Therapeutics Inc Research Articles

1084-P: Divergent Hypoglycemic Effects of Hepatic Directed Prandial Insulin: A 6-Month Study in Type 1 Diabetes Mellitus (T1DM)

Hepatic-directed insulin utilizes a hepatocyte-targeting moiety passively attaching free insulin, improving subcutaneous insulin’s hepatic biodistribution. We assessed injections of HDV-insulin lispro (HDV-L) vs. insulin lispro (LIS) in T1DM in a 26-week, multicenter, randomized, double-blind trial of 176 subjects (randomized 2:1 HDV-L:LIS) with A1C 7.0-10.5% treated with basal insulin glargine or degludec. Primary objective was HDV-L A1C non-inferiority (prespecified margin 0.4%). Mean A1C change to week 26 was -0.09% (HDV-L) and -0.16% (LIS), (estimated treatment difference, HDV-L - LIS: +0.09% [95% CI -0.18 to 0.35]), confirming HDV-L non-inferiority. A1C status modified treatment group effect on “severe” hypoglycemia (subjectively categorized by investigators as “mild,” “moderate,” “severe,” or “life threatening”) incidence (interaction p-value <.001), with less hypoglycemia in HDV-L vs. LIS in poor control but more hypoglycemia in HDV-L with better control. Thus, further analyses used subgroups (A1C ≥8.5% vs. <8.5%). HDV-L treated subjects ≥8.5% A1C reported less “severe” hypoglycemia than LIS (69 vs. 97/100 person-years, p=.03), and % time <54 mg/dL during week 26 trended lower (median 0.7% vs. 2.6%, p=.09). Conversely, with baseline A1C <8.5%, more “severe” hypoglycemia was reported with HDV-L (191 vs. 21, p=0.001), and time <54 mg/dL during week 26 trended higher (median 2.0% vs. 0.6%, p=0.16). All subjects showed similar A1C change for both treatments but HDV-L subjects with A1C≥8.5% improved A1C with ~25% less bolus insulin (p=0.02) but comparable basal (p=0.37) at endpoint. HDV-L and LIS subjects with A1C <8.5% both showed little difference in bolus/basal dosages at endpoint (p=0.86 and 0.90). Favorable total cholesterol change with HDV-L (-6.5 mg/dL) vs. LIS (+7.3 mg/dL) was seen (p<.01). No hepatic safety signals were identified. We conclude that of HDV-L is non-inferior to LIS and its liver-targeted component potentiates insulin effect. Disclosure D.C. Klonoff: Consultant; Self; EOFlow, Lifecare, Inc., Merck & Co., Inc., Novo Nordisk A/S, Roche Diagnostic USA, Voluntis USA. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. N.J. Cohen: None. W. Geho: Board Member; Self; Diasome Pharmaceuticals, Inc. D.B. Muchmore: Consultant; Self; ADOCIA, Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc., Zucara Therapeutics Inc. Stock/Shareholder; Self; Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc. Funding JDRF

979-P: Lower Glucose Thresholds for Hyperglycemia Alarm and Narrower Threshold Range for Hyper/Hypoglycemia Alarm on Continuous Glucose Monitoring Systems Correlate with Lower Average Glucose Levels and Longer Time-in-Range

Average glucose levels (AG) and glucose time-in-range (TIR; 70-180 mg/dL) are important glucose control measurements for patients with type 1 diabetes (T1D). Continuous glucose monitoring (CGM) systems provide audible alarms for actual/impending hyper/hypoglycemic events; however, there are little data regarding optimal CGM alarm settings to improve these measures. A cross-sectional observational study was conducted enrolling 91 T1D active CGM users (real-time CGM use >3 months and CGM usage time ≥70%). CGM alarm settings and two-week glucose data (total 28,133 hours) were analyzed. Glucose thresholds for hyperglycemia alarm and intra-threshold range (hyperglycemia minus hypoglycemia alarm thresholds) correlated positively with AG (P<0.001, P=0.003) and negatively with TIR (P=0.004, P=0.039, respectively). Compared to quartiles with higher hyperglycemia alarm thresholds and higher intra-threshold ranges; quartiles with, 1) lower glucose threshold settings for hyperglycemia alarm, and 2) lower intra-threshold ranges, were associated with up to 45 mg/dL lower AG and 20% longer TIR. These data indicate the benefits of lower glucose thresholds for hyperglycemia alarm and lower intra-threshold ranges in promoting lower glucose levels and longer glucose time-in-range. Disclosure Y. Lin: None. M. Hung: None. A. Sharma: None. O. Chan: Research Support; Self; Zucara Therapeutics Inc. M. Varner: None. D. Groat: None. D. Dopita: None. S. Fisher: None.

135-OR: A Novel Thiazolidinedione (TZD) with Minimal PPAR-γ Activity Maximized for Mitochondrial Pyruvate Carrier (MPC) Modulation: Six-Month Analysis of Glycemia in a 12-Month Nonalcoholic Steatohepatitis (NASH) Study

The MPC facilitates entry of pyruvate into the Krebs cycle and in the setting of over nutrition, is critical to adverse manifestations including T2D and NASH. MSDC-0602K is a novel insulin sensitizer engineered to modulate pyruvate utilization with minimal ppar-γ activity. The EMMINENCE study is examining its effects on NASH and glycemia. U.S. sites (57) enrolled 402 patients with liver biopsy evidence of NASH and fibrosis; >50% of subjects with T2D (not taking insulin/pioglitazone) with entry HbA1c ≤ 9.5%. Randomization was 1:1:1:1 to daily oral doses of MSDC-0602K (62.5, 125, and 250mg) or placebo. Safety and glycemia were examined when 328 subjects reached 6 mo visit: 59% female, median age 57, 52% diabetic. (See Table) No meaningful changes in lipids, heart rate or BP were noted. The % of subjects reporting 1 or more adverse events was equal across all 4 cohorts. Importantly, the frequency of peripheral edema was 11% at baseline and unchanged across cohorts at 6 months. MSDC-0602K shows potent effects on glycemic control parameters and insulin sensitization with modest expected weight gain and no evidence of peripheral edema at 6 months, a key ppar-γ related side effect of first generation TZDs. This drug shows promise for glycemic control in NASH patients with T2D/insulin resistance. Disclosure K. Cusi: Consultant; Self; Allergan, AstraZeneca, Genentech, Inc., Novo Nordisk Inc., Poxel SA, ProSciento. Research Support; Self; Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Research & Development, Novartis AG, Novo Nordisk Inc. O.G. Kolterman: Advisory Panel; Spouse/Partner; Intarcia Therapeutics, Inc. Advisory Panel; Self; Zafgen, Inc. Board Member; Self; American Diabetes Association, GlySens Incorporated, Viacyte, Inc. Consultant; Self; ADOCIA, Cirius Therapeutics Inc, DiaVacs Inc, JDRF, Nanoprecisionmedical, NuSirt Biopharma, Inc., Renova Therapeutics, Sensulin, LLC. Employee; Self; Whole Biome Inc. Stock/Shareholder; Self; Corcept Therapeutics, GI Therapeutics, Xeris Pharmaceuticals, Inc. Other Relationship; Spouse/Partner; American Diabetes Association. S.A. Harrison: Advisory Panel; Self; Gilead Sciences, Inc. H.C. Dittrich: Employee; Self; Cirius Therapeutics.

