Installment 1:1 - The Levels to Beta Cell Regeneration - Are Beta Cells Actually Gone?
- Bowie Matteson
- 1 day ago
- 5 min read
This is the first installment in a series examining the possibilities in beta cell regeneration. From addressing the current holes in our conceptual framework of how diabetes develops, the necessary foundational supports keeping the pancreas alive and balanced, and the resulting avenues of influence we have to allow sustainable growth - we'll explore it all. Because if diabetes is a system-wide imbalance, then beta cell loss is not the beginning of the story — it’s the visible consequence of deeper dysfunction.
And if that’s true, then the question becomes:
Can beta cells come back?
Not just survive. Not just be preserved. But actually regenerate.
🔬 Section 1: Are Beta Cells Actually Gone?
The Myth of “Zero”
Type 1 diabetes is often framed as a complete absence of insulin production.
Yet when we look closer, that idea starts to unravel.
Multiple studies have shown that individuals with long-standing type 1 diabetes can still retain measurable insulin production decades after diagnosis:
Residual C-peptide has been detected in individuals >50 years post-diagnosis (e.g., Joslin Diabetes Center Medalist Study; Keenan et al., 2010)
Histological analyses have identified insulin-positive beta cells in pancreata from long-duration T1D donors (Butler et al., 2003; Meier et al., 2005)
Even low-level endogenous insulin secretion has been associated with better metabolic outcomes and reduced complications (Rickels et al., 2020)
These aren’t edge cases—they’re clues.
Clues that suggest something important:
The pancreas may not be empty. It may be partially active, inconsistently active, or suppressed.
Presence vs. Function
C-peptide is often used as a proxy for beta cell presence. But what if it’s actually telling us something slightly different?
👉 Not “are beta cells there?”
👉 But “are beta cells actively functioning right now?”
Because a cell can exist without contributing meaningfully.
Just like:
A muscle can be present but weak
A neuron can be alive but not firing
A gland can exist but be underactive
A beta cell can be:
Alive
Structurally intact
But functionally silent
So are the low level C-peptide readings from those with T1D a sign of beta cell elimination? Or beta cell silence?
The Spectrum of Beta Cell States
Instead of thinking in binary terms—present or absent—we can begin to think in states:
Active → producing and releasing insulin properly
Stressed → struggling under metabolic load
Dedifferentiated → losing identity and function
Senescent → alive, but inactive and signaling distress
Dead → removed from the system
This reframing changes everything. Because now the question isn’t just:
“How many beta cells are left?”
It becomes:
“What state are they in?”
This new approach is supported by growing evidence that islet cells exhibit remarkable plasticity.
Studies have shown that under metabolic or inflammatory stress:
Beta cells can lose expression of identity genes (Pdx1, MafA)
Adopt progenitor-like profiles
Even shift toward alpha-like phenotypes in certain conditions
Key work by Talchai et al. (2012) demonstrated that beta cell failure in diabetes may involve dedifferentiation rather than outright death.
Similarly, Spijker et al. (2013) showed that human islet cells can display mixed or transitional identities, reinforcing the idea that cell state is fluid—not fixed. A cell can exhibit an "alpha" identity in one particular environment and convert to a "beta" identity in another. (** This was also found in the recent harmine research in beta cell regeneration from Andrew Stewart's laboratory)
And when it comes to addressing the needs of a T1D body, knowing the possible states of the beta cells (and the genes and cofactors that influence them) comes with their own unique prescriptive action. What are those specific cues driving the multiple identities of islet cells?
Instead of the broad-stroke "they're gone and need to be replaced" narrative that predominates the research world now, a state-specific beta cell gives researchers and scientists a more well-defined window of opportunity to explore therapies.The more specific the issue, the more targeted the approach can become.
Dedifferentiation: When Cells “Forget”
One of the more fascinating developments in recent research is the idea that beta cells can lose their identity.
