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T2D in youth remains challenging to manage and there is need for an expanded treatment armamentarium. The DINAMO study was designed to overcome recruitment difficulties that plagued previous T2D studies in youth. Within 3 years, DINAMO enrolled 158 patients aged to Disclosure 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. T. Danne: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG. Research Support; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG. Stock/Shareholder; DreaMed Diabetes, Ltd. W.V. Tamborlane: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Medtronic, Novo Nordisk, Sanofi, Takeda Pharmaceutical Company Limited. G.J. Klingensmith: Research Support; AstraZeneca, Novo Nordisk, Takeda Pharmaceutical Company Limited. Stock/Shareholder; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. C. Schroeder: Employee; Boehringer Ingelheim Inc. D. Neubacher: Employee; Boehringer Ingelheim International GmbH. N. Soleymanlou: Employee; Boehringer Ingelheim Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals Inc. J. Marquard: Employee; Boehringer Ingelheim Inc. P. Zeitler: Consultant; Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Takeda Pharmaceutical Company Limited. S.M. Willi: Advisory Panel; Boehringer Ingelheim International GmbH, Medtronic. Research Support; Jaeb Center for Health Research, Provention Bio, Inc. Other Relationship; National Institute of Diabetes and Digestive and Kidney Diseases. Funding Boehringer Ingelheim

While the Type 1 Diabetes Exchange data noted that diabetic ketoacidosis (DKA) is more common in those utilizing injection regimens than insulin pumps, DKA remains a risk for pump users, as it can precipitously develop if insulin infusion is interrupted. We sought to obtain more recent DKA admission data in T1D youth using insulin pumps and the impact of CGM on DKA rates. Methods: We characterized DKA data in insulin pump users from episodes between 12/20 and 6/2021 in an academic pediatric endocrine practice in which 68% were pump users. Results: Among 591 pump patients aged Conclusions: DKA events were relatively uncommon; most episodes occurred in adolescents in poor diabetes control. Notably, most events could have been avoided if users followed standard trouble shooting guidelines. Thus, education on DKA prevention should be reinforced at each visit, particularly for teens on pumps with higher A1c levels. Moreover, while CGM wearers had higher admission bicarbonate values, over 50% of those hospitalized for DKA wore a CGM, suggesting even pump users using CGM require frequent reinforcement of DKA prevention education. Disclosure E.Doyle: None. S.A.Weinzimer: Consultant; Dompé, Research Support; Abbott Diabetes, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc. W.V.Tamborlane: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Medtronic, Novo Nordisk, Sanofi, Takeda Pharmaceutical Company Limited.

Aim: To evaluate the efficacy and safety of once‑weekly exenatide (EQW) in youth with T2D. Methods: Participants (aged 10 to Results: Overall, 83 participants were randomized (exenatide: 59; placebo: 24); 72 completed 24-week treatment. Baseline characteristics were mostly balanced between groups. At 24 weeks, EQW was superior to placebo in lowering HbA1c; the least squares mean (LSM) change in HbA1c was −0.36% for EQW and +0.49% for placebo (between-group difference: −0.85%; P=0.012). Nonsignificant LSM differences from baseline to 24 weeks favoring EQW were observed for FG (−21.6 mg/dL; 95% CI: −49.0, 5.7; P=0.119), SBP (−2.8 mmHg; 95% CI: −8.0, 2.4; P=0.284), and body weight (−1.22 kg; 95% CI: −3.59, 1.15; P=0.307). EQW was well tolerated; AEs occurred in 61.0% and 73.9% and serious AEs in 3.4% and 4.3% of participants in the EQW and placebo groups, respectively. Conclusion: In youth with T2D sub-optimally controlled with current treatments, EQW was effective in improving metabolic control. EQW was well-tolerated and no AEs led to treatment discontinuation by the investigator. Disclosure W. V. Tamborlane: Consultant; Self; Medtronic, Sanofi, Other Relationship; Self; Tolerion, Inc. C. Sjostrom: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. R. Bishai: Employee; Self; AstraZeneca. D. Geller: None. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Self; Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. D. Al-abdulrazzaq: None. E. Karoly: None. O. Doehring: Employee; Self; AstraZeneca. D. Carter: Employee; Self; AstraZeneca. J. Monyak: Employee; Self; AstraZeneca.

Puberty is a known stage of insulin resistance in lean adolescents with or without T1D. Moreover, 25% of adolescents with T1D in clinical practice are overweight, which may further contribute to insulin resistance. The present study examines whether higher body fat aggravates insulin resistance in the liver, muscle, and adipose tissue in pubertal adolescents with T1D by performing a 2-step, 8 and 80 mU/m2/min hyperinsulinemic euglycemic clamp. Body Composition was measured by DEXA, abdominal fat by MRI and hepatic fat by MRI-proton density fat fraction (PDFF). Endogenous glucose production and glycerol turnover were traced with [6,6-2H2] glucose and [2H5]-glycerol (Figure). Participants (mean age 14.4±1.2 years, A1c 7.6±0.5%) with lower (22.9) and higher (36.7) mean % body fat had mean weights of 61.6 and 68.1 kg, BMI% 68.3 and 84.8, and PDFF 1.4 and 1.7%, respectively. Endogenous glucose production was partially suppressed across the body fat spectrum during the low dose insulin infusion. In contrast, those with higher body fat tended to have diminished suppression of glucose production during the high dose insulin infusion. Rates of lipolysis appear to be unaffected. Hence our preliminary findings suggest that on the spectrum of increasing body fat in pubertal adolescents with T1D, we start to see metabolic inflexibility in youth with a moderate degree of adiposity. Disclosure M. A. Van name: None. S. Siebel: None. E. M. Tichy: None. S. Caprio: None. W. V. Tamborlane: Consultant; Self; Medtronic, Sanofi, Other Relationship; Self; Tolerion, Inc. N. Santoro: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK115894-01A1)

Youth with T1D and high HbA1c are at higher risk of DKA. This study examined whether daily school-supervised basal insulin injections reduced the risk of morning ketosis in youth with high HbA1c. We hypothesized that glargine and degludec would reduce the risk of ketosis, and explored whether the prolonged action of degludec protects from ketosis after 2-4 days unsupervised injections. After a 2-4 week run-in, youth (10-18y) on injections with A1c ≥ 8.5% were randomized to supervised administration of either degludec or glargine for 4 months. School nurses observed daily fasting blood β-hydroxybutyrate (βHB) and glucose checks and basal insulin doses. During COVID closures, our research team is supervising procedures remotely. Twenty-four youth (mean age 14.4 ± 2.4 y, 67% F, HbA1c 11.6% ± 1.9%) were analyzed. Supervised injections of both basal insulins for 1-4 days progressively lowered the % participants with elevated βHB (Figure). The % of participants with elevated βHB after 2 days of unsupervised basal insulin tended to be greater in the glargine group. HbA1c did not change. None had DKA. In high risk youth with T1D, daily supervised insulin administration decreased the probability of elevated ketone levels the following school day, regardless of insulin type. A larger sample is needed to determine if degludec’s longer action profile offers additional protection from ketosis during days off from school. Disclosure L. M. Nally: None. M. A. Van name: None. O. K. Sosnoski: None. J. Sherr: Advisory Panel; Self; Cecelia Health, Insulet Corporation, Medtronic, Consultant; Self; Insulet Corporation, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Research Support; Self; Dexcom, Inc., Insulet Corporation, Medtronic, Speaker’s Bureau; Self; Lilly Diabetes. E. M. Tichy: None. K. Weyman: None. A. Steffen: None. S. Mccollum: None. V. Shabanova: None. W. V. Tamborlane: Consultant; Self; Medtronic, Sanofi, Other Relationship; Self; Tolerion, Inc. Funding National Institutes of Health (K12DK094714); Novo Nordisk

Background: Given the paucity of treatment options for youth with type 2 diabetes (T2D), insulin is commonly used to rapidly reverse gluco-toxicity. Subsequently, some youth with short duration T2D can be weaned off insulin soon after diagnosis. We analyzed data from the Pediatric Diabetes Consortium (PDC) Registry to determine how long glycemic control is maintained off insulin. Methods: Youth with T2D in the PDC Registry on metformin alone or lifestyle therapy alone upon registry enrollment but had previously been on insulin were included in this study (N=183). The primary outcome was time to treatment failure, defined by need to restart insulin or other diabetes medication (including metformin). Clinical data at enrollment and follow-up were analyzed using logistic regression to assess risk factors for treatment failure. Results: Of participants who had previously been on insulin therapy (58% female, 53% Hispanic, mean age 15 ± 2 years, median diabetes duration 1.7 years), 54% (98/183) experienced treatment failure. In the subgroup on metformin alone at enrollment (N=140), 45% restarted insulin, while in the lifestyle alone subgroup (N=43), 81% restarted insulin or other diabetes medication. Time to treatment failure was a median of 1.2 years. High HbA1c (mean 7.7% vs. 6.1% in the treatment failure group vs. non-failure group; p Conclusion: Youth with T2D previously treated with insulin have a high treatment failure rate on lifestyle or metformin therapy alone and are likely to restart insulin therapy. Youth with T2D should be monitored closely for worsening glycemic control. Disclosure R. Wolf: None. P. Cheng: None. R.L. Gal: None. L.C. Beaulieu: None. C. Kollman: Other Relationship; Self; Dexcom, Inc., Tandem Diabetes Care. E.M. Isganaitis: None. S.N. Magge: None. L.D. Mastrandrea: Board Member; Self; American Academy of Pediatrics. Research Support; Self; AstraZeneca, JDRF, Novo Nordisk Inc., Sanofi-Aventis. G.J. Klingensmith: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Sanofi US. Other Relationship; Self; Eisai Inc., MannKind Corporation. M.A. Van Name: None. Funding Boehringer Ingelheim; Novo Nordisk; Takeda Pharmaceutical Company Limited

