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Is medication to increase insulin production in type 2 diabetes a good idea?

17/2/2016

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Disclaimer: Always consult your diabetes care team before making changes to medication. The following blog post is not medical advice, nor is it a comprehensive review of medication, it is intended to make you the reader think about the diabetes medication you are taking or prescribing.
Research is essential to good medical practice, but sometimes logic gets short shrift in a time when more people 'know' the importance of randomised controlled trials than understand why these are important and what their limitations are.

In this blog I'll begin by asking the question – are medications that increase insulin production a good idea in type 2 diabetes? Let's think for a moment... 

Type 2 diabetes is often described as having two core components (yes, there is more to it, but let's keep it simple):

1) insulin resistance, meaning that the cells receiving instructions from the hormone insulin aren't very responsive (or selectively responsive in some cases); and

2) a reduction in the insulin producing capabilities of our pancreas, specifically the insulin producing beta-cells.

The common metaphor is that our body becomes 'deaf' to insulin (selective hearing might be more accurate), and our pancreas gets worn out from constantly having to ‘shout’, i.e. produce abnormally large amounts of insulin.

Research has shown that both marked insulin resistance and a reduced capacity to produce insulin are present, potentially for many years, before type 2 diabetes is diagnosed (1-3).

Post-mortem studies suggest a large reduction in beta-cell number at the time of diagnosis with further reductions over time (4,5), and recent work in living volunteers with type 2 diabetes showed an average 33% reduction in pancreas size compared to volunteers with normal glucose tolerance (6).
​
NB: although the capacity to produce insulin is impaired before diagnosis, in an attempt to overcome insulin resistance average insulin production is still much higher in most cases of ‘pre-diabetes’ and early type 2 diabetes than in those with normal metabolism. Translation – most people with type 2 diabetes have excessive blood insulin to go along with their excessive blood glucose.

So when you consider this, does it make sense to use medication that directly or indirectly stimulates the insulin producing beta-cells to produce more insulin? Is it a good idea to motivate the already ‘hoarse’ pancreas to ‘shout’ a little louder, say as opposed to addressing the prevailing deafness or doing something to help the pancreas rest, repair, and regrow to its original size?

I would have suggested the default answer is no it does not make sense, and the burden of evidence was on anyone who suggested otherwise.

The latest research by Professor Per-Olof Berggren’s group published in the journal Cell Metabolism set out to address this question (7). 

In quite an intricate experiment, his team first introduced human beta-cells into a ‘humanised’ mouse model, and then gave either liraglutide or saline.

Liraglutide is a glucagon-like peptide-1 (GLP-1) agonist, and basically makes beta-cells produce more insulin in response to glucose, among other effects.

When the above mentioned mice were given Liraglutide over 200 or more days, the effects at first were as expected, i.e. improved glucose control, but over time the medication made insulin production, and with it glucose control, worse.

As with all such studies, it’s hard to know how well such a finding in an animal model reflects what happens in humans, but bare in mind that human beta-cells were used to get as close as possible.

This isn’t the only concern with this and other GLP-1 analogues coming through in the research, but it is the finding that directly addresses the question at hand. 

Our bodies are very intricate systems with hormones and hormone-like substances sending multiple instructions to multiple sites, and the effects being the result of a fine balance between all the hormones/signals floating around during any given time.

Given this complexity, it is unsurprising that simply giving or stimulating the production of a hormone using a pill or injection never, by itself, restores normal function.

I see these findings as another important lesson to treat type 2 diabetes, which is a lifestyle related condition, with lifestyle modification when and wherever possible. That is after all what virtually all treatment guidelines have as step 1.

The recognised goal should be to reverse and not just ‘manage’ the condition, and restore health, not just delay disease a little longer.

Read more on that here:
Can Type 2 Diabetes be Reversed?
Very Low Calorie Diets & Type 2 Diabetes Reversal Part 1: Blood Glucose
​
References
1.    Cnop, M. et al. Progressive loss of beta-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes Care 30, 677–682 (2007).
2.    Festa, A., Williams, K., D'Agostino, R., Wagenknecht, L. E. & Haffner, S. M. The natural course of beta-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study. Diabetes 55, 1114–1120 (2006).
3.    Ferrannini, E. et al. Mode of onset of type 2 diabetes from normal or impaired glucose tolerance. Diabetes 53, 160–165 (2004).
4.    Butler, A. E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).
5.    Rahier, J., Guiot, Y., Goebbels, R. M., Sempoux, C. & Henquin, J. C. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab 10 Suppl 4, 32–42 (2008).
6.    Macauley, M., Percival, K., Thelwall, P. E., Hollingsworth, K. G. & Taylor, R. Altered volume, morphology and composition of the pancreas in type 2 diabetes. PLoS ONE 10, e0126825 (2015).
7.    Abdulreda, M. H., Rodriguez-Diaz, R., Caicedo, A. & Berggren, P.-O. Liraglutide Compromises Pancreatic b Cell Function in a Humanized Mouse Model. Cell Metab 1–7 (2016). doi:10.1016/j.cmet.2016.01.009
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High-Intensity Intermittent Training & Type 2 Diabetes

26/9/2015

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This blog has mainly been about nutrition so far, but exercise deserves a mention as well. Exercise, by using up glycogen (the storage form of glucose) and by mechanisms related to forceful muscle contraction, increases how much glucose the working and recently worked muscles take out of the blood (1-3).

Muscles are the body’s largest glycogen (stored glucose) tank because despite the liver storing more glycogen per gram, we have a lot more muscle than we do liver (4).

Picture
2-D cross-sectional view of glycogen: A core protein of glycogenin is surrounded by branches of glucose units.Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762.

After a meal, healthy young volunteers stored 26-35% of carbohydrates in muscle (5), whereas roughly 20% was stored in the liver (6). So this difference in storage capacity is partly reflected in what happens after meals.

Both muscle and liver represent finite tanks, unlike our fat stores, the muscle and liver don’t grow to accommodate demand for space. There is some increase in the volume of the cells: for example bodybuilders ‘carbohydrate load’ to make their muscles look bigger for a show; and we can develop enlarged fatty livers, but to my knowledge we don’t lay down new cells to act as tanks.

Problems begin when we exceed the capacity of our glucose tanks as this leads to glucose being converted to fat in a process called de novo lipogenesis – the making of new lipids (7-9).

However, not all of us have full use of the available tanks. Exercise and insulin are the signals for our muscles to take on as much glucose as they can, but in type 2 diabetes neither of these signals work as well (10,11).

Many hypothesise that the path to type 2 diabetes starts with muscles becoming insulin resistant and therefore taking up only minimal glucose (10). Certainly, by the time type 2 diabetes is diagnosed our muscles no longer act as good glucose stores (12).


Recent Studies 

Despite people with type 2 diabetes being on average somewhat resistant to the effects of exercise in terms of improving glucose control, in the majority of cases exercise helps (13,14). When looking at measures beyond glucose control, for example blood pressure and blood lipids, the benefits of exercise are even more compelling (14,15).

It’s these insights that led the team I was part of to examine a particularly potent and time efficient form of exercise – high-intensity intermittent training or ‘HIIT’. We wanted to know if this form of exercise (see my series on HIIT here) would benefit people with non-alcoholic fatty liver and type 2 diabetes in terms of glucose control, and heart health and function.

We assumed HIIT would be effective at using up glycogen stores because the higher the intensity of an exercise the more the muscle cells involved rely on using glucose, and the stronger the muscle contraction.

We did two studies that used exactly the same exercise programme (16,17). The studies differed in that the first contained only volunteers with a liver fat of 5% or more (16), and the second contained only volunteers who had been diagnosed with type 2 diabetes (17).

You can download and read the full articles by clicking: study 1; and study 2

The question we most wanted to answer is what effect exercise, specifically HIIT, would have on liver fat and glucose control if we took weight reduction out of the equation. To achieve that, we asked people to weigh themselves regularly and eat a little more if their weight was going down.

If you’re thinking that this seems a little odd, I’d agree, but in research we often try teasing things apart. Sometimes there is no good way of doing that, as was the case here.

But why would we want to know what exercise without weight reduction can achieve? Because for many people it’s the reality. See the article Exercise Won’t Make You Thin? for more on that.

Back to what we did. We randomised our two sets of volunteers to either a HIIT programme 3 times per week or no exercise for 12 weeks. We only included people who were doing less than an hour of exercise per week, so we didn’t ask anyone to stop what they were doing. We also gave the non-exercising volunteers our programme and a 12-week gym membership at the end.

I’m going to let you in on something that gets lost in the clear concise descriptions that make up published research – real life isn’t so clean. In real life some people get sick, snowed in, or go on holiday over a 12 week period, so some people had a break in their exercise routine, and had to make up the remaining time.

