The Metabolic-Hormonal Model of Weight Loss:Insulin, Ketosis, and the Clinical Frameworks of Westman, Fung, and Bikman

FUNCTIONAL MEDICINE PERSPECTIVE

By Yoon Hang “John” Kim, MD, MPH

Board-Certified in Preventive Medicine and Integrative/Holistic Medicine

Yoon Hang Kim MD|  directintegrativecare.com

1.  Introduction: A Paradigm in Transition

For more than half a century, mainstream clinical practice has approached obesity and its metabolic comorbidities through a single unifying lens: the energy-balance model. Patients have been told to “eat less and move more,” and when they fail — as the overwhelming majority predictably do — the failure has been attributed to inadequate willpower or poor adherence. The persistence of the obesity and type 2 diabetes pandemics despite decades of such advice suggests that the framework itself, not the patients, has been the primary problem.

A converging body of clinical and mechanistic evidence now supports an alternative paradigm: obesity, type 2 diabetes, and most features of metabolic syndrome are fundamentally hormonal and metabolic disorders in which chronic hyperinsulinemia and insulin resistance play a central, causal role (Ludwig et al., 2021; Bikman, 2020). In this model, the composition and timing of food intake — and the hormonal signals those inputs generate — are as important as total calories, and often more so. This article synthesizes the complementary clinical frameworks of three physicians and scientists who have contributed substantially to this paradigm shift: Eric C. Westman, MD, MHS (Duke University); Jason Fung, MD (University of Toronto); and Benjamin T. Bikman, PhD (Brigham Young University). It also situates their work within the broader framework of functional medicine, which insists that lasting metabolic recovery requires attention to the upstream drivers of insulin resistance.

Obesity is not a disorder of willpower. It is a disorder of substrate partitioning, regulated primarily by insulin. When we treat the hormone, the weight follows.

2.  From Calories to Hormones: Why the Old Model Failed

2.1  The limits of calories-in/calories-out (CICO)

The first law of thermodynamics is not in dispute. Energy cannot be created or destroyed. What the energy-balance model (EBM) fails to capture is that calories-in and calories-out are not independent variables; they are dynamically coupled through hormonal, neural, and metabolic regulation. Ludwig and colleagues, writing in the American Journal of Clinical Nutrition (2021), articulated the clearest formal critique yet: the EBM restates a principle of physics without incorporating the biology that governs whether an ingested calorie is oxidized, stored, or wasted as heat. Their carbohydrate-insulin model (CIM) proposes a reversal of causal direction — the hormonal response to a high-glycemic-load diet drives substrate partitioning toward adipose storage, and the resulting cellular starvation signal drives overeating (Ludwig et al., 2021).

2.2  Adaptive thermogenesis: the body defends its weight

The most compelling empirical evidence against a pure CICO model comes from the NIH’s follow-up of “The Biggest Loser” competitors. Fothergill and colleagues (2016) demonstrated that six years after the 30-week intervention, participants had regained an average of 41 kg of lost weight while their resting metabolic rate (RMR) remained 704 kcal/day below baseline — far more suppressed than body-composition changes could explain. Metabolic adaptation persisted at −499 kcal/day six years out, indicating that the body defends its previous weight through a large, durable suppression of energy expenditure. Calorie restriction alone, without addressing the hormonal drivers of fat storage, places the patient in a biological arms race they cannot win.

2.3  Insulin as the master regulator of fat storage

Insulin is the dominant anabolic hormone in human physiology. In adipose tissue, insulin simultaneously activates lipoprotein lipase (promoting triglyceride storage), upregulates acetyl-CoA carboxylase and fatty-acid synthase (driving de novo lipogenesis), and inhibits hormone-sensitive lipase (blocking lipolysis). Two biological conditions are therefore required for sustained fat accumulation: (1) positive energy balance and (2) an insulin signal sufficient to partition that energy into adipose rather than muscle, liver, or heat (Bikman, 2020; Ludwig et al., 2021). Chronic hyperinsulinemia accomplishes both. It promotes storage and, by keeping adipocytes locked in the fed state, prevents the body from mobilizing stored fat between meals — which in turn drives hunger, fatigue, and further food-seeking behavior.

You cannot burn fat in the presence of high insulin. This is not opinion; it is endocrinology. Insulin’s anti-lipolytic effect is among the most reliable phenomena in human metabolism.

