Insulin Requirements Research Articles

1159-P: Associations of HOMA2 with Clinical Outcomes in Type 2 Diabetes

Background: In patients with type 2 diabetes (T2D) negative for glutamic acid decarboxylase antibodies (GADA-) , the prognostic significance of insulin deficiency (ID) and insulin resistance (IR) remained uncertain. Methods: In 4590 patients with T2D consecutively enrolled to the Hong Kong Diabetes Register in 1995-2012 followed up till 2019, we measured GADA and fasting C peptide (CP) in stored samples at baseline. Using the updated homeostasis model assessment (HOMA2) , we defined below-median HOMA2-%B as ID and above-median HOMA2-IR as IR. We defined incident insulin use as the first insulin prescription of at least 28 days and used ICD-9 codes to define cardiovascular-renal diseases, severe hypoglycemia event (SHE) and all-cause mortality. We used Cox regression model to examine the associations between HOMA2 and clinical outcomes. Results: Amongst 3198 GADA- patients with available HOMA2 data, the median of HOMA2-%B was 52.4 (33.1, 60.9) and that of HOMA2-IR was 1.6 (1.1, 1.8) . The ID group was more likely to initiate insulin treatment [adjusted HR (95%CI) 1.26 (1.11-1.42) ] but less likely to progress to chronic kidney disease (CKD) , end-stage kidney disease (ESKD) and all-cause mortality than the non-ID group. The IR group had increased risks of incident insulin therapy [HR 1.13 (1.00-1.27) ], CKD, ESKD, and all-cause mortality than the non-IR group. Compared with the ID-/IR- group, the ID/IR group had the highest hazard of incident insulin use [HR 1.59 (1.30, 1.94) ], SHE and cardiovascular-renal diseases with HRs ranging from 1.45 to 2.09, although the associations for complications became insignificant after adjusting for metabolic factors and baseline treatments. Conclusions: In GADA- patients with T2D, ID and IR contributed differently to clinical outcomes with the co-existence of ID and IR associated with the highest risk of insulin requirement and adverse clinical outcomes. The assessment of ID and IR using HOMA2 improved risk stratification to identify high risk people for individualized intervention. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund

827-P: 2022 Update on the BCG Clinical Trial Programs in Advanced Type 1 Diabetes

The bacillus Calmette-Guerin (BCG) vaccine was first introduced a century ago for tuberculosis prevention and is today being tested in double-blinded, randomized clinical trials for treatment of diverse forms of autoimmunity, including type 1 diabetes (T1D) and multiple sclerosis (MS) . At our institution, multiple clinical protocols are underway to test various aspects of BCG’s ability to lower HbA1c, reduce insulin requirements and change day-to-day fluctuations in blood sugars. Clinical trial subjects are in study groups including: 1) Long-term follow up of a Phase I study of BCG vaccination in longstanding T1D to study the durability of lowered HbA1c values after BCG treatment; 2) Randomized, double-blinded Phase II clinical trial testing the BCG vaccine in adults with longstanding T1D to demonstrate the reproducibility of BCG’s effects seen in the Phase I trial; 3) Radiologic study to quantify and identify through FDG-CAT scans the organs and organ systems that utilize more sugar after BCG treatment; 4) Study in adults with longstanding T1D to evaluate the effects of two doses of BCG compared to 6 doses of BCG over 5 years of observation; and 5) A soon-to-launch multi-center clinical trial of adolescents with > 2 years since T1D diagnosis to evaluate the potential benefits of BCG vaccination in this cohort. Basic science studies at our institution continue to show that, even in subjects with no pancreas reserve, the effects of BCG on blood sugar are mediated by the restoration of regulated sugar transport in the lymphoid system to corrected aerobic glycolysis. Patients are also being monitored by RNAseq, epigenetics, Treg cell numbers and signature gene expression to better define the mechanism of BCG’s effects. Global studies on the beneficial off-target effects of BCG on the immune system show that the impact of multi-dose vaccination in MS and T1D is seen with 2 years of follow-up and that the effects appear durable without further treatment in both MS and T1D to 5+ years. Disclosure W.Kuhtreiber: None. E.Hostetter: None. A.H.Lee: None. N.Ng: None. G.Wolfe: None. A.Aristarkhova: None. H.Zheng: None. D.L.Faustman: None. Funding Iacocca Foundation

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 >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 <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, <70 mg/dL <1%, 71-250 88%, >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.

