Type 1 diabetes: A
progressive autoimmune
disease with lifelong
consequences
Tight glycemic regulation requires endogenous insulin production by pancreatic beta cells1,2
Type 1 diabetes is a progressive autoimmune disease characterized by the destruction of insulin-producing pancreatic beta cells across 3 stages8-10
Even minimal residual beta-cell function can impact clinical and economic outcomes
Observed clinical impact
Lower HbA1c and improved time in range16,17
Beta cell function
Increased probability of reaching A1c goals and time in range was observed in patients with higher residual beta-cell function
aResidual beta-cell function was assessed by testing meal-stimulated C-peptide concentrations. Information regarding severe hypoglycemia within the past year, current HbA1c, and daily insulin requirements was retrieved from the medical records and through patient interviews. Thirty-nine percent of children eligible for the study did not participate; however, analysis of the nonparticipant group showed no difference regarding age at diabetes onset, diabetes duration, and the value of last registered HbA1c.16
bStandard meal-stimulated C-peptide was used to assess residual beta-cell function.16
cA cross-sectional analysis of 2022 EMR data of 60,915 individuals with T1D from 26 diabetes centers in the United States.18
dAn A1c of 7% is appropriate for many children. Less stringent A1c goals such as 7.5% may be appropriate for patients who cannot articulate symptoms of hypoglycemia.19
eDue to its cross-sectional design, causality cannot be established; however, preserved beta-cell function likely improves glycemic control, rather than the reverse, as prior research shows tight control does not preserve beta-cell function. While UCPCR is a validated and noninvasive measure suitable for large studies, it is not the gold standard, so the impact of beta-cell function on CGM metrics and HbA1c may be underestimated. Participants used various CGM devices selected by their physicians, but correcting for device type did not alter results.17
fEstimated using postmeal UCPCR: undetectable (<0.01 nmol/mmol), low (0.01-0.2 nmol/mmol), intermediate (0.2-0.6 nmol/mmol), or high (>0.6 nmol/mmol).17
A1c, glycated hemoglobin; ADA, American Diabetes Association; CGM, continuous glucose monitoring; EMR, electronic medical record; HbA1c, hemoglobin A1c; T1D, type 1 diabetes; UCPCR, urinary C-peptide-to-creatinine ratio.
Fewer hypoglycemic events20
hypoglycemic events
Reduced incidence of severe hypoglycemic events was observed in patients with higher residual beta-cell function
aAn analysis conducted within the DCCT-EDIC cohort that evaluated residual beta-cell function in individuals with a median T1D duration of 35 years. Beta-cell function was assessed through C-peptide concentrations, measured at 9 time points during a 4-hour MMTT. Participants were categorized by peak C-peptide concentration (nonresponder, low, intermediate, or high), and associations with metabolic outcomes, severe hypoglycemia, and microvascular complications were examined.20
bBased on weekly self-reported nonsevere hypoglycemic events (mean: 1.8), a study of 1631 respondents aged >15 years from 7 countries (Austria, Denmark, Finland, Norway, Sweden, Switzerland, and the Netherlands) who had T1D and were on insulin treatment.21
cRate of severe hypoglycemia was 1.1 (median; range: 0.3-3.0) episodes per patient-year in 28 retrospective studies that included 25,765 unselected patients with T1D.22
DCCT-EDIC, Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications; MMTT, mixed meal tolerance test; T1D, type 1 diabetes.
Reduced DKA events23
hypoglycemic events
Fewer DKA events were observed in patients with higher residual beta-cell function23
aC-peptide was measured in an untimed blood sample in the SDRNT1BIO cohort of 6076 people with T1D monitored for an average of 5.2 years. Limitations included the reliance on a single untimed blood sample for measurement of C-peptide (instead of C-peptide levels measured with MMTT).23
bNonfasting serum C-peptide was measured in 5928 patients clinically diagnosed with T1D. Cohort characteristics and outcomes based on C-peptide levels were analyzed for 5732 patients for an average follow-up duration of 5.2 years.23
cPopulation-based analysis of the Diabetes Prospective Follow-up database of visits between January 1, 2006, and December 31, 2019, of patients with T1D between the ages of ≥6 months and <20 years.24
DKA, diabetic ketoacidosis; MMTT, mixed meal tolerance test; T1D, type 1 diabetes.
Reduced risk of microvascular complications26
hypoglycemic events
Lower risk of T1D-related microvascular complications was observed with higher residual beta-cell function26
*Results of a Finnish study combining longitudinal follow-up data on newly diagnosed individuals with T1D and cross-sectional long-duration data to investigate residual insulin secretion in patients with T1D and evaluate C-peptide levels over time and their link to complications (N=5586). This study has several limitations, including gaps in data due to its retrospective, longitudinal design and small sample sizes in the longitudinal cohorts. The C-peptide assay changed over time, and measurements were taken under nonstandardized conditions. The analysis may be subject to unmeasured and residual confounding, as well as potential selection bias in hazard ratio estimates.26
OR, odds ratio; T1D, type 1 diabetes.
