|Year : 2023 | Volume
| Issue : 1 | Page : 3-8
Diabetes remission: Myth or reality?
Ashok Kumar1, Shubha Laxmi Margekar2, Ravi Kumar1
1 Department of Medicine, Santosh Deemed to Be University, Ghaziabad, Uttar Pradesh, India
2 Department of Medicine, Lady Hardinge Medical College, New Delhi, India
|Date of Submission||04-Oct-2022|
|Date of Decision||25-Nov-2022|
|Date of Acceptance||27-Nov-2022|
|Date of Web Publication||09-Feb-2023|
Dr. Ashok Kumar
Department of Medicine, Santosh Deemed to Be University, No. 1, Ambedkar Road, Old Bus Stand, Ghaziabad - 201 001, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
The rising prevalence of diabetes mellitus (DM) increases the burden of morbidity and mortality worldwide. DM is recognized as an independent risk factor of cardiovascular mortality. Uncontrolled diabetes leads to various long-term microvascular and macrovascular complications. Optimum control of glycemia is desirable to prevent these complications to improve quality of life and decrease mortality. The concept of remission or reversal of diabetes is evolving for many decades and various definitions and approaches to achieve remission also have evolved. Obesity-related surgeries had shown remarkable control of blood glucose levels. Recently, therapy directed toward weight loss either by medical nutrition therapy, physical activity, or anti-diabetic medications seems promising in achieving remission of diabetes.
Keywords: Diabetes remission, obesity, physical activity, reversal
|How to cite this article:|
Kumar A, Margekar SL, Kumar R. Diabetes remission: Myth or reality?. Indian J Med Spec 2023;14:3-8
| Introduction|| |
Diabetes mellitus (DM) is a chronic, progressive, and disastrous, noncommunicable disease, the burden of which is increasing day by day. The pathogenesis of diabetes is complex and revolved around multiple factors such as genetic, environment, autoimmunity, and infection. As per the information provided by the International Diabetes Federation, around 463 million people were living with DM in 2019, and 4.2 million estimated deaths due to diabetes all over the world. India has the world's second-largest diabetic population with approximately 69 million people with diabetes.
Progression of diabetes is recognized by the development of microvascular and macrovascular complications which contribute to the burden of morbidity and mortality. Understanding of natural history, that in the presence of risk factors, genetic, and environmental factors play a crucial role in the development of frank DM via the stage of prediabetes.
Over the period, there is growing evidence that with the help of lifestyle, behavioral, and educational interventions in the management of Type 2 DM suggesting that there is a potential scope for metabolic reversal of diabetes.
| Concept of Diabetes Remission|| |
Genetic predisposition makes the individual susceptible for the development of diabetes under the modulation effect of environmental factors later in life. Environmental factor includes stress, dietary habits, sedentary lifestyle, exposure to toxins, pollutants, and access to a medical facility for management. Some susceptible individuals develop gestational diabetes, stress hyperglycemia, and steroid diabetes under the modulatory effects of the environment, in which blood glucose levels are raised transiently for some period of time. Blood glucose levels normalize after delivery in gestational diabetes mellitus, and steroid diabetes also normalizes after the withdrawal of steroids. The raised blood glucose in this condition is attributed to transient insulin resistance. Nevertheless, individuals with these attributes are at risk of developing DM in later life.
It has been observed that some individuals with DM which developed slowly over a period of time showed some control or sign of remission after weight loss.
| Evolution of Definition of Remission|| |
- In 2009 consensus statement of the American Diabetes Association (ADA) by Buse et al.proposed that remission is said by the achievement of glycemia below the diabetic range without any medication or surgical treatment. Three categories for remission were proposed.
- Partial remission: Attainment of hemoglobin A1C (HbA1C) below the threshold for diagnosis, i.e., <6.5% and fasting glucose between 100 and 125 mg/dl for at least 1 year without active medication
- Complete remission: Attainment of normoglycemia i.e., HbA1C <6.0% and fasting glucose <100 mg/dl for at least for 1 year without medication
- Prolonged remission: It is said to be when complete remission persisted for more than 5 years without active medication for DM.
- In 2019 Nagi et al. proposed diabetes remission as the Attainment of hyperglycemia below the threshold for diagnosis for at least 6 months without active medication.
- In 2021, Kalra et al. from India proposed the definition of diabetes remission as the attainment of glycemic control below the diagnostic threshold for at least 6 months with or without the use of lifestyle modification and/or the use of metformin.
- The joint consensus statement of four statutory bodies, ADA, the Endocrine Society, the European Association for the Study of Diabetes, and Diabetes UK, tried to curtail the debate, defined diabetes remission as the return of glycemic control below the diagnostic threshold proposed by WHO/ADA and the return to glycemic control need to be maintained for at least 3 months without any hypoglycemic therapy and this remission should be kept under review minimum annually.