That’s good to know, because it means you too can pick things back up if you’ve had voluntary or involuntary break.

The exercise sessions were always a challenge to describe, so I recorded instructions for each session. We gave our volunteers an mp3 player so that they only had to come to the gym, select the recording for whatever week they were in, and follow the instructions.

Basically everyone did a 5 minute warmup on a stationary bike (normal or recumbent) before going into their first interval of high-intensity pedalling (more on how to gauge intensity here). In the first week each interval was 2 minutes long, then the length of the interval went up by 10 seconds per week.

I wouldn’t recommend doing this indefinitely, 4 minutes intervals are about as long as you want them, so if you were to follow this programme past 13 weeks, think about reducing the active recovery period or some other option described here.

Everyone did 5 intervals in total per session. They also got a 3 minute active recovery between intervals. That gave them time to come off the bike, do a minute of light resistance training with an elastic band, and get back on the bike for the next interval.

One thing you learn when doing research upfront and personal, as opposed to reading published research, is that reporting average results for a group obscures as much as it reveals.

As researchers we hope that the average changes because at least then we can say something like  do this because people get better  or  don’t do this because people get worse.

More often though the reality is that some people get much better and others hardly change at all, so the message should be – this is worth trying, you might really benefit.

Marketers are seldom this honest, and we scientists get criticised for equivocating, but the reality is that results will vary. I’m guessing you care mostly about your results anyway.

So what did we find? Both studies showed that average liver fat went down, also, and despite our efforts to prevent it, average bodyweight went down (about 1 kg, or 2 lbs) mostly due to a reduction in fat mass. If anything lean body mass actually went up a little with HIIT.

Some people think lean mass just refers to muscle, but it actually refers to anything that isn't fat. Maybe people did gain a bit of muscle, or maybe they stored more glycogen, which is stored alongside extra water.

Both studies also showed improvements in some measures of heart form and function. This was a first for HIIT research, so we were very pleased to show some reversal of what we and others had previously shown to be changes associated with fatty liver and type 2 diabetes (18,19).

These were small studies in terms of the number of volunteers (16,17). That's largely because these tests are expensive to do, and the people who profit from exercise seldom support these kinds of studies, so the bill is often footed by charities and tax payers when governments pay.

The small number of volunteers means some of the other interesting findings aren’t as consistent between the two studies. Still, if we look at them both together, we see that on average HIIT improved liver health as indicated by a reduction in the liver enzyme ALT and AST.

In people with diabetes, there was also a small reduction in HbA1c after HIIT, and an improvement in 2-hour blood glucose – that’s blood glucose 2 hours after a 75 g glucose drink. Overall though, the improvements in glucose control were not as definitive as we were expecting.

We don’t have the data to tell us why with certainty, but there are two likely reasons:
  1. We asked people specifically not to change their diets, other than to eat a little more if they were loosing weight; and 
  2. We took our post study measurements, two or more days after the last exercise session.

Most people would be guided by hunger unless they are eating to a specific plan. The people taking part in these two studies would have preferred to reduce their weight, and reap the benefits, so we may have been hampering better results by being rigorous in our requirements.

The other factor is that many of the positive effects of exercise wear off quickly, and this includes glucose control. There are exceptions, but mostly we see the main benefit in a 24-48 hour window (more on that here).

We’ve also known, at least since the early 1980s that if you replace the used glucose with a carbohydrate rich meal shortly after exercise, the insulin sensitising effect of exercise mostly disappears (1). Once the glycogen stores are full, no more is going in.

For me the take home lesson is that diet and exercise go together when it comes to improving health, but that exercise deserves to be more widely recognised as important. This also means that if you can’t see yourself changing your eating habits, you can still benefit from changing your physical activity habits.

References: click here for a full set of references cited

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Very Low Calorie Diets & Type 2 Diabetes Reversal Part 5: Blood Pressure, Heart Form and Function, and Blood Lipids

26/7/2015

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We're back, this time with the last (probably) instalment on very low calorie diets for reversing type 2 diabetes. If you're familiar with previous parts, read on, otherwise check out the following for vital context: 

Click to read Can Type 2 Diabetes be Reversed
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part 1: Blood Glucose
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part 2: Insulin
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part 3: The Liver & Pancreas
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part 4: Glucose Tolerance

So we've seen that very low calorie diets can bring about rapid improvements in fasting blood glucose and insulin, the liver's response to insulin, and the function of the pancreas in terms of its release of insulin. 

We've also seen that maintaining these changes using the commonly prescribed low fat high carbohydrate diet alludes the majority of people, but by no means everyone.

Over the last two weeks we looked at the importance of liver and pancreas fat to put things into a clearer more useful context. Click here if you haven't read that article yet.

This week we're going to look at some important benefits of very low calorie diets in terms of blood pressure, the heart, and blood lipids (e.g. cholesterol). Because, let's face it, if you have type 2 diabetes or are well on your way to having it, some or all of these are also likely to be important to you.


Blood Pressure

Type 2 diabetes and hypertension (high blood pressure) often go hand-in-hand. 

One explanation for this link is that the hormones insulin, leptin, and aldosterone are elevated in type 2 diabetes, and these same hormones increase the activity of our sympathetic nervous system – that’s the part responsible for our stress or fight or flight response – which increases things like heart rate and blood pressure (1,2).

Having chronically or frequently high blood pressure is tough on our blood vessels, and is unsurprisingly linked to heart disease and risk of stroke. 

Given the link between insulin and blood pressure, and that we learned in part 2 and part 3 about reductions in insulin and insulin resistance, it’s unsurprising that very low calorie diets often lead to reductions in blood pressure (3,4).

The reductions in blood pressure were consistent with what normally would require one or more blood pressure lowering medications and resulted in some volunteers coming off their medication (3,4).

You can see specific results by downloading Table 5 as a pdf here (3-9).

Very low calorie diets consistently resulted in reductions of both systolic and diastolic blood pressure – that’s the bigger first number and the smaller second number that you get when measuring blood pressure, respectively.

The size of the reduction varied across studies, probably due to differences in starting values, diet duration, and degree of weight reduction.

So not only did insulin and blood glucose related measures tend to normalise, but blood pressure also often fell back into the normal range following very low calorie diets.

In one study that retested people 18 months after the very low calorie diet finished, blood pressure and heart rate went back up along with an increase in weight and fasting blood glucose (3).

However, in another study, one that involved some basic instructions on how to eat after the very low calorie diet, the improvements in blood pressure and the reduction in bodyweight were maintained (6).

The lesson once again being that the positive effects of the diet are largely undone by weight regain.

It’s worth mentioning that blood pressure changes rapidly all the time. When you get up out of a chair, your blood pressure should go up to compensate, when it doesn’t adjust fast enough you get light-headed.

When we talk about a long-term change, we mean blood pressure measured at more or less the same time of day under resting, often seated, conditions, and following five or so minutes of inactivity.


Heart Form and Function

One of the problems of having type 2 diabetes is that it leads to changes in the heart, some are more structure and some more function (10).

One of the things that often happens to the heart in type 2 diabetes is the left ventricle thickens (see image below).

Picture

Sixteen weeks of a very low calorie diet led to reduction in fat in and around the heart, and also led to physical remodelling of the heart leading to improved function (3,11,12).

So in addition to reducing fat in the liver and in the pancreas (see Part 3), very low calorie diets can reduce fat in the heart (11).

Interestingly, these changes were still there 18 months after the diet despite partial weight regain and associated worsening of glucose control (3). 

Some of the people in this study (5 out of 14) also followed an exercise programme during the very low calorie diet, and although the authors of the study say this had no effect, it isn’t clear how they tested whether or not it did (3), so I’m inclined to think it may have helped a little too.


Blood Lipids

Blood lipids are the collective term for things like cholesterol and triglycerides. In terms of common blood tests your doctor might order these include: total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein (HDL), and triglycerides (sometimes also called triacylglycerols).

A few things worth noting are that LDL is usually estimated, not directly measured. That means that it’s not always accurate. Also worth noting is that both LDL and HDL come in different ‘flavours’, and those ‘flavours’ have different implications for health.

The blood lipids that are commonly measured actually don’t give the most valuable information when it comes to health, but that’s a whole blog series on its own.

However, what is measured and reported in the majority of studies, including the ones reviewed in this article, is the same thing that is commonly measured when you get your checkup.

You can see specific results by downloading Table 6 as a pdf here (4,6,8,9,11,13-20).

The most consistent finding, and also the one with the largest change was a reduction in fasting triglycerides. That’s good news as high triglycerides show the body is not dealing well with fat (more on this in future posts).

