Yoon Hang Kim, MD, MPH

Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician

Direct Integrative Care

Published April 2026

Introduction: The Metabolic Crisis of Insulin Resistance

Type 2 diabetes mellitus and its precursor, insulin resistance, represent one of the most consequential metabolic crises of the modern era. Over 37 million Americans are living with diabetes, and an estimated 96 million more have prediabetes — a condition of chronic cellular insulin resistance that often goes unrecognized for years. Standard pharmacological management, while sometimes necessary, frequently addresses the downstream symptoms of elevated blood glucose rather than the upstream root cause: chronically elevated insulin.

A growing body of evidence — championed prominently by Canadian nephrologist and author Jason Fung, MD — now strongly supports that strategic dietary fasting, and in particular prolonged fasting protocols lasting 24 to 72 hours or more, can powerfully and rapidly reverse insulin resistance and, in many cases, achieve remission of type 2 diabetes without medications. This article reviews the mechanisms, clinical evidence, and practical implications of prolonged fasting as a metabolic therapy.

Part I: The Physiology of Insulin Resistance — A Fasting-Responsive Disease

To understand why prolonged fasting works, one must first understand what drives insulin resistance. Dr. Jason Fung, in his landmark book The Diabetes Code (2018), articulates what he calls the "overflow" hypothesis of insulin resistance: cells become resistant to insulin not from a random genetic defect, but because they are literally overfull with glucose — primarily in the form of hepatic and intracellular fat.

When dietary carbohydrates and calories are continuously consumed — particularly in the context of high meal frequency — insulin remains chronically elevated. This sustained hyperinsulinemia drives glucose into cells and, once storage capacity is exceeded, converts it to fat through de novo lipogenesis. The liver becomes fatty (NAFLD), skeletal muscle becomes lipotoxic, and the pancreatic beta cells themselves become insulin-resistant. The vicious cycle accelerates.

Fung's model predicts that the only durable solution is to lower insulin long enough and deeply enough to empty the cellular glucose surplus — to let the body "drain the bathtub." This cannot be achieved with medications alone; it requires insulin to fall to very low levels for a sustained period. And the most efficient way to accomplish this is through fasting.

Part II: Short-Term Mechanisms — How Fasting Reverses Insulin Resistance

Even brief periods of fasting initiate a cascade of favorable metabolic adaptations. During the first 24–72 hours of a prolonged fast, the following physiological changes occur:

1. Insulin Suppression

Within hours of the last meal, circulating insulin begins to fall. By 12–16 hours, insulin levels are significantly reduced. By 24–48 hours, insulin reaches near-basal levels. This drop in insulin is the central mechanism by which fasting breaks the hyperinsulinemia cycle. Low insulin signals the body to shift from fat storage to fat mobilization, and to begin drawing down hepatic glycogen and intracellular fat stores.

A pivotal 2011 study by Lim et al., published in Diabetologia, demonstrated that caloric restriction — even before significant weight loss — dramatically reduced intrahepatic fat and restored first-phase insulin secretion in type 2 diabetics within just 7 days. The authors concluded that type 2 diabetes is a reversible condition driven by chronic caloric surplus and hepatic fat accumulation, not irreversible beta cell loss. (Lim EL et al., Diabetologia 2011;54:2506–2514)

2. Hepatic Glycogen Depletion

After approximately 16–24 hours of fasting, hepatic glycogen stores — roughly 70–100 grams — are substantially depleted. This forces a metabolic transition from glucose oxidation to fatty acid oxidation. The liver begins producing ketone bodies (beta-hydroxybutyrate, acetoacetate), which serve as an efficient alternative fuel for the brain and peripheral tissues. This "metabolic switch" is associated with improved insulin sensitivity and reduced inflammatory signaling. Mattson et al. (2018) described this switch comprehensively in Cell Metabolism, noting that ketone production itself carries signaling properties that improve cellular insulin sensitivity. (Mattson MP et al., Cell Metab 2018;27(5):1005–1019)

