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REVIEW ARTICLE
Year : 2023 | Volume
: 14
| 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
Correspondence Address:
Dr. Ashok Kumar
Department of Medicine, Santosh Deemed to Be University, No. 1, Ambedkar Road, Old Bus Stand, Ghaziabad - 201 001, Uttar Pradesh
India
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/injms.injms_123_22
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
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.[1]
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.[1]
Concept of Diabetes RemissionGenetic 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.[2]
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 RemissionIn 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.[3]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 medicationComplete remission: Attainment of normoglycemia i.e., HbA1C <6.0% and fasting glucose <100 mg/dl for at least for 1 year without medicationProlonged 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.[4]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.[5]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.[6]
Taylor Twin Cycle HypothesisIt 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].[7],[8],[9],[10]
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.[6]
Figure 2: Possible mechanism of diabetes remission after bariatric surgeryThis 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.[9],[10]
Parameters of RemissionThere are several parameters have been proposed that formed the basis of the remission [Table 1].
Predictive Models for RemissionThere 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.[5]
Methods for Diabetes RemissionChanges 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.[5],[6][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 ModificationAs 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.[11],[16]
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.[12]
Physical activity
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.[17]
Role of Bariatric SurgeryThe 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.[18],[19]
Role of PharmacotherapyIn 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.[5]
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.[5]
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.[20]
Role of sodium glucose co-transporter 2 inhibitor
Evidence have shown that metformin and SGLT2i combination use can lead to remission of recent diabetes.[21]
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.[22],[23]
Role of InsulinStudies 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.[6]
Anti-Obesity Drug OrlistatThe 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.[24]
Counseling and Behavioural ChangeMost 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.[6]
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.[25]
ConclusionDM 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.
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Conflicts of interest
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References
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