Estimates of LDL-cholesterol generally went down or didn’t change. None of the studies looked beyond simply LDL-cholesterol concentration, so we don’t know if there were changes to the nature of the cholesterol.

Finally, HDL tended to remain the same or even go down slightly. This is likely due to the low fat, and at least in relative terms, high carbohydrates content of most of the diets used (21).

One study that does not appear in Table 6 because the results were represented in graphs rather than providing exact numbers for me to add to the table, compared higher carbohydrate/lower fat with lower carbohydrate/higher fat diets, and, as expected, found HDL increased in the latter group (22).

You may be wondering what happened long-term. When it comes to cholesterol there is no long-term as blood cholesterol is highly responsive to diet, and changes measurably within days of a change to diet or weight. In the case of triglycerides, you even get changes after a meal, which is why these measures are traditionally done after an overnight fast.


Warning!

I said it in an earlier blog, but this bares repeating – if you are planning on trying to reverse your type 2 diabetes, partly or fully, with diet and/or exercise, let your medical care team know so they can monitor you and adjust your medication. 

If you’ve read this miniseries of articles and taken most of it onboard, you’ll remember that dietary changes can drastically reduce blood glucose, insulin needs, and blood pressure. In practice this means that some or all of the medications/insulin you are on will need adjusting so you don’t end up with dangerously low blood glucose or blood pressure.

Also, the diets in the studies we’ve been looking into were specially formulated to make sure they provided enough of the essentials like vitamins and minerals. Simply working out a diet with 400-1000 kcal/day isn’t going to ensure you get what you need.


Take home messages from this series

Very low calorie diets can have a profound effect on the processes underlying type 2 diabetes. These include insulin production and insulin resistance, which together add up to better glucose control, but extend much further into improvements in blood pressure, heart health and fat metabolism. 

That can translate into a reversal of the symptoms for many, and a substantial reduction in the need for insulin and/or medication in others. Either way that translates into better health and function, and probably substantial financial savings.

The benefits are largely dependent on the weight reduction achieved then being maintained. For more explanations on why, check out Is type 2 diabetes all about the fat?. 

What all this means is that while very low calorie diets offer a fairly rapidly acting means to reverse type 2 diabetes, they are not a ‘cure’. 

To look for a one-off ‘cure’ for type 2 diabetes is to misunderstand the condition. This was the topic of the very first blog post: The Cure for Type 2 Diabetes is a Change in Perspective. 

Type 2 diabetes is a physiological state that you can move in and out of. A good way of thinking about it is as a repetitive strain injury to our metabolism. 

What that means is that to reverse type 2 diabetes permanently you need a long-term plan, whether or not that involves very low calorie diets at one or more points.

In future weeks we’ll look at other less drastic dietary options with a bigger safety margin. If you can’t wait and want to try a very low calorie diet, please seek professional help.

But for the next few weeks we’ll look at the central importance of exercise in helping improve glucose control along with other aspects of health. You’ll find that over in the MOVE blog here.

References: click here for a full list of references cited.

To learn more about type 2 diabetes and what you can do to better manage, and often reverse it, watch my free video education series. If you want one-on-one help dealing with your type 2 diabetes, contact me here to book a consultation.

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Is type 2 diabetes all about the fat? Part 2

14/7/2015

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In part 1 we looked at the types of fat: subcutaneous; visceral; and ectopic. We observed that, at least in terms of many aspects of health, visceral and ectopic fat are the problem. 

We also started looking at the idea that we all have a fat threshold, which when reached results in problems like type 2 diabetes.

We’ll explore this concept in more detail, look at how you might be able to check whether you’ve passed your fat threshold, and if so what you can do about it.


Measuring ectopic fat

So if fat in the organs is such a big problem, why haven’t you heard more about it? One reason is that it’s a slow road going from research to clinical practice. 

Count yourself lucky if you have access to a university hospital in which the consultants you see are actively engaged in groundbreaking research. 

Even the research sometimes moves slowly. Recognition of non-alcoholic fatty liver disease (NALFD) as a major health problem is new compared to recognition of alcoholic fatty liver for example.

Although recognition of the involvement of the pancreas in diabetes is a nearly century old discovery (1), getting a detailed look at the pancreas in a living person is something we've only recently developed methods for (2,3).

So another key reason for ectopic fat being a ‘new’ topic is the difficulty in measuring it.

Although relatively cheap readily available ultrasound technology gives some indication of liver fat, accurate measurements are really only achieved with magnetic resonance imaging and magnetic resonance spectroscopy (4).

The same is true for the pancreas, as the methods for a accurate assessment have only been developed very recently and also employ magnetic resonance technology (2,3).

Picture

Estimating ectopic fat

Most of us don’t have access to ultrasound let alone a magnetic resonance scanner, so we have to rely on things we do have more ready access to.

The easiest is a tape measure because there is usually a moderate relationship between waist circumference and visceral fat (5-7).

Being visibly lean with a flat stomach is obviously a pretty good indicator that visceral fat is low. On the other hand, having a bit of a paunch may not be due to a lot of visceral fat if you have a tendency to be bloated.

Liver and pancreas fat is another matter, although there is some correlation when looking at groups of people, this is unreliable in individuals.

There are also a few routine blood tests that are sometimes used to diagnose fatty liver, namely alanine aminotransferase (ALT), aspartate aminotransferase (AST), and sometimes gamma-glutamyl transferase (GGT), but these mostly indicate general liver injury (8), and are not very good at predicting fatty liver specifically (9-18).

The best way of knowing we don’t have a problem with ectopic fat is not having any signs of insulin resistance, glucose intolerance, or systemic inflammation. That means measures such as fasting insulin, fasting glucose, high-sensitivity C-reactive protein, and the oral glucose tolerance test described earlier in this blog here. 

Age is another factor. As we get older, we tend to shift fat into areas where it is more harmful (19). Luckily things don’t have to go this way as these MRI scans of the three peoples' thighs show. 

Picture

You can see from these images that exercise helps to maintain both muscle mass and prevent excessive intermuscular (between muscle) and intramuscular (within muscle) fat (20).


Is there a fat threshold

As mentioned in Part 1, there are those who are obese but have a relatively healthy metabolism (19,21-23), this remains the case even when more accurate measures for body fat than body mass index (BMI) are used to define obesity (24,25).

On the other hand there are people who have a BMI that places them in the normal or just overweight category yet have type 2 diabetes (26). I’m no fan of the BMI, but it is the most commonly reported measure that’s relevant here, and it's also something it only takes scales, a tape measure, and a chart or calculator to work out.

Read the scientific literature from a few decades ago and the association between obesity and type 2 diabetes wasn’t obvious; in fact body mass index wasn’t even found to correlate closely with the development of type 2 diabetes (27).

One large study tracking the development of newly diagnosed type 2 diabetes during the years of 1977 to 1991 showed that 36% of people, so about one in three, were diagnosed at a BMI of less than 25 kg/m2, or what is considered normal weight (26).

Of course type 2 diabetes and obesity were both far less common back in the 1970s and 1980s. Both have become more common over the last decades (28), and this has lead many to conclude there is a causal link.

The nature of that link is where the disagreement starts: does diabetes, or rather ‘pre-diabetes’ make people more prone to putting on excess fat, or does excess fat make people more prone to developing type 2 diabetes?

This is one of those chicken and egg arguments that get people riled up for no good reason. We’ve already discussed that ectopic and visceral fat are bad news for insulin sensitivity (see part 1). The rest I’ll leave for another post, or simply watch my online talks on insulin resistance here.

Beyond the potentially complex and varied beginnings of the road to type 2 diabetes, is the fat threshold hypothesis (26), which basically suggests we each have a certain amount of fat our body can store with no ill-effect, and that when we go above this, we begin to store excess fat in the wrong places discussed last week.

This concept is based on several observations:

1. Insulin resistance in people without type 2 diabetes is lower than insulin resistance in people with type 2 diabetes, and this is consistent among both those classified as obese and those not (29). Also, there is little difference in insulin resistance between obese and non-obese people with type 2 diabetes.

2. Some people with normal BMI can get type 2 diabetes (21,26).

3. Weight reduction in those with type 2 diabetes who are non-obese is as effective at inducing reversal of the condition as weight reduction in those who are classified as obese (30,31). Reversal of type 2 diabetes tended to require greater weight reduction among the obese than the non-obese (26).

4. Being obese but metabolically healthy to begin with is associated with a similar risk of type 2 diabetes in the future as being metabolically unhealthy but normal weight, but more than being metabolically healthy and normal weight (21).

5. Where fat is accumulated, so subcutaneous vs. visceral and ectopic differs in those who  go on to develop type 2 diabetes and those who don’t (19,32).

6. Even those considered metabolically healthy but obese sometimes improve insulin sensitivity with lifestyle changes that reduce abdominal fat (33,34).

