Genetics and Type 2 Diabetes

Diabetes-with-family-history-prevalence-city-20592 When I first diagnosed with Type 2 Diabetes (TD2) I immediately started to research the scientific literature for any clear genetic explanation of this highly prevalent disease, but I was unable to find any clear link between a specific genetic loci and occurrence of the disease; although, there were several papers making such links they were far from proving any such link.  However, a recent article in Scientific American (October 2015, pp56-59) has suggested one possible explanation of the growth of TD2 and a genetic cause that predates the evolution of Homo Sapiens!  Reflecting on this article I can understand how I would not have come across this explanation as the research has always been linked to a different disorder – Gout, or the “disease of Kings”.

Gout is caused by a build up of uric acid in the bloodstream, which can then crystallise in capillary vessels leading to immense pain.  Uric acid is swiftly removed from most animals through breakdown by an enzyme called Uricase, but humans and many primates lack a functional form of the gene responsible for production of this enzyme.  Apparently, the loss of function of this gene occurred some 15+ million years ago when a series of nonsense mutations inactivated the gene (Oda et al. Mol Biol Evol 2002;19:640–53).  The article proposes that the selective pressure for the loss of Uricase activity begins when apes moved from Africa to Europe, which at first provided a plentiful environment with a sub-tropical climate providing bountiful supplies of fruit for their diet (particularly figs).


However, this period saw the beginning of climate cooling and this drier cooler weather changed the European vegetation from a rich broadleaf forested area toward a savanna-like environment, with much less fruit available and much of this fruit (especially figs)now becoming seasonal and quite scarce during winter.  As cooling continued these European apes began to starve, therefore, the loss of the Uricase gene must have provided a selective advantage (Hayashi et al. Cell Biochem Biophys 2000;32:123–9).  The normal mammalian reaction to periods of starvation is to produce fat (e.g. for an energy supply during hibernation, or to provide sufficient energy to survive winters).  However, during prolonged periods of starvation foraging for food must continue, especially for primates that do not hibernate, and for this to be successful glucose is required by the brain.  This is achieved by an “insulin-resistance” effect.   The clue to this selective advantage lies with the fruit-rich diet that the apes in both Europe and Africa were consuming – digestion of fructose leads to production of uric acid and researchers have found that uric acid can trigger this switch to “insulin-resistance”.insulin-resistance The researchers proposal is that the loss of the Uricase gene led to a gradual development of the ability to switch to converting fructose to fat providing a better chance to survive food shortages during winter.  They also propose that these European apes may have brought this major selective advantage back to Africa as they migrated back to avoid cooling winters, they must have out-competed African apes and thus left the mutated Uricase gene that has been acquired by humans.

If this explanation of these genetic events is correct, we have a genetic explanation of TD2 – sometimes known as insulin-resistance – and what we have now is that processed foods, which often contain corn syrup, or table sugar, that are extremely rich in fructose, are being turned into fat because of the elevated uric acid levels in our bloodstream.  It would be exciting to think that new drugs could be developed against uric acid production, which might help reduce obesity and TD2.  Genetic Engineering may even hold the possibility of restoring Uricase production in the distant future.  In the meantime, as I have said before we must aim to increase regular exercise, reduce sugar intake and aim to make fresh fruit our only supply of fructose.  The antioxidants available in fresh fruit help to reduce many side effects of excess uric acid and reduce multiple diseases.

However, from a personal viewpoint I am left with something of a mystery as this genetic explanation does not explain familial occurrences of TD2, something I have personal experience of!  The best link between TD2 occurrences in families and an observed disorder is that TD2 is tightly linked to β-cell dysfunction in the pancreas (O’Rahilly, S.P. et al.  The Lancet , Volume 328 , Issue 8503 , 360 – 364), which is associated with insulin resistance (Kahn, 2003.  Diabetologia 46, 3-19), but the nature of this genetic link is complex and confused and involves amyloidosis of insulin.  A detailed description of this will follow.


Type 2 Diabetes should be taken very seriously

A little while ago I wrote a blog about my own experience with Type 2 Diabetes, where I made a point about unnecessary deaths due to this illness, but further reading has increased my awareness that many people in this country (and maybe elsewhere) are not taking the diagnosis of diabetes seriously enough!

Therefore, I thought I should write another blog about health problems associated with having Type 2 Diabetes in an attempt to explain the science behind the disease and clarify the risks involved.