1046-P: Day-to-Day Variability of Insulin Requirements in Inpatients on General Wards

Aim: To characterize variability of exogenous insulin requirements during fully closed-loop insulin delivery in hospitalized patients with hyperglycaemia requiring subcutaneous insulin. Methods: We retrospectively analyzed data from randomized trials investigating fully closed-loop insulin delivery for up to 15 days in inpatients with hyperglycaemia on general wards (type 1 diabetes excluded). We calculated insulin amounts delivered by closed-loop overnight (2300-0449), during breakfast (0500-1059), lunch (1100-1659), and evening meal (1700-2249). The coefficient of variation (CV) quantified between day and between night variability of insulin requirements in inpatients using closed-loop for at least 5 days. Results: Data from 487 days in 55 participants were analyzed [age 69(8)years, weight 100(32)kg, baseline HbA1c 8.0(2.1)%, duration of diabetes 18(13)years, duration of insulin 9(10)years, mean(SD)]; 14.5% of participants received dialysis, 29.1% enteral/parenteral nutrition and 21.8% steroids. Closed-loop directed insulin infusion rate was 1.6(0.8), 2.9(1.2), 3.1(1.4), 2.1(1.0)units/kg/h during overnight, breakfast, lunch, and evening meal periods, respectively. The CV of insulin delivery was higher between nights than between any of the daytime periods [overnight 54(21)% compared with 42(21)% at breakfast, 41(16)% lunchtime and 48(17)% dinner; p=0.001]. Conclusions: Overnight exogenous insulin requirements are more variable than daytime requirements. Particular attention needs to be paid to glucose management overnight to prevent dysglycaemia in inpatients receiving insulin therapy on general wards. Disclosure C.K. Boughton: None. L. Bally: None. H. Thabit: Research Support; Self; Dexcom, Inc. S. Hartnell: Advisory Panel; Self; Dexcom, Inc., JDRF. Speaker's Bureau; Self; Sanofi. D. Herzig: None. A. Vogt: None. E. Andereggen: None. Y. Ruan: None. M.E. Wilinska: None. M. Evans: Advisory Panel; Self; Dexcom, Inc., Medtronic, Roche Diabetes Care, Zucara Therapeutics Inc. Research Support; Self; MedImmune, Sanofi. Speaker's Bureau; Self; AstraZeneca. Other Relationship; Self; Abbott, Eli Lilly and Company, Novo Nordisk Inc. M.M. Wertli: None. A.P. Coll: None. C. Stettler: None. R. Hovorka: Advisory Panel; Self; Novo Nordisk A/S. Research Support; Self; Abbott, Dexcom, Inc., Medtronic. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. Other Relationship; Self; B. Braun Medical Inc., Medtronic.

115-LB: Optimal Sampling Duration of Hybrid Closed-Loop Therapy to Determine Long-Term Glycemic Control in Adults with Type 1 Diabetes

The time needed to reliably assess closed-loop performance in adults with sub-optimal glucose control (A1c 59 to 86 mmol/mol) including changes in behavioral adaptation is currently unknown. We combined data from 2 multi-national randomized closed-loop studies of 12-week duration (N=56; mean±SD, A1c 68±7mmol/mol, age 39±10 year, diabetes duration 21±9 year). For each participant, glucose sensor metrics were computed for the full 12-week period and restricting data to 60 time periods representing 1 to 60 days. For each metric, the association between the value from each sampling period and the value using all 12 weeks of data, determined using Pearson or Spearman correlation coefficient (r). The number of days needed to reach an ‘r’ value of 0.95 (equaling 90% of total variance) for different metrics, mean glucose, % time >180 mg/dl, 70-180mg/dL, >250mg/dL, <70mg/dl, <54mg/dl and coefficient of variation were 27, 24, 26, 33, 38, 49 and 47 days, respectively. Closed-loop usage was consistent throughout sampling periods between 80 and 82%. In conclusion, closed-loop studies of 4-week duration are likely to provide representative data for mean glucose, normoglycemia and hyperglycemia while 6 weeks may be required for a reliable estimate of hypoglycemia and glucose variability. Figure: Correlation coefficients of data collected over the full 12-week period and taken over the first 60 days. Disclosure L. Leelarathna: Advisory Panel; Self; Abbott, Dexcom, Inc., Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis. Research Support; Self; Dexcom, Inc., Novo Nordisk Inc. Speaker’s Bureau; Self; Insulet Corporation, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi. H. Thabit: Research Support; Self; Dexcom, Inc. M.E. Wilinska: None. L. Bally: None. J.K. Mader: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Prediktor Medical, Roche Diabetes Care, Sanofi. Speaker’s Bureau; Self; Abbott, AstraZeneca, Dexcom, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; decide Clinical Software GmbH. S. Arnolds: None. C. Benesch: None. T.R. Pieber: Advisory Panel; Self; ADOCIA, Arecor Limited, AstraZeneca, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. V.N. Shah: Advisory Panel; Self; Sanofi US. Consultant; Self; Dexcom, Inc. A.L. Carlson: Consultant; Self; Sanofi US. Research Support; Self; Abbott, Dexcom, Inc., JDRF, Medtronic, National Institutes of Health, Novo Nordisk A/S. R.M. Bergenstal: Research Support; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Glooko, Inc., Hygieia, JDRF, Johnson & Johnson Medical Devices Companies, Lilly Diabetes, Medtronic MiniMed, Inc., Merck & Co., Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Other Relationship; Self; Abbott, Helmsley Charitable Trust, Hygieia, Lilly Diabetes, Novo Nordisk Inc., Onduo LLC, Sanofi, UnitedHealth Group Inc. M. Evans: Advisory Panel; Self; Dexcom, Inc., Medtronic, Roche Diabetes Care, Zucara Therapeutics Inc. Research Support; Self; MedImmune, Sanofi. Speaker’s Bureau; Self; AstraZeneca. Other Relationship; Self; Abbott, Eli Lilly and Company, Novo Nordisk Inc. R. Hovorka: Advisory Panel; Self; Novo Nordisk A/S. Research Support; Self; Abbott, Dexcom, Inc., Medtronic. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. Other Relationship; Self; B. Braun Medical Inc., Medtronic.