GLP-1 analogues (GLP-1a) may change sweet food preferences but the neural mechanisms are not fully understood. We studied the effect of GLP-1a on neural responses to drinking high fructose corn syrup (HFCS) using fMRI in 5 lean (LN, BMI 21kg/m2, mean age 21, A1c 5.3%) and 7 obese (OB, BMI 38, age 26, A1c 5.5%) subjects. The OB group had a second fMRI after 3-mos treatment with liraglutide 3.0 mg daily. Food intake was evaluated by dietary recall. At baseline, OB group had increased cerebral blood flow (CBF) in regions implicated in reward/motivation (putamen) and taste perception (insula) vs. LN (p=.05). However, the OB group’s responses to HFCS changed markedly after 3-mos GLP-1a treatment. As shown in the Figure, CBF in OB group increased in regions related to impulse control (anterior cingulate cortex/ventromedial prefrontal cortex), taste perception (insula), and thalamus. It is also noteworthy that CBF did not increase in the reward/motivation region (putamen) during liraglutide treatment. Changes in neural responses to HFCS intake during GLP-1a treatment were accompanied by a 1080 kcal/d decrease in food intake (p50% decrease in daily sugar intake. These preliminary data suggest decreased food and sugar intake induced by GLP-1a may be related to neural mechanisms that promote impulse control while simultaneously suppressing dysregulated reward responses following sugar intake. Disclosure K. Joseph: None. J. Leventhal: None. S. Hwang: None. M. Knight: None. D. Seo: None. C. Lacadie: None. M.A. Van Name: None. S. Caprio: None. J. Sherr: Advisory Panel; Self; Bigfoot Biomedical, Cecelia Health. Consultant; Self; Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Medtronic, Sanofi, T1D Exchange. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Sanofi US. Other Relationship; Self; Eisai Inc., MannKind Corporation. R. Sinha: None. A.M. Jastreboff: Consultant; Self; Novo Nordisk Inc., Rhythm Pharmaceuticals. Funding American Diabetes Association (1-18-JDF-003 to A.M.J.)

The SENCE study in children < 8 yrs with T1D compared the efficacy of CGM combined with a family behavioral intervention (CGM + FBI) and CGM alone (Standard-CGM) with blood glucose monitoring (BGM) alone. Time in hypoglycemia fell in both CGM groups but was unaffected in the BGM group during the 26-week trial. After trial completion, both CGM groups extended their time on CGM for 26 weeks without additional education/behavioral intervention. This analysis assessed whether prolonged CGM use maintained durable reductions in time in hypoglycemia throughout the entire 52-week period. The extended study was completed by 45 of 50 in the CGM + FBI group and 42 of 44 in Standard-CGM. In these 87 kids, median age was 5.6 years and 31% were on insulin pumps. Differences in the two CGM groups were compared to masked baseline CGM data from run-in. Median time Conclusion: Sustained CGM use results in less hypoglycemia in young children with T1D. Disclosure M.A. Van Name: None. K. Miller: None. L. Kanapka: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Sanofi US. Other Relationship; Self; Eisai Inc., MannKind Corporation. L. DiMeglio: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust

Background: While consensus guidelines indicate that all youth with T2D should be treated with metformin ± insulin at diagnosis, >10% of patients were treated solely with diet/lifestyle on enrollment in the Pediatric Diabetes Consortium (PDC) T2D Registry. Methods: Clinical data was collected on 1,324 Registry patients (age 6 to Results: Of the 1,324 Registry patients, 163 (12%) were treated with diet/lifestyle alone on enrollment. Of these, 73% of were initially treated with metformin ± insulin at diagnosis. The diet/lifestyle and drug-treated groups did not differ by age, gender, diabetes duration, or BMI (Table). However, mean A1c was lower and the proportion of patients with A1c Conclusion: These data indicate that a substantial proportion of youth with T2D can maintain target A1c levels Disclosure W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. P. Cheng: None. R.L. Gal: None. L.C. Beaulieu: None. C. Kollman: None. M.A. Van Name: Research Support; Self; Novo Nordisk Inc. E.M. Isganaitis: None. L.D. Mastrandrea: Advisory Panel; Self; Pediatric Diabetes Consortium. Research Support; Self; AstraZeneca, JDRF, Novo Nordisk Inc., Sanofi-Aventis, T1D Exchange. Other Relationship; Self; Novo Nordisk Inc. G.J. Klingensmith: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. Research Support; Self; Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Dexcom, Inc. Funding Boehringer Ingelheim; Novo Nordisk; Takeda Pharmaceutical Company Limited

It is a common belief that females experience more hypoglycemia than males. We aimed to assess whether this was true in a cohort of healthy individuals without diabetes. In this multicenter study, healthy, nondiabetic children and adults (age 7 to 80 years, normal BMI, HbA1c Disclosure S. DuBose: None. Z. Li: None. V.N. Shah: Advisory Panel; Self; Sanofi US. Consultant; Self; Dexcom, Inc. J. Sherr: Advisory Panel; Self; Bigfoot Biomedical, Eli Lilly and Company, Insulet Corporation. Consultant; Self; Lexicon Pharmaceuticals, Inc., Medtronic, Sanofi. Research Support; Self; Dexcom, Inc., Insulet Corporation. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. 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. R. Beck: Other Relationship; Self; Abbott Laboratories, Ascensia Diabetes Care, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Lilly Diabetes, Roche Diabetes Care, Tandem Diabetes Care. Funding The Leona M. and Harry B. Helmsley Charitable Trust

Background: Racial differences in diabetes control and cardiovascular disease risk factors have been reported in youth with diabetes, with minority youth having worse glycemic control and comorbidities compared with non-Hispanic white (NHW) peers. Methods: We examined racial differences in comorbidities in youth ( Results: The mean age at presentation was 13.4 ± 2.4 years, and mean BMI Z-score was 2.30 ± 0.45. African-American (AA) and Hispanic (H) youth had higher HbA1c and lower C-peptide at diagnosis compared to NHW, with AA 3 times as likely to present in DKA compared with NHW. Microalbuminuria was present in 11%, hypertension in 34% and dyslipidemia in 42% with no significant differences in these comorbidities among racial groups. Nonalcoholic fatty liver disease (NAFLD) was diagnosed in 9% and 11% of H and NHW, respectively vs. 2% in AA (Table). Conclusion: Minority youth with T2D presented with worse metabolic control compared with NHW, with higher rates of DKA in AA youth. Comorbidities exist in a large percentage of youth with T2D independent of ethnicity, except for NAFLD being less prevalent in AA. Disclosure F. Bacha: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, Pediatric Diabetes Consortium. Other Relationship; Self; AstraZeneca, Jaeb Center for Health Research. P. Cheng: None. R.L. Gal: None. L.C. Beaulieu: None. C. Kollman: None. A. Adolph: None. I. Jindal: None. A.H. Shoemaker: Advisory Panel; Self; Rhythm Pharmaceuticals, Inc. Research Support; Self; AstraZeneca, GLWL Research Inc., Novo Nordisk Inc., Rhythm Pharmaceuticals, Inc., Soleno Therapeutics. R.M. Wolf: None. G.J. Klingensmith: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. Research Support; Self; Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Dexcom, Inc. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Funding Boehringer Ingelheim; Novo Nordisk; Takeda Pharmaceutical Company Limited

Background: Youth with T2D experience barriers to obtaining diabetes care. We evaluated whether healthcare utilization (HCU) was associated with glycemic outcomes in youth with T2D. Methods: We evaluated annual HCU in 1,324 T2D PDC youth by diabetes duration up to 13 years post diagnosis. Medical record and self-reported HCU data were collected at enrollment and annually. Frequency of diabetes related inpatient admissions, Emergency Department (ED), urgent care, Diabetes Management (DM), Registered Dietician (RD) visits, and 911 calls were collected. Results: After adjusting for age, gender, diabetes duration, and annual visits, those with ≥1 admission/year, regardless of admission reason, (16%) had a higher A1c vs. those without admission, 8.8 vs. 8.4% (p=0.002). Those with ≥2 DM office visits/year (75%) had lower A1c vs. those with 0-1 visits, 8.4 vs. 8.8% (p=0.001). BMI and A1c did not differ by number of RD visits (p=0.63 and 0.39 respectively); RD visits/year decreased over time. Conclusions: In T2D youth, hospitalizations and Disclosure G.J. Klingensmith: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. Research Support; Self; Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Dexcom, Inc. P. Cheng: None. R.L. Gal: None. L.C. Beaulieu: None. C. Kollman: None. R.L. Adams: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. L.M. Looper: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Funding Boehringer Ingelheim; Novo Nordisk; Takeda Pharmaceutical Company Limited

