Monday, March 28, 2016

Same genetic factor causes both type 1 and type 2 diabetes

Type 1 and type 2 diabetes may have the same underlying cause, namely "fragile" beta cells that are easily damaged by cellular stress. This was the conclusion of research by 29 researchers in Europe, Australia, and Canada led by Adrian Liston, who kindly sent me the full text of the paper. The research was published this month in the journal Nature Genetics.

The traditional view of diabetes is that types 1 and 2 are quite different. Type 1 is an autoimmune disease in which the body's own immune system destroys the beta cells, the cells that produce insulin, and the destruction is so great that patients must inject insulin.

Type 2 is thought to occur because of insulin resistance. Insulin resistance means the body can still produce insulin, but cells don't respond properly to it, so they are unable to overcome this resistance and may eventually die from "overwork."
 The liver produces glucose when it thinks glucose is needed, and insulin is supposed to shut this process down when glucose levels are adequate. But insulin resistance in the liver means that it keeps pouring out glucose into the bloodstream even after meals when glucose levels are high.

Because being overweight increases insulin resistance, obesity and rates of type 2 diabetes are associated, and some people call type 2 diabetes a "lifestyle disease" and blame patients with type 2 diabetes for "bringing it on themselves." For this reason, some people want to change the names of the two diseases so it's clear that they are different.

But now it seems that the underlying cause of both diseases is the same: a genetic defect in the beta cells that makes them more susceptible to various kinds of stress. Without the fragile beta cells, people can tolerate insulin resistance by simply producing a lot more insulin, and they can even tolerate an autommune attack on the beta cells as well.

This idea is consistent with the saying that "genetics loads the gun and the environment pulls the trigger." In both types of diabetes the gun is loaded. In type 1 an autoimmune attack pulls the trigger. In type two it's insulin resistance, especially in the liver.

I've always felt that type 1 and type 2 diabetes must have the same underlying cause. Otherwise, why would there be families in which some people had type 1 and others had type 2? Seems unlikely if there weren't some common trigger. Now we may know what that common factor is.

This research is complex. The researchers used NOD (nonobese diabetic) mice, which are very prone to get autoimmune diabetes and are considered a model for type 1 diabetes. Then they studied various strains of mice with altered genes, some resistant to stress and some sensitive.

Although the NOD mice get autoimmune diabetes, the researchers found that they also have genetic defects in glucose control that precede the autoimmune attack and cause cell death. The researchers suggested that the dying beta cells could trigger the autoimmune attack, and later, because there are fewer beta cells, the remaining ones would have to work harder. This insulin-producing overdrive is a form of stress, to which these mice are especially susceptible.

Models of type 2  diabetes usually involve mouse strains that are bred to get fat easily on a high-fat diet (in the wild mice don't eat a lot of fat, which is one reason they're so keen on peanut butter and cheese - -  until the trap goes off - - and standard mouse chow is low in fat). In type 2, it could be that the beta cells have to go into overdrive when calories, especially carbohydrates, are in excess, requiring the synthesis of tons of insulin because of insulin resistance, and this would cause cellular stress to  fragile beta cells. Someone with robust beta cells could eat a ton of food and have a lot of insulin resistance without destroying the beta cells.

The researchers also showed that in mice, a high-fat diet could mimic the genetic effects. Liston said that certain fats, especially palmitic acid, make the beta cells more fragile, and even mice without the genetically fragile beta cells developed diabetes when given a high-fat diet. However, it should be noted that the effects of a high-fat, high-carb diet can be very different from the effects of a high-fat, low-carb diet. And high-fat mouse diets are also usually full of carbohydrate.

The researchers suggest that the increased prevalence of a high-fat "Western diet" may partly explain the increased incidence of type 1 as well as type 2 diabetes. I wonder if the increased prevalence of toxins in our increasingly polluted environment could be the stress that kills the beta cells in those whose beta cells are fragile.

Because of the complexity of this research (these researchers spent 10 years working on it), it's not likely to be replicated in the near future. Nevertheless, it gives intriguing hints about where other research should go.

It suggests that for most people, some cellular stress is OK. But those whose families include people with either type of diabetes should realize that they may have the same genes and fragile beta cells, and they should be careful not to increase cellular stress through diet.

Finally, if both type 1 and type 2 are precipitated by the same genes, we should all work together to support research that will some day solve the puzzle of this very inconvenient disease instead of bickering about which type of diabetes is worse or who is to blame for getting the disease.


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