3.  Three Complementary Clinical Frameworks

Three contemporary thought leaders approach the insulin-centric model from different but reinforcing angles: Westman from clinical practice and nutritional trials, Fung from nephrology and therapeutic fasting, and Bikman from mechanistic physiology. Their frameworks do not compete; they triangulate.

3.1  Eric C. Westman, MD, MHS — Therapeutic Carbohydrate Restriction

Dr. Westman is Associate Professor of Medicine at Duke University and founder (with William S. Yancy Jr., MD) of the Duke Keto Medicine Clinic. He is a past president of the Obesity Medicine Association and has co-authored more than 100 peer-reviewed publications on low-carbohydrate therapy (Duke University, 2024). His clinical program has seen approximately 5,000 patients since 2006 and is one of the best-documented real-world implementations of ketogenic therapy for obesity and type 2 diabetes.

Westman’s practical prescription is deliberately simple: fewer than 20 grams of total carbohydrate per day, adequate protein (approximately 1.2–1.5 g/kg of reference body weight), and fat to satiety, drawn from unprocessed whole foods. His early pilot trial (Yancy, Foy, Chalecki, Vernon, & Westman, 2005) demonstrated a mean HbA1c reduction from 7.5 % to 6.3 % over 16 weeks in patients with type 2 diabetes, with concurrent reductions or discontinuation of diabetes medications. A subsequent randomized trial comparing the low-carbohydrate ketogenic diet to a low-glycemic-index diet in patients with T2D showed superior glycemic improvement and greater medication reduction in the LCKD arm over 24 weeks (Westman et al., 2008).

The clinical signature of Westman’s approach is de-prescribing. Insulin doses must be reduced on day one of the dietary change to prevent hypoglycemia. Sulfonylureas are typically stopped outright, SGLT-2 inhibitors are held because of the elevated risk of euglycemic diabetic ketoacidosis on a carbohydrate-restricted diet, and antihypertensive medications often require reduction within the first week as natriuresis lowers blood pressure. As Westman has argued in the Duke Health literature, “de-prescription of drugs is just not something physicians are taught” (Duke Health Referring Physicians, 2020), yet it is arguably the most important clinical skill in this practice area.

3.2  Jason Fung, MD — Therapeutic Fasting

Dr. Fung is a Toronto-based nephrologist whose observation that insulin therapy in diabetic patients consistently drove weight gain led him to reconceptualize type 2 diabetes as fundamentally a disease of hyperinsulinemia rather than hyperglycemia. His clinical innovation was to re-introduce therapeutic fasting — a medical intervention with a literature stretching back to the early 20th century — as a systematic, reproducible tool for lowering insulin.

Fung’s most-cited peer-reviewed work is the Furmli, Elmasry, Ramos, and Fung case series published in BMJ Case Reports (2018). Three men with insulin-dependent type 2 diabetes of 10–25 years’ duration were guided through alternate-day or three-times-weekly 24-hour fasts. Within one month — in one case within five days — all three patients discontinued their insulin injections while maintaining improved glycemic control. Two discontinued all oral hypoglycemic agents as well. All three lost 10–18 % of body weight and reduced HbA1c and waist circumference. While a three-patient case series cannot prove generalizability, the physiology it illustrates is instructive: extended fasting produces prolonged periods of low insulin, which restores hepatic insulin sensitivity and allows access to stored body fat for energy.

Fung distinguishes between time-restricted eating (eating windows of 6–10 hours daily), intermittent fasting (24-hour or longer fasts performed 1–3 times per week), and extended fasting (multi-day fasts performed under supervision). He emphasizes, importantly, that fasting differs physiologically from caloric restriction: during a true fast, basal metabolic rate is preserved or slightly elevated via noradrenergic activation, counter-regulatory hormones (growth hormone, glucagon, cortisol) rise, and autophagy is upregulated — none of which reliably occurs during chronic calorie restriction (Anton et al., 2018).

3.3  Benjamin T. Bikman, PhD — The Mechanistic Foundation

Dr. Bikman is Professor of Cell Biology and Physiology at Brigham Young University. He holds a PhD in Bioenergetics from East Carolina University and completed postdoctoral work at Duke-NUS Medical School in Singapore. His laboratory investigates the molecular mechanisms of insulin resistance, with a focus on ceramides, mitochondrial function, and the differential effects of insulin and ketones on adipose tissue biology (Bikman, n.d.).

