Beating type 2 diabetes into remissionBMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j4030 (Published 13 September 2017) Cite this as: BMJ 2017;358:j4030
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Type 2 Diabetes mellitus - Do we need a paradigm change in management?
Glucose and fructose, are benign molecules which are essential for the functioning and growth of almost every cell in the body. Glucose has got a very wide range of normal values in the tissues of the human body. This is probably because we need different sugar levels at different times in our lives (1). We need more sugar when we are active and less when we are inactive. The incidence of Type 2 Diabetes mellitus (DM) is increasing the world over (2). A global rise has been noted in the incidence of Type 2 DM from 415 million in 2015, to 642 million by 2040 and the appalling fact is that 5-20% of total healthcare expense is towards DM (3). There can be no two ways about it- high sugar is detrimental to all tissues in the body. But "how high is high sugar" ? This is difficult to define. We kept redefining, and have narrowed our definition to bring this ''high sugar status'' at much lower levels (4). In the bargain, many men and women, who would otherwise have led normal lives, are being categorized into Type 2 DM and are being treated with antidiabetic drugs with their known side effects (5–7).
It needs to be reinforced that, following the track from Type 1 Diabetes mellitus ( which is purely due to insulin deficiency) , we invented Type 2 Diabetes mellitus, which is actually secondary to weight gain due to improper diet and, or inadequate exercises, and we started treating the sugar with no discernible benefits for the patients (8). Hyperglycemia is a pathophysiological response to improper diet and, or inadequate exercises and it definitely leads to lot of undesirable complications (9-11).
Nowhere in science and medicine are we taught to relieve signs and symptoms without addressing the cause. For example, treating fever in a patient with sepsis, or headache in a patient with brain tumour! We always find the cause and try to treat the cause. Somehow gradually over the years, diabetes has become an exception to this rule. When a person is started on medications following which a blood sample reveals the right numbers, both the physicians and the patients are contented, unmindful of the potential side effects of the drugs given. We tend to ignore the fact that these medications are not given to treat the cause, but to get the sugars under control. Yes, there is a difference!
Primary care of elevated blood sugar is not focused on correcting the improper diet or improving the activities. Despite several decades of research and more than 53 drugs for the management of elevated blood sugar in Type 2 DM, we are nowhere near, in either curing the condition or preventing the consequences (12). If lifestyle is the cause of the problem, instead of paying attention to it, are we distracted today, with the sole objective of lowering blood sugar with drugs? (13). Giving a surrogate treatment for reducing the blood sugar alone would take us nowhere . On the other hand, it may only lead us to more problems.
Way back in 400 BC, Charak and Sushrut, physicians from ancient India described Diabetes as Madhumeha (honey urine) with two types, and that one type is due to excessive food and sugar intake. So let us get back to the drawing board and re-emphasize that men and women need to be active at all ages and correct overweight and Obesity (14).
Insulin resistance has been implicated in the pathophysiology of Type 2 DM (15). However it is not quite clear if insulin resistance is the cause or consequence of hyperglycemia and obesity. All persons with Type 2 DM do not have raised fasting insulin levels (16). Drugs used to treat Type 2 DM are supposed to be insulin sensitizers or insulin secretagogues. There is no drug without an adverse effect Insulin secretagogues, over a period of time, exhaust the Islet cells and all these patients eventually land in a state with a need for insulin therapy (5,6).
On the other hand, patients who are on drugs like insulin sensitizers and actively exercising at the same time, can have their blood sugar controlled , not clearly indicating if it is the effect of the drug or the modified lifestyle (17). Drugs like Metformin have also been shown to decrease exercise capacity, which is of definite concern (17). Insulin and all other drugs tend to treat only the high sugar levels which is only a sign of the underlying pathology. In other medical conditions like high serum bilirubin levels or raised blood urea, we try to treat the underlying problem. Whereas in Type 2 DM, the underlying pathology is not addressed completely. On the other hand, we tend to use drugs. Patients get a false sense of reassurance and do not change their lifestyle and continue to indulge in inappropriate diet and inadequate activities.
