It’s OK to Love Carbs... & Why You Might Want to Eat More of Them
I have tried the ketogenic diet.
I did it for 3 months in the lead up to my wedding. Admittedly, it was partially to see how svelte I could get for my wedding dress but I also wanted to see how it would affect my energy and well-being with autoimmune diseases (I have Hashimoto’s & Celiac Disease.)
Here is a quick summary of my experience:
I lost a bunch of weight out the gate (almost 10 lbs in less than 2 weeks!) and then I stalled. I stayed at that weight for 2 months in the lead up to my wedding but I didn’t stop the ketogenic diet because I was too afraid I would balloon the moment I ate another carb.
My bowels seemed to like the diet for the first month and then everything went haywire. I started seeing things I used to see when I was full blown celiac (like pieces of undigested food and some mucous… not cool!)
The same trend held for my energy and mental state. I was bouncing off the walls at first, I couldn’t believe how much energy I had. Then, I started to become anxious. I found myself becoming worse and worse at handling stress. I was much more emotional and eventually my energy tanked.
After my wedding I started to reintroduce carbohydrates in a slow and measured manner and sure enough, my energy and mood stabilized, my bowels sorted themselves out and yes, I gained most of the weight back.
But if we’re being honest, I should never have tried to lose weight. I am at a health (SEXY!) weight. I know my body likes being here because when I’m not counting macros or calories, this is where I stay no matter what. Evidentially, this is the weight my body functions optimally at.
Perhaps that is the first thing I should note for anyone trying to figure out where their carbohydrate consumption should be at. Are you trying to see if you should limit carbohydrates so that you can lose weight? Or are you seeing if you should limit them for your overall health?
This is the thing.
Restricting carbohydrates and/or the ketogenic diet will likely lead to weight loss, but at what cost?
That is what I’m really here to discuss.
Now, I don’t like to take a hard line on most things because nutritional science is very difficult to draw definitive conclusions from and it is constantly evolving as we learn more and more.
However, as of now, the science seems to indicate that it, in fact, ok to love carbs… and you may want to eat more of them… you’re welcome.
It’s All About the Insulin
When we consume carbohydrates, our blood sugar increases. When our blood sugar increases, our pancreas releases the hormone insulin. Insulin, then, shuttles that sugar (glucose) from our bloodstream into the cells for energy. Insulin also signals the liver to convert any excess glucose into glycogen, which can be stored in the liver and muscles for short term storage. If there is excess beyond that, insulin will signal the liver to turn glucose into triglycerides (fat) for long-term storage in adipose tissues.
This system is what allows us to get away with that extra scoop of ice cream or extra handful of M&M… until it doesn’t anymore.
When blood sugar levels become chronically elevated, our cells eventually get sick of listening to insulin and become less likely to open the door when it comes a knocking. Essentially, the cell adapts to become less sensitive to insulin by reducing the number of insulin receptors and suppressing the signalling within the cell that occurs when insulin does bind to a receptor.
Well, insulin doesn’t like to be ignored so what happens when the cell becomes less sensitive? Insulin calls in for backup. The pancreas secretes more and more insulin in an attempt to lower elevated blood glucose levels. Generally, the cells just become more and more resistant.
This is insulin resistance.
Insulin resistance is undeniable a bad thing. It promotes weight gain, because the sugar cant get into the cell so it’s got to go somewhere! It increases the risk of diabetes, cardiovascular disease, asthma, allergies, PCOS, chronic kidney disease and many autoimmune diseases.
Ummm, Megan? I thought you were here to tell me why eating carbs was good… not bad. Doesn’t this suggest I should cut carbs to avoid or reverse insulin resistance?
Well, if you do have diabetes or metabolic syndrome then it may make sense to track your carbohydrate consumption and measure your blood sugar levels after meals. And, of course shovelling back ice cream and M&M’s is not ideal.
For optimal health we always want to limit refined sources of sugar and carbohydrates.
However, I do not recommend turning to a ketogenic diet or going extremely low-carb to the point of limiting healthy carbohydrates like whole fruits & starchy vegetables the way “health” and diet trends seem to be directed these days.
This is because the picture I just painted of insulin’s role in the body is just one small piece of the puzzle.
Insulin plays numerous important roles in human health independent of its role in blood sugar management.
So, while we definitely don’t want to become insulin resistant, we also don’t want to eat so few carbs that we halt insulin signalling altogether. Doing so could lead to additional health problems and make weight management even more difficult in the long run.
As we explore some of insulin’s other important jobs in the human body, I think it will become pretty clear why too little insulin, or reduced insulin signalling, may have some serious consequences.
Insulin & The Immune System
As my focus is on autoimmune disease, I think it is important to start with how insulin interacts with your immune system.
In the innate immune system, insulin signalling activates neutrophils (the first line of defence actions infection or injury), aids their transport from blood into the tissues, and stimulates phagocytosis (the process in which these immune cells essentially eat and destroy pathogens).
Insulin signalling also increases phagocytosis in macrophages (immune cells found in all tissue in the body) and activates dendritic cells (immune cells found in barrier tissues).
Insulin also promotes activity of natural killer cells, responsible for destroying infected or cancerous cells.
When insulin levels are elevated, these effects result in generalized inflammation. However, we become insulin resistance or do not produce enough insulin (as on a low-carb diet) the activity of these cells of the innate immune system is impaired.
In the adaptive immune system (the one that remembers the chicken pox and prevents you from every getting it again, insulin activates CD4+ T cells. This includes a full range of helper T cells (also known as effector cells since they drive immune attacks) AND regulatory T cells (the guys that modulate these immune responses and prevent autoimmune disease).
When insulin is elevated, Th1 and Th17 helper T cell subsets (these guys are heavily implicated in allergic, immune and autoimmune conditions) become more stable and resistant to modulation by external factors.
Blocking insulin signalling results in lower cytokine production, reduced proliferation, reduced migration and increased apoptosis (cell death) of CD4+ T cells, INCLUDING reduced activity of regulatory T cells.
These effects of insulin on specific immune cells suggest that insulin is, in fact, required for a normal, healthy and balanced immune response. It also explains why chronically elevated insulin is inflammatory and why insulin resistance (ie. reduced insulin signalling) is associated with allergic, inflammatory and autoimmune diseases and reduced ability to fight off infection.
Seeing as insulin resistance leads to inflammation and increased susceptibility to infection, we expect to see the same when insulin signalling is impaired by a very low carbohydrate or ketogenic diet. Some studies observing a ketogenic diet have already documented this effect.
One study showed an increase in C-reactive protein (a blood marker of inflammation) during weight loss with a low-carb, high-fat diet.
Another study in patients with rheumatoid arthritis showed no benefit to they inflammatory cytokine IL-6 nor to T cell numbers or activation with a ketogenic diet.
Additionally, in an animal study of malignant gloomy, a ketogenic diet increased the numbers and activation of CD4+ T cells (especially Th1), while decreasing the population of regulatory T cells.
Furthermore, long-term studies of ketogenic diets in children with epilepsy show a trend toward reduced white blood cell and neutrophil counts, while also reporting increased vulnerability to serious infection due to ketogenic diets, affecting 10 - 15% of study participants.
So again, we don’t want chronically elevated blood sugar, but we also don’t want to lose insulin signalling altogether.
This becomes even more apparent when we consider insulin’s effects on our hormonal systems.
Insulin & The Sex Hormones
Insulin is an important factor in sex hormone balance.
Insulin acts synergistically with insulin-like growth factor 1 and follicular stimulating hormone (FSH) to enhance the production of estrogen and testosterone.
High levels of insulin are associated with low levels of sex-hormone binding globulin (SHBG). Just like it sounds SHBG binds to sex hormones (estrogen and testosterone) in the blood, rendering them inactive. This is important for maintaining a balance between testosterone and estrogen activity. It also aids in the migration of these sex hormones into specific tissues.
So, elevated insulin levels causes an excess of sex hormone production AND they are more active because they’re not bound to SHBG.
In women, hyperinsulinemia (elevated insulin levels) may lower estrogen levels but low estrogen levels increase insulin resistance. Because of this complicated system, insulin resistance is also associated with excess estrogen in some circumstances.
Here we can understand that once again, chronically elevated insulin levels are going to lead to excess hormone production, while inadequate insulin signalling may lead to low estrogen or testosterone and an overall imbalance.
In young, healthy rats, a ketogenic diet (which results in significantly lowered insulin signalling due to extremely limited carbohydrate consumption) suppressed sex hormones, including metabolites of progesterone and testosterone.
Additionally, a significant percentage of young women following long-term ketogenic diets for epilepsy report amenorrhea (loss fo menses) due to low hormone levels. This means they are not ovulating, making them effectively infertile due to a ketogenic diet.
As you may know, or have experienced for yourself, when one hormone system goes off, others tend to follow.
Who is next in line? Well, the adrenals definitely have something to say when insulin signalling goes haywire!
Insulin & The Adrenals
You adrenals are tiny glands that sit on top of your kidneys. They create all of your short-term and long-term stress hormones (ie. cortisol, epinephrine, & norepinephrine). They also create a portion of your sex hormones (and become the only glands to create estrogen for women once we move into menopause). On top of that they create mineralcortioids (ie. aldosterone & pregnenolone) to balance the mineral content of your blood.
First, I would like to point out the connection between the sex hormones and adrenal function. Before menopause, your adrenals are there to assist your gonads in making estrogen and testosterone. If they see an imbalance, they will help correct it. As discussed, if insulin is either chronically elevated, or insulin signalling is impaired, we will see imbalances and the adrenals will have to compensate, putting a strain on these tiny little glands when they have a lot of other jobs to do!
On top of that, insulin has its own affect directly on the adrenals. Insufficient insulin signalling, or insulin resistance, causes increased cortisol (your long-term stress hormone).
Chronically elevated cortisol levels leads to increased inflammation and may further impact the efficiency of the adrenal glands to contribute to hormone balance.
In this case, insulin signalling is extremely important for the overall function of the adrenals. This is one area that is well warned about for anyone attempting a ketogenic diet because the way in which these low carb diets halt insulin signalling yields quick and dramatic effects on the adrenals. Many people experience increased anxiety, irritability and inability to deal with stress, as I did. Eventually this can result in adrenal fatigue, leaving you lethargic and low in energy. When adrenal fatigue sets in, we also see our sex hormones become depleted as well. This is where we see another vicious cycle.
As you can see, everything is connected and insulin is a big part of that.
So what other hormones are affected by insulin? You guessed it…
Insulin & The Thyroid
Speaking of everything being connected, the thyroid gland produces hormones that control metabolism and influence the cardiovascular system, the immune system, and calcium homeostasis. Thyroid hormones increase our metabolism, control appetite, enhance nutrient absorption and improve gut motility. They also play an important role in glucose metabolism and stimulate the breakdown of fats.
T4 (the precursor to active thyroid hormone) is produced in the thyroid gland and converted into T3 (your active thyroid hormone). The conversion of T4 to T3 is made possible by a group of enzymes called deiodinases. There are 3 types of deiodinases, all present in different parts of the body.
Type 2 deiodinase is the most active type. In fact, it is approximately 1000x more active than either type 1 or type 3. Notably, the action of type 2 deiodinase in T3 production increases thyroid hormone signalling and blocking them can even cause localized hypothyroidism in various tissues. It is important, then, to understand that the activity of type 2 deiodinase is unregulated by insulin and decreased during fasting.
Therefore, insulin can stimulate the conversion of T4 to T3 via its effect on D2 activity. Without that action, thyroid function can severely plummet and we are seeing that in numerous studies on the ketogenic diet.
A recent study involving 120 perdiatric epilepsy patients following a ketogenic diet, subjects experienced an overall decrease in free T3 and a corresponding rise in TSH. 1 in 6 (20 of the 120) participants ended up with hypothyroidism requiring medication with levothyroxin within the just 6 months of beginning the study! And 8 of them developed hypothyroidism within the first month! Interestingly, women were more likely to develop hypothyroidism due to the ketogenic diet than men. However, thyroid suppression was evident in all participants, with an overall significant increase in TSH and decrease in free T3.
Proponents of a ketogenic diet will argue that reduced T3 is a symptom of weight loss in general but it should not induce clinical hypothyroidism! In fact, it is more often due to overweight individuals overproduction of thyroid hormone normalizing with healthy weight loss that this association even exists. Recent studies corroborate this theory, investigating the effect of weight loss via calorie restriction on thyroid function and identifying no increased risk of hypothyroidism with T3 and TSH remaining within normal lab ranges across the board.
A variety of other human and animal studies observing the effects of a ketogenic diet report reduced body temperature, fatigue, lethargy and torpor as significant side effects.
For these reasons, those with thyroid conditions may want to be especially careful about going too low carbohydrate.
But Megan… if I can’t go low carb, how am I supposed to lose body fat with hypothyroidism?
My suggestion would be to focus on muscle building.
Insulin and The Muscles
Building muscle protects against insulin resistance, diabetes and cardiovascular disease. Increase muscle mass also leads to increased metabolism and aids in weight management.
Once again, going too low carbohydrate can be problematic for muscle building. In fact, numerous human and animal studies observing ketogenic diets have demonstrated loss of lean muscle mass, with greater protein sparing than a comparable weight loss protocol using caloric deficit and balanced macronutrients.
On top of insulin’s role in shuttling glucose into the muscle cells for use as energy, insulin is also essential for protein metabolism in muscle. Insulin supports muscle growth and repair and prevents its breakdown. It does this by facilitating the transport of amino acids into the muscle tissue, making them available for muscle protein synthesis. Insulin will continue to reduce muscle protein breakdown independent of amino acid availability.
So… How Many Carbs Should I Eat?
Well, clearly we want to avoid insulin resistance, but avoiding or drastically cutting carbohydrate intake is not necessary and, as discussed, could be problematic. We tend to see a U-curve when it comes to the benefits of carbohydrates: too much or too little is not ideal.
We simply want to keep our blood sugar levels in a healthy range. This can be achieved simply by sticking to whole food sources of carbohydrates, like whole fruits and starchy vegetables. It is also advisable to eat them as part of a well-rounded meal that includes protein and non-starchy, high-fibre vegetables, like broccoli, cauliflower, kale, etc.
For those who already have insulin resistance or diabetes, tracking your carbohydrate portions and measuring your glucose levels after each meal is still advisable. I recommend working closely with your nutritionist or another health care practitioner to personalize a healthy approach to blood sugar management.
I would proposed that the amount of carbohydrates you need depends on how much you need to eat of different types of foods in order to reach your micronutrient requirements! When we take this approach, macronutrients end up being quite balanced.
When we eat too little of any macronutrient, we can become malnourished from a micronutrient perspective because different types of foods contain different types of nutrients and facilitate absorption in different ways.
For example, fat is required for the absorption of vitamins A, D, E and K, so not enough fat will result in lower levels of those nutrients and deprive us of essential fatty acids.
Inadequate protein intake can lead to insufficient essential amino acids, but animal foods (naturally high in protein) are also our predominant source of micronutrients such as B12, heme iron, zinc, pre-formed vitamin A, and vitamin D.
Meanwhile, without enough carbohydrates we can become deficient in fibre, and important nutrients found primarily in fruits and vegetables like vitamin C, vitamin K, potassium, magnesium, chromium, and phytochemicals including polyphenols, chlorophyll, carotenoids, isothiocyanates and organosulfur compounds.
For this reason, healthy ratios of calories from carbohydrates, fat, and protein, as supported by the Accepted Macronutrient Distribution Ranges (AMDR) established by the Food and Nutrition Board of the Institute of Medicine (using evidence from interventional trials with support of epidemiological evidence that suggest a role in the prevention or increase risk of chronic diseases, and based on ensuring sufficient intake of essential nutrients), look a little something like this:
20-35% calories from fat
20-35% calories from protein
30-60% calories from carbohydrate
Please note that these calories should ideally come from whole food sources and that each individual is different so there is definitely room for wiggling within these ranges.
People with copies of the ApoE4 gene may do better with fat intake closer to 15%
Studies that cap healthy fat intake at 35% do not take fat quality into account, so it may be very health to have fat intake upwards of 50% of total calories when coming from sources like EVOO, fish and pastured meats.
Carbohydrate quality is also important.
Sugars (even from whole food sources like fruit) shouldn’t make up more than 25% of total calories.
Added sugars (even honey or maple syrup) should account for less than 10% of calories
High fibre intake (upwards of 25g daily) is also important for optimal health
Seasonal variation may also be beneficial, typically leaning toward more protein and fat in the winter and more carbs in the summer.
The Bottom Line
The science seems to suggest that a balanced macronutrient intake is ideal for optimal health. However, everyone is different and if you feel best outside the suggested ranges, listen to your body. I just recommend avoiding macronutrient extremes. Protein and fat should not dip below 10% of calories and carbs should not dip below 20% for best health. All macronutrients offer important functions within the body and tend to come along with their own valuable micronutrients.
Insulin signalling affects many systems in the body including your immune system, hormone systems, thyroid, adrenals and even your muscles. This is a huge reason to avoid extreme carbohydrate restriction. The extreme low-carb and ketogenic approach poses some risks because of this.
So go ahead… have some sweet potato… how about a banana?
These are healthy foods and can be incorporated into a well-balanced diet without causing insulin resistance, diabetes or provoking inflammatory or autoimmune diseases.
If you have any questions, queries, comments or concerns, please feel free to drop me a line below! Let’s have a conversation!
Kisses & kombucha,
Abdulla H, Smith K, Atherton PJ, Idris I. Role of insulin in the regulation of human skeletal muscle protein synthesis and breakdown: a systematic review and meta-analysis. Diabetologia. 2016 Jan;59(1):44-55. doi: 10.1007/s00125-015-3751-0. Epub 2015 Sep 24.
Agnihothri RV, Courville AB, Linderman JD, et al. Moderate Weight Loss Is Sufficient to Affect Thyroid Hormone Homeostasis and Inhibit Its Peripheral Conversion. Thyroid. 2014;24(1):19-26. doi:10.1089/thy.2013.0055.
Amer J, Salhab A, Noureddin M, Doron S, Abu-Tair L, Ghantous R, Mahamid M, Safadi R. Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease. Hepatol Commun. 2018 Feb 14;2(3):285-298. doi: 10.1002/hep4.1146. eCollection 2018 Mar.
Arneth B. Activation of CD4+ and CD8+ T-lymphocytes by insulin and GAD in patients with type 1 or 2 diabetes mellitus. Endocr Connect. 2017 Nov;6(8):758-765. doi: 10.1530/EC-17-0230. Epub 2017 Oct 6.
Arneth BM. Activation of CD4 and CD8 T cell receptors and regulatory T cells in response to human proteins. PeerJ. 2018 Mar 9;6:e4462. doi: 10.7717/peerj.4462. eCollection 2018.
Bergqvist AG, Schall JI, Stallings VA, Zemel BS. Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am J Clin Nutr. 2008 Dec;88(6):1678-84. doi: 10.3945/ajcn.2008.26099.
Bertoli, S., Trentani, C., Ferraris, C., De Giorgis, V., Veggiotti, P., Tagliabue, A. Long-term effects of a ketogenic diet on body composition and bone mineralization in GLUT-1 deficiency syndrome: a case series. Nutrition. 2014 Jun;30(6):726-8. doi: 10.1016/j.nut.2014.01.005. Epub 2014 Jan 29.
Brooks DC, Bessey PQ, Black PR, Aoki TT, Wilmore DW. Insulin stimulates branched chain amino acid uptake and diminishes nitrogen flux from skeletal muscle of injured patients. J Surg Res. 1986 Apr;40(4):395-405.
Cervenka MC, Henry-Barron BJ, Kossoff EH. Is there a role for diet monotherapy in adult epilepsy? Epilepsy Behav Case Rep. 2016 Sep 20;7:6-9. doi: 10.1016/j.ebcr.2016.09.005. eCollection 2017.
Chang CK, Borer K, Lin PJ. Low-Carbohydrate-High-Fat Diet: Can it Help Exercise Performance? J Hum Kinet. 2017 Mar 12;56:81-92. doi: 10.1515/hukin-2017-0025. eCollection 2017 Feb.
Chrysohoou C, Panagiotakos D, Pitsavos C, Siasos G, Oikonomou E, Varlas J, Patialiakas A, Lazaros G, Psaltopoulou T, Zaromitidou M, Kourkouti P, Tousoulis D, Stefanadis C. Low total testosterone levels are associated with the metabolic syndrome in elderly men: the role of body weight, lipids, insulin resistance, and inflammation; the Ikaria study. Rev Diabet Stud. 2013 Spring;10(1):27-38. doi: 10.1900/RDS.2013.10.27. Epub 2013 May 10.
Coppola G, Veggiotti P, Cusmai R, Bertoli S, Cardinali S, Dionisi-Vici C, Elia M, Lispi ML, Sarnelli C, Tagliabue A, Toraldo C, Pascotto A. The ketogenic diet in children, adolescents and young adults with refractory epilepsy: an Italian multicentric experience. Epilepsy Res. 2002 Feb;48(3):221-7.
Corbould A. Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome? Diabetes Metab Res Rev. 2008 Oct;24(7):520-32. doi: 10.1002/dmrr.872.
Cordain L, Miller JB, Eaton SB, Mann N, Holt SH, Speth JD. Plant-animal subsistence ratios and macronutrient energy estimations in worldwide hunter-gatherer diets. Am J Clin Nutr. 2000 Mar;71(3):682-92.
Costa Rosa LF, Safi DA, Cury Y, Curi R. The effect of insulin on macrophage metabolism and function. Cell Biochem Funct. 1996 Mar;14(1):33-42.
Daka B, Rosen T, Jansson PA, Råstam L, Larsson CA, Lindblad U. Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden. Endocr Connect. 2012 Nov 19;2(1):18-22. doi: 10.1530/EC-12-0057. Print 2013 Mar 1.
Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA. Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S52-9. doi: 10.1016/S0168-8227(11)70014-6.
Drigo RA, Fonseca TL, Werneck-de-Castro JPS, Bianco AC. Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochimica et biophysica acta. 2013;1830(7):3956-3964. doi:10.1016/j.bbagen.2012.08.019.
Eaton SB & Konner M. “Paleolithic nutrition. A consideration of its nature and current implications.” N Engl J Med. 1985 Jan 31;312(5):283-9.
Elia M, Klepper J, Leiendecker B, Hartmann H. Ketogenic Diets in the Treatment of Epilepsy. Curr Pharm Des. 2017;23(37):5691-5701. doi: 10.2174/1381612823666170809101517.
Fischer HJ, Sie C, Schumann E, Witte AK, Dressel R, van den Brandt J, Reichardt HM. The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity. J Immunol. 2017 Mar 1;198(5):1910-1920. doi: 10.4049/jimmunol.1601011. Epub 2017 Jan 23.
Fraser DA, Thoen J, Bondhus S, Haugen M, Reseland JE, Djøseland O, Førre O, Kjeldsen-Kragh J. Reduction in serum leptin and IGF-1 but preserved T-lymphocyte numbers and activation after a ketogenic diet in rheumatoid arthritis patients. Clin Exp Rheumatol. 2000 Mar-Apr;18(2):209-14.
Fulzele K, Clemens TL. Novel functions for insulin in bone. Bone. 2012 Feb;50(2):452-6. doi: 10.1016/j.bone.2011.06.018. Epub 2011 Jun 24.
Gross LS, et al, Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment. Am J Clin Nutr. 2004 May;79(5):774-9.
Hall KD, Chen KY, Guo J, Lam YY, Leibel RL, Mayer LE, Reitman ML, Rosenbaum M, Smith SR, Walsh BT, Ravussin E. Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men. Am J Clin Nutr. 2016 Aug;104(2):324-33. doi: 10.3945/ajcn.116.133561. Epub 2016 Jul 6.
Hall KD, Chung ST. Low-carbohydrate diets for the treatment of obesity and type 2 diabetes. Curr Opin Clin Nutr Metab Care. 2018 Apr 18. doi: 10.1097/MCO.0000000000000470.
Hallböök T, Ji S, Maudsley S, Martin B. The effects of the ketogenic diet on behavior and cognition. Epilepsy Res. 2012 Jul;100(3):304-9. doi: 10.1016/j.eplepsyres.2011.04.017. Epub 2011 Aug 27.
Han JM, Patterson SJ, Speck M, Ehses JA, Levings MK. Insulin inhibits IL-10-mediated regulatory T cell function: implications for obesity. J Immunol. 2014 Jan 15;192(2):623-9. doi: 10.4049/jimmunol.1302181. Epub 2013 Dec 9.
Holloway CJ, Cochlin LE, Emmanuel Y, Murray A, Codreanu I, Edwards LM, Szmigielski C, Tyler DJ, Knight NS, Saxby BK, Lambert B, Thompson C, Neubauer S, Clarke K. A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects. Am J Clin Nutr. 2011 Apr;93(4):748-55. doi: 10.3945/ajcn.110.002758. Epub 2011 Jan 26.
Husemoen LL, Glümer C, Lau C, Pisinger C, Mørch LS, Linneberg A. Association of obesity and insulin resistance with asthma and aeroallergen sensitization. Allergy. 2008 May;63(5):575-82. doi: 10.1111/j.1398-9995.2007.01613.x.
Hylla S, et al. “Effects of resistant starch on the colon in healthy volunteers: possible implications for cancer prevention.” Am J Clin Nutr. 1998 Jan;67(1):136-42.
Jin HY. Prevalence of subclinical hypothyroidism in obese children or adolescents and association between thyroid hormone and the components of metabolic syndrome. J Paediatr Child Health. 2018 May 16. doi: 10.1111/jpc.13926
Johnston KL, et al. “Resistant starch improves insulin sensitivity in metabolic syndrome.” Diabet Med. 2010;27:391-397.
Kang HC, Chung DE, Kim DW, Kim HD. Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia. 2004 Sep;45(9):1116-23.
Kang HC, Kim YJ, Kim DW, Kim HD. Efficacy and safety of the ketogenic diet for intractable childhood epilepsy: Korean multicentric experience. Epilepsia. 2005 Feb;46(2):272-9.
Kapadia KB, Bhatt PA, Shah JS. Association between altered thyroid state and insulin resistance. Journal of Pharmacology & Pharmacotherapeutics. 2012;3(2):156-160. doi:10.4103/0976-500X.95517.
Kose E, Guzel O, Demir K, Arslan N. Changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy. J Pediatr Endocrinol Metab. 2017 Apr 1;30(4):411-416. doi: 10.1515/jpem-2016-0281.
Krikorian R, Shidler MD, Dangelo K, Couch SC, Benoit SC, Clegg DJ. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol Aging. 2012 Feb;33(2):425.e19-27. doi: 10.1016/j.neurobiolaging.2010.10.006. Epub 2010 Dec 3.
Lager I. The insulin-antagonistic effect of the counterregulatory hormones. J Intern Med Suppl. 1991;735:41-7.
Lambrechts DA, Bovens MJ, de la Parra NM, Hendriksen JG, Aldenkamp AP, Majoie MJ. Ketogenic diet effects on cognition, mood, and psychosocial adjustment in children. Acta Neurol Scand. 2013 Feb;127(2):103-8. doi: 10.1111/j.1600-0404.2012.01686.x. Epub 2012 Jun 12.
Laron Z. Insulin and the brain. Arch Physiol Biochem. 2009 May;115(2):112-6. doi: 10.1080/13813450902949012.
Lu H, Huang D, Yao K, Li C, Chang S, Dai D, Sun A, Zou Y, Qian J, Ge J. Insulin enhances dendritic cell maturation and scavenger receptor-mediated uptake of oxidised low-density lipoprotein, J Diab Comp 2015 29(4):465-71 doi: 10.1016/j.jdiacomp.2015.03.005.
Lussier DM, Woolf EC, Johnson JL, Brooks KS, Blattman JN, Scheck AC. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet. BMC Cancer. 2016 May 13;16:310. doi: 10.1186/s12885-016-2337-7.
Makris A, Darcey VL, Rosenbaum DL, Komaroff E, Vander Veur SS, Collins BN, Klein S, Wyatt HR, Foster GD. Similar effects on cognitive performance during high- and low-carbohydrate obesity treatment. Nutr Diabetes. 2013 Sep 23;3:e89. doi: 10.1038/nutd.2013.29.
Martinez-deMena R, Obregón M. Insulin increases the adrenergic stimulation of 5′ deiodinase activity and mRNA expression in rat brown adipocytes; role of MAPK and PI3K. J Mol Endocrinol. 2005 Feb;34(1):139-51.
Martinez-Sanchez ME, Hiriart M, Alvarez-Buylla ER. The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study. BMC Syst Biol. 2017 Jun 26;11(1):64. doi: 10.1186/s12918-017-0436-y.
Mavropoulos JC, Yancy WS, Hepburn J, Westman EC. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutr Metab (Lond). 2005 Dec 16;2:35.
Milne NT, Bucks RS, Davis WA, Davis TME, Pierson R, Starkstein SE, Bruce DG. Hippocampal atrophy, asymmetry, and cognition in type 2 diabetes mellitus. Brain Behav. 2017 Dec 22;8(1):e00741. doi: 10.1002/brb3.741. eCollection 2018 Jan.
Nakao R, Shimba S, Oishi K. Ketogenic diet induces expression of the muscle circadian gene Slc25a25 via neural pathway that might be involved in muscle thermogenesis. Sci Rep. 2017 Jun 6;7(1):2885. doi: 10.1038/s41598-017-03119-8.
Nguyen TTL, Chan LC, Borreginne K, Kale RP, Hu C, Tye SJ. A Review of Brain Insulin Signaling in Mood Disorders: From Biomarker to Clinical Target. Neurosci Biobehav Rev. 2018 May 11. pii: S0149-7634(17)30788-1. doi: 10.1016/j.neubiorev.2018.05.014.
Ni FF, Li CR, Liao JX, Wang GB, Lin SF, Xia Y, Wen JL. The effects of ketogenic diet on the Th17/Treg cells imbalance in patients with intractable childhood epilepsy. Seizure. 2016 May;38:17-22. doi: 10.1016/j.seizure.2016.03.006. Epub 2016 Mar 22.
Nici J, Hom J. Neuropsychological function in type 2 diabetes mellitus. Appl Neuropsychol Adult. 2018 May 4:1-9. doi: 10.1080/23279095.2018.1455683.
Nilsson AC, et al. “Including indigestible carbohydrates in the evening meal of healthy subjects improves glucose tolerance, lowers inflammatory markers, and increases satiety after a subsequent standardized breakfast.” J Nutr. 2008;138:732-739.
Nilsson J, Ericsson M, Joibari MM, Anderson F, Carlsson L, Nilsson SK, Sjödin A, Burén J2. A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice. Nutr Metab (Lond). 2016 Nov 15;13:79. doi: 10.1186/s12986-016-0132-8. eCollection 2016.
Palta P, Schneider AL, Biessels GJ, Touradji P, Hill-Briggs F. Magnitude of cognitive dysfunction in adults with type 2 diabetes: a meta-analysis of six cognitive domains and the most frequently reported neuropsychological tests within domains. J Int Neuropsychol Soc. 2014 Mar;20(3):278-91. doi: 10.1017/S1355617713001483. Epub 2014 Feb 20.
Paoli A. Ketogenic diet for obesity: friend or foe? Int J Environ Res Public Health. 2014 Feb 19;11(2):2092-107. doi: 10.3390/ijerph110202092.
Pasquali R, Casimirri F, De Iasio R, Mesini P, Boschi S, Chierici R, Flamia R, Biscotti M, Vicennati V. Insulin regulates testosterone and sex hormone-binding globulin concentrations in adult normal weight and obese men. J Clin Endocrinol Metab. 1995 Feb;80(2):654-8.
Pramojanee SN, Phimphilai M, Chattipakorn N, Chattipakorn SC. Possible roles of insulin signaling in osteoblasts. Endocr Res. 2014;39(4):144-51. doi: 10.3109/07435800.2013.879168. Epub 2014 Mar 28.
Pscherer S, Sandmann GH, Ehnert S, Nussler AK, Stöckle U, Freude T. Delayed Fracture Healing in Diabetics with Distal Radius Fractures. Acta Chir Orthop Traumatol Cech. 2017;84(1):24-29.
Ramm-Pettersen A, Stabell KE, Nakken KO, Selmer KK. Does ketogenic diet improve cognitive function in patients with GLUT1-DS? A 6- to 17-month follow-up study. Epilepsy Behav. 2014 Oct;39:111-5. doi: 10.1016/j.yebeh.2014.08.015. Epub 2014 Sep 18.
Rankin JW, Turpyn AD. Low carbohydrate, high fat diet increases C-reactive protein during weight loss. J Am Coll Nutr. 2007 Apr;26(2):163-9.
Rao PM, Kelly DM, Jones TH. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nat Rev Endocrinol. 2013 Aug;9(8):479-93. doi: 10.1038/nrendo.2013.122. Epub 2013 Jun 25.
Reagan LP. Insulin signaling effects on memory and mood. Curr Opin Pharmacol. 2007 Dec;7(6):633-7. Epub 2007 Nov 26.
Riddle RC, Clemens TL. Insulin, osteoblasts, and energy metabolism: why bone counts calories. The Journal of Clinical Investigation. 2014;124(4):1465-1467. doi:10.1172/JCI75554.
Sanches CP, Vianna AGD, Barreto FC. The impact of type 2 diabetes on bone metabolism. Diabetol Metab Syndr. 2017 Oct 19;9:85. doi: 10.1186/s13098-017-0278-1. eCollection 2017.
Schreck KC, Lwin M, Strowd RE, Henry-Barron BJ, Blakeley JO, Cervenka MC. Effect of ketogenic diets on leukocyte counts in patients with epilepsy. Nutr Neurosci. 2017 Dec 18:1-6. doi: 10.1080/1028415X.2017.1416740. [Epub ahead of print]
Shaw JA, Shetty P, Burns KD, Fergusson D, Knoll GA. C-peptide as a Therapy for Kidney Disease: A Systematic Review and Meta-Analysis. PLoS One. 2015 May 20;10(5):e0127439. doi: 10.1371/journal.pone.0127439. eCollection 2015.
Simm PJ, Bicknell-Royle J, Lawrie J, Nation J, Draffin K, Stewart KG, Cameron FJ, Scheffer IE, Mackay MT. The effect of the ketogenic diet on the developing skeleton. Epilepsy Res. 2017 Oct;136:62-66. doi: 10.1016/j.eplepsyres.2017.07.014. Epub 2017 Jul 26.
Souteiro P, Belo S, Oliveira SC, Neves JS, Magalhães D, Pedro J, Bettencourt-Silva R, Costa MM, Varela A, Queirós J, Freitas P, Carvalho D; AMTCO Group. Insulin resistance and sex hormone-binding globulin are independently correlated with low free testosterone levels in obese males. Andrologia. 2018 May 9:e13035. doi: 10.1111/and.13035. [Epub ahead of print]
Spielman LJ, Bahniwal M, Little JP, Walker DG, Klegeris A. Insulin Modulates In Vitro Secretion of Cytokines and Cytotoxins by Human Glial Cells. Curr Alzheimer Res. 2015;12(7):684-93.