First, let me summarise (you may also find the animation on this webpage useful) what diabetes is about and how it occurs – diabetes is a result of a misalignment between insulin levels and glucose levels in the bloodstream, which leads to incorrect glucose levels in the blood.  Blood glucose, which is the primary energy source for all the cells of the body, is produced from digestion of carbohydrates, sugars and fatty food and enters the bloodstream from the stomach or liver.  However, while the blood can circulate the glucose to all of the cells of the body, the glucose is not automatically taken up by these cells.  To enable uptake into muscle and other cells insulin is required, which is secreted by the pancreas and coexists in the bloodstream in balance with the level of glucose.  In Type 1 Diabetes the pancreas does not produce insulin, which means that the cells are unable to take up glucose, in turn this leads to high levels of blood sugar (hyperglycemia).  Type 2 Diabetes is more complex, but is primarily because the pancreas either produces insufficient insulin, or the insulin produced fails to function normally – often this is due to increased  levels of fats within the bloodstream that have blocked insulin uptake by the muscle cells.  This also leads to hyperglycemia, but also to increased insulin levels as the pancreas continues to release insulin in an attempt to enable muscle uptake of the increased glucose levels.  While the onset of Type 1 Diabetes (in terms of symptoms) is rapid, the onset of the symptoms of Type 2 Diabetes is often slow and can take as long as a decade, which means people often “live” with an undiagnosed condition and tend to ignore the problem (as was the case for me).  One molecular-based theory as to the cause of Type 2 diabetes is that aggregation of islet amyloid polypeptide (IAPP) leads to loss of the insulin-producing beta cells in the pancreas.  This theory has recent support from a biophysical study of the interaction of IAPP and the lipid membranes of the beta cells (Lee C-C et al., 2012. Biophys. J. 102(5):1059-1068).

One of the major symptoms of both types of diabetes in an increased likelihood of infection (Muller et al. (2005). Clinical Infectious Diseases, 2005. 41(3): p. 281-288) and slow healing of injuries or wounds.  Hyperglycemia is thought to enable or encourage bacterial growth in the bloodstream (perhaps through increased cell adhesion); although there is little direct evidence of this and a more likely explanation is that obesity, leading to the development of Type 2 Diabetes, impairs the immune response through an inflamation-related pathway (Geerlings & Hoepelman (1999). FEMS Immunology & Medical Microbiology, 26(3-4): p. 259-265; Wellen & Hotamisligil (2005). J Clin Invest, 2005. 115(5): p. 1111-9).  In addition, recovery from infection is slower in diabetic patients.  Yet this situation seems to be ignored by many patients, which may contribute to the incidence of infection.  Typical problems that arise from this situation are:

  1. An increased incidence of yeast infection (Candida or Thrush).
  2. Urinary infections.
  3. MRSA.
  4. Foot infections (foot ulcers).
  5. Diabetic neuropathy (nerve damage) causes problems with sensation.
  6. Diabetic retinopathy.

However, I am writing this blog to deliver a very specific message, one that I hope will make readers realise how serious this disease is and how easy it is to avoid serious complications through careful control of diet and exercise.  Diabetes has been linked to a wide range of complications, but one that I read about recently made me think – Alzheimer’s Disease (AD)! Meakin et al (2012. Biochemical Journal 441(1):285-296) have studied a mouse model with total absence of BACE1 ( a protein responsible for cleavage of the amyloid forming precursor protein, which leads to amyloidosis and AD).  Both AD patients and Type 2 diabetics have an increased incidence of obesity in later life and AD patients have an increased likelihood of Type 2 diabetes, but more importantly, AD patients also have increased insulin resistance and impaired glucose metabolism.

Alzheimer’s Disease is thought to be initiated by cleavage of amyloid precursor protein (APP) by the gene product of BACE1, this increases the basal levels of beta-amyloid proteins, which aggregate into the amyloids that form the plaques in the brain of AD patients.  Deletion of the BACE1 gene in mice avoids this process and leads to loss of plaque formation.  In contrast, increased levels of BACE1 production has been observed in AD patients.

So, the question remains does obesity and type 2 diabetes link with an increased risk to Alzheimer’s Disease and can this process be reversed through diet and drug-based control of BACE1 levels?  The answer seems to be yes, but more work is needed.  However, the message I want to get across is that anyone with Type 2 diabetes, whether they are on medication or not, and anyone who is obese, should seriously control the situation through diet (Eriksson & Lindgärde  1991. Diabetologia 34(12):891-898) and exercise (Kopp et al 2012. Diabetes Research and Clinical Practice 95(1):25-29), or you run the risk of serious outcomes!

Type 2 Diabetes – two years on….

Last week saw the second anniversary of the diagnosis of my Type 2 diabetes.  The initial measurements from the blood samples came as something of a shock:

  1. Blood sugar =15 mMol/L
  2. Cholesterol = 12 mMol/L
  3. Triglycerides = 15.6 mMol/L

In case you don’t know the blood sugar should be less than 7, the cholesterol around 3-4 and the triglycerides less than 1.7!

