December - 20188In My OpinionPhyllis PostTHE THREE MECHANISMS OF GLUCOSE TOXICITYJohn F. Burd, Ph.D., LysulinByGlucose is necessary to live, but uncontrolled or poorly controlled levels in the bloodstream are toxic Glucose is the essential source of energy for the human body. It primarily comes from eating carbohydrates. After eating, the glucose in our bloodstream rises, signaling the pancreas to produce insulin. The job of insulin is to remove the glucose from the bloodstream and transport it into our cells where it is used for energy production. When the body cannot control the amount of glucose in the bloodstream, it leads to a disease known as diabetes. There are two main classifications of diabetes, Type 1 and Type 2:· Type 1 diabetes is an auto immune disease where the pancreas has lost its ability to produce insulin, making insulin injections necessary to live. · Type 2 diabetes is the result of insulin resistance, resulting in high concentrations of glucose in the bloodstream. Therapy starts with attempts to control glucose through diet and exercise. If this fails, drugs are prescribed. If drugs do not work, insulin injections are required. Over 30 percent of people with Type 2 are using insulin injections to manage their glucose levels (1).It is estimated that by the year 2020 there will be 250 million people affected worldwide with Type 2 diabetes (2).Although everyone needs a certain amount of glucose for daily energy production, it is also toxic to the body. The toxicity is rooted in three mechanisms:· Insulin Depletion.· Insulin Resistance.· Protein Glycation.Insulin DepletionOur pancreas can produce only a certain amount of insulin during our lifetime. Continuously high levels of glucose force the pancreas to produce an increasing amount of insulin, leading to a premature depletion of this insulin supply. Eventually the pancreas can no longer make insulin and it becomes necessary to take insulin injections to make up the difference. Insulin ResistanceHigh glucose levels can also lead to insulin resistance. With insulin resistance, the insulin receptors on the cell surface no longer function as well as they should, requiring greater amounts of insulin to transport glucose into cells. This increased demand for insulin also accelerates its depletion. Shulman has provided a hypothesis on the mechanism of insulin resistance as follows (3).The Shulman hypothesis holds that increasing intracellular fatty acid metabolites, such as diacylglycerol, fatty acyl CoA's, or ceramides activates a serine/threonine kinase cascade (possibly initiated by protein kinase C), leading to phosphorylation of serine/threonine sites on insulin receptor substrates. Serine-phosphorylated forms of these proteins fail to associate with or to activate PI 3-kinase, resulting in decreased activation of glucose transport and other downstream events. If this hypothesis is correct, any perturbation that results in accumulation of intracellular fatty acyl CoA's or other fatty acid metabolites in muscle and liver, either through increased delivery or decreased metabolism, might be expected to induce insulin resistance. Evidence supporting this hypothesis comes from recent studies in transgenic mice that are almost totally devoid of fat because their adipocytes express the A-ZIP/F-1 protein, which blocks John F. Burd
< Page 7 | Page 9 >