Historically, diabetes has been believed to be a chronic disease that progresses over time, with gradual deterioration of beta cell function and worsening insulin resistance. By the time diabetes is diagnosed, beta cell function typically declines to around 50% of normal1. The pathophysiology of type 2 diabetes mellitus is complex and involves multiple organs. Understanding of the pathophysiology has evolved from the triumvariate–insulin resistance in the liver and muscle, and impaired insulin secretion–to the ominous octet, which includes increased lipolysis, increased glucose reabsorption in the kidneys, neurotransmitter dysfunction, hyperglucagonaemia and incretin deficiency2. Although there is no cure for diabetes, studies have shown that remission is feasible in obese patients and has been achieved through weight loss. In 2009, diabetes remission was defined in a consensus statement published in Diabetes Care, as the achievement of glycemic levels below the diabetic range in the absence of active pharmacologic or surgical therapy. Remission can be further characterized as partial or complete. Partial remission is defined as having a glycated hemoglobin (HbA1c) of <6.5%, and fasting glucose of 100-125 mg/dl (5.6-5.9 mmol/L), while complete remission is defined as a return to normal measures of glycemia with HbA1C of <6% and fasting glucose <100mg/dl (5.6mmol/L) of at least one year’s duration for both criteria3.
Diabetes remission following bariatric surgery is well recognized in obese patients and can be achieved not only in individuals on oral antidiabetic drugs but also in those on insulin4-6. Rates of remission vary depending on the type of bariatric procedure performed, with malabsorptive procedures (Roux-en-Y gastric bypass and biliary pancreatic diversion) being more effective than restrictive procedures (vertical sleeve gastrectomy or adjustable gastric banding). A 2009 meta-analysis of weight and diabetes following bariatric surgery found that, at one year, biliary pancreatic diversion resulted in type 2 diabetes remission in 95.1% of patients, Roux-en-Y in 80.3%, gastroplasty in 79.7% and adjustable gastric banding in 56.7%, of patients. In this study, complete diabetes remission was defined as outlined above. The reduction in excess body weight ranged from 46.2% (gastric banding) to 63.6% (biliary pancreatic diversion)7. Several factors have been identified as positive predictors for diabetes remission in those undergoing bariatric surgery, including: younger age, higher baseline body mass index, shorter duration of diabetes, lower HbA1c before surgery and not taking insulin. Prediction models such as the DiaRem score, ABCD score, and individualized metabolic surgery score, can provide further information about the outcome of metabolic surgery8. Bariatric surgery, however, is not widely accessible due to its high cost, lack of availability in some parts of the world, and the long-term need to monitor patients for micronutrient deficiencies.
Dietary control and lifestyle modification is often recommended to patients with diabetes. However, until recently, evidence for the efficacy of nonsurgical methods in inducing diabetes remission has been scarce. An ancillary analysis from the Action for Health in Diabetes (Look AHEAD) trial, found that, when compared with patients randomized to the diabetes support and education intervention group, patients randomized to the lifestyle-based weight loss intervention arm were 11.5% more likely to achieve remission (partial or complete) during the first year. At year four, the lifestyle-based weight loss group was 7.3% more likely to achieve partial or complete remission versus 2% in the diabetes support and education intervention group9.
The Diabetes Remission Clinical Trial (DiRECT) was the first randomized controlled trial to look at the primary outcome of diabetes remission following diet and lifestyle modification. Patients diagnosed with type 2 diabetes mellitus within the previous six years and between the ages of 20 to 60 years with a body mass index of 27-45 kg/m2, were recruited. A total of 306 individuals participated and were randomized into two groups. In the intervention arm, weight loss was achieved through a structured program of total diet replacement using a low energy formula diet of about 800 kcal/day for three months. This was followed by structured food reintroduction over 2-8 weeks and an ongoing structured program involving monthly visits to trained healthcare providers for weight loss maintenance. Participants continued their usual physical activity during the period of total diet replacement and subsequently increased their activity level during the food reintroduction phase. Step counters were provided with a goal of 15,000 steps per day. In this study, remission was defined as HbA1c <6·5% (<48 mmol/mol) after at least two months of discontinuing all antidiabetic medications. At 12 months, 24% of participants in the intervention group achieved a weight loss of 15 kg or more; diabetes remission was achieved in 46% (n=68) of these patients. In the control group, six participants (4%) achieved diabetes remission (odds ratio 19·7, 95% CI 7·8–49·8; p<0·0001).
Results varied with weight loss in the intervention arm, with 85% of those who lost 15 kg or more achieving remission10. Following a two-year extension period of the initial study, diabetes remission was 35.6%11. The underlying mechanism leading to diabetes remission was related to the loss of fat deposition in the liver and pancreas following weight loss. However, there were patients who did not achieve diabetes remission despite losing weight; these non-responders had a failure of recovery of first phase insulin response and had longer duration of diabetes duration.
Remission of type 2 diabetes in obese individuals is possible but requires significant commitment and motivation on the part of the patient. The trials discussed in this article address diabetes remission in obese patients only. Whether non-obese patients with type 2 diabetes can also achieve remission by following a low-calorie diet remains to be determined.
Pei Lin Chan, MBBS (IMU), MRCP (UK)
Read previous columns from Dr. Chan.