The first meeting with the “Diabetes Nurse” led to her saying I was unlikely to control this blood sugar level by diet alone, which for me, was like a red flag to a bull!  Maybe that was a good thing though as, after only a couple of weeks of a diet, I had reduced my blood sugar to 10.

So how did I do this, well I decided to cut out all sugar from my diet, which involved me not drinking Pepsi or Coke, no chocolate, ice cream, jams and having no sauces on food (tomato or brown), using saccharine whenever possible etc.  I checked the sugar level of all bottled and packaged food I used and stopped using it if the sugar was greater than 25% of the total volume/weight.  I also decided to eat fresh fruit as my main sugar intake and I make a fruit salad with melon, pineapple, apple, grapes, kiwi and peaches.  I also changed to regularly eating asparagus tips, fresh new potatoes, baby carrots (frozen, but still sweet) and sugar snaps with cooked meats such as lamb steaks or beef steaks.  Something I was bad at while working – breakfast – also changed and I now have a mix of Fruit and Fibre and Cornflakes for breakfast often with a banana.  Finally, I have tried to increase my intake of omega-3 fatty acids (fish oil), this is not easy as my wife cannot eat fish, but I have sild on toast and occasional mackerel (barbecued in the summer).  The result of this diet is that my sugar is now down to 6.5 and has been steady for two years (despite being told this would not be possible without medication), my cholesterol is 3.6; although I am taking statins and my triglycerides are 1.6.

I monitor my blood sugar using a simple “prick and sample” device by Accu-Check with a pen-like bayonet and a monitor that stores data.  I also have a blood pressure monitor by Omron and I monitor both monthly (I did this weekly during the first year, but this is too often and costly).  I also weigh myself regularly and the diet has led to the loss of one stone, which is good.  But the question I, and anyone facing the onset of this disease, must face up to is how overweight I was.  I am 5′ 10″ (1.78m) and weighed 13st 7lb (86kg), which, most people told me, was not large and by some people’s standards is not, but the real indicator is body mass and a quick calculation shows my BMI was 27.1, which is overweight!  At least not obese, I thought, but this calculation made me concentrate more on my diet.  My BMI is now 25.1, which makes me slightly overweight, so more work to do!  I need to lose 3lbs to be normal weight for my height, but my aim is to lose another 7lb if possible, over the next year, I think this will involve some extra exercise over the winter months.

So, what are my thoughts about this disease?  Well, from a personal point of view there are two major factors to consider – first, is quality of life and for me that means that I did not want to lose the idea of social drinking in a pub and eating out occasionally.  Second, is understanding the disease well enough to know that my diet and my lifestyle do not put me at risk.

In terms of quality of life, I think a major factor was being able to retire and lose any stress associated with my job.  I have started to drink a little more red wine, which contains anti-oxidants that are good for general health, but I still enjoy a beer and still have a good social life.  I take Ramipril ace-inhibitors to reduce my blood pressure, which is now fairly stable and reasonable (a family history of high blood pressure from my mother’s side of the family suggests BP will always be an issue for me).  As I mentioned above I also take statins to control cholesterol.

The main difference that I have noticed in my life is that diabetes raises the risk of infection (which is how I realised I had the disease initially), but it also makes healing slower.  This was illustrated earlier this year when I banged my shin in the bus (the driver braked too hard) and the scratch (that is all it seemed) became infected and I had to have penicillin to treat the wound!  I am now very cautious about injuries.  However, I still walk fast and walk to cricket matches, to local pubs for a beer and as much as possible whenever I go out.  Anyone who reads my blog will also realise I do other activities that are strenuous – like relining the fish pond.

Of course, the scientist in me made me begin to investigate the cause of Type 2 diabetes and the first thing I discovered was that, at the time (2 years ago), there was a lot of clinical observation published about Type 2 diabetes, but not much molecular analysis of the cause.  However, things are changing and a few papers have now described the nature of te disease.

Before trying to describe the science, here are a few terms and what they mean:

Glucose, is a sugar found in many foods (sometimes known as grape sugar), is an important energy source and makes up one-half of sucrose (sugar) the rest being fructose.
Fructose, is another sugar found in most fruits and some vegetables. It does not trigger insulin production and can be taken up by muscle, as an energy source, without insulin.
Insulin, is a hormone required to enable uptake of glucose by muscle and adipose cells.
Insulin Resistance (IR), a situation where muscle and adipose cells fail to respond to insulin and fail to uptake glucose as expected.  It is due to a loss insulin self-regulation by the normal insulin levels due to reduced insulin sensitivity.  Fats and triglycerides are associated with onset of IR.
The Pancreas,  beta-cells within the pancreas release (secrete) insulin.
Type 2 diabetes, linked to insulin resistance and insulin secretion problems, is a situation where excess blood sugar (glucose) is produced by reduced active-insulin levels.  This disrupts glucose production in liver, glucose uptake by muscle and release of fatty acids from adipose cells.  A useful (basic) summary is available in the animation at the site on this link.