765-P: Glycemic Outcomes across Total Daily Insulin Doses with the Omnipod 5 Automated Insulin Delivery System (AID) among People with Type 1 Diabetes (T1D) Ages 2 to 70 Years

AID systems must accommodate a wide range of insulin requirements safely and effectively to apply to a broad population. We evaluated glycemic outcomes among people ages 2 to 70y with T1D and baseline A1C<10% during a 3-mo home trial with the Omnipod 5 AID System, stratified by their baseline total daily insulin dose (TDD) during a 14-day standard therapy phase (ST, multiple daily injections or pump therapy) before AID use. No minimum TDD or weight was required to enter the study. Glycemic outcomes (time in range (TIR) 70-180 mg/dL, time below range (TBR) <70 mg/dL, time above range (TAR) >180 mg/dL) and change in TDD were evaluated across 6 ST TDD ranges, from <10U to ≥65U, during AID compared with ST. Participants (N=320) had a ST TDD of (mean ± SD) 34.8±21.7U (range 5.3-166.0U) . TDD during AID ranged from 5.0 to 110.7U; TDD increased slightly for those using <30U per day. TIR increased during AID across all TDD ranges (p<0.05, Table) . TAR and TBR were reduced in groups with TDD ≥10U and TDD ≥20U, respectively. Multiple linear regression indicated that older age and higher TIR during ST (both p<0.05) were associated with higher TIR during AID, while no relationship was found between ST TDD and TIR during AID (p=0.29, r2=0.57) . The Omnipod 5 System was safe and effective for a large cohort of people with T1D ages 2 to 70y across a wide range of insulin needs. Disclosure M.Schoelwer: Other Relationship; Dexcom, Inc., Research Support; Insulet Corporation, Medtronic, Tandem Diabetes Care, Inc. L.M.Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. J.Sherr: Advisory Panel; Bigfoot Biomedical, Inc., Cecelia Health, Insulet Corporation, Medtronic, Vertex Pharmaceuticals Incorporated, Consultant; Insulet Corporation, Lexicon Pharmaceuticals, Inc., Research Support; Dexcom, Inc., Insulet Corporation, Jaeb Center for Health Research, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Speaker's Bureau; Lilly Diabetes. C.J.Levy: Advisory Panel; Dexcom, Inc., Eli Lilly and Company, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, T1D Exchange, Tandem Diabetes Care, Inc. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. S.A.Macleish: Advisory Panel; Insulet Corporation. D.Desalvo: Consultant; Dexcom, Inc., Insulet Corporation, Research Support; Insulet Corporation. V.Shah: Advisory Panel; Medscape, Sanofi, Consultant; Dexcom, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk. A.Bhargava: Research Support; Abbott Diabetes, AbbVie Inc., Boehringer Ingelheim International GmbH, Boston Therapeutics, Inc., Covance, Dexcom, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Insulet Corporation, Kowa Pharmaceuticals America, Inc., Lexicon Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Medtronic, Novo Nordisk, Poxel SA, Quintiles, Sanofi, Senseonics, Tolerion, Inc., Viking Therapeutics, vTv Therapeutics. T.C.Jones: None. G.Aleppo: Consultant; Insulet Corporation, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Fractyl Health, Inc., Insulet Corporation, Novo Nordisk, Speaker's Bureau; Dexcom, Inc. B.W.Bode: Advisory Panel; CeQur SA, MannKind Corporation, Medtronic, Novo Nordisk, Zealand Pharma A/S, Consultant; Bigfoot Biomedical, Inc., Research Support; Abbott, Beta Bionics, Inc., Dexcom, Inc., Diasome, Dompé, Eli Lilly and Company, Insulet Corporation, IQVIA Inc., Jaeb Center for Health Research, Medtronic, Novo Nordisk, Provention Bio, Inc., REMD Biotherapeutics, Sanvita Medical, Senseonics, ViaCyte, Inc., Speaker's Bureau; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Insulet Corporation, MannKind Corporation, Novo Nordisk, Sanofi, Xeris Pharmaceuticals, Inc., Stock/Shareholder; AgaMatrix, Glytec, LLC. R.E.Gurlin: Employee; Insulet Corporation. T.T.Ly: Employee; Insulet Corporation, Stock/Shareholder; Insulet Corporation. Omnipod 5 research group: n/a. A.L.Carlson: Advisory Panel; MannKind Corporation, Employee; Bright Health Group, Other Relationship; Medtronic, Research Support; Funding This study was funded by Insulet Corporation.

