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Hypoglycemia and Ketosis - your thoughts?

BeautifulDay

Senior Member
Messages
372
I'm looking for your thoughts on this piece of my puzzle.

I'm not diabetic. My A1C is always normal. I have bouts of hypoglycemia, that sometimes can be controlled with small meals.That said, I know that when my hypoglycemia is being whacky (possible autonomic hypoglycemic issue that comes and goes), that a second cup of coffee or walking slowly on the treadmill for ten minutes without a glass of orange juice nearby is going to send me off into low blood sugar.

When it's being whacky and I've eaten regular meals, my sugar can be 67 or 80 (when it should be around 100 after eating). Again this doesn't happen all the time - like all the weird symptoms it comes and goes.

I recently bought the HealthyWise Urinalysis Test strips (with the ten tests, including ketones). I figured I'd use the urine test strips a few times a day to see how the test results compare to how I'm feeling at the time.

I'm finding the ketones are normal here and there, but when I'm feeling hypoglycemic (even after eating), my ketones are at the highest level possible on the strip (dark brown). Whereas, the rest of the time there are no ketones showing up in my urine.

What do you make of that? Fully fed (eating small meals and snacks regularly). Not dieting. And my sugar and ketone levels are fluctuating wildly during the day. In addition, the change in the blood glucose and the ketones in the urine are representative of how I'm feeling.

Do you have experience, studies, tests I should ask my doctor for, or recommendations to overcome this issue?

Thanks!
 

BeautifulDay

Senior Member
Messages
372
Thanks @pattismith In following the relevant links I found the following interesting.

"Clinical presentation of mitochondrial disorders in childhood.
Abstract
Respiratory-chain deficiencies have long been regarded as neuromuscular diseases. In fact, oxidative phosphorylation, i.e. adenosine triphosphate (ATP) synthesis by the respiratory chain, does not occur only in the neuromuscular system. Indeed, a number of non-neuromuscular organs and tissues are dependent upon mitochondrial energy supply. For this reason, a respiratory chain deficiency can theoretically give rise to any symptom, in any organ or tissue, at any age and with any mode of inheritance, owing to the twofold genetic origin of respiratory enzymes (nuclear DNA and mitochondrial DNA, mtDNA). In recent years, it has become increasingly clear that genetic defects of oxidative phosphorylation account for a large variety of clinical symptoms in childhood. Among 100 patients with respiratory-chain deficiencies identified in our centre, 56% presented with a non-neuromuscular symptom and 44% were referred for a neuromuscular problem. It appears that the diagnosis of a respiratory-chain deficiency is difficult initially when only one symptom is present. In contrast, this diagnosis is easier to consider when two seemingly unrelated symptoms are observed."
https://www.ncbi.nlm.nih.gov/pubmed/8884575

"Gastrointestinal manifestations of mitochondrial disease.
Abstract
Although non-specific gastrointestinal and hepatic symptoms are commonly found in most mitochondrial disorders, they are among the cardinal manifestations of several primary mitochondrial diseases, such as: mitochondrial neurogastrointestinal encephalomyopathy; mitochondrial DNA depletion syndrome; Alpers syndrome; and Pearson syndrome. Management of these heterogeneous disorders includes the empiric supplementation with various "mitochondrial cocktails," supportive therapies, and avoidance of drugs and conditions known to have a detrimental effect on the respiratory chain. There is a great need for improved methods of treatment and controlled clinical trials of existing therapies. Liver transplantation is successful in acquired cases; however neuromuscular involvement in primary mitochondrial disorders should be a contraindication for liver transplantation."
https://www.ncbi.nlm.nih.gov/pubmed/14562575

"Respiratory chain defects may present only with hypoglycemia.
Abstract
Hypoglycemia occasionally results from oxidative phosphorylation deficiency, associated with liver failure. Conversely, in some cases of respiratory chain defect, the impairment in glucose metabolism occurs with normal hepatic function. The mechanism for this hypoglycemia remains poorly understood. We report here three unrelated children with hypoglycemia as the presenting symptom associated with oxidative phosphorylation deficiency but without liver dysfunction. Two patients had, respectively, complex III and complex IV deficiency and presented with long fast hypoglycemia. During a fasting test, the first patient showed evidence for impaired gluconeogenesis (progressive increase of plasma lactate and no decrease of alanine levels), whereas the second patient appeared to have impaired fatty acid oxidation (hypoketotic hypoglycemia with increased levels of non esterified fatty acids). The third patient presented with both long and short fast hypoglycemia related to complex IV deficiency. The mechanism of hypoglycemia for this patient may have been partly related to GH insufficiency, whereas impaired glycogen metabolism possibly accounted for short fast hypoglycemia. We suggest that hypoglycemia can be the presenting symptom for respiratory chain defects, through the possible reduction in cofactors resulting from oxidative phosphorylation deficiency, and that respiratory chain defects should therefore be considered in the differential diagnosis of hypoglycemia."
https://www.ncbi.nlm.nih.gov/pubmed/15784700
 
Messages
15,786
I've only paid much attention to blood sugar and ketones since developing diabetes. But here are my observations, in case they help.