Bikman’s central thesis, articulated in his 2020 book Why We Get Sick and in numerous peer-reviewed publications, is that insulin resistance sits upstream of most contemporary chronic disease — not only type 2 diabetes and cardiovascular disease, but also Alzheimer’s disease, non-alcoholic fatty liver disease, polycystic ovary syndrome, erectile dysfunction, certain cancers, and many features of aging itself. He frames insulin resistance as a two-sided coin: on one face, some cells respond poorly to normal insulin signals; on the other, the pancreas compensates with chronically elevated insulin output (hyperinsulinemia). Both faces cause injury, but in different tissues (Bikman, 2020).

Bikman identifies three primary drivers of insulin resistance that should be familiar to any functional-medicine clinician: (1) chronically elevated insulin itself, which downregulates insulin receptor sensitivity through simple dose-response biology; (2) stress hormones, principally cortisol and epinephrine, which antagonize insulin action; and (3) inflammation — whether driven by obesity, gut dysbiosis, environmental toxins, or chronic infection — which impairs insulin receptor signaling at multiple post-receptor nodes. His clinical prescription aligns with Westman’s and Fung’s: control carbohydrates, prioritize protein, and do not fear dietary fat.

Importantly, Bikman has been a vocal advocate for measuring fasting insulin routinely in clinical care. The glucose-centric model of mainstream practice treats fasting glucose and HbA1c as early-warning sensors for metabolic disease, but these markers remain normal for years — often a decade or more — while fasting insulin climbs steadily upward as beta cells compensate for developing insulin resistance. By the time glucose becomes abnormal, the pathology has been in progress for years. Measuring fasting insulin inverts the diagnostic timeline and allows intervention when reversal is most feasible (Bikman, 2020).

4.  The Underlying Physiology

4.1  Insulin secretion and postprandial dynamics

Insulin is secreted from pancreatic beta cells primarily in response to dietary carbohydrate, which is rapidly hydrolyzed and absorbed as glucose. Protein also stimulates insulin, although to a lesser and more blunted degree, while dietary fat produces minimal insulin response. Glycemic index and glycemic load — the speed and magnitude of the postprandial glucose spike — are the principal determinants of the insulin response to a given meal. In a metabolically healthy adult, insulin rises sharply after a carbohydrate-rich meal, clears glucose into muscle and liver, and returns to baseline within 2–4 hours. In a Western eating pattern — three carbohydrate-containing meals plus snacks across a 14- to 16-hour eating window — insulin almost never returns to baseline. The patient lives in a state of chronic hyperinsulinemia.

4.2  Nutritional ketosis

When dietary carbohydrate falls below approximately 20–50 grams per day and insulin consequently falls, the liver shifts its metabolic output toward ketogenesis. Fatty acids are mobilized from adipose tissue, oxidized to acetyl-CoA in hepatocyte mitochondria, and condensed into the three ketone bodies: beta-hydroxybutyrate, acetoacetate, and acetone. Blood beta-hydroxybutyrate concentrations of 0.5–3.0 mmol/L define nutritional ketosis, which is physiologically distinct from the pathological diabetic ketoacidosis that can occur in type 1 diabetes at concentrations above 10 mmol/L with simultaneous hyperglycemia and acidemia (Volek & Phinney, 2011). Ketones are an efficient fuel for brain, heart, and skeletal muscle; beta-hydroxybutyrate also functions as a signaling molecule, inhibiting the NLRP3 inflammasome and class I histone deacetylases and thereby exerting anti-inflammatory and neuroprotective effects (Newman & Verdin, 2014).

4.3  Adaptive thermogenesis versus fasting physiology

A critical and often-missed distinction in weight-loss medicine is the difference between chronic caloric restriction and intermittent fasting. During sustained caloric restriction, the body down-regulates thyroid hormone conversion (T4 to T3), reduces sympathetic nervous system output, and suppresses resting metabolic rate to match the new lower intake — the adaptive thermogenesis documented in “The Biggest Loser” cohort (Fothergill et al., 2016). During a true fast of 16–72 hours, by contrast, insulin falls, glucagon and noradrenaline rise, growth hormone surges, and metabolic rate is preserved or even transiently increased for the first several days (Anton et al., 2018). This is the physiologic basis for the repeated clinical observation that intermittent fasting produces weight loss without the “metabolic slowdown” of conventional dieting.

5.  The Functional Medicine Overlay: Upstream Drivers

A narrow interpretation of the insulin-centric paradigm would reduce clinical care to “cut carbs and fast.” This would be a mistake. Functional medicine insists that hyperinsulinemia is a symptom — the measurable downstream consequence of multiple upstream drivers. In clinical practice, addressing carbohydrate intake alone often produces excellent early results but incomplete or temporary benefit if the underlying drivers are not also identified and treated. The primary upstream drivers include the following.

5.1  Sleep and circadian disruption

Donga and colleagues (2010), using the gold-standard hyperinsulinemic-euglycemic clamp, demonstrated that a single night of partial sleep restriction (4 hours versus 8 hours) produced measurable insulin resistance across multiple metabolic pathways in otherwise healthy adults. One week of sleep restriction to 5 hours per night reduces whole-body insulin sensitivity by approximately 16 –25 % (Buxton, Pavlova, Reid, Wang, & Simonson, 2010). Chronic short sleep, shift work, and irregular sleep-wake cycles are among the most common and least appreciated drivers of treatment-resistant insulin resistance. Clinically, restoring 7–9 hours of consolidated sleep with consistent timing is non-negotiable.

5.2  Chronic stress and cortisol

Cortisol is a potent insulin antagonist. Chronic HPA-axis activation — whether from occupational stress, relational distress, trauma, chronic infection, or overtraining — produces sustained cortisol elevation that drives gluconeogenesis, visceral adiposity, and muscle catabolism. Patients with normal carbohydrate intake and normal sleep can nevertheless remain insulin-resistant if their nervous system is chronically activated. Breathwork, vagal-tone exercises, meditation, and restorative relational practices are not soft adjuncts; they are metabolic interventions.

5.3  Gut dysbiosis and intestinal permeability

Impaired gut barrier function allows bacterial lipopolysaccharide (LPS) to translocate into the systemic circulation, producing low-grade endotoxemia that activates Toll-like receptor-4 signaling and impairs insulin receptor function at the cellular level. This mechanism is now well-established in obesity-associated insulin resistance (Cani et al., 2007). In practice, evaluation for small-intestinal bacterial overgrowth, dysbiosis, and food-driven immune activation is appropriate in patients whose metabolic parameters do not respond adequately to dietary carbohydrate restriction alone.

5.4  Thyroid, sex hormone, and adrenal dysfunction

Subclinical hypothyroidism, low testosterone in men, estrogen-progesterone imbalance in women, and adrenal dysregulation all contribute to insulin resistance. A comprehensive evaluation — including a full thyroid panel (not TSH alone), sex hormones with binding globulin, and cortisol rhythm when indicated — is essential in patients who do not respond fully to dietary and fasting interventions. Addressing these pathways is frequently what separates incomplete responders from full responders.

5.5  Environmental toxins and obesogens

A growing body of evidence implicates phthalates, bisphenol A (BPA), per- and polyfluoroalkyl substances (PFAS), persistent organic pollutants, and heavy metals as contributors to insulin resistance and adipogenesis — the so-called “obesogen hypothesis” (Heindel et al., 2017). Practical reduction strategies include filtering drinking water, reducing processed-food intake, minimizing plastic food contact, supporting hepatic biotransformation, and, when clinically appropriate, evaluating body burden.

5.6  Mitochondrial dysfunction and inflammation

Ceramide accumulation in skeletal muscle and liver impairs mitochondrial function and is a direct cause of insulin resistance at the cellular level — a body of work to which Dr. Bikman has contributed substantially (Bikman & Summers, 2011). Systemic inflammatory markers (hs-CRP, IL-6, TNF-α, ferritin) correlate with and predict insulin resistance. A genuinely root-cause approach therefore includes assessment of the inflammatory state and, when indicated, targeted interventions such as omega-3 supplementation, inflammation-driven food eliminations, and evaluation for chronic infection.

6.  Clinical Assessment Beyond HbA1c

The single most underused test in mainstream metabolic medicine is fasting insulin. HbA1c and fasting glucose can remain within the reference range for years while fasting insulin rises steadily; by the time glucose becomes abnormal, the patient has typically been hyperinsulinemic for a decade or more. A functional metabolic workup includes, at minimum, the markers in the table below.

The triglyceride-to-HDL ratio deserves special mention. McLaughlin and colleagues (2005), using the euglycemic clamp as gold standard, demonstrated that a TG/HDL ratio of ≥ 3.5 mg/dL identifies insulin-resistant individuals with sensitivity and specificity comparable to the formal metabolic-syndrome criteria, and superior performance for identifying the small, dense LDL phenotype. Because triglyceride and HDL are obtained on every routine lipid panel, the ratio is essentially free. A TG/HDL ratio under 1.5 is a strong indicator of metabolic health; above 3.5 it is a red flag. (Important caveat: the TG/HDL ratio is a less reliable marker of insulin resistance in individuals of African descent, in whom triglycerides tend to be lower and HDL higher even in the setting of documented insulin resistance; Sumner et al., 2005.)