755-P: Liraglutide plus Basal Insulin Combination Therapy in Japanese Old-Aged People with Type 2 Diabetes: Peak Age at 70s

Objective: In management type 2 diabetes (T2D) , it is required to pursue the A1C <7% Target avoiding hypoglycemia, especially in increased old aged population in Japan. We examined the effectiveness of liraglutide (Lira) and insulin degludec (IDeg) combination therapy in 134 Japanese persons with T2D. Methods: Hospitalized persons who started this combination therapy since year 2014 were recruited. Changes of HbA1c and basal Insulin doses were evaluated for 4.5 years after discharge. Glycemic variability (GV) was evaluated by ADRR in person who did SMBG. Since preserved β-cell function might influence the management, effectiveness was also compared by duration of T2D ≤ 5-year (SHORT; n=53) or > 5-year (LONG; n=81) . Persons in SHORT were with shorter duration of T2D than LONG (0.67±1.5 vs. 18.7±9.3 years: p<0.0001) , higher C-peptide Index (1.50±0.76 vs. 0.97±0.66: p<0.001) . Results: 1) Mean HbA1c in total had maintained ≤7.1% from 3rd to 54th month. But mean HbA1C in SHORT was remarkably improved, and had maintained ≤6.6% from 3th until 54th month with extremely lower ADRR score ∼5. 2) At hospitalization, maximum IDeg dose was 15.5±9.2 (6∼46) (SHORT) vs. 14.0±7.6 (4∼40) U/day (LONG) , because of higher HbA1C (12.3±2.3% vs. 10.3±2.4%: p<0.0001) at the baseline. But insulin requirement rapidly decreased in SHORT. On titration, IDeg was titrated not to reach BG <80mg/dL. IDeg could be quitted in ∼75% vs.∼15% at 24th month, respectively. On 3rd month in insulin user, IDeg dose decreased to 7.5±4.1U/day vs. 9.6±5.6U/day, despite lower Lira dose in SHORT with 0.66±0.15mg/day vs. in LONG 0.72±0.23mg/day. 3) Distribution of peak age in total was 70s, and the CKD rate was the more pronounced at 57% (25/44) . Although SHORT group were younger (60.8±11.7 vs. 70.8±11.0 years old: p<0.01) , they already had CKD in 32.1%. Conclusion: Lira based therapy is useful for attaining HbA1c Target with simple insulin titration, longer durability, and for pursuing reno-protection in whole generation with CKD. Disclosure K.Kashima: None. H.Shimizu: None. M.Yamada: None.

1211-P: Associations of C-peptide, HOMA2, and GADA with Insulin Initiation and Risk of Hypoglycemia in Type 2 Diabetes

Background: In patients with type 2 diabetes (T2D) and non-ketotic presentation, low C-peptide (CP) and positivity for glutamic acid decarboxylase antibodies (GADA+) indicate early insulin requirement. In GADA- patients, the associations of CP with insulin use, glycemic response and severe hypoglycemia event (SHE) are unknown. Methods: We measured fasting CP and GADA in 4590 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register in 1995-2012 followed up till 2019. The updated homeostasis model assessment (HOMA2) was derived from fasting CP and plasma glucose. We defined incident insulin use as the first insulin prescription of at least 28 days, glycemic response as HbA1c reduction at one year after insulin initiation, and SHE using ICD-9 codes. Linear and Cox regression models were applied for association analyses. Results: At enrolment, 32% had low CP (<250 pmol/L) and 5% were GADA+. In the low CP group, 7% were GADA+. In the GADA+ group, 50% had low CP. During a mean follow-up of 10.8 years, 58.6% were started on insulin after a median of 6.5 years. The GADA+ group was more likely to initiate insulin [adjusted HR (95% CI) 1.55 (1.26-1.91) ] and experienced SHE [HR 1.45 (1.08-1.95) ] than the GADA- group. In the GADA- group, low CP had lower hazards of insulin use [HR 0.86 (0.77-0.97) ] than high CP especially in patients with HOMA2-IR (insulin resistance) above median. The low CP group had higher HR of 1.34 (1.13-1.59) of SHE than the high CP group. In the GADA+ group, low CP was associated with increased risk of SHE [HR 1.81 (1.25, 2.62) ] but not in patients with high CP (P interaction= 0.01) . Both CP and GADA did not predict glycemia response after controlling for baseline HbA1c. Conclusions: In patients with T2D, CP interacted with GADA to influence disease progressions including early insulin therapy and SHE. C-peptide might be correlated with IR in patients with GADA-. These subphenotypes allowed more precise classification of beta cell function to guide personalized treatment. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.P.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund

183-LB: High Daily Doses of Insulin in Type 2 Diabetes—Predictors beyond Weight

In clinical practice, needing ≥ 200 units insulin/day is defined as severe insulin resistance. This study seeks to identify predictive characteristics of those with type 2 diabetes and severe insulin resistance (≥ 200 units insulin/day) vs. those using <100 units insulin/day. This retrospective cross-sectional study analyzed data for a six-month period gathered from a diabetes clinic electronic database. Compared were 59 patients using >200 units daily (high insulin users - HIU) vs. 59 patients using <100 units (low insulin users - LIU) . For the entire study group (n=118) , mean age was 57.7 ± 9.5 years, 66% were female and 52% Hispanic. Comparing groups, no differences seen in age, race, ethnicity, and A1c. Compared to LIU, HIU had more men (26 vs. 14, P=0.032) , higher BMI (41.8 ± 9.5 vs. 35.1 ± 6.6 kg/m2, p<0.001) , less physically active (42.5 (0.0, 120.0) vs. 140.0 (80.0, 180.0) min/week, p<0.001) , lower HDL (37.5 (32.0, 46.0) vs. 43.0 (37.0, 52.0) mg/dL, p=0.005) , higher insulin units/kg/day (2.3 ± 0.7 vs. 0.9 ± 0.3, p<0.001) , higher use of GLP1-RA medication (16 vs. 6, p=0.018) , higher incidence diabetic neuropathy (36 vs. 18, P<0.001) and co-morbid metabolic conditions like hypertension (58 vs. 50, p=0.024) , congestive heart failure (13 vs. 4, p=0.018) , metabolic liver disease (12 vs. 4, p=0.031) , and obstructive sleep apnea (18 v 7, p=0.013) . Per stepwise multivariate analysis, significant predictors of needing more insulin were being less active, lower HDL, co-morbid conditions like hypertension, neuropathy, obstructive sleep apnea, use of GLP1-RA and higher insulin/kg/day. Factors responsible for high insulin requirements go beyond weight alone as evidenced by higher insulin/kg/day in HIU. Insulin resistance may be exaggerated in the HIU by physical inactivity. Beta cell secretory dysfunction in HIU may also play a role as implied by their longer diabetes duration and higher rate of metabolic comorbid conditions. Disclosure J. Duron tabora: None. A. Amblee: n/a. B. Tahsin: n/a. L. Fogelfeld: Research Support; Lilly, Sanofi.

304-OR: Proteomic Profile and Inflammatory Response of Islet Stressomes Released during Isolation

Purpose: Islets undergo enormous stress during isolation and peri-transplant periods which causes a significant release of stressomes (exosomes released during stress) . Uncovering the biological role of such vesicles is vital for long-term graft function and survival. Here, we sought to identify the global protein content and significance of stressomes isolated during isolation in autologous islet transplantation (AIT) . Methods: Post-transplant stress was mimicked in vitro by exposing human islets to hypoxia and cytokines (Cyt+Hyp) . Stressome protein contents were characterized by mass spectrometry and immunoblotting. Similar stressomes were also isolated from the islet infusion bag samples of AIT recipients (N=20) . The stressome protein levels were correlated with 1-year AIT outcomes. Finally, these islet stressomes were treated to another set of purified islets and macrophages to find their uptake and immune response. Results: The mass spectrometry analysis has revealed the islet stressomes contain DAMP proteins like histones (H2B, H3, and H4) . The canonical ER stress signal plays a crucial role in the biogenesis of islet stressomes induced by (Cyt+Hyp) . Exosomes isolated from the infusion bags showed an elevated histone level in the insulin-dependent (ID) group. Moreover, high levels of DAMP proteins were positively correlated with increased post-transplant recipients insulin requirements (p=0.029) . The fluorescent confocal microscopy analysis has revealed these stressomes were easily uptaken by the macrophages and also conferred an inflammatory phenotype. Instead, the stressome treated islets showed elevated expression of innate immune receptors like TLR2 and AGTR1. Conclusion: The study has identified the islet stressome global protein content and briefs its prospective to induce islet inflammation and graft loss in AIT. Disclosure P.Saravanan: None. J.Kalivarathan: None. M.F.Levy: Research Support; Vertex Pharmaceuticals Incorporated, Speaker's Bureau; AbbVie Inc., Sanofi Genzyme. M.A.Kanak: None.

Glucose-Lowering Therapy beyond Insulin in Type 1 Diabetes: A Narrative Review on Existing Evidence from Randomized Controlled Trials and Clinical Perspective.

Background: In Type 1 diabetes (T1D), according to the most recent guidelines, the everyday glucose-lowering treatment is still restricted to the use of subcutaneous insulin, while multiple therapeutic options exist for Type 2 diabetes (T2D). Methods: For this narrative review we unsystematically screened PubMed and Embase to identify clinical trials which investigated glucose-lowering agents as an adjunct to insulin treatment in people with T1D. Published studies up to March 2022 were included. We discuss the safety and efficacy in modifying cardiovascular risk factors for each drug, the current status of research, and provide a clinical perspective. Results: For several adjunct agents, in T1D, the scientific evidence demonstrates improvements in HbA1c, reductions in the risk of hypoglycemia, and achievements of lower insulin requirements, as well as positive effects on cardiovascular risk factors, such as blood lipids, blood pressure, and weight. As the prevalence of obesity, the major driver for double diabetes, is rising, weight and cardiovascular risk factor management is becoming increasingly important in people with T1D. Conclusions: Adjunct glucose-lowering agents, intended to be used in T2D, bear the potential to beneficially impact on cardiovascular risk factors when investigated in the T1D population and are suggested to be more extensively considered as potentially disease-modifying drugs in the future and should be investigated for hard cardiovascular endpoints.