First of all, I'm never hypoglycemic. But when I was on gliclazide, my blood sugar would routinely dip below 5.0 (90), and I would always have a "false hypo" reaction lasting an hour or longer. That's not uncommon for a newly diagnosed diabetic getting their blood sugar down for the first time, but it didn't stop happening to me until I switched to a different med and my blood sugar stopped going that low.

Another problem is that my ketones become elevated at the lowest blood sugar level possible. When I'm over 13.0 (230), the ketones start accumulating, with accompanying symptoms, primarily headache and feeling like crap, from what I recall. After a week where my blood sugar average (fasting, pre-meals, bedtime) was 13.5 (240) the combination of mismanagement by my doctor and severe diarrhea from metformin resulted in my blood sugar peaking at 18.5 (335) and the symptoms of the first stage of diabetic ketoacidosis. It's unusual to be experiencing complications and symptoms at such relatively low levels.

I had blood drawn a few months ago, and there were indications of ketosis, namely elevated 3-methylhistidine, despite that my blood sugar was 7.3-7.4 (135). Around the same time, my c-peptide (reflecting insulin levels) tested high. I am on a drug which stimulates production of it, but only in response to high blood sugar ... and my blood sugar was a midday fasting (hadn't eaten breakfast) 6.0 (104).

The most recent thing I've noticed is that my fasting blood sugar is higher when my ME is worse, primarily due to over-exerting. With the victoza I inject now, what I eat for dinner seems entirely irrelevant to my fasting levels the next morning. But when I have a busy weekend, morning levels will be high for several days. If I push myself to the threshold of crashing, fasting levels might be high for an entire week. Though they'll be back to normal by lunch time each day.

I'm not sure as to what all of this might mean. Though I would speculate that diabetes in ME might be a reflection of a mitochondrial dysfunction, or at least highly complicated by having ME. Hence blood sugar weirdness might very well be present in ME patients, even prior to diabetes resulting.
 
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BeautifulDay

Senior Member
Messages
372
I've only paid much attention to blood sugar and ketones since developing diabetes. But here are my observations, in case they help. ....... I had blood drawn a few months ago, and there were indications of ketosis, namely elevated 3-methylhistidine, despite that my blood sugar was 7.3-7.4 (135). Around the same time, my c-peptide (reflecting insulin levels) tested high. ...... The most recent thing I've noticed is that my fasting blood sugar is higher when my ME is worse, primarily due to over-exerting. With the victoza I inject now, what I eat for dinner seems entirely irrelevant to my fasting levels the next morning. But when I have a busy weekend, morning levels will be high for several days. If I push myself to the threshold of crashing, fasting levels might be high for an entire week. Though they'll be back to normal by lunch time each day........ I would speculate that diabetes in ME might be a reflection of a mitochondrial dysfunction, or at least highly complicated by having ME. Hence blood sugar weirdness might very well be present in ME patients, even prior to diabetes resulting.

Very interesting @Valentijn

My mother (who also has Mitochondrial Disease) was hypoglycemic when younger and is now a type 2 diabetic. I wonder if there is a progression for some with Mito issues. For example, I went from POTS when young to low pulse pressure now. My heart is just too exhausted now to compensate for low blood pressure to bring on a tachycardia to get the blood to the brain.

You brought up so many interesting issues. My 3-methylhistidine is high. 3-Methyl-histidine urine 1852 umol/g creatinine (range 92-323). I didn't know that could be related to ketosis. Others in our family with MitoD also have high 3-methylhistidine. I'm going to do more research on ketosis and 3-methylhistidine. Thanks for that important info. It makes sense that when there is not enough glucose in the blood that breaking down the muscle for food would be an option.

Two of our daughters with MitoD in addition have high AST on blood tests. I wonder if those who are on a ketosis diet for too long can have high liver AST. Maybe getting the ketosis issue better under control will help with some of these issues.

Time to ask the kids to provide a urine sample. :meh: I know from past experience, going into doctors with photos of my sleep report from FitBit, my specific pathogenic mutations, and my blood pressure readings showing low pulse pressure -- got the doctors to perform the tests and then prove the issues. It's sad that sometimes, we have to do our leg work, and then doctors trying to prove us wrong with their own tests then prove that our at home equipment/tests were spot on. I realize FitBit, home genetics testing, and urine tests at home need to be taken with a grain of salt. Yet, when that's what we have access to - at least it's a place to start.
 
