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• Fall in HbA1c in relation to its initial value
  John S Greener
  Published on: 3 November 2023
• The Root Cause of Diabetes
  Charles R Fred
  Published on: 10 July 2023
• Remissions of type 2 diabetes in primary care. A counter response to Lean et al
  David Unwin
  Published on: 15 February 2021
• Remissions of type 2 diabetes in primary care
  Michael Lean, Naveed Sattar, Roy Taylor, Emilie Combet and Chaitong Churuangsuk
  Published on: 19 January 2021

• Published on: 3 November 2023

  Fall in HbA1c in relation to its initial value

  • John S Greener, Physician Retired

  Figure6 shows participants who started with the worst blood sugars (HbA1c) saw the greatest improvements in diabetic control. This impressive correlation is an illusion.
  If A are pretreatment values and B postreatment- A is being plotted against A minus B. Thus A appears on both X and Y axes .Thus the positive correlation.If A is always larger than B then A minus B is always positive as here

  Conflict of Interest:
  None declared.

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• Published on: 10 July 2023

  The Root Cause of Diabetes

  • Charles R Fred, Electrical Engineer None

  The Root Cause of Diabetes - BMJ rapid responses
  January 10, 2023, January 11, 2023
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  The Root Cause of Diabetes:

  Human evolution expects gluconeogenesis-derived glucose to be released little by little from the liver, just as needed. Humans, from the time of Stedman’s jaw mutation, 2.4 million years ago, could no longer grind plants to make them digestible, due to the weakened jaw muscles - enforcing a low-carb diet.

  So, as a result of adaptations during the next two million years, blood glucose would never rise very much or very fast and our beta cells would never be overtaxed. But now, eating cooked carbs causes blood glucose to rise massively and quickly, requiring massive and quick insulin secretion. And overstuffed glucose storage in the liver and muscles further aggravates this by requiring even more insulin to force in even more glucose - insulin resistance. This threatens the very survival of our beta cells.

  The main trigger of apoptosis is failure of a cell to perform its function. But requiring beta cells to massively and quickly secrete insulin violates “design” limits, tempting them into failure. When most of the beta cells have suffered apoptosis - that is diabetes.

  If, eight hours after eating, the pancreas is unable to supply enough insulin to push blood glucose below 90, there must be few surviving beta cells - and each of those few s...

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  The Root Cause of Diabetes - BMJ rapid responses
  January 10, 2023, January 11, 2023
  ------------------------------------------------------------------------

  The Root Cause of Diabetes:

  Human evolution expects gluconeogenesis-derived glucose to be released little by little from the liver, just as needed. Humans, from the time of Stedman’s jaw mutation, 2.4 million years ago, could no longer grind plants to make them digestible, due to the weakened jaw muscles - enforcing a low-carb diet.

  So, as a result of adaptations during the next two million years, blood glucose would never rise very much or very fast and our beta cells would never be overtaxed. But now, eating cooked carbs causes blood glucose to rise massively and quickly, requiring massive and quick insulin secretion. And overstuffed glucose storage in the liver and muscles further aggravates this by requiring even more insulin to force in even more glucose - insulin resistance. This threatens the very survival of our beta cells.

  The main trigger of apoptosis is failure of a cell to perform its function. But requiring beta cells to massively and quickly secrete insulin violates “design” limits, tempting them into failure. When most of the beta cells have suffered apoptosis - that is diabetes.

  If, eight hours after eating, the pancreas is unable to supply enough insulin to push blood glucose below 90, there must be few surviving beta cells - and each of those few survivors now is asked to secrete even more insulin. Thus an avalanche effect, fewer beta cells, more asked from each cell, faster apoptosis - diabetes as a progressive disease.

  Now there are three classes of beta cells. Some are working, supplying insulin to control blood glucose. Others are not working, but can be rescued. The rest are dead, irredeemably.

  Eating carbs will continue to overtax and kill the remaining beta cells. Or, stop eating carbs and the remaining beta cells, relieved of unnatural stress, can survive - keeping blood glucose within healthy bounds.

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  Conflict of Interest:
  None declared.

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• Published on: 15 February 2021

  Remissions of type 2 diabetes in primary care. A counter response to Lean et al

  • David Unwin, GP Norwood Surgery

  Remissions of type 2 diabetes in primary care. A counter response to Lean et al
  By Dr D Unwin and all of the authors.

