News: Therapy can push Type 2 diabetes into remission

[fgummett]

CTV.ca | Therapy can push Type 2 diabetes into remission (http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20080523/type2_diabetes_080523/20080523?hub=Health)

Updated Fri. May. 23 2008 8:13 AM ET

The Canadian Press

TORONTO -- Treating Type 2 diabetes early and aggressively with insulin therapy can push the disease into remission, suggests a new study that challenges the current paradigm of diabetes treatment.

The study, by Chinese scientists, showed that after a few days of intensive insulin treatment, a substantial number of people with newly diagnosed diabetes went into remission, which in some cases lasted at least a year.

"I think this is so provocative it would have to be confirmed with additional studies. But it's hard to dispute the findings of the study," said Dr. Daniel Drucker, a researcher with the University of Toronto's Banting and Best Diabetes Centre who was not involved in the work.

The premise behind the therapy is that by giving the failing beta cells of the pancreas a chance to rest, one might interrupt a cycle of decline and allow for some recovery. The beta cells produce the insulin the body needs to keep blood sugar levels in check; it is the inability of those cells to meet the body's insulin needs that triggers Type 2 diabetes.

The notion of early intervention has been explored before, but previous reports in the scientific literature have been based on small studies.

In this work, which will be published in Saturday's issue of the Lancet, Chinese scientists from nine centres randomly assigned 382 patients with newly diagnosed diabetes to receive either continuous insulin infusion (137 patients), multiple daily injections of insulin (124 patients) or oral diabetes drugs (121 patients).

Treatment was stopped after regular blood glucose levels were restored for a period of two weeks. Patients were then asked only to follow standard diabetes lifestyle interventions - eating an appropriate diet, maintaining weight control and exercising.

Those who received insulin were more likely to hit their blood glucose targets and to do it more quickly.

In fact, 97 per cent of those who received the continuous infusion had normal glucose levels within four days and 95 per cent of those who received insulin injections got there in 5.6 days. For those on the oral diabetes drugs, 85.3 per cent achieved normal glucose levels within 9.3 days.

After a year, 51 per cent of those who received insulin by infusion were still able to maintain normal blood sugar levels without drugs - in other words, were still in remission - and 45 per cent of those who received multiple daily injections were similarly able to control their blood sugar.

By contrast, only 27 per cent of those on the oral drugs were still in remission a year later.

"So this type of study forces us, I think, to start evaluating in more detail: Does it matter what kind of treatment we get initially?" said Drucker, who is also appointed to the Samuel Lunenfeld Research Institute at Toronto's Mount Sinai Hospital. Drucker co-authored a commentary on the study for the Lancet.

"And the suggestion obviously from this study is that it may matter how you control diabetes."

Until relatively recently, people newly diagnosed with Type 2 diabetes were counselled to try to lose weight if they were overweight, adapt their diets and increase their levels of physical activity, said Dr. Hertzel Gerstein, a diabetes expert from McMaster University in Hamilton, Ont., who also had no involvement in this study.

If that failed to bring blood sugar levels under control - and in many cases it did - oral drugs like metformin were prescribed. But by year 10, most Type 2 diabetics needed to take insulin injections, Gerstein said.

The treatment approach was essentially that when one option failed, another treatment or therapy was layered onto the regime.

"It may very well be that that approach is really trying to close the barn after the horses have run out of the barn," Gerstein said.

Within the past few years, treatment guidelines have been changed. Physicians are now urged to add oral drug treatment for Type 2 diabetes early after the diagnosis. But in North America at least, insulin remains a drug of last resort in most cases, Drucker said.

"We often reserve insulin therapy for those patients who have failed the oral therapies. And this study suggests that that might not be the correct or best course of action and that we should move (to) insulin much earlier on in the treatment paradigm."

Both Drucker and Gerstein said more study is needed to confirm the results and to answer questions like how long remission might last and whether repeating the effort to rest the beta cells once a person started to come out of remission might again reverse the process.

