Mechanisms Involved In Beta-cell Dysfunction In Diabetes 

Preserving beta cell function will maintain glucose homeostasis and may prevent diabetes.

Beta cell dysfunction is critical to the development of diabetes and often compounded by insulin resistance; glucose, however, is a critical determinant of beta cell function. This review focuses on mechanisms involved in the beta cell dysfunction and its correlation with glucose homeostasis and type 2 diabetes.

Generally, Islets of Langerhans, which consists of beta cells, alpha cells, delta cells, epsilon cells and pancreatic polypeptide (PP) cells, are saddled with the principal role of regulating glucose homeostasis. Being glucose sensing, the beta-cell synthesizes and secretes insulin as its primary role to maintain circulating glucose levels within physiological level. Thus, glucose is the most potent regulator for beta cell function through coordinated stimulation of insulin gene transcription, proinsulin biosynthesis, and insulin secretion.

Over the years, beta-cell function deteriorates slowly but steadily (2% per year) and precedes overt diabetes. Significant acceleration becomes obvious with the development of hyperglycemia and deteriorates regardless of the therapeutic regimen (Popa & Mota, 2013). 

A reduction in beta cell mass, differentiation status of beta cells is being attributed to net enhancement of the rate of beta cell dysfunction and death leading to progression of type 2 diabetes (T2D) (Nicola et al. 2019). Exposure of beta cells to the cellular stressors — Cytokine-mediated oxidative stress and inflammation, Peripheral free fatty acids (FFA) -induced inflammation, saturated FFA induced islet  inflammation — may disrupt the regulation of key genes involved in the maintenance of beta cell identity and decrease the beta cell population, which contributes to the manifestation of beta cell dysfunction.

However, the initial beta-cell dysfunctions are most likely to reflect intrinsic deficiencies, whereas the accelerated alterations in beta-cell function occurring after the development of overt hyperglycemia are attributed to glucolipotoxicity — genetic predisposition.

Long-term hyperglycemia and increased fatty acids are known to have deleterious effects on beta-cells functioning. The coexistence of insulin resistance and a background of genetic predisposition and elevation of glucose levels leads to decrease in insulin gene expression and insulin secretion, and decrease in insulin promoter activity.

Several mechanisms, such as: endoplasmic reticulum stress, mitochondrial dysfunction and reactive oxygen species production, islet inflammation and islet amyloid polypeptide increase, are proposed for glucolipotoxicity induced beta-cell dysfunction.

The newly synthesized secretory and transmembrane proteins are assembled and folded in endoplasmic reticulum (ER) and finally transported to their destination to function. Due to various stimuli and gene mutations, this folding activity can be overwhelmed, and a lot of these ER proteins get misfolded; accumulation of these misfolded proteins induces ER stress. However, these folding activities can be overwhelmed with the amount of proteins imported into the ER, triggering a signaling pathway (unfolded protein response -UPR), to adapt and respond to the ER stress. The hyperactivation of the UPR pathway for ER homeostasis is what plays a role in β cell dysfunction and death seen in T2D.

Beta cell mitochondria play a role in the insulin secretion process. They synthesize metabolites that couple glucose sensing to insulin granule during exocytosis and provide energy to support insulin secretion. Abnormal morphology and function of the mitochondria occurring usually before the onset of hyperglycemia play a role in beta-cell dysfunction. Also, the reactive oxygen species (ROS) produced by β-cell mitochondria during metabolic stress activate several stress-response pathways. Through Initiation of Phospholipid Peroxidation in β-Cells, ROS activates Uncoupling Protein 2 (UCP2)  which leads to leakage of protons across the mitochondrial inner membrane, and reduced β-cell ATP synthesis resulting to negative glucose-stimulated insulin secretion regulation, which is the major link between obesity, β-cell dysfunction, and T2DM. More so, persistent oxidative stress mediates beta-cell dysfunction and failure through several mechanisms, including; decreased insulin secretion, decreased insulin gene expression, mitochondrial dysfunction by peroxidation of membrane phospholipids, Islet inflammation due to activation of NF-kB pathway, beta-cells lipid accumulation, and increased islet amyloid polypeptide.

Understanding the pathophysiological mechanism for beta-cell dysfunction could be an important option for knowing the natural history of T2DM and maintaining an optimal glycemic control.

Practice Pearls:

• Normal beta cell integrity potentiates beta cell function which is necessary for the fluctuating metabolic demand for insulin – persistent hyperglycemia and hypo-stimulation may exhaust beta cells and limit their response to hyperglycemic excursions, respectively.
• Increasing levels of glucose, free fatty acids and deterioration in metabolic equilibrium increase beta-cell dysfunction, which eventually leads to beta-cell apoptosis.
• Clear understanding of the mechanism for beta-cell dysfunction is important in aiding the development of new and more effective diabetes management strategies.

References:

Simona Popa and Maria Mota “Beta-Cell Function and Failure in Type 2 Diabetes, Type 2 Diabetes” Kazuko Masuo, IntechOpen, 26, June 2013, doi; 10.5772/56467.

Nicola Jeffery, et al., “Cellular stressors may alter islet hormone cell proportions by moderation of alternative splicing patterns” Human Molecular Genetics, 17, May, 2019, ddz094, https://doi.org/10.1093/hmg/ddz094

Onyi Ibeji, PharmD. Candidate, LECOM School of Pharmacy