About the Author(s)


Salah Snouda Email symbol
Health Coaching and Metabolic Research, Snouda Health Coaching LTD, Manchester, United Kingdom

Citation


Snouda S. Reversal of type 2 diabetes through metabolic restoration: A narrative review. J. metab. health. 2026;9(1), a149. https://doi.org/10.4102/jmh.v9i1.149

Review

Reversal of type 2 diabetes through metabolic restoration: A narrative review

Salah Snouda

Received: 11 Mar. 2026; Accepted: 22 Apr. 2026; Published: 28 May 2026

Copyright: © 2026. The Author. Licensee: AOSIS.
This work is licensed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/).

Abstract

Background: Type 2 diabetes (T2D) is traditionally managed as an irreversible disease with escalating polypharmacy. However, evidence increasingly shows that durable remission is achievable.

Aim: This review synthesises evidence for T2D reversal, exploring pathophysiological mechanisms and clinical interventions that achieve remission, while addressing barriers to this paradigm shift.

Methods: A narrative literature review was conducted across major academic databases focusing on T2D remission, beta-cell dedifferentiation, the twin cycle hypothesis, and clinical interventions like bariatric surgery, very-low-calorie diets and carbohydrate restriction.

Results: T2D is primarily a disease of beta-cell dysfunction and dedifferentiation driven by chronic metabolic stress, not permanent cell death. Initiated by peripheral insulin resistance and hyperinsulinaemia, it culminates in glucolipotoxicity from ectopic fat in the liver and pancreas (the twin cycle hypothesis). Crucially, this process is reversible. Clinical trials demonstrate significant remission rates through weight loss and lifestyle interventions. The DiRECT trial achieved 46% remission at 1 year via very-low-calorie diets. Carbohydrate restriction models (e.g. Virta Health) showed 17.6% remission at 2 years with significant medication reduction. Bariatric surgery provides further proof of principle with up to 80% remission. Despite this, clinical inertia and systemic barriers slow the adoption of reversal as a primary goal.

Conclusion: T2D is a reversible metabolic condition. Clinical management must shift from lifelong symptom management to strategic reversal of underlying pathophysiology through interventions that reduce insulin demand, clear ectopic fat and restore metabolic health.

Contribution: This review provides an evidence-based framework for implementing T2D reversal in clinical practice, advocating for a new standard of care.

Keywords: type 2 diabetes; remission; reversal; beta-cell dedifferentiation; twin cycle hypothesis; ectopic fat; insulin resistance; metabolic restoration.

Introduction

For decades, the diagnosis of type 2 diabetes (T2D) has been delivered as a life sentence: a chronic, progressive disease to be managed, but never cured.1 The prevailing treatment paradigm has focused on glycaemic control through a steadily escalating regimen of oral medications and, ultimately, insulin. This approach, while capable of mitigating some of the microvascular complications of hyperglycaemia, has done little to stem the tide of the global diabetes epidemic and has implicitly accepted the disease’s presumed irreversibility. This therapeutic nihilism has not only placed an immense and growing burden on healthcare systems, but has also disempowered patients, resigning them to a lifetime of medication and managed decline.

However, a paradigm shift is underway. A confluence of evidence from basic science, clinical trials and real-world practice is challenging this long-held dogma. The central thesis of this new paradigm is simple yet revolutionary: T2D is not an irreversible condition, but a potentially reversible metabolic state.2 This review will synthesise the evidence supporting this claim, arguing that the primary goal of T2D management should be the achievement of durable, medication-free remission.