"Does this paper mean that we should start doing this for everybody? I think that this is still early data to make that type of a major change in approach," Gerstein said.

"I think that this type of research should certainly lead to other studies looking at this. And I think the time is ripe to do those studies."

"We have an epidemic of diabetes in Canada. ... If we can identify therapies that can reverse it and reverse it safely and effectively, I think that really needs to happen."

[Scrabblechick]

Very, very interesting study. But I have to wonder about people like me. My pancreas is over-producing insulin. It's not a case of me not having enough insulin. I've got PLENTY. I'm just apparently very insulin resistant. Would more insulin on top of what my body is already producing be an appropriate therapy, or would this be more for those T2s who don't produce quite enough insulin to start with?

Just wondering. Thanks for posting this. It's a fascinating read.

[Hammer]

Very, very interesting study. But I have to wonder about people like me. My pancreas is over-producing insulin. It's not a case of me not having enough insulin. I've got PLENTY. I'm just apparently very insulin resistant. Would more insulin on top of what my body is already producing be an appropriate therapy, or would this be more for those T2s who don't produce quite enough insulin to start with?



I would think that it would help you Scrabblechick. The idea is to give your pancreas a rest. If you take insulin, your pancreas doesn't need to keep operating at full capacity in an attempt to make more insulin. The thing is, you'd need to inject enough insulin so that your body doesn't call on your pancreas to make any.

I would think that the treatment would have to include another drug to make your body less insulin resistant, but the study didn't indicate that so I don't know how they'd get around that aspect of the treatment.

Maybe they found that the insulin resistance is a byproduct of the pancreas working at full capacity all the time, and if it were able to slow down and rest, the insulin resistance would decrease.

[Scrabblechick]

Good reasoning on that, Hammer! I hadn't thought of it that way. I'd guess it would be like a lot of T2s who are on Met and insulin now. Just earlier.

[shutterbug]

Very, very interesting study. But I have to wonder about people like me. My pancreas is over-producing insulin. It's not a case of me not having enough insulin. I've got PLENTY. I'm just apparently very insulin resistant. Would more insulin on top of what my body is already producing be an appropriate therapy, or would this be more for those T2s who don't produce quite enough insulin to start with?

Just wondering. Thanks for posting this. It's a fascinating read.


Good question. Also I've got a related question. If insulin resistance can be over come (by diet and exercise) for people like us, does that mean that our diabetes has gone into remission?

[BlueSky]

If someone is insulin resistant and insulin is injected, what happens? It would be great if this relieves pressure on the beta cells. But wouldn't injecting insulin make the insulin resistance even worse? In which case the beta cells won't be much better off, blood sugar won't improve much, and the patient is likely to put on more weight. :confused:

The presence/absence of insulin resistance would seem to be a big issue. 45-51% of subjects given insulin treatment responded well to it. And I guess the question is, how many of them were insulin resistant? As much as 20% of people diagnosed T2 are in fact T1.5, who are typically not insulin resistant. And all of them would have responded well to early insulin treatment. And there seem to be a lot of people being diagnosed as T2 who are not insulin resistant, and the are not antibody positive either :o

[Funnygrl]

Honestly, I'll say this not as anything meant to be taken personally by members of DF (since those of us here obviously want to manage our diabetes).

That being said, it's hard enough to get some newly diagnosed diabetics to test their bg or take metformin (my father, for example). Try getting them to to intensive insulin therapy, even temporarily? In most cases, not happening.

[Funnygrl]

BlueSky-

Excellent points. They say good research raises more questions.

I agree with your sentiments about type 1.5s not being insulin resistant, and of course they will respond well to insulin. However, the article stated that they were able to go into a remission for up to a year or more. I can't see the type 1.5s doing that, unless it were a honeymoon of sorts triggered (which is very possible, it seems).

Again, more questions.

[Hammer]

That was the question I had asked in another thread....if you're insulin resistant and take more insulin, what would happen. It seems that since I started taking Lantus, my numbers have gone down a good bit, but my fasting numbers never went as low as I wanted them to go, which is below 100. They seemed to stay around 120....till I started taking Byetta. Once I started on that, I got them below 100.