117-OR: Carvedilol Prevents Impairment of the Counterregulatory Response in Recurrently Hypoglycemic Diabetic Rats

It has been suggested that repeated activation of the adrenergic system during antecedent episodes of hypoglycemia may contribute to the development of counterregulatory failure. We previously showed that treatment with the non-specific β-blocker, carvedilol, can prevent counterregulatory failure in nondiabetic, recurrently hypoglycemic rats. The current study investigated whether carvedilol, can be used to prevent the development of counterregulatory failure in recurrently hypoglycemic diabetic rats. Sprague-Dawley rats were made diabetic with a single injection of streptozotocin (STZ; 60mg/kg; I.P.) One week after the induction of diabetes, carvedilol (4.5mg/kg QID; IP) treatment was started and continued for one week in one subgroup of STZ-diabetic rats. The remaining animals received a saline injection as controls. Three days later, the animals received either 3 bouts of insulin-induced hypoglycemia (RH) over the course of 3 days or they received 3 saline injections. On day 14, the animals underwent a hyperinsulinemic-hypoglycemic clamp to assess the counterregulatory hormone responses. Compared to hypoglycemia-naïve STZ Controls, glucose infusion rates were more than doubled in the STZ+RH animals (P<0.001) and this was associated with an ∼50% reduction in the epinephrine response to hypoglycemia. Treatment of STZ+RH animals with carvedilol improved the epinephrine responses to hypoglycemia. Of note, RH did not further diminish the glucagon response in STZ-diabetic rats. Our data suggests that carvedilol may be useful to prevent impairments in the counterregulatory response during recurring episodes of hypoglycemia in diabetic animals. Disclosure R. Farhat: None. O. Chan: Research Support; Self; Zucara Therapeutics Inc. G. Su: None. E. De Santana Van Vliet: None. Funding JDRF; National Institutes of Health

387-P: N-acetyl Cysteine Does Not Prevent Impaired Awareness of Hypoglycemia

Impaired awareness of hypoglycemia (IAH) is common in diabetes. Administration of N-acetyl cysteine (NAC) during episodes of hypoglycemia (HG) prevents the development of IAH in rodents (Fioramonti 2013). Here we tested the hypothesis that NAC will be effective in preventing IAH in healthy humans using a double blind cross over study design where subjects received either NAC or saline (S) in random order on day 1 of a 2 day protocol that involved 3 HG clamps. On day 1, 350 mg NAC or S was given IV over 5 hours starting 30 min before start of IV insulin (2 mg/kg/min). Blood glucose (BG) was targeted at 50 mg/dl for 2 hours, then at 95 mg/dl for 2 hours, then 50 mg/dl for 2 hours. After BG recovery subjects were sent home to return on day 2 for a final 2-hour HG clamp. During the 1st and 3rd HG periods, serum epinephrine (EPI) and hypoglycemic symptoms (HSx) were collected. Subjects received 25 mg diphenhydramine IV at 0 and 4 hours due to a high occurrence of drug reactions. Additional doses or odansetron were given as needed. EPI during clamp 1 was higher during NAC compared to S but the HSx were the same. No difference was seen between subjects who did or did not have a reaction to NAC. EPI and HSx on day 2 following NAC were lower than on day 1 but no different from response measured following S on day 1. NAC elicited many adverse events, enhanced EPI during HG, and did not alter EPI or HSx during HG on day 2 compared to S. Further development of IV NAC as a therapy for IAH is unwarranted. Disclosure A. Moheet: None. A. Kumar: None. L. Coles: None. N. Rubin: None. L.E. Eberly: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. Funding JDRF

67-LB: Time Spent in Glycaemic Ranges and Carbohydrate Intake during Cycling in Professional Cyclists with Type 1 Diabetes

Aim: This observational study examined in-ride interstitial glucose data and nutritional intake in a UCI-accredited professional cycling team with type 1 diabetes (T1D) over a nine-day training camp. Methods: Sixteen male professional road cyclists with T1D (age 27±4 years, T1D duration 11±5 years, BMI 21.6±1.5 kg·min-2, HbA1c 6.8±0.6 %, O2max 71.3±3.9 ml·kg·min-1) on multiple daily injections performed eight rides over nine days lasting between 2 and 6 h, traversing 56 to 182 km/day. Cycle glycemic information (G6, Dexcom) was collected, stratified into glycemic time in ranges; hypoglycemia (Level 1: 54-70, Level 2: <54 mg/dL), euglycemia (71-180 mg/dL) and hyperglycemia (Level 1: 181-299, Level 2: >299 mg/dL) and analyzed for time spent (%) within each range. Nutritional intake during each ride was determined and reported as median (range). Results: Average percentage time spent in euglycemia during cycling was 78±6% (daily range 70-86%). Hypoglycemia during cycling was 3±4% (range 0-11%, Level 1), and 1±2% (range 0-2%, Level 2). No hypoglycemic event required assistance. Percentage time spent in hyperglycemia during cycling was 17±7% (range 8-27%, Level 1), and 1±2 % (range 0-5%, Level 2). The contribution of carbohydrates, fat and protein to total in-ride energy intake was 83.8±15.4, 12.6±8.1 and 1.2±0.6 %, respectively. Macronutrient intake was dependent on cycle duration with greater carbohydrate intake rate on longer rides (2-hour cycle: 20 (4-82) g/h vs. 6-hour cycle: 51 (17-86) g/h). Conclusions: Professional cyclists with T1D maintained a large proportion of time in a euglycemic range during intense cycling sessions over a nine-day training period. The low occurrence of in-ride hypoglycemia, mostly at Level 1, suggests a protective role for consumption of carbohydrate-rich foods to maintain glycaemia, especially during longer rides. However, time spent in Level 1 hyperglycemia during cycling was notable and should be monitored. Disclosure O. McCarthy: None. O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. S.N. Scott: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Medtronic MiniMed, Inc., OmniPod. Stock/Shareholder; Self; Zucara Therapeutics Inc. M. Fisher: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Sanofi. F.Y. Fontana: None. K. Skroce: None. L. Festa: None. P.H. Lagrou: None. P. Southerland: Other Relationship; Self; Novo Nordisk Inc. C.A. Hayes: Other Relationship; Self; Novo Nordisk A/S. M.P. Christiansen: Research Support; Self; Abbott, Biolinq, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk A/S, Sanofi-Aventis, Xeris Pharmaceuticals, Inc. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. C. Stettler: None. R.M. Bracken: None.