Messages
15,786
It makes sense that when there is not enough glucose in the blood that breaking down the muscle for food would be an option.
Except in my case, there were normal levels of glucose, with indications of ketosis at the same time :p So it might not be the glucose levels causing ketosis.
 

pattismith

Senior Member
Messages
3,932
I had blood drawn a few months ago, and there were indications of ketosis, namely elevated 3-methylhistidine, despite that my blood sugar was 7.3-7.4 (135).

Do you know why your 3-methylhistine was high? It is supposed to be associated with muscle catabolism.
Could it be secondary to your medications? Did you had that before?
 
Messages
15,786
Do you know why your 3-methylhistine was high? It is supposed to be associated with muscle catabolism.
Ketosis is at least one cause for it.
Could it be secondary to your medications? Did you had that before?
I can't imagine it would be due to any meds I'm on. It has been elevated before in urine, years ago. At the same time it was high in my recent blood sample, it was also at the low end of the normal range in my urine.
 

BeautifulDay

Senior Member
Messages
372
Do you know why your 3-methylhistine was high? It is supposed to be associated with muscle catabolism.
Could it be secondary to your medications? Did you had that before?

For our family, we aren't on many medications other than the Mito Cocktail. I have to take two baby aspirins a day for an unrelated blood clotting disorder. We have one on low dose fluoxetine (sub-clinical level).
 
Messages
366
How I understand the issue in general, when the body goes into 'ketosis mode' it gets its energy from fats rather than blood glucose. I think the fats are converted to acetyl-CoA and acetyl-CoA is used to produce ketone-bodies, then these are an energy reserve, which can be utilized instead of the glycolysis pathway (?).

This is the first sentence on wikipedia 'ketosis':
Ketosis is a metabolic state in which some of the body's energy supply comes from ketone bodies in the blood, in contrast to a state of glycolysis in which blood glucose provides energy. As opposed to glycolysis, ketosis metabolizes fat to provide energy.


Possible reasons for ketosis:

1) So, as said before, ketosis seems to be a natural reaction to hypoglykemia or prolonged fasting. This might be because the body doesn't have sufficient energy supplies in the glucose area, so it stores more energy from fats as ketone bodies.


2) If I understand correctly, the general function of the glycolysis is also an issue. Not only with low blood glucose, but also with defect carbohydrate breakdown, the body might produce increased ketone bodies.

I found this study on respiratory mitochondrial diseases:
A critical approach to the therapy of mitochondrial respiratory chain and oxidative phosphorylation diseases
Mitochondrial respiratory chain diseases seem to not only cause dysfunction of the respiratory chain, but also high NADH levels. High NADH inhibits the pyruvate dehydrogenase.

From the study:
Respiratory chain defects result in NADH accumulation in the mitochondrial matrix and decreased ability to metabolize pyruvate. The excess pyruvate is reduced to lactate, especially as NADH tends to accumulate in respiratory-deficient cells. This results in increased lactate to pyruvate ratio in the cell cytosol and increased hydroxyl butyrate (OH-but) to acetoacetate (AcAc) ratio in the mitochondrial matrix.
(+a nice image at Fig.5)

High hydroxyl butyrate ratio seems to be a sign of ketosis: The beta-hydroxybutyrate (BHB)/acetoacetate ratio is typically between 3:1 and 7:1 in severe ketotic states. (Source)



So inhibited pyruvate dehydrogenase activity seems to be able to cause high lactate and increased ketone body synthesis.
Since ME/CFS also seems to have low pyruvate dehydrogenase function, this might increase ketones? I also had high ketones in a urine test at one point. They told me to take pyruvate dehyrogenase cofactors B1,2,3,5 Alpha lipoic acid or something like that. That didn't work well though.
Also, concerning diabetes, I read that insulin can directly stimulate the pyruvate dehydrogenase (source), don't know if that could cause some correspondence of diabetes and ME/CFS symptoms.

So, I don't really know what to do, but I think the ketone bodies can come from bad glucose utilization, or if @BeautifulDay your family has some genetic defects that inhibit pyruvate dehydrogenase or cause low glucose breakdown because of hypoglykemia.