Alcohol consumption has serious potential consequences for persons with type 1 diabetes (T1D). This study examined associations between alcohol consumption status and diabetes outcomes. Participants were N=933 adults at Type 1 Diabetes Exchange Registry clinics who completed an emailed set of standardized self-report instruments that included items on alcohol use; A1c values were extracted from charts and reported by clinics. Participants were on average (SD) age 38 (16) years, 61% female, and 90% non-Hispanic white, and mean (SD) A1c was 7.8% (1.5%). The sample was 61% (n = 567) current non-binge drinkers, 19% (n = 174) current binge drinkers, 11% (n = 103) had never consumed alcohol, and 9% (n = 89) former drinkers. After controlling for relevant covariates, there was a trend toward higher diabetes self-care scores in never drinkers compared to current non-binge drinkers, current binge drinkers, and former drinkers, and a trend towards lower diabetes distress scores relative to current non-binge drinkers and former drinkers. The odds of a history of severe hypoglycemia, and odds of a neuropathy diagnosis, were lower among never drinkers relative to former drinkers (adjusted p < .04). Never drinkers did not differ from other drinking status groups on frequency of self-monitoring blood glucose, A1c, history of diabetic ketoacidosis, or nephropathy diagnosis (adjusted p’s≤.01). BMI was higher among never drinkers compared to former drinkers and non-binge drinkers (adjusted p > .05). These results suggest that experiencing severe hypoglycemia and being diagnosed with neuropathy may motivate some drinkers to stop drinking, and that never drinkers have more salutary self-care and distress, but higher BMI. Strategies to help patients with T1D manage alcohol are warranted. Disclosure S.M. Alessi: None. N.C. Foster: None. C. Rash: None. M.A. Van Name: Research Support; Self; Novo Nordisk Inc. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. J. Wagner: None.

Background: The effect of dysglycemia on brain development and cognition is not well understood. Methods: In a multi-site study, we examined brain activation in 93 children with T1D (mean age 11.5 ± 1.8 years) and 57 nondiabetic children (mean age 11.8 ± 1.5 years) as they performed a classic executive function paradigm, the Go/No-Go task. Participants responded to letters flashed on a screen by a key press (Go) but not to the letter X (No-Go). Results: Despite similar task performance between the groups, children with T1D exhibited greater activation in executive control regions (dorsal anterior cingulate cortex, inferior frontal gyri, cerebellum and supramarginal gyri; p=0.010) and less suppression in the posterior node of the default mode network (DMN) compared to controls (p=0.006). Secondary analyses showed greater activation in executive control regions was associated in T1D with shorter response times and better parent-reported measures of executive function (ps Conclusion: These findings suggest that compensatory recruitment of executive control areas may act to offset T1D-related impairments in the DMN and, at least transiently, allow behavioral performance on Go/No-Go to be equivalent to that of nondiabetic controls. Disclosure L.C. Foland-Ross: None. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Novo Nordisk Inc., Profusa, Inc. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Beta Bionics, ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care. N. Mauras: Consultant; Self; Novo Nordisk Inc., PicoLife. Research Support; Self; Medtronic MiniMed, Inc. A. Arbelaez: None. N.H. White: None. T. Aye: None. D.M. Wilson: Advisory Panel; Self; Tolerion, Inc. Research Support; Self; Beta Bionics, Dexcom, Inc., Medtronic. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. S.A. Weinzimer: Consultant; Self; Eli Lilly and Company, Sanofi. Consultant; Spouse/Partner; Tandem Diabetes Care. Consultant; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Stock/Shareholder; Self; InsuLine Medical Ltd. E. Tsalikian: None. M. Tansey: Advisory Panel; Self; Daiichi Sankyo Company, Limited. A. Cato: None. T. Hershey: Research Support; Spouse/Partner; Sage Pharmaceuticals. L.A. Fox: None. G. Tong: None. K.A. Englert: Consultant; Self; PicoLife Technologies, LLC. P. Mazaika: None. A.L. Reiss: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (DIRECNET: U01HD-41906, HD-41908, HD-41915, HD-41918, HD-56526, R01HD078463, U54HD087011; National Center for Advancing Translational Sciences (UL1TR000448)

Background: Subtle but significant cognitive differences between youth with and without type 1 diabetes (T1D) have been observed and found to be related to chronic hyperglycemia. We report continued follow-up of prospectively acquired cognitive data obtained over 4.5 years in a large cohort of young children with and without T1D. Methods: 181 children with T1D and 90 age-matched nondiabetic controls underwent age-appropriate neuropsychological testing at three time points: baseline, 18 months, and approximately 2.9 years after the second visit (T1D group: 11.2 ± 1.9 y, HbA1c: 8.1 ± 1.0%, diabetes duration 6.4 y at the time of latest evaluation; control group: mean age 11.6 ± 1.7 years). Effects of T1D on cognition were estimated based on longitudinal mixed effects modeling after controlling for parental full-scale IQ. Results: The T1D group continued to show significantly lower scores on Full Scale IQ (Cohen’s d=-0.31, p=0.024), Verbal IQ (d=-0.33, p=0.009), and Vocabulary (d=-0.42, p=0.002) compared to nondiabetic controls at last follow-up. Processing speed, memory and learning were similar between the T1D and the control groups. Within the T1D group, there was a significant inverse relationship between HbA1c at last follow-up and Vocabulary (r=-0.307, p=0.001) as well as between HbA1c and VIQ (r=-0.200, p=0.037), controlling for parental IQ. Conclusion: In this large cohort of children with relatively well-controlled T1D followed for 4.5 years, differences in full-scale and verbal IQ persist over time compared to nondiabetic controls, and effects on vocabulary and verbal IQ are related to glycemic control. These findings further support the importance of optimizing glycemic control during this critical period of brain maturation. Disclosure S.A. Weinzimer: Consultant; Self; Eli Lilly and Company, Sanofi. Consultant; Spouse/Partner; Tandem Diabetes Care. Consultant; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Stock/Shareholder; Self; InsuLine Medical Ltd. J.M. Ambrosino: Consultant; Spouse/Partner; Eli Lilly and Company, Sanofi. Consultant; Self; Tandem Diabetes Care. Consultant; Spouse/Partner; Zealand Pharma A/S. Speaker's Bureau; Spouse/Partner; Insulet Corporation, Medtronic, Tandem Diabetes Care. Stock/Shareholder; Spouse/Partner; InsuLine Medical Ltd. A. Cato: None. B. Jo: None. K.A. Englert: Consultant; Self; PicoLife Technologies, LLC. N.H. White: None. A. Arbelaez: None. T. Hershey: Research Support; Spouse/Partner; Sage Pharmaceuticals. L.A. Fox: None. E. Tsalikian: None. M. Tansey: Advisory Panel; Self; Daiichi Sankyo Company, Limited. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Novo Nordisk Inc., Profusa, Inc. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Beta Bionics, ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care. T. Aye: None. D.M. Wilson: Advisory Panel; Self; Tolerion, Inc. Research Support; Self; Beta Bionics, Dexcom, Inc., Medtronic. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. A.L. Reiss: None. N. Mauras: Consultant; Self; Novo Nordisk Inc., PicoLife. Research Support; Self; Medtronic MiniMed, Inc. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (DIRECNET: U01HD-41906, HD-41908, HD-41915, HD-41918, HD-56526, R01HD-078463, U54HD087011); National Center for Advancing Translational Sciences (UL1TR000448)

Background: The extent to which glycemic exposure adversely impacts the developing brain in young children with early-onset type 1 diabetes (T1D) is controversial. Methods: As part of the multisite DirecNet Study, we performed structural MRI at three time points (baseline, 18 months and approximately 2.9 years after the second visit) in 137 children with T1D (age: 7.0 ± 1.7 years, lifetime average HbA1c: 8.0 ± 0.7%, and diabetes duration: 2.4 years at study entry) and 66 age-matched nondiabetic controls (7.0 1.8 years old). White matter (WM) and gray matter (GM) volumes in various brain regions-of-interest were determined by voxel-based morphometry (VBM). Total cumulative hyperglycemic exposure was determined as HbA1c area under the curve (lifetime A1c) from the time of diagnosis in T1D children. Results: Children with T1D had slower growth of total cortical and subcortical GM and WM than the nondiabetic controls at all timepoints. Gray matter regions (frontal, temporal, subcortical, and occipital cortex) showed less growth in the T1D compared to the control group (p Conclusion: This study demonstrates that children with early-onset T1D and worse glycemic control have slower cortical and subcortical GM and WM growth than nondiabetic controls, suggesting that hyperglycemia is detrimental to the developing brain during this critical period of rapid brain maturation. The long-term consequences of these early alterations in brain growth require further follow-up. Disclosure A. Arbelaez: None. S. O’Donoghue: None. N. Mauras: Consultant; Self; Novo Nordisk Inc., PicoLife. Research Support; Self; Medtronic MiniMed, Inc. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Novo Nordisk Inc., Profusa, Inc. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Beta Bionics, ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care. N.H. White: None. S.A. Weinzimer: Consultant; Self; Eli Lilly and Company, Sanofi. Consultant; Spouse/Partner; Tandem Diabetes Care. Consultant; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Stock/Shareholder; Self; InsuLine Medical Ltd. T. Aye: None. E. Tsalikian: None. D.M. Wilson: Advisory Panel; Self; Tolerion, Inc. Research Support; Self; Beta Bionics, Dexcom, Inc., Medtronic. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. M. Tansey: Advisory Panel; Self; Daiichi Sankyo Company, Limited. A. Cato: None. T. Hershey: Research Support; Spouse/Partner; Sage Pharmaceuticals. L.A. Fox: None. K.A. Englert: Consultant; Self; PicoLife Technologies, LLC. A.L. Reiss: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (DIRECNET: U01HD-41906, HD-41908, HD-41915, HD-41918, HD-56526, R01HD078463, U54HD087011; National Center for Advancing Translational Sciences (UL1TR000448)

