Network (WBAN) and a controller. The WBAN senses blood glucose and insulin concentration at regular intervals. The controller takes meal quantity as an input and estimates the maximum glucose level. The estimated glucose level is further used to predict the required insulin dose considering the patient-specific insulin sensitivity information. This insulin dose is then injected into the patient using an insulin pump. The proposed protocol is helpful for self-monitoring and automatic controlling of blood glucose level for type-1 diabetic patients.

Effect of hyperglycaemia in combination with moxifloxacin on cardiac repolarization in male and female patients with type I diabetes

BackgroundPatients with Type 1 diabetes mellitus have been shown to be at a two to ten-fold higher risk of sudden cardiac death (SCD) (Svane et al., Curr Cardiol 2020; 22:112) than the general population, but the underlying mechanism is unclear. Hyperglycaemia is a recognised cause of QTc prolongation; a state patients with type 1 diabetes are more prone to, potentially increasing their risk of ventricular arrhythmia. Understanding the QTc prolongation effect of both hyperglycaemia and the concomitant additive risk of commonly prescribed QTc-prolonging drugs such as Moxifloxacin may help to elucidate the mechanism of sudden cardiac death in this cohort. This single-blinded, placebo-controlled study investigated the extent to which hyperglycaemia prolongs the QTc in controlled conditions, and the potential additive risk of QTc-prolonging medications.Methods21 patients with type 1 diabetes mellitus were enrolled to a placebo-controlled crossover study at a single clinical trials unit. Patients underwent thorough QTc assessment throughout the study. A ‘hyperglycaemic clamp’ of oral and intravenous glucose was administered with a target blood glucose of > 25 mM and maintained for 2 h on day 1 and day 3, alongside placebo on day 1 and moxifloxacin on day 3. Day 2 served as a control day between the two active treatment days.Thorough QTc assessment was conducted at matched time points over 3 days, and regular blood sampling was undertaken at matched time intervals for glucose levels and moxifloxacin exposure.ResultsConcentration-effect modelling showed that acute hyperglycaemia prolonged the QTc interval in female and male volunteers with type 1 diabetes by a peak mean increase of 13 ms at 2 h. Peak mean QTc intervals after the administration of intravenous Moxifloxacin during the hyperglycaemic state were increased by a further 9 ms at 2 h, to 22 ms across the entire study population. Regression analysis suggested this additional increase was additive, not exponential.Hyperglycaemia was associated with a significantly greater mean QTc-prolonging effect in females, but the mean peak increase with the addition of moxifloxacin was the same for males and females. This apparent sex difference was likely due to the exclusive use of basal insulin in the male patients, which provided a low level of exogenous insulin during the study assessments thereby mitigating the effects of hyperglycaemia on QTc. This effect was partially overcome by Moxifloxacin administration, suggesting both hyperglycaemia and moxifloxacin prolong QTc by different mechanisms, based on subinterval analysis.ConclusionsHyperglycaemia was found to be a significant cause of QTc prolongation and the additional effect of a QTc-prolonging positive control (moxifloxacin) was found to be additive. Given the high risk of sudden cardiac death in type 1 diabetes mellitus, extra caution should be exercised when prescribing any medication in this cohort for QTc effects, and further research needs to be undertaken to elucidate the exact mechanism underlying this finding and explore the potential prescribing risk in diabetes.Trial RegistrationNCT number: NCT01984827.Graphical abstract

Neural Stem Cell Reactivation in Cultured Drosophila Brain Explants.

Neural stem cells (NSCs) have the ability to proliferate, differentiate, undergo apoptosis, and even enter and exit quiescence. Many of these processes are controlled by the complex interplay between NSC intrinsic genetic programs with NSC extrinsic factors, local and systemic. In the genetic model organism, Drosophila melanogaster, NSCs, known as neuroblasts (NBs), switch from quiescence to proliferation during the embryonic to larval transition. During this time, larvae emerge from their eggshells and begin crawling, seeking out dietary nutrients. In response to animal feeding, the fat body, an endocrine organ with lipid storage capacity, produces a signal, which is released systemically into the circulating hemolymph. In response to the fat body-derived signal (FBDS), Drosophila insulin-like peptides (Dilps) are produced and released from brain neurosecretory neurons and glia, leading to downstream activation of PI3-kinase growth signaling in NBs and their glial and tracheal niche. Although this is the current model for how NBs switch from quiescence to proliferation, the nature of the FBDS extrinsic cue remains elusive. To better understand how NB extrinsic systemic cues regulate exit from quiescence, a method was developed to culture early larval brains in vitro before animal feeding. With this method, exogenous factors can be supplied to the culture media and NB exit from quiescence assayed. We found that exogenous insulin is sufficient to reactivate NBs from quiescence in whole-brain explants. Because this method is well-suited for large-scale screens, we aim to identify additional extrinsic cues that regulate NB quiescence versus proliferation decisions. Because the genes and pathways that regulate NSC proliferation decisions are evolutionarily conserved, results from this assay could provide insight into improving regenerative therapies in the clinic.

A metamodel-based flexible insulin therapy for type 1 diabetes patients subjected to aerobic physical activity

Patients with type 1 diabetes are subject to exogenous insulin injections, whether manually or through (semi)automated insulin pumps. Basic knowledge of the patient’s characteristics and flexible insulin therapy (FIT) parameters are then needed. Specifically, artificial pancreas-like closed-loop insulin delivery systems are some of the most promising devices for substituting for endogenous insulin secretion in type 1 diabetes patients. However, these devices require self-reported information such as carbohydrates or physical activity from the patient, introducing potential miscalculations and delays that can have life-threatening consequences. Here, we display a metamodel for glucose-insulin dynamics that is subject to carbohydrate ingestion and aerobic physical activity. This metamodel incorporates major existing knowledge-based models. We derive comprehensive and universal definitions of the underlying FIT parameters to form an insulin sensitivity factor (ISF). In addition, the relevance of physical activity modelling is assessed, and the FIT is updated to take physical exercise into account. Specifically, we cope with physical activity by using heart rate sensors (watches) with a fully automated closed insulin loop, aiming to maximize the time spent in the glycaemic range (75.5% in the range and 1.3% below the range for hypoglycaemia on a virtual patient simulator).These mathematical parameter definitions are interesting on their own, may be new tools for assessing mathematical models and can ultimately be used in closed-loop artificial pancreas algorithms or to extend distinguished FIT.