The story of the Beta Cells and their role in autoimmune Type 1 Diabetes

How pancreatic beta cell reserve determines the course of the T1D journey^1-7

Autoimmune type 1 diabetes (T1D) is driven by the progressive and irreversible loss of beta cells.^8-11

While exogenous insulin therapy is effective, it cannot fully replicate the full spectrum of functions that beta cells perform in maintaining glucose homeostasis.^12-14

As such, it is the pancreatic beta cell reserve that determines the course of the autoimmune T1D journey.^1-7

It's time to recognise the role of beta cells beyond insulin.

It’s time to recognise the value of every single beta cell.

Mechanisms of disease in Autoimmune T1D

The progressive, irreversible decline of functional beta cell mass in autoimmune T1D can be detected up to 6 years before symptoms arise.^8-11,19,20 Autoantibody screening in this critical window of opportunity can help identify individuals at risk of progression to Stage 3 T1D, enabling a smoother transition to life with the condition.^21-27

T1D is an autoimmune condition characterised by the progressive and irreversible loss of beta cells^8-11

This loss drives^8,10,28:

• metabolic failure
• vascular complications
• and life-long dependence on replacement insulin therapy

The condition manifests in four distinct stages as functional beta cell mass progressively declines.^23,29,30 Stages are defined by the presence of autoantibodies, level of glycaemic control, symptoms, insulin dependence and duration of diabetes.^21,23,30

The four stages of autoimmune T1D^21,23,29,30

Adapted from Breakthrough T1D. The stages of type 1 diabetes. Accessed November 09 2025. https://jdrf.org.au/stages-of-type-1-diabetes/
^*Reversion to single autoantibody or negative status can occur in some people with previously confirmed multiple autoantibody positivity.²¹

**Beta cell mass is highly heterogeneous among people living with autoimmune T1D and may not correspond with severity of clinical presentation.³⁸

Beta cell dysfunction can be detected up to 6 years before symptom onset, accompanying islet autoantibody seroconversion.^19,20

Screening for T1D autoantibodies allows detection of beta cell dysfunction before symptoms appear^21,22

Screening allows individuals and their families to get ahead of autoimmune T1D, helping them to...^21-28:

• prevent diabetic ketoacidosis
• avoid misdiagnosis
• reduce stress at diagnosis
• minimise the risk of long-term complications

Diabetic ketoacidosis

Up to 70% of people who develop T1D present with DKA at diagnosis.^*21,39

A life-threatening medical emergency,³⁹ DKA is associated with:

• approximately half of all hospitalisations in people with autoimmune T1D^40,41
• a sustained negative effect on glycaemic control over time, increasing morbidity and mortality⁴²
• beta cell loss, compounding damage already caused by autoimmunity^18,42,43

Screening and monitoring programmes have lowered the rate of DKA at diagnosis by as much as 90%.^†25,44,45

*Frequencies of DKA range from approximately 15% to 70% across Europe and North America.³⁹
†In a public health screening programme that screened 90,632 children for autoimmune T1D islet autoantibodies in Bavaria, Germany, of the 62 children with presymptomatic autoimmune T1D who developed Stage 3 T1D, two (3.2%) were diagnosed with mild or moderate DKA without clinical symptoms, while 60 (96.8%) did not have DKA. The previously reported prevalence of DKA in unscreened children is over 20% in Germany.⁴⁴

Beta cells: going beyond insulin

In the field of Type 1 Diabetes, modern treatment regimens have dramatically improved symptom management, but it is difficult to precisely mimic the complex, multifaceted role that beta cells play in tissue health and glycaemic control.^12,13,46-48

Despite significant advances in T1D management, achieving glycaemic control remains challenging^12,13,49,50

Technological advances have undoubtedly improved the way we manage autoimmune T1D:

• new continuous glucose monitoring (CGM) devices provide people with glucose readings, trends, and alerts in real time.¹³
• automated insulin delivery (AID) systems automatically adjust insulin delivery based on a person’s glucose readings⁵⁰ However, not everyone has access to this technology,⁵¹ and a high proportion of people who do have access still do not achieve their glycaemic targets and continue to experience severe hypoglycaemic episodes.^*52

*Retrospective, observational study of 2,074 adults (≥18 years) enrolled from the US T1D Exchange Registry/online community. Participants completed a one-time survey on HbA1c, severe hypoglycaemic episodes and impaired awareness of hypoglycaemia. The majority of participants (91.7%) were using a CGM plus MDI, AID systems or pump. Severe hypoglycaemia was defined as a hypoglycaemic event in the past 12 months where the individual with T1D experienced low blood glucose levels that they were unable to treat themselves and needed help from others.⁵⁰

Beta cells are not only the exclusive producers of insulin^46-48

The pancreatic islet is a complex ‘mini organ’ composed of different cell types that work together to integrate systemic and local signals and tightly control blood glucose levels.^48,56

As such, beta cells do not exist in isolation, and, beyond insulin, release other hormones, peptides, neurotransmitters and metabolites vital to the complex cellular crosstalk that upholds the overall health and function of the pancreas.^47,48,56-59

Beyond insulin, signalling molecules released by beta cells include:

(Please find table with numbered with colour codes on component mapping version.)