Influence of the SARS-CoV-2 pandemic on paediatric patients with type 1 diabetes mellitus after one year of follow-up.

Lockdown during the SARS-CoV-2 pandemic generated uncertainty regarding its effects on the control of type 1 diabetes (DM1). Our study aims to evaluate the influence of the pandemic on the control of paediatric patients with DM1. Longitudinal, retrospective, observational study in patients with DM1 attended between 15/10/2019 and 15/03/2020. Data were collected at that visit and at the three subsequent visits. The second was remote in 50% of cases. The variables analysed were: type of insulin therapy, time in range (TIR), time in hypoglycaemia (THypo), time in hyperglycaemia (THyper), coefficient of variation (CV), glycosylated haemoglobin, insulin requirements and anthropometric data. 157 patients were recruited. At the post-lockdown visit, the TIR increased and the THyper decreased with respect to the first (p<0.00) and second (p<0.00) visits. Patients treated with subcutaneous infusion showed a higher TIR at the third visit (p=0.03) and lower insulin requirements at the fourth visit (p=0.03) compared to patients treated with multiple doses. Patients with a remote visit presented a higher TIR (p<0.00), a lower THyper (p=0.00) and lower insulin requirements (p=0.01) at the next visit. Patients aged less than 6years presented a lower glycosylated haemoglobin (p=0.01) and insulin requirements at the third (p=0.03) and fourth (p=0.01) visits, and a lower increase in body mass index (p=0.03) over the year. Metabolic control improved at the post-lockdown visit. Patients treated with subcutaneous infusion, those who had a remote visit during strict lockdown and those aged less than 6years had a better evolution.

Effect of Intraoperative Magnesium Sulfate Administration on Blood Glucose Control following Total Joint Arthroplasty in Patients with Diabetes.

Magnesium deficiency, which is known to be highly prevalent among patients with diabetes, has been associated with insulin resistance and poor glucose control. Here, we aimed to investigate the effects of intraoperative magnesium administration on postoperative glucose control in patients with diabetes. We retrospectively reviewed the medical records of patients with type 2 diabetes who had undergone total joint arthroplasty at a tertiary hospital, where intraoperative magnesium sulfate injections were frequently performed for postoperative analgesia. The patients were grouped based on whether treated with magnesium or not (magnesium vs. control groups). We investigated postoperative blood glucose levels and sliding scale insulin requirements. After propensity matching, 170 patients were allotted to each group. Both the mean glucose level and the incidence of a mean glucose level of >200mg/dL were significantly lower in the magnesium group than in the control group (p = 0.040 and 0.013, respectively). There was also a lower insulin requirement in the magnesium group (p = 0.043). Multivariate logistic regression revealed that magnesium treatment was significantly related to a less frequent incidence of a mean blood glucose level of >200 mg/dL (p = 0.047). This study demonstrated that magnesium sulfate infusion was associated with an improved postoperative blood glucose profile in patients with diabetes.

PEGDA microencapsulated allogeneic islets reverse canine diabetes without immunosuppression.

Protection of islets without systemic immunosuppression has been a long-sought goal in the islet transplant field. We conducted a pilot biocompatibility/safety study in healthy dogs followed by a dose-finding efficacy study in diabetic dogs using polyethylene glycol diacrylate (PEGDA) microencapsulated allogeneic canine islets. Prior to the transplants, characterization of the canine islets included the calculations determining the average cell number/islet equivalent. Following measurements of purity, insulin secretion, and insulin, DNA and ATP content, the islets were encapsulated and transplanted interperitoneally into dogs via a catheter, which predominantly attached to the omentum. In the healthy dogs, half of the microspheres injected contained canine islets, the other half of the omentum received empty PEGDA microspheres. In the biocompatibility study, healthy dogs received increasing doses of cells up to 1.7 M cells/kg body weight, yet no hypoglycemic events were recorded and the dogs presented with no adverse events. At necropsy the microspheres were identified and described as clear with attachment to the omentum. Several of the blood chemistry values that were abnormal prior to the transplants normalized after the transplant. The same observation was made for the diabetic dogs that received higher doses of canine islets. In all diabetic dogs, the insulin required to attempt to control blood glucose was cut by 50-100% after the transplant, down to no required insulin for the course of the 60-day study. The dogs had no adverse events and behavioral monitoring suggested normal activity after recovery from the transplant. The study provides evidence that PEGDA microencapsulated canine islets reversed the signs of diabetes without immunosuppression and led to states of insulin-independence or significantly lowered insulin requirements in the recipients.

