Ruminant Reality

The video of my presentation at the Ancestral Health Symposium 2012 has bee posted on YouTube.

I titled the talk "The Reality of Ruminants and Liebeg's Barrel: Examining the New 'Conventional Wisdom.'" (links are to previous posts) They say that whenever you give a talk you actually give three: There's the talk you plan to give; there's the one you give; and there's the one you think you should have given. The talk I think I should have given isn't too different from the one captured by this video.

Winter Workouts: staying warm and safe

Select the Right Clothes

Staying dry is essential.  Clothes specifically designed for cold weather wick away moisture from the body to keep you dry and warmer. For the layer that goes against
your skin look for “moisture wicking” on the label, as well as machine washable materials.  Avoid 100% cotton, it holds sweat and can lead to chills, muscle tightness and discomfort.

Wear Light Layers

Layers are important because if you get too hot, you can take some things off to cool down. Over your long sleeve moisture-wicking shirt, wear a fleece or wool pullover for insulation.  Add an outer layer that will repel water and block wind.

Use Reflective Gear

Since days are shorter, and it might be dark when you work out, make sure to wear easy- to- see colors and other reflective gear that can help drivers see you in the dark. There are reflective vests that are mesh, so as not to add weight and bulk that can be seen hundreds of feet away and offer 360-degree visibility. Flashing lights on bikes are another way to gain more visibility and ensure you can be seen even when you are working out in the dark.

Cover Your Head and Ears

Most heat escapes the body from the head. Hats can keep in heat, but look for hats made with moisture-wicking materials so as not to keep your head too sweaty. Headbands that cover the ears are also a great way to keep your head warm, without getting too sweaty.

Keep Hands and Feet Warm 

Protect your fingers and toes from frost bite.  Wear thin glove that can be layer inside heavier lined gloves or mittens.  Thermal socks are another essential winter workout item.

Indoor Alternatives 

 Be sensible in really nasty weather, do your workout indoors.  This is a great time to cross train and try a new activity.  Many gyms offer memberships on a month-to-month basis, which is a good opportunity to try a new class, start a weight training routine or try a new activity.

Patient Story: Proton Therapy for Non-Small Cell Lung Cancer

Proton Therapy Helped Me Share Moments with My Grandchildren
Kathy Brandt was diagnosed with non-small cell lung cancer in 2011 at her local hospital. After much research, and a recommendation from her brother-in-law, who is a physician, Kathy chose Penn Medicine for her lung cancer treatment, which included proton therapy. Today, Kathy is cancer free. 

You hear the word “cancer” and it's truly terrifying.

It was basically just a checkup with my pulmonologist because I have emphysema. He sent me for a chest X-ray and that is when they found the tumor in my lung. It was a terrifying time and thankfully I had strong family surrounding me - strong family helping me make decisions about what kind of treatment I should have. After that initial diagnosis, when you feel like you have been hit with a ton of bricks, then the decision needs to be made where you are going to seek treatment. My brother-in-law, who is a physician, along with my pulmonologist suggested I go to Penn Medicine for treatment.

Penn Medicine was a wonderful choice for us. They used a team approach.  I saw an oncologist, I saw a surgeon, and the radiologist is all located at Penn Medicine.  It was very comforting to know that all these people are just working to take care of you and to make you better.

I was diagnosed with non-small cell lung cancer at the end of June.  My surgery was the beginning of August and chemo started in September. It was finished in November.  I started proton therapy in December, which lasted for 4 weeks.

Deciding to Have Proton Therapy at Penn
I decided to go with the proton radiation because of the cancer’s proximity to my heart and spine. I chose proton therapy because I knew it would be more precise and would have less side effects and that was very important to me.

The Proton Therapy Experience
Every day for 5 weeks, I would leave work, come home, and my husband would take me to Penn for proton therapy. After the treatment, we’d go home and I’d spend time with my grandchildren and their parents, who were living with us at the time. My granddaughter was about 3 months old at the time. And I would take her, feed her, and just spend time with the people that meant the most to me.

I really felt wonderful. I continued to work the whole time I had proton therapy – I never missed a day of work, actually. I was a bit more tired than usual, but that was really the only side effect I felt.

When I completed proton therapy, I rang the bell.  Everybody in the waiting room clapped, and we went home and I think I had a very big glass of wine after treatment was finished.

After Proton Therapy
Today, I don’t sweat the small stuff.

