Monday, February 16, 2015

The Pentose Phosphate Pathway: The missing link between hormonal imbalances and carbohydrate metabolism?

I've taken a bit of time away from blogging because I've been swamped with clients and wanted to spend what free time I have reading.  I've come across some very interesting stuff that I believe plays a significant role in hormonal balance that no one is covering so I'll do my best to break it down in to digestible information.

Anabolic carbohydrate metabolism

When people think of carbohydrate metabolism, they immediately think of glycolysis and maybe even the citric acid cycle.  Both of these reactions are catabolic, they are oxidative processes that make ATP through the breakdown of glucose.  However, there is another pathway of glucose metabolism called the pentose phosphate pathway that is anabolic in nature.  The function of the pentose phosphate pathway is to produce reducing equivalents to power anabolic reactions, to produce ribose 5 phosphate(R5P) for the synthesis of DNA, and to help shuffle carbons between sugars so that they can be utilized again.  But why is this important?  Let's take a look.

Anaerobic glycolysis is the breakdown of glucose in the cytosol of cells.  The first step uses ATP to make glucose 6 phosphate(G6P) which can either continue along the pathway of glycolysis to make ATP or be directed through the pentose phosphate pathway to produce reducing equivalents and/or R5P.  The path that G6P takes is ultimately dictated by cellular needs.  To make this uber-confusing I'll post the steps of both pathways below.

It's not really important that you focus on the steps so much as the parallel pathways that glucose metabolism can take based on cellular needs.  Depending on cell type, there are different levels of pentose phosphate pathway activity.  Cells that are exposed to high levels of oxidative stress, that produce hormones, and that have a high turnover rate tend to have more flux through the pentose phosphate pathway.  But why?

The 2 phases of the pentose phosphate pathway

There are 2 phases of the pentose phosphate pathway, an oxidative phase and a non-oxidative phase, both shown below.

The oxidative phase of the pentose phosphate pathway

The oxidative phase reduces 2 nicotinamide adenine dinucleuotide phosphates (NADP+) to 2 NADPH, the reduced form.  This is important for 2 reasons.  First, NADPH is needed to convert oxidized glutathione to its reduced form.  Everyone and their mother who is trying to optimize health is likely taking some form of supplement or eating foods that promote glutathione production.  Glutathione is known as the master antioxidant as it goes around donating electrons to free radicals before they can react with cellular structures.  The problem is, once glutathione does this it's converted to its oxidized form which can no longer donate electrons.  In this form, glutathione is essentially worthless until NADPH reduces it back to the active form.  This converts NADPH back to NADP+ where the oxidative phase of the pentose phosphate pathway can swing back in and produce more NADPH.  For this reason, any cell that is subject to high levels of oxidative stress such as red blood cells and liver cells has a very active pentose phopshate pathway.  The figure below illustrates the process by which NADPH reduces oxidized glutathione.

Note that selenium is needed in order for glutathione to reduce free radicals and NADPH and riboflavin are needed to reduce oxidized glutathione back to its active form.  Without NADPH, glutathione remains inactive, something you most certainly do not want.  The pentose phosphate pathway is the primary way in which our cells make NADPH for this purpose.

In addition, cells of the immune system used NADPH to kill foreign pathogens through a process called the respiratory burst.  A decrease in the ratio of NADPH:NADP+ ratio will compromise the immune system and provide an environment where pathogens can evade killing by phagocytosis.