It is important to note that none of the researchers or bodies proposed the definition of a cure of diabetes, probably because of the progressive nature of disease pathology in which, there is progressive destruction of beta cells. Furthermore, the researchers avoided the term of reversal over remission in the context of DM as remission is well defined by the criteria.
| Taylor Twin Cycle Hypothesis|| |
It has been observed that normoglycemia occurs just within a week following Bariatric Surgery which was initially thought to be due to the effect on incretins, but being secondary regulatory hormones, this type of fast response seems less explanatory.
There appears to be a state of negative calorie balance soon after bariatric surgery and initiation of consumption of body energy reserves. Fatty acid accumulation in cytoplasm starts decreasing soon after surgery, and they are taken up by mitochondria for oxidation. Furthermore, the concentration of diacylglycerol, which was the product of the formation of fatty acid from triglycerides, started decreasing and cells were left out with either glucose or fat to use as fuel as per the need. These sequences of events lead to the generation of the Taylor twin cycle hypothesis, which seems an effort toward diabetes remission [Figure 1].,,,
Bariatric surgery seems to hit this process at the very beginning by creating gross negative balance and due to quick removal of excess toxic fat from the pancreas leads to improvement of beta-cell function [Figure 2]. It has been observed in studies that a mere 0.5 g deposition of fat in the pancreas can lead to gross beta-cell dysfunction causing hyperglycemia. Removal of this much small fat deposition can be very quick, possibly explaining the quick attainment of normoglycemia following surgery, however maintaining this reversal or remission need more efforts in terms of further dietary restriction and lifestyle modifications.
|Figure 2: Possible mechanism of diabetes remission after bariatric surgery|
Click here to view
This Taylor twin cycle hypothesis opens the avenue for research for designing medical intervention which can have a similar effect on energy balance to achieve normoglycemia without many invasive procedures.,
| Parameters of Remission|| |
There are several parameters have been proposed that formed the basis of the remission [Table 1].
| Predictive Models for Remission|| |
There are factors that can influence the outcome of remission programs such as surgery and assessment of these factors should be done before intervention for optimal outcome. It has been observed that higher body mass index (BMI), young age, shorter duration of diabetes, and better glycemic control before bariatric surgery influence remission. For the prediction of remission, three models have been introduced [Table 2], which seemed to be of more practical or clinical utility.
| Methods for Diabetes Remission|| |
Changes in lifestyle, physical activity, behavioral changes, and bariatric surgery seem to be different methods for Type 2 diabetes remission as per the existing literature. The ADA also suggests the inclusion of health programs for enhancing physical activity in high-risk groups and aiming for weight loss can be an effective strategy., [Table 3] shows the recent major intervention studies and meta-analyses related to diabetes remission with lifestyle intervention, digital behavior change, and surgical and pharmacotherapy.
| Lifestyle Modification|| |
As per the existing literature, intensive lifestyle modification in the form of a low-calorie diet and medical nutrition therapy (MNT) can bring diabetes remission in individuals.
Role of low-calorie diet
It has been observed in studies that metabolic changes caused by the restriction of calorie include, improvement of hepatic glucose output, beta-cell function, insulin sensitivity, visceral fat, and indices of insulin resistance; facilitate diabetes remission.,
Medical nutrition therapy
MNT is the backbone of the management of diabetes, and it has been observed through various studies, MNT aimed toward significant weight loss results in remission of diabetes. One of the major trials, Diabetes Remission Clinical Trial (DiRECT) shown the efficacy of MNT, 46% of study participants had diabetes remission as a result of lifestyle intervention aimed at weight loss. It was also seen that the remission rate was directly proportional to the degree of weight loss. The remission rate after 1 year was progressively 7% to 86% for increases in weight loss from 5 kg to 15 kg.
Physical activity is another pillar in the management of DM. Sufficient evidence is there, moderate level physical activity can lead to weight loss and reversal of type 2 DM. The recommended physical activity should be moderate-intensity aerobic exercises achieving 50%–70% of maximum heart rate for ≥150 min/week, at least 3 days in a week without any gap of 2 consecutive days.