It is clear from work by Professor Roy Taylor at the University of Newcastle upon Tyne that diet is key in the onset of the disease and one of the main problems in modern society is obesity.  His work has shown that Type 2 diabetes can be reversed by severe and strict control of the diet of obese patients (Lim, al. (2011).  Diabetologia 54, 2506-2514), which has allowed the onset of the disease to be tracked in reverse (a form of medical reverse engineering).  It is also clear from this work that the build up of fatty acids in the pancreas and liver is a key factor in the development of the disease, which appears to be through development of insulin resistance and that triglycerides in the blood lead to insulin resistance.  In addition, although pure fructose solution have been shown to stimulate triglyceride production, this is not the case for fruit-based fructose.

A good description of both the scientific background to Type 2 diabetes and recent developments in understanding the disease are described in (Gastaldelli (2011). Diabetes Research and Clinical Practice 93, S60-S65).  I will try to summarise this data in a comprehensible way, but I am not an expert in this field, so I apologise for any errors in my understanding of the subject……
Type 2 diabetes is a more progressive form of Insulin Resistance (IR), which is often associated with reduced insulin secretion from beta-cells in the pancreas.  Type 2 diabetes develops when beta-cell secretion of insulin is insufficient to overcome the IR of muscle and other cells that take up glucose.  There is a circular, degenerative pathway that leads first to IR and then Type 2 diabetes – increased levels of circulatory fatty acids lead to increased IR, which leads to impaired control, by insulin, of fatty acid conversion to triglycerides and hydrolysis of triglycerides to fatty acids.  This effect is associated with obesity and elevated fat levels in general.  At a molecular level, IR is linked to excessive activity of superoxide dismutase, which is an antioxidant.  In muscle, increased levels of fat is also associated with triglyceride build-up, which, in turn, leads to poor glucose metabolism.  In addition, increased fat influences insulin secretion and beta-cell function.  Excess fat leads to elevated levels of the inflammatory cytokines (TNFalpha/beta and IL6), which directly affect insulin-mediated glucose uptake.
Therefore, Type 2 diabetes has two components – impaired insulin secretion from beta-cells within the pancreas and increased IR as detailed above.  There are genetic components to the reduced function of beta cells and a loss of pancreatic mass is observed (Schäfer, et al. (2011). Diabetes Research and Clinical Practice 93, S9-S24), but that is not the main problem – reduced secretion is the key and a challenge to the reduced pancreas, with glucose, shows a changed initial release of insulin.  Genetic studies are advancing with genomic analysis of large populations making significant contributions to our understanding, which is further advanced by a mouse model system to study these gene variants.

So, what does all of this mean to you and I?  First, if you are aware of a genetic history of Type 2 diabetes, then make the following moves early to avoid onset (I should have done this, but I was unaware of the genetic factors).  The first step to avoid onset of Type 2 diabetes is to control fat levels in the body, to monitor triglycerides, which seem to be a key indicator of the onset of IR, which is a precursor of Type 2 diabetes and to ensure the diet contains a rich supply of antioxidants, which means lots of fresh fruit and vegetables.  Reduce the likelihood of inflammatory reactions within the body that may lead to further production of inflammatory cytokines – this means consume omega-3 fish oils, or eat oily fish such as mackerel.  Finally, there is evidence that physical activity can reduce the likelihood of developing Type 2 diabetes (Sanz, et al. (2010). Diabetes & Metabolism 36, 346-351; Eriksson & Lindgärde (1991). Diabetologia 34(12): p. 891-898), so exercise regularly within the limits of your capabilities.

As a postscript to the above (14/12/2011) I just read an article about the incidence of diabetes-related deaths in the UK and some important facts are apparent.  Perhaps the most important, but often least appreciated is that ALL of these deaths are avoidable with good monitoring and treatment.  But, there is huge variation in the quality of care across the UK NHS (see map).  A number of simple procedures would greatly reduce diabetes-related deaths:

  1. Education about improved diet and reduction in obesity.
  2. Improved communication about the risk of diabetes and the possible side effects of the disease.
  3. Help with local initiatives for healthy exercise and activity.
  4. Regular monitoring of “at risk” people and continued monitoring of diabetic patients.
  5. Accessible care for diabetics who are injured, have acquired an infection or have a risk of possible infection (e.g. foot ulcers or ingrown toenails).

I hope this all helps, but if you are concerned about any of this please contact your GP and discuss the options available to you.