Macronutrient Biochemistry: Clinical Applications

The Three Rivers of Metabolism

Imagine the body’s metabolism as three great rivers flowing into a single reservoir — the mitochondria. Protein, carbohydrate, and fat each enter through different tributaries, pass through different terrain, and carry different cargo. But they all converge at the Krebs cycle and the electron transport chain, where their energy is converted to ATP — the universal currency of cellular life.

Understanding macronutrient biochemistry is not academic exercise. It determines every clinical decision about diet: why ketogenic diets reverse epilepsy, why resistant starch feeds beneficial bacteria, why the elderly lose muscle even when eating “enough” protein, why vegetable oils cause more oxidative damage than butter, and why the cholesterol on your plate has almost nothing to do with the cholesterol in your blood.

This is the biochemistry that functional medicine practitioners need to prescribe food as medicine with precision.

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Protein: The Master Builder

Requirements: One Size Does Not Fit All

The RDA of 0.8 g/kg body weight was established to prevent deficiency in sedentary adults — it is the minimum to avoid protein malnutrition, not the optimum for health, muscle maintenance, immune function, or aging. Emerging research consistently shows this number is inadequate for most populations.

Requirements by population:

• Sedentary adults: 0.8 g/kg (RDA) — prevents deficiency but insufficient for optimal health. Many functional medicine practitioners consider 1.0-1.2 g/kg a better baseline.
• Active adults: 1.2-1.6 g/kg (ACSM/AND position statement). Supports recovery, immune function, and lean mass.
• Athletes and heavy training: 1.6-2.2 g/kg (Morton 2018 meta-analysis). The upper end for bodybuilders and strength athletes in caloric deficit.
• Elderly (over 65): 1.2-1.6 g/kg (Paddon-Jones and Leidy 2014, Bauer 2013). This is critically important — aging causes anabolic resistance (muscles become less responsive to protein’s muscle-building signal), requiring more protein per meal to stimulate the same degree of muscle protein synthesis. Sarcopenia (age-related muscle loss) begins in the fourth decade and accelerates after 65. Adequate protein is the primary nutritional defense.
• Pregnancy: 1.2 g/kg minimum (increasing in second and third trimesters). Fetal tissue construction, placental growth, expanded blood volume, and breast tissue development all require substantial amino acid supply.

The Leucine Threshold and Muscle Protein Synthesis

Muscle protein synthesis (MPS) — the process of building new muscle — is not a continuous process. It’s triggered in pulses by a sufficient dose of the branched-chain amino acid leucine. Katsanos 2006 demonstrated that approximately 2.5-3g of leucine per meal is required to maximally stimulate MPS through the mTOR pathway.

What this means practically:

• 30g of whey protein provides approximately 3g leucine — threshold hit
• 30g of chicken breast provides approximately 2.5g leucine — threshold hit
• 30g of rice protein provides approximately 1.5g leucine — threshold not hit (needs 45-50g to reach it)
• 30g of beans provides approximately 1g leucine — threshold not hit

This is why protein quality matters more than total grams, and why the elderly need larger portions per sitting — their anabolic threshold is elevated due to anabolic resistance.

Protein Quality: DIAAS and Bioavailability

The Digestible Indispensable Amino Acid Score (DIAAS) has replaced the older PDCAAS as the gold standard for protein quality assessment (FAO 2013). DIAAS measures the digestibility of each essential amino acid individually, rather than truncating at 1.0 like PDCAAS.

DIAAS scores (approximate):

• Whole egg: 1.13 (reference protein)
• Milk: 1.14
• Beef: 1.10
• Chicken: 1.08
• Whey protein: 1.09
• Soy protein isolate: 0.90
• Pea protein: 0.82
• Rice protein: 0.60
• Wheat gluten: 0.40

Animal vs plant protein — the nuanced view: Animal proteins are complete (all essential amino acids in adequate ratios) and highly bioavailable. Plant proteins are typically low in one or more essential amino acids (legumes: low methionine; grains: low lysine; most plants: low leucine) and less digestible. However, combining plant proteins (rice + beans, hummus + pita) creates a complete amino acid profile. The key clinical insight: plant-based athletes and elderly individuals need 20-30% more total protein to achieve equivalent amino acid delivery.

Clinical Implications of Protein

Muscle and aging: Sarcopenia (muscle wasting) is not inevitable aging — it’s preventable with adequate protein (1.2-1.6 g/kg) distributed across meals (minimum 30g per meal for the elderly) combined with resistance exercise. Muscle is a metabolic organ and an amino acid reservoir. Losing it accelerates frailty, falls, metabolic dysfunction, and mortality.

Immune function: Immunoglobulins (antibodies), complement proteins, and glutathione are all protein-dependent. Protein malnutrition is the most common cause of immunodeficiency worldwide.

Neurotransmitter synthesis: Every neurotransmitter precursor is an amino acid (tryptophan for serotonin, tyrosine for dopamine, glutamine for GABA). Inadequate protein intake directly impairs brain chemistry.

Blood sugar stabilization: Protein slows gastric emptying and reduces glycemic response when consumed with carbohydrates. Including 20-30g protein at every meal is one of the most effective blood sugar management strategies.

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Carbohydrates: The Spectrum from Medicine to Metabolic Poison

Glycemic Index, Glycemic Load, and Insulin Index

Glycemic Index (GI): Measures how quickly a food raises blood glucose compared to pure glucose (GI=100). High GI (>70): white bread, rice cakes, candy. Low GI (<55): legumes, most vegetables, berries.

Glycemic Load (GL): GI x grams of carbohydrate per serving / 100. More clinically useful because it accounts for portion size. Watermelon has a high GI (72) but low GL (4 per serving) because the carb content per serving is small.

Insulin Index: Measures insulin response, which doesn’t always parallel glucose response. Dairy protein stimulates significant insulin release despite modest glucose impact. Beef triggers insulin release. This index is relevant for insulin-resistant patients where the insulin response matters more than glucose alone.

Clinical utility and limitations: GI/GL are useful guides but not gospel. Individual glucose responses to the same food vary by 20-40% (Zeevi 2015 — personalized nutrition based on continuous glucose monitoring showed that glycemic responses are highly individual, driven by microbiome composition, meal context, sleep, and stress).

Fiber: The Microbiome’s Food

Fiber is not one substance — it’s a family of plant carbohydrates that resist human digestion. The distinction between types determines clinical application.

Soluble fiber: Dissolves in water, forms gel. Functions as a prebiotic (feeds beneficial gut bacteria), produces SCFAs through fermentation, binds cholesterol in the gut (reducing LDL), slows glucose absorption. Sources: oats, legumes, flaxseeds, apples, psyllium.

Insoluble fiber: Does not dissolve, adds bulk to stool, accelerates transit time, mechanically stimulates peristalsis. Sources: wheat bran, cellulose, lignans, vegetable skins.

Resistant starch: A form of starch that resists digestion in the small intestine and is fermented in the colon — functionally behaving like fiber. Four types:

• Type 1: Physically enclosed in seed/grain matrix (whole grains, legumes)
• Type 2: Native granular structure (raw potato, green banana, raw oats)
• Type 3: Retrograded starch — formed when cooked starchy foods are cooled. Cooked-then-cooled potatoes, rice, and pasta contain significantly more resistant starch than freshly cooked versions. This is why potato salad is different from a hot baked potato metabolically.
• Type 4: Chemically modified (industrial food additive)

Butyrate production: Resistant starch and soluble fiber fermentation produce short-chain fatty acids — acetate, propionate, and especially butyrate. Butyrate is the primary fuel for colonocytes, maintains gut barrier integrity, has anti-inflammatory properties (inhibits NF-kB), regulates gene expression (histone deacetylase inhibitor), and influences systemic metabolism.

Fructose: The Metabolic Troublemaker

Fructose is metabolized exclusively in the liver — unlike glucose, which can be used by every cell. The liver handles small amounts of fructose from whole fruit effortlessly. But the 60-80g/day from high-fructose corn syrup (HFCS) and added sugars in the standard American diet overwhelms hepatic capacity.

The cascade (Richard Johnson, University of Colorado research): Excess fructose → hepatic de novo lipogenesis (fat production in the liver) → elevated triglycerides → VLDL production → increased uric acid (fructose depletes ATP, generating purines, which convert to uric acid) → endothelial dysfunction → insulin resistance → non-alcoholic fatty liver disease (NAFLD).

Fruit vs HFCS: Whole fruit provides fructose wrapped in fiber, water, phytonutrients, and vitamins. The fiber slows absorption. The phytonutrients are anti-inflammatory. The dose per serving is modest (an apple contains about 13g fructose). HFCS in a 20-ounce soda provides 36g of free fructose hitting the liver in minutes, without any protective cofactors.

The distinction matters: Fruit restriction is not necessary for metabolically healthy individuals. HFCS and added sugar reduction is critical for everyone. The dose, the form, and the matrix determine the effect.

The Low-Carb Spectrum

• Moderate low-carb: Under 150g/day. Removes processed carbohydrates while retaining fruits, starchy vegetables, and legumes. Sustainable for most people, improves blood sugar and metabolic markers.
• Ketogenic: Under 50g/day. Forces metabolic shift to fat-based fuel (ketone bodies). Therapeutic for epilepsy (Charlie Foundation), type 2 diabetes reversal, obesity, neurodegenerative diseases. Requires careful planning to maintain nutrient adequacy.
• Strict keto: Under 20g/day. Deep ketosis. Used in therapeutic epilepsy and cancer adjunct protocols. Difficult to sustain long-term without clinical support.

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Fats: The Most Misunderstood Macronutrient

Saturated Fat: Context-Dependent

The blanket demonization of saturated fat is collapsing under the weight of nuanced evidence. The 2020 Cochrane meta-analysis showed that reducing saturated fat had no effect on all-cause mortality and only modest effects on cardiovascular events when replaced with polyunsaturated fat (not when replaced with carbohydrates).

Context matters:

• Coconut oil MCTs (medium-chain triglycerides): Caprylic acid (C8) and capric acid (C10) are metabolized directly in the liver into ketone bodies — they bypass lymphatic absorption and carnitine transport. These are functionally different from long-chain saturated fats.
• Processed meat saturated fat: Comes packaged with nitrites, heme iron overload, PAHs, and inflammatory compounds. The health effects may be driven by the total package, not the saturated fat per se.
• Lean mass hyper-responders (Dave Feldman research): Some metabolically healthy, lean individuals on low-carb diets show dramatically elevated LDL cholesterol driven by increased lipoprotein particle production to transport fat-based fuel. Their cardiovascular risk may be different than it appears from LDL alone. This is an active area of research.

Monounsaturated Fat: The Consensus Champion

Oleic acid (olive oil, avocado, macadamia nuts) is the one fat that every dietary philosophy agrees on — from vegan to carnivore, from Mediterranean to ketogenic. Universally anti-inflammatory, cardiovascular protective, and metabolically beneficial. EVOO’s polyphenols add phytonutrient benefits on top of the oleic acid base.

Polyunsaturated Fat: The Oxidation Risk

Omega-3 and omega-6 polyunsaturated fatty acids are essential. But their multiple double bonds make them highly susceptible to oxidation — heat, light, and air turn beneficial fats into harmful lipid peroxides and aldehydes.

The clinical rule: Do not cook with high-PUFA oils. Soybean, corn, sunflower, safflower, and grapeseed oils should never be used for high-heat cooking. At frying temperatures, they produce 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) — compounds linked to neurodegeneration, atherosclerosis, and cancer (Grootveld 2014).

Trans Fats: Industrial vs Natural

Industrial trans fats (partially hydrogenated oils) are the one fat that truly deserves universal condemnation. Created by forcing hydrogen into vegetable oils to solidify them. Increase LDL, decrease HDL, promote inflammation, endothelial dysfunction, and insulin resistance. Banned by FDA in 2018 but still present in some processed foods at levels below labeling threshold (“0g trans fat” can legally contain up to 0.5g per serving).

Natural trans fats: Conjugated linoleic acid (CLA) in ruminant fat (grass-fed beef, butter, lamb) is a naturally occurring trans fat with demonstrated anti-cancer, anti-obesity, and anti-inflammatory properties. CLA is fundamentally different from industrial trans fats despite sharing the “trans” configuration.

Dietary Cholesterol: The Rehabilitation

The 2015-2020 Dietary Guidelines for Americans removed the previous 300mg daily cholesterol limit, acknowledging that dietary cholesterol is a “nutrient of no concern for overconsumption.” The liver produces approximately 80% of circulating cholesterol endogenously and downregulates production when dietary intake increases (feedback regulation). For most people, eating eggs raises HDL and shifts LDL particle size from small-dense (atherogenic) to large-buoyant (benign).

The egg rehabilitation: Eggs are one of nature’s most complete foods — complete protein, choline (one of the most common deficiencies in the Western diet), lutein/zeaxanthin, B12, selenium, fat-soluble vitamins. Fear of dietary cholesterol from eggs was based on flawed ecological reasoning from the 1960s.

Cooking Oils: Ranked by Safety

Best for high-heat cooking (high smoke point, low PUFA, oxidation-stable):

1. Avocado oil: 520F smoke point, high oleic acid
2. Ghee (clarified butter): 485F smoke point, minimal milk solids (reduced burning)
3. Coconut oil: 400F smoke point, highly saturated (resists oxidation)
4. Tallow/lard (grass-fed): 370-400F, traditional cooking fats, heat-stable

Best for low-heat and finishing: 5. Extra virgin olive oil: 375F smoke point (adequate for gentle sauteing despite myths), best used for dressings, finishing, and low-temperature cooking to preserve polyphenols

Avoid for cooking (high PUFA, oxidation-prone):

• Canola oil (though a moderate option for baking due to lower PUFA than soy)
• Soybean oil
• Corn oil
• Sunflower oil (regular; high-oleic sunflower is an exception)
• Safflower oil
• Grapeseed oil (extremely high PUFA)

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The Integration: Macronutrient Biochemistry as Clinical Tool

Every patient’s macronutrient needs are individual. An elderly sarcopenic woman needs different protein strategies than a young athlete. A metabolic syndrome patient needs different carbohydrate strategies than a lean endurance runner. A patient with neurodegeneration needs different fat strategies than one with gallbladder disease.

Functional medicine does not prescribe one macronutrient ratio for all humans. It asks: what does this body, with this genetics, this metabolic state, this disease process, and this lifestyle, need to function optimally? The biochemistry provides the map. The patient’s response provides the compass.

When you understand the rivers of metabolism — how protein, carbohydrate, and fat each flow through their own pathways into the common pool of cellular energy and structure — you stop seeing food as calories and start seeing it as biochemical information.

What information is your food sending to your cells right now?