I would tell anyone to feel very comfortable going to Penn Medicine, and I would tell anyone to also feel very comfortable in choosing proton therapy simply because of the fewer side effects and its extreme precision.  I would recommend Penn Medicine wholeheartedly.  I cannot say enough good things about my experience.

Learn More About Proton Therapy at Penn Medicine
Proton therapy is a non-invasive, incredibly precise cancer treatment that uses a beam of protons moving at very high speeds to destroy the DNA of cancer cells killing them and preventing them from multiplying.

Unlike conventional radiation that can affect surrounding healthy tissue as it enters the body and targets the tumor, proton therapy’s precise, high dose of radiation is extremely targeted. This targeted precision causes less damage to healthy, surrounding tissue.

Watch the full video of Kathy's experience.

Learn more about proton therapy, or schedule a consultation with a radiation oncologist at Penn Medicine. 

Abramson Cancer Center at Penn Medicine Valley Forge is Now Open

Expert Cancer Care is Now Just Around the Corner 

When faced with a cancer diagnosis, patients and their families deserve the best. As world-renowned experts in cancer care, Penn physicians offer the most advanced treatment options, groundbreaking research and the compassionate care patients and families need before, during and after a cancer diagnosis.

Penn Medicine is pleased to offer residents of the Valley Forge community that same level of care closer to home at the new Abramson Cancer Center at Penn Medicine Valley Forge.

Designed to offer patients the best experience possible, this brand new two-floor and 18-exam room facility features a broad range of cancer services including:

• Office consultations
• Second opinions
• Chemotherapy treatments in a newly designed infusion suite
• Radiation therapy
• Laboratory services
• Access to the latest clinical trials, research, and cutting edge treatments like proton therapy — the most advanced and precise form of radiation therapy in the world
• 
  

Learn more about the new Abramson Cancer Center at Penn Medicine

Nonprofit Regional Health Plans

As the US health system moves towards the 2014 launching of health exchanges and other components of Obamacare, regional nonprofit health plans are poised to take a distinctively important role.

An article in today's New York Times described the steps Florida Blue, which covers 4 million Floridians - 30 percent of the Florida insurance market - is taking. The  proposal for a "public option" like Medicare for all that would compete with private insurers crashed and burned in the health reform process, but regional nonprofits like Florida Blue are carrying out the function that was envisioned for the public option. Nonprofits can't function without making a margin beyond their expenses, but their structure allows them to be more mission-driven and locally connected than investor-owned plans.

For much of my clinical career I practiced at the nonprofit Harvard Community Health Plan (HCHP) HMO. My late father, who lived in Florida, know how much I respected HCHP, and asked me if he should join an HMO. At that time none of his choices were nonprofits, and I'd read about various scandals in the Florida market. If he'd been living in Massachusetts I would have encouraged him to join HCHP where I and my family got our care, but I advised him against the HMO route in Florida.

Medical care is ultimately local. It works best when clinicians and their organizations are part of the local community. This passage in the article stood out for me:

“Florida Blue has the same problems everyone else has,” said Dr. Michael A. Wasylik, an orthopedic surgeon in Tampa who works with insurers through the Florida Medical Association, but “they have a better trust relationship with doctors.” The local representatives are better able to address doctors’ concerns, he said.

Health reform won't get anywhere without enthusiastic participation from the clinical community. Insurers can facilitate reform, but they can't make it happen. Engagement with the local community, and above all the kind of trust that Dr. Wasylik refers to, are key. If the national for-profit giants can compete successfully with regional nonprofits like Florida Blue, more power to them. But if the narrow margins and need for highly collaborative relationships with the clinical community make Obamacare an undesirable business opportunity, regional nonprofits like Florida Blue will flourish.

Ignoring Families Can be Fatal

Yesterday in Heathrow Airport on my way home from Singapore I wrote a post about how US medical ethics ignores families and overemphasizes individual "autonomy." When I got home I read a painful story in the New York Times that confirmed the potential harm from the way ethics and law lead clinicians to treat individuals as isolated units: "Drowned in a Stream of Prescriptions: Addict's Parents Couldn't Halt Flow of Attention Deficit Drug.

Richard Fee, an intelligent, popular student who hoped to go to medical school, became addicted to stimulants in college. He faked symptoms of ADHD and received increasing doses of stimulants over a two year period. He ultimately became psychotic, and when the stimulants were stopped, became depressed (not unusual during stimulant withdrawal) and hung himself. The central points of the story are (1) how psychiatry has degenerated into brief "med checks" in which prescriptions are written without adequate thought about what's really going on and (2) how the pharmaceutical industry has succeeded in pushing medication use way beyond what good health and good practice call for.

But having just come from a conference on  "The Ethics of Family Involvement in Healthcare," I was transfixed by what happened when Richard's father, who was terrified about his son's deterioration, and who understood the addiction problem, tried to talk with Richard's psychiatrist: 

In late December, Mr. Fee drove to Dominion Psychiatric and asked to see Dr. Ellison, who explained that federal privacy laws forbade any discussion of an adult patient, even with the patient’s father. Mr. Fee said he had tried unsuccessfully to detail Richard’s bizarre behavior, assuming that Richard had not shared such details with his doctor.


“I can’t talk to you,” Mr. Fee recalled Dr. Ellison telling him. “I did this one time with another family, sat down and talked with them, and I ended up getting sued. I can’t talk with you unless your son comes with you.”

Mr. Fee said he had turned to leave but distinctly recalls warning Dr. Ellison, “You keep giving Adderall to my son, you’re going to kill him.”

I heard about situations like this again and again during my years of psychiatric practice. Whereas in Singapore respect for the family can lead to ignoring the patient, in the US respect for the individual can lead to grotesque stonewalling of the family. Dr. Ellison was not wrong that privacy laws emphasize the individual's right to privacy and to control access to information about him, but skillful clinicians learn how to (a) recognize the law but (b) do what's right for the patient. Law precluded Dr. Ellison from giving information to Richard's father, but it did not preclude listening to his father, explaining why he would not give out information without Richard's permission, thanking the father for his concern, and creating an opportunity for further connection.

Years ago I had a patient who (a) was in a suicidal crisis, (b) hated the hospital and had not benefitted from previous admissions, and (c) had responsible, caring friends who (d) were able to provide support and (e) would want to do so. My patient and I had a version of the following dialogue:

Patient: I won't go to the hospital!
Me: I don't want you in the hospital, but we have to keep you safe, and we'll need help from XYZ.
Patient: You can't talk with them.
Me: Since I know how much you hate the hospital and believe we can get you better without it, I'm going to talk with XYZ, but I want to do it with your permission.
Patient: You can't talk with XYZ - what about privacy and my rights?
Me: Your most important right is to be alive until  your time comes. I'd like to have your permission to talk with XYZ, but I'm going to do it one way or the other...

My  patient ultimately grudging agreed, XYZ came to the office, and we got through the crisis. But I'd meant what I'd said - if my patient had not given me permission I would have contacted XYZ. It made no sense for law to give me the power to impose involuntary hospital commitment but to forbid me from getting help from caring and competent friends without permission.

As Dr. Johnson taught us, the law can be an ass. US laws surrounding informational privacy are well-intended, but they're too simple-minded to apply to all human situations. Richard Fee might be alive if the medical establishment had not treated him as an isolated atom suffering from a deficiency of stimulant medication.

Western Bioethics Ignores the Family

At the end of my stay in Singapore I participated in a conference on "The Ethics of Family Involvement in Healthcare," sponsored by an international research consortium I'd not encountered before but whose mission I was totally in sync with:

Despite many attempts to broaden its ethical gaze beyond the patient-centered focus of traditional medical ethics, bioethics remains strongly individualistic. The patient is treated as a self-interested individual unencumbered by personal relationships, and the principle of self-determination is dominant. However, many areas of biomedicine call for a more relational perspective. This international collaborative project on family ethics is about just that.

In my clinical work I've been very attentive to the family context of my patients, but in my work on ethics it's the neglect of the individual's responsibilities as part of a society that I've attended to. I've argued ad infinitum that medical ethics - especially in the US - has attended too exclusively to the needs and interests of the "numerator" (the individual) without attending to the needs and interests of the "denominator" (the society the individual is part of). In the US that focus has led to wildly excessive health expenditures and neglect of public health and other social goods.