Observed economic impact
hypoglycemic events
Improving clinical outcomes in T1D may be associated with reduced cost burdens
For all such economic outcomes, a 3% growth rate was applied to all future years to account for increasing per-capita health expenditure in the United States, as averaged between 2007 and 2016.
*Limitations included limited data sources in quantifying the psychological burden and other intangible costs associated with T1D.27
†A key limitation was reliance on medical record data, which lacked consistent information on key social determinants of health such as employment status, family caregiving responsibilities, incarceration history, emergency care use, and diabetes education involvement.25
A1c, glycated hemoglobin; DKA, diabetic ketoacidosis; HbA1c, hemoglobin A1c; T1D, type 1 diabetes.
C-peptide is used to assess pancreatic beta-cell function
C-peptide is a byproduct of insulin biogenesis and is released by beta cells at a 1:1 ratio with insulin28
ADA, American Diabetes Association; DKA, diabetic ketoacidosis; FDA, US Food and Drug Administration; HbA1c, hemoglobin A1c; T1D, type 1 diabetes.
References: 1. Röder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med. 2016;48(3):e219. doi:10.1038/emm.2016.6 2. Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464(7293):1293-1300. doi:10.1038/nature08933 3. Holt RIG, DeVries JH, Hess-Fischl A, et al. The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2021;64(12):2609-2652. doi:10.1007/s00125-021-05568-3 4. Kaestner KH, Campbell-Thompson M, Dor Y, et al. What is a β cell? – Chapter I in the Human Islet Research Network (HIRN) review series. Mol Metab. 2021;53:101323. doi:10.1016/j.molmet.2021.101323 5. Xie Z, Chang C, Zhou Z. Molecular mechanisms in autoimmune type 1 diabetes: a critical review. Clin Rev Allergy Immunol. 2014;47(2):174-192. doi:10.1007/s12016-014-8422-2 6. Yoon JW, Jun HS. Autoimmune destruction of pancreatic beta cells. Am J Ther. 2005;12(6):580-591. doi:10.1097/01.mjt.0000178767.67857.63 7. Eizirik DL, Pasquali L, Cnop M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol. 2020;16(7):349-362. doi:10.1038/s41574-020-0355-7 8. Toren E, Burnette KS, Banerjee RR, Hunter CS, Tse HM. Partners in crime: beta-cells and autoimmune responses complicit in type 1 diabetes pathogenesis. Front Immunol. 2021;12:756548. doi:10.3389/fimmu.2021.756548 9. Skyler JS, Bakris GL, Bonifacio E, et al. Differentiation of diabetes by pathophysiology, natural history, and prognosis. Diabetes. 2017;66(2):241-255. doi:10.2337/db16-0806 10. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015;38(10):1964-1974. doi:10.2337/dc15-1419 11. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018;391(10138):2449-2462. doi:10.1016/S0140-6736(18)31320-5 12. American Diabetes Association Professional Practice Committee. Diagnosis and classification of diabetes: standards of care in diabetes-2025. Diabetes Care. 2025;48(suppl 1):S27-S49. doi:10.2337/dc25-S002 13. Mortensen HB, Hougaard P, Swift P, et al. New definition for the partial remission period in children and adolescents with type 1 diabetes. Diabetes Care. 2009;32(8):1384-1390. doi:10.2337/dc08-1987 14. Haller MJ, Bell KJ, Besser REJ, et al. ISPAD Clinical Practice Consensus Guidelines 2024: screening, staging, and strategies to preserve beta-cell function in children and adolescents with type 1 diabetes. Horm Res Paediatr. 2024;97(6):529-545. doi:10.1159/000543035 15. Sundheim B, Hirani K, Blaschke M, Lemos JRN, Mittal R. Pre-type 1 diabetes in adolescents and teens: screening, nutritional interventions, beta-cell preservation, and psychosocial impacts. J Clin Med. 2025;14(2):383. doi:10.3390/jcm14020383 16. Sørensen JS, Johannesen J, Pociot F, et al. Residual β-cell function 3-6 years after onset of type 1 diabetes reduces risk of severe hypoglycemia in children and adolescents. Diabetes Care. 2013;36(11):3454-3459. doi:10.2337/dc13-0418 17. Fuhri Snethlage CM, McDonald TJ, Oram RD, et al. Residual β-cell function is associated with longer time in range in individuals with type 1 diabetes. Diabetes Care. 2024;47(7):1114-1121. doi:10.2337/dc23-0776 18. Ebekozien O, Noor N, DiMeglio L, et al. 2022 state of type 1 diabetes in the U.S.—real world T1D exchange multicenter data from over 60,000 people. Diabetes. 2023;72(suppl 1):1456-P. doi:10.2337/db23-1456-P 19. American Diabetes Association Professional Practice Committee. 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes-2025. Diabetes Care. 2025;48(1)(suppl 1):S128-S145. doi:10.2337/dc25-S006 20. Gubitosi-Klug RA, Braffett BH, Hitt S, et al. Residual β cell function in long-term type 1 diabetes associates with reduced incidence of hypoglycemia. J Clin Invest. 