65-LB: Sweet Performance: Associations of Maximum Physiological Performance and Diabetes in a Group of World Class Road Cyclists with Type 1 Diabetes

Aim: This study investigated whether markers related to type 1 diabetes (T1D) influence cardiopulmonary exercise (CPX) test performance in a group of world class road cyclists with T1D. Methods: Fifteen elite male road cyclists with T1D (age 27±4 years, T1D duration 11±5 years, BMI 21.6±1.5 kg·min-2, HbA1c 6.8±0.6%) performed a ramped (10 W per min) CPX test to exhaustion. Adjusted stepwise linear regression analysis was performed to investigate relationships between markers of T1D control and absolute maximum markers of performance, maximum oxygen consumption (V O2max), maximum power output (Pmax) and maximum heart rate (HRmax). Associations between submaximal CPX parameters and V O2max, Pmax and HRmax were also investigated. Results: Starting-CPX blood glucose (BG), post-CPX BG, ΔBG, T1D duration, HbA1c and BMI were not associated with V O2max (r2=0.51, P=0.32) and Pmax (r2=0.48, P=0.37) during CPX testing. However, HRmax was associated with T1D duration (r2=0.31, P=0.03). CO2 expiration at the lactate turn point 2 (V CO2LTP2) and power at the heart rate turn point (PHRTP) were associated with V O2max (r2=0.87, P<0.0001). These results were also associated when adjusted for T1D parameters (r2=0.95, p=0.002). Pmax was solely associated with V O2HRTP (r2=0.71, P<0.0001). Also, this association remained significant when adjusted for T1D parameters (r2=0.86, P=0.03). HRmax was associated with ventilation at the LTP2 (VELTP2), LactateLTP1, VCO2LTP2 and PLTP2 (r2=0.91, P=0.002). When this result was adjusted for T1D parameters the association was significant (r2=0.93, P=0.05). Conclusion: This is the first dataset presenting CPX data from a world class cycle team with T1D. The study shows that not all markers of maximum physiological performance are influenced by T1D, solely HRmax by T1D duration. Yet, maximum performance is dependent on several submaximal cardiopulmonary markers of performance. Disclosure M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. O. McCarthy: None. S.N. Scott: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Medtronic MiniMed, Inc., OmniPod. Stock/Shareholder; Self; Zucara Therapeutics Inc. F.Y. Fontana: None. K. Skroce: None. M.P. Christiansen: Research Support; Self; Abbott, Biolinq, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk A/S, Sanofi-Aventis, Xeris Pharmaceuticals, Inc. L. Festa: None. M. Fisher: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Sanofi. C.A. Hayes: Other Relationship; Self; Novo Nordisk A/S. P. Southerland: Other Relationship; Self; Novo Nordisk Inc. C. Stettler: None. P.H. Lagrou: None. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. R.M. Bracken: None. Funding Novo Nordisk A/S

14-LB: Somatostatin Receptor 2 Antagonism Enhances Plasma Glucagon Levels during Insulin-Induced Hypoglycemia in a Rodent Model of Type 2 Diabetes Mellitus

Somatostatin Receptor 2 antagonists (SSTR2a) increase glucagon counter-regulation to hypoglycemia in various rodent models of type-1 diabetes mellitus. Here we investigated the efficacy of SSTR2a in improving glucagon counter-regulation in a rat model of type-2 diabetes mellitus (T2DM). For this, male Sprague Dawley rats (n=18) were given a high fat diet for 3 weeks, followed by low-dose streptozotocin exposure (35 mg/kg, IP) to induce T2DM. Rats were then divided into SSTR2a treatment (PRL-2903, 10 mg/kg) or vehicle (n=9 for each) 1-hour before insulin-induced hypoglycemia (3 IU/kg NovoRapid). This process was repeated 1 week later in a cross-over design, with the data pooled over SSTR2a and vehicle treatments. A group of normal-chow-fed rats (n=3) served as nondiabetic controls. Mean blood glucose levels were higher at 20, 30, 40, and 50 minutes post insulin administration in the T2DM rats treated with PRL-2903, as compared to vehicle (p ≤ 0.05). The number of T2DM rats that developed biochemical hypoglycemia (blood glucose ≤ 3.5 mmol/L) tended to be less with PRL-2903 (5/18) vs. vehicle (9/18). Compared with vehicle treatment, PRL-2903 promoted higher plasma glucagon counter-regulation, as indicated by area under curve (AUC) analysis (p < 0.05). Thus, SSTR2a treatment improves the attenuated glucagon response to hypoglycemia in T2DM rats. Disclosure M. Nejad-Mansouri: None. P. Zaree Bavani: None. J. Aiken: None. N.C. DSouza: None. E.G. Hoffman: None. R. Liggins: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc. Speaker’s Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc. Stock/Shareholder; Self; Zucara Therapeutics Inc. Funding National Research Council Canada; Zucara Therapeutics

2046-P: NS-0200 (Leucine-Metformin-Sildenafil) Reduces Weight in Obese Subjects: A 24-Week Randomized Trial

