Materials and Methods
Ethical Considerations
The study protocol was approved by the Ethics Committee and institutional review at our hospitals and was compliant with the Helsinki Declaration. Each patient provided a signed informed consent after being made aware of the current standards of treatment for T2DM and understanding the risks and benefits associated with the procedure.
Patients
Seventy patients with uncontrolled T2DM received RYGB at Daping Hospital during the period of May 2010 to December 2015; all the patients are Asiatic populations. The inclusion criteria were as follows: diagnosis of T2DM or other important co-morbidity based on the criteria of the American Diabetes Association (ADA) [
16], from 18 to 60 years of age, BMI > 25 kg/m
2 (based on China’s obesity and type 2 diabetes surgical treatment guidelines (2014)). A patient would be excluded if he or she had previously undergone bariatric surgery or other complex abdominal surgery, as were those with established diagnoses of type 1 diabetes, latent adult autoimmune diabetes, malignancy, pregnancy, neurologic disease, or cardiovascular disease.
Prior to the operation, each patient was assessed by a multidisciplinary team (MDT) comprised of a surgeon, endocrinologist, anesthetist, psychiatrist, and dietician. Moreover, each patient underwent a routine preoperative workup and counseling in addition to a detailed diabetic workup. The preoperative and postoperative data sets were collected and entered into a database. Preoperatively, we collected data on patient demographics, height, weight, BMI, waist circumference, co-morbidity, duration of T2DM, medication use, fasting plasma glucose (FPG), 2-hour postprandial glucose (2hPG), and glycosylated hemoglobin (HbA1c). Additionally, the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), uric acid, insulin, and fasting plasma C-peptide were assessed before surgery and 1, 3, 6, 12, and 24 months postsurgery.
Surgical Methods
Laparoscopic RYGB was performed by a single surgeon. For LRYGB, five trocars were used, constructing a 30–50-ml gastric pouch. The length of the biliopancreatic limb was 50–100 cm, and the Roux limb was 100–150 cm. The gastrojejunostomy was created by a staple technique with an anastomosis 1.5–2.0 cm in diameter, and the mesenteric and Petersen defects were closed.
Endpoints
The primary endpoint was the difference in the rate of T2DM remission between the two groups, with the recommendation from an expert consensus meeting organized by the American Diabetes Association [
17]. Complete remission was defined as a fasting glucose level of less than 5.6 mmol/L and a glycated hemoglobin level of less than 6.0% for at least a year without active pharmacologic therapy. Partial remission was defined as a fasting glucose level of 5.6–6.9 mmol/L and a glycated hemoglobin level of less than 6.5% for at least a year without active pharmacologic therapy. Improvement of diabetes was defined as a glycated hemoglobin level of less than 7% for at least a year.
The secondary endpoints were changes from baseline in levels of BMI, waist circumference, FPG, 2hPG, HbA1c%, C-peptide, and levels of plasma TC, TG, HDL, and LDL at 2 years.
Statistical Analysis
Statistical analysis was performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). Graphs were made using a commercially available software package (GraphPad prism for Windows). Baseline comparisons were performed using chi-square test, paired t test, and one-way ANOVA. Continuous variables were expressed as mean ± standard deviation; continuous variables were compared using Student ANOVA for repeated measurement, and two-tailed p value < 0.05 was considered statistically significant.
Discussion
The aim of the present study was to compare the effects of RYGB on 47 T2DM patients with BMI < 30 kg/m
2 and 23 T2DM patients with BMI > 30 kg/m
2. We wondered whether the lower BMI group would have the same good postoperative response as the higher BMI group. This study confirmed that RYGB was safe and might be useful to treat low BMI T2DM patients, which were consistent with previous reports of non-obese T2DM patients [
7,
18‐
23].
We found that 28.2% of patients in the BMI < 30 kg/m
2 group had complete remission of T2DM at 12 months postsurgery with an acceptable number of complications. The complete remission are similar to some recent report [
12,
24‐
26], especially those about low BMI patients reported by Dixon et al. [
24] and Liang et al. [
12], but are lower than those reported by Huang et al. [
13]. Dixon et al. [
24] reported that glycemic control was achieved in 31 (30%) T2DM patients with BMI < 30 kg/m
2 at 12 months. Liang et al. [
12] found that 25% of patients with BMI < 28 kg/m
2 had complete remission of T2DM at 12 months. Huang et al. [
13] reported that 14 (63.6%) patients with a BMI of 25–35 kg/m
2 showed T2DM remission when treated by RYGB. Such discrepancies could be explained by the greater severity and longer duration of diabetes in our low BMI population, as well as a stricter definition of remission. Currently, the most important discussion about metabolic surgery should be improvement rather than the complete remission of diabetes, and the ultimate goal of diabetes care should be minimization of end organ damage, particularly vascular complications, instead of reducing the remission of diabetes. Chen Y et al. [
5] reported that although complete remission rate can be significantly reduced after long-term follow-up, all patients still had better glycemic control and less number or dosage of medications than before surgery, which might result in reduced vascular complications. A recent RCT and an accompanying editorial highlight that despite the 0% diabetes remission at 5 years, there are also having more than 80% of patients in the surgery group achieved the ADA treatment goal of glycated hemoglobin A1c less than 7.0% and had a greater reduction of diabetes-related complications than patients who received medical treatment [
27,
28]. Our study did not show significant difference in the improvement (HbA1c < 7.0%) of T2DM between groups. This means that patients in the BMI < 30 kg/m
2 group also benefit from gastric bypass surgery even if they have a lower complete remission of diabetes.
The metabolic mechanisms leading to improved glycemic control after metabolic surgery have been partly elucidated. Several mechanisms have been proposed, including increased insulin sensitivity by calorie restriction, subsequent weight loss, decreased secretion of ghrelin and anti-incretin factor, stimulated glucagon-like-peptide-1 (GLP-1) and peptide YY secretion by the rapid transport of nutrient to the distal intestine causes weight loss, increased bile acid, changed gut microbiota, altered most adepokine levels, and probably additional undiscovered effects [
29]. It is increasingly clear that the gut plays a major role in glucose homeostasis, regulating both insulin secretion and sensitivity. These theories illustrate that T2DM remission after RYGB was not necessarily associated with weight loss. And further studies have shown that “foregut and hindgut theory” plays an important role in the treatment of T2DM; bypass of the duodenum and jejunum can directly control T2DM without significant weight loss [
30,
31]. In this study, the BMI decrease in the lower BMI group was less than that of the higher BMI group, but the efficacy of T2DM treatment was similar and this result is consistent with the previous theory. However, while in some studies, the low weight loss observed in T2DM patients did not affect the capacity of RYGB to induce diabetes remission and substantially improve insulin sensitivity; several recent studies have demonstrated the importance of weight loss on T2DM remission in lower BMI patients. Lee et al. [
14] observed that weight loss remained the dominant influence on the remission of T2DM following metabolic surgery in non-obese patients. The Korean study also found that the remission of T2DM was related to postsurgical weight loss of more than 12% [
32]. Thus, the weight loss effect on diabetes remission is still controversial and more clinical trials will be necessary before a conclusion can be made.
Numerous studies have demonstrated the high levels of metabolic risk factors at relatively low levels of BMI among Asian population because they have significantly high level of subcutaneous and visceral fat, which corresponds to high risk of cardiovascular and metabolic disease [
33,
34]. When it comes to the prevalence of uncontrolled T2DM accompanied by low BMI, there is an urgent need for treatment of T2DM in Asians. Therefore, BMI is regarded as the indication for the appropriateness of metabolic surgery is insufficient [
35]. After continuous adjustment and updating, the International Diabetes Federation has recommended that any patient of Asian ethnicity with T2DM should be conditionally eligible for bariatric surgery if his or her BMI is between 27.5 and 32.5 kg/m
2 and he or she has HbA1c > 7.5% despite fully optimized conventional therapy. Additionally, patients are eligible if their weight is increasing or if other weight responsive co-morbidities are not achieving targets on conventional therapies [
36]. Thus, the subjects of this study are mildly obese uncontrolled T2DM with BMI < 30 kg/m
2.
Although expansion of the RYGB criteria to include lower BMI patients with T2DM is attractive, the issue of the safety needs to be proposed. There was no mortality, no need of reoperation in this study, and the overall morbidity of 7.1% was similar to that of 9 and 10.3% for metabolic surgery in lower BMI patients, as mentioned in two reports by Fried et al. [
37] and Huang et al. [
13]. In the study by Cohen et al. [
38], there was no mortality in a series of 37 patients after RYGB. The combined results of our and others’ study indicate that RYGB in T2DM patients with low BMI can be performed with no mortality and that most of the associated complications can be managed successfully.
Diabetes mellitus is a major risk of cardiovascular disease. Although glycemic control is the primary goal of management, the ultimate objective is to reduce end organ both microvascular (diabetic, nephropathy, neuropathy, retinopathy) and macrovascular (stroke, coronary artery disease, peripheral vascular disease) complications of T2DM. In T2DM patients with obesity, insulin resistance is associated with lipid metabolism. This pattern of lipid abnormalities is thought to be secondary to insulin resistance [
39]. In the study by Iaconelli et al. [
40], reductions in the levels of triglycerides and LDL cholesterol after biliopancreatic diversion helped normalize insulin sensitivity and to reduce rates of cardiovascular events. Baza et al. [
41] found that RYGB induced significant improvement in TG and HDL levels, which might be related to the weight loss and improved insulin resistance. In our study, lipid metabolism was improved in the two groups of patients, although there was no significant statistical difference between those groups. The improvement of the lipid profile might explain the cardiovascular benefits in many studies. Thus, we concluded that RYGB can improve the patients’ cardiovascular risk factors, which may in turn improve their life expectancy in the coming years.
In Asian populations, most T2DM patients have a BMI below 35 kg/m
2 and impaired islet function during the early stage of disease [
2]. Wang GF et al. [
42] indicated that old age is associated with lower insulin sensitivity and diminished insulin secretion; duration of diabetes is also known to reflect the residual β-cell mass in T2DM patients. In our study, patients with BMI < 30 kg/m
2 are significantly older and have longer duration of diabetes. It may indicate that most of low BMI patients with T2DM would have “worse” diabetes. Also, our research has demonstrated that the patients in the BMI < 30 kg/m
2 group had a lower complete remission rate than the BMI > 30 kg/m
2 group. Nevertheless, previous studies have shown patients with older age and long diabetes duration were less likely to achieve T2DM remission after bariatric surgery [
42,
43]. Therefore, the lower remission rate in the BMI < 30 kg/m
2 group may be the result of multiple factors; if we exclude the influence of age and diabetes duration, the complete remission of the BMI < 30 kg/m
2 group may be much higher.
This study had several limitations. First, the case number was relatively small, although fulfilling the sample-size requirement, larger multicenter studies will be necessary in order to confirm our findings. Secondly, although the early operative outcome was satisfactory in terms of safety and glycemic control, long-term data to determine late complications and maintenance of diabetes remission are required. The follow-up period was not long enough to study the final outcome in the two groups of patients.