Acute C-peptide Response Research Articles

Effects of a Carbohydrate-Restricted Diet on β-Cell Response in Adults With Type 2 Diabetes

Abstract Context β-Cell response to glucose is compromised in individuals with type 2 diabetes (T2D), possibly due in part to excessive carbohydrate consumption. Objective This study was conducted to determine if a eucaloric carbohydrate-restricted (CR) diet (∼9% energy from carbohydrate, 65% energy from fat), compared to a eucaloric higher carbohydrate (HC) diet (∼55% energy from carbohydrate, 20% energy from fat), would improve β-cell response to glucose in participants with T2D. Methods Participants were 57 African American and European American adults with T2D not using insulin. Medications were discontinued 1 to 2 weeks prior to baseline testing. A hyperglycemic clamp was used to assess the acute (first-phase) and maximal (arginine-stimulated) C-peptide response to glucose at baseline and after 12 weeks of controlled diet therapy (all food provided). An oral glucose tolerance test (OGTT) was used to assess the disposition index (DI). Results At 12 weeks, a statistically significant effect of diet was observed on acute C-peptide response (2-fold greater with the CR diet; P < .01). For maximal C-peptide, a significant effect of diet was observed (22% greater with the CR diet; P < .05), as was a significant diet-by-race interaction (P < .05), indicating that the diet effect was specific to European Americans (48% greater with the CR diet; P < .01). OGTT results showed a significant effect of diet on DI at 12 weeks (32% greater with the CR diet; P < .05). Conclusion These results suggest that a eucaloric CR diet has beneficial effects on β-cell function in patients with mild T2D.

51-LB: Race Specific Effects of a Carbohydrate-Restricted Diet on Acute and Maximal C Peptide Response to Glucose in Adults with Type 2 Diabetes

Beta-cell response to glucose is compromised in individuals with type 2 diabetes (T2D), possibly due to lipid infiltration of the pancreas from excessive carbohydrate consumption. This study was conducted to determine if a eucaloric carbohydrate restricted diet (~9% energy from carbohydrate, 65% energy from fat), compared to a eucaloric fat restricted diet (~55% energy from carbohydrate, 20%energy from fat), would improve beta-cell response to glucose in participants with T2D. Participants were 43 African American and European American adults with T2D not using insulin. Medications were discontinued 1-2 weeks (depending upon the medication) prior to baseline testing. A hyperglycemic clamp was used to assess the acute (first-phase) and maximal (arginine-stimulated) C-peptide responses to glucose at baseline and after 12 weeks of controlled diet therapy (all food provided). Based on the detection of a race-by-diet interaction (P=0.06), data were analyzed within each race group. At 12 weeks, a significant effect of diet was observed by ANCOVA on acute C-peptide response in African Americans (2-fold greater with the carbohydrate restricted diet, P<0.05), and on maximal C-peptide response in European Americans (50% greater with the carbohydrate restricted diet, P<0.01), after adjusting for change in body weight. Paired t-test revealed an improvement in acute C-peptide response within African Americans on the carbohydrate restricted diet (P<0.01) from baseline to week 12, and an improvement in maximal C-peptide response within European Americans on the carbohydrate restricted diet (P<0.01). No changes in beta-cell function were observed in response to the fat restricted diet. These results suggest that a carbohydrate restricted diet has beneficial effects on beta-cell function that are race-specific and independent of weight loss. Disclosure B. Gower: Consultant; Abbott. A. M. Goss: Advisory Panel; Novo Nordisk, Consultant; Weight Watchers International. W. Garvey: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Eli Lilly and Company, Merck & Co., Inc., Alnylam Pharmaceuticals, Inc., Fractyl Health, Inc., Inogen, Research Support; Novo Nordisk, Eli Lilly and Company, Epitomee, Pfizer Inc., Neurovalens. Funding National Institutes of Health (R01DK116726)

1098-P: Association of Sleep with ß-Cell Response and Insulin Sensitivity in Youth