We previously showed leucine to activate the SIrt1/AMPK/NO pathway and to synergize with other activators of this pathway, and developed NS-0200 (leucine-metformin-sildenafil combination) to treat diseases of energy dysregulation. During a previous trial of NS-0200 of nonalcoholic fatty liver disease we noted significant weight loss induced by NS-0200. Accordingly, we have conducted a 24-week placebo-controlled double-blind trial in 258 weight-stable obese subjects to evaluate the effects of leucine (1.1 g) + sildenafil (1 or 4 mg) with or without metformin (500 mg) administered b.i.d. on weight loss in the absence of lifestyle modification; data presented are for the 202 per-protocol completers. Leu/Met/Sil 1.0 or 4.0 mg and Leu/Sil 4.0 mg produced significant weight loss, while LeuSil 1.0 mg did not. Leu/Met/Sil 1.0 mg exerted the greatest effect (2% placebo-adjusted weight loss, p<0.01), with a greater effect in subjects with BMI<40 (2.9% weight loss, 23% of subjects achieved ≥ 5% weight loss). Markedly greater effects were found in African-American (AA) subjects (6% weight loss, p<0.01) and those with BMI 35-39.9 (4.2% weight loss, p<0.001). These sub-group differences were explained, in part, by differences in baseline insulin and insulin resistance. 71% of AA had insulin ≥ 8 mU/L and HOMAIR>2, vs. 42% in Caucasians, and Leu/Met/Sil 1.0 resulted in a 61% decrease in both insulin and HOMAIR(p<0.009) in AA. Similarly, treated subjects with BMI 35-39.9 had ∼two-fold elevations in insulin and HOMAIR vs. those with BMI<35, and 77% had insulin ≥ 8 mU/L and HOMAIR>2 (p=0.017); those with elevated insulin at baseline lost ∼twice as much weight as those with lower insulin (-3.8 vs. -1.8%), and 30% of this subgroup achieved 5% weight loss vs. 6% of placebo. These data indicate NS-0200 results in significant 6-month weight loss, especially in insulin-resistant subjects, and suggest therapeutic utility for obese insulin-resistant individuals. Disclosure M.B. Zemel: Board Member; Self; NuSirt Biopharma, Inc. Employee; Self; NuSirt Biopharma, Inc. Stock/Shareholder; Self; NuSirt Biopharma, Inc. O.G. Kolterman: Advisory Panel; Spouse/Partner; Intarcia Therapeutics, Inc. Advisory Panel; Self; Zafgen, Inc. Board Member; Self; American Diabetes Association, GlySens Incorporated, Viacyte, Inc. Consultant; Self; ADOCIA, Cirius Therapeutics Inc, DiaVacs Inc, JDRF, Nanoprecisionmedical, NuSirt Biopharma, Inc., Renova Therapeutics, Sensulin, LLC. Employee; Self; Whole Biome Inc. Stock/Shareholder; Self; Corcept Therapeutics, GI Therapeutics, Xeris Pharmaceuticals, Inc. Other Relationship; Spouse/Partner; American Diabetes Association. O. Flores: None. G. Fleming: Advisory Panel; Self; ADOCIA, Biocon. Consultant; Self; Enanta Pharmaceuticals, Inc., InsuLine Medical Ltd., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Merck KGaA, Oramed Pharmaceuticals, Orgenesis Ltd., Sanofi. Employee; Self; Tolerion, Inc. F.L. Greenway: Advisory Panel; Self; BAROnova, Gelesis, Jenny Craig - Curves, Novartis Pharmaceuticals Corporation, NuSirt Biopharma, Inc., Zafgen, Inc. Consultant; Self; Academic Technology Ventures, Basic Research, General Nutrition Corporation, Melior Discoveries. Research Support; Self; Microbiome Therapeutics. Stock/Shareholder; Self; Plensat, Slim Health Nutrition. Other Relationship; Self; Neuroquest. Funding NuSirt Biopharma, Inc.

1039-P: Hybrid Closed-Loop in Adults with Type 1 Diabetes: Impact of Baseline A1c on Glucose Outcomes and Insulin Delivery

We evaluated the impact of baseline A1c on the performance of day-and-night hybrid closed-loop (CL) applying Cambridge control algorithm over 4 weeks in adults with type 1 diabetes. We combined data from 3 multi-national randomized studies [N=85; three groups defined: A1c <7.5% (N=28, 6.8±0.4%; mean±SD), 7.5 to 8.49% (N=32, 7.9±0.3%) and ≥8.5% (N=25, 9.0±0.4%)]. No differences were observed in the duration of diabetes (p=0.79), age (p=0.85) or BMI (p=0.27) between groups, but the mean pre-study total daily insulin dose was higher in those with higher A1c (0.53 vs. 0.59 vs. 0.64 U/kg/day, respectively, p=0.017). Individuals with lower baseline A1c achieved a higher time in range (70-180 mg/dl) and lower mean glucose by reducing time spent >180 mg/dl without an increase in the time <70 mg/dl (Table). Median time <54 mg/dl was low in all groups (0.5%, 0.4% and 0.2%, p=0.37). Total daily insulin dose, % of bolus insulin and the controller effort, defined as the amount of insulin delivered by closed-loop relative to usual basal, were significantly different between groups (p=0.001). Despite significantly higher controller effort, those with higher baseline A1c achieved a lower time in target range than those with lower A1c, who administer a higher percentage of insulin as bolus insulin, which is outside the control of hybrid CL. Education about optimal bolus use may achieve better outcomes with hybrid CL. Disclosure L. Leelarathna: Advisory Panel; Self; Abbott, Dexcom, Inc., Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis. Research Support; Self; Dexcom, Inc., Novo Nordisk Inc. Speaker's Bureau; Self; Insulet Corporation, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi. H. Thabit: Research Support; Self; Dexcom, Inc. M.E. Wilinska: None. L. Bally: None. J.K. Mader: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Prediktor Medical, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; Abbott, AstraZeneca, Dexcom, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; decide Clinical Software GmbH. S. Arnolds: None. T.R. Pieber: Advisory Panel; Self; ADOCIA, Arecor Limited, AstraZeneca, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Novo Nordisk A/S. V.N. Shah: Advisory Panel; Self; Sanofi US. Consultant; Self; Dexcom, Inc. A. Carlson: Consultant; Self; Sanofi US. Research Support; Self; Abbott, Dexcom, Inc., JDRF, Medtronic, National Institutes of Health, Novo Nordisk A/S. R.M. Bergenstal: Research Support; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Glooko, Inc., Hygieia, JDRF, Johnson & Johnson Medical Devices Companies, Lilly Diabetes, Medtronic MiniMed, Inc., Merck & Co., Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Other Relationship; Self; Abbott, Helmsley Charitable Trust, Hygieia, Lilly Diabetes, Novo Nordisk Inc., Onduo LLC, Sanofi, UnitedHealth Group Inc. M. Evans: Advisory Panel; Self; Dexcom, Inc., Medtronic, Roche Diabetes Care, Zucara Therapeutics Inc. Research Support; Self; MedImmune, Sanofi. Speaker's Bureau; Self; AstraZeneca. Other Relationship; Self; Abbott, Eli Lilly and Company, Novo Nordisk Inc. R. Hovorka: Advisory Panel; Self; Novo Nordisk A/S. Research Support; Self; Abbott, Dexcom, Inc., Medtronic. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. Other Relationship; Self; B. Braun Medical Inc., Medtronic. Funding JDRF; European Union; National Institute for Health Research Cambridge Biomedical Research Centre; Medtronic; Abbott Diabetes care