From that experience, I would say that even though you're insulin resistant, adding insulin to your meds will help. The thing is, is the additional insulin being entirely used, or is there an excess of it in your system? If there's an excess, that can cause other problems, so unless you have an insulin level test, you don't know if you have an excess or not.

Another question does come to mind though.....is the injected insulin, like Lantus, the exact same as the insulin your body produces? I'm wondering because maybe the insulin your body produces is chemically different than the injected insulin. This difference, no matter how small, may be enough of a difference to allow your body to use it and not reject it.

I would like to know what the difference is between the terms "cured" and "gone into remission for the rest of your life". When I read about the gastric bypass surgery causing type 2 diabetes to go into remission in 85-90% of those who had it, and the patients were still diabetes free some 12 years later, then why don't they just say it's cured? If you're free from some disease for the rest of your life, isn't that cured? Do you have to live for a certain number of years after the surgery, then die from something unrelated to diabetes, in order for doctors to say you were cured?

[Schlep]

The sentence that caught my attention when I first read this is that they went into remission for up to a year. So it was not in my opinion such a great discovery as up to a year could mean a couple of months.

This meaning that the body was just adjusting itself to the treatment and in the long run served no real advantage as we all know insulin will control diabetes quicker than pills.

I was told that if it was not for the fact that people hated taking needles they would (when diagnosed) go directly to insulin rather than pills.

IMO remission for 6 months to a year is nothing for a possible life long disease.

[fgummett]

I did not get on well with Metformin's side effects nor was it giving me good control, so I started on MDI (basal + bolus) Insulin within a year of Dx (I had not seen a doctor in 12 years so who know how long I had actually already had D). Insulin was/is my only medication for the D. I was, and still am obese, and my Dx of Metabolic Disorder leads me to assume I had Insulin Resistance (IR). The extra insulin quickly brought my sugars under good control. I'm not sure how/if additional insulin is thought to increase IR..? It seems to me that even with IR some of the insulin must still be working or the BS would go as high as in Type 1, plus the pancreas is working overtime. So injecting insulin, for me at least, seemed to help, but clearly was not early enough to fit in with this study. I can also add that, on occasion, I have taken a "day off" from the Insulin [Pump] and I used to find that my sugars remained fairly well controlled; suggesting that the Pancreas had indeed been resting. However, based on more recent experience I would have to say that is no longer the case... without Insulin even for a short period and my BS is BS! Just my 2 cents :)

[BlueSky]

.... I'm not sure how/if additional insulin is thought to increase IR..? ...
In terms of the traditional definition of insulin resistance, increasing the supply of the hormone causes down regulation of insulin receptors on the cell surface. There are fewer points of entry into cells for all the glucose out there, so blood sugar goes up. This is how injecting insulin could be expected to intensify insulin resistance. Here is a more technical description of the process :
Receptor downregulation

[edit] Mechanism

For insulin, the process of downregulation occurs when there are elevated levels of the hormone in the blood. When insulin binds to its receptors on the surface of a cell, endocytosis of the hormone receptor complex is initiated, only to be subsequently attacked by intracellular lysosomal enzymes. The internalization is multi-purposed, as it provides the pathway for degradation of the hormone and also a way to regulate the number of sites that are available for binding on the cell’s surface. At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding. The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell’s sensitivity to the elevated hormone concentration. The process of decreasing the number of receptor sites is virtually the same for all hormones; it only varies in the receptor hormone complex.

