Sunday, June 9, 2013

Mitochondrial Dysfunction and Type 2 Diabetes

If you would like basic some information on mitochondria, oxidative phosphorylation, etc, take a look at mitochondrial dysfunction 

Mitochondrial Dysfunction in Type 2 Diabetes

Mitochondrial dysfunction has been found in type 2 diabetics (T2Ds) and in animal models of T2D:

  • T2Ds have impaired metabolic flexibility (associated with insulin resistance), and impaired mitochondrial function* [1]
  • Among diabetics, mtDNA mutations are associated with a lower glucose stimulated insulin secretion (GSIS) [2]
  • Mitochondrial function is impaired in the heart of an animal model of T2D [3]
  • In animal models of T2D, oxidative stress and mitochondrial dysfunction precede T2D [2] 

And mitochondrial genetics are associated with T2D: 
 
  • Mice with impaired mtDNA expression specifically in β cells are hyperglycemic and have impaired GSIS [2]
  • Polymorphisms in mtDNA are associated with T2D [4]
  • A type of diabetes called mitochondrial diabetes is due to inherited mtDNA mutations [5]
  • About a 1/3 of people with Friedreich́s ataxia (caused by a mtDNA mutation) develop T2D [6] 

* Impaired mitochondrial function (-12.5%) was independent of VO2 max (a measure of fitness) and was a weak predictor of RER (r2=0.19).  RER was only 3 points higher in T2Ds [1] 

Why the Pancreatic β Cells? 

The pancreatic β cells have an abnormal glucose metabolism that is ideal for a sensor, but makes them especially vulnerable to oxidative stress and mitochondrial dysfunction 

Normal Cells
Pancreatic Beta Cells
Glucose transporters (GLUT4) are packaged and sent to the cell membrane in response to insulin
The beta cell glucose transporters (GLUT1) aren't dependent on insulin, so glucose can freely diffuse into the cell at all times, and the glucose content in the cytosol is proportional to blood glucose
Oxidative phosphorylation is determined by the energy demands of the cell
Oxidative phosphorylation is determined by the availability of glucose
Glycolysis inhibits further glycolysis.  For example G6P (an intermediary of glycolysis) inhibits glucokinase (the enzyme that catalyses the first step of glycolysis)
Glucokinase is not inhibited by G6P
Pyruvate dehydrogenase (PDH), which puts pyruvate into the citric acid cycle, strongly decrease in activity in response to high glucose levels
The activity of PDH is only decreased by 22% in response to high glucose levels
Can metabolise glucose to lactate
Can’t metabolise glucose to lactate.  Glucose can only be metabolised through oxidative phosphorylation
[7]

In addition, pancreatic beta cells have low levels of antioxidant enzymes (30% of the amount of SOD as the liver and 5% of the catalase and glutathione peroxidase) [8] and insulin secretion is highly energy dependent, which generally means more OXPHOS and more ROS [2] 

A Basic Model of How Mitochondrial Dysfunction Causes Type 2 Diabetes 

Pancreatic β cells can be forced to into more oxidative phosphorylation than they require.  Oxidative phosphorylation produces ROS, but pancreatic β cells have low levels of antioxidants, making them are vulnerable to oxidative stress. 

Energy overload and oxidative stress can impair mitochondrial function by inhibiting the activity of the electron transport chain.  Oxidative stress can also damage proteins, lipids and DNA.  mtDNA can’t be repaired and β cells have a poor capacity for DNA repair.  The damage from oxidative stress is a vicious cycle where macromolecule damage leads to poor function, which leads to worse function, which leads to more ROS and more oxidative stress.  The resulting mitochondrial dysfunction impairs insulin secretion and initiates apoptosis.  Both β cell dysfunction and β cell loss seem necessary for T2D to develop [2] [6] [9] 

One of the few ways β cells can protect themselves is by increasing uncoupling protein 2 (UCP2) levels, which is up regulated in T2Ds [6].  UCPs reduce the opportunity for superoxide production but also reduce ATP generation.  This is a double edged sword because while UCP2 protects the mitochondria, ATP is necessary for insulin secretion [7]. 

* While T1D and T2D have different underlying pathologies, they both involve β cell dysfunction and death, which interestingly seems to be largely mediated by impaired mitochondrial function and mitochondrial apoptotic signalling pathways [2] 

** 10 minutes of intense oxidative stress to β cells damaged mitochondria, increased mitochondrial ROS production and increased apoptosis, and reduced oxygen consumption, ATP production and insulin secretion for days.  But it also increased gene expression for SOD, catalase and UCP2, which made them more resilient to exposure 3 weeks later.  A kind of mitochondrial hormesis [10] 

Insulin Resistance and Type 2 Diabetes 

So far it seems that too much glucose >> T2D, and that the ‘pancreatic burnout’ theory of T2D is right, in a way.  But there’s another piece of the puzzle.  As we know, glucose normally stimulates insulin release and insulin happens to be a pro-growth, anti-apoptotic hormone. 

In β cells, activation of the insulin receptor is essential for growth [7].  β cell insulin receptor knock out (βIRKO) mice have increased apoptosis and decreased proliferation of β cells, reduced β cell mass and impaired glucose tolerance [11].  To use another severe animal model, liver insulin receptor knock out (LIRKO) mice are hyperglycemic and hyperinsulinemic, but don’t develop T2D because they compensate for liver insulin resistance by increasing beta cells* [12] 

So under healthy conditions it seems that:
High glycemic load >> high insulin release >> compensatory growth of β cells 

In humans [2] and animal models [13] [14] insulin resistance precedes** T2D.  With insulin resistance, the β cells won’t receive the pro-growth signals of insulin while being inundated with lots of glucose that they must metabolise through oxidative phosphorylation.  Given the adaptability of β cells to oxidative stress and the pro-growth effects of insulin, it would seem like T2D could only develop in the presence of insulin resistance and/or persistent oxidative stress 

* So if insulin resistance is so bad, why don’t LIRKO mice develop T2D?  I’m not sure, perhaps because their insulin resistance isn’t caused by an underlying pathology (such as chronic inflammation) so their β cells remain insulin sensitive.  That being said I don’t have long term data of LIRKO mice but I suspect that while they may not develop T2D, they aren’t particularly healthy either.  Also see Evelyn's comment about NEFA 

** For information on insulin resistance see Overweight but Insulin Sensitive and Normal Weight but Insulin Resistant: Part 3 and Stephan Guyunet’s seven part series (see Part 1, 2, 3, 4, 5, 6, 7)

4 comments:

  1. "The pancreatic β cells have an abnormal glucose metabolism that is ideal for a sensor, but makes them especially vulnerable to oxidative stress and mitochondrial dysfunction "

    A wonderful way of putting this!

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    1. Thanks Evelyn.

      Well done on being asked to contribute to Alan Aragon's Research Review.

      This post has a fair bit of common ground with your posts on T2D and the endoplasmic reticulum, pro-insulin, etc. Mitochondrial dysfunction and endoplasmic reticulum stress tend to occur together. I think we're approaching the same thing from different angles

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  2. BTW Steven, I'm pretty sure that the LIRKO mouse doesn't get diabetic because it has suppressed instead of elevated NEFA. The fatty acids mess up the beta cell first. UCP's can't keep up? That seems a likely mechanism.

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    1. That's interesting. I guess that's because their adipocytes remain insulin sensitive

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