This hypothesis also offers up an explanation why very low calorie diets (see here), with or without bariatric surgery aren’t always successful, and the effects don’t necessarily last – some of the volunteers simply aren’t dropping or staying below their personal fat threshold.

Physical activity and physical fitness are two potentially major modifiers for this relationship. Being more active and fitter reduces the risk of type 2 diabetes and a host of related conditions even when there is a lot of excess fat (35). 

That may well be because the fat is less likely to be visceral or ectopic. I’ll do a series on this in my MOVE blog.

I’d be irresponsible to not note that for many who begin as obese but metabolically healthy, this period of metabolic health only lasts a while before problems begin (32,36-38).


Take homes

Where we store fat matters to our health, so it’s worth focusing on approaches shown to reduce visceral and ectopic fat.

Not everyone who is obese has metabolic problems, but the health outlook for the vast majority of people who would be classified as obese would be improved if they became leaner.

That said, restoring metabolism or maintaining healthy metabolism is the goal for health before above and beyond weight reduction.

Finally, as we get older, the any protection we have from the ill-effects of excess fat goes down, and this trend needs to be actively countered, especially with physical activity/exercise.

In the next and final instalment of this series we’ll delve into the importance of the type of fat and its metabolism. That won’t be for a while though. Next week we finish looking at very low calorie diets; specifically their effects on inflammation, blood pressure, and heart health.

References: click here for a full list of references.

To learn more about type 2 diabetes and what you can do to better manage, and often reverse it, watch my free video education series. If you want one-on-one help dealing with your type 2 diabetes, contact me here to book a consultation.
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Is type 2 diabetes all about the fat? Part 1

7/7/2015

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Yes, type 2 diabetes may well be all about the fat. I’m not talking about fat in the diet, which has born the brunt of the blame, sometimes undeservedly. I am talking about fat in our body, especially the fat you don’t see.

A bit of jargon: in everyday language we tend to call the solid form of fat fat and the liquid form oil. These are both based on room temperature conditions. In the body we tend to use the collective term lipid to refer to both fat and oil.

Doctors most commonly use the term lipid when talking about blood lipid profile, e.g. triglycerides and cholesterol. But lipids are spread throughout the body and essential to life.

Lipids make up the membrane around our cells, so not a single cell is fat free. Also, most cells can use fat as fuel, so it’s normal to have some fat in our cells and therefore pretty much throughout our body.

That should already make it clear that lipids are part of our very structure. Lipids also form key parts of the communication systems of our bodies. 

Our cells use specific lipids to communicate with each other, for example a group of molecules called eicosanoids are made from specific fats and help regulate inflammation.

Cholesterol, yet another lipid, is needed to make steroid hormones such as cortisol, oestrogen, and testosterone. Although that's not all it's needed for.

So lipids are part of our structure and a means of communication in the body. What we probably think of though when we think of fat is energy. 

Whereas we can only store a few hundred grams of carbohydrate, and don't really store protein at all, we can store many kilograms of fat.

Where and how we store this fat plays a big part in determining our health prospects.


Where's the fat?

While carbohydrates are stored predominantly as muscle and liver glycogen, we actually have specialised cells to store fat. These cells are called adipocytes. Clusters of adipocytes are often referred to as adipose tissue.

We tend to divide adipose tissue into two pools. We call the most visible fat, the fat under the skin, subcutaneous fat. And we call the fat around the organs visceral fat.

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Lastly we have fat inside our organs, sometimes referred to as ectopic fat (ectopic meaning it doesn't belong). 

It's normal to have some fat in our cells for the purposes described above, but we don't normally see the kind of distinct droplets you see in the adipocytes in other cells.

However, in conditions like fatty liver (1), fatty heart (2), and fatty pancreas (3), cell types other than adipocytes begin to store excess fat. Excess fat in our muscles can also be a problem (4).

In the case of the liver we call these cells hepatocytes. You can see white droplets of fat in the hepatocytes of someone with fatty liver below. Healthy livers don't have this salami-like look!

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Why do we care?

Fat isn't all created equal when it comes to health. Subcutaneous fat, although it gets the most discrimination in the media and real life isn't the big problem, at least not for our metabolism.

You’ve probably heard that ‘belly fat’ is more detrimental than general subcutaneous fat. The research confirms this by clearly showing close associations between visceral, and to some extent abdominal subcutaneous fat, with cardiovascular and metabolic (e.g. diabetes) health (5-12).

Beyond where the adipose tissue is, it can itself be more or less healthy (7). Good quality adipose tissue has the capacity to expand and store surplus fat.

When fat storage in subcutaneous fat is impaired for some reason, any excess fat gets shunted to the visceral adipose tissue or into the organs.

The problem is we can't see when this is happening because this 'ectopic' fat doesn't necessarily reflect the visible fat we can see or measure. Consider the two livers below. 


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Both these people have similar a similar proportion of fat in their livers (10-12%) as measured by magnetic resonance spectroscopy – a very good way to measure liver fat (13). However, they differ greatly in their body fat and the amount of visceral fat.

Liver fat of greater than 3-5%, depending on the method of assessment, is considered excessive (14-16), so both these people qualified as having non-alcoholic fatty liver. 

Visceral fat often gives a good indication of liver fat such that when visceral fat is high, so is liver fat and liver insulin resistance (9).

That said, the problems of visceral fat and liver fat don’t always go hand-in-hand (17). In other words, fatty liver on its own is a problem.


The problem of excess liver fat

The most common type of fatty liver these days is non-alcoholic fatty liver disease or ‘NAFLD’ (18), which is exactly what it sounds like – fatty liver in people with moderate-to-no alcohol consumptions. Another major type of fatty liver is alcoholic fatty liver (19). 

Fatty liver can cause a number of liver conditions, but because the liver is so central to how our body deals with lipids, carbohydrates, and most everything else we ingest or otherwise absorb, the effects of impaired liver health can often be seen throughout the body.

The liver specific problems include progression to inflammation and fibrosis (scaring) called steatohepatitis, most commonly non-alcoholic steatohepatitis or ‘NASH’ (20). In some cases this can then lead onto liver cirrhosis and/or liver cancer, specifically hepatocellular carcinoma (21,22).

The liver is heavily involved in dealing with drugs, medication and otherwise, and its ability to do so is changes when it becomes fatty (23-26).

The most likely follow-on to NAFLD is cardiovascular (i.e. heart and blood vessel) disease (20). This is followed by various non-liver cancers (27-29), with the clearest association being to colon cancer (30-33).

Given that this blog has talked quite a bit about the importance of the liver in glucose regulation, it should come as no surprise that fatty liver is often associated with type 2 diabetes and the ‘prediabetic’ conditions of metabolic syndrome, impaired fasting glucose, and impaired glucose tolerance (20).

Lastly, liver fat seems to predict kidney disease even when we try to take the influence of diabetes out of the equation (literally as we use statistical methods to do this) (34-38).

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Of course just because there is an association between one thing and another, e.g. liver fat and diabetes, doesn’t mean one thing causes another. That said, if you read part 3 of the series on very low calorie diets for reversing type 2 diabetes you’ll see that reduction in liver fat corresponds to improvements in liver insulin resistance and glucose control.

These findings, and experimental work suggest that excess liver fat does have a cause and effect relationship, at least with the mechanisms underlying type 2 diabetes.


Fat and the pancreas

If you’ve been following this blog, you’ll know that the pancreas also gets fatty as well as shrinking and changing shape in type 2 diabetes (3,39-41). 

Reduction of pancreatic fat occurs with weight reduction and closely mirrors improvements in beta-cell (the cells that produce insulin) function (3,39,42).

So in the pancreas too we see excess fat leading to impaired function, and reductions in intra-organ (within-organ) fat leading to improved function.


Fat muscle

Fat and muscle might seem mutually exclusive until you think of a well marbled steak, or you look at the image below depicting two thighs. The one on the left is lean, the one on the right fatty, much like that well marbled steak.

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High intramuscular fat, i.e. fat within the muscle, is associated with muscle insulin resistance (4). 

That’s bad news when you consider that normally our blood stream is intended to only carry about a teaspoon of glucose, our liver is good for 100 g or so, but our muscles can take up a few hundred grams (43). 

The exact amounts depend on how much blood, how big a liver, and how much muscle, but you can see there’s going to be a problem if the organ with the biggest capacity gets taken out of the picture.

What should happen after a carbohydrate containing meal is that a good proportion of that carbohydrate should be shuttled into our muscles. This doesn’t happen in type 2 diabetes, at least not while we’re sedentary, so the liver has to deal with the resulting glucose, and what it doesn’t deal with spills over into the blood and other tissue (44).

