Browsing by Subject "Hypoglycemic agents"
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Item A Randomized Clinical Trial Assessing Continuous Glucose Monitoring (CGM) Use With Standardized Education With or Without a Family Behavioral Intervention Compared With Fingerstick Blood Glucose Monitoring in Very Young Children With Type 1 Diabetes(American Diabetes Association, 2021) Strategies to Enhance New CGM Use in Early Childhood (SENCE) Study Group; Pediatrics, School of MedicineObjective: This study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to <8 years with type 1 diabetes. Research design and methods: This was a multicenter (N = 14), 6-month, randomized controlled trial including 143 youth 2 to <8 years of age with type 1 diabetes. Primary analysis included treatment group comparisons of percent time in range (TIR) (70-180 mg/dL) across follow-up visits. Results: Approximately 90% of participants in the CGM groups used CGM ≥6 days/week at 6 months. Between-group TIR comparisons showed no significant changes: CGM+FBI vs. BGM 3.2% (95% CI -0.5, 7.0), Standard-CGM vs. BGM 0.5% (-2.6 to 3.6), CGM+FBI vs. Standard-CGM 2.7% (-0.6, 6.1). Mean time with glucose level <70 mg/dL was reduced from baseline to follow-up in the CGM+FBI (from 5.2% to 2.6%) and Standard-CGM (5.8% to 2.5%) groups, compared with 5.4% to 5.8% with BGM (CGM+FBI vs. BGM, P < 0.001, and Standard-CGM vs. BGM, P < 0.001). No severe hypoglycemic events occurred in the CGM+FBI group, one occurred in the Standard-CGM group, and five occurred in the BGM group. CGM+FBI parents reported greater reductions in diabetes burden and fear of hypoglycemia compared with Standard-CGM (P = 0.008 and 0.04) and BGM (P = 0.02 and 0.002). Conclusions: CGM used consistently over a 6-month period in young children with type 1 diabetes did not improve TIR but did significantly reduce time in hypoglycemia. The FBI benefited parental well-being.Item Connecting Rodent and Human Pharmacokinetic Models for the Design and Translation of Glucose-Responsive Insulin(American Diabetes Association, 2020-08) Yang, Jing Fan; Gong, Xun; Bakh, Naveed A.; Carr, Kelley; Phillips, Nelson F.B.; Ismail-Beigi, Faramarz; Weiss, Michael A.; Strano, Michael S.; Biochemistry and Molecular Biology, School of MedicineDespite considerable progress, development of glucose-responsive insulins (GRIs) still largely depends on empirical knowledge and tedious experimentation-especially on rodents. To assist the rational design and clinical translation of the therapeutic, we present a Pharmacokinetic Algorithm Mapping GRI Efficacies in Rodents and Humans (PAMERAH) built upon our previous human model. PAMERAH constitutes a framework for predicting the therapeutic efficacy of a GRI candidate from its user-specified mechanism of action, kinetics, and dosage, which we show is accurate when checked against data from experiments and literature. Results from simulated glucose clamps also agree quantitatively with recent GRI publications. We demonstrate that the model can be used to explore the vast number of permutations constituting the GRI parameter space and thereby identify the optimal design ranges that yield desired performance. A design guide aside, PAMERAH more importantly can facilitate GRI's clinical translation by connecting each candidate's efficacies in rats, mice, and humans. The resultant mapping helps to find GRIs that appear promising in rodents but underperform in humans (i.e., false positives). Conversely, it also allows for the discovery of optimal human GRI dynamics not captured by experiments on a rodent population (false negatives). We condense such information onto a "translatability grid" as a straightforward, visual guide for GRI development.Item Effect of Tight Glycemic Control on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial(American Medical Association, 2023) McVean, Jennifer; Forlenza, Gregory P.; Beck, Roy W.; Bauza, Colleen; Bailey, Ryan; Buckingham, Bruce; DiMeglio, Linda A.; Sherr, Jennifer L.; Clements, Mark; Neyman, Anna; Evans-Molina, Carmella; Sims, Emily K.; Messer, Laurel H.; Ekhlaspour, Laya; McDonough, Ryan; Van Name, Michelle; Rojas, Diana; Beasley, Shannon; DuBose, Stephanie; Kollman, Craig; Moran, Antoinette; CLVer Study Group; Pediatrics, School of MedicineImportance: Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing glucotoxicity. Previous studies have been hampered by an inability to achieve tight glycemic goals. Objective: To determine the effectiveness of intensive diabetes management to achieve near normalization of glucose levels on preservation of pancreatic beta cell function in youth with newly diagnosed type 1 diabetes. Design, setting, and participants: This randomized, double-blind, clinical trial was conducted at 6 centers in the US (randomizations from July 20, 2020, to October 13, 2021; follow-up completed September 15, 2022) and included youths with newly diagnosed type 1 diabetes aged 7 to 17 years. Interventions: Random assignment to intensive diabetes management, which