Abstract Context Postprandial hyperglycemia remains a challenge in type 1 diabetes (T1D) due, in part, to dysregulated increases in plasma glucagon levels after meals. Objective This study was undertaken to examine whether 3 to 4 weeks of therapy with pramlintide or liraglutide might help to blunt postprandial hyperglycemia in T1D by suppressing plasma glucagon responses to mixed-meal feedings. Design Two parallel studies were conducted in which participants underwent mixed-meal tolerance tests (MMTTs) without premeal bolus insulin administration before and after 3 to 4 weeks of treatment with either pramlintide (8 participants aged 20 ± 3 years, hemoglobin A1c 6.9 ± 0.5%) or liraglutide (10 participants aged 22 ± 3 years, hemoglobin A1c 7.6 ± 0.9%). Results Compared with pretreatment responses to the MMTT, treatment with pramlintide reduced the peak increment in glucagon from 32 ± 16 to 23 ± 12 pg/mL (P < 0.02). In addition, the incremental area under the plasma glucagon curve from 0 to 120 minutes dropped from 1988 ± 590 to 737 ± 577 pg/mL/min (P < 0.001), which was accompanied by a similar reduction in the meal-stimulated increase in the plasma glucose curve from 11,963 ± 1424 mg/dL/min pretreatment vs 2493 ± 1854 mg/dL/min after treatment (P < 0.01). In contrast, treatment with liraglutide had no effect on plasma glucagon and glucose responses during the MMTT. Conclusions Adjunctive treatment with pramlintide may provide an effective means to blunt postmeal hyperglycemia in T1D by suppressing dysregulated plasma glucagon responses. In contrast, plasma glucose and glucagon responses were unchanged after 3 to 4 weeks of treatment with liraglutide. Postprandial hyperglycemia remains a challenge in type 1 diabetes (T1D) due to a number of factors that include delays in the absorption and action of premeal boluses of insulin from the subcutaneous space and dysregulated glucagon secretion in response to mixed-meal feedings (1–5). In individuals without diabetes, plasma glucagon levels change very little after eating a mixed meal that includes protein and carbohydrates because the stimulation of glucagon secretion by increases in plasma amino acids is offset by the suppression of glucagon secretion by increases in plasma glucose levels. In contrast, it has been demonstrated that children with T1D have higher plasma glucagon responses after mixed-meal feedings compared with healthy peers (3). Moreover, plasma glucagon responses to mixed-meal feeding increase over time, presumably due to the progressive loss of residual β-cell function (1, 6). Due to the adverse impact of postprandial hyperglycemia on overall glycemic control and the risk of complications (7, 8), it has been suggested that treatment with agents approved for use in type 2 diabetes may be effective in lowering postprandial glucose peaks in T1D by mechanisms independent of stimulation of insulin secretion (9, 10). Specifically, sodium-glucose cotransporter 2 inhibitors reduce plasma glucose by lowering the renal threshold for glucose excretion (11), whereas it has been suggested that the glucose-lowering effects of both pramlintide (an analog of amylin) and liraglutide (a glucagon-like peptide-1 agonist) are due, in part, to slowing of gastric emptying and suppression of exaggerated postmeal increases in plasma glucagon (12, 13). In two parallel studies, we used a full closed-loop (CL) insulin delivery system to control postmeal glucose excursions before and after 3 to 4 weeks of treatment with pramlintide and liraglutide at maximally recommended doses. Those studies showed durable slowing of gastric emptying with pramlintide but not with liraglutide (14). In those studies, we also performed mixed-meal tolerance tests (MMTTs) in the morning following 24 hours of CL control to examine and compare whether 3 to 4 weeks of treatment with pramlintide or liraglutide suppressed meal-stimulated increases in plasma glucagon in T1D (14). The results of these MMTTs are reported in this study. Materials and Methods Participants Participants were eligible to enroll in the pramlintide and liraglutide studies if they had a clinical diagnosis of T1D for at least 1 year, hemoglobin A1c ≤9% (≤75 mmol/mol), and a normal hematocrit and serum creatinine level. Participants were excluded if they had a history of an eating disorder, celiac disease, gastroparesis, another disorder of intestinal absorption or motility, a history of a hypoglycemic seizure in the past 3 months, another chronic medical condition (except treated hypothyroidism), current use of medications (other than insulin) known to affect blood glucose level or gastrointestinal motility, and prior adverse reactions to the drug under study. Female participants could not be pregnant or lactating. The studies were reviewed and approved by the Yale University Human Investigation Committee, and written informed consent was obtained by adult participants. Parental consent with participant assent was obtained for participants <18 years. Procedures Dose-titration phase Participants in the studies underwent two 24-hour periods of CL glucose control before and after 3 to 4 weeks of treatment with pramlintide or liraglutide (14). During outpatient treatment, the dose of pramlintide was uptitrated from 30 to 60 μg given 15 minutes prior to each meal, and the once-daily dosing of liraglutide before breakfast was uptitrated from 0.6 to 1.8 mg/d. In both studies, insulin doses were adjusted, as needed, by frequent telephone contacts with the study participants. MMTTs In each study, the participants underwent two MMTTs, the first performed before therapy with pramlintide or liraglutide and the second performed after 3 to 4 weeks of treatment with one of the drugs. All MMTTs were performed at ∼8 am in the morning after an 8- to 12-hour overnight fast, during which glucose levels were regulated with a Medtronic CL system (Medtronic, Northridge, CA) (14). The CL system used in both of these studies consisted of four components: a Medtronic Paradigm 715 insulin pump, a Medtronic MiniLink REAL-Time transmitter (MMT-7703) adapted for 1-min transmission, a Medtronic continuous glucose sensor (Sof-Sensor in the pramlintide study and an Enlite sensor in the liraglutide study), and the Medtronic external Physiological Insulin Delivery algorithm modified to include insulin feedback, which was on a laptop computer (all from Medtronic). An intravenous catheter was used for frequent blood sampling during the MMTTs. At the start of the 4-hour MMTTs, baseline samples for measurement of plasma glucose and plasma glucagon were obtained, the CL system was shut off, and participants were placed back on their usual open-loop basal rate settings. Participants then consumed 6 mL/kg of Boost High Protein 6 cc/kg (Nestlé HealthCare Nutrition, Fremont, MI) to a maximum dose of 360 mL. Additional blood samples for measurements of plasma glucose and plasma glucagon were obtained every 15 to 30 minutes for 240 minutes following ingestion of Boost High Protein (3); the macronutrient content per 100 mL of Boost High Protein is protein 6.3 g, carbohydrate 13.9 g, and fat 2.5g. During the second MMTT for each participant, pramlintide (60 μg) or liraglutide (1.8 mg) was injected just prior to meal ingestion. The primary outcome of the two parallel studies reported in this study was the difference in the incremental area under the curve (iAUC) in plasma glucagon levels from baseline to 120 minutes (Glucagon iAUC0–120 min). Secondary outcomes included the iAUC in plasma glucagon levels from 120 to 240 minutes (Glucagon iAUC120–240 min), incremental area under the meal-stimulated increase in the plasma glucose curve from 0 to 120 minutes (Glucose iAUC0–120 min), incremental area under the meal-stimulated increase in the plasma glucose curve from 120 to 240 minutes (Glucose iAUC120–240 min), changes in peak plasma glucagon and peak plasma glucose levels, and the time-to-peak for glucagon and glucose over 240 minutes. Breakfast during CL Participants in the liraglutide group had their glucagon and glucose response to breakfast assessed during the 24-hour CL admissions. Meals were self-selected and not limited by calorie or carbohydrate content. Samples were obtained every 15 to 30 minutes for 180 minutes after the breakfast to assess both glucose and glucagon levels. CL insulin delivery was maintained during the meal test. Laboratory measurements Plasma glucose was analyzed using the YSI 2300 STAT Plus glucose analyzer (YSI Life Sciences, Yellow Springs, OH). Glucagon was measured by a double-antibody radioimmunoassay (GL-32K; EMD Millipore, Burlington, MA). The lower limit of detection of plasma glucagon was 20 pg/mL, and the higher limit of the standard assay curve was 400 pg/mL. The accuracy of the assay was 97 ± 0.8%. Statistical considerations Comparisons between the pretreatment and during treatment measurements were calculated using the paired Student t test for continuous variables. Fisher exact test was adopted for categorical variables. Changes in plasma glucose and glucagon during the MMTTs were expressed as incremental values from baseline (0 minutes) to the specified time points. The iAUCs and peak value for both plasma glucose and glucagon were calculated as difference from the baseline measure (0 minutes). Data are expressed as mean ± standard deviation (SD). Data were analyzed using Prism 7 software (GraphPad Software, Inc., La Jolla, CA). Results Participants Ten out of 11 participants who enrolled in the CL study (14) with liraglutide agreed to undergo the two MMTTs, as did 8 out of 10 participants from the pramlintide study. The clinical characteristics of the 10 liraglutide and 8 pramlintide participants are shown in Table 1. Table 1. Baseline Characteristics Clinical Characteristics Liraglutide (n = 10) Pramlintide (n = 8) P Sex (female/male) 6/4 5/3 >0.99 Age, y (age range) 21.9 ± 3.5 (18–27) 19.6 ± 2.8 (16–23) 0.151 BMI, kg/m2 23.5 ± 2.9 23.0 ± 1.5 0.665 Hemoglobin A1c at enrollment, % (mmol/mol) 7.5 ± 1.0 (58.0 ± 10.9) 6.9 ± 0.5 (52.0 ± 5.5) 0.142 Diabetes’ duration, y 9.9 ± 6.5 9.4 ± 4.6 0.857 Weight, kg 67.1 ± 9.6 70.7 ± 14.6 0.537 Total daily insulin dose, U/kg/d 0.8 ± 0.1 0.9 ± 0.3 0.355 Clinical Characteristics Liraglutide (n = 10) Pramlintide (n = 8) P Sex (female/male) 6/4 5/3 >0.99 Age, y (age range) 21.9 ± 3.5 (18–27) 19.6 ± 2.8 (16–23) 0.151 BMI, kg/m2 23.5 ± 2.9 23.0 ± 1.5 0.665 Hemoglobin A1c at enrollment, % (mmol/mol) 7.5 ± 1.0 (58.0 ± 10.9) 6.9 ± 0.5 (52.0 ± 5.5) 0.142 Diabetes’ duration, y 9.9 ± 6.5 9.4 ± 4.6 0.857 Weight, kg 67.1 ± 9.6 70.7 ± 14.6 0.537 Total daily insulin dose, U/kg/d 0.8 ± 0.1 0.9 ± 0.3 0.355 Data are mean (SD) unless otherwise indicated. Abbreviation: BMI, body mass index. View Large MMTT results Baseline plasma glucagon and glucose levels As shown in Table 2, in each of the experiments, overnight CL insulin delivery resulted in baseline fasting plasma glucagon and glucose levels that were similar in both groups of subjects both before and during treatment with pramlintide and liraglutide. Table 2. Baseline Glucose and Glucagon Values Prior to and Posttreatment With Adjunctive Therapy Pretreatment Posttreatment P Pramlintide Glucose, mg/dL 121 ± 22 115 ± 21 0.586 Glucagon, pg/mL 42 ± 22 45 ± 19 0.775 Liraglutide Glucose, mg/dL 100 ± 16 116 ± 27 0.124 Glucagon, pg/mL 52 ± 19 47 ± 19 0.563 Pretreatment Posttreatment P Pramlintide Glucose, mg/dL 121 ± 22 115 ± 21 0.586 Glucagon, pg/mL 42 ± 22 45 ± 19 0.775 Liraglutide Glucose, mg/dL 100 ± 16 116 ± 27 0.124 Glucagon, pg/mL 52 ± 19 47 ± 19 0.563 Data are mean (SD) unless otherwise indicated. View Large Increments in plasma glucagon and glucose before and during treatment with pramlintide The patterns of incremental changes in plasma glucagon and glucose before and during treatment with pramlintide are shown in Fig. 1A and 1B, respectively. During the first 2 hours of the MMTTs, treatment with pramlintide markedly reduced the rise in plasma glucagon levels following meal ingestion (Fig. 1A), and increases in plasma glucose levels were also blunted (Fig. 1B). Moreover, between 2 and 4 hours, glucagon levels remained suppressed during treatment with pramlintide (Fig. 1A), even in the face of a delayed rise in plasma glucose levels (Fig. 1B). As shown in Table 3, adjunctive therapy with pramlintide markedly suppressed Glucagon iAUC0–120 min and the peak increment in plasma glucagon, as well as Glucose iAUC0–120 min, Glucose iAUC120–240 min, and the peak increment in glucose. Pramlintide treatment also delayed the time-to-peak glucagon and glucose levels (Table 3). Figure 1. View largeDownload slide Glucagon and glucose profile during MMTT. Glucagon profile before and after the treatment with (A) pramlintide and (C) liraglutide during MMTT. Glucose profile before and after the treatment with (B) pramlintide and (D) liraglutide during MMTT. Glucagon and glucose are expressed as incremental value from the baseline. Figure 1. View largeDownload slide Glucagon and glucose profile during MMTT. Glucagon profile before and after the treatment with (A) pramlintide and (C) liraglutide during MMTT. Glucose profile before and after the treatment with (B) pramlintide and (D) liraglutide during MMTT. Glucagon and glucose are expressed as incremental value from the baseline. Table 3. Outcome Measures Liraglutide Pramlintide Pretreatment Posttreatment P Pretreatment Posttreatment P Glucagon Glucagon iAUC0–120, pg/min/mL 1904 ± 651 1801 ± 906 0.774 1988 ± 590 737 ± 577 0.0007 Glucagon iAUC120–240, pg/min/mL 311 ± 564 701 ± 860 0.246 560 ± 807 933 ± 789 0.366 Glucagon incremental peak, pg/mL 29 ± 16 35 ± 20 0.309 32 ± 16 23 ± 12 0.026 Glucagon time-to-peak, min 47 ± 30 64 ± 41 0.281 49 ± 22 173 ± 66 0.0097 Glucose Glucose iAUC0–120, mg/min/dL 13,001 ± 1207 12,029 ± 1500 0.619 11,963 ± 1424 2493 ± 1854 <0.0001 Glucose iAUC120–240, mg/min/dL 20,241 ± 1794 18,135 ± 2580 0.138 17,505 ± 2721 13,397 ± 2841 0.051 Glucose incremental peak, mg/dL 200 ± 29 171 ± 47 0.070 181 ± 46 150 ± 63 0.011 Glucose time-to-peak, min 132 ± 41 135 ± 29 0.85 128 ± 31 221 ± 32 <0.001 Liraglutide Pramlintide Pretreatment Posttreatment P Pretreatment Posttreatment P Glucagon Glucagon iAUC0–120, pg/min/mL 1904 ± 651 1801 ± 906 0.774 1988 ± 590 737 ± 577 0.0007 Glucagon iAUC120–240, pg/min/mL 311 ± 564 701 ± 860 0.246 560 ± 807 933 ± 789 0.366 Glucagon incremental peak, pg/mL 29 ± 16 35 ± 20 0.309 32 ± 16 23 ± 12 0.026 Glucagon time-to-peak, min 47 ± 30 64 ± 41 0.281 49 ± 22 173 ± 66 0.0097 Glucose Glucose iAUC0–120, mg/min/dL 13,001 ± 1207 12,029 ± 1500 0.619 11,963 ± 1424 2493 ± 1854 <0.0001 Glucose iAUC120–240, mg/min/dL 20,241 ± 1794 18,135 ± 2580 0.138 17,505 ± 2721 13,397 ± 2841 0.051 Glucose incremental peak, mg/dL 200 ± 29 171 ± 47 0.070 181 ± 46 150 ± 63 0.011 Glucose time-to-peak, min 132 ± 41 135 ± 29 0.85 128 ± 31 221 ± 32 <0.001 Data are mean (SD) unless otherwise indicated. P values in boldface are significant. View Large Increments in plasma glucagon and glucose before and during treatment with liraglutide The incremental changes in plasma glucagon and glucose before and during treatment with liraglutide are shown in Fig. 1C and 1D, respectively. As seen in these figures, after 3 to 4 weeks of liraglutide treatment, there were no noteworthy differences in the plasma glucagon and glucose responses during the first 120 minutes and second 120 minutes following Boost ingestion. As shown in Table 3, the peak increment in plasma glucagon, time-to-peak glucagon, and iAUC for glucagon were not significantly different before and during treatment with liraglutide. Furthermore, there were no marked changes in the peak increment in plasma glucose, time-to-peak glucose, and iAUC for glucose after treatment with liraglutide. Plasma glucagon and glucose responses during CL insulin delivery before and during treatment with liraglutide To validate that a liquid meal response would be reflective of the physiologic changes in glucagon and glucose following a standard meal under controlled insulin delivery conditions, a self-selected breakfast was provided to participants during both CL admissions. The average macronutrient content of the standardized breakfast was 75 ± 49 g of carbohydrates, 24 ± 16 g of protein, and 17 ± 14 g of fat. Corroborating the findings demonstrated during the MMTT, no difference in the glucagon or glucose response was appreciated in the 3 hours following the standardized breakfast meal (Fig. 2 and Supplemental Table 1). Figure 2. View largeDownload slide Change in glucagon and glucose levels during full CL insulin delivery with a standardized breakfast prior to and 3 to 4 weeks posttreatment with liraglutide. Figure 2. View largeDownload slide Change in glucagon and glucose levels during full CL insulin delivery with a standardized breakfast prior to and 3 to 4 weeks posttreatment with liraglutide. Discussion Pramlintide and liraglutide have been widely investigated as adjunctive therapies aimed at limiting postmeal hyperglycemia in T1D (9, 12, 14–25) due to putative modes of action that include the ability to suppress dysregulated glucagon responses to mixed-meal feedings, slowing of gastric motility, and earlier satiety (9, 26, 27). It should be noted, however, that clinical studies have demonstrated differences between the two drugs on glucose control, glucagon secretion, and gastric emptying (14, 16, 18, 19, 22, 28–30), with liraglutide surprisingly increasing the glucagon responses to mixed-meal feedings after chronic treatment in type 2 diabetes and pramlintide being highly effective in delaying gastric emptying but with conflicting effects on glucagon secretion in T1D (14, 24). Our parallel studies of the use of pramlintide and liraglutide as adjunctive agents to improve control of postprandial glucose excursions during CL insulin delivery provided a unique opportunity to examine and compare the effects of these agents on dysregulated increases in plasma glucagon levels after meals (14). Consequently, the most important findings of the current study are that we were unable to observe any suppressive effects of liraglutide on plasma glucagon responses to mixed-meal feedings or any suggestion of a delay in gastric emptying after only 3 to 4 weeks of treatment. In contrast, marked suppression of 2-hour plasma glucagon, as well as reduced and delayed increases in plasma glucose levels, were sustained after the same duration of treatment with pramlintide. These findings are consistent with previous studies that supported approval of pramlintide for use as an adjunctive agent in T1D (12, 22, 23, 30, 31) and more recent phase 3 studies of liraglutide that indicated little improvement in metabolic control in patients with T1D (16, 17, 20). Our results are also consistent with previous reports indicating that liraglutide is a less effective drug of its class in modulating the gastric motility, with more pronounced action from short-term glucagon-like peptide-1 analogs, like exenatide or lixisenatide (26, 32). As noted in our previous publication in this group of patients (24) and by others (19, 33), liraglutide may be of benefit to overweight or obese patients with T1D due to its suppression of appetite, which may support weight loss and reductions in insulin doses (17, 27). A strength of the study is that the MMTTs were performed after completion of 24 hours of CL insulin delivery, including overnight control just prior to the start of the MMTTs, with the last meal being consumed >12 hours earlier. Most MMTT protocols mandate that fasting glucose levels between 70 and 200 mg/dL be achieved prior to meal ingestion. Our use of the CL system ensured that participants had even tighter glycemic control, thus minimizing the potential confounding effects of differences in fasting plasma glucose prior to performance of the procedure. Even plasma glucagon levels were similar prior to the conduct of the pre- and posttreatment MMTTs performed. Use of the CL system also ensured precision in regard to the insulin delivery prior to the start of the MMTTs, eliminating a potential confounding factor of overinsulinization prior to meal ingestion. Thus, in both sets of experiments, the only difference between the two MMTTs in each participant was the injection of the study drug prior to the second MMTT. Compared with the sharp increases in plasma glucagon and plasma glucose during the pretreatment MMTT, only a slight increase in plasma glucagon and glucose levels was observed during the first 60 minutes of the MMTT during treatment with pramlintide (Fig. 1D). However, it is possible that diminished increases in plasma glucagon and plasma glucose during the first 2 hours of the MMTT were both due to delays in gastric emptying rather than by suppression of glucagon secretion by pramlintide. Arguing against this conclusion is the observation that the relatively flat glucagon response following meal ingestion with pramlintide was present for the full 4 hours of the MMTT, despite delayed absorption of carbohydrate and amino acids and corresponding increases in plasma glucose after meal ingestion. These data suggest that the ability of pramlintide to mitigate postmeal hyperglycemia is related to both its ability to delay gastric emptying and suppress α-cell secretion. A limitation of the current study was that it was not designed to allow for formalized comparison between the two agents. However, comparison of the individual treatments prior to and posttreatment in the two separate cohorts studied allows extrapolation of how the two adjunctive therapies may differ. It should also be noted that studies examining physiologic changes induced by pharmacologic agents often have larger sample sizes. However, the present analysis is a substudy nested within inpatient CL studies that were designed to examine the feasibility and potential efficacy of adjunctive therapies in conjunction with CL insulin delivery. Although our sample size is relatively small, it was sufficient to show a change in hormonal response during treatment with pramlintide. Although we have no direct means of assessing participants’ compliance in taking the study drugs during the outpatient phase of the studies, participants were contacted frequently by telephone during this time. These phone calls allowed investigators to encourage compliance and assess for adverse effects of the study medications. Importantly, all participants in both studies tolerated the full therapeutic doses of the drugs during the inpatient studies, which would have been unlikely if they had not been compliant in the outpatient dose-titration phase. Finally, as a surrogate marker for compliance, it is notable that during both studies, participants on average had a lowering of their total daily insulin dose (24). Finally, it is possible that use of a standardized meal instead of a liquid mixed meal would have provided better approximation of how these therapies impact day-to-day life. Although not performed in the pramlintide study, plasma glucagon responses to a standardized breakfast during CL insulin delivery were assessed in the liraglutide study. Furthermore, the standard breakfast meal study conducted during the inpatient CL admissions provided the opportunity to see if dynamic insulin delivery affected the results of meal-stimulated glucagon and glucose responses. As demonstrated in Fig. 2, no difference was appreciated with the standard meal, thus providing justification for assessment of the MMTT in the present analysis (Supplemental Table 1) and confirming the reliability of the use of MMTT, instead of a real meal, to assess the effect of the adjunctive therapy on glucagon and glucose response. In conclusion, this study has highlighted that liraglutide did not suppress dysregulated increases in plasma glucagon responses to meals even after a relatively short period of treatment. We have also confirmed the effect of pramlintide in limiting the early meal-stimulated increases in plasma glucagon and glucose levels. However, the requirement for subcutaneous injections of pramlintide before each meal has limited the use of this agent in patients with T1D in clinical practice. Abbreviations: CL closed-loop Glucagon iAUC0–120 min incremental area under the plasma glucagon curve from 0 to 120 minutes Glucagon iAUC120–240min incremental area under the curve in plasma glucagon levels from 120 to 240 minutes Glucose iAUC0–120 min incremental area under the meal-stimulated increase in the plasma glucose curve from 0 to 120 minutes Glucose iAUC120–240 min incremental area under the meal-stimulated increase in the plasma glucose curve from 120 to 240 minutes iAUC incremental area under the curve MMTT mixed-meal tolerance test SD standard deviation T1D type 1 diabetes. Acknowledgments The authors thank the participants and families, the health care professionals and staff of the Yale Children’s Diabetes Program, the Yale Center for Clinical Investigation, and the dedicated nursing staff of the Hospital Research Unit for support and participation that made this project possible. Financial Support: This study was supported by JDRF Grants 22-2009-799, 17-2013-5, and 5-ECR-2014-112-A-N (to J.S.); National Institutes of Health Grants R01-DK-085618, K12-DK-094714, UL1-TR-000142, and P30-DK-45735 (to W.T.); and the International Society for Pediatric and Adolescent Diabetes Research Fellowship Program 2016 (to A.G.). Author Contributions: A.G. researched data and wrote the manuscript. J.S. and W.T. researched data, contributed to the discussion, and reviewed and edited the manuscript. M.V., L.C, M.Z., E.T., K.W., E.C., and S.W. researched data and contributed to the discussion. Disclosure Summary: Medtronic Diabetes provided the pumps, sensors, infusion sets, reservoirs, and laptop computers for the closed-loop experiments. J.S. is a consultant for Medtronic Diabetes and is on advisory boards for Bigfoot Biomedical and Insulet. E.C. is a speaker for Novo Nordisk. S.W. is a consultant for Medtronic Diabetes and Insulet. W.T. is a consultant for Eli Lilly and Company, Medtronic Diabetes, Novo Nordisk, and Sanofi. The remaining authors have nothing to disclose. References 1. Brown RJ, Sinaii N, Rother KI. Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes. Diabetes Care . 2008; 31( 7): 1403– 1404. Google Scholar CrossRef Search ADS PubMed 2. Dinneen S, Alzaid A, Turk D, Rizza R. Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. Diabetologia . 1995; 38( 3): 337– 343. Google Scholar CrossRef Search ADS PubMed 3. Sherr J, Tsalikian E, Fox L, Buckingham B, Weinzimer S, Tamborlane WV, White NH, Arbelaez AM, Kollman C, Ruedy KJ, Cheng P, Beck RW; Diabetes Research in Children Network. Evolution of abnormal plasma glucagon responses to mixed-meal feedings in youth with type 1 diabetes during the first 2 years after diagnosis. Diabetes Care . 2014; 37( 6): 1741– 1744. Google Scholar CrossRef Search ADS PubMed 4. Pörksen S, Nielsen LB, Kaas A, Kocova M, Chiarelli F, Orskov C, Holst JJ, Ploug KB, Hougaard P, Hansen L, Mortensen HB; Hvidøre Study Group on Childhood Diabetes. Meal-stimulated glucagon release is associated with postprandial blood glucose level and does not interfere with glycemic control in children and adolescents with new-onset type 1 diabetes. J Clin Endocrinol Metab . 2007; 92( 8): 2910– 2916. Google Scholar CrossRef Search ADS PubMed 5. Weinzimer SA, Steil GM, Swan KL, Dziura J, Kurtz N, Tamborlane WV. Fully automated closed-loop insulin delivery versus semiautomated hybrid control in pediatric patients with type 1 diabetes using an artificial pancreas. Diabetes Care . 2008; 31( 5): 934– 939. Google Scholar CrossRef Search ADS PubMed 6. Fredheim S, Andersen ML, Pörksen S, Nielsen LB, Pipper C, Hansen L, Holst JJ, Thomsen J, Johannesen J, Mortensen HB, Svensson J. The influence of glucagon on postprandial hyperglycaemia in children 5 years after onset of type 1 diabetes. Diabetologia . 2015; 58( 4): 828– 834. Google Scholar CrossRef Search ADS PubMed 7. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care . 2003; 26( 3): 881– 885. Google Scholar CrossRef Search ADS PubMed 8. Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA . 2006; 295( 14): 1681– 1687. Google Scholar CrossRef Search ADS PubMed 9. Bode BW, Garg SK. The emerging role of adjunctive noninsulin antihyperglycemic therapy in the management of type 1 diabetes. Endocr Pract . 2016; 22( 2): 220– 230. Google Scholar CrossRef Search ADS PubMed 10. Ang KH, Sherr JL. Moving beyond subcutaneous insulin: the application of adjunctive therapies to the treatment of type 1 diabetes. Expert Opin Drug Deliv . 2017; 14( 9): 1113– 1131. Google Scholar CrossRef Search ADS PubMed 11. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, Neal B. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol . 2016; 4( 5): 411– 419. Google Scholar CrossRef Search ADS PubMed 12. Hinshaw L, Schiavon M, Dadlani V, Mallad A, Dalla Man C, Bharucha A, Basu R, Geske JR, Carter RE, Cobelli C, Basu A, Kudva YC. Effect of pramlintide on postprandial glucose fluxes in type 1 diabetes. J Clin Endocrinol Metab . 2016; 101( 5): 1954– 1962. Google Scholar CrossRef Search ADS PubMed 13. Meier JJ, Rosenstock J, Hincelin-Méry A, Roy-Duval C, Delfolie A, Coester HV, Menge BA, Forst T, Kapitza C. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial. Diabetes Care . 2015; 38( 7): 1263– 1273. Google Scholar CrossRef Search ADS PubMed 14. Sherr JL, Patel NS, Michaud CI, Palau-Collazo MM, Van Name MA, Tamborlane WV, Cengiz E, Carria LR, Tichy EM, Weinzimer SA. Mitigating meal-related glycemic excursions in an insulin-sparing manner during closed-loop insulin delivery: the beneficial effects of adjunctive pramlintide and liraglutide. Diabetes Care . 2016; 39( 7): 1127– 1134. Google Scholar CrossRef Search ADS PubMed 15. Frandsen CS, Dejgaard TF, Madsbad S. Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. Lancet Diabetes Endocrinol . 2016; 4( 9): 766– 780. Google Scholar CrossRef Search ADS PubMed 16. Ahrén B, Hirsch IB, Pieber TR, Mathieu C, Gómez-Peralta F, Hansen TK, Philotheou A, Birch S, Christiansen E, Jensen TJ, Buse JB; ADJUNCT TWO Investigators. Efficacy and safety of liraglutide added to capped insulin treatment in subjects with type 1 diabetes: The ADJUNCT TWO Randomized Trial. Diabetes Care . 2016; 39( 10): 1693– 1701. Google Scholar CrossRef Search ADS PubMed 17. Dejgaard TF, Frandsen CS, Hansen TS, Almdal T, Urhammer S, Pedersen-Bjergaard U, Jensen T, Jensen AK, Holst JJ, Tarnow L, Knop FK, Madsbad S, Andersen HU. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol . 2016; 4( 3): 221– 232. Google Scholar CrossRef Search ADS PubMed 18. Ilkowitz JT, Katikaneni R, Cantwell M, Ramchandani N, Heptulla RA. Adjuvant liraglutide and insulin versus insulin monotherapy in the closed-loop system in type 1 diabetes: a randomized open-labeled crossover design trial. J Diabetes Sci Technol . 2016; 10( 5): 1108– 1114. Google Scholar CrossRef Search ADS PubMed 19. Kuhadiya ND, Dhindsa S, Ghanim H, Mehta A, Makdissi A, Batra M, Sandhu S, Hejna J, Green K, Bellini N, Yang M, Chaudhuri A, Dandona P. Addition of liraglutide to insulin in patients with type 1 diabetes: a randomized placebo-controlled clinical trial of 12 weeks. Diabetes Care . 2016; 39( 6): 1027– 1035. Google Scholar CrossRef Search ADS PubMed 20. Mathieu C, Zinman B, Hemmingsson JU, Woo V, Colman P, Christiansen E, Linder M, Bode B; ADJUNCT ONE Investigators. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diabetes Care . 2016; 39( 10): 1702– 1710. Google Scholar CrossRef Search ADS PubMed 21. Chase HP, Lutz K, Pencek R, Zhang B, Porter L. Pramlintide lowered glucose excursions and was well-tolerated in adolescents with type 1 diabetes: results from a randomized, single-blind, placebo-controlled, crossover study. J Pediatr . 2009; 155( 3): 369– 373. Google Scholar CrossRef Search ADS PubMed 22. Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, Strobel S, Lutz K, Kolterman O. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care . 2006; 29( 10): 2189– 2195. Google Scholar CrossRef Search ADS PubMed 23. Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, Maggs DG, Kolterman OG, Chandran M, Mudaliar SR, Henry RR. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care . 2003; 26( 1): 1– 8. Google Scholar CrossRef Search ADS PubMed 24. Weinzimer SA, Sherr JL, Cengiz E, Kim G, Ruiz JL, Carria L, Voskanyan G, Roy A, Tamborlane WV. Effect of pramlintide on prandial glycemic excursions during closed-loop control in adolescents and young adults with type 1 diabetes. Diabetes Care . 2012; 35( 10): 1994– 1999. Google Scholar CrossRef Search ADS PubMed 25. Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, Weyer C, Kolterman OG. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care . 2002; 25( 4): 724– 730. Google Scholar CrossRef Search ADS PubMed 26. Smits MM, Tonneijck L, Muskiet MH, Kramer MH, Cahen DL, van Raalte DH. Gastrointestinal actions of glucagon-like peptide-1-based therapies: glycaemic control beyond the pancreas. Diabetes Obes Metab . 2016; 18( 3): 224– 235. Google Scholar CrossRef Search ADS PubMed 27. Anderberg RH, Richard JE, Eerola K, López-Ferreras L, Banke E, Hansson C, Nissbrandt H, Berqquist F, Gribble FM, Reimann F, Wernstedt Asterholm I, Lamy CM, Skibicka KP. Glucagon-like peptide 1 and its analogs act in the dorsal raphe and modulate central serotonin to reduce appetite and body weight. Diabetes . 2017; 66( 4): 1062– 1073. Google Scholar CrossRef Search ADS PubMed 28. Retnakaran R, Kramer CK, Choi H, Swaminathan B, Zinman B. Liraglutide and the preservation of pancreatic β-cell function in early type 2 diabetes: the LIBRA trial. Diabetes Care . 2014; 37( 12): 3270– 3278. Google Scholar CrossRef Search ADS PubMed 29. Seino Y, Kaneko S, Fukuda S, Osonoi T, Shiraiwa T, Nishijima K, Bosch-Traberg H, Kaku K. Combination therapy with liraglutide and insulin in Japanese patients with type 2 diabetes: A 36-week, randomized, double-blind, parallel-group trial. J Diabetes Investig . 2016; 7( 4): 565– 573. Google Scholar CrossRef Search ADS PubMed 30. Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, Weyer C, Kolterman OG. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med . 2004; 21( 11): 1204– 1212. Google Scholar CrossRef Search ADS PubMed 31. Nyholm B, Orskov L, Hove KY, Gravholt CH, Møller N, Alberti KG, Moyses C, Kolterman O, Schmitz O. The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus. Metabolism . 1999; 48( 7): 935– 941. Google Scholar CrossRef Search ADS PubMed 32. Jelsing J, Vrang N, Hansen G, Raun K, Tang-Christensen M, Knudsen LB. Liraglutide: short-lived effect on gastric emptying -- long lasting effects on body weight. Diabetes Obes Metab . 2012; 14( 6): 531– 538. Google Scholar CrossRef Search ADS PubMed 33. Kuhadiya ND, Malik R, Bellini NJ, Patterson JL, Traina A, Makdissi A, Dandona P. Liraglutide as additional treatment to insulin in obese patients with type 1 diabetes mellitus. Endocr Pract . 2013; 19( 6): 963– 967. Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society
Journal of Clinical Endocrinology and Metabolism – Oxford University Press
Published: Mar 1, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.
All for just $49/month
Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.
Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.
It’s easy to organize your research with our built-in tools.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera