Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2025 Apr 1;48(4):623-631.
doi: 10.2337/dc24-2419.

Differential Treatment Effects on β-Cell Function Using Model-Based Parameters in Type 2 Diabetes: Results From the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

Kristina M Utzschneider  1 , Mark Tripputi  2 , Nicole M Butera  2 , Andrea Mari  3 , Samuel P Rosin  2 , Mary Ann Banerji  4 , Richard M Bergenstal  5 , Necole Brown  4 , Anders L Carlson  5 , Ralph A DeFronzo  6 , Michaela R Gramzinski  2 , Tasma Harindhanavudhi  7 , Alexandra Kozedub  8 , William I Sivitz  9 , Michael W Steffes  10 , Ashok Balasubramanyam  11 , Neda Rasouli  12 ; GRADE Research Group
Collaborators, Affiliations
Randomized Controlled Trial

Differential Treatment Effects on β-Cell Function Using Model-Based Parameters in Type 2 Diabetes: Results From the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

Kristina M Utzschneider et al. Diabetes Care. .

Abstract

Objective: To evaluate how model-based parameters of β-cell function change with glucose-lowering treatment and associate with glycemic deterioration in adults with type 2 diabetes (T2D).

Research design and methods: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), β-cell function parameters derived from mathematical modeling of oral glucose tolerance tests were assessed at baseline (N = 4,712) and 1, 3, and 5 years following randomization to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin. Parameters included insulin secretion rate (ISR), glucose sensitivity (insulin response to glucose), rate sensitivity (early insulin response), and potentiation. Linear mixed-effects models were used to compare changes across treatments. With Cox proportional hazards and Classification And Regression Tree (CART) analyses we evaluated associations between model parameters and glycemic failure (A1C >7.5%; 58.5 mmol/mol).

Results: β-Cell function parameters increased variably at year 1 across treatments but subsequently declined for all treatments. Statistically significant changes were noted. Liraglutide led to the greatest increases in ISR, glucose sensitivity and potentiation, remaining above baseline at study end. Sitagliptin improved glucose sensitivity, with modest effects on other parameters. Glimepiride temporarily increased ISR and rate sensitivity but minimally increased glucose sensitivity or potentiation. Rate sensitivity increased most with glargine. Higher β-cell function parameters were protective against glycemic deterioration, but treatment did not alter the relationship between these parameters and glycemic outcomes.

Conclusions: Common glucose-lowering medications impact different physiologic components of β-cell function in T2D. Regardless of treatment modality, lower β-cell function associated with early glycemic failure, and β-cell function progressively declined after initial improvement.

PubMed Disclaimer

Conflict of interest statement

Duality of Interest. K.M.U. reports grants or contracts from AVID Radiopharmaceuticals and Lilly and consulting fees and travel support from Nevro outside the submitted work. M.A.B. reports grants from Eli Lilly for clinical trials made to her institution; payment for presenting grand rounds on diabetes; and participation on a data safety monitoring board for Oramed Pharmaceuticals outside the submitted work. RM.B. has received research support, has acted as a consultant, or has been on the scientific advisory board for Abbott Diabetes Care, Ascensia Diabetes Care, CeQur, Dexcom, Eli Lilly, Embecta, Hygieia, Insulet, Medtronic, Novo Nordisk, Onduo, Roche Diabetes Care, Tandem Diabetes Care, Sanofi, United Healthcare, Vertex Pharmaceuticals, and Zealand Pharma. The employer of R.M.B., nonprofit HealthPartners Institute, contracts for his services, and he receives no personal income from these activities. A.L.C. reports consulting or advisory board work with Novo Nordisk, MannKind, and Zealand Pharma outside the submitted work. HealthPartners Institute/International Diabetes Center at Park Nicollet employs A.L.C. and contracts with the following companies for his services as a clinical research investigator or consultant outside the submitted work: Novo Nordisk, Medtronic/Companion Medical, Insulet, Sanofi, Dexcom, Abbott, Eli Lilly, United Health, and Tandem Diabetes Care (no personal income from any of these services goes to A.C.). R.A.D. reports grants from Boehringer Ingelheim, AstraZeneca, and 89bio; payment or honoraria from AstraZeneca, Corcept Therapeutics, and Renalytix; and participation on a data safety monitoring or advisory board for AstraZeneca, Novo Nordisk, Corcept Therapeutics, and Boehringer Ingelheim outside the submitted work. N.R. reports grants from Novo Nordisk, consulting fees from Novo Nordisk and Eli Lilly, and receipt of equipment, materials, drugs, medical writing gifts, or other services from Novo Nordisk outside the submitted work. No other potential conflicts of interest relevant to this article were reported.

References

    1. U.K. Prospective Diabetes Study Group . U.K. Prospective Diabetes Study 16: overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes 1995;44:1249–1258 - PubMed
    1. Wajchenberg BL. Beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev 2007;28:187–218 - PubMed
    1. Rasouli N, Younes N, Ghosh A, et al. ; GRADE Research Group . Longitudinal effects of glucose-lowering medications on β-cell responses and insulin sensitivity in type 2 diabetes: the GRADE randomized clinical trial. Diabetes Care 2024;47:580–588 - PMC - PubMed
    1. Utzschneider KM, Younes N, Butera NM, et al. ; GRADE Research Group . Impact of insulin sensitivity and β-cell function over time on glycemic outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE): differential treatment effects of dual therapy. Diabetes Care 2024;47:571–579 - PMC - PubMed
    1. Mari A, Schmitz O, Gastaldelli A, Oestergaard T, Nyholm B, Ferrannini E.. Meal and oral glucose tests for assessment of beta -cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab 2002;283:E1159–E1166 - PubMed

Publication types

MeSH terms