Is There a Type 4 Diabetes?

A new type of diabetes in older people of normal weight has been proposed, and the authors suggest calling it type 4 diabetes. Well, OK, this hasn't been found in people yet, but only in mice, and mouse results often don't translated into human results, but the idea is intriguing.

The two main types of diabetes currently accepted are type 1, which is autoimmune, and type 2, which is caused by insulin resistance. Some type 1 patients have some insulin resistance and some type 2 patients have some autoantibodies, but in general types 1 and 2 have different causes.

Type 3 diabetes is what some people call Alzheimer's disease, meaning insulin resistance in the brain. Others use type 3 to mean family members of someone who has diabetes, some use it to refer to gestational diabetes, and some use type 3 to mean people whose diabetes is related to exposure to electromagnetic radiation. Definitions of type 1.5 diabetes also differ. Some use it to mean LADA (latent autoimmune diabetes of adults), which is like type 1 in older people but tends to progress more slowly. Others use it to mean people with both types 1 and 2, or "double diabetes." 

Another type of diabetes is MODY, or maturity onset diabetes of the young, which is monogenic. There are several types of MODY.

So now we may have another type of diabetes, which seems to be found in lean elderly mice in which  insulin resistance is caused not by obesity but simply by aging. The interesting thing is that this type of diabetes doesn't respond to weight loss but can be treated, at least in mice, by using antibodies to deplete the fat cells of immune cells called regulatory T cells, or Tregs. The Tregs in fat are called fTregs.

What is interesting about the Tregs is that they have been considered "good" immune cells. The Tregs control the immune system and can dampen down an immune response that is too large. There is some evidence that people with type 1 diabetes don't have enough Tregs so their immune system goes into overdrive and attacks their own tissues, including the beta cells in the pancreas.

One recent study showed that removing cells producing Tregs from people with type 1 diabetes,  culturing them in medium until they increased 1,500 fold, and then reintroducing them back into the patients produced no side effects. It is hoped that further trials show that they dampen the autoimmune attack.

But in the case of type 4 diabetes, the problem is not too few Tregs but too many in the fat cells, the fTregs. When the Salk Institute researchers, led by Ronald Evans, looked at the fTregs of obese mice with type 2 diabetes, they found that the level was lower than normal. But when they looked at the fTregs of aged lean mice with age-associated insulin resistance, they found that the levels were high (5%, compared with 0.4% in  young mice and 0.1% in obese mice). Their publication in Nature is behind a paywall, but Evans kindly sent me a copy of the full text.

When they depleted the fat of the excess fTregs by giving them a specific antibody, their metabolic abnormalities improved, glucose and insulin levels were lower, their fat cells were smaller, their serum free fatty levels were reduced to almost half of their previous levels, and they were leaner despite increased food consumption. Giving the same antibody to mice with type 2 diabetes had no effect.

As noted, this research has not yet been duplicated in humans. But the idea is exciting, because many older people diagnosed with type 2 diabetes find that weight loss has no effect. Others are diagnosed with type 2 even though they are active and of normal weight. If type 4 diabetes turns out to exist in humans, this would explain these anomalies.

Stay tuned. Evans said the research has generated a lot of interest, and I hope it's followed up in several labs, which offers the greatest possibility of confirmation.