In a recent review published in Experimental & Molecular Medicine, researchers examined current evidence on the reasons and implications of pancreatic beta-cell failure and its potential reversibility as a type 2 diabetes (T2D) therapy.
Study: Reversing pancreatic β-cell dedifferentiation in the treatment of type 2 diabetes. Image Credit: KaterynaNovikova/Shutterstock.com
Background
Diabetes is a chronic metabolic disorder characterized by insulin failure, leading to peripheral resistance and pancreatic beta-cell failure.
This leads to hyperglycemia, altered lipid metabolism, and beta-cell failure. Insulin secretion by pancreatic beta-cells is crucial for glucose homeostasis, and re-establishing beta-cell identity is vital for disease modification.
About the review
In the review, researchers presented beta-cell failure reversibility as a therapeutic approach for type 2 diabetes.
Changes in the fate of beta cells in type 2 diabetes
Sustained metabolic stress and insulin resistance are significant factors in hyperinsulinemia development. In this condition, peripheral tissues become less responsive to insulin due to insulin signaling alterations and effectors.
This leads to increased gluconeogenesis and decreased glycogen synthesis in the liver, reduced glucose uptake by muscles and adipocytes, and excessive lipogenesis, resulting in beta-cell failure and the loss of beta-cell mass.
Inflammatory cytokine molecules promote insulin resistance via several mechanisms, including lowering the number of insulin receptors and reducing catalytic activity, increasing insulin receptor and insulin receptor substrate-1 (IRS) phosphorylation, increasing tyrosine phosphatase activity, decreasing phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) kinase activity, and altered glucose transporter type 4 (GLUT-4) function.
Insulin resistance causes decreased glycogen synthesis, increased glucose generation, and excessive lipogenesis in the liver, all of which contribute to the development of fatty liver and an increase in free fatty acid (FFA) levels in the plasma and reactive oxygen species (ROS) in the beta cells.
Metabolic stressors, such as excessive calorie intake, physical inactivity, and obesity, promote insulin resistance. Pancreatic beta-cells produce more insulin to compensate for insulin resistance, resulting in hyperinsulinemia.
Recent research indicates that the fundamental cause of beta-cell mass loss in response to metabolic stress is an alteration in beta-cell identity due to dedifferentiation or trans-differentiation to non-functional endocrine progenitor non-beta cells, which express neurogenin3 and aldehyde dehydrogenase 1A3 (Aldh1a3).
This process involves the loss of mature beta-cell characteristics and the acquisition of alternative cell fates, leading to a reduced capacity for insulin secretion and impaired glucose metabolism.
Metabolic stress exacerbates mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, unfolded protein response (UPR) activation, and thyroid adenoma-associated (THADA) genet upregulation, which results in reduced glucose uptake by muscles and adipocytes and contributes to beta-cell failure and the loss of beta-cell mass, leading to hyperglycemia.
Chronic hyperglycemia promotes inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) overexpression, which degrades proinsulin messenger ribonucleic acid (mRNA) and increases the rates of glycolysis, the tricarboxylic acid (TCA) cycle, and pyruvate oxidation, which contribute to β-cell failure.
Reversibility of beta cell failure in managing type 2 diabetes
Single-cell RNA sequencing is valuable for studying the pancreatic islet cellular repertoire among normal and type 2 diabetes patients, including non-diabetic beta cells, T2D beta or alpha cells, and non-diabetic alpha cells.
Identifying major master controllers of all cells, including the dedifferentiated forms of beta-cells, can lead to identifying prospective therapeutic targets.
Small chemical inhibitors targeting important regulators of beta-cellular dedifferentiation, including Aldh1a3 and broad complex-tram track-bric a brac and Cap'n'collar homology 2 (BACH2), might be promising methods to reverse the identity of beta-cells and cure T2D.
Treatment methods for beta-cell failure are divided into two categories: raising cell number and improving insulin secretion. Stimulation of beta-cell growth and suppression of beta-cellular apoptosis are other proposed methods, although no medications to attain this purpose are currently approved.
Human studies have demonstrated that continuous adherence to low-calorie diets can restore glycemic control and improve glycemia levels for a long period, even after the illness starts.
Treatment with phlorizin can prevent blood sugar increases by restoring insulin messenger ribonucleic acid expression and beta-cell development markers.
A recent study employing Aldh1a3 cell lineage tracking discovered that dedifferentiated beta cells may be reconverted to mature, functioning beta cells. In murine animals, pharmacological and genetic Aldh1a3 ablation has improved beta-cellular function by boosting insulin production and beta-cell proliferation.
Clustered, regularly interspaced short palindromic repeats (CRISPR)-regulated functional experiments in pancreatic islets of humans have revealed that the transcriptional signature of type 2 diabetes could be reversed following BACH2 inhibition.
In diabetic mice, treatment with BACH inhibitors lowered hyperglycemia and restored beta-cell function. Since BACH inhibitors are already licensed by the Food and Drug Administration (FDA) for treating multiple sclerosis, there lies an immediate chance to examine this route in human studies.
Conclusion
Based on the review findings, beta-cell failure is caused by stress, factors like ER and oxidative stress, mitochondrial dysfunction, and alterations in beta-cell identity.
To address this, converting dedifferentiated beta cells to their differentiated forms is a promising therapeutic approach.
Technological and analytical advances can uncover disease-specific genomic risk factors and subpopulations, allowing for individualized, precision-based therapies.
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