Understanding Oxidants and Diabetes Complications

You may have heard about the importance of incorporating antioxidants into your diet. Antioxidants are molecules that are either made in the body or ingested in the form of different vitamins and minerals, and they help to clean up the messes left behind by the cellular processes of metabolism. These leftovers are called reactive oxygen species (or ROS), and evidence shows they can play a role in diabetic complications.“There’s a normal level of oxidants that you need, so it’s not their fault [that they can contribute to complications],” says Robert Stanton, Chief, Kidney and Hypertension Section at Joslin Diabetes Center and Associate Professor of Medicine at Harvard Medical School. . “They just need to be regulated normally.”ROS form during energy generation processes in our cells. To create energy, cells take electrons away from the nutrients we eat and hand them off to oxygen. When this occurs smoothly, the relative low levels of ROS produced do not cause problems. However, sometimes this process leaves ROS with too many unpaired elections. Electrons like to pair up with things, and this can lead to the unpaired electrons of the ROS attaching to molecules that they shouldn’t.Antioxidants can swoop in and couple their electrons to those unpaired ones in the ROS, keeping them from interfering with normal cellular functions. Your cells normally produce their own forms of antioxidants that are capable of handling the normal amount of ROS produced. But environmental stress, including things like exposure to too much UV light, cigarette smoke, and high blood glucose, can cause the body to produce more ROS than antioxidants can keep up with.When ROS run amok, “they change the structure of proteins, sugars, and lipids so they don’t work properly,” says Dr. Stanton. “Membranes will get stuck, proteins don’t work well, normal cellular processes break down.”In people with diabetes, this can lead to an increase in diabetic complications. A recent Joslin study may have pointed to one of the reasons why. The study suggests that a certain protein in the body has a duel function as both an antioxidant and a watch dog against the malfunctioning of cells. When there are too many ROS in the body, these proteins are overwhelmed by their antioxidant duties and neglect their other protector duties, leading to an interruption of normal cell function and, eventually, diabetic complications.Dr. Keith BlackwellThe research was done in the lab of Keith Blackwell, M.D., Ph.D., Associate Research Director and co-head of the Section on Islet Cell and Regenerative Biology at Joslin Diabetes Center and Professor of Genetics at Harvard Medical School.The research team studied this protein, known as IRE-1. IRE-1’s usual job is to monitor the proteins being folded inside the cell’s endoplasmic reticulum. IRE-1 alerts the cells if the proteins are malformed, giving the cells a chance to fix their mistakes before the bad proteins circulate in the body. But as it turns out, that’s not IRE-1’s only job. In a recently published paper, the researchers announced that when in the presence of oxidants, IRE-1 turns off its protein monitoring function and switches on antioxidant-mode.“IRE-1 really has two faces,” Dr. Blackwell says. “On the one hand, it senses misfolded proteins inside the endoplasmic reticulum, and it turns on a corrective mechanism called the unfolded protein response (UPR). On the other hand, when IRE-1 gets a signal from ROS molecules outside the endoplasmic reticulum, it shuts off the UPR response and turns on an antioxidant response.”When ROS levels are normal and healthy, this is actually a positive turn of events. It allows IRE-1 to exercise its two different functions, keeping the body clear of oxidants while also monitoring the cells’ production of proteins.Problems arise when there are too many oxidants. Then, IRE-1 does one of two things. It either focuses solely on clearing out oxidants, or it bolsters its protection of the cell from other stressors. Either way, one of the functions remains unattended.For example, the endoplasmic reticulum of beta cells produces the protein insulin. When blood sugars are too high, levels of oxidants increase. This damages the beta cell on two levels: its endoplasmic reticulum is battered by either insulin resistance (from type 2 diabetes) or an autoimmune attack (from type 1 diabetes) while also being assaulted by high levels of ROS.“Beta cells then would rely on IRE-1 to protect the ER, and this could have a negative effect on antioxidant defenses,” Dr. Blackwell says. The same could hold true for tissues in the body susceptible to diabetic complications. The researchers plan to study this process in more depth to understand if it could be a target for new diabetes medications.This may make it sound like consuming a certain amount of antioxidants through foods or supplements would help boost the body’s natural antioxidant response and potentially reduce the effects of diabetic complications. But Dr. Blackwell cautions against taking that idea too far, as it could interrupt the positive ROS/IRE-1 interactions.“Blindly consuming large doses of antioxidants is probably not the best idea,” he says. “While your intent would be to protect yourself from damage, you’re also potentially interfering with normal ROS signals that are helpful and important.”https://goo.gl/TjGxdS