Youth with type 1 diabetes (T1D) who have A1c levels ≥ 9% have a 13-fold higher rate of diabetic ketoacidosis (DKA) than youth with A1c Methods: Youth ages 8-18 years with uncontrolled T1D (A1c> 8.5%) on MDI treatment were enrolled in the study. Blood glucose (BG) and blood β-hydroxybutyrate (BHB) levels were measured by school personnel in the AM on arrival to school. Results: 14 patients (age 15 ± 2.3 years) enrolled in the study had A1c 10.7 ± 1.5% (range 8.8 - 14.0%). BHB or urine ketones were measured on 125 school days; ketone levels were small (0.6-0.9 mmol/L) on 6.4% of days (mean BHB 0.7+0.1 mmol/L) and moderate/large (>0.9 mmol/L) on 10.4% of days (mean BHB 2.1+1.4 mmol/L) (Figure). BG ranged between 147 to >600 mg/dL on days with elevated BHB levels; all were without other signs or symptoms of DKA. Conclusions: Unrecognized mild to moderate ketosis during regular school attendance is common in youth with uncontrolled T1D on MDI therapy. Novel strategies, such as having school personnel supervise injections of long-acting basal insulin, are needed to support reliable insulin dosing to prevent ketosis in youth with uncontrolled T1D at risk for DKA Disclosure L.M. Nally: None. S. Elahi: None. M.A. Van Name: Research Support; Self; Novo Nordisk Inc. A. Steffen: None. E.M. Tichy: None. A.D. Urban: None. K. Weyman: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Funding Novo Nordisk

Tobacco use confers unique risks to persons with type 1 diabetes (T1D). This study examined associations between tobacco use and diabetes outcomes using the Type 1 Diabetes Exchange Registry. Participants (N=933) were adults who completed an emailed set of standardized self-report instruments that included items on tobacco use. Participants were on average (SD) 38 (16) years of age, 61% female, and 90% non-Hispanic white. The majority had never used tobacco products (55%, n = 515); 18% (n = 166) were current users and 27% (n = 252) were former users. After controlling for relevant covariates, diabetes self-care scores and frequency of self-monitoring of blood glucose were lower among current users vs. never and former users, adjusted ps ≤ .01. Chart-extracted A1c values and participant-reported diabetes distress scores were higher among current users vs. never or former users, adjusted ps ≤ .001. BMI was lower among current smokers relative to never and former users, adjusted p = .04, but the odds of a nephropathy diagnosis or history of severe hypoglycemia or hospitalization for diabetic ketoacidosis did not differ by tobacco status. Among current users and relative to non-daily use, daily use was associated with significantly worse outcomes on diabetes self-care and diabetes distress scores and A1c values. These cross-sectional comparisons suggest that current tobacco use, particularly daily use, is associated with worse status on several clinical indicators outside BMI. Former users do not evidence these negative impacts on diabetes outcomes. Future research should assess whether better functional status on clinical indicators of diabetes management are causally related to successful smoking cessation. In this sample, smoking rates among individuals with T1D were higher than the national average, suggesting a need for evidence-based tobacco cessation strategies directed toward this high risk group. Disclosure C. Rash: None. J. Wagner: None. S.M. Alessi: None. N.C. Foster: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. M.A. Van Name: Research Support; Self; Novo Nordisk Inc.

Objective: This randomized, controlled trial evaluated a monetary-based reinforcement intervention for increasing self-monitoring blood glucose (SMBG) among youth with poorly controlled type 1 diabetes. SMBG frequency was the primary outcome, A1c was the secondary outcome. Methods: After a 2-week baseline, 60 youth age 12-19 years with 7.5% but ≤13% were randomized to enhanced usual care (EUC) or Reinforcers. The Reinforcers group earned monetary rewards for SMBG and associated behaviors such as uploading glucose meters, completing pattern recognition forms, and reviewing results with clinicians. Reinforcers were withdrawn at 24 weeks. A follow-up evaluation occurred at 36 weeks. Results: Randomization produced groups that did not differ on any demographic or clinical characteristics. Participants in the Reinforcers group increased the proportion of days they completed ≥4 SMBG from 14.6% at baseline to 64.4%, 47.5%, and 37.8% at 6, 12, and 24 weeks, respectively. In contrast EUC participants declined from 22.7% at baseline to 17.5%, 10.5%, and 11.1% (ps Conclusions: Monetary-based reinforcement of adolescents with type 1 diabetes caused durable increases in SMBG. Modification of the reinforcement structure may be needed to sustain improved metabolic control in this challenging age group. Disclosure J. Wagner: None. K. Weyman: None. E.M. Tichy: None. E. Cengiz: Advisory Panel; Self; Abvance, ADOCIA, MannKind Corporation, Novo Nordisk Inc. Speaker's Bureau; Self; Novo Nordisk Inc. K. Zajac: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited.

Despite the availability of the first automated hybrid closed-loop (HCL) system for type 1 diabetes (T1D), many youth do not use the automated feature. This 18-week prospective pilot study evaluates the impact of behavioral economic principles on 670G HCL system use in adolescents and young adults with T1D. Small monetary rewards were given for wearing/calibrating the CGM and using “auto mode.” For each of these tasks, participants received $1/day with a $3/week bonus for sustained use, with the bonus increasing by $5/week for every consecutive week the CGM is worn, up to $13/week. Participants were also rewarded for giving at least 3 meal boluses/day ($1/day), and uploading glycemic data ($5/week). However, if participants failed to perform diabetes tasks, rewards decreased to their original values. Data from 16 participants (16.2±2.5 years, 56% F) were collected at baseline, 6, 12, and 18 weeks. Of those not wearing a CGM at enrollment (88%), 86% had used a CGM previously and chose to discontinue its use. Participants used the CGM on most days, and gave at least 4 meal boluses/day consistently. HbA1c decreased by 0.5% from baseline to 6 weeks and was maintained at 12-18 weeks (p70% of time during reinforcement. Disclosure L.M. Nally: None. J. Wagner: None. M.A. Van Name: Research Support; Self; Novo Nordisk Inc. J. Sherr: Advisory Panel; Self; Bigfoot Biomedical, Eli Lilly and Company, Insulet Corporation. Consultant; Self; Lexicon Pharmaceuticals, Inc., Medtronic, Sanofi. Research Support; Self; Dexcom, Inc., Insulet Corporation. K. Zajac: None. J.L. Finnegan: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Funding National Institutes of Health (1DP3DK097705-01)

In this report, we examined and compared changes in diabetes technology use and HbA1c levels from data collected in 22,470 participants in the T1DX clinic registry (mean age 26±18 years, duration 14±13 years) between 2016 and 2017 with registry data collected from 25,529 participants (mean age 22±17 years, duration 10±12 years) between 2010 and 2012. There was a moderate increase in insulin pump use across all age groups from 57% in the 2010-12 cohort to 63% in the 2016-17 cohort. In contrast, continuous glucose monitoring (CGM) use rose sharply from 7% to 28%, with the most dramatic increase in the preadolescent and young child groups (4% to 35% for participants Conclusion: In the T1D Exchange registry, HbA1c levels have increased although HbA1c remains lower in CGM users than non-users. Disclosure N.C. Foster: None. K. Miller: None. L. DiMeglio: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., Medtronic, Sanofi, Caladrius Biosciences, Inc., Janssen Research & Development, Xeris Pharmaceuticals, Inc., Sanofi. D.M. Maahs: Advisory Panel; Self; Insulet Corporation. Consultant; Self; Abbott. Research Support; Self; Medtronic, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Roche Diabetes Care Health and Digital Solutions. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. R.M. Bergenstal: Research Support; Self; Johnson & Johnson Services, Inc.. Consultant; Self; Johnson & Johnson Services, Inc.. Research Support; Self; Abbott. Advisory Panel; Self; Abbott. Research Support; Self; Becton, Dickinson and Company. Consultant; Self; Becton, Dickinson and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Takeda Pharmaceuticals U.S.A., Inc., Dexcom, Inc.. Stock/Shareholder; Self; Merck & Co., Inc.. Research Support; Self; Eli Lilly and Company, Sanofi. Advisory Panel; Self; Sanofi, Roche Pharma. Research Support; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Medtronic. Consultant; Self; Medtronic. Research Support; Self; Hygieia. Advisory Panel; Self; Hygieia, Glooko, Inc.. Research Support; Self; JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases. M.A. Clements: Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Glooko, Inc. M.R. Rickels: Consultant; Self; Hua Medicine, Xeris Pharmaceuticals, Inc.. E. Smith: None. B.A. Olson: None. R. Beck: Consultant; Self; Eli Lilly and Company. Research Support; Self; Abbott. Consultant; Self; Bigfoot Biomedical. Research Support; Self; Dexcom, Inc.. Consultant; Self; Insulet Corporation. Research Support; Self; Roche Diabetes Care Health and Digital Solutions. Consultant; Self; Merck & Co., Inc., Xeris Pharmaceuticals, Inc..

