OBES SURG DOI 10.1007/s11695-014-1206-1
ORIGINAL CONTRIBUTIONS
Effects of Gastric Bypass on Type 2 Diabetes in Patients with BMI 30 to 35 Nicola Scopinaro & Giovanni F. Adami & Francesco S. Papadia & Giovanni Camerini & Flavia Carlini & Lucia Briatore & Gabriella Andraghetti & Mariafrancesca Catalano & Renzo Cordera
# Springer Science+Business Media New York 2014
Abstract Background This study aims to investigate if the benefits on glycemic control following Roux-en-Y gastric bypass (RYGB) in morbidly obese type 2 diabetes (T2DM) patients are maintained in the 30–35 kg/m2 BMI (body mass index) range, comparing results with those in literature. Methods The study participants were twenty T2DM patients aging 35–70 years, BMI 30.0–34.9 kg/m2, minimum diabetes duration 3 years, glycosylated haemoglobin (HbA1c) ≥7.5 % despite good clinical practice medical therapy, submitted to laparoscopic RYGB, and monitored during 36 months. Twenty-seven matched diabetic patients as controls. Results Five females, mean age 57 (42–69)years, weight 96.0 (70–111)kg, BMI 32.9 (30.3–34.9)kg/m2, waist circumference 112 (100–128)cm, diabetes duration 14 (3–28)years, HbA1c 9.5 (7.5–14.2)%, and C-peptide 3.2 (1,6–9.1)mcg/l. Ten patients were on insulin. There was no mortality, and there were two major late complications. BMI and waist decreased stabilizing around 25 kg/m2 and 92 cm. Fasting serum glucose and HbA1c reached values around 150 mg/dl and 7 %, which subsequently maintained. There was remission in 25 % of cases, control 45 %, and all the others improved. HOMA-IR and insulin sensitivity index normalized at 1 month, then ClinicalTrials.gov Identifier: NCT00996294 N. Scopinaro : G. F. Adami : F. S. Papadia : G. Camerini : F. Carlini : M. Catalano Department of Surgery, University of Genoa, School of Medicine, Genoa, Italy L. Briatore : G. Andraghetti : R. Cordera Department of Endocrinology, University of Genoa, School of Medicine, Genoa, Italy N. Scopinaro (*) DISC–Università di Genova, Azienda Ospedaliera Universitaria “San Martino”, Largo Rosanna Benzi, 8, 16132 Genoa, Italy e-mail: [email protected]
maintained. AIR and insulinogenic index showed no postoperative changes. Diabetes remission correlated negatively with duration (p7 % at 2– 3 years. Conclusions Glycemic control obtained by RYGB in this study was less good than that reported by others, apparently due to different patient selection criteria. Our results do not support RYGB weight loss-independent effect on beta-cell function in the T2DM patients with BMI 30–35 kg/m2. Keywords Bariatric surgery . Gastric bypass . Type 2 diabetes mellitus
Introduction The beneficial effect of bariatric surgery on glycemic control in type 2 diabetes patients has been known for a long time [1, 2]. This has proved to be maintained at long [2, 3] and very long term [4]. A meta-analysis on 135,000 morbidly obese subjects [5] demonstrated that the type 2 diabetes mellitus remission rate increases with increasing weight loss, with the minimum belonging to adjustable silicone gastric banding (ASGB) and the maximum being attained by biliopancreatic diversion (BPD). Though weight loss alone, by decreasing insulin resistance, certainly improves glucose homeostasis, “specific,” i.e., weight loss independent, mechanisms were hypothesized [6]. These mechanisms would be involved in Roux-en-Y gastric bypass (RYGB) and BPD with both the decrease in insulin resistance [7, 8] and the improvement of beta-cell function [9, 10] observed after the two bariatric procedures.
OBES SURG
The vast majority of type 2 diabetic patients are not morbidly obese, being included in the range of BMI from 25 to 35 kg/m2. If RYGB and BPD possess specific beneficial actions on type 2 diabetes mellitus, independent of weight loss, these actions should be maintained in the lower body mass index (BMI) ranges, where the weight loss effects, due to the lower starting weight, are expected to be largely inferior to those in the morbidly obese patients. As no prospective study on this population was available, in 2007 we started a clinical trial where 30 type 2 diabetes mellitus patients with BMI 25 to 35 kg/m2 were submitted to BPD and 20 with BMI 30 to 35 kg/m2 to RYGB. The results obtained in the BPD patients were already published, both considered altogether [11] and comparing the mildly obese with the simply overweight groups in a 2-year follow-up [12]. The results obtained in the 20 type 2 diabetes mellitus patients with a BMI from 30 to 35 kg/m2 submitted to RYGB are here reported with a complete 3-year follow-up.
Materials and Methods Patient Population Twenty subjects were enrolled in the study. Inclusion criteria were the following: type 2 diabetes as per American Diabetes Association (ADA) criteria [13], age between 35–70 years, BMI between 30.0–34.9 kg/m2, minimum diabetes duration 3 years, glycated hemoglobin (HbA1c) ≥7.5 % despite medical therapy according to good clinical practice (GCP), and full consent to participate in a clinical study. Exclusion criteria were the following: positivity for antiislet antibodies; C-peptide lower than 0.5 ng/ml; pregnancy; severe current inflammatory, neurologic, or cardiovascular illness; malignancy; contraindications to obesity surgery or specifically to RYGB; and any other condition that in the judgement of the investigators, could threaten patients’ safety or bias study results. Twenty-seven patients with type 2 diabetes were matched for gender, age, BMI, diabetes duration, and HbA1c to those undergoing surgery and served as control group were also prospectively studied. When high HbA1c values made it impossible to find a suitable match, the two patients with the highest available value were chosen. The study was approved by the institutional Ethics Committee and complies with the Helsinki declaration of 1975, as revised in 2000. All patients gave written informed consent. Surgical Procedure The operation consisted of creating a 15 to 30-ml vertical gastric pouch, using linear 45-mm surgical staplers. An antecolic Roux-en-Y reconstruction was then made, with a
100-cm biliopancreatic limb and a 250-cm alimentary limb. The gastroenterostomy was done manually according to the technique described by Higa [14], and the end-to-side enteroenterostomy was created using a 45-mm linear stapler, with manual closure of the joint defect. The pouch volume was measured using a condom tightened to the tip of a nasogastric tube and filled with saline against a pressure of 30 cm H2O. All intestinal measurements were taken on the bowel fully stretched, halfway between the mesenteric and the antimesenteric border. Peri and postoperative management was the standard one for RYGB at our institution. Follow-up Antidiabetic Medical Care Patients in the study were asked to measure, with the frequency deemed appropriate case by case, serum glucose level, with their own instant blood sugar measurement device (dextrostix), in fasting conditions, and before meal(s) and 2 h after meal(s). In order to minimize beta-cell glucotoxicity, excessively high serum glucose levels were corrected by single day injection of a long-acting insulin, as long as this proved to be necessary. Cutoff levels for insulin administration were 150 mg/dl in fasting conditions and/or 200 mg/dl 2 h after meal. Insulin was reduced or stopped when these targets could be met consistently over time. This policy proved to be highly effective in improving the 1 year remission rate in type 2 diabetes mellitus morbidly obese patients undergoing RYGB [15]. Drug administration in the control group was managed by the diabetologist on a case-by-case basis according to GCP. Follow-up Evaluations Preoperatively and 1, 4, 8, and 12 months following surgery, and then every 6th month until the 3rd year, all patients received complete physical examination and routine blood chemistry. At the same times, insulin resistance was evaluated by homeostatic model of assessment-insulin resistance (HOMA-IR). Insulin secretion was assessed by acute insulin response (AIR) to intravenous glucose load preoperatively and at 1, 12, 24, and 36 months (Fig. 1). Oral glucose tolerance test (OGTT) was performed preoperatively and 1 year after operation (Fig. 2) in 16 patients, with calculation of the insulinogenic index (IGI) and insulin sensitivity index (ISI). C-peptide serum concentration was also measured. Type 2 diabetes patients in the control group were also seen as frequently as deemed necessary by the diabetologist, with pre and postmeal glucose checks (dextrostix). Body weight (BW) was determined to the nearest 0.1 kg, and waist circumference (waist) was measured to the nearest centimeter. Waist was considered abnormally high when >102 cm in men and >88 cm in women. Hypertension was defined as a systolic blood pressure of ≥140 mmHg and/or
OBES SURG 20
µIU/Ml
15
10
mean AIR
n.s.
n.s.
n.s.
5
0 preop.
1 month
12 months
36 months
Fig. 1 AIR in 16 subjects preoperatively and 1 year after RYGB. Mean serum insulin values. AIR acute insulin response to intravenous glucose load, RYGB Roux-en-Y gastric bypass, Preop. preoperatively, n.s. not significant vs. preop
diastolic blood pressure of ≥90 mmHg, or chronically taking antihypertensive drugs. Hypertriglyceridemia was defined as a serum triglyceride concentration ≥150 mg/dl, hypercholesterolemia as a serum total cholesterol ≥200 mg/dl; high-density lipoprotein (HDL) cholesterol serum concentration was considered low when
ORIGINAL CONTRIBUTIONS
Effects of Gastric Bypass on Type 2 Diabetes in Patients with BMI 30 to 35 Nicola Scopinaro & Giovanni F. Adami & Francesco S. Papadia & Giovanni Camerini & Flavia Carlini & Lucia Briatore & Gabriella Andraghetti & Mariafrancesca Catalano & Renzo Cordera
# Springer Science+Business Media New York 2014
Abstract Background This study aims to investigate if the benefits on glycemic control following Roux-en-Y gastric bypass (RYGB) in morbidly obese type 2 diabetes (T2DM) patients are maintained in the 30–35 kg/m2 BMI (body mass index) range, comparing results with those in literature. Methods The study participants were twenty T2DM patients aging 35–70 years, BMI 30.0–34.9 kg/m2, minimum diabetes duration 3 years, glycosylated haemoglobin (HbA1c) ≥7.5 % despite good clinical practice medical therapy, submitted to laparoscopic RYGB, and monitored during 36 months. Twenty-seven matched diabetic patients as controls. Results Five females, mean age 57 (42–69)years, weight 96.0 (70–111)kg, BMI 32.9 (30.3–34.9)kg/m2, waist circumference 112 (100–128)cm, diabetes duration 14 (3–28)years, HbA1c 9.5 (7.5–14.2)%, and C-peptide 3.2 (1,6–9.1)mcg/l. Ten patients were on insulin. There was no mortality, and there were two major late complications. BMI and waist decreased stabilizing around 25 kg/m2 and 92 cm. Fasting serum glucose and HbA1c reached values around 150 mg/dl and 7 %, which subsequently maintained. There was remission in 25 % of cases, control 45 %, and all the others improved. HOMA-IR and insulin sensitivity index normalized at 1 month, then ClinicalTrials.gov Identifier: NCT00996294 N. Scopinaro : G. F. Adami : F. S. Papadia : G. Camerini : F. Carlini : M. Catalano Department of Surgery, University of Genoa, School of Medicine, Genoa, Italy L. Briatore : G. Andraghetti : R. Cordera Department of Endocrinology, University of Genoa, School of Medicine, Genoa, Italy N. Scopinaro (*) DISC–Università di Genova, Azienda Ospedaliera Universitaria “San Martino”, Largo Rosanna Benzi, 8, 16132 Genoa, Italy e-mail: [email protected]
maintained. AIR and insulinogenic index showed no postoperative changes. Diabetes remission correlated negatively with duration (p7 % at 2– 3 years. Conclusions Glycemic control obtained by RYGB in this study was less good than that reported by others, apparently due to different patient selection criteria. Our results do not support RYGB weight loss-independent effect on beta-cell function in the T2DM patients with BMI 30–35 kg/m2. Keywords Bariatric surgery . Gastric bypass . Type 2 diabetes mellitus
Introduction The beneficial effect of bariatric surgery on glycemic control in type 2 diabetes patients has been known for a long time [1, 2]. This has proved to be maintained at long [2, 3] and very long term [4]. A meta-analysis on 135,000 morbidly obese subjects [5] demonstrated that the type 2 diabetes mellitus remission rate increases with increasing weight loss, with the minimum belonging to adjustable silicone gastric banding (ASGB) and the maximum being attained by biliopancreatic diversion (BPD). Though weight loss alone, by decreasing insulin resistance, certainly improves glucose homeostasis, “specific,” i.e., weight loss independent, mechanisms were hypothesized [6]. These mechanisms would be involved in Roux-en-Y gastric bypass (RYGB) and BPD with both the decrease in insulin resistance [7, 8] and the improvement of beta-cell function [9, 10] observed after the two bariatric procedures.
OBES SURG
The vast majority of type 2 diabetic patients are not morbidly obese, being included in the range of BMI from 25 to 35 kg/m2. If RYGB and BPD possess specific beneficial actions on type 2 diabetes mellitus, independent of weight loss, these actions should be maintained in the lower body mass index (BMI) ranges, where the weight loss effects, due to the lower starting weight, are expected to be largely inferior to those in the morbidly obese patients. As no prospective study on this population was available, in 2007 we started a clinical trial where 30 type 2 diabetes mellitus patients with BMI 25 to 35 kg/m2 were submitted to BPD and 20 with BMI 30 to 35 kg/m2 to RYGB. The results obtained in the BPD patients were already published, both considered altogether [11] and comparing the mildly obese with the simply overweight groups in a 2-year follow-up [12]. The results obtained in the 20 type 2 diabetes mellitus patients with a BMI from 30 to 35 kg/m2 submitted to RYGB are here reported with a complete 3-year follow-up.