Srikanthan P, Karlamangla AS. Muscle mass index as a predictor of longevity in older adults. Am J Med. 2014 Jun;127(6):547-53. doi: 10.1016/j.amjmed.2014.02.007. Epub 2014 Feb 18.
Strain G, Zumoff B, Rosner W, Pi-Sunyer X. The relationship between serum levels of insulin and sex hormone-binding globulin in men: the effect of weight loss. J Clin Endocrinol Metab. 1994 Oct;79(4):1173-6.
Ströhle A & Hahn A. “Diets of modern hunter-gatherers vary substantially in their carbohydrate content depending on ecoenvironments: results from an ethnographic analysis.” Nutr Res. 2011 Jun;31(6):429-35.
Suba Z. Interplay between insulin resistance and estrogen deficiency as co- activators in carcinogenesis. Pathol Oncol Res. 2012 Apr;18(2):123-33. doi: 10.1007/s12253-011-9466-8. Epub 2011 Oct 9.
Sunahara KK, Sannomiya P, Martins JO. Briefs on insulin and innate immune response. Cell Physiol Biochem. 2012;29(1-2):1-8. doi: 10.1159/000337579. Epub 2012 Mar 1.
Thienel M, Wilhelm I, Benedict C, Born J, Hallschmid M. Intranasal insulin decreases circulating cortisol concentrations during early sleep in elderly humans. Neurobiol Aging. 2017 Jun;54:170-174. doi: 10.1016/j.neurobiolaging.2017.03.006. Epub 2017 Mar 14.
Tinsley GM, Willoughby DS. Fat-Free Mass Changes During Ketogenic Diets and the Potential Role of Resistance Training. Int J Sport Nutr Exerc Metab. 2016 Feb;26(1):78-92. doi: 10.1123/ijsnem.2015-0070. Epub 2015 Aug 12.
Trierweiler H, Kisielewicz G, Hoffmann Jonasson T, Rasmussen Petterle R, Aguiar Moreira C, Zeghbi Cochenski Borba V. Sarcopenia: a chronic complication of type 2 diabetes mellitus. Diabetol Metab Syndr. 2018 Apr 3;10:25. doi: 10.1186/s13098-018-0326-5. eCollection 2018.
Vazquez JA, Adibi SA. Protein sparing during treatment of obesity: ketogenic versus nonketogenic very low calorie diet. Metabolism. 1992 Apr;41(4):406-14.
Wahren J, Larsson C. C-peptide: new findings and therapeutic possibilities. Diabetes Res Clin Pract. 2015 Mar;107(3):309-19. doi: 10.1016/j.diabres.2015.01.016. Epub 2015 Jan 21.
White AM, Johnston CS, Swan PD, Tjonn SL, Sears B. Blood ketones are directly related to fatigue and perceived effort during exercise in overweight adults adhering to low-carbohydrate diets for weight loss: a pilot study. J Am Diet Assoc. 2007 Oct;107(10):1792-6.
Wilson JM, Lowery RP, Roberts MD, Sharp MH, Joy JM, Shields KA, Partl J, Volek JS, D’Agostino D. The Effects of Ketogenic Dieting on Body Composition, Strength, Power, and Hormonal Profiles in Resistance Training Males. J Strength Cond Res. 2017 Apr 7. doi: 10.1519/JSC.0000000000001935.
Wing RR, Vazquez JA, Ryan CM 1995 Cognitive effects of ketogenic weight-reducing diets. Int J Obes Relat Metab Disord 19:811–816
Wroble KA, Trott MN, Schweitzer GG, Rahman RS, Kelly PV, Weiss EP. Low-carbohydrate, ketogenic diet impairs anaerobic exercise performance in exercise-trained women and men: a randomized-sequence crossover trial. J Sports Med Phys Fitness. 2018 Apr 4. doi: 10.23736/S0022-4707.18.08318-4.
Yosten GLC, Maric-Bilkan C, Luppi P, Wahren J. Physiological effects and therapeutic potential of proinsulin C-peptide. Am J Physiol Endocrinol Metab. 2014 Dec 1; 307(11): E955–E968. Published online 2014 Sep 23. doi: 10.1152/ajpendo.00130.2014
Zhang B, Wang J, Shen S, Liu J, Sun J, Gu T, Ye X, Zhu D, Bi Y. Association of Androgen Excess with Glucose Intolerance in Women with Polycystic Ovary Syndrome. Biomed Res Int. 2018 Mar 8;2018:6869705. doi: 10.1155/2018/6869705. eCollection 2018.
Zhao Q, Stafstrom CE, Fu DD, Hu Y, Holmes GL. Detrimental effects of the ketogenic diet on cognitive function in rats. Pediatr Res. 2004 Mar;55(3):498-506. Epub 2004 Jan 7
Zhao WQ, Alkon DL. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol. 2001 May 25;177(1-2):125-34.
Zhao WQ, Chen H, Quon MJ, Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol. 2004 Apr 19;490(1-3):71-81.