We will first explore the foundational science that has overturned the old model of β-cell death, replacing it with a new understanding of β-cell dedifferentiation – a process that is not only preventable, but also reversible.3 We will then examine the underlying pathophysiology, starting with peripheral insulin resistance and hyperinsulinaemia as the initiating upstream defects,4 before moving to the ‘twin cycle hypothesis’, a powerful explanatory model that identifies ectopic fat accumulation in the liver and pancreas as the central driver of the metabolic dysfunction that leads to overt T2D.5

Next, we will review the compelling clinical evidence from landmark trials such as Diabetes Remission Clinical Trial (DiRECT), the work of Virta Health, primary care interventions and studies on bariatric surgery. These studies demonstrate that significant weight loss and reduction in insulin demand, achieved through various interventions, can lead to high rates of T2D remission.6,7,8 Finally, we will address the significant barriers – clinical, educational and systemic – that have hindered the widespread adoption of a reversal-focused approach and propose a path forward for a new standard of care.

This is not merely an academic exercise. The reclassification of T2D from an irreversible disease to a reversible condition has profound implications for millions of patients worldwide. It offers the promise of liberation from lifelong medication and the restoration of metabolic health. The evidence is clear; the mission must now be to translate this evidence into clinical practice.

Methods

This article is a narrative review of the scientific literature. A comprehensive search was conducted using the PubMed, Google Scholar and ScienceDirect databases for articles published up to March 2026. The search strategy included a combination of keywords and Medical Subject Headings (MeSH) terms such as ‘type 2 diabetes’, ‘remission’, ‘reversal’, ‘aetiology’, ‘pathophysiology’, ‘insulin resistance’, ‘hyperinsulinaemia’, ‘beta-cell dedifferentiation’, ‘glucotoxicity’, ‘lipotoxicity’, ‘twin cycle hypothesis’, ‘ectopic fat’, ‘DiRECT’, ‘Virta Health’, ‘bariatric surgery’, ‘very-low-calorie diet’, ‘ketogenic diet’ and ‘therapeutic fasting’.

Articles were selected for inclusion based on their relevance to the pathophysiology and clinical management of T2D reversal. Priority was given to landmark studies, systematic reviews, meta-analyses and recent clinical trials. The reference lists of key articles were also manually searched to identify additional relevant publications. This narrative review was designed to synthesise the current evidence for metabolic restoration as a pathway to T2D remission, with particular emphasis on the twin cycle hypothesis and its clinical applications. It does not claim to be a systematic or exhaustive review of all T2D pathophysiology frameworks, but rather focuses on the mechanisms most directly relevant to clinical reversal strategies. The scope primarily addresses established T2D, although the mechanistic principles discussed apply equally, and perhaps more powerfully, to early intervention in pre-diabetes.

The upstream drivers: Insulin resistance and hyperinsulinaemia

While the clinical diagnosis of T2D is defined by hyperglycaemia, the pathophysiological process begins decades earlier with the development of peripheral insulin resistance. Foundational work by Shulman and colleagues using nuclear magnetic resonance spectroscopy has established that insulin resistance in skeletal muscle is the primary initiating defect in the pathogenesis of T2D.4,9

When skeletal muscle, the body’s primary glucose disposal unit, becomes resistant to insulin action, postprandial glucose uptake is impaired. In response, the pancreatic β-cells must secrete increasing amounts of insulin to maintain normoglycemia, leading to a state of chronic compensatory hyperinsulinaemia. This elevated systemic insulin demand is a critical construct in understanding both the aetiology and the reversal of the disease.

Hyperinsulinaemia drives further metabolic dysfunction by promoting de novo lipogenesis in the liver and inhibiting lipolysis in adipose tissue. This environment facilitates the accumulation of ectopic fat – lipid deposits in non-adipose tissues such as the liver and skeletal muscle. Several complementary frameworks explain this process. The ceramide hypothesis, for instance, posits that the accumulation of specific lipid metabolites, such as ceramides, directly interferes with insulin signalling pathways, creating a lipid-centric mechanism for insulin resistance.10,11 Furthermore, the expansion of adipose tissue, particularly visceral fat, is associated with chronic low-grade systemic inflammation. Adipocytes and infiltrating macrophages secrete pro-inflammatory cytokines, such as tumour necrosis factor-alpha, which further exacerbate insulin resistance, creating a self-amplifying cycle of metabolic decline.12

These upstream events – skeletal muscle insulin resistance, hyperinsulinaemia, ectopic fat deposition and chronic inflammation – set the stage for the eventual failure of the pancreatic β-cells and the onset of overt clinical diabetes.