Under stress—whether from inflammation, oxidative damage, ER stress, or metabolic overload—beta cells may:
Reduce expression of key identity markers (like Pdx1, MafA)
Decrease insulin production
Begin to resemble more primitive or progenitor-like cells (IE. devolve)
This process is called dedifferentiation.
And it introduces a powerful possibility:
What if some beta cells haven’t been destroyed…but have instead “gone offline”?
This process has been linked to:
FOXO1 depletion or dysfunction (Talchai et al., 2012)
Chronic activation of stress pathways like:
JNK
NF-κB
PERK (Unfolded Protein Response pathway)
When we start to talk about the specific genes, proteins and transcription factors involved in diabetes, the whole process of healing starts to feel far away. After all, the average diabetic isn't a geneticist or PhD. But it doesn't have to be that way. As the gardeners of our own bodily "soil" (AKA cellular environments), healing can feel more approachable through the lens of nutrition.
Nutrient Cofactors & Drivers of Identity Loss
Beta cell identity is not just genetic—it is nutrient and environment dependent.
Loss of function has been associated with disruptions in:
Mitochondrial metabolism (ATP deficiency → weak signaling)
Zinc handling (ZnT8 dysfunction) → impaired insulin crystallization
Magnesium deficiency → impaired ATP stability
Vitamin A signaling → impacts transcriptional regulation
Iron/redox imbalance → oxidative damage to transcription machinery
In T1D and related metabolic stress states, many of these systems are compromised.
A Protective Adaptation?
From a systems perspective, this makes sense.
If a beta cell is overwhelmed by:
excessive demand
Inadequate nutrient supply
oxidative stress
misfolded proteins
inflammatory signals
…it may be safer for the body to downregulate its activity than to continue operating under damaging conditions.
In other words:
Silence may be a form of protection. Not failure.
Structural vs Functional Loss
This leads to a critical distinction:
Structural loss → the cell is physically gone
Functional loss → the cell is present, but not contributing
Evidence suggests that both may occur in T1D—but not necessarily to the same extent in all individuals.
And this opens the door to a different kind of question:
Not just: “How many beta cells are left?”
But: “How many are capable of functioning if conditions improve?”
A Different Starting Point
This shift matters.
Because if the pancreas is not completely devoid of beta cells—but instead inactive, suppressed, or structurally altered—
Then regeneration is not just about creating something new.
It may also involve:
relieving cellular stress
restoring metabolic signaling
reestablishing transcriptional identity
and reactivating dormant cells
Closing Thought
The story of beta cells in type 1 diabetes may not be one of total loss.
It may be a story of interruption.
Of cells that are still present… but waiting for the right conditions to function again.
Suggested References
Keenan, H. A., Sun, J. K., Levine, J., et al. (2010). Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes, 59(11), 2846–2853.
Butler, A. E., Janson, J., Bonner-Weir, S., et al. (2003). Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes, 52(1), 102–110.
Meier, J. J., Bhushan, A., Butler, A. E., et al. (2005). Sustained beta cell apoptosis in patients with long-standing type 1 diabetes. Diabetologia, 48(11), 2221–2228.
Rickels, M. R., Evans-Molina, C., Bahnson, H. T., et al. (2020). High residual C-peptide likely contributes to glycemic control in type 1 diabetes. Diabetes Care, 43(3), 534–540.
Talchai, C., Xuan, S., Lin, H. V., et al. (2012). Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell, 150(6), 1223–1234.
Spijker, H. S., Song, H., Ellenbroek, J. H., et al. (2013). Loss of β-cell identity occurs in type 2 diabetes and is associated with islet cell plasticity. Nature Communications, 4, 1–10.
Wang, Y., Kumar, N., Sakamoto, K., Smith, C. A., Jain, R., & Domínguez-Bendala, J. (2024). Cycling alpha cells convert to beta cells: New insights into harmine and beta cell regeneration. Cell Reports Medicine. https://doi.org/10.1016/j.xcrm.2024.100803
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