Browsing by Author "Ferrannini, Ele"

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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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    Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
    (Nature Publishing Group, 2015-01-29) Wessel, Jennifer; Chu, Audrey Y.; Willems, Sara M.; Wang, Shuai; Yaghootkar, Hanieh; Brody, Jennifer A.; Dauriz, Marco; Hivert, Marie-France; Raghavan, Sridharan; Lipovich, Leonard; Hidalgo, Bertha; Fox, Keolu; Huffman, Jennifer E.; An, Ping; Lu, Yingchang; Rasmussen-Torvik, Laura J.; Grarup, Niels; Ehm, Margaret G.; Li, Li; Baldridge, Abigail S.; Stančáková, Alena; Abrol, Ravinder; Besse, Céline; Boland, Anne; Bork-Jensen, Jette; Fornage, Myriam; Freitag, Daniel F.; Garcia, Melissa E.; Guo, Xiuqing; Hara, Kazuo; Isaacs, Aaron; Jakobsdottir, Johanna; Lange, Leslie A.; Layton, Jill C.; Li, Man; Hua Zhao, Jing; Meidtner, Karina; Morrison, Alanna C.; Nalls, Mike A.; Peters, Marjolein J.; Sabater-Lleal, Maria; Schurmann, Claudia; Silveira, Angela; Smith, Albert V.; Southam, Lorraine; Stoiber, Marcus H.; Strawbridge, Rona J.; Taylor, Kent D.; Varga, Tibor V.; Allin, Kristine H.; Amin, Najaf; Aponte, Jennifer L.; Aung, Tin; Barbieri, Caterina; Bihlmeyer, Nathan A.; Boehnke, Michael; Bombieri, Cristina; Bowden, Donald W.; Burns, Sean M.; Chen, Yuning; Chen, Yii-DerI; Cheng, Ching-Yu; Correa, Adolfo; Czajkowski, Jacek; Dehghan, Abbas; Ehret, Georg B.; Eiriksdottir, Gudny; Escher, Stefan A.; Farmaki, Aliki-Eleni; Frånberg, Mattias; Gambaro, Giovanni; Giulianini, Franco; Goddard, William A.; Goel, Anuj; Gottesman, Omri; Grove, Megan L.; Gustafsson, Stefan; Hai, Yang; Hallmans, Göran; Heo, Jiyoung; Hoffmann, Per; Ikram, Mohammad K.; Jensen, Richard A.; Jørgensen, Marit E.; Jørgensen, Torben; Karaleftheri, Maria; Khor, Chiea C.; Kirkpatrick, Andrea; Kraja, Aldi T.; Kuusisto, Johanna; Lange, Ethan M.; Lee, I. T.; Lee, Wen-Jane; Leong, Aaron; Liao, Jiemin; Liu, Chunyu; Liu, Yongmei; Lindgren, Cecilia M.; Linneberg, Allan; Malerba, Giovanni; Mamakou, Vasiliki; Marouli, Eirini; Maruthur, Nisa M.; Matchan, Angela; McKean-Cowdin, Roberta; McLeod, Olga; Metcalf, Ginger A.; Mohlke, Karen L.; Muzny, Donna M.; Ntalla, Ioanna; Palmer, Nicholette D.; Pasko, Dorota; Peter, Andreas; Rayner, Nigel W.; Renström, Frida; Rice, Ken; Sala, Cinzia F.; Sennblad, Bengt; Serafetinidis, Ioannis; Smith, Jennifer A.; Soranzo, Nicole; Speliotes, Elizabeth K.; Stahl, Eli A.; Stirrups, Kathleen; Tentolouris, Nikos; Thanopoulou, Anastasia; Torres, Mina; Traglia, Michela; Tsafantakis, Emmanouil; Javad, Sundas; Yanek, Lisa R.; Zengini, Eleni; Becker, Diane M.; Bis, Joshua C.; Brown, James B.; Adrienne Cupples, L.; Hansen, Torben; Ingelsson, Erik; Karter, Andrew J.; Lorenzo, Carlos; Mathias, Rasika A.; Norris, Jill M.; Peloso, Gina M.; Sheu, Wayne H.-H.; Toniolo, Daniela; Vaidya, Dhananjay; Varma, Rohit; Wagenknecht, Lynne E.; Boeing, Heiner; Bottinger, Erwin P.; Dedoussis, George; Deloukas, Panos; Ferrannini, Ele; Franco, Oscar H.; Franks, Paul W.; Gibbs, Richard A.; Gudnason, Vilmundur; Hamsten, Anders; Harris, Tamara B.; Hattersley, Andrew T.; Hayward, Caroline; Hofman, Albert; Jansson, Jan-Håkan; Langenberg, Claudia; Launer, Lenore J.; Levy, Daniel; Oostra, Ben A.; O'Donnell, Christopher J.; O'Rahilly, Stephen; Padmanabhan, Sandosh; Pankow, James S.; Polasek, Ozren; Province, Michael A.; Rich, Stephen S.; Ridker, Paul M.; Rudan, Igor; Schulze, Matthias B.; Smith, Blair H.; Uitterlinden, André G.; Walker, Mark; Watkins, Hugh; Wong, Tien Y.; Zeggini, Eleftheria; Laakso, Markku; Borecki, Ingrid B.; Chasman, Daniel I.; Pedersen, Oluf; Psaty, Bruce M.; Shyong Tai, E.; van Duijn, Cornelia M.; Wareham, Nicholas J.; Waterworth, Dawn M.; Boerwinkle, Eric; Linda Kao, W. H.; Florez, Jose C.; Loos, Ruth J. F.; Wilson, James G.; Frayling, Timothy M.; Siscovick, David S.; Dupuis, Josée; Rotter, Jerome I.; Meigs, James B.; Scott, Robert A.; Goodarzi, Mark O.; Department of Epidemiology, Richard M. Fairbanks School of Public Health
    Fasting ​glucose and ​insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in ​GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early ​insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h ​glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at ​G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ​ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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    The effect of age on longitudinal measures of beta cell function and insulin sensitivity during the progression of early stage type 1 diabetes