included use of an automated insulin delivery system (n = 61), or standard care, which included use of a continuous glucose monitor (n = 52), as part of a factorial design in which participants weighing 30 kg or more also were assigned to receive either oral verapamil or placebo. Main outcomes and measures: The primary outcome was mixed-meal tolerance test-stimulated C-peptide area under the curve (a measure of pancreatic beta cell function) 52 weeks from diagnosis. Results: Among 113 participants (mean [SD] age, 11.8 [2.8] years; 49 females [43%]; mean [SD] time from diagnosis to randomization, 24 [5] days), 108 (96%) completed the trial. The mean C-peptide area under the curve decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group, and from 0.60 to 0.50 pmol/mL in the standard care group (treatment group difference, -0.01 [95% CI, -0.11 to 0.10]; P = .89). The mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% in the intensive management group vs 64% in the standard care group (adjusted difference, 16% [95% CI, 10% to 22%]). One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group. Conclusions and relevance: In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks.Item Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial(American Medical Association, 2023) Forlenza, Gregory P.; McVean, Jennifer; Beck, Roy W.; Bauza, Colleen; Bailey, Ryan; Buckingham, Bruce; DiMeglio, Linda A.; Sherr, Jennifer L.; Clements, Mark; Neyman, Anna; Evans-Molina, Carmella; Sims, Emily K.; Messer, Laurel H.; Ekhlaspour, Laya; McDonough, Ryan; Van Name, Michelle; Rojas, Diana; Beasley, Shannon; DuBose, Stephanie; Kollman, Craig; Moran, Antoinette; CLVer Study Group; Pediatrics, School of MedicineImportance: In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes. Objective: To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes. Design, setting, and participants: This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022. Interventions: Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care. Main outcomes and measures: The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes. Results: Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment. Conclusions and relevance: In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy.Item The Evolution of Hemoglobin A1c Targets for Youth With Type 1 Diabetes: Rationale and Supporting Evidence(American Diabetes Association, 2021) Redondo, Maria J.; Libman, Ingrid; Maahs, David M.; Lyons, Sarah K.; Saraco, Mindy; Reusch, Jane; Rodriguez, Henry; DiMeglio, Linda A.; Pediatrics, School of MedicineThe American Diabetes Association 2020 Standards of Medical Care in Diabetes (Standards of Care) recommends a hemoglobin A1c (A1C) of <7% (53 mmol/mol) for many children with type 1 diabetes (T1D), with an emphasis on target personalization. A higher A1C target of <7.5% may be more suitable for youth who cannot articulate symptoms of hypoglycemia or have hypoglycemia unawareness and for those who do not have access to analog insulins or advanced diabetes technologies or who cannot monitor blood glucose regularly. Even less stringent A1C targets (e.g., <8%) may be warranted for children with a history of severe hypoglycemia, severe morbidities, or short life expectancy. During the "honeymoon" period and in situations where lower mean glycemia is achievable without excessive hypoglycemia or reduced quality of life, an A1C <6.5% may be safe and effective. Here, we provide a historical perspective of A1C targets in pediatrics and highlight evidence demonstrating detrimental effects of hyperglycemia in children and adolescents, including increased likelihood of brain structure and neurocognitive abnormalities, microvascular and macrovascular complications, long-term effects, and increased mortality. We also review data supporting a decrease over time in overall severe hypoglycemia risk for youth with T1D, partly associated with the use of newer insulins and devices, and weakened association between lower A1C and severe hypoglycemia risk. We present common barriers to achieving glycemic targets in pediatric diabetes and discuss some strategies to address them. We aim to raise awareness within the community on Standards of Care updates that impact this crucial goal in pediatric diabetes management.Item Glucagon-Like Peptide 1 Receptor Activation Augments Cardiac Output and Improves Cardiac Efficiency in Obese Swine After Myocardial Infarction(American Diabetes Association, 2017-08) Sassoon, Daniel J.; Tune, Johnathan D.; Mather, Kieren J.; Noblet, Jillian N.; Eagleson, Mackenzie A.; Conteh, Abass M.; Sturek, Joshua T.; Goodwill, Adam G.; Cellular and Integrative Physiology, School of MedicineThis study tested the hypothesis that glucagon-like peptide 1 (GLP-1) therapies improve cardiac contractile function at rest and in response to adrenergic stimulation in obese swine after myocardial infarction. Obese Ossabaw swine were subjected to gradually developing regional coronary occlusion using an ameroid occluder placed around the left