Impact of prolonged requirement for insulin on 90-day mortality in critically ill patients without previous diabetic treatments: a post hoc analysis of the CONTROLING randomized control trial

BackgroundStress hyperglycemia can persist during an intensive care unit (ICU) stay and result in prolonged requirement for insulin (PRI). The impact of PRI on ICU patient outcomes is not known. We evaluated the relationship between PRI and Day 90 mortality in ICU patients without previous diabetic treatments.MethodsThis is a post hoc analysis of the CONTROLING trial, involving 12 French ICUs. Patients in the personalized glucose control arm with an ICU length of stay ≥ 5 days and who had never previously received diabetic treatments (oral drugs or insulin) were included. Personalized blood glucose targets were estimated on their preadmission usual glycemia as estimated by their glycated A1c hemoglobin (HbA1C). PRI was defined by insulin requirement. The relationship between PRI on Day 5 and 90-day mortality was assessed by Cox survival models with inverse probability of treatment weighting (IPTW). Glycemic control was defined as at least one blood glucose value below the blood glucose target value on Day 5.ResultsA total of 476 patients were included, of whom 62.4% were male, with a median age of 66 (54–76) years. Median values for SAPS II and HbA1C were 50 (37.5–64) and 5.7 (5.4–6.1)%, respectively. PRI was observed in 364/476 (72.5%) patients on Day 5. 90-day mortality was 23.1% in the whole cohort, 25.3% in the PRI group and 16.1% in the non-PRI group (p < 0.01). IPTW analysis showed that PRI on Day 5 was not associated with Day 90 mortality (IPTWHR = 1.22; CI 95% 0.84–1.75; p = 0.29), whereas PRI without glycemic control was associated with an increased risk of death at Day 90 (IPTWHR = 3.34; CI 95% 1.26–8.83; p < 0.01).ConclusionIn ICU patients without previous diabetic treatments, only PRI without glycemic control on Day 5 was associated with an increased risk of death. Additional studies are required to determine the factors contributing to these results.

Predicting factors of insulin requirement in gestational diabetes mellitus

Predicting factors of insulin requirement in gestational diabetes mellitus

Clinical and nutritional risk factors for insulin requirement during gestational diabetes mellitus

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The effect of intentional underestimation of the food carbohydrate content and other diet-related negligence on glycaemic patterns in patient utilizing the loop-based do-it-yourself artificial pancreas systems

Artificial pancreas systems (APS) are supposed to minimize the workload of managing type 1 diabetes mellitus for patients, but even APS users are still supposed to count carbohydrates and announce meals to achieve the best control. Here, we present the effect of intentional underestimation of food carbohydrate content and other diet-related negligence on glycaemic patterns in patients utilizing a loop-based APS. Since the patient started using the “Loop”, his glycaemic control has been satisfactory (glycated haemoglobin: 6.7% (50 mmol/mol) to 6.4% (46 mmol/mol). The problems with glycaemic control occurred when the patient went on holiday. During this period, the patient deliberately underestimated his carbohydrate meal content announced to the APS. He also used the “override” function (set to 70–80% of normal insulin requirements), which reduced the amount of insulin delivered. The patient tended to consume more alcohol and routinely consumed high glycaemic index products during this period of time. The food bolus was delivered either just before or even during meals. No loop system settings were modified. An intentional underestimation of food carbohydrate content led to the deterioration of glycaemic control in the user of the loop-based APS; however, one can speculate that with some dietary modifications (e.g. limiting carbohydrate intake) the patient could achieve better glycaemic patterns.

Partial Clinical Remission of Type 1 Diabetes: The Need for an Integrated Functional Definition Based on Insulin-Dose Adjusted A1c and Insulin Sensitivity Score.