Continuous glucose monitoring (CGM) has become an invaluable tool even in non-diabetic patients. Two weeks of CGM data reveal the individual’s unique glycemic responses to specific foods, meal combinations, exercise, sleep, and stress — information that no laboratory snapshot can provide and that empowers patients to make genuinely personalized decisions. Body composition should be assessed by DEXA when available; BMI is an insensitive and often misleading marker of metabolic health, particularly in patients with the “thin-outside, fat-inside” (TOFI) phenotype whose visceral and ectopic fat is disproportionate to their body weight.

7.  Implementation: A Sequential Clinical Protocol

The following protocol represents one reasonable clinical sequence. It should be tailored to the individual patient’s medical history, current medications, clinical phenotype, and personal preferences. Changes are introduced sequentially rather than simultaneously, both to improve adherence and to identify which interventions are producing the benefit.

1. Therapeutic carbohydrate restriction. Ketogenic (< 20–30 g/day of total carbohydrate) for the first 8–12 weeks to drive rapid metabolic reset, glycemic improvement, and medication reduction. Moderate low-carbohydrate (50–100 g/day) is often appropriate for long-term maintenance in many patients, although a subset with more severe metabolic derangement benefits from continued ketogenic therapy. Adequate protein (1.2–1.6 g/kg of reference body weight) is protective against lean mass loss.
2. Time-restricted eating. Begin at 12 hours overnight fast and progress to 14–16 hours as tolerated over several weeks. Eating windows of 6–8 hours (16:8 pattern) are sustainable for most patients and lower 24-hour insulin exposure substantially.
3. Selective intermittent or extended fasting. In appropriately selected and supervised patients, 24-hour fasts one to three times weekly, or occasional 36–72-hour fasts, can accelerate insulin resistance reversal and weight loss (Furmli et al., 2018). This intervention requires careful medication management and is not appropriate for all patients.
4. Resistance training. Skeletal muscle is the largest glucose sink in the body and the primary determinant of metabolic flexibility. Two to three resistance training sessions per week, progressing in load over time, should be considered as important as any dietary intervention. Walking after meals — even 10–15 minutes — substantially reduces postprandial glucose.
5. Sleep optimization. Seven to nine hours per night with a consistent schedule, good sleep hygiene, and evaluation for obstructive sleep apnea in appropriate patients.
6. Stress and nervous system regulation. Breathwork, vagal-tone exercises, meditation, time in nature, and honest appraisal of relationships and workload.
7. Targeted supplementation, when clinically indicated. This may include magnesium, omega-3 fatty acids, vitamin D to 40–60 ng/mL, berberine, inositols (particularly in PCOS), alpha-lipoic acid, and others based on individual biochemistry.
8. Systematic de-prescribing. Diabetes medications (insulin, sulfonylureas, SGLT-2 inhibitors) and antihypertensives will often need rapid reduction as metabolic parameters normalize. This must be planned proactively, not reactively.

8.  The Evidence Base for Reversibility

Two landmark trials have transformed the conversation about whether type 2 diabetes is reversible.

8.1  The DiRECT trial

Lean and colleagues (2018), in the UK-based Diabetes Remission Clinical Trial (DiRECT), randomized 306 adults with type 2 diabetes (duration ≤ 6 years, BMI 27–45 kg/m², not on insulin) to either best-practice guideline care or an intensive weight-management program delivered in routine primary care. The intervention consisted of a total-diet-replacement formula (825–853 kcal/day) for 12–20 weeks, stepped food reintroduction, and structured maintenance. At 12 months, 46 % of intervention participants versus 4 % of controls achieved remission (HbA1c < 6.5 % off all diabetes medications). Critically, remission was dose-dependent on weight loss: 86 % of those who lost ≥ 15 kg achieved remission. At the 24-month follow-up, 36 % remained in remission, with 70 % of those who maintained weight loss > 15 kg still in remission (Lean et al., 2019). The DiRECT trial established, within the mainstream clinical literature, that type 2 diabetes is not necessarily a chronic progressive disease.

8.2  The Virta-Health continuous care trial

Hallberg and colleagues (2018), and subsequently Athinarayanan et al. (2019) and McKenzie et al. (2024), reported the outcomes of a 262-patient non-randomized trial of a continuous-care intervention (CCI) combining nutritional ketosis (< 30 g carbohydrate/day) with telehealth-enabled clinician and health-coach support. At one year, intervention patients achieved a mean HbA1c reduction of 1.3 percentage points, mean weight loss of 12 %, and discontinuation of insulin in 94 % of users. At two years, benefits were largely sustained. At five years, 20 % of five-year completers remained in full remission, and 32.5 % had reversed to HbA1c < 6.5 % on no medication or metformin alone. Triglycerides fell by 18.4 % and HDL-C rose by 17.4 %, with no significant adverse change in LDL-C or total cholesterol. The Virta data represent among the longest and best-documented real-world outcomes for a ketogenic therapeutic intervention in type 2 diabetes (McKenzie et al., 2024).

8.3  Fung and colleagues: therapeutic fasting

Furmli, Elmasry, Ramos, and Fung (2018) reported in BMJ Case Reports three patients with insulin-dependent type 2 diabetes (10–25 years’ duration) who discontinued insulin therapy within 5–18 days of initiating alternate-day or triweekly 24-hour fasts. All three lost 10–18 % of body weight and reduced HbA1c and waist circumference. While the literature on therapeutic fasting remains smaller and earlier-stage than that on ketogenic therapy, the mechanistic plausibility and reproducibility across Fung’s clinical population are substantial.

8.4  Consensus acknowledgment

The American Diabetes Association and European Association for the Study of Diabetes, in their joint consensus report on the management of hyperglycemia in type 2 diabetes (Davies et al., 2018) and in subsequent ADA Standards of Care updates, have formally acknowledged low-carbohydrate eating patterns as one of several evidence-supported medical-nutrition therapy options. This represents a notable shift from the low-fat, high-carbohydrate recommendations that dominated clinical practice for decades.

9.  Safety Considerations

The interventions described in this article are powerful. That is both their strength and their risk. Several specific considerations require emphasis.

• Medication hypoglycemia. Patients on insulin and/or sulfonylureas face immediate risk of hypoglycemia when carbohydrate intake is sharply reduced or meals are skipped. Insulin doses often need to be reduced by 30–50 % on day one; sulfonylureas are typically discontinued outright. Close clinical supervision and frequent glucose monitoring are essential.
• Euglycemic DKA. SGLT-2 inhibitors (canagliflozin, empagliflozin, dapagliflozin) increase the risk of euglycemic diabetic ketoacidosis when combined with carbohydrate restriction and should generally be held before initiating a ketogenic diet.
• Antihypertensive adjustment. Carbohydrate restriction produces natriuresis and modest volume contraction within days. Diuretics and antihypertensives frequently require reduction in the first week to prevent symptomatic hypotension.
• Electrolyte replacement. Adequate sodium (3–5 g/day for most patients), potassium, and magnesium are essential during the first several weeks of ketogenic adaptation to prevent “keto flu” symptoms — which are largely electrolyte-driven.
• Contraindications and cautions. Extended fasting should be approached with particular caution or avoided in the following: history of eating disorder, significant underweight (BMI < 18.5), pregnancy, lactation, active cancer (requires oncology coordination), advanced renal disease, advanced hepatic disease, type 1 diabetes (possible under close supervision but not as a primary intervention), and certain inborn errors of metabolism. Pediatric implementation requires specialist oversight.
• LDL-C monitoring. A subset of patients on ketogenic diets experience elevated LDL-C, sometimes substantially. The interpretation is nuanced — ApoB, LDL particle number, and triglyceride-to-HDL ratio often remain favorable — but the elevation should be monitored and discussed with the patient, and modifications considered when warranted.
• Thyroid and adrenal status. Aggressive caloric restriction or prolonged fasting should not be layered onto untreated hypothyroidism or adrenal insufficiency. Evaluate first; intervene second.

10.  Clinical Integration: A Unified Framework

The three frameworks profiled here — Westman’s therapeutic carbohydrate restriction, Fung’s therapeutic fasting, and Bikman’s mechanistic insulin-resistance physiology — converge on a unified clinical model that can be stated simply: lower insulin, restore insulin sensitivity, and allow the body’s regulatory systems to do what they were designed to do. Functional medicine extends this model by insisting that the drivers of hyperinsulinemia are multifactorial and that lasting metabolic recovery requires addressing sleep, stress, inflammation, gut health, hormonal balance, environmental exposures, and mitochondrial health alongside the dietary intervention.

In clinical practice, the patient whose metabolic parameters do not respond adequately to carbohydrate restriction and time-restricted eating alone is almost always telling the clinician that one or more upstream drivers remain unaddressed. The most common culprits, in approximate order of frequency in my clinical experience, are inadequate sleep, unrecognized chronic stress, subclinical thyroid or adrenal dysfunction, gut-derived inflammation, perimenopausal hormonal shifts in women, and insufficient resistance training. Systematic evaluation of each of these domains is the work of functional medicine.

The most elegant prescription in this practice area is not a medication — it is de-prescribing. When the underlying physiology is corrected, the drugs often become unnecessary. That is what reversal means.

Ultimately, the insulin-centric paradigm is not a diet, a fasting protocol, or a single prescription. It is a coherent physiological model, supported by an increasingly robust clinical literature, that restores hope to patients who have been told their metabolic disease is chronic, progressive, and manageable only with lifelong medication. For many patients — not all, but many — it is reversible. The clinician’s task is to identify which patients are candidates, guide them through the transition safely, and remain vigilant for the upstream drivers that must be addressed for the gains to endure.

11.  References

Anton, S. D., Moehl, K., Donahoo, W. T., Marosi, K., Lee, S. A., Mainous, A. G., III, … Mattson, M. P. (2018). Flipping the metabolic switch: Understanding and applying the health benefits of fasting. Obesity (Silver Spring), 26(2), 254–268. https://doi.org/10.1002/oby.22065

Athinarayanan, S. J., Adams, R. N., Hallberg, S. J., McKenzie, A. L., Bhanpuri, N. H., Campbell, W. W., … McCarter, J. P. (2019). Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: A 2-year non-randomized clinical trial. Frontiers in Endocrinology, 10, 348. https://doi.org/10.3389/fendo.2019.00348

Bikman, B. T. (2020). Why we get sick: The hidden epidemic at the root of most chronic disease — and how to fight it. BenBella Books.

Bikman, B. T. (n.d.). Faculty profile, Department of Cell Biology and Physiology, Brigham Young University. Retrieved from https://cell.byu.edu/directory/benjamin-bikman

Bikman, B. T., & Summers, S. A. (2011). Ceramides as modulators of cellular and whole-body metabolism. Journal of Clinical Investigation, 121(11), 4222–4230. https://doi.org/10.1172/JCI57144

Buxton, O. M., Pavlova, M., Reid, E. W., Wang, W., Simonson, D. C., & Adler, G. K. (2010). Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes, 59(9), 2126–2133. https://doi.org/10.2337/db09-0699

Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., … Burcelin, R. (2007). Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 56(7), 1761–1772. https://doi.org/10.2337/db06-1491

Davies, M. J., D’Alessio, D. A., Fradkin, J., Kernan, W. N., Mathieu, C., Mingrone, G., … Buse, J. B. (2018). Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care, 41(12), 2669–2701. https://doi.org/10.2337/dci18-0033

Donga, E., van Dijk, M., van Dijk, J. G., Biermasz, N. R., Lammers, G.-J., van Kralingen, K. W., … Romijn, J. A. (2010). A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. Journal of Clinical Endocrinology & Metabolism, 95(6), 2963–2968. https://doi.org/10.1210/jc.2009-2430

Duke Health Referring Physicians. (2020, July 28). Low-carb, ketogenic diet most effective with lifestyle counseling, adherence. Retrieved from https://physicians.dukehealth.org/articles/low-carb-ketogenic-diet-most-effective-lifestyle-counseling-adherence

Duke University. (2024). Eric Charles Westman — Scholars@Duke faculty profile. Retrieved from https://scholars.duke.edu/person/ewestman

Fothergill, E., Guo, J., Howard, L., Kerns, J. C., Knuth, N. D., Brychta, R., … Hall, K. D. (2016). Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. Obesity (Silver Spring), 24(8), 1612–1619. https://doi.org/10.1002/oby.21538

Furmli, S., Elmasry, R., Ramos, M., & Fung, J. (2018). Therapeutic use of intermittent fasting for people with type 2 diabetes as an alternative to insulin. BMJ Case Reports, 2018, bcr2017221854. https://doi.org/10.1136/bcr-2017-221854

Hallberg, S. J., McKenzie, A. L., Williams, P. T., Bhanpuri, N. H., Peters, A. L., Campbell, W. W., … Volek, J. S. (2018). Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: An open-label, non-randomized, controlled study. Diabetes Therapy, 9(2), 583–612. https://doi.org/10.1007/s13300-018-0373-9

Heindel, J. J., Blumberg, B., Cave, M., Machtinger, R., Mantovani, A., Mendez, M. A., … vom Saal, F. (2017). Metabolism disrupting chemicals and metabolic disorders. Reproductive Toxicology, 68, 3–33. https://doi.org/10.1016/j.reprotox.2016.10.001

Lean, M. E. J., Leslie, W. S., Barnes, A. C., Brosnahan, N., Thom, G., McCombie, L., … Taylor, R. (2018). Primary care-led weight management for remission of type 2 diabetes (DiRECT): An open-label, cluster-randomised trial. The Lancet, 391(10120), 541–551. https://doi.org/10.1016/S0140-6736(17)33102-1

Lean, M. E. J., Leslie, W. S., Barnes, A. C., Brosnahan, N., Thom, G., McCombie, L., … Taylor, R. (2019). Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. The Lancet Diabetes & Endocrinology, 7(5), 344–355. https://doi.org/10.1016/S2213-8587(19)30068-3

Ludwig, D. S., Aronne, L. J., Astrup, A., de Cabo, R., Cantley, L. C., Friedman, M. I., … Ebbeling, C. B. (2021). The carbohydrate-insulin model: A physiological perspective on the obesity pandemic. American Journal of Clinical Nutrition, 114(6), 1873–1885. https://doi.org/10.1093/ajcn/nqab270

McKenzie, A. L., Athinarayanan, S. J., Van Tieghem, M. R., Volk, B. M., Roberts, C. G. P., Adams, R. N., … Hallberg, S. J. (2024). 5-year effects of a novel continuous remote care model with carbohydrate-restricted nutrition therapy including nutritional ketosis in type 2 diabetes: An extension study. Diabetes Research and Clinical Practice, 217, 111898. https://doi.org/10.1016/j.diabres.2024.111898

McLaughlin, T., Reaven, G., Abbasi, F., Lamendola, C., Saad, M., Waters, D., … Krauss, R. M. (2005). Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? American Journal of Cardiology, 96(3), 399–404. https://doi.org/10.1016/j.amjcard.2005.03.085

Newman, J. C., & Verdin, E. (2014). β-Hydroxybutyrate: Much more than a metabolite. Diabetes Research and Clinical Practice, 106(2), 173–181. https://doi.org/10.1016/j.diabres.2014.08.009

Sumner, A. E., Finley, K. B., Genovese, D. J., Criqui, M. H., & Boston, R. C. (2005). Fasting triglyceride and the triglyceride-HDL cholesterol ratio are not markers of insulin resistance in African Americans. Archives of Internal Medicine, 165(12), 1395–1400. https://doi.org/10.1001/archinte.165.12.1395

Volek, J. S., & Phinney, S. D. (2011). The art and science of low carbohydrate living. Beyond Obesity LLC.

Westman, E. C., Yancy, W. S., Jr., Mavropoulos, J. C., Marquart, M., & McDuffie, J. R. (2008). The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutrition & Metabolism, 5, 36. https://doi.org/10.1186/1743-7075-5-36

Westman, E. C., Tondt, J., Maguire, E., & Yancy, W. S., Jr. (2018). Implementing a low-carbohydrate, ketogenic diet to manage type 2 diabetes mellitus. Expert Review of Endocrinology & Metabolism, 13(5), 263–272. https://doi.org/10.1080/17446651.2018.1523713

Yancy, W. S., Jr., Foy, M., Chalecki, A. M., Vernon, M. C., & Westman, E. C. (2005). A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutrition & Metabolism, 2, 34. https://doi.org/10.1186/1743-7075-2-34

About the Author

Yoon Hang “John” Kim, MD, MPH is a board-certified physician in Preventive Medicine and Integrative/Holistic Medicine and the founder of Direct Integrative Care, a membership-based telemedicine practice serving patients across Iowa, Illinois, Missouri, Texas, Georgia, and Florida. He is a UCLA-trained Medical Acupuncturist, an Osher Fellow at the University of Arizona’s Andrew Weil Center for Integrative Medicine, and an Institute for Functional Medicine (IFM) Scholar. Dr. Kim has authored three books and more than 20 articles on low-dose naltrexone (LDN) and leads the 9,000-member LDN Support Group community. He has more than 20 years of experience in integrative and functional medicine and has built integrative programs at Miami Cancer Institute and the University of Kansas.