The progression of angiopathy or metabolic dysfunction is continuous in patients with Type 2 Diabetes mellitus. There is evidence that tight glycemic control does not help in preventing microvascular or macrovascular complications (18). This clearly indicates the underlying pathology of inappropriate diet and inadequate exercises, unless corrected, is not going to rectify the problem of Type 2 DM.
In an era where researchers are voicing their opinion on 'Beating type 2 diabetes into remission' and 'Reversing type 2 diabetes',(19) our emphasis and the most appropriate management of Type 2 Diabetes mellitus should be on dietary modification and adequate physical activity. Drugs should only be used to prevent hyperglycemia related emergencies, which are very rare (20) On the other hand, drugs which are used to manage Type 2 DM can induce hypoglycemia which may even prove fatal (7).
Thiruvalluvar, a Tamil poet and philosopher said many centuries ago,
நோய்நாடி நோய்முதல் நாடி அதுதணிக்கும்
வாய்நாடி வாய்ப்பச் செயல்
which implies that every physician has to first diagnose the illness, trace its cause and then seek the proper remedy and apply it with skill.
1. Passmore R, Durnin JV. Human energy expenditure. Physiol Rev. 1955 Oct;35(4):801–40.
2. Mayer-Davis EJ, Lawrence JM, Dabelea D, Divers J, Isom S, Dolan L, et al. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002–2012. N Engl J Med. 2017 Apr 13;376(15):1419–29.
3.. Herman WH. The Global Burden of Diabetes: An Overview. In: Diabetes Mellitus in Developing Countries and Underserved Communities. Springer, Cham; 2017.. p. 1–5. Available from: https://link.springer.com/chapter/10.1007/978-3-319-41559-8_1
4. Drive ADA 2451 C, Arlington S 900, Va 22202 1-800-Diabetes. History of Diabetes [Internet]. American Diabetes Association. Available from: http://www.diabetes.org/research-and-practice/student-resources/history-...
5. Lupi R, Del Prato S. Beta-cell apoptosis in type 2 diabetes: quantitative and functional consequences. Diabetes Metab. 2008 Feb;34 Suppl 2:S56-64.
6. Maedler K, Carr RD, Bosco D, Zuellig RA, Berney T, Donath MY. Sulfonylurea induced beta-cell apoptosis in cultured human islets. J Clin Endocrinol Metab. 2005 Jan;90(1):501–6.
7. Cryer PE. Death During Intensive Glycemic Therapy of Diabetes: Mechanisms and Implications. Am J Med. 2011 Nov;124(11):993–6.
8. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care. 1994 Sep;17(9):961–9.
9. Wilmot EG, Edwardson CL, Achana FA, Davies MJ, Gorely T, Gray LJ, et al. Sedentary time in adults and the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis. Diabetologia. 2012 Nov;55(11):2895–905.
10. Schulze MB, Manson JE, Ludwig DS, Colditz GA, Stampfer MJ, Willett WC, et al. Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA. 2004 Aug 25;292(8):927–34.
11. Eaton SB, Eaton SB. Physical Inactivity, Obesity, and Type 2 Diabetes: An Evolutionary Perspective. Res Q Exerc Sport. 2017 Mar;88(1):1–8.
12. Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of Diabetes and Diabetes-Related Complications. Phys Ther. 2008 Nov 1;88(11):1254–64.
13. Li G, Zhang P, Wang J, An Y, Gong Q, Gregg EW, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol. 2014 Jun;2(6):474–80.
14. Björntorp P. Metabolic implications of body fat distribution. Diabetes Care. 1991 Dec;14(12):1132–43.
15. Gallagher EJ, LeRoith D, Karnieli E. The metabolic syndrome--from insulin resistance to obesity and diabetes. Endocrinol Metab Clin North Am. 2008 Sep;37(3):559–579, vii.
16. Wilson PWF, Meigs JB, Sullivan L, Fox CS, Nathan DM, D’Agostino RB. Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. Arch Intern Med. 2007 May 28;167(10):1068–74.
17. Cadeddu C, Nocco S, Lucia C, Deidda M, Bina A, Fabio O, et al. Effects of metformin and exercise training, alone or in association, on cardio-pulmonary performance and quality of life in insulin resistance patients. Cardiovasc Diabetol. 2014 May 15;13:93.
18. Rodríguez-Gutiérrez R, Montori VM. Glycemic Control for Patients With Type 2 Diabetes Mellitus: Our Evolving Faith in the Face of Evidence. Circ Cardiovasc Qual Outcomes. 2016 Sep;9(5):504–12.
19. McCombie L, Leslie W, Taylor R, Kennon B, Sattar N, Lean MEJ. Beating type 2 diabetes into remission. BMJ. 2017 Sep 13;358:j4030.
20. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, et al. Prevention of Type 2 Diabetes Mellitus by Changes in Lifestyle among Subjects with Impaired Glucose Tolerance. N Engl J Med. 2001 May 3;344(18):1343–50
Competing interests: No competing interests
Many of the issues raised with the use of HbA1c to determine diabetes remission were encountered a decade ago when HbA1c was being considered as a diagnostic tool. Time has not made them any less valid.
Firstly there is discordance between fasting and/or 2hr postprandial glucose and HbA1c. Data from NHANES suggested that 1% of the cohort would have diabetes diagnosed by both fasting plasma glucose and 2-hour plasma glucose, but not by HbA1c (1). For this group of individuals, how should remission be determined?
Secondly, the contribution of postprandial glucose to HbA1c is greater for lower HbA1c values (2). The 2-hour OGTT glucose levels would better reflect an impairment of beta-cell function - the key pathophysiological defect of diabetes – for these individuals. Perhaps it would be better to restrict the term ‘remission’ for cases where beta-cell function can be more directly measured?
Thirdly and perhaps the most important, all definitions for the presence of DM have, by definition, been glucose-centric. In recent years, there has been a reappraisal of the goals for therapy for an individual with type 2 diabetes. It is recognised that a comprehensive approach to risk assessment, and management of metabolic risk factors can offset the risk of cardiovascular disease (3, 4). Cardiovascular disease is the major cause of morbidity and mortality for individuals with diabetes. The continuum of vascular risk extends below the threshold for diabetes: for example, an individual with HbA1c 6.0 to <6.5% has a risk of coronary artery disease that is 78% higher than for those whose Hb1c is 5.0 to <5.5% (5). The evolution of pre-existing microvascular and macrovascular disease is not necessarily halted by glucose normalisation. In ADVANCE, near-normalization of glucose reduced new or worsening nephropathy, but not eye or foot complications. In ACCORD, near-normalization of glucose did not reduce composite measures of advanced microvascular complications (6). Equating diabetes resolution solely with glucose normalisation may serve to undermine a holistic approach to patient management.
1. Cowie CC, Rust KF, Byrd-Holt DD, Gregg EW, Ford ES, Geiss LS, et al. Prevalence of diabetes and high risk for diabetes using A1C criteria in the U.S. population in 1988-2006. Diabetes Care. 2010;33(3):562-8.
2. Monnier L, Colette C. Contributions of fasting and postprandial glucose to hemoglobin A1c. Endocr Pract. 2006;12 Suppl 1:42-6.
3. Fox CS, Golden SH, Anderson C, Bray GA, Burke LE, de Boer IH, et al. Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association. Diabetes Care. 2015;38(9):1777-803.
4. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580-91.
5. Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010;362(9):800-11.
6. O'Connor PJ, Ismail-Beigi F. Near-Normalization of Glucose and Microvascular Diabetes Complications: Data from ACCORD and ADVANCE. Ther Adv Endocrinol Metab. 2011;2(1):17-26.
Competing interests: No competing interests
That is an ongoing article around the risk of obesity.
The risk not only Diabetes 2 but also hypertension, cardio-vascular diseases, gastro - intestinal and gall bladder diseases in addition to musclo-skeletal system . The subject of nutrition with regard to body requirement for the quality and quantity of food is unknown in the education in schools or university.
We need in UK and all over the world a new educated generation to adjust the food and drink intake.
Even within the health professionals doctors and nurses obesity is alarming.
By combating obesity this can have a huge impact on NHS budget, the economy of the country
and the whole world in addition to improving health and quality of life.
M E Tageldin
Competing interests: No competing interests
Diabetes is a metabolic dysfunctional state where there is a defect in insulin production/synthesis/release or in its action, receptor number, post-receptor defect or what we call insulin resistance.
It is not a battle of wits but it is a state of health that challenges your mental resolve and balance - say, keeping your blood glucose levels with minimal fluctuations, controlling your diet and developing a mental state of considering diabetes a normal state of your body. What I mean is instead of taking it as a pathophysiological manifestation it needs to be taken as a life style adjustment of an individual to the blood glucose level or HbA1c changing one's perspective to suit the needs and demands of the state of health.
There is no question of a remission or precipitation of adverse outcomes of diabetes if one considers the metabolic state of diabetic patient as one that has to be dealt with as one deals with the normal routine of life.
Competing interests: No competing interests
As Louise McCombie and colleagues state in their paper, there is little doubt that, from a pathophysiological perspective, remission of type 2 diabetes is probably achievable for many patients. Apparently, this is not supported by current medical records, which suggest that remission is almost non-existent. Many colleagues will argue that this is reality in practice, since sustainable remission, sometimes referred to as reversal, is hampered by a diversity of motivational and environmental factors.
However, McCombie et al. raise another important point, highlighting the lack of consensus regarding criteria to define type 2 diabetes remission. Availability of such consensus will not only facilitate the socio-economic debate on lifestyle as therapeutic option, but may also be of practical value in monitoring and stimulating individual efforts to change unhealthy behavior. Hyperglycemia, dyslipidemia and hypertension are caused by systemic low-grade inflammation, ectopic fat deposition and (compensatory) hyperinsulinemia, brought about by a variety of lifestyle features. Clearly, lifestyle intervention doesn’t bring permanent remission overnight, and complete remission may not be accomplishable in all patients. In line with existing consensus viewpoints, the authors make a case to use HBA1c and glucose values to define criteria for remission. However, as active implementers of a therapeutic lifestyle program for type 2 diabetic patients, which is currently attracting considerable attention in the Netherlands (http://keerdiabetes2om.nl), we would like to suggest the possibility of including reduction of medication dose as an additional criterion for remission.
The group program spans 24 months and involves individualized intensive nutrition, behavioral and lifestyle coaching, education, cookery classes and physician-guided medication management. One major Dutch health insurance company is currently sponsoring a pilot involving 1.900 patients, while discussions with other organizations and authorities on further implementation are actively ongoing. Faced with stakeholders working with short term economic horizons, we were challenged to include reduction of medication dose in a working definition of remission. Inspired by Buse and colleagues (2009), a consensus group comprising experts in internal medicine, diabetes, endocrinology, pharmacology, medical physiology and bio-statistics arrived at the following definition of remission of type 2 diabetes:
(Partial) remission of type 2 diabetes is achieved if one of the following three criteria is met:
1. Patients using insulin and/or GLP-1 analogues at the onset of the program were allowed to terminate their use of this medication
2. Patients who used oral medication (except Metformin) at the onset of the program were allowed to terminate oral medication (except Metformin).
3. Patients who used Metformin at the onset of the program don’t have to use diabetes medication any longer.
And if one of the following two criteria is met:
1. Patients who had a HBA1c lower than 58 at the onset of the program have reached a HBA1c of 53 or lower.
2. Patients who had a HBA1c higher than 58 at the onset of the program show decrease of at least 10 percent of their HBA1c -value.
This working definition is currently used to evaluate the outcome of our program. Realizing that there always remains room for further discussion, the undersigned are very interested in learning the opinions of colleagues and organizations involved in similar activities.
John Buse et al., How do we define cure of diabetes? Diabetes Care, volume 32, number 11, November 2009.
Conflict of interest
Prof Renger Witkamp PhD is chairperson of the advisory board of the “Voeding Leeft” foundation which is the initiator of the “KeerDiabetes2om” lifestyle program referred to in the letter, for which he is not receiving any financial compensation. He reports no financial interest in companies active in diabetes management, nor any other conflicts of interest relevant to the contents of this letter.
Prof Hanno Pijl, MD PhD is chair of the scientific advisory board of the “Keer Diabetes2 Om” lifestyle program referred to in the letter, for which he is not receiving any financial compensation. He reports receiving speakers’ fees for lectures on lifestyle management of type 2 diabetes from Sanofi.
Prof Marianne de Visser PhD is member of the board of the “Voeding Leeft” foundation which is the initiator of the “Keer Diabetes2 Om” lifestyle program referred to in the letter, for which she is not receiving any financial compensation. She reports no financial interest in companies active in diabetes management, nor any other conflicts of interest relevant to the contents of this letter.
Peter Voshol, PhD is co-founder of “Voeding Leeft” foundation which is the initiator of the “keerdiabetes2om” lifestyle program referred to in the letter, for which he is not receiving any financial compensation. He reports receiving speakers’ fees for lectures on the physiology of type 2 diabetes from Arts en Voeding foundation and Food Basics.
Tamara de Weijer, MD is general practitioner and chair of the Arts en Voeding Foundation. She reports no other conflicts of interest relevant to the contents of this letter.
Maaike de Vries, PhD is director of Keer Diabetes2 Om. She reports no other conflicts of interest relevant to the contents of this letter.
Competing interests: See text
My General Practice sees me annually for a health check-up. It was noticed that my fasting 'blood sugar' was rising and five years ago I had a glucose tolerance test that showed I was diabetic. I was offered drugs but decide to lose weight and manage my diet.
As a result I have lost 13kg and stayed between 71-72kg. My body/mass index is 24.3kg/m2, less than 25. My HbA1c has remained at 42-44mmol/mol over the past five years. I have no complications of diabetes. My BP has only once been as high as 130/70, usually it is <120/< 80. Curiously I have raised cholesterol and have had CABG with 4 vessel grafts in 1993, pacemaker for heart block in 2004 and TAVI in 2014. I am 88 years of age and walk two miles a day.
My personal experience is that the amount of food I need is so much less than would conventionally be considered modest. This is associated with hunger that while it gets less rarely does not cause a daily urge to eat more than my diet allows. It is often forgotten that when you reach your target weight you can only eat a little more each day and on no account can you expect to go back to your previous intake. I find that hunger is the driving force to 'relapse'. It is a very powerful drive and if denied is not only uncomfortable but provokes great anxiety.
As I specialised in addiction I came to recognise that my problems with food are closely allied to if not identical with an addiction. In the past I relapsed into over-eating in a manner identical to relapse with alcohol or other 'drug' use. When I applied to myself that which my patients had taught me I managed to control my intake of food. The challenge is to be a controlled eater, which may be as challenging as being a controlled drinker or other drug user. For example, many of those on methadone to manage their dependence on heroin are long-term controlled drug users in much the same way as we dieters have to be long-term controlled food users. Fortunately we are not quite so stigmatised!
David Marjot MB BS, FRCPsych. DPM.
Competing interests: No competing interests