Advancing Research on Pancreatic Beta Cells for Diabetes Treatment

The number of diabetes cases has been rising tremendously. In the absence of a definitive cure, scientists are researching pancreatic beta-islets to develop an effective therapy. They produce and secrete insulin in response to blood glucose concentrations. An in-depth understanding of the pancreatic beta cells will allow the discovery of new therapeutic targets and preventive measures.

Pancreatic Beta Cells

The central role of Pancreatic Beta Cells has prompted a considerable amount of research on them. They are one of the four types of islet cells present in the pancreas and constitute 50-70% of cellular composition in islets of Langerhans. The ultrastructure studies identified them by the presence of insulin granules. One cell reportedly contains approximately 10000 granules located near the plasma membrane. In type 2 diabetes, these cells display several changes in the granules and organelles. The amount of insulin decreases, and the endoplasmic reticulum increases. Mitochondria transforms from elongated to round shape with modified cisternae appearance. It also shows reduced electron density and volume.

Insulin Secretion 

The secretion of insulin hormone occurs not only by nutrient stimuli but also through neuronal and hormonal stimuli.  However, glucose remains the primary stimulus. Glucose transporter on the cell surface transports glucose inside the cytoplasm. The glucose undergoes glycolysis, and the metabolites enter the tricarboxylic acid (TCA) cycle. These pathways lead to the formation of ATP by oxidative phosphorylation. The elevated levels of ATP act via potassium-ATP channels to depolarize the plasma membrane, triggering the opening of voltage-gated calcium ion channels. The augmented calcium ion influx leads to the exocytosis of insulin granules. Several other nutrients and hormones also modify the calcium ion gradient to stimulate insulin release.

Pancreatic Beta Cell Pathophysiology

Diabetes is a metabolic disorder characterized by rising blood glucose levels. The cause behind its development has broadly classified diabetes into- Type 1 diabetes (results from beta cell destruction and lack of insulin) and Type 2 diabetes (results from insulin resistance).  Elevated glucose deposits on blood vessels and nerves, resulting in retinopathy, neuropathy, nephropathy, and peripheral arterial disease.

Omics Study 

Researchers have been expanding their database around the beta cell genome and transcriptome changes in diabetes. For example, genes for glucose transporter protein and glucose metabolizing enzyme downregulate in type 2 diabetes. Additionally, the redox protein genes such as NADPH oxidase, catalase, and GSH peroxidase increase whereas Mn or Cu/Zn superoxide dismutases diminish. Similar studies have reported significant changes in the expression of genes related to mitochondrial function, exocytosis, and ubiquitin-proteasome complex in diabetic islets, indicating their role in the underlying pathophysiology.

Pancreatic Beta Cell Regeneration

The regeneration of beta cells has become a focal point of research. The beta cell mass increases in the early stages of life but declines with age. Several approaches targeted the regeneration process, like generating new cells, inhibiting cell death, and suppressing dedifferentiation.

Increasing the cell number: This approach utilizes three sources and mechanisms.

• Existing beta cells replicate into more cells.
• Surrounding cells, such as alpha- and gamma- cells, transdifferentiate into beta cells.
• Progenitors/ precursors differentiate into new beta cells by neogenesis.

Insulin receptor substrate 2/phosphoinositide 3-kinase (PI3K)/protein kinase B or Akt signalling pathway regulates the amount of beta cell proliferation. Akt activates the cell cycle kinase for cell proliferation. Several other pathways such as GSK3, Ras/Raf/Erk, NFATS and c-myc also regulate the proliferation process. The inhibitors of the cell cycle in beta cells and that of specific transcription factors in alpha- and gamma-cells drive proliferation and transdifferentiation, respectively. Osteoprotegerin and denosumab also promote cell proliferation via the NF-κB signaling pathway. Furthermore, mTOR and transforming growth factor-β (TGFβ) have been under investigation in this regard. For neogenesis, various stem cells and pancreatic progenitors have been used. Their successful in vitro transformation to functional beta cells has been evident. A recent study has actually shown normal blood glucose levels and absence of insulin dependency after the infusion of cells derived by neogenesis.

Inhibiting cell death: Another strategy for cell regeneration is to increase cell survival. Researchers have explored it more in light of the alterations in the redox-related proteins. According to the findings, oxidative stress disrupts insulin secretion and antioxidants increase cell survival by suppressing cell death pathways. A study by Singh et al. demonstrated reduced rate of diabetes development after administering an anti-apoptotic protein.

Suppressing cell dedifferentiation: Diabetic beta islets lose their maturation characteristics and dedifferentiate into progenitors. The changes in gene expression pattern, structure, and function accompany it. The concept holds value over other approaches, which emphasise only enhancing cell survival. Angiotensin-converting enzyme (ACE) inhibitors reduce dedifferentiation by the NF-κB pathway.

Conclusion

Diabetes has been a rising medical and economic burden, resulting in diverse comorbidities. The current medications fail to provide lasting effects and also cause organ toxicity in long-term use. It has urged the scientific community to accelerate the research on insulin-producing islet cells. Kosheeka strengthens such research goals by providing pancreatic beta cells. Their team conducts rigorous quality checks at each step of cell processing and characterization on each batch for assured quality.