66-LB: Greater Time Spent in Hypoglycemia during Night Compared with Day during Intensified Training in Professional Cyclists with Type 1 Diabetes—A Prospective Observational Study

Aim: To compare time spent in pre-specified glycemic ranges in day and night-time during intensive training in professional cyclists with type 1 diabetes (T1D). Methods: Fifteen male professional cyclists with T1D on multiple daily injections (age 27±4 years, duration T1D 11±5 years, BMI 21.6±1.5 kg·min-2, HbA1c 7.2±0.7%, O2max 73±4 ml·kg·min-1) performed road cycle sessions (50-90% of the anaerobic threshold, duration 1-6 hours) over 9 consecutive days. Time spent in pre-specified glycemic ranges was compared between day and night time using paired t-test and Wilcoxon matched-pairs signed rank test, P≤0.05. Results: Overall glycemia is shown in Figure 1. More time was spent in level 1 (54-70 mg·dl-1) (6±5% vs. 4±3%, P=0.05) and level 2 hypoglycemia (<54 mg·dL-1) (3±5% vs. 1±4%, P=0.002) during night vs. day periods. During daytime, more time was spent in level 2 hyperglycemia (>299 mg dL-1) (night 0.2±0.4% vs. day 1.4±2.3%, P=0.02). Conclusion: Professional cyclists with T1D spent more time in hypoglycemia during the night compared to day-time during intensified training. Long-lasting insulin-sensitizing effects of endurance exercise may suggest a greater need for additional pre-bed carbohydrates and/or insulin dose reductions. Disclosure O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. O. McCarthy: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Medtronic MiniMed, Inc., OmniPod. Stock/Shareholder; Self; Zucara Therapeutics Inc. F.Y. Fontana: None. K. Skroce: None. L. Festa: None. P.H. Lagrou: None. P. Southerland: Other Relationship; Self; Novo Nordisk Inc. M.P. Christiansen: Research Support; Self; Abbott, Biolinq, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk A/S, Sanofi-Aventis, Xeris Pharmaceuticals, Inc. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. C. Stettler: None. S.N. Scott: None. M. Fisher: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Sanofi. C.A. Hayes: Other Relationship; Self; Novo Nordisk A/S. R.M. Bracken: None. Funding Novo Nordisk A/S

396-P: SGLT2 Inhibition Suppresses Glucagon Response to Hypoglycemia in Male but Not Female Rats with Streptozotocin-Induced Type 1 Diabetes

Sodium glucose co-transporter 2 inhibitors (SGLT2i) show promise as an add-on to insulin therapy in patients with type 1 diabetes (T1D), however their effect on glucagon secretion in T1D is not yet known. Increases in glucagon have the potential to protect against hypoglycemia that may develop from insulin overtreatment or exercise. We investigated whether 8 days of SGLT2i treatment (10mg/kg empagliflozin, 2x/day) altered plasma glucagon concentrations in response to voluntary running wheel activity and insulin-induced hypoglycemia in male and female Wistar rats with streptozotocin-induced T1D. SGLT2 inhibition did not alter basal or post-exercise glucagon concentrations and did not affect exercise-associated changes in blood glucose (BG) levels. Additionally, SGLT2 inhibition did not alter voluntary activity levels. However, in males, SGLT2 inhibition lowered plasma glucagon response during an insulin tolerance test (+22.7±30.8 pg/mL vs. +40.4±48.6 pg/mL, p=0.02) and decreased the time taken to reach hypoglycemia (30±13.4 min vs. 63.8±17.2 min, p<0.0001), as compared to placebo. We also observed novel sex differences in the response of BG and glucagon concentrations to voluntary exercise. In female rats alone, voluntary exercise decreased BG concentrations (-2.9±2.6 mM vs. +1.7±1.8 mM, p=0.0003) and led to lower post-exercise glucagon concentrations (37.3±47.9 pg/mL vs. 117.9±86.0 pg/mL, p=0.01), as compared to inactive animals. On average, voluntary activity levels were higher in females than in males (539.2±199.4 m vs. 308.4±215.6 m, p=0.02), however running distances were not correlated with changes in BG levels during exercise (r2=0.02). Our finding of increased hypoglycemia risk with SGLT2i has concerning implications for its use as an adjunct to insulin therapy in T1D. The novel sex differences that we observed should be investigated in individuals with T1D to determine their human applicability and potential mechanisms. Disclosure C.A. Greenberg: None. E.R. Mandel: None. A.M. Pasieka: None. M. Jahangiriesmaili: None. J. Tremblay: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc. Stock/Shareholder; Self; Zucara Therapeutics Inc.

741-P: More Time-in-Range during Days with Structured Exercise vs. Sedentary Days in Adults with Type 1 Diabetes