Sodium-glucose cotransporter-2 (SGLT2) inhibition reduces hyperfiltration in adults with T1D, likely by inducing natriuresis, which stimulates tubuloglomerular feedback. This exploratory analysis aimed to examine whether these renal effects occur acutely within 24 hours of SGLT2 inhibition following a single exposure to empagliflozin (EMPA) in youth with T2D. In this single-administration, open-label, randomized, parallel-group study (NCT02121483), 27 patients with T2D (mean age 14.1 years, 67% girls, mean BMI 35.5 kg/m2) received EMPA 5, 10 or 25 mg. The effects of EMPA on fractional sodium excretion (FENa+) and estimated GFR (eGFR as assessed by Zappitelli-combined creatinine and cystatin C equation) were investigated by pooling the three doses of EMPA for analyses. At baseline, mean (SD) baseline FENa+ was 0.55% (0.46), and eGFR was 123.4 ml/min/1.73m2 (15.6). After a single dose of EMPA, the adjusted mean change from baseline in FENa+ was +0.81% (95% CI 0.27, 1.36; p=0.006). The adjusted mean change from baseline in eGFR was -5.5 ml/min/1.73m2 (95% CI -8.3, -2.7; p=0.0006). In eGFR subgroups of interest, eGFR decreased by -6.7 (9.7) ml/min/1.73m2 in patients with hyperfiltration (n=8, eGFR >119.1 ml/min/1.73m2, [95th percentile of eGFR for obese youth in NHANES]) and by -5.0 (6.0) ml/min/1.73m2 in patients with normofiltration (n=19). SGLT2 inhibition following a single dose of EMPA was associated with acute natriuresis and attenuation of elevated GFR in youth with T2D, suggesting a reduction in intraglomerular pressure. Further mechanistic studies are required to define changes in renal function, and longer-term trials examining renal protective effects in youth with diabetes are needed. Disclosure P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. G. Simons: Employee; Self; Boehringer Ingelheim GmbH. S. Hantel: Employee; Self; Boehringer Ingelheim GmbH. M. von Eynatten: Employee; Self; Boehringer Ingelheim GmbH. J.T. George: Employee; Self; Boehringer Ingelheim GmbH. J. Marquard: Employee; Self; Boehringer Ingelheim GmbH. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc..

Background: Treatment options for youth with type 2 diabetes (T2D) are limited compared to those for adults with T2D. As pediatric clinical trials in T2D are difficult to complete, due to lower prevalence and population related recruitment challenges, clinical sites are often reluctant to participate. Protocol design, often not appropriate for pediatrics, administrative and financial burden related to study participation further reduce site interest. Methods: The Pediatric Diabetes Consortium (PDC) is a network of 49 U.S. diabetes centers working together to improve care for children with diabetes. Recognizing challenges associated with pediatric T2D clinical trial participation, the PDC developed a network model to improve efficiency for both sites and sponsors. Innovations: A consulting group was formed to assist with protocol design appropriate for T2D pediatric studies. A PDC master agreement with sites eliminates need for negotiation of standard contract language between sponsor and each site, allowing for a single contract between the PDC and sponsor. A single budget, based upon a clinical trial budget template, reflecting actual site costs, is negotiated by the PDC for all sites. Central archiving of site metrics eliminates need for a feasibility survey before site selection occurs. Monthly site calls led by an investigator oversight committee provide opportunities to discuss enrollment strategies, study challenges and best practices, and provide real-time feedback to sponsor. Conclusion: Efficiencies established by the PDC network model reduce workload for sites and start-up timeline for sponsors. Population-appropriate trial design improves recruitment opportunities. Ongoing site engagement helps to identify and mitigate protocol issues in real-time. The network model improves likelihood of successful trial operations. To date, 26 PDC sites have participated in at least 1 of 3 studies, enrolling 137 across studies so far, contributing to successful recruitment ahead of projected schedule. Disclosure R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc.. K.D. Keelin: None. J.E. Less: None. B.A. Nelson: Speaker's Bureau; Self; Dexcom, Inc.. K.A. Wintergerst: None. G.J. Klingensmith: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Foundation. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc..

Objective: To describe the characteristics of youth diagnosed with T2D who have tested positive for ≥1 islet autoantibody (IA) and to examine the persistence of IA over time. Methods: Youth enrolled in the PDC T2D Registry with ≥2 years follow-up after diagnosis and ≥1 positive IA at any time were identified. T2D was determined using ADA guidelines. IAs were measured at each PDC site according to local practice and included IAA, GADA, IA-2A, ZnT8A, and ICA. Positive IAA tests were excluded if measured after insulin initiation. Clinical characteristics, clinical presentation, and treatment over time were analyzed. Results: Positive IA is an exclusion for enrollment in the PDC T2D Registry; however, on review of the ∼1,300 youth in the PDC, 38 were found to have IA. A single IA was found in 35 and >1 IA in 3 participants. GADA was most common (N=32); 3 were persistently positive, 13 converted to negative, 8 became positive after a negative GADA, and 8 had only 1 IA determination. Positive IAA (N=5), IA-2A (N=4) and ZnT8 (N=1) were uncommon or rare, no positive ICA were found. At diagnosis, those IA positive were more likely to be treated with insulin (95% vs. 73%) but with similar HbA1c (10.4% vs. 10.0%). At last visit, those IA positive had longer diabetes duration (5.7 years. vs. 4.8 years.) and higher insulin use (71% vs. 59%) compared to the IA negative cohort, but HbA1c levels were similar (8.7% vs. 9.0%). Age at diagnosis, race/ethnicity, percent male, and BMI were not different between those with and without IA. Conclusion: Most IA positive youth with a T2D phenotype require insulin at diagnosis and more IA positive than IA negative youth require insulin during follow-up treatment. These findings suggest the importance of IA ascertainment at diagnosis and in those failing oral therapy. In T2D youth GADA is the most common IA; yield from ZnT8 and ICA determinations is low; fluctuations in IA positivity are not uncommon. Additional study of youth with T2D phenotype and IA is needed. Disclosure G.J. Klingensmith: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Foundation. P. Cheng: None. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. M.M. Kelsey: Other Relationship; Self; Daiichi Sankyo Company, Limited, Merck Sharp & Dohme Corp. C. Kollman: Research Support; Self; JDRF, Bigfoot Biomedical, Dexcom, Inc., Tandem Diabetes Care, Inc., Medtronic MiniMed, Inc., Helmsley Charitable Trust.

Objective: To compare characteristics of youth with T1D (n = 484) vs. T2D (n = 1169) in the PDC. Methods: Participants were 10 to Results: T2D youth were more likely to be female (62 vs. 45%, p Conclusion: While families of youth with T2D face greater socio-economic obstacles and risk factors for poor diabetes outcomes, the greater retention of residual endogenous insulin secretion likely contributes to the increased ability of T2D youth to to maintain target HbA1c levels over time. Disclosure W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. P. Cheng: None. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. C. Kollman: Research Support; Self; JDRF, Bigfoot Biomedical, Dexcom, Inc., Tandem Diabetes Care, Inc., Medtronic MiniMed, Inc., Helmsley Charitable Trust. M.A. Van Name: None. J.L. Lynch: Other Relationship; Self; Novo Nordisk Inc.. Research Support; Self; Daiichi Sankyo Company, Limited. B.A. Nelson: Speaker's Bureau; Self; Dexcom, Inc..

Diabetic kidney disease (DKD) is a major complication of T1D. To better understand the risks of developing DKD, we evaluated risk factors in participants from the T1D Exchange registry who completed 5-year follow-up. Participants had at least two eGFR and albuminuria measurements recorded during the 5 year period; also T1D duration ≥1 year, age ≥10 years, eGFR ≥60 ml/minute and no documented albuminuria at enrollment. Adverse kidney outcomes were defined as eGFR Disclosure J.B. McGill: Research Support; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Aegerion Pharmaceuticals. Consultant; Self; Bayer AG, Dexcom, Inc., Intarcia Therapeutics, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., MannKind Corporation. Research Support; Self; Novartis Pharmaceuticals Corporation. Consultant; Self; Novo Nordisk A/S. M. Wu: None. R. Pop-Busui: Research Support; Self; AstraZeneca. K.R. Mizokami-Stout: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. G. Aleppo: Research Support; Self; AstraZeneca, Novo Nordisk Inc.. Consultant; Self; Dexcom, Inc.. Advisory Panel; Self; Novo Nordisk Inc.. R. Gubitosi-Klug: None. M.J. Haller: None. S.M. Willi: Advisory Panel; Self; Boehringer Ingelheim GmbH. Other Relationship; Self; Caladrius Biosciences, Inc.. Consultant; Self; GlaxoSmithKline plc., JAEB Center For Health Research. N.C. Foster: None. C. Zimmerman: None. I. Libman: Consultant; Self; Novo Nordisk A/S. S. Polsky: Research Support; Self; Dexcom, Inc.. Other Relationship; Self; T1D Exchange. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. M.R. Rickels: Consultant; Self; Hua Medicine, Xeris Pharmaceuticals, Inc..

