Browsing by Subject "Blood glucose"

Now showing 1 - 10 of 24
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    100 years of insulin: celebrating the past, present and future of diabetes therapy
    (Springer Nature, 2021) Sims, Emily K.; Carr, Alice L.J.; Oram, Richard A.; DiMeglio, Linda A.; Evans-Molina, Carmella; Pediatrics, School of Medicine
    The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.
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    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 Medicine
    Objective: 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.
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    Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study
    (American Diabetes Association, 2021) Sam, Susan; Edelstein, Sharon L.; Arslanian, Silva A.; Barengolts, Elena; Buchanan, Thomas A.; Caprio, Sonia; Ehrmann, David A.; Hannon, Tamara S.; Hogan Tjaden, Ashley; Kahn, Steven E.; Mather, Kieren J.; Tripputi, Mark; Utzschneider, Kristina M.; Xiang, Anny H.; Nadeau, Kristen J.; The RISE Consortium; Pediatrics, School of Medicine
    Objective: To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study. Research design and methods: A total of 91 youth (10-19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA1c increase ≥0.5% from baseline). Results: Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05-0.96, P = 0.044). In both age-groups, lower baseline clamp-derived β-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05). Conclusions: Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.
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    Dietary Intervention for Glucose Tolerance In Teens (DIG IT): Protocol of a randomized controlled trial using health coaching to prevent youth-onset type 2 diabetes
    (Elsevier, 2017-02) Wagner, Kelly A.; Braun, Ethan; Armah, Seth M.; Horan, Diarmuid; Smith, Lisa G.; Pike, Julie; Tu, Wanzhu; Hamilton, Marc T.; Delp, Edward J.; Campbell, Wayne W.; Boushey, Carol J.; Hannon, Tamara S.; Gletsu-Miller, Nana; Pediatrics, School of Medicine
    BACKGROUND: Youth-onset type 2 diabetes (T2D) is a disease that is newly emerging and behavioral strategies for its prevention are limited. Interventions that target the lifestyle behaviors of adolescents, to improve poor dietary quality and reduce excessive sedentariness, promise to reduce the risk of developing T2D. Health coaching is effective for promoting healthy behaviors in patients who have chronic disease, but few experimental studies are in adolescents. This randomized controlled trial, in adolescents with prediabetes, will determine the effectiveness of a health coaching intervention to facilitate adoption of healthy diet and activity behaviors that delay or prevent development of T2D. METHODS/DESIGN: The Dietary Intervention for Glucose Tolerance In Teens (DIG IT) trial will involve an evaluation of a health coaching intervention in adolescents with prediabetes. Eligible participants will be randomized to receive 6months of health coaching or a single dietary consultation that is standard-of-care. The primary outcome will be 2-hour oral glucose tolerance test concentration. Secondary outcomes will include measures of glycemia and insulin action as well as dietary, physical activity and sedentary behaviors measured using an electronic food record, and by inclinometer. Data will be collected before and after the intervention (at 6months) and at 12months (to assess sustainability). DISCUSSION: This trial will determine whether a health coaching intervention, a personalized and low-cost approach to modify dietary and activity behaviors, is effective and sustainable for prevention of youth-onset T2D, relative to standard-of-care. Health coaching has the potential to be widely implemented in clinical or community settings.
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    Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study
    (American Diabetes Association, 2021) Kahn, Steven E.; Edelstein, Sharon L.; Arslanian, Silva A.; Barengolts, Elena; Caprio, Sonia; Ehrmann, David A.; Hannon, Tamara S.; Marcovina, Santica; Mather, Kieren J.; Nadeau, Kristen J.; Utzschneider, Kristina M.; Xiang, Anny H.; Buchanan, Thomas A.; The RISE Consortium; Pediatrics, School of Medicine
    Objective: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols. Research design and methods: Glucagon was measured in three randomized, parallel, clinical studies: 1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; 2) 267 adults studied at the same time points and treated with MET, G/M, or liraglutide plus metformin (L+M) or given placebo (PLAC); and 3) 88 adults studied at baseline and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose, and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs). Results: No change in fasting glucagon, steady-state glucagon, or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all P ≤ 0.005), which was maintained 3 months after treatment withdrawal (all P < 0.01). LB in adults also reduced fasting glucagon, steady-state glucagon, and AGR at 12 and 24 months (P < 0.05 for all, except AGR at 12 months [P = 0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss. Conclusions: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributable to weight loss in both interventions.
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    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 Medicine
    Importance: 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.
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    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 Medicine
    The 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.
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    Hyperglucagonemia Does Not Explain the β-Cell Hyperresponsiveness and Insulin Resistance in Dysglycemic Youth Compared With Adults: Lessons From the RISE Study
    (American Diabetes Association, 2021) Kahn, Steven E.; Mather, Kieren J.; Arslanian, Silva A.; Barengolts, Elena; Buchanan, Thomas A.; Caprio, Sonia; Ehrmann, David A.; Hannon, Tamara S.; Marcovina, Santica; Nadeau, Kristen J.; Utzschneider, Kristina M.; Xiang, Anny H.; Edelstein, Sharon L.; The RISE Consortium; Medicine, School of Medicine
    Objective: To determine whether β-cell hyperresponsiveness and insulin resistance in youth versus adults in the Restoring Insulin Secretion (RISE) Study are related to increased glucagon release. Research design and methods: In 66 youth and 350 adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (drug naive), we performed hyperglycemic clamps and oral glucose tolerance tests (OGTTs). From clamps we quantified insulin sensitivity (M/I), plasma fasting glucagon and C-peptide, steady-state glucagon and C-peptide at glucose of 11.1 mmol/L, and arginine-stimulated glucagon (acute glucagon response [AGR]) and C-peptide (ACPRmax) responses at glucose >25 mmol/L. Results: Mean ± SD fasting glucagon (7.63 ± 3.47 vs. 8.55 ± 4.47 pmol/L; P = 0.063) and steady-state glucagon (2.24 ± 1.46 vs. 2.49 ± 1.96 pmol/L, P = 0.234) were not different in youth and adults, respectively, while AGR was lower in youth (14.1 ± 5.2 vs. 16.8 ± 8.8 pmol/L, P = 0.001). Significant age-group differences in insulin sensitivity, fasting C-peptide, steady-state C-peptide, and ACPRmax were not related to glucagon. Fasting glucose and glucagon were positively correlated in adults (r = 0.133, P = 0.012) and negatively correlated in youth (r = -0.143, P = 0.251). In both age-groups, higher fasting glucagon was associated with higher fasting C-peptide (youth r = 0.209, P = 0.091; adults r = 0.335, P < 0.001) and lower insulin sensitivity (youth r = -0.228, P = 0.066; adults r = -0.324, P < 0.001). With comparable fasting glucagon, youth had greater C-peptide and lower insulin sensitivity. OGTT suppression of glucagon was greater in youth. Conclusions: Youth with IGT or recently diagnosed type 2 diabetes (drug naive) have hyperresponsive β-cells and lower insulin sensitivity, but their glucagon concentrations are not increased compared with those in adults. Thus, α-cell dysfunction does not appear to explain the difference in β-cell function and insulin sensitivity in youth versus adults.
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    Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
    (Elsevier, 2021) Gitelman, Stephen E.; Bundy, Brian N.; Ferrannini, Ele; Lim, Noha; Blanchfield, J. Lori; DiMeglio, Linda A.; Felner, Eric I.; Gaglia, Jason L.; Gottlieb, Peter A.; Long, S. Alice; Mari, Andrea; Mirmira, Raghavendra G.; Raskin, Philip; Sanda, Srinath; Tsalikian, Eva; Wentworth, John M.; Willi, Steven M.; Krischer, Jeffrey P.; Bluestone, Jeffrey A.; Gleevec Trial Study Group; Pediatrics, School of Medicine
    Background: Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes. Methods: We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L-1 on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed). Findings: Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI -0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events. Interpretation: A 26-week course of imatinib preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required.
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    Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes
    (American Diabetes Association, 2022) Nathan, Brandon M.; Redondo, Maria J.; Ismail, Heba; Jacobsen, Laura; Sims, Emily K.; Palmer, Jerry; Skyler, Jay; Bocchino, Laura; Geyer, Susan; Sosenko, Jay M.; Pediatrics, School of Medicine
    Objective: We assessed whether Index60, a composite measure of fasting C-peptide, 60-min C-peptide, and 60-min glucose, could improve the metabolic staging of type 1 diabetes for progression to clinical disease (stage 3) among autoantibody-positive (Ab+) individuals with normal 2-h glucose values (<140 mg/dL). Research design and methods: We analyzed 3,058 Type 1 Diabetes TrialNet Pathway to Prevention participants with 2-h glucose <140 mg/dL and Index60 <1.00 values from baseline oral glucose tolerance tests. Characteristics associated with type 1 diabetes (younger age, greater Ab+, higher HLA DR3-DQ2/DR4-DQ8 prevalence, and lower C-peptide) were compared among four mutually exclusive groups: top 2-h glucose quartile only (HI-2HGLU), top Index60 quartile only (HI-IND60), both top quartiles (HI-BOTH), and neither top quartile (LO-BOTH). Additionally, within the 2-h glucose distribution of <140 mg/dL and separately within the Index60 <1.00 distribution, comparisons were made between those above or below the medians. Results: HI-IND60 and HI-BOTH were younger, with greater frequency of more than two Ab+, and lower C-peptide levels, than either HI-2HGLU or LO-BOTH (all P < 0.001). The cumulative incidence for stage 3 was greater for HI-IND60 and HI-BOTH than for either HI-2HGLU or LO-BOTH (all P < 0.001). Those with Index60 values above the median were younger and had higher frequency of two or more Ab+ (P < 0.001) and DR3-DQ2/DR4-DQ8 prevalence (P < 0.001) and lower area under the curve (AUC) C-peptide levels (P < 0.001) than those below. Those above the 2-h glucose median had higher AUC C-peptide levels (P < 0.001), but otherwise did not differ from those below. Conclusions: Index60 identifies individuals with characteristics of type 1 diabetes at appreciable risk for progression who would otherwise be missed by 2-h glucose staging criteria.