Poor sleep may be associated with reduced β-cell response or decreased insulin sensitivity in youth. We explored whether sleep duration, sleep quality or obstructive sleep apnea (OSA) risk factors were associated with measures of β-cell response or insulin sensitivity in youth. At baseline, 88 youth (10-19 yrs of age) with recently diagnosed T2D or prediabetes completed validated questionnaires (Sleep Disturbances Scale and Cleveland Adolescent Sleepiness) in the Restoring Insulin Secretion (RISE) Study. Hyperglycemic clamps measured insulin sensitivity (steady state glucose infusion rate/insulin [M/I]) and β-cell responses: acute (0-10 min) C-peptide response to glucose (ACPRg), steady-state C-peptide at a glucose of 11.1 mmol/L (SSCP), and arginine-stimulated maximum C-peptide responses at glucose >25 mmol/L (ACPRmax). Linear regression models explored the independent association between sleep variables and clamp measures, adjusted for age, race/ethnicity, sex, Tanner stage, metformin use and BMI. Models including β-cell responses were adjusted for M/I to account for the role of insulin sensitivity in β-cell function. The cohort was 70% female, 28% white, 25% black, 36% Hispanic; age 14.3±2.0 yrs and BMI 36.9±6.4 kg/m2 (mean±SD). Using ADA criteria, 60% had prediabetes and 40% had T2D; 27% reported metformin use. Sleep duration <8 h was reported in 59%; 57% reported daytime sleepiness; 28% reported poor sleep quality; 29% had high risk for OSA. Low sleep duration (<8 h) was associated with a trend for lower ACPRg (p=0.069). No sleep variables (sleep duration or quality, OSA risk) were associated with clamp-derived outcomes in unadjusted or adjusted linear regression models. In youth with prediabetes or T2D, subjective measures of sleep quantity, sleep quality and OSA risk were not independently associated with β-cell response or insulin sensitivity. Further research using objective measures of sleep may better delineate the relationship between sleep and β-cell function in youth. Disclosure K.A.Temple: None. A.H.Tjaden: None. S.Manchanda: Advisory Panel; Inspire. D.Ehrmann: None. K.J.Nadeau: None. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. B.Mokhlesi: None. Rise consortium: n/a. Funding American Diabetes Association (1-20-RISE-01 to S.E.); National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute

Is β-Cell Dysfunction Present in Adult Autoantibody Negative Relatives of Individuals with Type 1 Diabetes Mellitus?

Background/Objective: Individuals with a family history of type 1 diabetes mellitus (T1D) are at increased genetic risk for T1D. Previous studies identified the presence of β-cell dysfunction before clinical onset and diagnosis of T1D. However, it is unclear if β-cell dysfunction predates islet autoimmunity in individuals at high genetic risk. Our objective was to test β-cell function in islet antibody negative adults who have a first-degree relative with T1D. We hypothesized that individuals at genetic risk for T1D would exhibit β-cell dysfunction even without detectable islet autoimmunity.Methods: We used ordinary one-way and Brown-Forsythe ANOVA to compare the repeated mixed meal tolerance test (MMTT) and hyperglycemic clamp glucose-stimulated β-cell response and function measures between three groups of individuals: normoglycemic adults without T1D family history age, sex, and BMI-matched islet antibody negative first-degree relatives of individuals with T1D, and islet antibody positive first-degree relatives of individuals with T1D.Results: Neither the MMTT first-phase insulin secretion measures (c-peptide0-15 minutes, c-peptide0-30 minutes, insulin0-15 minutes, insulin0-30 minutes), nor second-phase measures (c-peptide0-120 minutes, insulin0-120 minutes, and glucose0-120 minutes) showed a statistically significant difference between groups. The clamp acute c-peptide response to glucose, insulin sensitivity, c-peptide steady state, first-phase β-cell function, and second-phase β-cell function were similar between subject groups in both visits. Fasting proinsulin:c-peptide ratios, a biomarker of β-cell stress, were also similar between participant groups.Conclusion and Impact: Our data suggest that genetically at-risk autoantibody negative adult relatives of individuals with T1D do not demonstrate β-cell dysfunction compared to controls. Studies show that β-cell ER dysfunction preceding T1D onset is more striking in younger children. Thus, our findings may reflect the use of an adult study population. Alternatively, β-cell dysfunction in T1D may require initial autoimmune activation. This study will contribute to the growing understanding of risk factors contributing to T1D development.This project was funded, in part, with support from the Research Training Program in Diabetes and Obesity funded, in part by grant 3T32DK064466 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding also provided by JDRF grant 2-SRA-2017-498-M-B.

A randomized controlled pilot trial of etanercept and alpha-1 antitrypsin to improve autologous islet engraftment

BackgroundIn total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence. MethodsWe randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT. ResultsWe observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females. ConclusionOur randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment. Clinical trial notationThis study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).

828-P: Preservation of ß-Cell Function in Pancreatic Insufficient Cystic Fibrosis (CF) with Highly Effective CFTR Modulator Therapy

CF related diabetes is common with pancreatic insufficient CF (PI-CF) . Highly effective modulator therapy enhances aberrant CF transmembrane conductance regulator (CFTR) function and improves pulmonary and nutritional status. Ivacaftor therapy for indicated CFTR mutations enhanced insulin secretion to glucose-potentiated arginine (GPA) testing; however the effects of elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta™) on β-cell function have not been assessed. We retrospectively compared changes in GPA measures performed on two visits in individuals with PI-CF without diabetes and who were 1) initiated on ETI after the baseline visit (ETI group) vs. 2) not treated with CFTR modulator therapy (controls) . ETI participants (mean±SD age 27±9 years) and 8 matched controls were followed up after a median (IQR) 5.8 (3.7-6.7) and 2.7 (1.9-3.0) years, respectively (p=0.001) , with ETI initiation 1.1 (0.2-1.2) years before the follow-up visit. Weight increased in both groups, but by more in the ETI group (p<0.01) . No differences in lung function or HbA1c were observed; however, improvement in oral glucose tolerance test 2-hour glucose was observed in the ETI group (p<0.05) that was different by trend from the change seen in controls (p=0.09) . Acute insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls (p<0.05) but not in the ETI group, while C-peptide changes differed between groups (p<0.05) . A trend towards lower acute proinsulin response was seen in the ETI group (p=0.07) with the change different between groups (p<0.05) . Deterioration in the proinsulin secretory ratio was observed in the control (p<0.05) but not the ETI group (between group change, p=0.01) . ETI therapy appears to preserve β-cell function in CF through effects on glucose-dependent insulin secretion and proinsulin processing. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF. Disclosure A.Flatt: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. A.Kelly: Research Support; vTv Therapeutics. S.Sheikh: None. A.J.Peleckis: None. K.Gallagher: None. P.Alvarado: None. D.Hadjiliadis: Advisory Panel; AstraZeneca, Research Support; Mylan N.V. D.Stefanovski: None. R.J.Gallop: None. R.C.Rubenstein: None. Funding Public Health Service research grants (RDK97830; K23 DK107937; UL1 TR001878) and National Institutes of Health (P30 DK19525) .

114-OR: A Randomized Clinical Trial of Etanercept and Alpha-1 Antitrypsin in TPIAT

Total pancreatectomy with islet auto-transplant (TPIAT) can relieve pain for patients with intractable pancreatitis. However, inflammatory damage to transplanted islets from the instant blood mediated inflammatory response (IBMIR) limits the IAT's success. We hypothesized blockade of IBMIR would improve islet engraftment, resulting in improved islet function. We randomized 43 participants to A1AT (90 mg/kg IV x6 doses) , or etanercept (50 mg then 25 mg SQ x 5 doses) , or standard care in a 1:1:1 ratio. Islet graft function was assessed with mixed meal tolerance test (MMTT) , intravenous glucose tolerance test (IVGTT) , glucose-potentiated arginine-induced insulin secretion (GPAIS) , HbA1c, and insulin use 3 months and 1 year after TPIAT. Acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) 3 months after TPIAT were higher in the etanercept-treated group (p<0.025, Fig 1) , but neither treatment differed significantly from controls at 1 year (Fig 1) . MMTT, GPAIS, HbA1c, and insulin use did not differ between groups. Multivariate modelling suggested a sex-specific response, with females on A1AT showing the most robust insulin secretion from GPAIS at 1 year (p≤0.033) . In conclusion, this randomized pilot study suggests etanercept may improve early islet engraftment. The long-term effect of etanercept or A1AT on islet engraftment is less clear, though speculatively females may have a sex-specific benefit. Disclosure T.R.Abdel-karim: None. J.S.Hodges: None. T.L.Pruett: None. K.Ramanathan: None. G.Beilman: None. M.Bellin: Advisory Panel; Insulet Corporation, Research Support; Dexcom, Inc., Viacyte. Funding National Institute of Health (R01DK109914)

Liver Fat Reduction After Gastric Banding and Associations with Changes in Insulin Sensitivity and β-Cell Function.

The aim of this study was to examine the relationship between changes in liver fat and changes in insulin sensitivity and β-cell function 2 years after gastric banding surgery. Data included 23 adults with the surgery who had prediabetes or type 2 diabetes for less than 1 year and BMI 30 to 40 kg/m2 at baseline. Body adiposity measures including liver fat content (LFC), insulin sensitivity (M/I), and β-cell responses (acute, steady-state, and arginine-stimulated maximum C-peptide) were assessed at baseline and 2 years after surgery. Regression models were used to assess associations adjusted for age and sex. Two years after surgery, all measures of body adiposity, LFC, fasting and 2-hour glucose, and hemoglobin A1c significantly decreased; M/I significantly increased; and β-cell responses adjusted for M/I did not change significantly. Among adiposity measures, reduction in LFC had the strongest association with M/I increase (r = -0.61, P = 0.003). Among β-cell measures, change in LFC was associated with change in acute C-peptide response to arginine at maximal glycemic potentiation adjusted for M/I (r = 0.66, P = 0.007). Significant reductions in glycemic measures and increase in M/I were observed in individuals with LFC loss >2.5%. Reduction in LFC after gastric banding surgery appears to be an important factor associated with long-term improvements in insulin sensitivity and glycemic profiles in adults with obesity and prediabetes or early type 2 diabetes.

Performance of modified Igls criteria to evaluate islet autograft function after total pancreatectomy with islet autotransplantation - a retrospective study.

The Igls criteria assess islet function after islet allotransplant, based on C-peptide, insulin use, hemoglobin A1c, and severe hypoglycemia. However, these criteria as currently defined cannot be applied to total pancreatectomy islet autotransplant (TPIAT) patients. We tested modified criteria for assessing islet function in a large cohort of TPIAT patients (n=379). Metabolic outcomes were assessed. We assigned Auto-Igls class to each patient as able and evaluated the utility, validity, and perioperative risk factors of Auto-Igls at 1-year post-IAT. We tested the association of Auto-Igls with independent measures of islet graft function, specifically continuous glucose monitoring (CGM) data or acute C-peptide response to glucose (ACRglu) from intravenous glucose tolerance tests. An Auto-Igls class was assigned to 264 patients (69%). Among patients who could not be classified, most were missing exact insulin dose. Seventy-three percent of TPIAT recipients were classified as optimal or good at 1year. The only significant predictor of Auto-Igls class was islet mass transplanted (P<0.0001). Auto-Igls class was associated with percent time in range (70-140mg/dl) on CGM (P=0.02) and ACRglu (P<0.0001). Modified Igls classification for IAT permits simple, comprehensive assessment of metabolic outcomes after TPIAT and is associated with other islet functional measures.

1792-P: Measures of ß-Cell Function from Two-Step Hyperglycemic Clamps: Relation to Glycemia

We derived β-cell measures compensating for insulin resistance (disposition indices [DI]) from two-step hyperglycemic clamps with arginine stimulation, and examined their associations with glycemia cross-sectionally and longitudinally after treatment. Data included 355 adults (age 23-66 y; 51% female) and 89 youth (age 10-19 y; 71% female) from the RISE Consortium studies. Clamps were done at baseline and after 12 mo treatment with medications or gastric banding. Insulin sensitivity was quanitfied as M/I. β-cell responses included acute insulin (AIRg) and C-peptide (ACPRg) responses to glucose; steady-state C-peptide (SSCP) at glucose ∼11.1 mmol/L; and maximum insulin (AIRmax) or C-peptide (ACPRmax) responses to arginine at glucose &amp;gt;25 mmol/L. DIs were calculated from M/I and β-cell responses as [responses x (M/I)-b ]. The Table shows the correlations between each DI and glucose at baseline, and changes after treatment. The correlations were higher in youth than adults, except for changes in AIRmax or ACPRmax and 2-hour glucose. The correlations for ACPRg and AIRg were generally higher, followed by SSCP and then maximal responses. Thus, in the RISE cohorts, measures of early β-cell response were more strongly associated with glycemia than were late responses, with stronger correlations in youth. This underscores different contributions of early and late insulin secretion in the regulation of glycemia. Disclosure A. Xiang: None. T.S. Hannon: None. K.J. Mather: Research Support; Self; Abbott, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. E. Barengolts: None. M. Cree-Green: Advisory Panel; Self; Novo Nordisk Inc. K.J. Nadeau: None. S. Sam: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc. T.A. Buchanan: None. T. Consortium: None. Funding American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases

1782-P: Impact of Treatment with Medication vs. Laparoscopic Gastric Banding (GB) on ß-Cell Function in Adults with Impaired Glucose Tolerance (IGT) or Type 2 Diabetes (T2D) in the Restoring Insulin Secretion (RISE) Study

The RISE Consortium conducted a study in adults with IGT or recently diagnosed T2D to determine if β-cell function can be conserved or improved. Participants were randomized to GB, metformin, liraglutide + metformin (L+M), or placebo. β-cell function was assessed at baseline (BAS) and at 12 mo (12M) on therapy. Hyperglycemic clamp measures of β-cell function were: acute C-peptide (CP) response to glucose (ACPRg), steady-state CP (SSCP) at a plasma glucose of 11.1 mmol/L and maximal CP response to arginine, a non-glucose secretogogue, at a plasma glucose &amp;gt;25 mmol/L (ACPRmax). At BAS, BMI, ACPRg, SSCP, and ACPRmax were similar across groups. BMI was lower at 12M in all treatment groups and unchanged in those on placebo (Table). Analyses were adjusted for age, sex, and race. Participants randomized to L+M had significant increases in ACPRg and SSCP. There was also a modest but significant attenuation in ACPRmax in the L+M group. In contrast, participants who received GB or metformin alone had no change in β-cell function. Liraglutide appears to result in increased acute and steady-state responses, but greater β-cell “exhaustion” evidenced by a relative reduction in the CP response to arginine. Mechanisms responsible for this finding and its long-term implications are needed. Disclosure D.A. Ehrmann: None. S. Edelstein: None. A. Xiang: None. T.A. Buchanan: None. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. S. Caprio: None. K.J. Mather: Research Support; Self; Abbott, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. K.J. Nadeau: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc. T. Consortium: None. Funding American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases

1268-P: Associations between ß-Cell Function and Cognitive Measures following Treatment in Youth with Impaired Glucose Tolerance (IGT) or Recently Diagnosed Type 2 Diabetes (T2D)

In cross-sectional studies, adolescents with T2D show poorer cognition than normoglycemic youth. In the Restoring Insulin Secretion (RISE) Study, we assessed longitudinal relationships between insulin sensitivity, β-cell function and cognition in 72 youth (mean age 14.3±2.0, 10-18 y) with IGT or recently diagnosed T2D, randomized to 12 months of metformin (MET) or 3 months of glargine followed by 9 months of metformin (G/M). Hyperglycemic clamps were used to measure insulin sensitivity and β-cell responses: acute (0-10 min) C-peptide response to glucose, steady-state C-peptide (SSCP) at glucose of 11.1 mmol/L, and arginine-stimulated maximum C-peptide response (ACPRmax) at glucose &amp;gt;25 mmol/L. A cognitive battery (CogStateTM and story recall) assessed 1) reaction time; 2) visual discrimination; 3) attention and working memory; and 4) learning and episodic memory. A composite measure of cognition was constructed by scaling the sum of the four domain scores. Linear regression models were fit to assess relationships between cognition, treatment and β-cell function. Treatment group models were adjusted for baseline cognitive function, HbA1c and fasting glucose. β-cell models were adjusted for baseline cognitive and β-cell function. Cognitive composite scores improved over the 12-month treatment period (p&amp;lt;0.001), with no differences between treatment arms. Greater baseline ACPRmax predicted greater improvement in composite scores over 12 months in the G/M (p&amp;lt;0.05), but not MET group (p=0.61). Change in SSCP over the 12-month treatment was positively associated with increased composite scores in the G/M (p&amp;lt;0.05) but not MET group (p=0.35). Thus, improved cognition over the 12-month treatment with G/M in adolescents with IGT or early T2D may be related to practice effects with repeated testing, to changes in β-cell function or to other impacts of insulin treatment. Disclosure S. Craft: Advisory Panel; Self; vTv Therapeutics. M. Tripputi: None. S. Edelstein: None. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. A. Claxton: Employee; Self; Alkermes plc. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. E. Barengolts: None. T.S. Hannon: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc. K.J. Mather: Research Support; Self; Abbott, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. B. Mokhlesi: None. K.J. Nadeau: None. A. Sanderlin: None. K.A. Temple: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Merck &amp; Co., Inc. T. Consortium: None. Funding American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases

1600-P: One Hour OGTT Plasma Glucose as a Biomarker of ß-Cell Function

Progression of hyperglycemia is mediated by loss of β-cell function, but we lack a marker which would be sufficiently accurate and convenient to use in large prospective trials. To determine if the 1 hour OGTT plasma glucose (1hrOGTT) could serve such a purpose, we compared it to standard measures of the disposition index (DI, insulin secretion*insulin action) in 584 European adults without known diabetes in the Relationship between Insulin Sensitivity and Cardiovascular Disease Risk (RISC) study dataset, to predict progression over 3 years. Measures included DImodeling (OGTT modeling β-cell glucose sensitivity*insulin sensitivity), DI-ISI ([0-30min ΔC-peptide/Δglucose]*[1/fasting insulin]), DIclamp (acute C-peptide response to glucose*euglycemic clamp glucose disposal [M/I]), and DIhybrid (OGTT modeling β-cell glucose sensitivity*M/I). Using ADA OGTT criteria, for predicting progression from normal glucose to any dysglycemia (diabetes [DM, FPG &amp;gt;126 or 2hrPG &amp;gt;200 mg/dl] or prediabetes [IFG, FPG 100-125, or IGT, 2hrPG 140-199 mg/dl], n=115), the area under receiver operating characteristic curves (ROC) for the 1hrOGTT was 0.637 vs. 0.607, 0.602, 0.565, and 0.582 for DImodeling, DI-ISI, DIclamp, and DIhybrid, respectively. For non-high risk progressing to high risk dysglycemia ([DM] or [IFG + IGT], n=40), the 1hrOGTT ROC was 0.790 vs. 0.738, 0.737, 0.647, and 0.729 for the DI indices, respectively, and for non-DM progressing to DM (n=6), the 1hrOGTT ROC was 0.910, vs. 0.899, 0.822, 0.741, and 0.837 for the DI indices, respectively. Conclusions: The 1hrOGTT plasma glucose level appears to be comparable or superior to the DI based on more labor-intensive and costly direct assessments of insulin secretion and action in predicting progression of hyperglycemia over 3 years. Consideration should be given to use of the 1hrOGTT glucose as both an accurate and convenient indirect measure of β-cell function in clinical trials, and possibly also of the risk of development and progression of hyperglycemia in clinical practice. Disclosure B.T. Legvold: None. A. Zhang: None. M.K. Rhee: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. L.R. Staimez: None. K. Utzschneider: Other Relationship; Self; Medtronic. L.P. Savoye: None. J.R. Petrie: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Advanced Clinical Intelligence, IQVIA. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Merck KGaA, Novo Nordisk A/S. B. Balkau: None. L.S. Phillips: Research Support; Self; AbbVie Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis. Other Relationship; Self; Diasyst, Janssen Pharmaceuticals, Inc. Funding U.S. Department of Veterans Affairs (CX001025, BX003340, CX001737); National Institutes of Health (DK099716, DK091958, DK098246, DK111024, AI133172)

364-OR: Igls Classification for Islet Autotransplantation

Background: The Igls criteria for assessing islet function after allotransplantation cannot be directly applied to islet autotransplantation (IAT) patients due to differences in baseline characteristics of IAT patients (insulin independent and C-peptide positive). Methods: We tested modified criteria (Auto-Igls) for assessing islet function in a large cohort of total pancreatectomy-IAT (TPIAT) patients from 2010-2018 (n=379). Metabolic outcomes post-IAT were assessed (Table 1). We assigned an Auto-Igls class to each patient as able, and evaluated the utility, validity, and perioperative predictors of Auto-Igls at 1 year post-IAT. We associated Auto-Igls with independent measures of islet graft function where available: continuous glucose monitoring (CGM) data or acute c-peptide response to glucose (ACRglu) from intravenous glucose tolerance tests. Results: Auto-Igls class was assigned to 264 patients (69%). Of the 115 patients who could not be classified, most (74%) were missing exact insulin u/kg/day. The only significant predictor of Auto-Igls class was the islet mass transplanted (p&amp;lt;0.0001). Higher percent time in range (70-140 mg/dL) on CGM and higher ACRglu were associated with a better Auto-Igls class (p=0.02 and p&amp;lt;0.0001, respectively). Discussion: The modified Igls criteria for IAT permit a simple, comprehensive assessment of metabolic outcomes after TPIAT, and is associated with other measures of islet function. Disclosure K.R. McEachron: None. Y. Yang: None. T.L. Pruett: None. M. Bellin: Research Support; Self; Dexcom, Inc., Viacyte, Inc. Other Relationship; Self; Insulet Corporation. Funding National Institutes of Health (T32DK108733, R01DK109124)

Impact of acute-phase insulin secretion on glycemic variability in insulin-treated patients with type 2 diabetes.

The association between β-cell function and glycemic variability remains to be clarified in insulin-treated patients with type 2 diabetes. Therefore, the study sought to examine the association of various indices of β-cell function with glycemic variability in Chinese insulin-treated patients with type 2 diabetes. Glycemic variability was assessed by the coefficient of variation (CV) of glucose levels with the use of continuous glucose monitoring (CGM). Basal β-cell function was evaluated by fasting C-peptide (FCP) and the homeostasis model assessment 2 for β-cell function (HOMA2-%β). Postload β-cell function was measured by 2-hour C-peptide (2hCP) and the acute C-peptide response (ACPR) to arginine. When a cutoff value of CV ≥ 36% was used to define unstable glucose, the multivariable-adjusted odds ratios for labile glycemic control were 0.34 (95% CI 0.18-0.64) for each 1 ng/mL increase in ACPR, 0.47 (95% CI 0.27-0.81) for each 1 ng/mL increase in FCP, 0.77 (95% CI 0.61-0.97) for each 1 ng/mL increase in 2hCP, and 1.00 (95% CI 0.98-1.01) for each 1% increase in HOMA2-%β. When we further adjusted for 2hCP and HOMA2-%β in the ACPR and FCP analyses, and adjusted for ACPR or FCP in the 2hCP analyses, only ACPR but not FCP or 2hPC remained to be a significant and inverse predictor for labile glycemic control. ACPR evaluated by the arginine stimulation test may be superior to other commonly used β-cell function parameters to reflect glycemic fluctuation in insulin-treated patients with type 2 diabetes.