    (Springer, 2023) Ferrannini, Ele; Mari, Andrea; Monaco, Gabriela S. F.; Skyler, Jay S.; Evans-Molina, Carmella; Pediatrics, School of Medicine
    Aim/hypothesis: The risk of progressing from autoantibody positivity to type 1 diabetes is inversely related to age. Separately, whether age influences patterns of C-peptide loss or changes in insulin sensitivity in autoantibody-positive individuals who progress to stage 3 type 1 diabetes is unclear. Methods: Beta cell function and insulin sensitivity were determined by modelling of OGTTs performed in 658 autoantibody-positive participants followed longitudinally in the Diabetes Prevention Trial-Type 1 (DPT-1). In this secondary analysis of DPT-1 data, time trajectories of beta cell function and insulin sensitivity were analysed in participants who progressed to type 1 diabetes (progressors) to address the impact of age on patterns of metabolic progression to diabetes. Results: Among the entire DPT-1 cohort, the highest discriminant age for type 1 diabetes risk was 14 years, with participants aged <14 years being twice as likely to progress to type 1 diabetes as those aged ≥14 years. At study entry, beta cell glucose sensitivity was impaired to a similar extent in progressors aged <14 years and progressors aged ≥14 years. From study entry to stage 3 type 1 diabetes onset, beta cell glucose sensitivity and insulin sensitivity declined in both progressor groups. However, there were no significant differences in the yearly rate of decline in either glucose sensitivity (-13.7 [21.2] vs -11.9 [21.5] pmol min-1 m-2 [mmol/l]-1, median [IQR], p=0.52) or insulin sensitivity (-22 [37] vs -14 [40] ml min-1 m-2, median [IQR], p=0.07) between progressors aged <14 years and progressors aged ≥14 years. Conclusions/interpretation: Our data indicate that during progression to stage 3 type 1 diabetes, rates of change in declining glucose and insulin sensitivity are not significantly different between progressors aged <14 years and progressors aged ≥14 years. These data suggest there is a predictable course of declining metabolic function during the progression to type 1 diabetes that is not influenced by age.
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    β-Cell Glucose Sensitivity to Assess Changes in β-Cell Function in Recent-Onset Stage 3 Type 1 Diabetes
    (American Diabetes Association, 2023) Gitelman, Stephen E.; Evans-Molina, Carmella; Guolo, Annamaria; Mari, Andrea; Ferrannini, Ele; Pediatrics, School of Medicine
    Following a diagnosis of type 1 diabetes (T1D), persisting C-peptide secretion leads to improved glycemic control and outcomes. Residual β-cell function is often assessed with serial mixed-meal tolerance tests, but these tests do not correlate well with clinical outcomes. Herein, we instead use β-cell glucose sensitivity (βGS) to assess changes in β-cell function, incorporating insulin secretion for a given serum glucose into the assessment of β-cell function. We evaluated changes in βGS in individuals enrolled in the placebo arm of 10 T1D trials performed at diabetes onset. We found that βGS showed a more rapid decline in children, as compared with adolescents and adults. Individuals in the top quartile of βGS baseline distribution had a slower rate in loss of glycemic control time over time. Notably, half of this group were children and adolescents. Finally, to identify predictors of glycemic control throughout follow-up, we ran multivariate Cox models and found that incorporating βGS significantly improved the overall model. Taken together, these data suggest that βGS may be of great utility in predicting those more likely to have a more robust clinical remission and may be of use in design of new-onset diabetes clinical trials and in evaluating response to therapies. Article highlights: We undertook this study to better predict β-cell loss following type 1 diabetes diagnosis. We set out to answer whether β-cell glucose sensitivity (βGS) improves means to evaluate β-cell function postdiagnosis and whether βGS correlates with clinical outcomes. We found that βGS declines faster in children, subjects in the top baseline quartile of βGS exhibit slower β-cell decline (half are children), and incorporating βGS into multivariate Cox models for glycemic improves the model. The implications of our findings are that βGS predicts those likely to have robust clinical remissions and may help with clinical trials design.