2021;131(3):e143011. doi:10.1172/JCI143011 21. Östenson CG, Geelhoed-Duijvestijn P, Lahtela J, Weitgasser R, Jensen MM, Pedersen-Bjergaard U. Self-reported non-severe hypoglycaemic events in Europe. Diabet Med. 2014;31(1):92-101. doi:10.1111/dme.12261 22. Pedersen-Bjergaard U, Thorsteinsson B. Reporting severe hypoglycemia in type 1 diabetes: facts and pitfalls. Curr Diab Rep. 2017;17(12):131. doi:10.1007/s11892-017-0965-1 23. Jeyam A, Colhoun H, McGurnaghan S, et al. Clinical impact of residual C-peptide secretion in type 1 diabetes on glycemia and microvascular complications. Diabetes Care. 2021;44(2):390-398. doi:10.2337/dc20-0567 24. Hammersen J, Tittel SR, Warncke K, et al. Previous diabetic ketoacidosis as a risk factor for recurrence in a large prospective contemporary pediatric cohort: results from the DPV initiative. Pediatr Diabetes. 2021;22(3):455-462. doi:10.1111/pedi.13185 25. Lyerla R, Johnson-Rabbett B, Shakally A, Magar R, Alameddine H, Fish L. Recurrent DKA results in high societal costs – a retrospective study identifying social predictors of recurrence for potential future intervention. Clin Diabetes Endocrinol. 2021;7(1):13. doi:10.1186/s40842-021-00127-6 26. Harsunen M, Haukka J, Harjutsalo V, et al. Residual insulin secretion in individuals with type 1 diabetes in Finland: longitudinal and cross-sectional analyses. Lancet Diabetes Endocrinol. 2023;11(7):465-473. doi:10.1016/S2213-8587(23)00123-7 27. Ward K, Pan C, Shinde M, Rieuthavorn J, Hegde S, Gaebler JA. Modeling the Total Economic Value of Novel Type 1 Diabetes (T1D) Therapeutic Concepts. Health Advances. January 2020. Accessed June 6, 2025. https://t1dfund.org/wp-content/uploads/2020/02/Health-Advances-T1D-Concept-Value-White-Paper-2020.pdf 28. Leighton E, Sainsbury CA, Jones GC. A practical review of C-peptide testing in diabetes. Diabetes Ther. 2017;8(3):475-487. doi:10.1007/s13300-017-0265-4 29. Maddaloni E, Bolli GB, Frier BM, et al. C-peptide determination in the diagnosis of type of diabetes and its management: a clinical perspective. Diabetes Obes Metab. 2022;24(10):1912-1926. doi:10.1111/dom.14785 30. Stankute I, Dobrovolskiene R, Danyte E, Steponaviciute R, Schwitzgebel VM, Verkauskiene R. Pancreatic beta-cell function dynamics in youth with GCK, HNF1A, and KCNJ11 genes mutations during mixed meal tolerance test. Pediatr Diabetes. 2022;23(7):1009-1016. doi:10.1111/pedi.13404 31. Jones AG, Hattersley AT. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet Med. 2013;30(7):803-817. doi:10.1111/dme.12159 32. Yang Y, Hua QX, Liu J, et al. Solution structure of proinsulin: connecting domain flexibility and prohormone processing. J Biol Chem. 2010;285(11):7847-7851. doi:10.1074/jbc.C109.084921 33. Palmer JP, Fleming GA, Greenbaum CJ, et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes. 2004;53(1):250-264. doi:10.2337/diabetes.53.1.250 34. Design of Clinical Trials in New-Onset Type 1 Diabetes: Regulatory Considerations for Drug Development. Critical Path Institute (C-Path). June 15-16, 2021. Accessed June 6, 2025. https://media.c-path.org/wp-content/uploads/20240427170243/WorkshopSummary-1.pdf
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Beta cell function
Increased probability of reaching A1c goals and time in range was observed in patients with higher residual beta-cell function
aResidual beta-cell function was assessed by testing meal-stimulated C-peptide concentrations. Information regarding severe hypoglycemia within the past year, current HbA1c, and daily insulin requirements was retrieved from the medical records and through patient interviews. Thirty-nine percent of children eligible for the study did not participate; however, analysis of the nonparticipant group showed no difference regarding age at diabetes onset, diabetes duration, and the value of last registered HbA1c.16
bStandard meal-stimulated C-peptide was used to assess residual beta-cell function.16
cA cross-sectional analysis of 2022 EMR data of 60,915 individuals with T1D from 26 diabetes centers in the United States.18
dAn A1c of 7% is appropriate for many children. Less stringent A1c goals such as 7.5% may be appropriate for patients who cannot articulate symptoms of hypoglycemia.19
eDue to its cross-sectional design, causality cannot be established; however, preserved beta-cell function likely improves glycemic control, rather than the reverse, as prior research shows tight control does not preserve beta-cell function. While UCPCR is a validated and noninvasive measure suitable for large studies, it is not the gold standard, so the impact of beta-cell function on CGM metrics and HbA1c may be underestimated. Participants used various CGM devices selected by their physicians, but correcting for device type did not alter results.17
fEstimated using postmeal UCPCR: undetectable (<0.01 nmol/mmol), low (0.01-0.2 nmol/mmol), intermediate (0.2-0.6 nmol/mmol), or high (>0.6 nmol/mmol).17
A1c, glycated hemoglobin; ADA, American Diabetes Association; CGM, continuous glucose monitoring; EMR, electronic medical record; HbA1c, hemoglobin A1c; T1D, type 1 diabetes; UCPCR, urinary C-peptide-to-creatinine ratio.