anterior descending coronary artery. Animals received subcutaneous injections of saline or liraglutide (0.005-0.015 mg/kg/day) for 30 days after ameroid placement. Cardiac performance was assessed at rest and in response to sympathomimetic challenge (dobutamine 0.3-10 μg/kg/min) using a left ventricular pressure/volume catheter. Liraglutide increased diastolic relaxation (dP/dt; Tau 1/2; Tau 1/e) during dobutamine stimulation (P < 0.01) despite having no influence on the magnitude of myocardial infarction. The slope of the end-systolic pressure volume relationship (i.e., contractility) increased with dobutamine after liraglutide (P < 0.001) but not saline administration (P = 0.63). Liraglutide enhanced the slope of the relationship between cardiac power and pressure volume area (i.e., cardiac efficiency) with dobutamine (P = 0.017). Hearts from animals treated with liraglutide demonstrated decreased β1-adrenoreceptor expression. These data support that GLP-1 agonism augments cardiac efficiency via attenuation of maladaptive sympathetic signaling in the setting of obesity and myocardial infarction.Item ISPAD Clinical Practice Consensus Guidelines 2022: Exercise in children and adolescents with diabetes(Wiley, 2022) Adolfsson, Peter; Taplin, Craig E.; Zaharieva, Dessi P.; Pemberton, John; Davis, Elizabeth A.; Riddell, Michael C.; McGavock, Jonathan; Moser, Othmar; Szadkowska, Agnieszka; Lopez, Prudence; Santiprabhob, Jeerunda; Frattolin, Elena; Griffiths, Gavin; DiMeglio, Linda A.; Pediatrics, School of MedicineItem Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants(American Diabetes Association, 2016-02) Hivert, Marie-France; Christophi, Costas A.; Franks, Paul W.; Jablonski, Kathleen A.; Ehrmann, David A.; Kahn, Steven E.; Horton, Edward S.; Pollin, Toni I.; Mather, Kieren J.; Perreault, Leigh; Barrett-Connor, Elizabeth; Knowler, William C.; Florez, Jose C.; Department of Medicine, IU School of MedicineLarge genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (β = -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (β = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants.Item Lived experience of CamAPS FX closed loop system in youth with type 1 diabetes and their parents(Wiley, 2022) Hood, Korey K.; Garcia-Willingham, Natasha; Hanes, Sarah; Tanenbaum, Molly L.; Ware, Julia; Boughton, Charlotte K.; Allen, Janet M.; Wilinska, Malgorzata E.; Tauschmann, Martin; Denvir, Louise; Thankamony, Ajay; Campbell, Fiona; Wadwa, R. Paul; Buckingham, Bruce A.; Davis, Nikki; DiMeglio, Linda A.; Mauras, Nelly; Besser, Rachel E. J.; Ghatak, Atrayee; Weinzimer, Stuart A.; Fox, D. Steven; Kanapka, Lauren; Kollman, Craig; Sibayan, Judy; Beck, Roy W.; Hovorka, Roman; DAN05 ConsortiumAim: To examine changes in the lived experience of type 1 diabetes after use of hybrid closed loop (CL), including the CamAPS FX CL system. Materials and methods: The primary study was conducted as an open-label, single-period, randomized, parallel design contrasting CL versus insulin pump (with or without continuous glucose monitoring). Participants were asked to complete patient-reported outcomes before starting CL and 3 and 6 months later. Surveys assessed diabetes distress, hypoglycaemia concerns and quality of life. Qualitative focus group data were collected at the completion of the study. Results: In this sample of 98 youth (age range 6-18, mean age 12.7 ± 2.8 years) and their parents, CL use was not associated with psychosocial benefits overall. However, the subgroup (n = 12) using the CamAPS FX system showed modest improvements in quality of life and parent distress, reinforced by both survey (p < .05) and focus group responses. There were no negative effects of CL use reported by study participants. Conclusions: Closed loop use via the CamAPS FX system was associated with modest improvements in aspects of the lived experience of managing type 1 diabetes in youth and their families. Further refinements of the system may optimize the user experience.Item Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial(American Medical Association, 2023) Boggess, Kim A.; Valint, Arielle; Refuerzo, Jerrie S.; Zork, Noelia; Battarbee, Ashley N.; Eichelberger, Kacey; Ramos, Gladys A.; Olson, Gayle; Durnwald, Celeste; Landon, Mark B.; Aagaard, Kjersti M.; Wallace, Kedra; Scifres, Christina; Rosen, Todd; Mulla, Wadia; Valent, Amy; Longo, Sherri; Young, Laura; Marquis, M. Alison; Thomas, Sonia; Britt, Ashley; Berry, Diane; Obstetrics and Gynecology, School of MedicineImportance: Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. Objective: To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome. Design, setting, and participants: This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022. Intervention: Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. Main outcome and measures: The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy. Results: Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group. Conclusions and relevance: Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation.