The ketogenic diet has taken the wellness world by storm, with health professionals and laypeople alike touting its remarkable health benefits. While patient enthusiasm is often high at the beginning of a ketogenic diet, many people fall off the “keto bandwagon” due to the diet’s restrictive nature. Ketosis-supporting phytonutrients offer a novel solution to this problem, allowing your patients to break a strict ketogenic diet with some healthy carbohydrates while seamlessly re-entering ketosis the next day. This strategy promotes metabolic flexibility and makes keto a realistic and attainable diet for your patients.
What is Ketosis?
The ketogenic diet is a high-fat, moderate-protein, low-carbohydrate food plan. The typical macronutrient ratios are 60-75% of calories from fat, 15-30% from protein, and 5-10% from carbohydrates. By strictly limiting carbs, the ketogenic diet creates a metabolic shift in the body from using glucose as a primary fuel to burning body fat and ketones, small water-soluble compounds produced via the breakdown of fats in the liver.
Once synthesized, ketones are rapidly taken up by the brain, heart, and skeletal muscle, where they are broken down to produce ATP, the body’s primary energy “currency.” The three ketones produced during ketosis - beta-hydroxybutyrate, acetoacetate, and acetone – can be measured in the blood using a simple ketone meter.
The utilization of ketones for energy production is referred to as “ketosis.” Our human ancestors regularly entered ketosis due to limited food availability and periods of fasting, a practice that has evolutionarily programmed us to derive immense health benefits from this metabolic process.
Biochemical Actions of Ketosis
The health benefits of ketosis are realized through its impact on multiple cell-signaling pathways and physiological processes.
AMP-activated protein kinase (AMPK) is a nutrient-sensing enzyme that functions as a central regulator of metabolism and energy production in the body. AMPK is activated by a variety of inputs, including calorie restriction, lowered blood insulin levels, and exercise. Conversely, it is inhibited by hyperinsulinemia, chronic overnutrition, and obesity.1-3 AMPK works rapidly to restore cellular ATP levels and modulates two downstream signaling pathways, mTOR and PPAR.4 AMPK activation is associated with reduced inflammation, weight loss, enhanced insulin sensitivity and muscle function, and healthy aging.5-7
Mechanistic target of rapamycin (mTOR) is an anabolic pathway that coordinates cell growth. It is activated by food intake and regulates vital processes such as learning, memory, and response to exercise.8,9 However, in the case of mTOR, it is possible to have too much of a good thing! Excessive activation of mTOR is linked to cancer, type II diabetes, obesity, neurodegeneration, and accelerated aging.10
AMPK is the primary inhibitor of mTOR. One of the primary benefits of a ketogenic or fasting state is that it blocks mTOR through increased AMPK activity, thus inhibiting uncontrolled cell growth, proliferation, and oxidative stress.
Peroxisome proliferator-activated receptors (PPARs) are transcription factors activated by AMPK and involved in energy metabolism, immunity, and inflammation.11 PPARα is a chief regulator of ketosis, inducing the expression of genes necessary for fatty acid oxidation and ketone biosynthesis.12 PPARγ supports the metabolic benefits of ketosis by enhancing insulin sensitivity and glucose utilization.
Β-hydroxybutyrate is the most abundant ketone body in circulation when the body is in a state of ketosis. In addition to serving as an energy substrate, it functions as a signaling molecule, epigenetically regulating genes involved in neuroprotection and inflammation.13
Autophagy is the cellular process by which damaged, dysfunctional proteins and cellular components are degraded and recycled. This “cellular housecleaning,” potently activated by ketosis, keeps cells healthy and spry, ready to take on the stressors of daily living.14
Reactive oxygen species (ROS) are chemically-reactive compounds produced in response to environmental stressors such as pesticides, heavy metals, and UV light. They are also natural byproducts of mitochondrial respiration, the process by which our cells make ATP for energy. While excessive production of ROS is harmful, moderate levels of mitochondrial ROS induce mitohormesis, an adaptive response that increases resistance to oxidative stress.15 Nutritional ketosis is a potent activator of mitohormesis and thereby enhances mitochondrial health.
The Health Benefits of Ketosis
Blood Sugar Control and Weight Management
A shocking 9% of the U.S. population has diabetes while 33% have prediabetes and 72% are categorized as overweight or obese.16-18 The “eat less, exercise more” directive has unfortunately failed the countless people suffering from these health conditions. The ketogenic diet is a promising alternative to conventional dietary guidelines for the millions of adults struggling with their blood sugar and body weight. It dramatically decreases blood sugar and hemoglobin A1c in people with metabolic syndrome and type 2 diabetes, significantly reduces visceral fat, and preserves lean mass.19-21
A ketogenic diet enhances mitochondrial function, boosting activity of the body’s energy powerhouses. Ketones also “burn clean” compared to glucose, creating abundant energy without an excess of harmful free radicals.
Enhanced Cognition and Reduced Neuroinflammation
Unlike glucose, ketones readily cross the blood-brain barrier, making them a preferred fuel source for the brain. For this reason, a ketogenic diet offers profound brain health benefits including improved glutamate/GABA balance, enhanced cognition, learning, memory, and mitochondrial function, and reduced oxidative stress.22,23 The anti-inflammatory and neuroprotective benefits of a ketogenic diet have demonstrated efficacy in the treatment of epilepsy, Alzheimer’s disease, malignant glioma, and traumatic brain injury.24,25
Nutritional Support for Ketosis
While a ketogenic diet offers numerous health benefits, it is difficult to follow long-term due to its severe restriction of carbohydrates. However, by incorporating botanicals that support the critical metabolic pathways and signaling molecules activated by a ketogenic diet, it is possible for your patients to obtain the benefits of ketosis without daily carbohydrate deprivation!
Diindolylmethane (DIM) is a sulfur-based compound found in cruciferous vegetables. It potentiates tumor cell death by regulating micro-RNAs associated with autophagy and activates AMPK.26,27
Quercetin is a flavonoid with potent antioxidant activities mediated largely by AMPK activation.28 It also improves glucose and lipid metabolism via interactions with PPARγ, thus supporting the metabolic changes induced by ketosis.29
Milk thistle is a renowned botanical for supporting the health of the liver, the primary site of ketone production. It also inhibits mTOR, induces autophagy, and decreases blood sugar, hemoglobin A1c, and insulin.30-32
Resveratrol, the antioxidant to which the health benefits of red wine are attributed, has many ketosis-supporting effects. It stimulates AMPK, inhibits mTOR, and induces autophagy.33,34 Interestingly, it also promotes mitophagy, the selective degradation of mitochondria by autophagy; this allows only the healthiest mitochondria to survive, supporting efficient cellular energy production.35
Berberine, a bitter compound found in the roots of several plants including Oregon grape, barberry, and goldenseal, is a potent AMPK activator. In fact, it has the same mechanism of action as metformin and significantly decreases blood sugar while activating fat-burning processes.36
In addition to tasting wonderful, cinnamon offers powerful metabolic support. It reduces fasting blood glucose and HbA1c while inhibiting mTOR and activating AMPK.37-39
By using these nutrients when practicing a ketogenic diet, you can enjoy greater dietary flexibility by eating an increased amount of healthy carbohydrates at dinner and seamlessly return to ketosis the next day. These ingredients, therefore, promote metabolic flexibility making keto a truly sustainable lifestyle diet over the long-term.
While ketosis historically reflected a time of deprivation for our ancestors, it needn’t be a struggle today! By incorporating select botanicals into your patients' protocols, you can help them ease into ketosis and reap the numerous health benefits this ancient metabolic pathway has to offer.
Sponsored by Quicksilver Scientific, the makers of Keto Before 6™, a revolutionary phytonutrient formula to help accelerate the body’s ability to get into ketosis.
- Valentine RJ, et al. Insulin inhibits AMPK activity and phosphorylates AMPK Ser485/491 through Akt in hepatocytes, myotubes and incubated rat skeletal muscle. Arch Biochem Biophys. 2014; 562: 62-69.
- Weikel KA, et al. Unraveling the actions of AMP-activated protein kinase in metabolic diseases: Systemic to molecular insights. Metabolism. 2016; 65(5): 634-645.
- Lopez M. Hypothalamic AMPK and energy balance. Eur J Clin Invest. 2018; 48(9): e12996.
- Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf). 2009; 196(1): 65-80.
- Lyons CL, Roche HM. Nutritional modulation of AMPK-impact upon metabolic-inflammation. Int J Mol Sci. 2018; 19(10): 3092.
- Kjobsted R, et al. AMPK in skeletal muscle function and metabolism. FASEB J. 2018; 32(4): 1741-1777.
- McCarty MF. AMPK activation—protean potential for boosting healthspan. Age (Dordr). 2014; 36(2): 641-663.
- Pereyra M, et al. mTORC1 controls long-term memory retrieval. Sci Reports. 2018; 8: 8759.
- Yoon MS. mTOR as a key regulator in maintaining skeletal muscle mass. Front Physiol. 2017; 8: 788.
- Saxton RA. mTOR signaling in growth, metabolism, and disease. Cell. 2017; 168(6): 960-976.
- Tyaqi S, et al. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. J Adv Pharm Technol Res. 2011; 2(4): 236-240.