The sleeping beta-cell: Dedifferentiation, not death

The classical understanding of T2D pathophysiology was that chronic hyperglycaemia and metabolic stress led to progressive and irreversible apoptosis (programmed cell death) of pancreatic β-cells.13 This model underpinned the rationale for a strategy of managed decline, as lost β-cells were considered gone forever. However, a series of landmark studies has overturned this dogma, revealing that the primary mechanism of β-cell failure is not death, but dedifferentiation.3,14

In a seminal 2012 paper, Talchai et al.3 used lineage-tracing techniques in mouse models to demonstrate that under metabolic stress, β-cells do not die but instead lose their mature identity, reverting to a progenitor-like state. These dedifferentiated cells lose the expression of key genes required for insulin synthesis and secretion, such as MAF BZIP transcription factor A (MafA) and Pancreatic and duodenal homeoBox 1 (Pdx1), and may even begin to express markers of other endocrine cell types, such as glucagon.15

Crucially, this process was found to be reversible. Subsequent studies confirmed these findings in human T2D, observing evidence of β-cell dedifferentiation in pancreatic tissue from diabetic individuals.16 Wang et al. further demonstrated that this process could be reversed in vivo with intensive insulin therapy, leading to the redifferentiation of progenitor-like cells back into functional, insulin-producing β-cells.16

This distinction between apoptosis and dedifferentiation is not merely semantic; it is the biological foundation for the entire concept of T2D reversal. If β-cells were permanently lost, remission would be impossible. The discovery that they are merely ‘sleeping’ – dedifferentiated but still present – means that if the underlying metabolic stress can be removed, these cells can be awakened and restored to full function. The question then becomes: What is the nature of this metabolic stress?

Glucotoxicity and lipotoxicity: Downstream consequences of metabolic overload

The metabolic stress that drives β-cell dedifferentiation is a direct consequence of chronic energy overload, manifesting as two distinct but related phenomena: glucotoxicity and lipotoxicity.18 These are not the initiating agents of the disease, but rather the downstream consequences of sustained hyperinsulinaemia and insulin resistance.17,18

Glucotoxicity refers to the damaging effects of chronically elevated blood glucose levels. While β-cells are designed to sense and respond to glucose, their capacity to metabolise it is finite. Persistent hyperglycaemia overwhelms this capacity, leading to a build-up of reactive oxygen species and triggering oxidative stress.19 This oxidative stress disrupts the finely tuned machinery of insulin secretion and directly promotes the process of dedifferentiation by suppressing the expression of key β-cell identity genes.20

Lipotoxicity refers to the deleterious effects of elevated levels of free fatty acids (FFAs) and their metabolites. In the context of insulin resistance and energy surplus, adipose tissue becomes dysfunctional, leading to the spillover of FFAs into the circulation and their accumulation in non-adipose tissues, including the pancreas. These ectopic lipid deposits, particularly saturated fatty acids like palmitate, are directly toxic to β-cells, inducing endoplasmic reticulum stress, mitochondrial dysfunction, and ultimately, dedifferentiation and dysfunction.21

The combined effect of these toxicities creates a vicious cycle that perpetuates β-cell failure. This understanding is operationalised in the twin cycle hypothesis, which provides a clinically actionable model for intervention.

Review findings

The twin cycle hypothesis

Proposed by Roy Taylor and his team at Newcastle University, the twin cycle hypothesis provides a clinically validated framework for understanding the final stages of T2D pathogenesis.5 It posits that T2D is caused by the interaction of two self-reinforcing cycles of ectopic fat accumulation, primarily in the liver and the pancreas:

Cycle 1: The Liver. The process begins with a chronic positive energy balance in the context of existing peripheral insulin resistance, leading to the accumulation of fat in the liver (hepatic steatosis). This excess liver fat causes severe hepatic insulin resistance, meaning the liver no longer responds appropriately to insulin signals to suppress glucose production. The result is an elevated rate of hepatic gluconeogenesis, leading to higher fasting blood glucose levels. This, in turn, stimulates the pancreas to produce even more insulin, exacerbating the state of chronic hyperinsulinaemia. This hyperinsulinaemia further promotes de novo lipogenesis (the creation of new fat) in the liver, completing a vicious cycle of fat accumulation and insulin resistance.

Cycle 2: The Pancreas. The fat-laden, insulin-resistant liver begins to export excess triglycerides in the form of very-low-density lipoproteins. This increases the delivery of FFAs to the rest of the body. When the storage capacity of subcutaneous adipose tissue is exceeded – a concept known as the ‘personal fat threshold’ – this excess fat begins to accumulate in other organs, most critically, the pancreas.22 This ectopic pancreatic fat accumulation leads to lipotoxicity, β-cell dysfunction and dedifferentiation, as described above. As β-cell function declines, insulin secretion can no longer keep pace with the ever-increasing demand imposed by peripheral and hepatic insulin resistance, and overt T2D emerges.

It is important to note that the twin cycle hypothesis represents one of several complementary mechanistic frameworks for understanding T2D pathophysiology. The carbohydrate-insulin model, proposed by Ludwig and Ebbeling23, emphasises the role of dietary carbohydrate in driving hyperinsulinaemia as a primary defect that partitions energy towards fat storage. Similarly, the ceramide hypothesis offers a lipid-centric account of insulin resistance.10 These models are not mutually exclusive; rather, they illuminate different facets of a complex metabolic process. The present review focuses heavily on the twin cycle framework because of its direct clinical applicability: it predicts that if T2D is caused by excess fat in the liver and pancreas, then removing that fat – through any intervention that sufficiently lowers insulin demand and induces a negative energy balance – should reverse the disease.

The clinical evidence for reversal

The ultimate proof of the T2D reversal paradigm comes from clinical trials demonstrating that interventions capable of inducing significant weight loss, reducing insulin demand and eliminating ectopic fat can lead to durable, medication-free remission. The twin cycle hypothesis predicts that remission should follow any intervention that sufficiently reduces ectopic hepatic and pancreatic fat, regardless of the specific macronutrient composition. This is consistent with the observed success of various dietary and surgical approaches.

Bariatric surgery: The proof of principle

Long before dietary interventions were seriously considered for remission, bariatric surgery provided the first compelling evidence that T2D was a reversible condition. Studies have consistently shown that procedures like Roux-en-Y gastric bypass and sleeve gastrectomy can lead to remission rates as high as 80% in the short term, with long-term data showing durable remission in a significant proportion of patients.8,24 While the mechanisms are complex and involve rapid hormonal changes (such as increased Glucagon-like peptide-1 [GLP-1] and Peptide YY [PYY] secretion) in addition to weight loss, the dramatic success of bariatric surgery served as a crucial proof of principle: T2D is not an immutable fate. It operates by drastically reducing caloric intake and altering gut anatomy, which rapidly lowers insulin demand and mobilises ectopic fat stores.

The Diabetes Remission Clinical Trial: Remission in primary care

The DiRECT, published in The Lancet in 2018, is a landmark clinical trial in the field of T2D reversal.6 This cluster-randomised trial, conducted in 49 primary care practices in the UK, tested whether a structured weight management programme could achieve remission in individuals with established T2D (up to 6 years duration). The intervention consisted of a 12–20-week very-low-calorie diet (VLCD) of ~850 kcal/day using total diet replacement, followed by structured food reintroduction and long-term weight loss maintenance support.

The results were stunning. At 12 months, 46% of participants in the intervention group achieved remission (defined as HbA1c < 6.5% off all glucose-lowering medications), compared to just 4% in the control group receiving standard guideline-based care. Remission was tightly correlated with the degree of weight loss: 86% of those who lost > 15 kg achieved remission. Follow-up data at 2 years showed that 36% of the intervention group remained in remission, demonstrating the durability of the effect.25 The DiRECT trial proved that T2D remission was not a niche phenomenon achievable only with extreme surgery, but a realistic goal for a significant proportion of patients within a primary care setting. The VLCD approach effectively starves the liver of incoming energy, forcing the mobilisation of hepatic and pancreatic fat, thereby breaking the twin cycle and restoring β-cell function.

Low-carbohydrate diets and continuous care: The Virta Health model

Concurrent with the DiRECT trial, research by Virta Health in the United States demonstrated a powerful effect using a different approach: a very-low-carbohydrate ketogenic diet (VLCKD) combined with a continuous remote care model. By drastically reducing dietary carbohydrate intake, this approach acts as a primary lever for reducing systemic insulin demand, thereby facilitating lipolysis and the clearance of ectopic fat.

In a non-randomised controlled trial, this intervention led to significant metabolic improvements at 1 year, with 94% of those on insulin being able to reduce or eliminate their dosage.7 Two-year results from this study require careful interpretation regarding terminology. The authors reported that 53.5% of participants met the criteria for diabetes reversal (defined as HbA1c < 6.5% without diabetes medications, or with metformin only). However, the actual remission rate (defined strictly as HbA1c < 6.5% without any diabetes medication, maintained for at least 1 year) was 17.6%.26

It should be noted that the Virta Health trial was a non-randomised, open-label study involving a self-selected, highly motivated population enrolled through a commercial programme, and the investigators declared financial conflicts of interest. While the metabolic outcomes – particularly the substantial reduction in medication dependency and HbA1c – are noteworthy and clinically highly significant, these methodological limitations mean the absolute remission rates are not directly comparable to the randomised DiRECT trial. Nonetheless, the data strongly support carbohydrate restriction as an effective mechanism for lowering insulin demand and achieving metabolic restoration.

Primary care low-carbohydrate interventions

Further evidence for the efficacy of carbohydrate restriction comes from real-world primary care settings. Dr. David Unwin and colleagues in the UK have published extensive data demonstrating the success of a lower-carbohydrate dietary approach implemented in routine clinical practice. In an 8-year service evaluation of patients with T2D and pre-diabetes, this approach achieved significant weight loss, improvements in renal function and substantial reductions in medication usage.27,28 Notably, among patients with T2D who chose the low-carbohydrate approach, a significant proportion achieved drug-free remission, highlighting the viability of this intervention outside of highly controlled clinical trial environments.29

Broadening the dietary framework: Fasting and plant-based approaches

The principle that reducing insulin demand and ectopic fat leads to remission is not exclusive to VLCDs or low-carbohydrate diets. Therapeutic fasting encompasses various protocols, ranging from time-restricted eating (e.g. 16:8) to intermittent fasting (e.g. 5:2) and extended fasts. These protocols operate on the same fundamental mechanism: extending the periods during which insulin levels are suppressed, thereby enabling lipolysis and the clearance of ectopic fat. Recent randomised trials have demonstrated that a 5:2 intermittent fasting diet can achieve better glycaemic control and higher remission rates than standard of care medications.30

Furthermore, Mediterranean-style dietary patterns and plant-based low-fat diets have also demonstrated efficacy in improving glycaemic control and facilitating remission. Studies have shown that a low-carbohydrate Mediterranean diet can result in higher rates of diabetes remission and delayed need for medication compared to a standard low-fat diet.31,32 Similarly, intensive plant-based interventions have shown significant metabolic benefits.33 The optimal dietary approach for any individual patient is ultimately the one that achieves sufficient reduction in insulin demand, corrects the ectopic fat burden and can be sustained long term.

Implications and recommendations

Discussion: From management to reversal

The cumulative evidence from basic science and clinical trials is unequivocal: T2D is a reversible disease. The old paradigm of inevitable progression and lifelong medication management is obsolete and must be replaced by a new standard of care that prioritises remission as the primary therapeutic goal.

This requires a fundamental shift in clinical practice. The conversation with a newly diagnosed patient should no longer be about which medication to start, but about which strategy to employ to achieve remission. The choice of intervention – whether a VLCD, a VLCKD, therapeutic fasting, or a Mediterranean pattern – can be tailored to the individual patient’s preferences and circumstances. The key is the explicit goal: the reversal of the disease process through the reduction of insulin demand and the clearance of ectopic fat, not just the management of its downstream symptoms.

However, significant barriers to the adoption of this new paradigm remain. Clinical inertia, rooted in decades of the old dogma, is a powerful force. While the influence of the pharmaceutical industry and the financial structure of healthcare systems – which often reimburse for medications rather than intensive dietary counselling – play a role,34,35 simpler and more practical explanations are equally relevant. Medical education currently provides limited training in clinical nutrition and metabolic interventions. Furthermore, standard primary care consultation times, often limited to 15 min, are insufficient to provide the intensive support required for sustained behaviour change.

Long-term adherence remains a critical challenge across all dietary interventions. Adherence rates beyond 2 years are modest, and whether patients are able to maintain normal glycaemia after initial success depends heavily on continuous support and the sustainability of the chosen lifestyle changes. Additionally, clinicians must navigate specific clinical considerations associated with certain diets; for example, low-density lipoprotein cholesterol elevation has been observed in some patients on ketogenic diets. While the clinical significance of this finding in the context of improved metabolic health remains an area of active debate, it requires monitoring in clinical practice.

Overcoming these barriers will require a concerted effort from clinicians, researchers, policymakers and patients. Clinical guidelines must be updated to reflect the current evidence and establish remission as the primary treatment target, as the American College of Lifestyle Medicine has recently done.36 Medical education must be reformed to ensure that future generations of physicians are trained in the principles of metabolic restoration. Most importantly, patients must be empowered with the knowledge that they are not destined for a lifetime of diabetes, but that remission is within their reach.

Conclusion

Type 2 diabetes is not the chronic, progressive disease it was once thought to be. It is a reversible metabolic condition initiated by insulin resistance and hyperinsulinaemia, and ultimately driven by ectopic fat accumulation in the liver and pancreas, which causes β-cell dedifferentiation and dysfunction. A wealth of clinical evidence has now demonstrated that interventions capable of lowering insulin demand, inducing significant weight loss and reducing this ectopic fat can achieve durable, medication-free remission in a substantial proportion of patients. The time has come to abandon the outdated paradigm of disease management and embrace a new standard of care focused on metabolic restoration and the reversal of T2D.

Acknowledgements

The author wishes to acknowledge the contributions of the researchers whose landmark studies made this review possible, including Prof. Roy Taylor and colleagues for the DiRECT trial, Dr Sarah Hallberg and the Virta Health research team, and the pioneering work of Talchai et al. on beta-cell dedifferentiation. No additional individuals contributed to this work beyond the named author.

During the preparation of this work, the author used OpenAI GPT-4, GPT-4 2026 to assist with literature search, data synthesis and initial manuscript drafting. All content was independently reviewed, verified against primary sources and approved by the author. The author takes full responsibility for the accuracy and integrity of the final manuscript. The content was reviewed and edited by the author, who takes full responsibility for its accuracy.

Competing interests

The author declares that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.

CRediT authorship contribution

Salah Snouda: Conceptualisation, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualisation, Writing – original draft, Writing – review & editing. The author confirms that this work is entirely their own, has reviewed the article, approved the final version for submission and publication and takes full responsibility for the integrity of its findings.

Ethical considerations

This article followed all ethical standards for research without direct contact with human or animal subjects.

Funding information

The author received no financial support for the research, authorship and/or publication of this article.

Data availability

Data sharing is not applicable to this article as no new data were created or analysed in this study.

Disclaimer

The views and opinions expressed in this article are those of the author and are the product of professional research. They do not necessarily reflect the official policy or position of any affiliated institution, funder, agency, or that of the publisher. The author is responsible for this article’s results, findings, and content.

References

  1. American Diabetes Association. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of care in diabetes – 2024. Diabetes Care. 2024;47(suppl 1):S145–S158. https://doi.org/10.2337/dc24-S008
  2. Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ. Reversing type 2 diabetes: A narrative review of the evidence. Nutrients. 2019;11(4):766. https://doi.org/10.3390/nu11040766
  3. Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012;150(6):1223–1234. https://doi.org/10.1016/j.cell.2012.07.029
  4. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000;106(2):171–176. https://doi.org/10.1172/JCI10583
  5. Taylor R. The twin cycle hypothesis of type 2 diabetes aetiology. Diabetologia. 2008;51(8):1327–1332. https://doi.org/10.1007/s00125-008-1066-5
  6. Lean ME, 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. https://doi.org/10.1016/S0140-6736(17)33102-1
  7. Hallberg SJ, McKenzie AL, Williams PT, et al. 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 Ther. 2018;9(2):583–612. https://doi.org/10.1007/s13300-018-0373-9
  8. Sjöström L, Peltonen M, Jacobson P, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA. 2014;311(22):2297–2304. https://doi.org/10.1001/jama.2014.5988
  9. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371(12):1131–1141. https://doi.org/10.1056/NEJMra1011035
  10. Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res. 2006;45(1):42–72. https://doi.org/10.1016/j.plipres.2005.11.002
  11. Chaurasia B, Summers SA. Ceramides in metabolism: Key lipotoxic players. Annu Rev Physiol. 2021;83:303–330. https://doi.org/10.1146/annurev-physiol-031620-093815
  12. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91. https://doi.org/10.1126/science.7678183
  13. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–110. https://doi.org/10.2337/diabetes.52.1.102
  14. White MG, Marshall J, Butler J, et al. Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway. Elife. 2014;3:e02809. https://doi.org/10.7554/eLife.02809
  15. Cinti F, Bouchi R, Kim-Muller JY, et al. Evidence of β-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016;101(3):1044–1054. https://doi.org/10.1210/jc.2015-2860
  16. Wang Z, York NW, Nichols CG, Remedi MS. Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab. 2014;19(5):872–882. https://doi.org/10.1016/j.cmet.2014.03.010
  17. Poitout V, Robertson RP. Glucolipotoxicity: Fuel excess and beta-cell dysfunction. Endocr Rev. 2008;29(3):351–366. https://doi.org/10.1210/er.2007-0023
  18. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H. Glucose toxicity in beta-cells: Type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes. 2003;52(3):581–587. https://doi.org/10.2337/diabetes.52.3.581
  19. Wang Y, Wang Y, Wang Z, et al. Glucotoxicity leads to β-cell dedifferentiation during hyperglycemia. J Mol Endocrinol. 2021;66(3):155–165. https://doi.org/10.1530/JME-20-0255
  20. Al-Mrabeh A, Hollingsworth KG, Shaw JAM, Taylor R. Pathogenesis and remission of type 2 diabetes: What has the twin cycle hypothesis taught us? Cardiovasc Endocrinol Metab. 2020;9(4):132–142. https://doi.org/10.1097/XCE.0000000000000201
  21. Taylor R, Al-Mrabeh A, Zhyzhneuskaya S, et al. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery. Cell Metab. 2018;28(4):547–556.e3. https://doi.org/10.1016/j.cmet.2018.07.003
  22. Courcoulas AP, Patti ME, Hu B, et al. Long-term outcomes of medical management vs bariatric surgery in type 2 diabetes. JAMA. 2024;331(8):654–664. https://doi.org/10.1001/jama.2024.0318
  23. Ludwig DS, Ebbeling CB. The carbohydrate-insulin model of obesity: Beyond ‘calories in, calories out’. JAMA Intern Med. 2018;178(8):1098–1103. https://doi.org/10.1001/jamainternmed.2018.2933
  24. Lean MEJ, Leslie WS, Barnes AC, et al. 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. Lancet Diabetes Endocrinol. 2019;7(5):344–355. https://doi.org/10.1016/S2213-8587(19)30068-3
  25. Athinarayanan SJ, Adams RN, Hallberg SJ, et al. Long-term effects of a novel continuous remote care model for type 2 diabetes reversal: An open-label, non-randomized, controlled study. Diabetes Ther. 2019;10(5):1779–1793. https://doi.org/10.1007/s13300-019-0653-z
  26. Athinarayanan SJ, Adams RN, Hallberg SJ, et al. 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. Front Endocrinol (Lausanne). 2019;10:348. https://doi.org/10.3389/fendo.2019.00348
  27. Unwin D, Unwin J, Crocombe D, Delon C, Guess N, Wong C. Renal function in patients following a low carbohydrate diet for type 2 diabetes: A review of the evidence and a secondary analysis of routine clinic data. BMJ Nutr Prev Health. 2021;4(1):257–268.
  28. Unwin D, Khalid AA, Unwin J, et al. Insights from a general practice service evaluation supporting a lower carbohydrate diet in patients with type 2 diabetes mellitus and prediabetes: A secondary analysis of routine clinic data including HbA1c, weight and prescribing over 6 years. BMJ Nutr Prev Health. 2020;3(2):274–284. https://doi.org/10.1136/bmjnph-2020-000072
  29. Unwin D, Delon C, Unwin J, Tobin S, Taylor R. What predicts drug-free type 2 diabetes remission? Insights from an 8-year general practice service evaluation. BMJ Nutr Prev Health. 2023;6(1):46–55. https://doi.org/10.1136/bmjnph-2022-000544
  30. Guo L, Li N, Ma L, et al. A 5:2 intermittent fasting meal replacement diet and glycemic control in a randomized clinical trial of adults with type 2 diabetes. JAMA Netw Open. 2024;7(2):e2354632. https://doi.org/10.1001/jamanetworkopen.2023.54632
  31. Esposito K, Maiorino MI, Ciotola M, et al. Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: A randomized trial. Ann Intern Med. 2009;151(5):306–314. https://doi.org/10.7326/0003-4819-151-5-200909010-00004
  32. Esposito K, Maiorino MI, Petrizzo M, Bellastella G, Giugliano D. The effects of a Mediterranean diet on the need for diabetes drugs and remission of newly diagnosed type 2 diabetes: Follow-up of a randomized trial. Diabetes Care. 2014;37(7):1824–1830. https://doi.org/10.2337/dc13-2899
  33. Barnard ND, Cohen J, Jenkins DJ, et al. A low-fat vegan diet and a conventional diabetes diet in the treatment of type 2 diabetes: A randomized, controlled, 74-wk clinical trial. Am J Clin Nutr. 2009;89(5):1588S–1596S. https://doi.org/10.3945/ajcn.2009.26736H
  34. Hunt LM, Kreiner M, Brody H. Are corporations re-defining illness and health? The case of type 2 diabetes. Int J Health Serv. 2021;51(4):514–525. https://doi.org/10.1177/00207314211022299
  35. Choudhry NK, Stelfox HT, Detsky AS. Relationships between authors of clinical practice guidelines and the pharmaceutical industry. JAMA. 2002;287(5):612–617. https://doi.org/10.1001/jama.287.5.612
  36. Kelly J, St. Onge E, Miller L, et al. Lifestyle interventions for treatment and remission of type 2 diabetes and prediabetes in adults: A clinical practice guideline from the American College of Lifestyle Medicine. Am J Lifestyle Med. 2025;19(1):4–25. https://doi.org/10.1177/15598276251325488


Crossref Citations

No related citations found.