Substance use can have adverse effects on many health conditions, yet little is known about the prevalence of use in individuals with type 1 diabetes (T1D). We evaluated the frequency of use and problem use of psychoactive substances in adults with T1D. Standardized instruments for assessing tobacco, alcohol, and psychoactive substance use were emailed to 4311 adult participants at 69 T1D Exchange Clinic Registry centers. A total of 936 respondents (61% female, 90% non-hispanic white, age 38±16 years) completed the survey. In the sample, tobacco use was reported by 166 (18%) participants in the past year and 51 (5%) daily (Figure 1). Past year alcohol use was reported by 742 (79%) participants, past month use by 592 (63%) and daily or near daily use by 87 (9%). Use of any other psychoactive substance in the past year was reported by 228 respondents (24%), with marijuana being the most commonly used substance (Figure 2). Past year problem use of these substances was noted in 31 (3%) respondents. Adults with T1D in the U.S. use substances at rates that meet or exceed that of the general population; problematic use occurs at rates similar to the general population. These data delineate the need to inquire about regular, intermittent and problematic use of nicotine, alcohol, and other substances in individuals with T1D. A better understanding of the impact of moderate and occasional use of substances on T1D management and clinical outcomes is also needed. Disclosure N. Petry: None. N.C. Foster: None. E. Cengiz: Advisory Panel; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; MannKind Corporation, ADOCIA, Arecor. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. J. Wagner: None. S. Polsky: Research Support; Self; Dexcom, Inc.. Other Relationship; Self; T1D Exchange. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases.

Introduction: Youth with T2D are at risk for additional cardiovascular (CVD) diseases such as hypertension (HT) and hyperlipidemia (HLD). We examined healthcare provider (HCP) self-reported practices regarding management and treatment of HT and HLD in youth with T2D. Methods: An electronic survey collected information from prescribing HCPs from Pediatric Diabetes Consortium sites regarding their usual treatment of and barriers related to treatment of HT and HLD in youth with T2D. Results: Respondents (N=70) were predominately female (67%) from urban (77%) academic centers (70%). HT and HLD treatment recommendations focused on lifestyle modifications including healthy eating, weight loss, physical activity, dietitian/nutritionist referral, and improving glycemic control. Medication was recommended initially more than half of time to treat HT and HLD (51% and 62%, respectively). If HT or HLD persisted for an additional 6-12 months, >80% of HCPs would choose to add additional treatment. Less than half of HCPs reported that treatment of HT and HLD is generally effective most/all of the time (42% and 34%, respectively). HCPs reported that obstacles to treatment from the patient’s perspective included lack of support to make lifestyle changes (78%), difficulty following-through with lifestyle changes (80%), lack of motivation to control diseases (68%), socioeconomic challenges (62%), and transportation difficulties (54%). Concerns regarding patient adherence (50%) and inability to focus on both diabetes and HT/HDL due to shortness of visits (42%) were the most commonly cited barriers by HCPs. Conclusion: Given that youth with T2D have high risk of developing CVD complications, HCP approaches to treat both HT and HLD are important. Notably, the majority report their recommendations are ineffective. Patient-related barriers are the biggest challenge to effective treatment; future research should explore ways to mitigate these barriers. Disclosure L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc.. P. Cheng: None. M. Katz: None. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. M.A. Van Name: None. N. Bansal: None. C. Kollman: Research Support; Self; JDRF, Bigfoot Biomedical, Dexcom, Inc., Tandem Diabetes Care, Inc., Medtronic MiniMed, Inc., Helmsley Charitable Trust. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc..

In 2014, the American Diabetes Association lowered its recommended HbA1c target for children with type 1 diabetes (T1D) from Disclosure J. Wood: None. C. Boyle: None. M. Quinn: None. J.C. Wong: Research Support; Self; Dexcom, Inc.. Other Relationship; Self; Tidepool Project. M.J. Haller: None. B.A. Nelson: Speaker's Bureau; Self; Dexcom, Inc.. M.J. Haller: None. D. Schatz: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. L. Fox: None. P. Prahalad: None. S. Corathers: None. D.M. Maahs: Advisory Panel; Self; Insulet Corporation. Consultant; Self; Abbott. Research Support; Self; Medtronic, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Roche Diabetes Care Health and Digital Solutions. G.T. Alonso: None. D.J. DeSalvo: Consultant; Self; Dexcom, Inc.. Speaker's Bureau; Self; Insulet Corporation. R. Wadwa: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc., Novo Nordisk Inc., MannKind Corporation, Bigfoot Biomedical. L. DiMeglio: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., Medtronic, Sanofi, Caladrius Biosciences, Inc., Janssen Research & Development, Xeris Pharmaceuticals, Inc., Sanofi.

Enthusiasm for SGLT2 inhibitors as adjunctive agents for T1D has been tempered by increased risk of DKA, especially in pump treated patients susceptible to interruptions of basal insulin due to infusion site failures. Our insulin interruption study showed that failure to recognize early metabolic decompensation in SGLT2i-treated T1D patients relates to blunted increases in plasma glucose (PG) rather than accelerated ketogenesis (Δ PG 99±13 vs. 197±24 mg/dL, p Disclosure S. Siebel: None. N.S. Patel: Consultant; Self; Janssen Pharmaceuticals, Inc.. A. Galderisi: None. L.R. Carria: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. J. Sherr: Consultant; Self; Medtronic MiniMed, Inc.. Advisory Panel; Self; Insulet Corporation, Eli Lilly and Company, Bigfoot Biomedical.

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to

OBJECTIVE The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents. RESULTS During 10 years of follow-up, HbA1c (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P = 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%). CONCLUSIONS Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.

Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4–10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (±SD) HbA1c level was 7.9 ± 0.9% (63 ± 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes.

The profile of insulin secretion and the role of proinsulin processing across the spectrum of glucose tolerance in obese youth have not been studied. The aims of this study were to define the role of insulin secretion and proinsulin processing in glucose regulation in obese youth. We performed hyperglycemic clamps to assess insulin secretion, applying a model of glucose-stimulated insulin secretion to the glucose and C-peptide concentration data. Thirty obese youth with normal glucose tolerance (NGT), 22 with impaired glucose tolerance (IGT), and 10 with type 2 diabetes were studied. The three groups had comparable anthropometric measures and insulin sensitivity. The glucose sensitivity of first-phase secretion showed a significant stepwise decline from NGT to IGT and from IGT to type 2 diabetes. The glucose sensitivity of second-phase secretion was similar in NGT and IGT subjects yet was significantly lower in subjects with type 2 diabetes. Proinsulin-to-insulin ratios were comparable during first- and second-phase secretion between subjects with NGT and IGT and were significantly increased in type 2 diabetes. Obese youth with IGT have a significant defect in first-phase insulin secretion, while a defect in second-phase secretion and proinsulin processing is specific for type 2 diabetes in this age-group.

We have previously reported that a glucosensor integrating hormonal responses to hypoglycemia is located in the ventromedial hypothalamus (VMH) and that local VMH glucose perfusion blocks counterregulatory hormone responses. To determine whether the by-product of glucose metabolism, lactate, can function within the VMH as an alternative for glucose, we delivered lactate locally to the VMH, during systemic hypoglycemia. For this purpose, we combined bilateral VMH microdialysis perfusion (metabolically active l-lactate or its nonmetabolizable d-isomer) with a euglycemic-hypoglycemic clamp in conscious chronically catheterized Sprague-Dawley rats. Local VMH perfusion with l-lactate decreased counterregulatory hormone responses to hypoglycemia by 80–85% as compared with the nonmetabolizable d-lactate control. Moreover, hormonal suppression with l-lactate was accompanied by an approximate fourfold increase in the amount of exogenous glucose infused to maintain a stable hypoglycemic plateau (P < 0.05). In conclusion, the glucose-sensing mechanism in the VMH responds to lactate and, thus, is not specific for glucose. This implies that the VMH may act as a fuel sensor rather than as a glucose sensor.

Previous studies have demonstrated that the ventromedial hypothalamus (VMH) plays a critical role in sensing and responding to systemic hypoglycemia. To evaluate the mechanisms of defective counterregulation caused by iatrogenic hypoglycemia and diabetes per se, we delivered 2-deoxy-glucose (2-DG) via microdialysis into the VMH to produce localized cellular glucopenia in the absence of systemic hypoglycemia. Three groups of awake chronically catheterized rats were studied: 1) nondiabetic (with a mean daily glucose [MDG] of 6.9 mmol/l) BB control rats (n = 5); 2) chronically hypoglycemic nondiabetic (3-4 weeks, with an MDG of 2.7 mmol/l) BB rats (n = 5); and 3) moderately hyperglycemic insulin-treated diabetic (with an MDG of 12.4 mmol/l) BB rats (n = 8). In hypoglycemic rats, both glucagon and catecholamine responses to VMH glucopenia were markedly (77-93%) suppressed. In diabetic rats, VMH 2-DG perfusion was totally ineffective in stimulating glucagon release. The epinephrine response, but not the norepinephrine response, was also diminished by 38% in the diabetic group. We conclude that impaired counterregulation after chronic hypoglycemia may result from alterations of the VMH or its efferent pathways. In diabetes, the capacity of VMH glucopenia to activate the sympathoadrenal system is only modestly diminished; however, the communication between the VMH and the alpha-cell is totally interrupted.

We used microdialysis to distinguish the effects of hyperinsulinemia and hypoglycemia on glucose, gluconeogenic substrate, and catecholamine levels in adipose and muscle extracellular fluid (ECF). Ten lean humans (six males and four females) were studied during baseline and hyperinsulinemic (3 mU x kg-1 x min-1 for 3 h) euglycemia (5.0 mmol/l) and hypoglycemia (2.8 mmol/l). In muscle and adipose, basal ECF glucose was lower (muscle, 3.5 +/- 0.2 mmol/l; adipose tissue, 3.3 +/- 0.2 mmol/l) and lactate was higher (muscle, 2.2 +/- 0.2 mmol/l; adipose, 1.5 +/- 0.3 mmol/l) than respective plasma values (glucose, 4.9 +/- 0.1 mmol/l; lactate, 0.7 +/- 0.1 mmol/l), whereas alanine was higher in muscle ECF (379 +/- 22 micromol/l) than adipose tissue (306 +/- 22 micromol/l) and plasma (273 +/- 33 micromol/l). Plasma catecholamines (unchanged during euglycemia) rose during hypoglycemia with epinephrine, increasing approximately fivefold more than norepinephrine. In contrast, the hypoglycemia-induced increments in muscle dialysate norepinephrine and epinephrine were similar, suggesting local generation of norepinephrine. Compared with euglycemia, hypoglycemia produced a greater increase in lactate and a smaller reduction in alanine in muscle ECF, whereas hypoglycemia caused a greater relative fall in ECF glucose concentrations in muscle (72 +/- 16%) and adipose tissue (69 +/- 9%) than in plasma (42 +/- 3%) (P < 0.05). We conclude that hypoglycemia increases the generation of norepinephrine and gluconeogenic substrates in key target tissues, while increasing the plasma-tissue concentration gradient for glucose. These changes suggest the stimulation of glucose extraction by peripheral tissues, despite systemic counterregulatory hormone release and local sympathetic activation.

IDDM subjects lose the ability to release glucagon during hypoglycemia. Because replacement of basal levels of amino acids enhances the glucagon response to hypoglycemia in healthy subjects, we tested whether raising amino acid levels during hypoglycemia could reverse the defective α-cell response in IDDM patients. For this purpose, 11 IDDM patients (HbA1 9.4 ± 0.6%) and 8 healthy, nondiabetic subjects received two hypoglycemic insulin clamp studies (0.8 mU.kg−1 · min−1) in which plasma glucose was clamped at 55 mg/dl (3.08 mM) for 180 min. During one of the studies, an infusion of amino acids was superimposed between 120 and 180 min (0.3 g.kg−1 · h−1). This dose of amino acids had a small effect on plasma glucagon levels during euglycemic hyperinsulinemia that was comparable in normal and IDDM subjects. In healthy control subjects, plasma glucagon rose by 80% during the initial hypoglycemic phase of the study. The addition of amino acids produced a further sharp (200–250 ng/L, P < 0.02) rise in plasma glucagon, such a change did not occur in the absence of amino acids. In contrast, plasma glucagon in IDDM patients failed to increase during hypoglycemia alone and rose by only 40–50 ng/L (P < 0.05 vs. controls) when amino acid infusion was superimposed, even though plasma amino acid levels rose to the same extent in IDDM and control subjects. More importantly, the rise in glucagon produced by amino acids was comparable during hypoglycemic and euglycemic hyperinsulinemia in the IDDM patients, results strikingly different from those observed in nondiabetic control subjects. We conclude that hypoglycemia greatly amplifies the α-cell response to hyperaminoacidemia in healthy subjects but not in IDDM.

Studies performed in adults with long-standing obesity suggest a reduced lipolytic sensitivity to catecholamines in subcutaneous abdominal adipose tissue (AT). We used microdialysis to study the in situ lipolytic effects of dobutamine (selective beta1-agonist) and terbutaline (selective beta2-agonist) on glycerol release (lipolytic index) in abdominal subcutaneous AT in 10 obese girls aged 13-17 years, BMI 38 +/- 2.1 kg/m2, and in 7 lean girls aged 11-17 years, BMI 21 +/- 1.1 kg/m2, and compared them with 10 obese women aged 21-39 years, BMI 36 +/- 1.6 kg/m2, and 10 lean women aged 18-42 years, BMI 21 +/- 0.4 kg/m2. Terbutaline at 10(-6) mol/l stimulated glycerol release more efficiently in lean girls than in obese girls (peak response approximately 350 vs. 150% of control, P < 0.01). At the lower concentration of agonist, no significant difference was seen. In women, terbutaline was more effective in lean than in obese women in stimulating glycerol release at both 10(-8) mol/l (peak response lean approximately 175% vs. obese 125% of control) and 10(-6) mol/l (approximately 300 vs. 150% of control, P < 0.05). No significant difference in glycerol release between obese and lean girls or women was detected with selective beta1-stimulation. Our data demonstrate a specific impairment in the capacity of beta2-adrenergic agonists to promote lipolysis in subcutaneous abdominal adipose tissue of obese adolescent girls and women. Thus, decreased mobilization of fat during activation of the adrenergic system might be present early in the development of adolescent obesity.

In poorly controlled insulin-dependent diabetes mellitus (IDDM), hyperglycemia fails to inhibit the pituitary response to growth hormone-releasing factor (GRF). To evaluate whether this derangement is reversed by a simultaneous elevation of circulating insulin, 0.3 micrograms/kg i.v. GRF 1-40 was administered to nine poorly controlled IDDM subjects (HbA1 greater than 11.1%) with and without concomitant infusion of insulin. In the absence of insulin, the poorly controlled IDDM subjects demonstrated a growth hormone response to GRF similar to that of nondiabetic subjects, despite marked hyperglycemia (approximately 16.8 mM). When insulin was infused into these same patients (insulin clamp) to produce combined hyperinsulinemia (528 +/- 90 pM) and hyperglycemia (16.5 +/- 1.98 mM), the GRF-induced growth hormone rise was markedly exaggerated (65 +/- 11 vs. 20 +/- 4 micrograms/L without insulin infusion, P less than 0.001). This enhancement of GRF-stimulated growth hormone release by insulin was strikingly attenuated (22 +/- 7 micrograms/L) in five well-controlled diabetic subjects studied under conditions of similar hyperinsulinemia (486 +/- 84 pM) and hyperglycemia (16.41 +/- 0.95 mM). In contrast, in nondiabetic subjects, acute hyperinsulinemia reduced the growth hormone response to GRF. We conclude that the failure of hyperglycemia to block the pituitary response to GRF in poorly controlled diabetes is not attributable to the lack of a coincident increase in circulating insulin. The paradoxical stimulatory effect of insulin on GRF-induced growth hormone release may contribute to the high spontaneous growth hormone levels characteristically seen in poorly controlled insulin-treated patients, and its attenuation after intensive insulin therapy may contribute to the reversal of growth hormone hypersecretion in well-controlled diabetic patients.

To evaluate the effects of childhood and poorly controlled insulin-dependent diabetes mellitus (IDDM) on counterregulatory hormone and symptomatic responses to hypoglycemia, we studied 16 nondiabetic children (13 +/- 2 yr), 19 nondiabetic adults (26 +/- 3 yr), and 13 children with IDDM (14 +/- 2 yr, HbA, 15.1 +/- 3.3%) during a gradual reduction in plasma glucose with the glucose-clamp technique. Plasma glucose was reduced from approximately 5 to approximately 2.8 mM over 240 min with serial assessment of counterregulatory hormone levels and symptom awareness. The plasma glucose level that triggered a sustained rise in plasma epinephrine was consistently higher in nondiabetic children than in adults (3.9 +/- 0.06 vs. 3.2 +/- 0.06 mM, P less than 0.001). Poorly controlled IDDM further elevated the glucose threshold for epinephrine release to normoglycemic levels (4.9 +/- 0.2 mM, P less than 0.001 vs. both control groups). Age and IDDM also produced an upward shift in the glucose level at which growth hormone release and symptom awareness were initiated. In contrast to the effect on glucose thresholds, maximal epinephrine responses and symptom scores were increased only by age and not IDDM (2-fold higher in children). We conclude that childhood and poor diabetes control independently contribute to an upward shift in glucose thresholds for counterregulatory hormone release and symptom awareness during mild hypoglycemia. Normoglycemic counterregulation may interfere with efforts to control diabetes in young patients.

To evaluate the impact of mild hypoglycemia on CNS function in healthy adults, we measured brain stem auditory evoked potentials and P300 potentials (elicited by cognitive processing of auditory stimuli) during hypoglycemic or euglycemic insulin clamps (80 mU · m−2 · min−1). In the hypoglycemic clamp study (n = 8), plasma glucose was allowed to fall from 4.6 to 3 mM in hourly ∼0.5-mM steps and subsequently returned to euglycemic baseline levels. In the euglycemic clamp study (n = 8), plasma glucose was maintained at baseline levels throughout. Neither brain stem nor P300 responses changed during the euglycemic control study; symptoms and counterregulatory hormones were also unaffected. During the hypoglycemia study, epinephrine and growth hormone rose once plasma glucose reached 3.4 ± 0.1 mM. Brain stem and P300 potentials remained unchanged until the 3-mM glucose step, when neurophysiological changes suddenly developed in conjunction with reported symptoms. At this glucose level, the wave V component of the brain stem potential was selectively altered in 7 of 8 subjects. Furthermore, P300 latency significantly increased, and amplitude diminished. Changes in both brain stem and cortical (P300) responses reversed when euglycemia was restored. We conclude that modest reductions in plasma glucose (to 3 mM) produce marked alterations in both brain stem and cortical responses to auditory stimuli. These changes in neural function appear at the same time as symptoms and follow rather than precede the rise in counterregulatory hormones during hypoglycemia. Our data suggest that the adverse effects of mild hypoglycemia on brain function are not limited to higher centers but also involve the brain stem.