Despite advances in the characterization of partial clinical remission (PR) of type 1 diabetes, an accurate definition of PR remains problematic. Two recent studies in children with new-onset T1D demonstrated serious limitations of the present gold standard definition of PR, a stimulated C-peptide (SCP) concentration of >300 pmol/L. The first study employed the concept of insulin sensitivity score (ISS) to show that 55% of subjects with new-onset T1D and a detectable SCP level of >300 pmol/L had low insulin sensitivity (IS) and thus might not be in remission when assessed by insulin-dose adjusted A1c (IDAA1c), an acceptable clinical marker of PR. The second study, a randomized controlled trial of vitamin D (ergocalciferol) administration in children and adolescents with new-onset T1D, demonstrated no significant difference in SCP between the ergocalciferol and placebo groups, but showed a significant blunting of the temporal trend in both A1c and IDAA1c in the ergocalciferol group. These two recent studies indicate the poor specificity and sensitivity of SCP to adequately characterize PR and thus call for a re-examination of current approaches to the definition of PR. They demonstrate the limited sensitivity of SCP, a static biochemical test, to detect the complex physiological changes that occur during PR such as changes in insulin sensitivity, insulin requirements, body weight, and physical activity. These shortcomings call for a broader definition of PR using a combination of functional markers such as IDAA1c and ISS to provide a valid assessment of PR that reaches beyond the static changes in SCP alone.

MO626: Risk of Type 2 Diabetes After Stress Hyperglycaemia in Surviving Neurological Patients Admitted to ICU: Assessment of Insulin Need in Pancreatic Donation

Abstract BACKGROUND AND AIMS ‘Stress hyperglycaemia’ is a condition characterized by elevated blood glucose levels during stress or illness. It is often multifactorial and leads to transient insulin resistance and/or insulin deficiency in critical ill patients. Patients with stress hyperglycaemia could be potential pancreas donors, although there is some concern about the influence of donor insulin use on pancreas graft survival. Studies have reported that stress hyperglycaemia increases the risk toward the development of type 2 diabetes (T2D) on the long term, but the patient profiles were of those not usually considered for pancreas donation. The objective of our study was to assess the impact of insulin requirements during intensive care unit (ICU) in surviving patients who otherwise would be potentially eligible for pancreas donation. The risk of T2D at 3 years after discharge was assessed to understand the pancreas function recovery after stress hyperglycaemia. METHOD we developed a retrospective study including patients admitted in the ICU between March 2011 and December 2017 due to severe neurological acute conditions [subarachnoid haemorrhage (SAH), head trauma, non-SAH haemorrhage or stroke]. Inclusion criteria were as follows: severe neurological condition requiring need for intubation, age &amp;lt;56 years and survival at discharge. Exclusion criteria included: obesity (BMI ≥30), diagnosis of diabetes prior to admission, HVB, HVC or HIV positive and lost to follow-up &amp;lt;3 years. Baseline characteristics, length of hospital and ICU stay, peak AST/ALT and amilase/lipase, insulin use during admission as well as variables associated with hyperglycaemia (use of parenteral nutrition, infections, use of corticosteroids or propofol sedation) were collected from patient's electronic medical records of our institution. Primary endpoint was diagnosis of T2D at 3 years after discharge (HbA1C ≥6.5% or fasting plasma glucose ≥126 mg/dL). RESULTS A total of 76 patients were included, with insulin requirement during ICU admission reported in only 5 (6.6%). Median age was 45 years (IQR 35–52), 50% were males, median Charlson index was 0, and 25 (32.9%) had present or past smoking habit. Hypertension was present in 11 (14.5%) and dyslipidaemia in 7 (9.2%). The main admission cause was SAH in 45 patients (59.2%) followed by head trauma in 21 (27.6%). As for hyperglycaemic factors, during admission, 6 (7.9%) received parenteral nutrition, 48 (63%) had an infectious complication, 51 (67%) received corticosteroids and 49 (64.5%) were under propofol sedation. A total of 55 (72.4%) received noradrenaline. Median amylase, lipase, AST and ALT peak were 115 U/L (69.5–233), 70 U/L (34–222), 51 U/L (33.25–101.5) and 94 U/L (35.5–165), respectively. Median ICU and hospital stay were 10 (5–17.75) and 29 (19–42.75) days, respectively. Those who required insulin had longer ICU stay compared with the median of the overall cohort (25 versus 10 days); all of them received corticosteroids and were diagnosed with SAH. At 3 years of follow-up, only three patients (3.9%) were diagnosed with T2D, but none of them had received insulin during admission. One patient was diagnosed 7 months after discharge and the other two were diagnosed 1 year after discharge. Three patients died during the follow-up, but any of them also required insulin during admission. CONCLUSION Insulin requirement in patients with severe neurological acute conditions who could meet criteria for pancreas donation was less common than expected, despite large use of corticoids, infectious complications and propofol sedation as hyperglycaemic factors. Remarkably, only three patients were diagnosed of T2D during the follow-up and none of them received insulin during admission. Prospective studies are needed in order to understand pancreas recovery after stress hyperglycaemia.