Materials and Methods Patient Population Twenty subjects were enrolled in the study. Inclusion criteria were the following: type 2 diabetes as per American Diabetes Association (ADA) criteria [13], age between 35–70 years, BMI between 30.0–34.9 kg/m2, minimum diabetes duration 3 years, glycated hemoglobin (HbA1c) ≥7.5 % despite medical therapy according to good clinical practice (GCP), and full consent to participate in a clinical study. Exclusion criteria were the following: positivity for antiislet antibodies; C-peptide lower than 0.5 ng/ml; pregnancy; severe current inflammatory, neurologic, or cardiovascular illness; malignancy; contraindications to obesity surgery or specifically to RYGB; and any other condition that in the judgement of the investigators, could threaten patients’ safety or bias study results. Twenty-seven patients with type 2 diabetes were matched for gender, age, BMI, diabetes duration, and HbA1c to those undergoing surgery and served as control group were also prospectively studied. When high HbA1c values made it impossible to find a suitable match, the two patients with the highest available value were chosen. The study was approved by the institutional Ethics Committee and complies with the Helsinki declaration of 1975, as revised in 2000. All patients gave written informed consent. Surgical Procedure The operation consisted of creating a 15 to 30-ml vertical gastric pouch, using linear 45-mm surgical staplers. An antecolic Roux-en-Y reconstruction was then made, with a
100-cm biliopancreatic limb and a 250-cm alimentary limb. The gastroenterostomy was done manually according to the technique described by Higa [14], and the end-to-side enteroenterostomy was created using a 45-mm linear stapler, with manual closure of the joint defect. The pouch volume was measured using a condom tightened to the tip of a nasogastric tube and filled with saline against a pressure of 30 cm H2O. All intestinal measurements were taken on the bowel fully stretched, halfway between the mesenteric and the antimesenteric border. Peri and postoperative management was the standard one for RYGB at our institution. Follow-up Antidiabetic Medical Care Patients in the study were asked to measure, with the frequency deemed appropriate case by case, serum glucose level, with their own instant blood sugar measurement device (dextrostix), in fasting conditions, and before meal(s) and 2 h after meal(s). In order to minimize beta-cell glucotoxicity, excessively high serum glucose levels were corrected by single day injection of a long-acting insulin, as long as this proved to be necessary. Cutoff levels for insulin administration were 150 mg/dl in fasting conditions and/or 200 mg/dl 2 h after meal. Insulin was reduced or stopped when these targets could be met consistently over time. This policy proved to be highly effective in improving the 1 year remission rate in type 2 diabetes mellitus morbidly obese patients undergoing RYGB [15]. Drug administration in the control group was managed by the diabetologist on a case-by-case basis according to GCP. Follow-up Evaluations Preoperatively and 1, 4, 8, and 12 months following surgery, and then every 6th month until the 3rd year, all patients received complete physical examination and routine blood chemistry. At the same times, insulin resistance was evaluated by homeostatic model of assessment-insulin resistance (HOMA-IR). Insulin secretion was assessed by acute insulin response (AIR) to intravenous glucose load preoperatively and at 1, 12, 24, and 36 months (Fig. 1). Oral glucose tolerance test (OGTT) was performed preoperatively and 1 year after operation (Fig. 2) in 16 patients, with calculation of the insulinogenic index (IGI) and insulin sensitivity index (ISI). C-peptide serum concentration was also measured. Type 2 diabetes patients in the control group were also seen as frequently as deemed necessary by the diabetologist, with pre and postmeal glucose checks (dextrostix). Body weight (BW) was determined to the nearest 0.1 kg, and waist circumference (waist) was measured to the nearest centimeter. Waist was considered abnormally high when >102 cm in men and >88 cm in women. Hypertension was defined as a systolic blood pressure of ≥140 mmHg and/or
OBES SURG 20
µIU/Ml
15
10
mean AIR
n.s.
n.s.
n.s.
5
0 preop.
1 month
12 months
36 months
Fig. 1 AIR in 16 subjects preoperatively and 1 year after RYGB. Mean serum insulin values. AIR acute insulin response to intravenous glucose load, RYGB Roux-en-Y gastric bypass, Preop. preoperatively, n.s. not significant vs. preop
diastolic blood pressure of ≥90 mmHg, or chronically taking antihypertensive drugs. Hypertriglyceridemia was defined as a serum triglyceride concentration ≥150 mg/dl, hypercholesterolemia as a serum total cholesterol ≥200 mg/dl; high-density lipoprotein (HDL) cholesterol serum concentration was considered low when