To examine the impact of diabetes and its treatment on plasma free-fatty acid (FFA) and oxidative fuel metabolism during hypoglycemia, we combined indirect calorimetry with [3-3H]glucose during a 4-h low-dose insulin infusion (plasma insulin approximately 2-fold above basal) in six poorly controlled and nine well-controlled insulin-dependent diabetes mellitus (IDDM) patients and in six healthy subjects. Diabetic subjects received insulin overnight to maintain euglycemia before study. Although free-insulin levels and counterregulatory hormone responses were similar, the plasma glucose fall was more pronounced in well-controlled diabetic subjects. In well-controlled diabetic and healthy subjects, the small increment in insulin rapidly suppressed plasma FFA and fat oxidation by approximately 50% and stimulated carbohydrate oxidation by approximately 80%. In contrast, plasma FFA levels did not fall in poorly controlled diabetic subjects, and glucose oxidation was not stimulated. To determine whether this resistance to the antilipolytic effect of insulin occurs in the absence of hypoglycemic counterregulation, we used a sequential low-dose euglycemic insulin clamp (0.2, 0.3, and 0.5 mU.kg-1.min-1). In healthy subjects, plasma FFA was nearly maximally suppressed at the lowest insulin dose. In contrast, plasma FFA remained persistently elevated in poorly controlled diabetic subjects at each insulin dose. However, the insulin dose-response curve for suppression of plasma FFA was near normal in well-controlled subjects. We conclude that poorly controlled IDDM diabetic patients are resistant to the antilipolytic effects of insulin and show impaired stimulation of glucose oxidation during insulin-induced hypoglycemia. Amelioration of these defects in well-controlled patients may be another factor contributing to the higher risk of hypoglycemia during intensified insulin therapy.

The efficacy and feasibility of the insulin infusion pump in pregnancy were examined in seven class D to FR diabetics, maintained on the pump at home from 10 to 29 wk gestation until delivery. An improvement in glucose control was achieved within the first month and sustained to term. Home monitoring demonstrated a fall in mean blood glucose levels from 135 mg/dl range 98–175, prepump) to 104 mg/dl (range 84–120) and a 25–30% reduction in standard deviations during pump treatment. Furthermore, glycosylated hemoglobin levels were normalized in each patient. During periodic inpatient evaluations, mean 24-h plasma glucose levels were slightly, but not significantly, lower after pump treatment (97 vs. 86 mg/dl). However, glycemic excursions were strikingly diminished; MAGE values and standard deviations fell by 45% and 34%, respectively. The total daily insulin dose required at the start of pump treatment was 31% less than the conventional dose used before the pump (P < 0.002). Thereafter the insulin dose increased by approximately 2.5 U/wk, with the basal infusion remaining at 40% of the total dose throughout the pregnancy. All infants were born at term, had no macrosomia or neonatal problems, and had normal intravenous glucose tolerance tests at 2 h of age. We conclude that the insulin infusion pump, managed at home, is a highly efficient way to achieve normal or near-normal glucose levels in the pregnant diabetic.

To evaluate the effect of strict glycemie control of insulin-dependent diabetes mellitus (IDDM) on the plasma glucose threshold initiating counterregulatory hormone responses to hypoglycemia, we used the glucose clamp technique to produce a standardized gradual glucose decline from 90 to 40 mg/dl in seven young IDDM patients before and after 2–6 mo of intensified insulin therapy. Before intensive therapy [hemoglobin A1 (HbA1) 9.6 ± 1.1%], epinephrine responses were triggered at a higher plasma glucose level (67 ± 4 mg/dl) than in normal control subjects (56 ± 1 mg/dl, P < .05), and clinical symptoms of hypoglycemia appeared at glucose levels of 50–60 mg/dl. After intensive therapy (HbA, 7.1 ± 0.7%), the glucose threshold for epinephrine release consistently declined to values (46 ± 2 mg/dl) below normal (P < .01). Furthermore, epinephrine concentrations were markedly reduced at each hypoglycemie level, and a greater hypoglycemie stimulus was required to elicit symptoms. The glucose threshold stimulating release of growth hormone also significantly declined after intensive therapy. We conclude that strict glycemie control of IDDM lowers the plasma glucose level required to generate epinephrine release during hypoglycemia. This may diminish patient recognition of moderate hypoglycemia and increase the risk of severe hypoglycemia in intensively treated IDDM.

The plasma growth hormone, epinephrine, and norephinephrine responses to cycle ergometer exercise (15 min at 1 W/kg) were examined in 10 juvenile-onset, insulin-dependent diabetics (ages 10–32 yr) during conventional insulin treatment and after 7 and 14 days of treatment with a portable subcutaneous insulin infusion system that normalizes plasma glucose. During conventional insulin treatment (mean plasma glucose, 205 ± 22 mg/dl), the growth hormone response to exercise was sevenfold greater than in normal controls (P < 0.01). After 1 wk of insulin pump treatment (mean plasma glucose, 89 ± 3), the growth hormone response fell 62% (P < 0.001); by 2 wk the growth hormone response had fallen 83% (P < 0.001) to values comparable to those of controls. Exercise resulted in a two- to threefold rise in plasma epinephrine in diabetics (P < 0.001) during conventional treatment but failed to elicit a consistent increment in epinephrine in normal control subjects or in the diabetic patients after 14 days of pump treatment. The rise in plasma norepiriephrine after exercise in conventionally treated diabetic patients was 12-fold greater than in healthy control subjects (P < 0.025) but fell 82% (P < 0.001) after 7 days and 88% (P < 0.001) after 14 days of pump treatment to values similar to those of controls. These data indicate that treatment of insulin-dependent diabetics with a subcutaneous portable insulin infusion system that normalizes plasma glucose results in normalization of the growth hormone and catecholamine response to exercise within 7 to 14 days of institution of treatment.

Tissue sensitivity to insulin was studied using the euglycemic insulin clamp technique (Δ plasma insulin above basal 90 μU/ml) in eight patients with type I diabetes mellitus (IDDM) before and after 4–8 mo of continuous subcutaneous insulin infusion (CSII) and in 36 age-matched control subjects. Institution of CSII was associated with significant improvements in glycosylated hemoglobin (HbA1) (11.2 ± 0.6% versus 8.1 ± 0.4%; P Insulin-mediated glucose metabolism in the diabetic patients pre-CSII (3.92 ± 0.36 mg/kg min) was reduced by 44% compared with controls (7.03 ± 0.22 mg/kg min; P < 0.001). After 4–8 mo of improved glycemic control, improved tissue sensitivity to insulin was observed (5.33 ± 0.75 mg/kg·min; P < 0.05 versus pre- CSII). However, insulin-mediated glucose utilization still remained significantly below control values (P < 0.01). During hyperinsulinemia, hepatic glucose production (3-3H-glucose) was suppressed by over 90% in diabetic patients (pre- and post-CSII) and in control subjects. We conclude that near-normalization of glucose metabolism with CSII partially corrects, but does not restore to normal, insulin-stimulated glucose uptake in IDDM. Our failure to totally reverse the impaired response of peripheral tissues to insulin in IDDM patients may be attributed to inadequate metabolic correction, the peripheral route of insulin administration, or a primary defect in glucose metabolism.

To test the hypothesis that variations in rate of glucose fall influence counterregulatory hormone responses to hypoglycemia, we have modified the glucose-clamp technique to provide a reproducible hypoglycemic stimulus in normal and type I diabetic subjects that varied only in the rate of glucose fall. Responsive elevations in plasma epinephrine and norepinephrine and in growth hormone, glucagon, and cortisol were not significantly affected by a ninefold change in the rate at which plasma glucose was lowered from 83 ± 1 to 50 ± 1 mg/dl in normal subjects. Similarly, wide variation in the rate of fall produced no substantive differences in counterregulatory hormone responses to hypoglycemia in diabetic subjects. The plasma glucose threshold at which epinephrine release began, determined from the slow-fall studies, was 63 ± 3 mg/dl in normal subjects but exhibited a wide range (48-74 mg/dl). Similar values were found in the diabetics. Thresholds for growth hormone, cortisol, and glucagon were slightly lower, ranging from 45 to 68 mg/dl in the normals. Our data suggest that counterregulatory hormone responses to hypoglycemia are triggered by the glucose level per se and not by its rate of fall. Furthermore, individual differences in glucose thresholds for epinephrine release may contribute to variations in the glucose level associated with hypoglycemic symptoms.

To evaluate the mechanism underlying raised growth hormone levels in diabetes, we compared the response to growth hormone–releasing factor (GRF) in type I diabetic and healthy control subjects. In 12 poorly controlled diabetic subjects (fasting plasma glucose 276 ± 27 mg/dl) basal serum growth hormone levels were elevated by 200–300% (P < 0.02), yet the incremental increase in growth hormone after GRF injection was no greater than in control subjects. Furthermore, five additional diabetic subjects with normal growth hormone levels after long-term insulin pump treatment also showed an identical response to GRF. Thus, raised basal growth hormone levels in diabetes and the fall that follows intensive insulin treatment may reflect changes in hypothalamic regulation of, rather than in pituitary responsiveness to, GRF. However, when five normal subjects were restudied during glucose infusion, even quite modest hyperglycemie (plasma glucose ∼150 mg/dl) caused marked suppression of the response to GRF (P < 0.005). Thus, the “normal” response to GRF in poorly controlled diabetes is actually inappropriate. Failure of the pituitary to suppress in response to hyperglycemie in diabetes implies a second abnormality that may further aggravate disordered growth hormone secretion.