| Role of Bariatric Surgery|| |
The role of bariatric surgery also known as metabolic surgery has been well established as a treatment option for morbidly obese patients with associated metabolic disorders like type 2 DM. The approved indications of bariatric surgery in DM are BMI >40 Kg/m2 or >35 Kg/m2 with obesity-related complications. Sleeve gastrectomy and Roux-en-Y gastric bypass are the most common surgery in obese patients. Diabetes remission has been observed in more than one-third of patients undergoing surgery, also remission was higher in patients who have lost more weight after surgery.,
| Role of Pharmacotherapy|| |
In the remission of type 2 DM, pharmacotherapy plays an important role as nonsurgical modality. Insulin sensitizers, glucose load reducers, and insulin secretagogs are the three classes of noninsulin glucose-lowering agents. Insulin sensitizers work to lower insulin resistance and can be direct acting like metformin and pioglitazone or indirect-acting like pramlintide and bromocriptine. Alpha-glucosidase inhibitor (AGI) and sodium-glucose co-transporter 2 inhibitor (SGLT2i) decreases blood glucose levels by delay in adsorption in the gut and excretion enhancer action of SGLT2i in the kidney, respectively, therefore worked as nutrient load reducers.
Calorie restriction mimetics constitute another avenue that can be considered for diabetes remission. These are the pharmacological agents which can cause calorie restriction and weight loss by virtue of their mechanism of action. Several noninsulin glucose lowering drugs like SGLT2 inhibitors have glucosuria effects as calorie-waster, delaying the absorption of glucose by AGIs and appetite suppressing the action of glucose-like peptide 1 receptor agonists can be considered as calorie restriction mimetics.
Role of insulin sensitizers in remission of diabetes mellitus
There has been evidence that a combination of pioglitazone and metformin has achieved pharmacological remission for more than 6 months after withdrawal of insulin secretagogues (sulphonylureas) in more than 36% of cases. This shows the promising role of metformin and pioglitazone in inducing remission of Type 2 DM.
Role of sodium glucose co-transporter 2 inhibitor
Evidence have shown that metformin and SGLT2i combination use can lead to remission of recent diabetes.
Alpha-glucosidase role in remission
By delaying the absorption of carbohydrates from the gut, the AGI can reduce the postprandial hyperglycemia without the use of sulphonylureas or insulin. Along with metformin, AGI is helpful in a significant loss in one of the randomized controlled trial. Lower rates of progression to type 2 DM was noticed in one of the observational study comprising 66 high-risk individuals with impaired glucose tolerance.,
| Role of Insulin|| |
Studies have shown intensive insulin therapy for 2–3 weeks when given in the early course of Diabetes (Ideally <2 years) can induce glycemic remission. In a meta-analysis induction of remission was seen in 46% of cases at 1 year and 42% at 2 years with short-term insulin therapy.
| Anti-Obesity Drug Orlistat|| |
The drug orlistat is available for more than two decades but seems to be overlooked for its use. Orlistat is a peripheral lipase inhibitor with no systemic absorption and an excellent safety profile. Many studies in the literature have shown improvements in glycemic control by promoting weight loss by the use of the drug. Digestion and absorption of free fatty acids blocked by orlistat by virtue of its mechanism of action. Greater recovery of insulin sensitivity has been seen in patients treated with orlistat, along with behavioral interventions plus placebo.
| Counseling and Behavioural Change|| |
Most of the diabetes remission therapy aims at significant weight loss. It has been observed that weight regain can be significantly slowed after starting of normal diet, by following of cognitive behavior therapy with structured psychological support.
The evidence from the positive online weight reduction study suggests that this digital behavior change program – "digital written content with occasional brief nurse follow-up – can be upscaled that improves outcomes from dietary approaches to weight loss and better outcomes if combined with all approaches to T2DM reversal" and diabetes remission can be sustained longer.
| Conclusion|| |
DM is a chronic, progressive and disastrous, noncommunicable disease with the growing burden. The complex pathophysiology of genetic and environmental interplay leads to progressive pancreatic beta cell failure making this disease incurable. Current evidence suggests that diabetes remission can be achieved with various modalities aiming toward weight loss, like physical activity, MNT, obesity surgery, and with the use of antidiabetic medications. The concept seems to be more useful if used early in individuals who are at higher risk for DM. The sustainment of remission is the most challenging which requires tremendous patient motivation and a multidisciplinary approach. Remission of DM will have a significant impact on chronic complications of DM even attained for some time during the life of an individual.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Brown A, McArdle P, Taplin J, Unwin D, Unwin J, Deakin T, et al.
Dietary strategies for remission of type 2 diabetes: A narrative review. J Hum Nutr Diet 2022;35:165-78.
Riddle MC, Cefalu WT, Evans PH, Gerstein HC, Nauck MA, Oh WK, et al.
Consensus report: Definition and interpretation of remission in type 2 diabetes. J Clin Endocrinol Metab 2022;107:1-9.
Buse JB, Caprio S, Cefalu WT, Ceriello A, Del Prato S, Inzucchi SE, et al.
How do we define cure of diabetes?. Diabetes Care 2009;32:2133-5.
Nagi D, Hambling C, Taylor R. Remission of type 2 diabetes: a position statement from the Association of British Clinical Diabetologists (ABCD) and the Primary Care Diabetes Society (PCDS). British Journal of Diabetes 2019;19:73-6.
Kalra S, Bantwal G, Kapoor N, Sahay R, Bhattacharya S, Anne B, et al.
Quantifying remission probability in type 2 diabetes mellitus. Clin Pract 2021;11:850-9.
Shibib L, Al-Qaisi M, Ahmed A, Miras AD, Nott D, Pelling M, et al.
Reversal and remission of T2DM – An update for practitioners. Vasc Health Risk Manag 2022;18:417-43.
Guidone C, Manco M, Valera-Mora E, Iaconelli A, Gniuli D, Mari A, et al.
Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Diabetes 2006;55:2025-31. doi:10.2337/db06-0068
Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: Unravelling the mechanism. Lancet 2010;375:2267-77.
Taylor R. Banting memorial lecture 2012: reversing the twin cycles of T2DM. Diabet Med 2013;30:267–75.
Taylor R. Banting memorial lecture 2012: Reversing the twin cycles of type 2 diabetes. Diabet Med 2013;30:267-75.
Goldenberg JZ, Day A, Brinkworth GD, Sato J, Yamada S, Jönsson T, et al.
Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: Systematic review and meta-analysis of published and unpublished randomized trial data. BMJ 2021;372:m4743.
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;391:541-51.
Little P, Stuart B, Hobbs FR, Kelly J, Smith ER, Bradbury KJ, et al.
Randomised controlled trial and economic analysis of an internet-based weight management programme: POWeR+ (positive online weight reduction). Health Technol Assess 2017;21:1-62.
Sheng B, Truong K, Spitler H, Zhang L, Tong X, Chen L. The long-term effects of bariatric surgery on type 2 diabetes remission, microvascular and macrovascular complications, and mortality: A systematic review and meta-analysis. Obes Surg 2017;27:2724-32.
McInnes N, Hall S, Sultan F, Aronson R, Hramiak I, Harris S, et al.
Remission of type 2 diabetes following a short-term intervention with insulin glargine, metformin, and dapagliflozin. J Clin Endocrinol Metab 2020;105:dgaa248.
Bhatt AA, Choudhari PK, Mahajan RR, Sayyad MG, Pratyush DD, Hasan I, et al.
Effect of a low-calorie diet on restoration of normoglycemia in obese subjects with type 2 diabetes. Indian J Endocrinol Metab 2017;21:776-80.
Taylor R, Barnes AC. Can type 2 diabetes be reversed and how can this best be achieved? James lind alliance research priority number one. Diabet Med 2019;36:308-15.
Salminen P, Helmiö M, Ovaska J, Juuti A, Leivonen M, Peromaa-Haavisto P, et al.
Effect of laparoscopic sleeve gastrectomy versus laparoscopic roux-en-y gastric bypass on weight loss at 5 years among patients with morbid obesity: The SLEEVEPASS randomized clinical trial. JAMA 2018;319:241-54.
Purnell JQ, Selzer F, Wahed AS, Pender J, Pories W, Pomp A, et al.
Type 2 diabetes remission rates after laparoscopic gastric bypass and gastric banding: results of the longitudinal assessment of bariatric surgery study. Diabetes Care 2016;39:1101-7.
Panikar V, Joshi SR, Bukkawar A, Nasikkar N, Santwana C. Induction of long-term glycemic control in type 2 diabetic patients using pioglitazone and metformin combination. J Assoc Physicians India 2007;55:333-7.
Sugiyama S, Jinnouchi H, Hieshima K, Kurinami N, Jinnouchi K. Type 2 diabetes remission and substantial body weight reduction achieved with metformin and a sodium-glucose cotransporter 2 inhibitor. Cureus 2020;12:e7110.
Oh TJ, Yu JM, Min KW, Son HS, Lee MK, Yoon KH, et al.
Efficacy and safety of voglibose plus metformin in patients with type 2 diabetes mellitus: A randomized controlled trial. Diabetes Metab J 2019;43:276-86.
Riyaz MS, Joseph KN, Saba M. Role of voglibose in prevention of type 2 diabetes in established case of impaired glucose tolerance: An observation study. Int J Res Med Sci 2015;3:1453-6.
Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27:155-61.
Little P, Stuart B, Hobbs FR, Kelly J, Smith ER, Bradbury KJ, et al.
An internet-based intervention with brief nurse support to manage obesity in primary care (POWeR+): A pragmatic, parallel-group, randomised controlled trial. Lancet Diabetes Endocrinol 2016;4:821-8.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]