In 1989, during my first visit to India, I visited the psychiatry department at Banaras Hindu University. A resident who was Indian by birth but who'd lived in the US through his teen age years and seemed very American was showing me around. On a hospital ward I saw an older woman combing the hair of young adult patient. I asked about what I interpreted as remarkable nursing care. The resident explained that this was her mother, and that patients were accompanied in the hospital by family members. I then asked a very American question - weren't the patients worried about privacy and confidentiality? The resident, despite having grown up in the US, simply didn't understand my question. He explained that their worry was about not being extruded from the family.

My question showed that I'd been more influenced  than I'd realized by the tendency in US psychiatry to blame the family for the patient's problems. When I trained as a resident (1965 - 1968) and did a fellowship at the Family Studies Unit at the National Institute of Health (1968 - 1970), the concept of the "schizophrenogenic mother" was still widely accepted. When I was responsible for a hospital unit at the Massachusetts Mental Health Center (1970 - 1973), I was concerned that many staff members had a hostile view towards families, and often made them feel unwelcome, and I did teaching sessions about the important role of families as caretakers. But at Banaras Hindu University my reaction focused on fear of not having privacy, not fear losing family ties.

I believe the tendency of US medical ethics to see the individual as an atom of self-interest and threatened rights comes from two main sources - (a) the anti-family tilt of American culture in the last half of the 20th century and (b) an effort to give the patient more authority and power in the patient/physician relationship. This latter aim has led to a beneficial and overdue rebalancing of the interaction between patient and physician elegantly conceptualized in the concept of "shared decision making," but US medical ethics needs to incorporate more recognition of the role of "families of origin" and "families of choice" in the ethical equation.

There's no way to make clinical ethics tidy. Sometimes families are intrusive, hurtful, and even profoundly destructive. Somtimes they are nurturing and crucial for an individual's well being. And, as most of us have experienced, family involvement is typically a blend of delight and exasperation. Sorting out the situation is what makes the health professions so challenging, so important, and so much fun!

Protein, Ketogenesis, and Glucose Oxidation

In our last post, we discussed the relationship between protein and blood sugar in ketogenic dieters.

Despite all the evidence we have brought to bear suggesting that increased protein does not increase GNG, there is an important line of argument that does support the idea that increased protein increases GNG. Although the data is indirect, and some of it is poorly documented, it is compelling.

This supporting argument is the relationship between protein and glucose oxidation (the use of glucose as fuel). As we mentioned in our last post, the rate of GNG is not what we really care about as keto dieters.

What we want to know is whether excess protein leads to using a higher total amount of glucose as fuel. The amount of glucose oxidation matters, because the benefits we expect to gain from a keto diet are probably a result of using ketones for fuel instead of glucose whenever we can.

In Brief

• Excess protein probably results in lower ketone levels. Although there is a paucity of hard clinical evidence, there are several reasons to believe this is true.
• There appears to be an inverse relationship between ketone levels and glucose oxidation.
• Therefore, increasing protein probably increases glucose oxidation.

If so, then

• Eating more protein would reduce the benefits of a ketogenic diet, by making it less ketogenic, and increasing glucose oxidation.
• This would need to be reconciled with the combined evidence that I/G appears to be the main determinant of ketogenesis, and yet doesn't appear to change in keto dieters eating protein.

As always, we'd like to see experimental confirmation of these ideas instead of just relying on the "chains of plausible mechanism" outlined here. Chains of plausible mechanism can be broken by a single weak link, or by other effects that we didn't take into account.

Protein and Ketogenesis

It is already widely believed and asserted that excess protein reduces ketone production. For example, this is stated in Peter Attia's blog, which we highly recommend ⁰, and in Volek and Phinney's excellent book, The Art and Science of Low Carbohydrate Living ¹. However, as far as we are aware, there aren't any experiments that measure this directly and without confounders. The mechanism cited is the rise in insulin that protein induces. In our previous article, we presented evidence that the insulin-to-glucagon ratio is not significantly changed in response to protein in ketogenic dieters. That article also cites evidence that the insulin-to-glucagon ratio (I/G) is an accurate predictor (and perhaps even cause) of glucose regulation. Moreover, there is evidence that ketogenesis is itself regulated by the insulin-to-glucagon ratio ², ³, ⁴. So we don't find that explanation particularly compelling. Nonetheless, there may be other lines of evidence that we are not yet aware of.

The following indirect argument suggests that protein inhibits ketogenesis. There appears to be an inverse relationship between ketosis and blood sugar ⁵. We have already shown that protein raises blood sugar in ketogenic dieters. Together, this would seem to indicate that protein decreases ketosis.

If protein inhibits ketogenesis, then the following argument can be made that protein increases glucose oxidation. It would make intuitive sense that higher blood ketone concentrations would correspond to lower levels of glucose oxidation, since ketones can usually replace glucose for fuel. In fact, in some studies, an inverse relationship has been shown to hold between glucose oxidation and serum ketone levels in people fasting for short periods ⁶, and in epileptic children ⁷. (See also the the Randle Cycle.) Therefore, if protein inhibits ketogenesis, it very likely increases glucose oxidation.

Can we determine the effect of protein on glucose oxidation directly?

Scientists do have ways to measure glucose oxidation, for example through indirect calorimetry. We can measure respiratory quotient (RQ): the proportion of oxygen in exhalation is used to infer the proportion of fat and glucose being used, by taking advantage of the fact that oxidizing fat and oxidizing glucose require different amounts of oxygen. Then you can combine this with resting energy expenditure (REE), a measure of calories expended, to determine the total amount of glucose being used for energy. Observations that would indicate more glucose oxidation include: higher energy expenditure at the same RQ, or higher RQ at the same energy expenditure.

If such an effect is confirmed, knowing its magnitude would be equally important. I.e., how much extra glucose oxidation would be expected from a certain amount of excess protein? Is it linear, or is there a large effect at the beginning, and very little effect after, or some other relationship? All of this is far from clear to us. We would love to see it addressed experimentally, since even though we are inclined to believe it, there are some potential confounders, including changes in fat and calorie intake, and differential effects of different types of fat and protein.

Conclusion

There is evidence that protein does not increase the rate of GNG. There is evidence that I/G, which appears to control glucose production and ketogenesis, does not change in keto dieters when they eat protein. Nonetheless, there are compelling arguments that protein increases glucose oxidation in keto dieters. Experiments will need to be done to reconcile these seeming contradictions.

In the meantime, limiting protein to levels that are known to be adequate seems prudent.

Further Reading

Lucas Tafur has an interesting and relevant article entitled Safe starches, blood glucose and insulin.

References

⁰ Evidence type: authority

Both insulin and glucose (probably by causing the secretion of insulin) suppress ketones. This is why, for example, consuming more than about 50 gm of carbohydrates per day and/or more than about 120-150 gm of protein per day makes it difficult to be in nutritional ketosis – too much insulin secretion.

¹ Evidence type: authority
Stephen J. Phinney and Jeff S. Volek. The Art and Science of Low Carbohydrate Living: An Expert Guide to Making the Life-Saving Benefits of Carbohydrate Restriction Sustainable and Enjoyable. Beyond Obesity LLC (May 19, 2011). ISBN-10: 0983490708

Another reason to avoid eating too much protein is that it has a modest insulin stimulating effect that reduces ketone production. While this effect is much less gram-for-gram than carbohydrates, higher protein intakes reduce one's keto-adaptation and thus the metabolic benefits of the diet.

² Evidence type: review of experiments
Foster DW, McGarry JD. The regulation of ketogenesis. Ciba Found Symp. 1982;87:120-31.

(Emphasis ours)

Abstract

Ketone bodies accumulate in the plasma in conditions of fasting and uncontrolled diabetes. The initiating event is a change in the molar ratio of glucagon:insulin. Insulin deficiency triggers the lipolytic process in adipose tissue with the result that free fatty acids pass into the plasma for uptake by liver and other tissues. Glucagon appears to be the primary hormone involved in the induction of fatty acid oxidation and ketogenesis in the liver. It acts by acutely dropping hepatic malonyl-CoA concentrations as a consequence of inhibitory effects exerted in the glycolytic pathway and on acetyl-CoA carboxylase (EC 6.4.1.2). The fall in malonyl-CoA concentration activates carnitine acyltransferase I (EC 2.3.1.21) such that long-chain fatty acids can be transported through the inner mitochondrial membrane to the enzymes of fatty acid oxidation and ketogenesis. The latter are high-capacity systems assuring that fatty acids entering the mitochondria are rapidly oxidized to ketone bodies. Thus, the rate-controlling step for ketogenesis is carnitine acyltransferase I. Administration of food after a fast, or of insulin to the diabetic subject, reduces plasma free fatty acid concentrations, increases the liver concentration of malonyl-CoA, inhibits carnitine acyltransferase I and reverses the ketogenic process.

³ Evidence type: experiment (non-human animals)
Ubukata E, Mokuda O, Sakamoto Y, Shimizu N. Effect of various glucagon/insulin molar ratios on blood ketone body levels in rats by use of osmotic minipumps. Diabetes Res Clin Pract. 1996 Sep;34(1):1-6.

Abstract

The bihormonal control by insulin and glucagon of blood ketone body level was studied. Mixed solutions with various molar ratios of glucagon and insulin (G/I) were subcutaneously infused continuously for five days by use of the osmotic minipump in the normal rats. The concentrations of insulin and glucagon solution were set at the high G/I molar ratio, the moderate G/I molar ratio and the low G/I molar ratio. In addition, the moderate G/I molar ratio group was divided into three sub-groups: low glucagon and low insulin, moderate glucagon and moderate insulin, and high glucagon and high insulin. After five days, the rats were decapitated to measure plasma ketone body, free fatty acid (FFA), glucose, insulin and glucagon. The FFA level was not significantly different among three groups. The glucose level was not different between the high and moderate G/I molar ratio groups, and decreased in the low G/I molar ratio group. 3-beta-hydroxybutyrate (3-OHBA) and acetoacetate (AcAc) levels in the high G/I molar ratio group were elevated, and 3-OHBA level in the low G/I molar ratio group was lowered compared to those in the moderate G/I molar ratio group. Among three moderate G/I molar ratio sub-groups, there was no difference in 3-OHBA and AcAc levels. These results demonstrate that plasma ketone body levels are controlled by the plasma G/I molar ratio.

⁴ Evidence type:
Fukao T, Lopaschuk GD, Mitchell GA. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fatty Acids. 2004 Mar;70(3):243-51.

(Emphasis ours)

Abstract

Ketone bodies become major body fuels during fasting and consumption of a high-fat, low-carbohydrate (ketogenic) diet. Hyperketonemia is associated with potential health benefits. Ketone body synthesis (ketogenesis) is the last recognizable step of lipid energy metabolism, a pathway that links dietary lipids and adipose triglycerides to the Krebs cycle and respiratory chain and has three highly regulated control points: (1) adipocyte lipolysis, (2) mitochondrial fatty acids entry, controlled by the inhibition of carnitine palmityl transferase I by malonyl coenzyme A (CoA) and (3) mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase, which catalyzes the irreversible first step of ketone body synthesis. Each step is suppressed by an elevated circulating insulin level or insulin/glucagon ratio. The utilization of ketone bodies (ketolysis) also determines circulating ketone body levels. Consideration of ketone body metabolism reveals the mechanisms underlying the extreme fragility of dietary ketosis to carbohydrate intake and highlights areas for further study.

(But note that this suggests that there may be a pathway for suppression by elevated insulin alone.) ⁵ Evidence type: review of experiments
Amanda E. Greene, Mariana T. Todorova, Richard McGowan, Thomas N. Seyfried. Caloric Restriction Inhibits Seizure Susceptibility in Epileptic EL Mice by Reducing Blood Glucose. Epilepsia. Volume 42, Issue 11, pages 1371–1378, November 2001. DOI: 10.1046/j.1528-1157.2001.17601.x

Our findings in mice together with those in humans indicate that CR, like fasting, lowers blood glucose levels while inducing ketosis (1,41–44). This contrasts with studies of the KD, in which blood glucose levels are not reduced in association with ketosis (5,15). It is interesting to note that the antiseizure effect of the KD was greater when it was administered under restricted than under ad libitum conditions (12), suggesting that reduced blood glucose levels may enhance the efficacy of the KD. Despite evidence for an inverse relation between blood glucose and ketone levels in normal humans and humans with epilepsy under fasting or the KD (45), little attention has been given to the possibility that these dietary therapies prevent seizures through an effect on blood glucose levels. From previous neurochemical studies and from our statistical analyses, we show that blood glucose levels determine both blood ketone levels and seizure susceptibility in EL mice and emphasize the importance of blood glucose as a predictor of epileptogenesis in this epilepsy model.