Here it’s not just a case of where the fat is, but why it’s there. Athletes also tend to have higher intramuscular fat, but exercise itself sensitises muscle to insulin (45). Will look at this in more detail in future posts.


Is there a fat threshold?

The question is why, when we clearly have the capacity to store fat in relatively safe subcutaneous adipose tissue, does it end up around and inside our organs?

We have several specific and highly detailed explanations involving endless acronyms that are hard to pronounce and stand for names that are even harder to pronounce. However, one elegant high level explanation is that we have a fat threshold.

In other words, we have a certain set capacity, that if exceeded leads us to store fat in the wrong places and in the wrong way. 

A fat threshold elegantly explains why some people can have a very high body fat and yet have a relatively normal metabolism, and another person can be relatively lean and have the problems we commonly associate with obesity, including type 2 diabetes (46). 

Have another look at the earlier image of the relatively lean man (20% body fat) with a similarly fatty liver to a  woman with a body fat percentage of 45%, to see a real-world example.

So to recap. Fat under the skin isn’t the main problem, fat surrounding the organs, and excess fat within the cells of organs is the big problem. These types of fat aren’t always very closely linked, so what you can see won’t necessarily tell you about what you can’t see.

In part 2, we’ll explore how ectopic fat is measured, and how you can get an idea if it’s a problem without expensive scans. Most importantly, we’ll explore the concept of the fat thresh-hold and how understanding some of the reasoning behind it can help you focus on actions that will reverse the problem.

Click here to read part 2.

References: click here for a full list of references

To learn more about type 2 diabetes and what you can do to better manage, and often reverse it, watch my free video education series. If you want one-on-one help dealing with your type 2 diabetes, contact me here to book a consultation.
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Very Low Calorie Diets & Type 2 Diabetes Reversal Part 4: Glucose Tolerance

28/6/2015

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The story so far is that very low calorie diets can reverse type 2 diabetes, and even when they don’’t go that far, they can bring about rapid – within days – improvements in fasting glucose, insulin, liver and pancreas function, and thereby big reductions in the need for medication.

To learn more about all that, including the actual diets, check out earlier parts to this series:

Click to read Can Type 2 Diabetes be Reversed
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part 1: Blood Glucose
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part 2: Insulin
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part 3: The Liver & Pancreas

Now that you’re caught up, or if you’ve been part of this journey all along, welcome back.

It’s great to know that very low calorie diets can bring fasting glucose down, and that it helps with insulin. Then again, you would expect eating less would make the job of dealing with what we eat easier on our bodies.

So what you really want to know is what happens after the diet. What would happen with a normal meal? There are a few main ways of testing this:

  1. Oral glucose tolerance;
  2. Intravenous glucose tolerance test; and
  3. Mixed meal test


Oral Glucose Tolerance Test

The oral glucose tolerance test is exactly that, you get given a glucose drink (the oral and glucose part of the name), and your blood glucose is measured before and after (the tolerance part). 

Tests are done after an overnight fast. Blood glucose is measured to give a fasting blood glucose. The dose of glucose is commonly 75 g, but can sometimes be 50 g or 100 g. This has to be drunk within a 5 minute window.

The oral glucose tolerance test is used both in clinical practice to diagnose type 2 diabetes, and in research. The difference tends to be how often blood glucose is measured.

To diagnose type 2 diabetes, all that’s needed is a fasting blood glucose, and a blood glucose 2 hours after the glucose drink. In research you’ll often see blood glucose being measured at several time points throughout the 2 hours and sometimes after the two hours.

You may also see other things measured in the research setting, e.g. insulin response. Some examples of results for different levels of glucose tolerance are shown below.

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You can see from the graph that the ‘normal’ glucose tolerant person experiences a more modest rise in blood glucose than the person who has impaired glucose tolerance, or type 2 diabetes.

With insulin the picture is different. The normal insulin sensitive person has an intermediate rise in insulin, and this is enough to get the job done. 

The person with type 2 diabetes can’t produce enough insulin anymore. While the person with impaired glucose tolerance is topping the chart with insulin production. They can still produce quite a bit, but not fast enough to control blood glucose well.

There are also people with type 2 diabetes whose blood glucose is still going up after two hours, and who produce less insulin. But these graphs give you some idea of the differences in response.


Intravenous Glucose Tolerance

The intravenous glucose tolerance test is similar to the oral glucose tolerance test described above, but the glucose is injected into a vein (1-3).

The intravenous glucose tolerance test has its uses, but is somewhat artificial in that is avoids all the processes that happen with actually eating, so it doesn’t reflect a person’s response to food as well as the oral glucose tolerance test.

This test also isn’t used for diagnosis of type 2 diabetes. The information from this type of test informed part 3, so I won’t repeat it here.


Mixed Meal Test

Mixed meal tests arguably mimic real life more closely than either the oral or intravenous glucose tolerance test. Although the ‘meal’ in question often isn’t what most people would eat, often being some form of meal replacement drink (4,5).


What Happens to Glucose Tolerance After Very Low Calorie Diets?

I’ll use the name of the first author when discussing specific studies so that you can find the details of that study in the tables in previous parts in case you want more details about a given study (mostly Table 1). Unfortunately not many studies assessed glucose tolerance in a way that is accessible to most people. 

Laferrére and colleagues (2008) did a three hour oral glucose tolerance test with 50 g of glucose (3). Two-hour glucose improved from 10.2 mmol/L to 9.6 mmol/L, which is fairly modest given that this wasn’t the typical 75 g glucose load used to diagnose the condition. Worth knowing is that the people in this study were still in the morbidly obese category (average BMI 43.3 reduced to 39.6).

Lingvay and colleagues (2013) used a mixed meal test, so again, you can’t compare it to the classic 75 g oral glucose tolerance test used for diagnosis (5). The graph below tells the story best.

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I had to modify the graph slightly but apologise if it's still somewhat confusing. The squares show the average blood glucose and the bars coming out of the squares show the variation – some volunteer's results were higher and some lower. What is clear though is that glucose response to the meal went down after the diet.

The study by Lim and colleagues (2011) did a two-hour oral glucose tolerance test, but not until 12 weeks after people finished with the very low calorie diets, and after an average 3.1 kg (6.8 lbs) weight regain (6). Average fasting glucose was 6.1 mmol/L and 2 hour glucose 10.3 mmol/L, so volunteers were back at the high end of impaired glucose tolerance, at least on average. 


How Long Does it all Last?

You stay fit/strong as long as you keep up the training that got you there. In fact it usually takes less effort to maintain a change than to make it in the first place. That same rule applies here. 

Those few studies that reassessed their volunteers weeks or even months after the end of the diet send a mixed message. 

Jonker and colleagues (2014) reassessed their volunteers 18 months after the diet (7). On the downside, weight, HbA1c, and fasting glucose, all went back up. On the upside they were still lower than before the diet, just not as low as immediately after it. 

It’s interesting that the same study described in the paper by Snel and colleagues (2012) showed that along with the weight regain, liver fat and visceral fat also came back up after 18 months, although not as high as before the diet (8). You may remember from part 3 that liver response to insulin improved as liver fat went down.

This study also looked at many aspects of heart health and function, some of which remained improved at 18 months (7). The problem here is that volunteers ‘were reintroduced to a regular diet’ with no description of what that was.

A study by Jazet and colleagues (2007) had a more long-term focus in that insulin dependent volunteers were first put on a 30 day very low calorie diet (9). 

Then volunteers were advised to slowly transition from having exclusively meal replacement drinks to having meals introduced at 1 meal (an extra 200 kcal/day) every 2-4 weeks (9). Their energy requirements were calculated and they were informed of these, but the volunteers were free to eat how they wanted, and saw their doctor every three months.

The results of this approach were a slightly lower (average) weight and therefore BMI at 18 months than immediately after the very low calorie diet (9).  Unsurprisingly under the circumstances, improvements in fasting blood glucose and HbA1c were maintained for the full 18 months. Again these were the average result. Some volunteers regained weight and had to go back on insulin and/or other diabetes medication.

Of course there’s no reason why a very low calorie diet can only be done once. One study looked at two 12 week rounds of a very low calorie diet (400-500 kcal/day) separated by 12 weeks of a low calorie diet (1000-1200 kcal/day), and followed by another 12 weeks of low calorie diet (10).

The intermittent very low calorie diet group was compared to a low calorie diet group who were prescribed 1000-1200 kcal/day for the whole 48 weeks (10). Some key results are shown in the graphs below.  
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What the graphs show is that the very low calorie diet (VLCD) dropped the weight more than the low calorie diet (LCD) (10). You can see from the first and second graph that the first 12 weeks (3 months) made the biggest difference to both weight and glucose control reflected in HbA1c. 