  Firstly, we would like to thank Professor Lean and colleagues for their emphasis on the huge amount of common ground and agreement between us. We believe that drugs alone are very unlikely to solve the global burden of type 2 diabetes (T2D) and that the best solution lies more closely aligned with the actual cause of this disease.

  The emphasis on drug-free T2D remission in our paper is because we feel it offers a “beacon of hope” to so many people with T2D. We have seen this idea inspire many to change their lifestyle with improved health markers as a result. Much of the credit for this should go to the great work done by the DiRECT team, particularly to Professors Lean and Taylor.
  Re: “we must draw attention to a statement in this paper, now being widely quoted “Drug-free T2D remission occurred in 46% of participants”.
  In our paper we stated in the introduction that, “we hoped to answer the following question: for those patients choosing a lower carbohydrate diet to manage their T2D or prediabetes, when we compare ‘baseline data’ to ‘latest follow up’ what are the outcomes in terms of body weight, glycaemic control and effect on diabetes medication prescribing.”
  We wish to make it clear that our remission rate of 46% relates to those 128 individuals choosing the approach (27% of the practice T2D population, n=473). T...

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  Remissions of type 2 diabetes in primary care. A counter response to Lean et al
  By Dr D Unwin and all of the authors.

  Firstly, we would like to thank Professor Lean and colleagues for their emphasis on the huge amount of common ground and agreement between us. We believe that drugs alone are very unlikely to solve the global burden of type 2 diabetes (T2D) and that the best solution lies more closely aligned with the actual cause of this disease.

  The emphasis on drug-free T2D remission in our paper is because we feel it offers a “beacon of hope” to so many people with T2D. We have seen this idea inspire many to change their lifestyle with improved health markers as a result. Much of the credit for this should go to the great work done by the DiRECT team, particularly to Professors Lean and Taylor.
  Re: “we must draw attention to a statement in this paper, now being widely quoted “Drug-free T2D remission occurred in 46% of participants”.
  In our paper we stated in the introduction that, “we hoped to answer the following question: for those patients choosing a lower carbohydrate diet to manage their T2D or prediabetes, when we compare ‘baseline data’ to ‘latest follow up’ what are the outcomes in terms of body weight, glycaemic control and effect on diabetes medication prescribing.”
  We wish to make it clear that our remission rate of 46% relates to those 128 individuals choosing the approach (27% of the practice T2D population, n=473). This may be useful information to individuals wanting a better understanding of what they may achieve if they choose the service offered at the Norwood Surgery. It is also possible to look at the remission rate from a different perspective, for the practice as a whole, in which case we get a remission rate of 12.5%. Both figures are correct but differ depending upon the framing; individual or practice-wide.
  Looking at the how patients were recruited into the DiRECT Study (1). The 49 primary care practices in their cluster randomisation had a mean population of 5700 patients, divided between 23 assigned to the intervention group (approx. 131K patients) and 26 to the usual care treatment (approx. 148K patients). Based on these figures, if we were to estimate proportions, based on a conservative assumption that 6% of these patients might have T2D, the eligible populations might be of the order of 7900 and 8900 respectively, from which the 2 sets of 129 recruited participants would represent about 1.6% and 1.5%, respectively, of potentially eligible patients. It is important to acknowledge the DiRECT recruitment window was a much shorter time period than the duration of our service evaluation. Nonetheless, it can be seen this is a third basis for a ‘remission rate’, one that is based on a small percentage of the actual population studied in this case.
  From all of this it can be seen we agree with Lean et al that comparisons between ‘remission rates’ need care and a defined perspective, which may be individual or organizational.
  We thank Lean et al for pointing out that the DiRECT study (1) used a 825–853 kcal/day formula diet. The paper has been amended.
  We were particularly pleased to see the interest Lean et al showed in the results we achieved for older (>65 years) patients. The risk of adverse drug effects, such as hypoglycaemic episodes, is particularly high in this group (2). Therefore, safe and effective management approaches centred on diet and lifestyle modification, that are less dependent on medications, are especially welcome for this population. Many of whom may already be taking medications to address co-morbidities with the subsequent concerns associated with polypharmacy.
  Finally, we agree that the totality of evidence should guide practice in evidence-based medicine and concur wholeheartedly with the call for more high-quality research in this area. We would add that we must also be cognisant of different interpretations of the existing body of evidence; for example, the American Diabetes Society’s most recent consensus includes “reducing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia and may be applied in a variety of eating patterns that meet individual needs and preferences” (3). It is this persisting uncertainty that points to the importance of individual choice when it comes to diet, something we have integrated in our clinical service model.

  1. Lean MEJ, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. The Lancet. 2018;391(10120):541-51.
  2. Zammitt NN, Frier BM. Hypoglycemia in Type 2 Diabetes. Pathophysiology, frequency, and effects of different treatment modalities. 2005;28(12):2948-61.
  3. Association AD. Introduction: Standards of Medical Care in Diabetes—2020. Diabetes Care. 2020;43(Supplement 1):S1-S2.

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  Conflict of Interest:
  None declared.

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• Published on: 19 January 2021

  Remissions of type 2 diabetes in primary care

  • Michael Lean, Physician University of Glasgow
  • Other Contributors:
    • Naveed Sattar, Physician
    • Roy Taylor, Physician
    • Emilie Combet, University Senior Lecturer
    • Chaitong Churuangsuk, Physician

  We wish to comment on the common ground and agreement that we have with the work being done by Dr David Unwin, to help people lose weight and get remissions of type 2 diabetes, and to clear up the confusion (on Twitter and elsewhere, amongst patients and professionals) which resulted from the way his audit has been presented. Most importantly, we draw attention to inappropriate comparison with intention-to-treat RCT data on remissions.
  We have previously called for high-quality clinical audits to be published in the more prominent journals (1), so it is pleasing to see the data from Unwin et al from a single practice application of advice for a low-carb diet to patients diagnosed with type 2 diabetes or prediabetes (2). They offer much that is of real value, confirming that achieving such good weight losses in a real-life setting improves all cardiometabolic risk factors, including HbA1c, BP and lipids. They also confirm that most of these metabolic benefits of weight loss, a consistent finding in RCTs, also apply to older people (over 65 years) and with longer durations of diabetes (3, 4).
  That noted, we must draw attention to a statement in this paper, now being widely quoted “Drug-free T2D remission occurred in 46% of participants”. Remarkably, 46% was the exact remission rate reported for DiRECT, a randomised controlled trial. This figure for DiRECT is 46% of all those people with T2D who were randomised to commence the programme, analysed by ‘intention...

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  We wish to comment on the common ground and agreement that we have with the work being done by Dr David Unwin, to help people lose weight and get remissions of type 2 diabetes, and to clear up the confusion (on Twitter and elsewhere, amongst patients and professionals) which resulted from the way his audit has been presented. Most importantly, we draw attention to inappropriate comparison with intention-to-treat RCT data on remissions.
  We have previously called for high-quality clinical audits to be published in the more prominent journals (1), so it is pleasing to see the data from Unwin et al from a single practice application of advice for a low-carb diet to patients diagnosed with type 2 diabetes or prediabetes (2). They offer much that is of real value, confirming that achieving such good weight losses in a real-life setting improves all cardiometabolic risk factors, including HbA1c, BP and lipids. They also confirm that most of these metabolic benefits of weight loss, a consistent finding in RCTs, also apply to older people (over 65 years) and with longer durations of diabetes (3, 4).
  That noted, we must draw attention to a statement in this paper, now being widely quoted “Drug-free T2D remission occurred in 46% of participants”. Remarkably, 46% was the exact remission rate reported for DiRECT, a randomised controlled trial. This figure for DiRECT is 46% of all those people with T2D who were randomised to commence the programme, analysed by ‘intention to treat’, which included all those who did not complete the programme as not having achieved remission (5). In contrast, Unwin et al offered low carb advice to all their patients with T2D, currently n=472, among whom 128 ‘persisted’ with the low-carb diet for an average of 23 months, and drug-free remissions were achieved by 59 patients. Hence the ‘46% remissions’ is a ‘completers’ analysis, for people who chose the diet and ‘persisted’. This is quite different from an intention to treat result, needed to inform practice and policy. Unwin et al do not mention how many of their patients declined, or failed to ‘persist’ with, the diet, but we calculate their results represent a true remission rate of 12.5% of their T2D practice.
  Unwin et al should be proud of this result, achieved with minimal expense. But it is misleading for readers to quote a 46% remissions from an incomplete ‘completers’ audit to try to draw parallels with the 46% remissions at 12 months, or 36% at 24 months, from an intention to treat analysis of DiRECT. The remission rate among those who ‘persisted’ with the DiRECT intervention as intended, and lost over 15kg, was 86% at 12 months and 83% at 24 months.
  Unwin et al misrepresent the Diabetes UK-funded DiRECT trial as having used a “VLCD of <800 calories per day”. Instead, DiRECT used a structured weight management programme called Counterweight-Plus, which includes a 12-week period of total diet replacement, with an 830 kilocalorie/day formula diet (which is outwith the legal definition of a VLCD) to induce weight loss and remissions, during which patients prepare to adopt a new style of food-based diet for long-term maintenance (6).
  Finally, Unwin et al emphasize the exclusion from DiRECT of people aged over 65, which was a requirement for ethical approvals, and to be able to complete and report a planned 5-years follow-up. This does not mean the DIRECT intervention would not work in older people. Emerging evidence suggests that less weight gain is needed for T2D to develop in older people, so remissions may require less weight loss, and indeed we observed slightly greater likelihood of remission at 2 years in older participants in DiRECT (7). Clinical interventions in old age need to be balanced against benefits: the life-years lost from diabetes are substantially greater with younger onset, but trivial when diabetes onset emerges after 70 or 80 years of age (8).
  Unwin et al should be applauded for their sustained efforts to secure remissions of T2D, both to improve patients’ wellbeing and to reduce drug prescribing costs, and for their efforts to check the rise of T2D by giving dietary advice to people with prediabetes. However, their beliefs and emphasis on carbohydrate restriction are not supported by the totality of the evidence. Meta-analyses have found no clinically significant advantage to low carbohydrate diets for effects on weight or HbA1c in treatment of diabetes (9). Our recent systematic review and quality assessment of the published meta-analyses on low-carbohydrate diets reported that the published evidence is skewed by a consistent tendency for eye-catching ‘positive’ trials to be published in the higher impact journals, despite being of lower scientific quality, with greater risk of bias (10).
  We agree that high intake of inappropriate carbohydrate, especially unnecessary added sugars, will increase blood glucose acutely, and chronically with repeated consumption, for people with T2D. However, elevation of blood glucose or HbA1c is a manifestation of an underlying disease-process, whereby weight gain in (epi-)genetically susceptible individuals causes ectopic lipid accumulation and functional impairment in vital organs (11). We owe it to the whole community to provide the best possible evidence in this important and exciting area, with both well-designed randomised trials in real-life settings, and careful complete audits of practice, to evaluate approaches for sustained remission of diabetes.

  References
  1. Lean M, Hankey C. Keeping it off: the challenge of weight-loss maintenance. Lancet Diabetes Endocrinol. 2018;6(9):681-3.
  2. Unwin D, Khalid AA, Unwin J, Crocombe D, Delon C, Martyn K, 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:bmjnph-2020-000072.
  3. The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145-54.
  4. The Look AHEAD Research Group. Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Control Clin Trials. 2003;24(5):610-28.
  5. Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018;391(10120):541-51.
  6. Leslie WS, Ford I, Sattar N, Hollingsworth KG, Adamson A, Sniehotta FF, et al. The Diabetes Remission Clinical Trial (DiRECT): protocol for a cluster randomised trial. BMC Fam Pract. 2016;17:20.
  7. Thom G, Messow CM, Leslie WS, Barnes AC, Brosnahan N, McCombie L, et al. Predictors of type 2 diabetes remission in the Diabetes Remission Clinical Trial (DiRECT). Diabet Med. 2020:e14395.
  8. Sattar N, Rawshani A, Franzen S, Rawshani A, Svensson AM, Rosengren A, et al. Age at Diagnosis of Type 2 Diabetes Mellitus and Associations With Cardiovascular and Mortality Risks. Circulation. 2019;139(19):2228-37.
  9. Korsmo-Haugen HK, Brurberg KG, Mann J, Aas AM. Carbohydrate quantity in the dietary management of type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab. 2019;21(1):15-27.
  10. Churuangsuk C, Kherouf M, Combet E, Lean M. Low-carbohydrate diets for overweight and obesity: a systematic review of the systematic reviews. Obes Rev. 2018;19(12):1700-18.
  11. Taylor R, Al-Mrabeh A, Zhyzhneuskaya S, Peters C, Barnes AC, Aribisala BS, et al. Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for beta Cell Recovery. Cell Metab. 2018;28(4):547-56 e3.

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  Conflict of Interest:
  None declared.

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