- Grabacka M, et al. Regulation of ketone body metabolism and the role of PPARα. Int J Mol Sci. 2016; 17(12): pii: E2093.
- Newman JC, Verdin E. Ketone bodies as signaling metabolites. Cell. 2013; 25(1): 42-52.
- Mizushima N, et al. Autophagy fights disease through cellular self-digestion. Nature. 2008; 451(7182): 1069-1075.
- Miller VJ, et al. Nutritional ketosis and mitohormesis: Potential implications for mitochondrial function and human health. J Nutr Metab. 2018; 2018: 5157645.
- “National Diabetes Statistics Report, 2017.” Centers for Disease Control and Prevention, US Dept of Health and Human Services; 2017. https://www.cdc.gov/diabetes/data/statistics/statistics-report.html.
- “Prediabetes: Your chance to prevent type 2 diabetes.” Centers for Disease Control and Prevention. 2018. https://www.cdc.gov/diabetes/basics/prediabetes.html.
- “Obesity and overweight.” Centers for Disease Control and Prevention. 2016. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm.
- Gershuni VM, et al. Nutritional ketosis for weight management and reversal of metabolic syndrome. Curr Nutr Rep. 2018; 7(3): 97-106.
- Hussain TA, et al. Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition. 2012; 28(10): 1016-1021.
- Gomez-Arbalaez D, et al. Body composition changes after very-low-calorie ketogenic diet in obesity evaluated by 3 standardized methods. J Clin Endocrinol Metab. 2017; 102(2): 488-498.
- Hernandez AR, et al. A ketogenic diet improves cognition and has biochemical effects in prefrontal cortex that are dissociable from hippocampus. Front Aging Neurosci. 2018; 10:391.
- Gano LB, et al. Ketogenic diets, mitochondria, and neurological diseases. J Lipid Res. 2014; 55: 2211-2228.
- McDonald TJW, et al. The expanding role of ketogenic diets in adult neurological disorders. Brain Sci. 2018; 8(8): 148.
- McDougall A, et al. The ketogenic diet as a treatment for traumatic brain injury: a scoping review. Brain Injury. 2018; 32(4): 416-422.
- Ye Y, et al. 3,3'-Diindolylmethane induces anti-human gastric cancer cells by the miR-30e-ATG5 modulating autophagy. Biochem Pharmacol. 2016; 115: 77-84.
- Ahmad A, et al. Targeted regulation of PI3K/Akt/mTOR/NF-κB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy. Anticancer Agents Med Chem. 2013; 13(7): 1002-1013.
- Shen Y, et al. Quercetin and its metabolites improve vessel function by inducing eNOS activity via phosphorylation of AMPK. Biochem Pharmacol. 2012; 84(8): 1036-1044.
- Beekmann K, et al. The effect of quercetin and kaempferol aglycones and glucuronides on peroxisome proliferator-activated receptor-gamma (PPAR-γ). Food Funct. 2015; 6(4): 1098-1107.
- Gharagozloo M, et al. Silymarin inhibits cell cycle progression and mTOR activity in activated human T cells: Therapeutic implications for autoimmune diseases. Basic Clin Pharmacol Toxicol. 2012; 112(4): 251-256.
- Jiang K, et al. Silibinin, a natural flavonoid, induces autophagy via ROS-dependent mitochondrial dysfunction and loss of ATP involving BNIP3 in human MCF7 breast cancer cells. Oncol Rep. 2015; 33(6): 2711-2718.
- Voroneanu L, et al. Silymarin in type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. J Diabetes Res. 2016; 2016: 5147468.
- Lan F, et al. Resveratrol-induced AMP-activated protein kinase activation is cell-type dependent: Lessons from basic research for clinical application. Nutrients. 2017; 9(7): 751.
- Park D, et al. Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition. Sci Reports. 2016; 6: 21772.
- Kuno A, et al. Resveratrol ameliorates mitophagy disturbance and improves cardiac pathophysiology of dystrophin-deficient mdx mice. Sci Reports. 2018; 8: 15555.
- Wang H, et al. Metformin and berberine, two versatile drugs in treatment of common metabolic diseases. Oncotarget. 2018; 9(11): 10135-10146.
- Santos HO, da Silva GAR. To what extent does cinnamon administration improve the glycemic and lipid profiles? Clin Nutr ESPEN. 2018; 27: 1-9.
- Schriner SE, et al. Extension of Drosophila lifespan by cinnamon through a sex-specific dependence on the insulin receptor substrate chico. Exp Gerontol. 2014; 60:220-230.
- Shen Y, et al. Cinnamon extract enhances glucose uptake in 3T3-L1 adipocytes and C2C12 myocytes by inducing LKB1-AMP-activated protein kinase signaling. PLoS One. 2014; 9(2): e87894.