[edit] Cases

To illustrate this process we shall look at the insulin receptor sites on the target cells of a type 2 diabetic. Due to the elevated levels of blood glucose from excessive feeding in an overweight individual, the β-cells (islets of Langerhans) in the pancreas must release more insulin than normally emitted to match the demand and return the blood to homeostatic levels. The near-constant increase in blood insulin levels results from an effort to match the increase in blood glucose, which will cause receptor sites on the person’s cell to downregulate and decrease the number of receptors for insulin, increasing the subject’s resistance by decreasing sensitivity to this hormone. There is also a hepatic decrease in sensitivity to insulin. This can be seen in the continuing gluconeogenesis in the liver even when blood glucose levels are elevated. This is the more common process of insulin resistance, which in turn leads to adult onset diabetes in that subject.
Downregulation and upregulation - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/Downregulation)

I think part of the problem is that, when talking about "insulin resistance", we are not always talking about the same thing. IR has become a catch-all phrase for people with high blood sugar who are not anti-body positive (T1). While the down-regulation process is no doubt a valid explanation, it is not the full story. ;)

[fgummett]

Due to the elevated levels of blood glucose from excessive feeding in an overweight individual, the β-cells (islets of Langerhans) in the pancreas must release more insulin than normally emitted to match the demand and return the blood to homeostatic levelsThanks for the clarification BlueSky :) It does make some sense but I think we are dealing with a chicken and egg situation here... the quote I have clipped above seems to imply that the overeating comes first but based on my reading and my own experience during the onset of my type 2 D, I now firmly believe that dysregulation (sic?) of the sugar metabolism occurs first and that leads to the overeating and so on, in a vicious cycle. If what you quoted is the whole story (and I acknowledge that you suggest it isn't) I fail to see how my injecting additional Insulin could could improve my BS control, unless my Pancreas had already been overloaded and was failing; which I don't believe it was at that time.

[BlueSky]

Due to the elevated levels of blood glucose from excessive feeding in an overweight individual, the β-cells (islets of Langerhans) in the pancreas must release more insulin than normally emitted ...
Frank,

This is not an attempt to explain the T2 diabetes phenomenon. All that is being said here is that, in an overweight individual, there must have been "excessive feeding". This is what caused the individual in question to be overweight. And if carbohydrate was a major source of calories, insulin resistance develops.

It is well known that normal weight people can also become "insulin resistant". Perhaps it is caused by carbohydrate being the main source of calories too. It begs the question of what level of carbohydrate consumption causes the number of insulin receptors to be down-regulated. Surprisingly, no research appears to have been done on this.

While it is true that large amounts of carbo were consumed by our paleolithic ancestors, gorging on carbo rich foods happened periodically. Like in summer when fruit was in season. In winter, protein/fat rich animal foods were relied on. This dooesn't happen anymore. High-carb eating is relentless. Perhaps this is what causes the regulation mechanism to break down.

Interestingly, we are born with over 30,000 insulin receptors, per cell. This number drops as we progress through childhood, down to about 7,000 in an a young insulin-sensitive adult. The fact that, in many people, the number of insulin receptors just keeps on dropping must surely have something to do with modern living conditions. The fact that most jobs are sedentary, there is no shortage of food, and we typically we get more calories from carbohydrate than at any time in our evolutionary past.

Having said all that, there are no doubt other factors involved. We just don't understand them very well. ;)

[jacobsam622]

I was treated with insulin for three days when I was first diagnosed and I didn't go into remission. I didn't put on weight until the prediabetes started. I was on prevacid and 1% of the people who took during phase three development ended up with diabetes. I was on vioxx and 1% of the people who took it during phase three development ended up with diabetes. I took steroids for three weeks because of a pinched nerve in my lower back and a common side effect of steroids is high BG. I wonder if the combination of three drugs led to insulin resistance which in turn over worked the pancreas. And all of that led to weight gain which in turn raised the insulin resistance to the point that I started losing weight. The drugs we take for other ailments can sometimes cause other things to go wrong. :eek:

[REDLAN]

I read the wiki article - the article is poorly written, but the author is largely correct about the role of insulin in downregulation of insulin receptors.

