A ray of optimism has emerged in the battle against Type 1 diabetes as scientists have unveiled that an already-available medication has the potential to halt the onset of this condition.
In 2012, Dr. Anath Shalev, a researcher at the University of Alabama at Birmingham (UAB), made a significant discovery regarding the potential of verapamil, a long-established blood pressure medication, to reverse diabetes in animal models.
Subsequently, in 2018, Shalev’s team successfully translated these findings into a randomized, controlled clinical trial, demonstrating a remarkable improvement in beta cell function for one year among human subjects recently diagnosed with Type 1 diabetes.
By the following year, in a small follow-up study, Shalev and her colleagues observed that adults with Type 1 diabetes who took oral verapamil required less daily insulin and exhibited evidence of positive immune modulation for up to two years following their initial diagnosis.
Now, researchers at UAB, under the leadership of Dr. Guanlan Xu and Dr. Shalev, have delved even deeper into the mechanism responsible for verapamil’s favorable effects.
In a paper published in the journal Diabetes, they reveal that verapamil, when administered to individuals with Type 1 diabetes, prevents the decline of insulin-like growth factor 1 (IGF-1) compared to those who did not receive verapamil.
Furthermore, their research shows that verapamil actively stimulates IGF-1 signaling within pancreatic beta cells.
Type 1 diabetes is an autoimmune condition that leads to the loss of pancreatic beta cells responsible for insulin production. To replace this crucial hormone for blood sugar regulation, patients must rely on external insulin delivered via injections or pumps, which also puts them at risk of dangerously low blood sugar levels. Presently, there is no available oral treatment for this condition.
Apart from Dr. Shalev’s study involving adults, a recent independent investigation focusing on children with Type 1 diabetes has corroborated that verapamil effectively preserves beta cell function when compared to children not taking the medication.
In their Diabetes study, Dr. Xu, Dr. Shalev, and their team conducted a comprehensive proteomics analysis of serum samples from Dr. Shalev’s adult study, both at the outset and one year after receiving either verapamil or a placebo.
Their analysis identified 59 proteins that exhibited significant changes in abundance over time, with IGF-1 ranking among the top five proteins displaying differential changes. While the placebo group experienced a substantial decline in IGF-1 levels from the beginning to the one-year mark, this decline was notably mitigated in the verapamil group.
Notably, prior research had already established a connection between serum IGF-1 levels and the preservation of beta cell function, a relationship that was also confirmed for the verapamil group by the UAB researchers. This preservation was measured by the beta cells’ ability to continue producing insulin within the pancreatic islets.
Additionally, RNA sequencing of human pancreatic islets treated with or without verapamil revealed a significant decrease in the expression of four IGF binding proteins in response to verapamil.
This decrease in proteins that bind to IGF-1 allows IGF-1 to interact more effectively with its receptor, initiating the IGF-1 signaling pathway that subsequently influences gene expression within the beta cell. To quantify this increased signaling, they observed that verapamil indeed activated the IGF-1 receptor and its downstream effector, AKT, as evidenced by increased phosphorylation of both.
Conversely, when human islets were exposed to inflammatory cytokines associated with Type 1 diabetes, as well as islets from a mouse model of Type 1 diabetes, the researchers noted a significant increase in the expression of IGF binding protein 3, the most abundant member of the IGF binding protein family. These findings suggest that under Type 1 diabetes conditions, the expression of IGF binding proteins is upregulated.
The Shalev research team had previously demonstrated increased expression of TXNIP, a protein linked to programmed cell death and beta cell dysfunction, during diabetes. They had also shown that verapamil inhibits beta-cell expression of TXNIP, resulting in beneficial anti-diabetic effects.
In their current study, the researchers have expanded on these findings by showing that overexpression of human TXNIP significantly increases the expression of IGF-binding protein 3. In contrast, TXNIP-deficient islets exhibited reduced expression of IGF-binding protein 3. Furthermore, overexpression of TXNIP led to a significant decrease in the phosphorylation activation of the IGF-1 receptor.
Dr. Shalev summarizes their findings by stating, “Thus, our results reveal IGF-1 signaling as yet another previously unappreciated pathway affected by verapamil and TXNIP that may contribute to the beneficial verapamil effects in the context of Type 1 diabetes.”
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