Beta cells also display remarkable functional heterogeneity, differing in their insulin secretion capacity and responsiveness to glucose and other stimuli, and allowing for precise, adaptable and robust glucose regulation.^46,57

C-PEPTIDE: A measure of beta cell function

Produced in a 1:1 molecular ratio with insulin, C-peptide is a direct, quantitative and reliable measure of beta cell function.^6,16,19,65

C-peptide is a more reliable measure of beta cell function than endogenous insulin because it^19,65:

1. has a slower rate of degradation

2. has a less variable rate of clearance

3. is not impacted by exogenous insulin

C-peptide is being increasingly recognised for its utility across clinical and research settings. In clinical practice, it can be used to differentiate between types of diabetes, and growing evidence suggests it may also help predict future level of glycaemic control and risk of complications.^65-67

In research settings, C-peptide is serving as a valuable biomarker for assessing response to immunomodulatory treatment.^6,68

The impact of residual beta cell function

The link between beta cell activity and clinical outcomes offers a strong, practical rationale for valuing and monitoring beta cell function in the management of autoimmune T1D.^1-6,12-17,19

Greater residual beta cell activity is linked to improved outcomes^1-6,12-17,19

The pancreatic beta cell reserve determines the course of the autoimmune T1D journey^1-7 with higher versus lower residual beta cell activity, as indicated by C-peptide, associated with:

Time in range by level of C-peptide^*15

Adapted from Snethlage CMF, et al. Diabetes Care. 2024;47:1114-1121.

*Cross-sectional cohort study of 489 Dutch adults with autoimmune T1D (median duration 15 years) assessing associations between residual beta cell function (measured by UCPCR), alpha cell function (glucagon/glucose ratio) and CGM metrics, including time in range, variability and hypoglycaemia. A higher UCPCR correlated with a longer time in range (r=0.330, p<0.05), and correlated negatively with both HbA1c levels (r= –0.183, p<0.05) and total daily insulin dose (r= –0.183, p<0.05). UCPCR values: undetectable: <0.01 nmol/mmol; low: 0.01–0.2 nmol/mmol; intermediate: 0.2–0.6 nmol/mmol; high: >0.6 nmol/mmol.¹⁵

2. Reduced incidence of severe hypoglycaemia

Incidence of severe hypoglycaemia is significantly associated with level of residual beta cell function, as indicated by level of C-peptide.^4†

Proportion of people with a history of severe hypoglycaemia^†‡4

Adapted from Gubitosi-Klug RA, et al. J Clin Invest. 2021;131(3):e143011.

†Observational study of the DCCT/EDIC cohort (mean duration of T1D ~35 years). Serum C-peptide was measured during a 4-hour MMT. Associations with metabolic outcomes and complications were explored among non-responders (all C-peptide values after meal <3 pmol/L) and three categories of responders.⁴ ‡Hypoglycaemia requiring assistance.⁴ §Based on Cochran-Armitage trend test.⁴

3. Reduced likelihood of DKA

Individuals with higher versus lower residual beta cell activity are significantly less likely to experience DKA both at the time of diagnosis and 12 months after diagnosis.^II18

Longitudinal C-peptide levels according to DKA status at time of diagnosis^II18

Adapted from Mortensen HB, et al. Pediatr Diabetes. 2010;11(4):218-226.

^IIProspective, observational cohort study of 275 children with newly diagnosed T1D conducted across 18 centres in Europe and Japan, assessing predictors of residual beta cell function and glycaemic control over the first 12 months post-diagnosis using serial mixed-meal C-peptide tests, autoantibody levels, HLA typing, and HbA1c measurements. DKA with standard bicarbonate <15 mmol/L was associated with significantly poorer residual beta cell function 1 (p=0.004) and 12 months (p=0.0003) after diagnosis.¹⁸

4. Reduced risk of microvascular complications

Individuals with higher versus lower residual beta cell activity are at lower risk of long-term microvascular complications such as:

Even relatively low residual beta cell activity correlates with an increased likelihood of achieving recommended HbA1c targets and a reduced prevalence of severe hypoglycaemia^2,4

Individuals with low residual beta cell function are still 2x more likely to achieve HbA1c <7.5% compared to individuals with no residual beta cell function.^¶2

Individuals with a HbA1c <7.5% by level of C-peptide^¶

¶Cross-sectional study of 342 Danish children (aged 4.8–18.9 years) with autoimmune T1D (duration 3–6 years) assessing residual beta cell function via meal- stimulated C-peptide and evaluating associations with hypoglycaemia, HbA1c and insulin needs. C-peptide levels: none: <40 pmol/L; low: 40–200 pmol/L; high: ≥200 pmol/L.² #Logistic regression analysis adjusted for sex, age, pubertal status, diabetes duration, and insulin administration technique.²

Relatively low residual beta cell activity is also associated with a protective effect against hypoglycaemia. In the DCCT, C-peptide levels above the detection threshold of 30 pmol/L were significantly associated with a lower prevalence of severe hypoglycaemia throughout the entire study period.⁴

Summary

Resources

Explore the Betaverse and deepen your knowledge!

Resources to use in consultation with people affected by T1D

Discussing T1D with people can be challenging. These materials can help guide conversations with people affected by T1D, from explaining the autoimmune process to making sense of screening results, so you can better support people in your care and their relatives throughout their T1D journey.