What happens is that the receptors are more rapidly internalised within the cell in the presence of high levels of insulin. Some cells seem to be much more sensitive to downregulation than others. Fat cells seem to be particularly sensitive (they're also the cell culture of choice for researchers investigating downregulation of insulin receptors). Other cells seem to vary in the sensitivity of downregulation. With rat liver cells, there is no downregulation at all. I could not find any specific references for muscle cells, only passing references that insulin receptor downregulation occurs. Further to this it would appear that cells that are more easily downregulated, also recycle the receptors more quickly than those that dowregulate more slowly.

I think what you have described here is a homeostatic mechanism for controlling the distribution of food energy. You eat - glucose, triglycerides and amino acids enter the blood stream go to the liver for initial processing. Food stimulates the production of insulin, and where do you want all this energy to go first? Well that would be the muscles and organs, only once all these are full, do you want your fat cells to take their share. So we find fat cells are most sensitive to downregulation - they turn off first in response to insulin, muscle cells come next, and the liver doesn't downregulate at all - you want the liver to be able to convert any excess glucose into fat, and then stuff it into the fat cells.

Does insulin cause insulin resistance? In normal individuals, the answer is clearly no. Once insulin levels drop to normal after food has been processed, then, those fat cells will rapidly recycle their insulin receptors. In someone with type 2, then high circulating levels of insulin could exacerbate insulin resistance.

As a mechanism for causing type 2, then I think it is dubious - this mechanism would seem to indicate that insulin resistance should begin in fat cells, whereas in type 2 it appears to be muscles that are first affected by insulin resistance.

The simple fact is that there are literally hundreds of regulatory enzymes (known as kinases), whose job it is to regulate cellular metabolism by activating/deactivating other proteins, or by turning genes on/off. They then interact in complicated ways, which are poorly understood. Type 2 is without doubt a multi-factorial disease, there isn't a simple explanation. They still don't know how insulin resistance causes beta cell degradation - there is no reason that it should - the explanation that they wear out can not be demonstrated in the laboratory. In rats and mice there appears to be an inflammatory response, which causes the degradation of beta cell function.

While it is true that large amounts of carbo were consumed by our paleolithic ancestors, gorging on carbo rich foods happened periodically. Like in summer when fruit was in season. In winter, protein/fat rich animal foods were relied on. This dooesn't happen anymore. High-carb eating is relentless. Perhaps this is what causes the regulation mechanism to break down.

The paleolithic argument comes out again! This argument only applies to a small subset of paleolithic peoples - those living in Europe, and to a certain extent America, during the ice age (they were supposed to have crossed to the states from russia/across the ice bridge that was there) - these peoples would have lived a similar lifestyle to the Inuit. Unsurprisingly however, large numbers of paleolithic peoples lived further south, where it was warmer. It is no coincidence that iran/iraq/southern turkey was the birthplace of civilization - 10,000+ years ago, this area was very fertile, and warm. Around these areas, you will find grind stones, and lots of them - they were in use well before the advent of traditional agriculture. They were used for pigment grinding, BUT also for grinding grass seeds.

From modern studies of paleolithic peoples i.e. what remains of the few hunter gatherers. It is clear that they ate a very wide variety of foods. In warmer climes, most calories tend to come from plants. Plants are convenient - you know where they grow, they can't run away, and generally they are a reliable food source. For instance, australian aborigine's derived around 70%+ of their calories from carbohydrates, and ate very low levels of fat (around 8%)

There is no evidence linking carbohydrate consumption with type 2 diabetes. Just to confuse things, in Japan with a major leap in type 2 diabetes, they are blaming the rise on the fact that people have deviated from the traditional diet, which was very high in carbohydrates (60%-70% of calories from carbs).

[REDLAN]

I read the wiki article - the article is poorly written, but the author is largely correct about the role of insulin in downregulation of insulin receptors.

What happens is that the receptors are more rapidly internalised within the cell in the presence of high levels of insulin. Some cells seem to be much more sensitive to downregulation than others. Fat cells seem to be particularly sensitive (they're also the cell culture of choice for researchers investigating downregulation of insulin receptors). Other cells seem to vary in the sensitivity of downregulation. With rat liver cells, there is no downregulation at all. I could not find any specific references for muscle cells, only passing references that insulin receptor downregulation occurs. Further to this it would appear that cells that are more easily downregulated, also recycle the receptors more quickly than those that dowregulate more slowly.