PET Imaging of Pancreatic Dopamine D2 and D3 Receptor Density with 11C-(+)-PHNO in Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D2 and D3 receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (11C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14-30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20-30 min; spleen as reference region) demonstrated a statistically significant reduction (-36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20-30 min) (R2 = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) (R2 = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20-30 min) (R2 = 0.57, P = 0.05), nor did mean baseline proinsulin (R2 = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D3 receptor and dopamine D2 receptor in HCs. No colocalization of the dopamine D3 receptor or dopamine D2 receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D3 receptor, dopamine D2 receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D3 receptor and dopamine D2 receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for 11C-(+)-PHNO, a dopamine D3 receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.

Utility of arginine stimulation testing in preoperative assessment of children undergoing total pancreatectomy with islet autotransplantation.

Metabolic outcomes after total pancreatectomy with islet autotransplantation (TPIAT) are influenced by the islet mass transplanted. Preclinical and clinical studies indicate that insulin and C-peptide levels measured after intravenous administration of the beta cell secretagogue arginine can be used to estimate the available islet mass. We sought to determine if preoperative arginine stimulation test (AST) results predicted transplanted islet mass and metabolic outcomes in pediatric patients undergoing TPIAT. We evaluated the association of preoperative C-peptide and insulin responses to AST with islet isolation metrics using linear regression, and with postoperative insulin independence using logistic regression. Twenty-six TPIAT patients underwent preoperative AST from 2015 to 2018. The acute C-peptide response to arginine (ACRarg) was correlated with isolated islet equivalents (IEQ; r=0.59, P=0.002) and islet number (IPN; r=0.48, P=0.013). The acute insulin response to arginine (AIRarg) was not significantly correlated with IEQ (r=0.38, P=0.095) or IPN (r=0.41, P=0.071). Neither ACRarg nor AIRarg was associated with insulin use at 6months postoperatively. Preoperative C-peptide response to arginine correlates with islet mass available for transplant in pediatric TPIAT patients. AST represents an additional tool before autotransplant to provide counseling on likely islet mass and to inform quality improvements of islet isolation techniques.

Association of Habitual Daily Physical Activity With Glucose Tolerance and β-Cell Function in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes From the Restoring Insulin Secretion (RISE) Study.

We examined the relationship between habitual daily physical activity and measures of glucose tolerance, insulin sensitivity, and β-cell responses in adults with impaired glucose tolerance (IGT) or drug-naive, recently diagnosed type 2 diabetes. Participants included 230 adults (mean ± SD age 54.5 ± 8.5 years, BMI 35 ± 5.5 kg/m2; 42.6% women) who underwent a 3-h oral glucose tolerance test (OGTT) and hyperglycemic clamp. Wrist accelerometers worn for 7 consecutive days measured total physical activity counts (TAC) (daily mean 233,460 [∼50th percentile for age]). We evaluated whether TAC was associated with fasting plasma glucose, OGTT 2-h plasma glucose or glucose incremental area under the curve (G-iAUC), hyperglycemic clamp measures of insulin sensitivity (steady-state glucose infusion rate/insulin [M/I]) and β-cell responses (acute C-peptide response to glucose, steady-state C-peptide, and maximal β-cell response), and OGTT C-peptide index (ΔC-peptide0-30/Δglucose0-30). After adjustments for confounders, there was no association of TAC with fasting plasma glucose, 2-h glucose, or G-iAUC. Higher TAC was associated with higher insulin sensitivity (M/I). After adjusting for M/I, higher TAC was not associated with measures of β-cell response. In adults with IGT or drug-naive, recently diagnosed type 2 diabetes, higher levels of habitual physical activity are associated with higher insulin sensitivity. Further studies are needed to understand why higher levels of physical activity are not associated with better β-cell response.