The next reason that the oxidative phase is important is because reducing power is needed for all anabolic processes.  This includes the biosynthesis of hormones, so there are high levels of pentose phosphate activity in the adrenal and sex glands.  With insufficient reducing power in the form of NADPH, hormonal balance can be thrown out of whack.  This includes the adrenal and sex hormones as well as the the thyroid, but for a different reason.  Several reversible hormonal conversions are dependent on the ratio of NADPH to NADP+ including:

                                                    DHEA                     <---->  Androstenediol
                                                    Androstenedione   <---->  Testosterone
                                                    Estrone                   <---->  Estradiol
                                                    Cortisone               <---->  Cortisol

NADPH causes the conversions to go from left to right while NADP+ causes them to go from right to left.  So what does this mean?  NADPH will convert androstenedione to testosterone while NADP+ will convert testosterone to androstenedione.  In other words, reduced flux through the oxidative arm of the pentose phosphate pathway will negatively impact testosterone levels in men because there will be more NADP+ than NADPH which favors androstenedione over testosterone.

I am no expert on women's hormonal issues, but given the fact that estrone is the predominant form of estrogen in postmenopausal women while estradiol is the predominant form in women of reproductive age, I'll go out on a limb and say this conversion is likely detrimental.

On the adrenal side of things, reduced flux through the oxidative arm of the pentose phosphate pathway will negatively impact cortisol levels by favoring cortisone production.  Since cortisol has greater glucocorticoid activity and cortisone has no mineralocorticoid activity, this can have a pretty significant effect on glucose levels, inflammation, and electrolyte balance.

Since these hormonal conversions occur in the endoplasmic reticulum(ER) of cells, the ratio of NADPH:NADP+ within the ER can have a pretty significant effect on hormonal balance.  Reduced flux through the pentose phosphate pathway and high levels of oxidative stress are 2 factors that can decrease this ratio leading to poor hormonal balance.

With the thyroid, the proposed mechanism by which reduced flux through the oxidative arm of the pentose phosphate pathway may negatively impact hormone production is through a reduction in glutathione function.  The thyroid relies on hydrogen peroxide, a free radical, for thyroid hormone synthesis.  Without sufficient levels of reduced glutathione to keep this in check, the thyroid can become damaged, inflamed, and thyroid function can become compromised.

The non-oxidative phase of the pentose phosphate pathway

The non-oxidative arm of the pentose phosphate pathway is also important, especially in tissues with high rates of cell turnover.  The non-oxidative arm of the pentose phosphate pathway essentially interconverts sugars in to different forms.  One of those sugars, R5P, is necessary for DNA production. Cells with high turnover rates such as epithelial cells in the gut are dependent on sufficient flux through the non-oxidative arm to produce enough DNA for replication.  The non-oxidative arm also gives the pentose phosphate pathway flexibility.  By interconverting sugars, the non-oxidative arm can create sugars that can re-enter glycolysis to generate pyruvate or feed back in to the oxidative arm to create more NADPH.

The non-oxidative arm allows the pentose phosphate pathway and glycolytic pathways to work synergistically to meet cell needs.  There are essentially 4 modes of pentose phosphate pathway activity that can be used to increase energy levels, increase reducing power, provide building blocks for DNA, or a combination of these functions.

Figure 20.24. Four Modes of the Pentose Phosphate Pathway.  
The yield of each mode is:

Mode 1-6 G6P makes 5 R5P
Mode 2-1 G6P makes 1 R5P and 2 NADPH
Mode 3 -1 G6P makes 12 NADPH
Mode 4-3 G6P make 6 NADPH, 8 ATP, & 5 pyruvate and NADH which can be used to create more ATP

As you can see, carbohydrate metabolism is a lot more than simply breaking down glucose to use for energy.  Carbohydrate metabolism also has anabolic effects via the pentose phosphate pathway.  Decreased flux through the pentose phosphate pathway can increase oxidative stress and negatively impact hormonal balance and cellular reproduction.  There is compelling scientific evidence that altered flux through the pentose phosphate pathway may be at the root of adrenal dysfunction, increased inflammation, and some gut pathologies including SIBO.  In addition, many metabolic consequences of Type 2 diabetes can alter flux through the pentose phosphate pathway and there are many blood markers we see in Type 2 diabetes that indicate this.  If there is enough demand I may pull some of that stuff out, so read, like, and share.