I think what you have described here is a homeostatic mechanism for controlling the distribution of food energy. You eat - glucose, triglycerides and amino acids enter the blood stream go to the liver for initial processing. Food stimulates the production of insulin, and where do you want all this energy to go first? Well that would be the muscles and organs, only once all these are full, do you want your fat cells to take their share. So we find fat cells are most sensitive to downregulation - they turn off first in response to insulin, muscle cells come next, and the liver doesn't downregulate at all - you want the liver to be able to convert any excess glucose into fat, and then stuff it into the fat cells.

Does insulin cause insulin resistance? In normal individuals, the answer is clearly no. Once insulin levels drop to normal after food has been processed, then, those fat cells will rapidly recycle their insulin receptors. In someone with type 2, then high circulating levels of insulin could exacerbate insulin resistance.

As a mechanism for causing type 2, then I think it is dubious - this mechanism would seem to indicate that insulin resistance should begin in fat cells, whereas in type 2 it appears to be muscles that are first affected by insulin resistance.

The simple fact is that there are literally hundreds of regulatory enzymes (known as kinases), whose job it is to regulate cellular metabolism by activating/deactivating other proteins, or by turning genes on/off. They then interact in complicated ways, which are poorly understood. Type 2 is without doubt a multi-factorial disease, there isn't a simple explanation. They still don't know how insulin resistance causes beta cell degradation - there is no reason that it should - the explanation that they wear out can not be demonstrated in the laboratory. In rats and mice there appears to be an inflammatory response, which causes the degradation of beta cell function.

While it is true that large amounts of carbo were consumed by our paleolithic ancestors, gorging on carbo rich foods happened periodically. Like in summer when fruit was in season. In winter, protein/fat rich animal foods were relied on. This dooesn't happen anymore. High-carb eating is relentless. Perhaps this is what causes the regulation mechanism to break down.

The paleolithic argument comes out again! This argument only applies to a small subset of paleolithic peoples - those living in Europe, and to a certain extent America, during the ice age (they were supposed to have crossed to the states from russia/across the ice bridge that was there) - these peoples would have lived a similar lifestyle to the Inuit. Unsurprisingly however, large numbers of paleolithic peoples lived further south, where it was warmer. It is no coincidence that iran/iraq/southern turkey was the birthplace of civilization - 10,000+ years ago, this area was very fertile, and warm. Around these areas, you will find grind stones, and lots of them - they were in use well before the advent of traditional agriculture. They were used for pigment grinding, BUT also for grinding grass seeds.

From modern studies of paleolithic peoples i.e. what remains of the few hunter gatherers. It is clear that they ate a very wide variety of foods. In warmer climes, most calories tend to come from plants. Plants are convenient - you know where they grow, they can't run away, and generally they are a reliable food source. For instance, australian aborigine's derived around 70%+ of their calories from carbohydrates, and ate very low levels of fat (around 8%)

There is no evidence linking carbohydrate consumption with type 2 diabetes. Just to confuse things, in Japan with a major leap in type 2 diabetes, they are blaming the rise on the fact that people have deviated from the traditional diet, which was very high in carbohydrates (60%-70% of calories from carbs).

the quote I have clipped above seems to imply that the overeating comes first but based on my reading and my own experience during the onset of my type 2 D, I now firmly believe that dysregulation (sic?) of the sugar metabolism occurs first and that leads to the overeating and so on, in a vicious cycle.

The wiki author is misinformed and is relying on stereotypes of obesity. I have to say I agree that I believe that the misregulation of insulin metabolism occurs prior to the weight gain - in fact I believe it is the misregulation that is primarily the cause of the weight gain. It's the only thing that explains the 20% of type 2 who are of a normal weight.

[REDLAN]

apologies for the double post :o

could a Moderator delete the first one?