1826-P: Comparison of OGTT-Model Measures with the Hyperglycemic Clamp in Youth and Adults with IGT or Early Type 2 Diabetes (DM)

The Restoring Insulin Secretion (RISE) Study found that compared to adults (A), youth (Y) with early DM (33 Y, 104 A) or IGT (53 Y, 250 A) have higher insulin and C-peptide responses, even after adjusting for differences in insulin sensitivity. To better understand these differences, we compared mathematical modeling data from OGTTs to those from a hyperglycemic clamp within the RISE Study. Modeled measures were the dose-response relationship between glucose and insulin secretion (glucose sensitivity [GS], rate sensitivity [RS]) and the oral glucose insulin sensitivity index (OGIS). Clamp measures were insulin sensitivity (steady state glucose infusion rate/insulin [M/I]), acute (0-10 minutes) C-peptide (ACPRg) and insulin (AIRg) responses to glucose, steady-state C-peptide (SSCP) at plasma glucose of 11.1 mmol/L, and arginine-stimulated maximum C-peptide (ACPRmax) response at glucose &amp;gt;25 mmol/L. Linear regression models were fit to assess relationships between OGTT model and clamp measures by age group. GS (r2 = 0.29, p&amp;lt;0.01) and RS (r2 = 0.22, p&amp;lt;0.01) were inversely correlated with M/I. GS was directly correlated with ACPRg (r2 = 0.55, p&amp;lt;0.01), AIRg (r2 = 0.52, p&amp;lt;0.01), SSCP (r2 = 0.46, p&amp;lt;0.01) and ACPRmax (r2 = 0.33, p&amp;lt;0.01), with a steeper slope in Y vs. A for AIRg and ACPRg vs. GS (p’s &amp;lt; 0.01), and in IGT vs. DM for ACPRg vs. GS (p=0.03). RS was directly correlated with ACPRg (slope r2 = 0.55, p&amp;lt;0.01), with a steeper slope in Y vs. A (P &amp;lt; 0.01) and in IGT vs. DM (p=0.04). M/I was directly correlated with OGIS (r2 = 0.34, p&amp;lt;0.01). The inverse correlation of GS with M/I in both Y and A suggests that differences in insulin sensitivity should be accounted for when comparing GS across groups. The fact that relationships between acute insulin and C-peptide responses from the clamp and GS and RS from OGTTs differed between Y and A, while these relationships were similar for SSCP and ACPRmax, suggest fundamental differences exist in the early-phase response between Y and A with IGT or early DM. Disclosure K. Utzschneider: Consultant; Self; Novo Nordisk Inc. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. M. Tripputi: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. K.J. Nadeau: None. S. Edelstein: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. S.A. Arslanian: None. M. Cree-Green: None. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery. S. Caprio: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S. R. Consortium: None. Funding American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases

1561-P: Associations between ß-Cell Function and Cognitive Measures Differ in Youth vs. Adults with Impaired Glucose Tolerance (IGT) or Early Type 2 Diabetes (T2D)

Insulin resistance and impaired β-cell function are associated with risk of cognitive decline in adults over 65 y of age. Their impact on cognition in youth and adults &amp;lt;65 y is less clear. We assessed the relationship between insulin sensitivity, β-cell function and cognition in never or briefly-treated youth (n=71, mean age 14.2±2.0, 10-18 y) and treatment-naïve adults (n=236, mean age 54.4±8.6, 26-66 y) with IGT or early T2D in the Restoring Insulin Secretion (RISE) Study. Hyperglycemic clamps were used to measure insulin sensitivity (steady state glucose infusion rate/insulin [M/I]) and β-cell responses: acute (0-10 min) C-peptide (ACPRg) response to glucose, steady-state C-peptide (SSCP) at a serum glucose of 11.1 mmol/L, and arginine-stimulated maximum C-peptide (ACPRmax) responses at glucose &amp;gt;25 mmol/L. The cognitive battery (CogStateTM and story recall) assessed 1) psychomotor speed; 2) visual pattern separation; 3) visual attention and working memory; and 4) verbal learning and episodic memory. Linear regression models were fit to assess relationships between cognition and clamp measures by age group, adjusted for age, education (adults only), race, sex, and diabetes status. Models including β-cell responses were also adjusted for M/I to account for the role of insulin sensitivity to modulate β-cell function. M/I was not associated with cognitive outcomes for adults or children. For adults, reaction time was slower for participants with worse β-cell function assessed by ACPRg and ACPRmax (p&amp;lt;0.05). Lower SSCP in adults was associated with worse visual pattern separation (p&amp;lt;0.05), a test sensitive to risk for age-related cognitive decline, whereas in youth higher SSCP associated with trends for lower scores for learning (p=0.065) and memory (p=0.052). These results suggest that the relationships between β-cell function and specific cognitive domains differ in a developmentally-dependent manner. Disclosure S. Craft: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Eli Lilly and Company. A. Claxton: Employee; Self; Alkermes. M. Tripputi: None. S. Edelstein: None. S.A. Arslanian: None. K.A. Temple: None. K.J. Nadeau: None. A. Sanderlin: None. M. Espeland: Research Support; Self; National Institutes of Health. Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals, Inc. B. Mokhlesi: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research &amp; Development, Merck &amp; Co., Inc., Novo Nordisk Inc. R. Consortium: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases