Molecular Basis of Type 2 Diabetes

Type 2 diabetes develops when there is too little insulin secreted and/or insulin resistance occurs. Insulin resistance is a condition where the cells that insulin act on do not respond to insulin correctly. This can happen if there is a malfunction in the insulin receptor's ability to form a signaling cascade. Lower secretion of insulin occurs when beta cells in the pancreas become functionally damaged. This damage can be caused by 1) glucotoxicity, 2) oxidative stress, 3) lipotoxicity, and 4) inflammation, as shown below. 

1) Glucotoxicity

Glucotoxicity is damage to the beta cells caused by hyperglycemia. The beta cells which secrete insulin are very sensitive to the level of glucose in the blood. Impairment in the negative feedback loop between insulin action and insulin secretion results in elevated glucose levels in the blood. Excessive exposure to elevated blood glucose levels has negative effects on insulin synthesis, release, and cell survival.

2) Oxidative Stress

When there is excessive glucose metabolism in the beta cell, it can produce reactive oxygen species. Unfortunately, beta cells do not have many antioxidant enzymes which makes them susceptible to oxidative stress. Oxidative stress increases the protein kinase inhibitor, decreases the ATP/ADP ratio and Ca²⁺ influx resulting in cell death, and lower insulin activity and secretion. Additionally, oxidative stress causes abnormal changes to the intracellular component of the receptor preventing further signaling.

3) Lipotoxicity

Lipotoxicity is damage to the beta cells caused by an excessive amount of free fatty acids. This induces endoplasmic reticulum stress by through the activation of the apoptotic unfolded protein response pathways.

4) Inflammation 

Glucotoxicity and lipotoxicity can trigger inflammatory responses in beta cells. In beta cells, there can be an increased number of chemokines and cytokines produced. IL-1β is a cytokine that can lead to beta cell impairment and cell death. 

When glucotoxicity and lipotoxicity occurs, Sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) which functions in Ca²⁺ mobilization becomes inhibited. Prevention of Ca²⁺ mobilizations in turns prevents the insulin exocytosis. Furthermore, an increase in glucose levels increases proinsulin biosynthesis and islet amyloid polypeptides (IAAP) leading to an accumulation of misfolded insulin and IAAP and an increase of oxidative protein-folding-mediated reactive oxygen species (ROS). This alters physiological ER Ca²⁺ mobilization and favors proapoptotic signaling and induces interleukin (IL)-1 β (beta cell inflammation).