Association Between Cell Death and Diabetes

Pyroptosis causes cell death, leading to beta-cell dysfunction and diabetes mellitus.

The life cycle of most living organisms has programmed cell death as one of its standard components. Pyroptosis and apoptosis are examples of cell death. Pyroptosis can be caused by bacterial infection; the mechanism of cell death involves activating a protease named caspase. These proteases, activated by NOD-like receptors, contribute to the transformation of interleukin-1 into mature inflammatory cytokines that rupture the plasma membrane and cause cell death. Some pathological conditions such as angina pectoralis or high blood pressure play an essential role in pyroptosis.   

A defect in the beta cells of the pancreas impairs insulin secretion and causes diabetes mellitus. Elevated blood glucose impairs nitrogen balance. Patients who experience persistent uncontrolled hyperglycemia are exposed to other complications such as organ dysfunction, organ failure, nonfunctional carbohydrate or fat metabolism. Prolonged hyperglycemia is manifested by ketoacidosis, blurred vision, and glucosuria. Retinopathy is a common complication of hyperglycemia, affecting about 4.1 million US adult diabetes patients who ultimately develop blurred vision. Type 1 diabetes mellitus is caused by dysfunction of the beta cells caused by autoimmune antibodies. The pancreatic cell abnormality prevents insulin secretion, and little insulin is found in the blood.  

In contrast, type 2 diabetes mellitus patients have variable insulin concentration in the blood, ranging from very low for some patients, regular for others, and very high in certain patients. Laura et al. postulated that disrupted glucoreceptors of the beta cells mainly cause type 2 diabetes mellitus. (Sharma et al. 13558). Diabetes is defined as a progressive disease because the severity is related to the duration of the disease. In type 1 diabetes, for example, apoptosis of the beta cells decreases insulin production, and the decrease worsens with time to reach a level where the patient relies totally on exogenous insulin to control blood glucose. Lymphocytes, CD4, and macrophages are also among the causes of diabetes.  

Triplet reports that CD4 cell activation precedes diabetes development, and CD8 cells damage diabetic patients (Sharma et al. 13559). In patients with an impaired immune system, cytotoxic T cells stimulated by TH1 induce beta-cell death and diabetes mellitus. Cytokines and free radicals produced by interferon-gamma are toxic to pancreatic beta cells as well. Patients who experience damage of the beta-cell without a repair mechanism develop diabetes. Citizens in developing countries are more likely to develop type 2 diabetes after age 40, caused by a fat-rich diet, lack of exercise, and obesity. Patients with uncontrolled blood glucose are at risk for developing ketoacidosis. Impaired beta cells put patients at risk for hyperinsulinemia and insulin resistance caused by glucose overproduction and reduced glycogenolysis.  

Subjects who experience insulin resistance release inflammatory markers from adipose tissues. The glucose-like peptide is a fat-soluble hormone that mediates beta cells’ response to insulin resistance. Patients with insulin resistance related to obesity can improve their health by modifying their diet and increasing physical exercise. Fat deposition, stress, and inflammatory process cause obesity, which induces insulin resistance and diabetes mellitus. Inflammasomes contribute to diabetes mellitus by facilitating oxidative stress and metabolic processes such as the Krebs cycle or the arachidonic pathway. Inflammasomes involved in diabetes mellitus are activated by the elevation of the blood concentration of ROS. ROS is produced in mammalian cells by mitochondrial electron transport and NADPH oxidase. Pyroptosis is thought to be a physiological response to ROS. 

The overproduction of ROS and ATP causes metabolic stress. Caspase-1 facilitates pro-inflammatory cytokines, which deplete beta cells and cause pyroptosis. We can therefore state that inflammation is an essential contributor to the onset of diabetes mellitus. The most common inflammatory markers are NLRP2, NLRP3, and NLRP4. The latter was reported to initiate pyroptosis, which is involved in the onset and progression of diabetes mellitus. Inflammatory cytokines produce signal 1 and signal 2. Signal 2 promotes the formation of NLRP3 and caspase 1, all of which are involved in pyroptosis and diabetes mellitus.  

ROS activates NLRP3. After activation, NLRP3 has positive feedback on ROS by causing an efflux of potassium ions that further enable ROS production and further activate NLRP3 causing pyroptosis and type 2 diabetes mellitus. The phenomenon is arrested by maintaining an elevated intracellular potassium ion concentration. Efflux of chloride ions and elevated calcium ions concentration also contribute to ROS production and activation of NLRP3 and induction of pyroptosis. It can be concluded that pyroptosis is a defense mechanism that develops against diabetes-related inflammation. ROS, which depends on the cell concentration in calcium, chloride, and potassium, is activated by caspase and causes pyroptosis. 

Practice pearls: 

• Cell death by pyroptosis has a significant contribution to the onset and progression of diabetes mellitus. 
• The intracellular concentration of ions such as potassium, chloride, and calcium produces ROS, activating NLRP3, which induces pyroptosis. 
• The onset of diabetes mellitus is preceded by CD4 cell activation; CD8, also known as cytotoxic T cells, damage diabetes patients. 

Sharma I., Behl T. et al. Exploring the Focal Role of Pyroptosis in Diabetes Mellitus. Biointerface Research in Applied Chemistry. Vol 11, no 5 pp 13557-13572, 2021. https://biointerfaceresearch.com. October 2021, DOI:10.33263/BRIAC115.1355713572   

The Eye Diseases Prevalence Research Group. The Prevalence of Diabetic Retinopathy Among Adults in the United States. Arch Ophthalmol. 2004; 

Pierre Djemgou, PharmD candidate class of 2022, University of South Florida