What you’ll also notice in the third graph is that greater weight reduction resulted in greater improvement in HbA1c (10).

What the published results can’t tell us is if the volunteers who stayed in the study, and not everyone did, actually followed the diet. The fact that weight and HbA1c went up toward the end, suggests that either discipline wavered – I know mine would – or that the volunteers energy requirements dipped below the 1000-1200 kcal/day they were consuming.

The longest running study assessed people five years after a very low calorie diet lasting six or more weeks as chosen by the volunteers (11). After the diet, volunteers were advised to eat a low fat, low refined carbohydrate diet; whether they did is unclear.

After five years this group were roughly where they started in terms of glucose, and weight and therefore BMI (11). The group that got intensive lifestyle counselling didn’t see any major improvements in the first year, but was better off at five years.

Interestingly, many people who reported following a very low calorie diet on their own (outside of research) also reported being diabetes free for longer than the volunteers in the studies discussed above (12). We don’t know how, or how long, because they aren’t being formally monitored.

These somewhat disappointing results demonstrate what the very first blog discussed – to think in terms of a ‘cure’ for type 2 diabetes is to ignore that type 2 diabetes is a miss-adaptation to environmental factors. 

By that I mean the environment that the liver, pancreas, muscles, and other organs find themselves in, e.g. in terms of food and toxins. Change that environment sufficiently, and the symptoms will go away. But if it changes back sufficiently, the symptoms will reappear.

Bare in mind that most of these studies didn’t set out to teach volunteers the skills they would need to maintain their improvements. 

In fact, I’d argue none of them did, because most researchers still held/hold to the idea that everyone, including those with type 2 diabetes, should eat a high carbohydrate low fat diet, when this really doesn’t make a lot of sense in a World where insulin resistance and glucose intolerance is fast becoming the norm (13,14).

Next week we’re taking a break from this series to look more closely at the importance of excess liver and pancreas fat to type 2 diabetes and address questions like why some people who aren’t obese get symptoms and some who are very obese don’t. We also begin to look beyond very low calorie diets for reversing type 2 diabetes. 

Click here to read part 5.

References: click here for a full list of references

To learn more about type 2 diabetes and what you can do to better manage, and often reverse it, watch my free video education series. If you want one-on-one help dealing with your type 2 diabetes, contact me here to book a consultation.
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Very Low Calorie Diets & Type 2 Diabetes Reversal Part 3: The Liver & Pancreas

27/6/2015

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We’ve been talking about very low calorie diets in type 2 diabetes for a couple of weeks now. If you haven’t already, check out the links below to get up to speed and get the crucial context for what follows:

Click to read Can Type 2 Diabetes be Reversed
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part 1: Blood Glucose
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part  2: Insulin

To quickly recap, very low calorie diets, generally 300-1000 kcal/day, can cause dramatic improvements in blood glucose, insulin sensitivity, and insulin production.

That may be good enough for you to give it a go, but actually understanding what's going on will give you more options to achieve your health goals. So let’s look a little closer at type 2 diabetes generally and the effects of very low calorie diets specifically.


Your Liver as Your Blood Glucose Regulator

The liver is a key player in blood glucose regulation because it can store, make, convert, and release glucose. In other words, it can take up excess glucose from the blood to bring blood glucose down, or release glucose into the blood to bring the glucose concentration up. 

The liver is pretty special in that it can do a number of things with regards to glucose (1):
  • It can convert fructose and galactose into glucose. 

  • It can convert certain components of proteins and fats, as well as lactate and some other things into glucose in a process called gluconeogenesis (gluco for glucose, neo for new, and genesis for making).

  • The liver can store the glucose, whether it came from the diet as glucose, was made from the conversion of fructose or galactose, or made via gluconeogenesis. The storage form of glucose is glycogen (think animal version of starch). The process is called glycogenesis (glyco for glycogen and genesis for making). 

  • The liver can also break down the stored glycogen back to glucose in a process called glycogenolysis (glyco for glycogen and lysis for breaking up).

  • The liver can convert excess glucose into fat by a process called de novo lipogenesis (lipid is the collective term for fats and oils, and de novo implies new).

Hopefully you’re getting the picture that these things work in overlapping cycles, much of it isn’t a one way street. Below you can see a very simplified diagram of what’s going on.
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In a large part these processes in the liver are directed by insulin (made by the beta-cells of your pancreas), and glucagon (made by the alpha-cells of your pancreas) (1). 

Insulin, providing the liver responds normally to it, tells the liver to store glucose by converting it to glycogen; that’s as opposed to releasing glucose into the blood (2). 

At the same time, insulin tells the liver to reduce gluconeogenesis and glycogenolysis (1). Insulin also tells the liver to increase conversion of glucose to fat via de novo lipogenesis (3-5).

Glucagon, again assuming a normal response, tells the liver to release glucose, which we’ve now seen can come from a breakdown of glycogen via glycogenolysis (6). Contrary to what you may read elsewhere, the effect of glucagon on gluconeogenesis isn’t so clear cut (7), but that probably doesn’t matter to you.

Insulin and glucagon are always floating around in our blood streams, but the ratio changes. It’s not so much an on/off switch, as it is like a set of dials on your stereo to adjust left/right balance and base/treble output.

If this is new to you, I know the terms can be a little confusing at first. When you learn them, you’ll be better able to understand your condition, and better at spotting poor advice, so hang in there.


The Insulin Resistant Liver

One of the organs that can become insulin resistant is the liver, especially when it starts to store excess fat (8-10). 

This insulin resistance is somewhat selective in that not all messages from insulin are ignored equally. Basically, the insulin resistant liver doesn’t respond to insulin’s message to store glucose, instead the liver keeps releasing glucose when it should be holding onto it (11). 

Another problem is that the liver does respond to the signal to convert glucose to fat, above we called that de novo lipogenesis. Normally we only see any serious de novo lipogenesis going on for a few hours after a carbohydrate containing meal (12). 

In people with type 2 diabetes, metabolic syndrome, and in people with the closely related condition non-alcoholic fatty liver disease, de novo lipogenesis is switched on 24/7 (4,13-16).

Some of this is likely also not helped by glucagon being chronically high (17). Recent research shows that metformin, the most commonly used diabetes medication, actually works to counter the effects of glucagon (18).

For more on this, check out my video series on reversing type 2 diabetes here.

The Pancreas in Type 2 Diabetes

If insulin resistance is one side of the type 2 diabetes coin, insulin under-production is the other. 

Although people with type 2 diabetes often have chronically high blood insulin concentrations, research shows us that the peak capacity for insulin production by the pancreas often starts to decline well before the problem is bad enough to result in a diagnosis of diabetes (19-21).

It’s the beta-cells of the pancreas that produce insulin, so we talk about this reduced capacity as a loss of beta-cell function. That loss of function is on average 50% by the time type 2 diabetes is diagnosed (19). This decline usually continues despite medication (22). 

Recent work shows that the pancreases of people with type 2 diabetes don’t just loose function, but also shrink, change shape, and become fatty (23-26). Bare that in mind when we look at what happens to the pancreas after a very low calorie diet.


What happens to the liver during a very low calorie diet in someone with type 2 diabetes?

The wording of this question is important, because not everyone’s liver will respond the same way to calorie restriction. This caused a lot of concern in the past as it was known that starvation made the liver store more fat (27). In a liver that already has excess fat stores, like we see in type 2 diabetes and other conditions, things work a little differently as we’re about to see.

Only a few studies discussed in part 1 and part 2 have looked at the liver specifically, but the results are striking. The findings of Lim and colleagues are summarised nicely in the graphs below (23).

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Basically what these graphs show is a rapid – within one week – reduction in blood glucose (graph a), an equally rapid reduction in glucose release by the liver (graph b), and a more gradual reduction in liver fat (graph c).

Another study showed this reduction in glucose release from the liver was already substantial after just two days of a very low calorie diet (28). This was despite stopping volunteers’ medication.

These and other studies show that the liver rapidly becomes more insulin sensitive, and explains a lot of the rapid reduction in fasting glucose we discussed in part 1 (23,28,29).

Another study reported a liver fat reduction from 21% to 3% after 16 weeks of very low calorie diet (30). Similar diets also reduce liver fat in obese non-diabetic volunteers (31). Liver fat reduction is therefore a goal when it comes to reversing type 2 diabetes.


What happens to the pancreas during a very low calorie diet in someone with type 2 diabetes?

In part 2 of this series we saw that estimates of beta-cell function improved with very low calorie diets. More direct measures improve too, so we can conclude that the pancreas can, given the right circumstances, recover even in people on insulin (23,25).

Also, much as with the liver, the excess fat in the pancreas goes down (23,25). As fat goes down, function goes up. By function, I mean that the pancreas regains its responsiveness to rising blood glucose, and becomes more capable of releasing insulin (23,32).