⁶ Evidence type: experiment
J.A. Romijn, M.H. Godfried, M.J.T. Hommes, E. Endert, H.P. Sauerwein. Decreased glucose oxidation during short-term starvation. Metabolism, Volume 39, Issue 5, May 1990, Pages 525–530. http://dx.doi.org/10.1016/0026-0495(90)90012-2

(Emphasis ours)

Abstract

Prolonged fasting (for days or weeks) decreases glucose production and oxidation. The effects of short-term starvation (ie, < 24 hours) on glucose metabolism are not known. To evaluate this issue, glucose oxidation and glucose turnover were measured after 16-hour and subsequently after 22-hour fasting. Glucose oxidation was calculated by indirect calorimetry in 12 healthy men (age 22 to 44 years); glucose turnover was measured by primed, continuous infusion of 3-3H-glucose in eight of these 12 volunteers. After 16-hour fasting net glucose oxidation was 0.59 ± 0.17 mg · kg−1 · min−1 and glucose tissue uptake 2.34 ± 0.12 mg · kg−1 · min−1. No correlation was found between net glucose oxidation and glucose tissue uptake. Prolonging fasting with an addtional 6 hours resulted in decreases of respiratory quotient (0.77 ± 0.01 v 0.72 ± 0.01) (P < .005), plasma glucose concentration (4.7 ± 0.1 v 4.6 ± 0.1 mmol/L) (P < .05), glucose tissue uptake (2.10 ± 0.12 mg · kg−1 · min−1)(P < .05), net glucose oxidation (0.09 ± 0.04 mg · kg−1 · min−1)(P < .005), and plasma insulin concentration (8 ± 1 v 6 ± 1 mU/L) (P < .005). Net glucose oxidation expressed as a percentage of glucose tissue uptake decreased from 22% ± 8% to 2% ± 1% (P < .05). There was no net glucose oxidation in seven of 12 controls after 22-hour fasting. Serum free fatty acid (FFA) concentration (364 ± 34 to 575 ± 48 μmol/L) (P < .005) and plasma ketone body concentration (104 ± 23 to 242 ± 38 μmol/L) (P < .005) increased between 16- and 22-hour fasting. After 16-hour fasting an inverse correlation was found between ketone body concentration and net glucose oxidation (P < .05) and between ketone body concentration and net glucose oxidation expressed as a percentage of glucose tissue uptake (P = .07). No significant correlation could be demonstrated between FFA and ketone body concentration and between FFA and net glucose oxidation. It is concluded that glucose oxidation decreases rapidly even within 1 day of starvation. This may be explained by physiological mechanisms like decreased insulin action and/or inhibition of glucose oxidation by ketone bodies, even in relatively low concentrations.

⁷ Evidence type: experiment
M. W. Haymond, C. Howard, E. Ben-Galim, and D. C. DeVivo. Effects of ketosis on glucose flux in children and adults AJP - Endo October 1, 1983 vol. 245 no. 4 E373-E378

Abstract

Sequential glucose flux [rate of appearance - rate of disappearance] studies were carried out in five normal and six epileptic children and ten adult volunteers using [6,6-2H2]glucose to determine the effect of ketosis on carbohydrate homeostasis in children and adults. All subjects were studied after 14 and 30-38 h of fasting while consuming a normal diet and the epileptic children under 14 h of fasting while consuming an isocaloric ketogenic diet (75% fat wt/wt). Glucose flux, when expressed per kilogram body weight, was inversely correlated with the degree of ketosis in children (P less than 0.001) and in adults (P less than 0.01), but not when both children and adults were considered together (r = 0.078). When glucose flux was corrected for estimated brain weight, the relationship between glucose flux and ketonemia was linearly related in children (P less than 0.001), in adults (P less than 0.02), and when all subjects were considered together (P less than 0.001). The inverse relationship between ketonemia and glucose flux corrected for estimated brain mass is consistent with a partial replacement of glucose by ketone bodies for cerebral metabolism and may provide a more rational means of expressing glucose flux data to take into account the higher brain-to-body ratio in children.

...

An inverse relationship was observed between ketone body concentration and glucose utilization whether expressed on a body weight or estimated brain weight basis. The relationship between glucose utilization (on a brain weight basis) and ketone body concentration may not be completely linear because glucose utilization appears to approach a minimum of 20-30 µmol·min⁻¹ 100 g estimated brain⁻¹ at ketone body concentration of 5 mM or greater. This observation suggests that a basal requirement for glucose utilization may exist that cannot be supplanted by ketone bodies regardless of their plasma concentration and is in keeping with the observation that a basal glucose oxidation rate is required by brain tissue for optimum utilization of ketone bodies (13).