hypoglycemic events
Reduced incidence of severe hypoglycemic events was observed in patients with higher residual beta-cell function
aAn analysis conducted within the DCCT-EDIC cohort that evaluated residual beta-cell function in individuals with a median T1D duration of 35 years. Beta-cell function was assessed through C-peptide concentrations, measured at 9 time points during a 4-hour MMTT. Participants were categorized by peak C-peptide concentration (nonresponder, low, intermediate, or high), and associations with metabolic outcomes, severe hypoglycemia, and microvascular complications were examined.20
bBased on weekly self-reported nonsevere hypoglycemic events (mean: 1.8), a study of 1631 respondents aged >15 years from 7 countries (Austria, Denmark, Finland, Norway, Sweden, Switzerland, and the Netherlands) who had T1D and were on insulin treatment.21
cRate of severe hypoglycemia was 1.1 (median; range: 0.3-3.0) episodes per patient-year in 28 retrospective studies that included 25,765 unselected patients with T1D.22
DCCT-EDIC, Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications; MMTT, mixed meal tolerance test; T1D, type 1 diabetes.
hypoglycemic events
Fewer DKA events were observed in patients with higher residual beta-cell function23
aC-peptide was measured in an untimed blood sample in the SDRNT1BIO cohort of 6076 people with T1D monitored for an average of 5.2 years. Limitations included the reliance on a single untimed blood sample for measurement of C-peptide (instead of C-peptide levels measured with MMTT).23
bNonfasting serum C-peptide was measured in 5928 patients clinically diagnosed with T1D. Cohort characteristics and outcomes based on C-peptide levels were analyzed for 5732 patients for an average follow-up duration of 5.2 years.23
cPopulation-based analysis of the Diabetes Prospective Follow-up database of visits between January 1, 2006, and December 31, 2019, of patients with T1D between the ages of ≥6 months and <20 years.24
DKA, diabetic ketoacidosis; MMTT, mixed meal tolerance test; T1D, type 1 diabetes.
hypoglycemic events
Lower risk of T1D-related microvascular complications was observed with higher residual beta-cell function26
*Results of a Finnish study combining longitudinal follow-up data on newly diagnosed individuals with T1D and cross-sectional long-duration data to investigate residual insulin secretion in patients with T1D and evaluate C-peptide levels over time and their link to complications (N=5586). This study has several limitations, including gaps in data due to its retrospective, longitudinal design and small sample sizes in the longitudinal cohorts. The C-peptide assay changed over time, and measurements were taken under nonstandardized conditions. The analysis may be subject to unmeasured and residual confounding, as well as potential selection bias in hazard ratio estimates.26
OR, odds ratio; T1D, type 1 diabetes.
hypoglycemic events
Improving clinical outcomes in T1D may be associated with reduced cost burdens
For all such economic outcomes, a 3% growth rate was applied to all future years to account for increasing per-capita health expenditure in the United States, as averaged between 2007 and 2016.
*Limitations included limited data sources in quantifying the psychological burden and other intangible costs associated with T1D.27
†A key limitation was reliance on medical record data, which lacked consistent information on key social determinants of health such as employment status, family caregiving responsibilities, incarceration history, emergency care use, and diabetes education involvement.25
A1c, glycated hemoglobin; DKA, diabetic ketoacidosis; HbA1c, hemoglobin A1c; T1D, type 1 diabetes.