Structured exercise can help patients with type 1 diabetes (T1D) achieve physical activity targets, however the effects of exercise type on percent time in range (TIR) and glucose variability are unclear. The Type 1 Diabetes Exercise Initiative Pilot Study provided the opportunity to examine glycemic control on structured exercise days compared to sedentary days. Adults with T1D ([mean ± SD] age= 32 ± 14 years; HbA1C= 7.8 ± 1.6%), using a continuous glucose monitor, were assigned to complete twice weekly aerobic, interval or resistance exercise sessions, using study-developed instructional videos for a period of 4 weeks. TIR was higher (Figure 1) and mean glucose concentration was lower overall on exercise days compared with sedentary days (160 ± 52 vs. 176 ± 49 mg/dL, P<0.001). Glucose variability was similar between exercise and sedentary days (coefficient of variation: 36 ± 12% vs. 37% ± 12%). In summary, participants had lower 24-hour mean glucose levels and a greater percent time in range on active days compared with inactive days. Disclosure M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc. Stock/Shareholder; Self; Zucara Therapeutics Inc. Z. Li: None. R. Beck: Other Relationship; Self; Abbott Laboratories, Ascensia Diabetes Care, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Lilly Diabetes, Roche Diabetes Care, Tandem Diabetes Care. R.L. Gal: None. P.G. Jacobs: Stock/Shareholder; Self; Pacific Diabetes Technologies. J.R. Castle: Advisory Panel; Self; Novo Nordisk Inc., Zealand Pharma A/S. Consultant; Self; Dexcom, Inc. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. M.B. Gillingham: None. M.A. Clements: Advisory Panel; Self; Glooko, Inc. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Medtronic. S.R. Patton: None. E. Dassau: Consultant; Self; Eli Lilly and Company, Insulet Corporation. Research Support; Self; Dexcom, Inc., DreaMed Diabetes, Ltd., Insulet Corporation, Roche Diabetes Care, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Speaker's Bureau; Self; Roche Diabetes Care. Other Relationship; Self; ModAGC. F.J. Doyle: Consultant; Self; ModeAGC. Other Relationship; Self; Insulet Corporation. C.K. Martin: Advisory Panel; Self; EHE. Consultant; Self; ACAP Health, Florida Hospital, WW, Zafgen, Inc. Other Relationship; Self; Academy of Nutrition and Dietetics. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. M.R. Rickels: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust

728-P: Accuracy of Energy Expenditure Measurements by Activity Monitors in Type 1 Diabetes and Control Subjects

Physical activity monitors have become increasingly popular in recent years and researchers have started integrating these devices into artificial pancreas (AP) systems to improve the management of T1D. The accuracy of these devices at measuring energy expenditure (EE) may be important for the function of AP systems. Most research to date has determined the accuracy of activity monitors during steady state aerobic exercise in healthy individuals. In this study, the accuracy of the Fitbit Ionic and Garmin vívosmart 3 at measuring EE was assessed against indirect calorimetry (Cosmed K5) during 5 forms of non-steady state activities in individuals with and without T1D. Fourteen adults (Age: 25.8 ± 8.1 year; BMI: 24.1 ± 3.4 kg/m2; 8 T1D) performed a VO2 peak test, resistance exercise, activities of daily living, and high-intensity interval training on treadmill and cycle ergometer, while wearing a Fitbit and Garmin watch. A significant difference in accuracy was displayed by Garmin between individuals with T1D and healthy controls (T1D: 22.6 ± 35.4%; Control: -15.6 ± 24.0%, P<0.0001), but no such difference was exhibited by Fitbit (T1D: 13.5 ± 35.8%; Control: 19.5 ± 37.0%) (Figure). In summary, the Garmin vívosmart 3 overestimates EE during physical activity in individuals with T1D as compared to healthy controls. This difference may need to be addressed before integrating these devices into AP systems. Disclosure R. Pooni: None. S. McGaugh: None. R. Patel: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; Medtronic MiniMed, Inc., OmniPod. Stock/Shareholder; Self; Zucara Therapeutics Inc.

758-P: Medical Food (MF) with Butyrate Producing (BP)+Mucin Regulating (MR) Microbes Improves Glucose Control (GC) in T2D

Studies show that BP+MR are decreased inT2D; the impact of administering specific strains has not been reported. A 12-week, double blind, placebo-controlled study of 2 MFs prepared GMP using only GRAS constituents (MF-1: BP; MF-2: BP + MR) in T2D (drug naive + metformin ± SFU, n=76), showed improved GC. See Table for demographics and key results. The primary endpoint was change from baseline (∆) in total glucose AUC0-180 min during a Boost Plus™ (720 cal) MTT. At 12 weeks, MF-2 yielded significant ∆s in both total (T) and incremental (I) glucose AUC0-180 min, (p=0.05 and 0.007 respectively). MF-1 improved only I glucose AUC0-180 min (p=0.05). Neither MF-1 or MF-2 impacted fasting glucose, T or I insulin AUC0-180 min, weight, BMI, HOMA-IR, lipids, or c-reactive protein. No safety or tolerability concerns were observed. Pre and post fecal microbial analyses are pending. Post hoc analyses revealed 2 interesting results. 1) SFU subjects across both study groups showed minimal response while subjects not using SFUs had greater ∆s in both T glucose AUC0-180 min (-24.4%) and placebo-corrected ∆ A1c (-0.7%). 2) MF-2 showed significant reductions in ALT consistent with improved liver health. In conclusion, 1) Interventions directed at increasing BP+MR may be of benefit in T2D. 2) MF-2 appears to be a safe and effective non-pharmacologic intervention for T2D which merits further investigation. Disclosure O.G. Kolterman: Advisory Panel; Spouse/Partner; Intarcia Therapeutics, Inc. Advisory Panel; Self; Zafgen, Inc. Board Member; Self; American Diabetes Association, GlySens Incorporated, Viacyte, Inc. Consultant; Self; ADOCIA, Cirius Therapeutics Inc, DiaVacs Inc, JDRF, Nanoprecisionmedical, NuSirt Biopharma, Inc., Renova Therapeutics, Sensulin, LLC. Employee; Self; Whole Biome Inc. Stock/Shareholder; Self; Corcept Therapeutics, GI Therapeutics, Xeris Pharmaceuticals, Inc. Other Relationship; Spouse/Partner; American Diabetes Association. F. Perraudeau: Employee; Self; Whole Biome. M.S. Iyer: Employee; Self; Whole Biome Inc. J.S. Eid: Board Member; Self; Whole Biome Inc. J. Bullard: Employee; Self; Whole Biome Inc. Stock/Shareholder; Self; Whole Biome Inc. M.F. Schicklberger: Employee; Self; Whole Biome Inc. A. Cheng: None. N. Justice: Employee; Self; Whole Biome. P. McMurdie: Employee; Self; Whole Biome, Inc. B. Stoneburner: None. J. Gines: Employee; Self; Whole Biome Inc. S. Tyagi: None. C. Cutcliffe: Employee; Self; Whole Biome Inc.

2095-P: Association between Markers of Neuro and Systemic Inflammation and Cognitive Function in Obesity

Obesity is associated with alterations in brain structure and cognitive impairment. The mechanisms underlying obesity related decline in cognitive function are not well understood. Obesity related chronic systemic inflammation is postulated to be one of the potential mechanisms leading to cognitive dysfunction. It is unknown whether inflammation impacts brain areas important for higher level cognition such as the anterior cingulate cortex (ACC). Elevated myo-inositol (Ins), as measured by magnetic resonance spectroscopy (MRS), may be a marker of neuroinflammation and reflects activated astrocytes and microglia. We hypothesized that obese subjects (OB) will have higher ACC Ins compared to normal weight controls (CON) and that higher Ins will be associated with elevated blood inflammatory markers and reduced cognitive performance. We examined neurochemical profile from a 24x24x12mm3 voxel over the ACC using 1H MRS at 3 and 7 Tesla (T), in 5 nondiabetic OB (age 33 ± 5 years, BMI 43 ± 6 kg/m2) and 4 CON (age 36 ± 3 years, BMI 23 ± 3 kg/m2). Subjects also underwent cognitive testing and measurement of blood inflammatory markers. MR spectra were quantified using LCModel and the concentrations are expressed as a ratio to total creatine (tCr). There was a strong trend of higher Ins/tCr in ACC in OB compared to CON both at 3T (0.96 ± 0.06 vs. 0.88 ± 0.05, p =0.07) and 7T (0.91 ± 0.07 vs. 0.83 ± 0.08, p =0.17). Pearson correlations were used to test the relationship between Ins/tCr and markers of inflammation among all subjects. Higher blood inflammatory markers were associated with higher Ins/tCr (3T) in ACC (CRP, r=.74, p= 0.04; TNF α, r=.89, p=0.003) and with low levels of crystallized ability as measured by the NIH Toolbox Cognition Battery (CRP, r=-.73, p=0.03). Higher ACC Ins/tCr was also associated with poorer performance on a measure of fine motor coordination (r=.93, p=0.001). These data support the hypothesis that inflammation may contribute to the pathogenesis of brain and cognitive alterations in obesity. Disclosure A. Khan: None. J.M. Joers: None. M. Luciana: None. N. Rubin: None. Y. Siddiqui: None. S. Mangia: None. L.E. Eberly: None. S. Ikramuddin: Research Support; Self; Medtronic. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. G. Oz: None. A. Moheet: None. Funding National Institutes of Health

402-P: Higher Glucose Thresholds for Hypoglycemia Alarms on Continuous Glucose Monitoring Systems Correlate with Less Time in Hypoglycemia

Based on the set glucose thresholds for hypoglycemia alarms, continuous glucose monitoring (CGM) systems can provide audible alerts that notify individuals for actual/impending hypoglycemic events. While CGMs have been shown to reduce hypoglycemic events in patients with type 1 diabetes (T1D), there are little data demonstrating the association between glucose thresholds for hypoglycemia alarms and clinical hypoglycemia outcomes. This cross-sectional observational study enrolled 83 T1D patients with CGM use >3 months, active CGM usage time ≥70% and activated (i.e., turned “on”) hypoglycemia alarms. CGM settings and two-week CGM glucose data (total 25,683 hours) were analyzed. Glucose thresholds for hypoglycemia alarms (mean: 74 ± 8 mg/dL; range: 60-100 mg/dL) correlated inversely with time in hypoglycemia (both glucose <54 and <70 mg/dL) (Figure 1a). When comparing the cohort with hypoglycemia alarm threshold settings at glucose level ≤70 mg/dL (n=42), threshold settings ≥75 mg/dL (n=41) were associated with a 74% and 60% reduction in hypoglycemia time (<54 and <70 mg/dL, respectively) (Figure 1b). All subjects with hypoglycemia alarm set at glucose ≥75 mg/dL spent less than 3% of time with glucose <54 mg/dL. The current data support the use of higher glucose thresholds on CGM hypoglycemia alarms to decrease the time in hypoglycemia in patients with T1D. Disclosure Y. Lin: None. M. Hung: None. A. Sharma: None. O. Chan: Research Support; Self; Zucara Therapeutics Inc. M. Varner: None. D. Groat: None. D. Dopita: None. S. Fisher: None.

1047-P: Can Closed-Loop Overcome High Day-to-Day Variability of Insulin Needs in Inpatients on General Wards?

Aim: To assess the ability of fully closed-loop insulin delivery to accommodate day-to-day variability in insulin requirements in noncritical care setting. Methods: We retrospectively analyzed insulin delivery during closed-loop studies in inpatients with hyperglycaemia requiring insulin on general wards (type 1 diabetes excluded). Coefficient of variation (CV) quantified day-to-day variability of insulin requirements over 5 to 15 days of closed-loop use. Participants were stratified into tertiles according to variability of insulin requirements. Results: Data from 487 days (55 participants) were analyzed. Participants with higher CV of insulin requirements had comparable mean glucose (149 vs. 153mg/dL; P=0.59; Table) and time in target glucose 100-180mg/dL (67.8 vs. 67.9%; P=0.99) to those with lower CV. There was no increase in hypoglycemia in those with higher CV (P=0.67). Those with higher CV were younger than those with lower CV (66 vs. 72years; P=0.037). Weight, gender, HbA1c, diabetes/insulin duration, use of steroids/dialysis/nutrition support were comparable (ns). Conclusions: Fully closed-loop insulin delivery can accommodate highly variable insulin requirements without compromising glucose control or increasing the risk of hypoglycaemia in inpatients receiving insulin therapy on general wards. Disclosure C.K. Boughton: None. L. Bally: None. H. Thabit: Research Support; Self; Dexcom, Inc. S. Hartnell: Advisory Panel; Self; Dexcom, Inc., JDRF. Speaker's Bureau; Self; Sanofi. D. Herzig: None. A. Vogt: None. E. Andereggen: None. Y. Ruan: None. M.E. Wilinska: None. M. Evans: Advisory Panel; Self; Dexcom, Inc., Medtronic, Roche Diabetes Care, Zucara Therapeutics Inc. Research Support; Self; MedImmune, Sanofi. Speaker's Bureau; Self; AstraZeneca. Other Relationship; Self; Abbott, Eli Lilly and Company, Novo Nordisk Inc. M.M. Wertli: None. A.P. Coll: None. C. Stettler: None. R. Hovorka: Advisory Panel; Self; Novo Nordisk A/S. Research Support; Self; Abbott, Dexcom, Inc., Medtronic. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. Other Relationship; Self; B. Braun Medical Inc., Medtronic.