This process in the pancreas is slower though, probably because the pancreas, unlike the liver, isn’t well equipped to shift fat.


What about glucagon?

One study that provided 1000 kcal/day for an average 10 kg weight reduction over an average of 8 weeks found glucagon reductions across the board (33). By that I mean fasting, peak, and during an oral glucose tolerance test. The other studies didn’t look specifically at glucagon.


Take home message

Very low calorie diets reduce fat in the liver and in the pancreas. The result is that the liver becomes more responsive to insulin, and the pancreas recovers in terms of both insulin production and appropriate response to glucose.


Warning!

I said it in an earlier blog, but this bares repeating – if you are planning on trying to reverse your type 2 diabetes, partly or fully, with diet and/or exercise, let your medical care team know so they can monitor you and adjust your medication to keep you safe.

That brings us to the end of part 3. In part 4 we’ll look at how all the changes discussed so far actually translate into glucose tolerance, in other words, how the body copes with carbohydrates. 

This is really the big question because it’s all fine and good for things to look great while on a low calorie diet, but you can’t keep it up forever, so what matters is what happens afterwards.

Click here to read part 4.

References: click here for a full list of references

To learn more about type 2 diabetes and what you can do to better manage, and often reverse it, watch my free video education series. If you want one-on-one help dealing with your type 2 diabetes, contact me here to book a consultation.
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Very Low Calorie Diets & Type 2 Diabetes Reversal Part 2: Insulin

17/6/2015

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In the last blog article we began to explore the research into very low calorie diets and the reversal of type 2 diabetes. You’ll need to have read the previous posts to give this one the right context:

Click to read Can Type 2 Diabetes be Reversed
Click to read Very Low Calorie Diets & Type 2 Diabetes Reversal Part 1: Blood Glucose

I’d also recommend opening Table 1 and Table 2 from last week's post, as I’m not going to repeat those study details (1-21).

Now that you’re up to be speed with what happens to fasting glucose, HbA1c, and body weight with very low calorie diets, let’s look under the hood and see what's going on in terms of insulin resistance. 


What happens to insulin and insulin resistance on very low calorie diets?

Type 2 diabetes is defined by two key problems:

  1. the body, presumably your body if you’re reading this, is resistant to the signals from insulin (watch the videos here to learn more about this); and 
  2. the pancreas has lost some or even much of it’s capacity to produce insulin.

Early in the progression of type 2 diabetes, problem one is more prominent. The body responds by keeping insulin high. When the pancreas becomes impaired, insulin therapy is the treatment of choice in most guidelines. So as you look at the fasting insulin results in Table 3, keep that in mind.

What you might see from the table is that fasting insulin is really all over the place. Partly this is because some people were on insulin therapy, and others weren’t. For the most part, very low calorie diets led to clear and substantial reduction in fasting insulin. 

In the last post we saw that very low calorie diets reduced fasting blood glucose. What these two results tell us, is that after a very low calorie diet, the bodies’ of people with type 2 diabetes need less insulin to control their blood glucose.

Two things in our diet can have a big effect on insulin – carbohydrates and proteins (22-26). Given that both are likely to be lower in a very low calorie diet than someone’s normal diet, seeing lower insulin may come as no surprise, but remember these are fasting values, the volunteers hadn’t eaten for 10-12 hours before the blood samples were taken.

Fasting insulin isn’t a great measure by itself because it doesn’t tell us much about what’s going on. What we want is some indicator that looks at the both the amount of insulin and how well that insulin is doing its job. There some very involved procedures that can tell us in detail what’s happening where, but let’s start with the simpler options more commonly used.

A common way to gauge insulin resistance is called the Homeostasis Model Assessment or simply HOMA. This takes into account both blood glucose and blood insulin. There are newer and older versions (27). The newer version – HOMA2 – is more accurate, so I’ve calculated that where possible.

You can see the change in HOMA2 following very low calorie diets by clicking Table 4. You’ll see there are three results when calculating HOMA2:

  1. HOMA2-IR, which refers to insulin resistance. The bigger the number the worse the resistance. 
  2. HOMA2-%B, which reflects how well the β-cells of the pancreas (the cells that make, store, and release insulin) are working. A higher number is better.
  3. HOMA2-%S, which tells us how insulin sensitive a person is. The higher the number, the better.

Despite HOMA2 not being the best method for assessing these things and some uncertainties about the use of medication in different studies, the picture that the results draw is one of reduced insulin resistance/improved insulin sensitivity, and improved β-cell function.

So to recap what we now know – very low calorie diets reduce fasting blood glucose and insulin resistance, and improve how well the pancreas functions. That’s exactly what we want when trying to reverse type 2 diabetes.

Next week we stay with the very low calorie diets by looking at what better more direct methods tell us is happening with the liver and pancreas. The liver is as central to glucose regulation as the pancreas, and plays a big role in type 2 diabetes, so stay tuned.

Click here to read part 3.

References: click here for a full list of references.

To learn more about type 2 diabetes and what you can do to better manage, and often reverse it, watch my free video education series. If you want one-on-one help dealing with your type 2 diabetes, contact me here to book a consultation.
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Very Low Calorie Diets & Type 2 Diabetes Reversal Part 1: Blood Glucose

9/6/2015

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In the last post we answered the question can type 2 diabetes be reversed with a confident yes in many people. For a copy of that article, click here.

We also acknowledged that the two most studied methods for turning back the metabolic clock on type 2 diabetes were bariatric surgery, and very low calorie diets. These are similar in that both involve a period of eating very little, but of course surgery involves an invasive procedure and in many cases irreversible or hard to reverse physical changes.

As I’m a nutritionist and clinical exercise physiologist and not a surgeon or medical doctor by training, I’ll leave the discussion of bariatric surgery behind and focus on what can be done without an operating theatre.

So this week we’ll start to look at very low calorie diets, what they are, what they do in terms of helping to improve and sometimes reverse type 2 diabetes, and how we think they work. As it’s a big topic, this will become a little miniseries of posts over the next few weeks.


What is a very low calorie diet?

There is no absolute definition for a very low calorie diet, so for practical purposes I’m going to say it’s between 300-1000 kcal/day. Most of the studies discussed below used liquid meal replacements to ensure adequate amounts of essential nutrients.


The Studies

The truth is that very low calorie diets in type 2 diabetes are nothing new. So called ‘starvation diets’ were being used to treat people with diabetes at least as far back as 1915 before the discovery of insulin (1). 

In this article we’ll look at most (I couldn’t get every paper) of the more recent work (2-21). For those of you interested in specific details about individual studies such as how many people were included, their age and body mass index (BMI), diabetes duration and treatment, and specific diet, click here for Table 1 in pdf format.

All the studies I discuss below enrolled people diagnosed with type 2 diabetes, and in general they confirmed this diagnosis as part of the study. 

If you look at the table 1, you’ll notice that most of the studies had fewer than 20 people. This counts as a pretty small number, but that’s because this kind of study is expensive and time consuming to run. The more closely people are monitored and the more involved the methods used, the more expensive a study is.

Looking at the table, you might also notice that the volunteer groups in these studies varied quite a bit from study to study. Some studies looked at people with a recent diagnosis of type 2 diabetes on minimal or no medication, while other studies included people on insulin who had had diabetes for over a decade.

The BMIs also vary from mildly overweight to clearly obese even if you quibble about BMI as an indicator of body fat.

The studies also differ in duration from a few days to a few months. That’s why they also differ in weight change.



What effects did very low calorie diets have on blood glucose?

To see the results of individual studies, click here for Table 2 in pdf format. 

All the studies showed a clear reduction in fasting blood glucose, and/or HbA1c. What’s worth knowing is that these improvements often came despite volunteers being taken off insulin and/or diabetes medication.

Few studies showed a complete normalisation of fasting blood glucose. To put this in context though, most studies that involved a very low calorie diet for more than a week produced average fasting blood glucose results that were below the 7.9 mmol/L that many organisations consider diagnostic for type 2 diabetes. 

HbA1c also went down accordingly. As severe calorie restriction also reduces carbohydrates relative to normal recommended diets, this comes as no surprise.

From most doctors' perspectives, if they follow standard guidelines, many of the volunteers in these studies went back to just having impaired fasting glucose, or what some call prediabetes. Some also reversed their diabetes completely.

That’s a heartening result when you consider that some of these studies involved people who had relatively poorly controlled type 2 diabetes for many years. There was more to be undone than could be achieved in a few weeks or even months, but huge progress was made, and it's a shame the studies were limited by time or weight reduction targets.

Three studies reported having some or all of their participants doing exercise (6,8,19), but only one study included a diet only and diet + exercise group for direct comparison (8). 