3. Reduction of Ectopic and Visceral Fat

One of the most compelling benefits of prolonged fasting is mobilization of ectopic fat — fat stored in the liver, pancreas, skeletal muscle, and visceral adipose tissue. Research by Taylor and colleagues at Newcastle University demonstrated that targeted reduction of pancreatic and hepatic fat is associated with restoration of first-phase insulin secretion and reversal of type 2 diabetes. During a 72-hour fast, the body preferentially mobilizes these ectopic fat stores before significantly catabolizing lean muscle mass, especially in the context of electrolyte-supported fasting. (Taylor R, Diabetes Care 2013;36(4):1047–1055)

4. Downregulation of mTOR and Activation of AMPK/Autophagy

Prolonged fasting activates AMP-activated protein kinase (AMPK), the cell's primary energy-sensing enzyme, while simultaneously suppressing mammalian target of rapamycin (mTOR). This metabolic shift promotes autophagy — the cellular "self-cleaning" process — which removes dysfunctional mitochondria and protein aggregates that impair insulin signaling. Enhanced mitochondrial biogenesis and improved mitochondrial efficiency directly improve cellular glucose uptake independent of insulin.

De Cabo and Mattson, writing in the New England Journal of Medicine in 2019, concluded that intermittent fasting — including prolonged fasting — exerts broad metabolic benefits through AMPK activation, SIRT1 upregulation, and reduction of oxidative stress, all of which converge on improved insulin sensitivity. (de Cabo R, Mattson MP. N Engl J Med 2019;381:2541–2551)

5. Reduction in Inflammatory Cytokines

Insulin resistance is closely linked with chronic low-grade inflammation — elevated IL-6, TNF-alpha, and CRP. Prolonged fasting has been shown to reduce circulating inflammatory markers measurably within 24–72 hours. By reducing NF-κB activation (a key inflammatory transcription factor) and upregulating anti-inflammatory pathways, fasting directly addresses one of the molecular underpinnings of insulin resistance. This is particularly relevant given the documented role of visceral adipose tissue as an endocrine organ secreting pro-inflammatory adipokines.

Part III: Clinical Evidence for Prolonged Fasting and Diabetes Reversal

While much research has focused on intermittent fasting (16:8, 5:2), emerging evidence specifically supports prolonged fasting — defined here as consecutive 48–72+ hour fasts performed periodically — as a powerful metabolic reset.

Jason Fung, MD: Clinical Case Series and Therapeutic Fasting Protocol

Dr. Jason Fung, co-founder of the Intensive Dietary Management (IDM) program in Toronto, Canada, has published and presented extensive clinical data supporting therapeutic fasting for type 2 diabetes reversal. In a landmark 2018 case series published in BMJ Case Reports, Fung and colleagues — Furmli, Elmasry, and Ramos — documented three patients with longstanding type 2 diabetes (durations of 10–25 years) who achieved complete insulin independence after undertaking a therapeutic fasting protocol.

The protocol involved 24-hour fasts three times per week or alternate-day 24-hour fasts. Results were striking: all three patients were able to discontinue insulin within one month. HbA1c values dropped significantly (one from 10.5% to 7.0% within 10 months). Waist circumference, body weight, and fasting glucose all normalized. Notably, no adverse events were reported. The authors concluded that fasting "can be a safe and effective management strategy for T2DM, with potential for T2DM reversal." (Furmli S, Elmasry R, Ramos M, Fung J. BMJ Case Reports 2018;2018:bcr-2017-221854)

In his 2016 book The Complete Guide to Fasting (co-authored with Jimmy Moore) and his 2018 book The Diabetes Code, Dr. Fung presents an extensive theoretical and clinical framework for understanding type 2 diabetes as a dietary disease — specifically one of insulin excess — and makes the case that the only treatment with potential for true reversal (not just management) is one that lowers insulin: specifically, a low-carbohydrate diet combined with therapeutic fasting.

Fung argues that while pharmacological agents like metformin and GLP-1 agonists offer metabolic benefits, they do not address the central defect: chronic hyperinsulinemia. Only dietary interventions that genuinely lower insulin — prolonged fasting chief among them — can allow the cellular insulin resistance to resolve. He cites the "fat overflow" model as the unifying explanation for why fasting reverses diabetes so efficiently: once the overfull cells are emptied through lipolysis and ketogenesis, insulin sensitivity rapidly returns.

The Newcastle Diet Studies: Proof of Concept

Professor Roy Taylor and his team at Newcastle University demonstrated that type 2 diabetes could be reversed through aggressive caloric restriction, specifically through their DIRECT trial and predecessor studies. While using liquid meal replacements rather than water fasting, the mechanism was equivalent: sustained insulin suppression and rapid mobilization of hepatic and pancreatic fat.

The landmark DiRECT trial (2018), published in The Lancet, showed that 46% of participants achieved diabetes remission (HbA1c < 6.5% without medications) at 12 months through a calorie-restricted dietary intervention, with 24% achieving remission at 24 months. Nearly 9 in 10 of those who achieved at least 15 kg of weight loss went into remission. These findings confirmed that diabetes remission is a realistic and achievable clinical goal — not an aberration. (Lean MEJ et al., Lancet 2018;391(10120):541–551)

Fasting-Mimicking Diet and Prolonged Fasting: Cellular Regeneration

Valter Longo and colleagues at the University of Southern California published compelling data on a 5-day calorie-restricted fasting-mimicking diet (FMD). In a randomized trial published in Cell Metabolism in 2017, three monthly cycles of the 5-day FMD reduced fasting glucose, trunk fat, blood pressure, IGF-1, and systolic blood pressure in participants at elevated metabolic risk. Crucially, the study found improvements in insulin sensitivity and fasting glucose that persisted between cycles, suggesting that repeated prolonged fasting reshapes metabolic homeostasis — not merely producing transient shifts. (Brandhorst S et al., Cell Metab 2015;22(1):86–99; Wei M et al., Sci Transl Med 2017;9(377):eaai8700)

Perhaps most striking, animal data from Cheng et al. (2014), published in Cell Stem Cell, demonstrated that cycles of prolonged fasting (72 hours) triggered pancreatic beta cell regeneration in a mouse model of type 1-like diabetes induced by streptozotocin. While extrapolation to humans must be cautious, this suggests that periodic prolonged fasting may not only reverse insulin resistance but potentially regenerate compromised beta cell function. (Cheng CW et al., Cell Stem Cell 2014;14(6):810–823)

Part IV: The 3-Day (72-Hour) Fasting Protocol — Clinical Application

Based on available evidence, a structured 72-hour fasting protocol — performed once monthly or more frequently as clinically guided — represents one of the most potent short-term metabolic resets available for insulin-resistant and type 2 diabetic patients.

Arnason et al. (2017), in a prospective pilot study published in World Journal of Diabetes, studied alternate-day fasting (24-hour fasts) in patients with type 2 diabetes. Over two weeks, participants demonstrated significant reductions in fasting glucose (from 163 to 127 mg/dL), HbA1c, and body weight, without adverse hypoglycemic events when medications were appropriately managed. (Arnason TG et al., World J Diabetes 2017;8(4):154–164)

Contraindications and Safety Considerations

Prolonged fasting is not appropriate for everyone. Absolute contraindications include: active eating disorders, pregnancy or breastfeeding, type 1 diabetes (without intensive medical supervision), significant malnutrition, severe adrenal insufficiency, and advanced cardiac or renal disease. Relative contraindications include medications requiring food (especially sulfonylureas, SGLT2 inhibitors, and insulin) that require dose adjustment or discontinuation before fasting.

At Direct Integrative Care, prolonged fasting protocols are introduced within a comprehensive integrative framework that includes laboratory monitoring, medication adjustment, electrolyte supplementation (sodium, potassium, magnesium), and close clinical follow-up. Hypoglycemia risk is the primary safety concern for medicated diabetics and must be managed proactively by reducing or eliminating glucose-lowering agents before fasting begins.

Part V: Combining Prolonged Fasting with a Low-Carbohydrate Diet

The synergistic combination of periodic prolonged fasting and a low-carbohydrate (or ketogenic) dietary pattern is well-supported by both physiological reasoning and clinical evidence. Fasting depletes glycogen and initiates fat adaptation; a low-carbohydrate diet maintains a lower insulin baseline between fasts and prevents the re-accumulation of ectopic fat. Together, they constitute a comprehensive therapeutic strategy for diabetes reversal.

Dr. Fung consistently advocates for this combined approach in his clinical practice. In the IDM program, patients typically begin with a therapeutic fasting trial (24–36 hours initially, increasing to 48–72 hours over time) while simultaneously adopting a low-carbohydrate dietary pattern. Results published and presented from this program indicate that the majority of type 2 diabetic patients who comply with the protocol are able to reduce or eliminate diabetes medications within weeks to months.

Patterson and Sears, in their 2017 review in the Annual Review of Nutrition, synthesized multiple lines of evidence supporting intermittent and prolonged fasting for metabolic improvement, including weight loss, reduced inflammation, improved lipid profiles, and enhanced insulin sensitivity. They noted that the metabolic benefits of fasting appear to exceed what would be predicted from weight loss alone, suggesting fasting-specific mechanisms independent of caloric restriction. (Patterson RE, Sears DD. Annu Rev Nutr 2017;37:371–393)

Conclusion: Rethinking Diabetes as a Reversible Disease

For decades, type 2 diabetes was treated as a chronic, progressive condition requiring lifelong medication escalation. The paradigm is shifting. Driven by the clinical advocacy of physicians like Dr. Jason Fung and supported by an expanding evidence base — from Newcastle to the Salk Institute to the IDM program in Toronto — we now understand that type 2 diabetes, in the majority of cases, is a reversible metabolic condition driven by dietary patterns and correctable by the same means.

Prolonged fasting — particularly structured 48–72 hour fasts repeated periodically — represents one of the most potent, low-cost, pharmacologically elegant interventions available. It works not by suppressing symptoms but by addressing root causes: emptying overfull cells, lowering chronically elevated insulin, mobilizing ectopic fat, and restoring the insulin-signaling cascade that chronic dietary excess had disrupted.

This is the vision of integrative and functional medicine: not to manage disease indefinitely, but to understand it mechanistically and reverse it when possible. At Direct Integrative Care, we work with patients individually to design medically supervised fasting protocols tailored to their metabolic status, medications, and goals — always with safety first and remission as the aspiration.

References

1. Fung J, Moore J. The Complete Guide to Fasting: Heal Your Body Through Intermittent, Alternate-Day, and Extended Fasting. Victory Belt Publishing; 2016.

2. Fung J. The Diabetes Code: Prevent and Reverse Type 2 Diabetes Naturally. Greystone Books; 2018.

3. Furmli S, Elmasry R, Ramos M, Fung J. Therapeutic use of intermittent fasting for people with type 2 diabetes as an alternative to insulin. BMJ Case Reports. 2018;2018:bcr-2017-221854.

4. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54(10):2506–2514.

5. Lean MEJ, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018;391(10120):541–551.

6. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med. 2019;381(26):2541–2551.

7. Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci. 2018;19(2):63–80.

8. Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377):eaai8700.

9. Brandhorst S, Choi IY, Wei M, et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015;22(1):86–99.

10. Cheng CW, Adams GB, Perin L, et al. Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression. Cell Stem Cell. 2014;14(6):810–823.

11. Arnason TG, Bowen MW, Mansell KD. Effects of intermittent fasting on health markers in those with type 2 diabetes: A pilot study. World J Diabetes. 2017;8(4):154–164.

12. Patterson RE, Sears DD. Metabolic Effects of Intermittent Fasting. Annu Rev Nutr. 2017;37:371–393.

13. Taylor R. Banting Memorial Lecture 2012: reversing the twin cycles of Type 2 diabetes. Diabet Med. 2013;30(3):267–275.

14. Fung J, Berger A. Therapeutic Fasting as a Potential Effective Treatment for Type 2 Diabetes: A 4-month case study. Journal of Insulin Resistance. 2017;2(1):1–4.