A detailed study of four different animal models for producing insulin resistance and type 2 diabetes has shown that in each case the treatments result in an increase in mitochondrial superoxide. The conclusion of the authors is that insulin resistance is a mechanism used by cells to stop entrance of additional glucose. When an excess of glucose products already energizing mitochondria causes oxidative stress by the accumulation of reactive oxygen species (ROS), one of those ROS, superoxide, switches off the insulin response. Insulin resistance is a defense mechanism to avoid cellular oxidation damage by blocking increased glucose transport into cells in response to insulin.
Insulin Reduces Blood Sugar by Triggering Glucose Transport into Cells
Glucose can’t cross membranes without the help of a transport protein, GLUT4. A small number of GLUT4 membrane transport proteins are always produced to maintain a supply of glucose for the metabolism of the cell. Insulin produced in the islet cells of the pancreas in response to high blood glucose levels triggers cells to add more GLUT4 to their membranes. In most cases, the extra glucose just increases the metabolism of the cell, but cells can only handle so much glucose before their mitochondria are overloaded.
Excess Glucose Overloads Mitochondria and Produces Superoxide
Cytoplasmic enzymes of the Glycolysis pathway convert glucose into pyruvate, ATP and a high energy electron carrier, NADH. The pyruvate and NADH are transported into mitochondria where carbon dioxide is produced via the Tricarboxylic Acid Cycle and the high energy electrons pass through the electron transport chain to produce ATP and are ultimately added to oxygen in a low energy state to produce water. If ATP production has been maximized, no more electrons can flow through the electron transport chain and the extra high energy electrons start to interact directly with oxygen molecules to produce superoxide. Superoxide is very aggressive chemically and results in oxidation stress.
Treatments that Produce Insulin Resistance Also Produce Superoxide
The authors of the study used a special dye that becomes fluorescent when exposed to superoxide in mitochondria. Mouse fat or muscle cells were treated with continuous high levels of insulin, inflammatory cytokine (TNF-alfa) or anti-inflammatory corticosteroid (dexamethasone) and the amount of fluorescence/superoxide was measured. Insulin resistance was measured by how much glucose transport increased in response to an insulin challenge. All of the treatments that reduced insulin response also increased superoxide.
Superoxide Dismutase Eliminates Superoxide
Superoxide in small amounts can be converted to hydrogen peroxide by the enzyme superoxide dismutase. Mouse lines with more or less mitochondrial superoxide dismutase respond differently than normal mice to conditions that would otherwise affect superoxide levels. For example, mice designed to produce only 60% of the normal amount of mitochondrial SOD are much more sensitive to developing insulin resistance, whereas mice producing enhanced levels of SOD do not develop insulin resistance. This provided further proof that superoxide accumulation somehow was stopping the normal response to insulin that would trigger additional glucose import.
Cells Control Intracellular Glucose Levels in Response to ATP and Superoxide
The conclusion of the studies is that cells are able to control their cellular levels of glucose to supply their metabolism with energy. If the cells run low on ATP, more GLUT4 will be moved to the cytoplasmic membrane and glucose import with increase to meet needs. If a systemic need of the body signals excess blood sugar by insulin production, then cells can compensate to some extent by increasing GLUT4, importing more glucose and increasing cellular metabolism. If too much cellular glucose is already present, the cells also apparently have a control system that responds to accumulating mitochondrial superoxide by shutting off the ability to respond to insulin. Thus, insulin resistance is a defense mechanism to prevent oxidation damage by excess cellular glucose.
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