Interestingly, people who also exercised lost more body fat in total and also a higher proportion of body fat than those just doing the very low calorie diet (8). That means they kept more of their lean mass, probably muscle, which we’ll see in future posts is a good thing. What isn’t clear from this study is how much exercise helped with glucose control.


What happens with very low calorie diets?

An obvious result of very low calorie diets is weight reduction (see table 2), and more importantly fat reduction. The interesting thing is that the benefits often kick in before there’s been a big weight change.

Take a look at the graphs below to see weight change and then change in fasting blood glucose over time in the few studies that measured these at multiple time points. Have a close look at the x-axis (along the bottom), you’ll see it is evenly spaced.

Graphs of Blood Glucose & Weight

What should stand out is that there are big changes in fasting glucose early on. In the study of the least severe type 2 diabetes, we see that most of the change happened in the first week (11). In fact, blood glucose came within the normal range within 7 days, although it continued to improve all the way out to 8 weeks when the diet was stopped. 

The study with the highest blood glucose at the start only lasted seven days, but we still see a rapid and drastic improvement in blood glucose despite volunteers being taken off metformin and/or having their insulin doses adjusted down (18).

The middle study in the orange and red lines compared lower and higher carbohydrate diets (19). I wouldn’t read too much into the small differences you see, because: 1) at 1000 kcal/day the study was higher in calories than most of these kinds of studies; 2) the carbohydrate content was above that of very low carbohydrate diets in both groups; 3) this was in a group of Japanese volunteers only in the overweight category, whereas most of other relevant studies were done in those well into the obese category.

All that said, we still see a nice rapid reduction in the first two weeks, followed by a slower reduction in the third and fourth week (19).

In the next blog post we’ll look more under the hood of these studies to see what might explain the findings, and what that might mean for you.

Warning!

This is all inspiring stuff, but these kind of diets need to be done with the help of an informed medical team. There’s a reason why many of the studies involved taking people off their medication and/or insulin. With too much medication, and how much is too much is an individual thing, there is a very real risk of blood glucose going dangerously low. 

These diets and the associated weight reduction can also lower blood pressure by a lot. We’ll discuss that in future posts. For now just be aware that some people also have to adjust their blood pressure medication to avoid dangerously low blood pressure.

I have a simple rule I wish everyone understood: natural or synthetic, diet, exercise, or medication – if it has an effect it can have side-effects.

Click here to read part 2.

References: click here for a full list of references.

To learn more about type 2 diabetes and what you can do to better manage, and often reverse it, watch my free video education series. If you want one-on-one help dealing with your type 2 diabetes, contact me here to book a consultation.
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Can Type 2 Diabetes be Reversed?

29/5/2015

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The short answer is YES, in many cases type 2 diabetes can be reversed. 

This whole article covers the longer answer, but first I’d like to say a few words about your diabetes care team, assuming you have one. These are likely to be intelligent, hard working, well educated men and women who care about you, and about their professional reputation. They are likely to follow national/professional guidelines, and have probably been taught that type 2 diabetes is chronic and progressive. That’s also what their experience with the majority of their patients has reinforced. 

They may or may not be immediately supportive of any attempts by you to reverse your type 2 diabetes. They are important to involve in the process as they allow you to keep an eye on how well anything you do is or isn’t working for you.

If you are on insulin or any other treatment that can lead to hypoglycaemia (excessively low blood glucose), you must proceed cautiously.

If you decide to take steps to reverse your diabetes by following this site, and/or working with me one-on-one, please print the copy of this report here, and take one to each of your immediate care team, e.g. your doctor, nurse, dietician etc. Please also get the go ahead from your doctor before taking up any vigorous exercise.


When is type 2 diabetes considered reversed or in remission? 

The short answer is that it’s when you no longer meet the criteria for type 2 diabetes as shown in the table below.
Picture
Different criteria for reversal or remission exist (1), and the studies cited in this article have used different criteria. For practical purposes, reversal or remission would mean normal fasting glucose and normal HbA1c. Stricter criteria have been used in some studies that measured insulin production and insulin resistance more directly, but such measurements are usually only done in studies and not widely available.


How can type 2 diabetes be reversed?

A few approaches to reverse type 2 diabetes have been documented in peer-reviewed studies. To date, the major focus has been on bariatric surgery which basically forces people to eat considerably less than they otherwise would (2-4).

Because of the relative success of gastric surgery, especially gastric bypass, many have speculated that it is something about the procedure that makes it so beneficial (5,6). However, studies have shown that very low calorie diets (400-800 kcal/day) on their own have similar effects in terms of both weight reduction and reversing type 2 diabetes when calorie reduction is similar to that immediately following bariatric surgery (7-12).

Less extreme diets, and diet and exercise combinations have also been studied (13-17). There is some research suggesting that it is carbohydrate reduction not exclusively calorie reduction that is responsible for the positive effects (18-20). Very low calorie diets are by their nature low carbohydrate in absolute terms (as opposed to percentage terms). More on that in future posts.


How quickly can type 2 diabetes be reversed?

Fasting, especially when this is continued past 24 hours can have a dramatic effect in terms of reducing blood glucose (21). Unsurprisingly then, the bulk of improvement in glucose control following calorie restriction with (22-24), and without bariatric surgery are commonly observed within a week (9,11,25).


Who can and who can’t reverse their type 2 diabetes?

There is no definitive answer. Duration and severity of diabetes in terms of drug and/or insulin treatment, as well as weight reduction following low calorie intake with and without bariatric surgery appear important (26-30).

In practical terms, it’s quicker and easier to reverse type 2 diabetes if you’ve been diagnosed more recently, and/or are on minimal or no medication, and not on insulin. This makes sense, the less damage there is to undo, the quicker and easier it is to undo it.


What are the benefits of reversing type 2 diabetes?

Everyone will have different reasons for wanting to try and reverse their diabetes, so the perceived benefits are also going to be individual. Eliminating the need for medication eliminates any related costs and side-effects, including hypoglycaemia, especially for those previously taking insulin. There is limited research showing what happens long-term after bariatric surgery, what there is shows that the risk of heart attacks goes down (31). The same would be expected for other diabetes related complications, but without large studies lasting decades, it’s not possible to say by what degree.

Improvements with lifestyle changes without surgery are likely to be even greater, although more difficult to sustain. The reason is that the more changes you make to improve your health, the more benefits you would expect. Surgery just forces people to eat smaller amounts, it doesn’t require people to eat a more health promoting diet, exercise regularly, or otherwise live a more health promoting life. 


Can reversal of type 2 diabetes be sustained?

The thing to understand is that if you do reverse your diabetes, you aren’t ‘cured’ (please see previous article). If the underlying drivers of diabetes return, so will the condition. Baring other conditions that affect the pancreas, diabetes remission is likely to last as long dietary, exercise, and other aspects of lifestyle support it. 

It comes down to the types and numbers of changes to how you live that you make, and how well they are or aren't supported by the people and environment around you.


If you can’t sustain reversal of type 2 diabetes indefinitely, are there benefits?

Even if type 2 diabetes eventually returns, you still get extra years of better health, quality of life and financial savings. There is even work showing that heart and related aspects of health stay improved for many months, maybe years following weight regain (31-34).


Conclusion

There is now substantial reputable evidence published in peer reviewed scientific journals that type 2 diabetes can be reversed in a large proportion of people. 

Reversal can be complete, in that normal insulin and glucose metabolism is restored without medication, or partial, which includes reduction to complete removal of medication and/or insulin therapy.

Reversal of type 2 diabetes has been achieved using different forms of bariatric surgery, very low calorie diets, and lifestyle related weight reduction.

Given this evidence, it is incorrect to describe type 2 diabetes as either irreversible or inevitably progressive. Even if reversal is not fully achieved or not sustained indefinitely, their is considerable benefit to aiming for reversal.

To learn more about type 2 diabetes and what you can do to better manage, and often reverse it, watch my free video education series. If you want one-on-one help dealing with your type 2 diabetes, contact me here to book a consultation.

References: click here for a full list of references cited.
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    Author - Dr Christian Thoma

    I'm a nutritionist (MSc) and certified clinical exercise physiologist (PhD & ACSM-CEP) who specialises in helping people with type 2 diabetes to optimally manage and, where possible, reverse their condition. Learn more about me under Diabetes Doctor.

    Articles are Referenced

    You'll see numbers in a smaller font and in brackets throughout many of the blogs. If you match that number to the reference provided at the end of each post, you'll be able to see where specific information comes from - usually individual scientific studies or well conducted summaries of studies published in the scientific literature. This is to: 1) show you I don't expect you to just believe me because of my qualifications; 2) you can verify what I say by reading the reference; and 3) you can see where you might get more information on a very specific topic.

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