Abstract #1184998: A Case of using U-500 During Pregnancy for Optimal Glycemic Control

Insulin resistance is a common and challenging complication faced by many women during pregnancy. Due to severe resistance, patients can have very high insulin requirements making its management challenging for physicians. This has been a well-established phenomenon due to the human placental lactogen which decreases insulin sensitivity in pregnant women. U-500 regular insulin is a concentrated insulin used in patients with high insulin requirements however its use during pregnancy has not been fully established. We present a case of a pregnant female who was insulin naive prior to pregnancy, who was successfully managed with U-500 to achieve optimal glycemic control. A 24 year old woman with history of Type 2 diabetes (controlled by diet alone) presented to her endocrinologist at 8 weeks gestation. Her last Hemoglobin A1c prior to pregnancy was 7.1%. Due to elevated fasting blood sugars, she was initially started on Metformin 1 gram twice a day along with Glargine 10 units daily. Due to persistently elevated fasting and post prandial blood sugars, meal time insulin was also initiated using Lispro. Patient’s insulin had to be gradually up titrated to 100 units daily in her first trimester using the traditional basal bolus regimen. She continued to have increasing insulin requirements, peaking at 300 units in the third trimester with the abovementioned basal bolus regimen. The decision was made to switch patient to U-500 to assist with glucose optimization. With the use of U-500, patient was able to maintain the required tight pregnancy blood glucose goals. For the remainder of her pregnancy, she stayed on U-500 100 units thrice daily. Patient eventually delivered a 6 pound healthy baby without any complications. Post-partum, patient’s insulin requirements improved significantly within the first two weeks and was taken off all insulin. She continues to remain well controlled on only Metformin 1g twice a day. The use of U-500 is typically for patients requiring more than 200 units of insulin daily. There have not been enough studies with the use of U-500 in the pregnant population. We present a case where U-500 was safely used in a pregnant woman in the setting of extreme insulin resistance for a safe and healthy pregnancy. Furthermore, to our knowledge there have been no cases showing the use of U-500 during pregnancy with complete resolution of insulin requirement post-partum. Our case demonstrates that U-500 can be considered in clinical trials for further assessment of its safety and efficacy in pregnant subjects with severe insulin resistance.

An Exercise‐Driven, Insulin‐Independent Glucose Uptake Pathway in Contracting Skeletal Muscle

Glucose uptake by skeletal muscles, which import and store up to 80% of circulating glucose, plays a major role in glucose homeostasis. Prior research has focused largely on the insulin regulated GLUT4 transporter, which mediates glucose uptake in quiescent (non‐contracting) muscles using a canonical insulin‐dependent translocation mechanism. An ongoing paradox in the field is that actively contracting muscles take up glucose at 50‐100x greater rates than quiescent muscles, despite declining insulin levels. For this reason, exercise is a potent treatment for disorders of insulin insufficiency and insulin resistance. However, despite more than 30 years of study, the mechanism by which contracting muscles take up glucose without a requirement for insulin remains incompletely understood. It is proposed that GLUT4‐translocation occurs using signaling pathways that bypass the insulin receptor. However, no GLUT4 models have accounted for all the glucose taken up by contracting muscles or the great discrepancy between measured GLUT4 translocation (2‐fold increase in membrane density) and glucose uptake rate (50‐100‐fold increase), suggesting the existence of additional mechanisms. The goals of this study were to:i) develop a technology based on Inductively Coupled Plasma‐Mass Spectroscopy (ICP‐MS) that allows simultaneous detection of multiple transported species, including 13C‐labeled hexoses; and ii) test the hypothesis that contraction‐stimulated glucose uptake may be linked to Na,K‐ATPase (NKA) transport, which is also dramatically stimulated during muscle contraction. We measured uptake of Rb (a congener for K+), and 13C‐[6C]‐D‐glucose or 13C‐[6C]‐2‐deoxy glucose in isolated mouse EDL muscles stimulated to contract ex vivo. Muscles were obtained from WT mice. Glucose uptake was measured for 5 min at 32 C in a physiological solution containing 200 mM tracer RbCl and 11mM 13C glucose. Following uptake, the Rb and 13C content of the muscle were measured by ICP‐MS. We achieved a Limit of Detection of 54uM for 13C glucose in mouse muscle. This detection power for 13C by ICP‐MS is entirely new and was achieved by combining technical approaches: i) introduction of 13C‐based hexose substrates; ii) modifications to sample preparation that reduce background carbon; iii) ratiometric monitoring of the 13C/12C signal; and iv) 13C‐optimized instrument conditions. Contracting skeletal muscle took up 13C‐[6C]‐labeled‐D‐glucose at a rate of 10.8 mM/g‐min, and Rb at a rate of 1.2 mM/g‐min. The ability to detect glucose and other carbon‐based organic compounds by ICP‐MS is expected to advance studies of coupled transport and other biological processes that require multi‐species detection.