Wow, this turned into a long and muddled post:wide-eyed::D
 
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Isaiah 58:11

Senior Member
Messages
116
Location
A Sun-Scorched Land
I have had hypoglycemia on labs a few times and have tested ketones, but never used ketones strips with my glucometer. I have, however, had the ketone issue you describe. It seems to be solved by taking 2 grams of acetyl-l carnitine daily. I have had a demonstrable carnitine deficiency though, so I have no idea if it would work for you. I think the problem is that without it I absolutely cannot use fats for energy and so my ketones shoot up and I start burning muscle for energy (also shown on labs).
 

BeautifulDay

Senior Member
Messages
372
Wow, this turned into a long and muddled post:wide-eyed::D

@PinkPanda I didn't think it was too long or muddled. It's a very complex issue and I thank you and everyone who has responded with input, experiences, studies..... (and also anyone who will respond in the future with additional thoughts, experiences, studies ..... to add to our discussion).
 

BeautifulDay

Senior Member
Messages
372
I have had hypoglycemia on labs a few times and have tested ketones, but never used ketones strips with my glucometer. I have, however, had the ketone issue you describe. It seems to be solved by taking 2 grams of acetyl-l carnitine daily. I have had a demonstrable carnitine deficiency though, so I have no idea if it would work for you. I think the problem is that without it I absolutely cannot use fats for energy and so my ketones shoot up and I start burning muscle for energy (also shown on labs).

@Isaiah 58:11 Again, very interesting. I'm going to look up our labs and also go back in my notes on acetyl-l carnitine. I don't remember anything about it at the moment.
 

pattismith

Senior Member
Messages
3,932
Ketosis is at least one cause for it.

I can't imagine it would be due to any meds I'm on. It has been elevated before in urine, years ago. At the same time it was high in my recent blood sample, it was also at the low end of the normal range in my urine.

are you sure it is ketosis that is a cause for high 3 methylhistidine?

I read that 3 methylhistidine is excreted in urine in ketosis starvation (as a result of muscle catabolism),
and also in non acido-ketosis diabete.
http://www.sciencedirect.com/science/article/pii/0026049582901342

Ketosis is a result of burning fats, while 3 methylhistidine results from muscle catabolism, so it seems to me that it can happen independantly even thought often concomitant.

Do you explain why it can be high in blood and not in urine? Is it excreted in urine only if a certain level is reached?
 

Hip

Senior Member
Messages
17,824
I have bouts of hypoglycemia, that sometimes can be controlled with small meals.That said, I know that when my hypoglycemia is being whacky (possible autonomic hypoglycemic issue that comes and goes), that a second cup of coffee or walking slowly on the treadmill for ten minutes without a glass of orange juice nearby is going to send me off into low blood sugar.

Are these hypoglycemic episode something you have measured on a blood glucose meter?

Hypoglycemia is defined as blood glucose levels dropping under 4 mmol/L (= 72 mg/dL). Ref: 1
 

pattismith

Senior Member
Messages
3,932
I found this study on respiratory mitochondrial diseases:
A critical approach to the therapy of mitochondrial respiratory chain and oxidative phosphorylation diseases
Mitochondrial respiratory chain diseases seem to not only cause dysfunction of the respiratory chain, but also high NADH levels. High NADH inhibits the pyruvate dehydrogenase.

From the study:
Respiratory chain defects result in NADH accumulation in the mitochondrial matrix and decreased ability to metabolize pyruvate. The excess pyruvate is reduced to lactate, especially as NADH tends to accumulate in respiratory-deficient cells. This results in increased lactate to pyruvate ratio in the cell cytosol and increased hydroxyl butyrate (OH-but) to acetoacetate (AcAc) ratio in the mitochondrial matrix.
(+a nice image at Fig.5)

very interesting!
I tryed to take NADH oral or sublingual, and took no advantage from it uptodate...Maybe you gave me the explanation?!
In fact if I increase my NADH intake, and if I really have a mitochondrial disorder, I suppose My lactates will raise...thank you!
 
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BeautifulDay

Senior Member
Messages
372
Are these hypoglycemic episode something you have measured on a blood glucose meter?

Hypoglycemia is defined as blood glucose levels dropping under 4 mmol/L (= 72 mg/dL). Ref: 1

Yes. My husband has a glucometer for his diabetes. When I've felt the shakiness coming on from low blood sugar, he's checked it for me multiple times. It's a much different feeling than low pulse pressure and my other symptoms.
 

BeautifulDay

Senior Member
Messages
372
low blood sugar (2).jpg
We've been tracking my blood sugar for about a year now. My husband didn't believe that I knew when it was dipping low. I proved to him that I could tell when it was dipping 100% of the time. It's a specific set of symptoms (a little woozy, a little hunger, a certain type of hot flash, and the pending doom that I'm going to get very ornery if I don't get sugar soon). Here was my first reading last year on his glucometer.