ABSTRACT
We report case details of a morbidly obese patient with type 2 diabetes mellitus (T2DM) who became a failure of diabetes remission after laparoscopic sleeve gastrectomy (LSG). He had a marked improvement of hyperglycemia after the revision surgery using Roux‐en‐Y gastric bypass (RYGB), where passage failure of a solid food intake at the gastric angle portion disappeared after the revision surgery. Interestingly, he showed improvements of insulin and a marked glicentin secretions with minor changes in glucagon related peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) secretions in the oral glucose tolerance test OGTT after the RYGB surgery compared with post‐LSG. Although a marked increase in glucose‐induced glicentin secretion after RYGB surgery with increased insulin secretion, further studies are needed to confirm if the increased glicentin secretion after RYGB surgery is linked to stimulation of insulin secretion.
Keywords: glicentin, glycemic control, insulin secretion, metabolic surgery
Glucose‐induced hypersecretion of glicentin was found in patients undergone RY‐GB surgery. Glicentin stimulated glucose‐induced insulin secretion. Glicentin hypersecretion is related to diabetes remission after RY‐GB surgery.
INTRODUCTION
Roux‐en‐Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) are currently the most widely used effective procedures that achieve satisfactory weight loss and the remission of type 2 diabetes mellitus (T2DM) 1 , 2 . In our hospital's obesity surgery department, 150 morbidly obese patients with or without diabetes have undergone metabolic surgery by the LSG procedure, since 2011. In sleeve gastrectomy, the stomach is resected longitudinally and sutured into a narrow tubular shape. Thus, some patients result in the passage failure of solid food at the gastric angle portion without any anatomical obstruction. We have undergone a revision surgery in those cases using RYGB. Only one in those patients has received the revision surgery due to a failure of diabetes remission after the LSG. This case report demonstrated why this patient achieved a marked improvement in glycemic control after RYGB compared to LSG by assessing the changes in stimulation of insulin secretion, insulin sensitivity, and glucagon suppression, in relation to gut hormone secretion during the oral glucose tolerance test (OGTT) in the post‐RYGB patients.
CASE REPORT
A 65‐year‐old Japanese male patient was firstly diagnosed with type 2 diabetes mellitus at a medical checkup in 2011. Intensive insulin treatment was initiated for glycemic control in 2014, and his body weight (BW) finally increased to 115 kg. He visited our obesity outpatient clinic to achieve an appropriate BW reduction through bariatric surgery. At the first visit, he had hypertension, dyslipidemia, and fatty liver with a 45 kg/m2 body mass index (BMI). His HbA1c levels were at around 10% under the treatment with a daily long‐acting insulin (20 units) and ultrarapid insulin (36 units) as well as daily doses of pioglitazone 30 mg, linagliptin 5 mg, and metformin 500 mg. His diabetic complications included stage 2 nephropathy and mild neuropathy, but without retinopathy or macrovascular complications. The total ABCD score in this patient was 5 points resulting from 3 points in BMI 45 kg/m2, 2 points in serum C‐peptide reactivity 4.4 ng/mL, 0 point in age 65 years old, and 0 point in 13 years of diabetes duration. Thus, the indication for metabolic surgery was well met 3 . A 1‐year after the LSG, his BW had fallen to 78.7 kg (Table 1), but the HbA1c levels did not improve because of impaired insulin sensitivity (Matsuda index 2.2, HOMA‐R 5.2) compared to the previously reported our patient's data (Matsuda index 5.6, HOMA‐R 1.1) 4 (Table 2). To control their glucose levels prior to RYGB surgery, the patients required daily injections of 22 units of insulin and 0.9 mg liraglutide with high mean HbA1c levels (9.6%) during post‐LSG (Figure 1). He frequently complained nausea and vomiting as symptoms of post‐operative functional gastric angle stenosis and gastro‐esophageal reflux after eating solid food.
Table 1.
Changes in the patient's body weight and laboratory data at the initial visit and after laparoscopic sleeve gastrectomy and then the following revision surgery using Roux‐en‐Y gastric bypass
| First visit | Post‐LSG | Post‐RYGB | |
|---|---|---|---|
| Body weight, kg | 114.1 | 78.7 | 73.9 |
| HbA1c, % | 10.5 | 11.4 | 7.3 |
| U‐CPR excretion, μg/day | 69 | 56 | 70 |
| AST, U/L | 38 | 23 | 21 |
| ALT, U/L | 46 | 31 | 26 |
| TG, mg/dL | 312 | 177 | 124 |
| LDL‐C, mg/dL | 62 | 97 | 43 |
| HDL‐C, mg/dL | 47 | 63 | 60 |
| Uric acid, mg/dL | 7.0 | 5.9 | 4.9 |
| ACR, mg/g creatinine | 15.0 | 15.5 | 4.0 |
| eGFR, mL/min/1.73 m2 | 58.7 | 70.2 | 73.7 |
ACR, albumin creatinine ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase; eGFR, estimated glomerular filtration rate; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; LSG, laparoscopic sleeve gastrectomy; RYGB, Roux‐en‐Y gastric bypass; TG, triglycerides; U‐CPR, urinary C‐peptide reactivity.
Table 2.
Changes in the plasma glucose, insulin, glucagon, insulin sensitivity, and insulin secretory parameters during the 75‐g oral glucose tolerance test (OGTT) after 6‐month post‐laparoscopic sleeve gastrectomy (LSG), and 6‐ month post‐Roux‐en‐Y gastric bypass (RYGB) surgeries in a markedly obese patient with type 2 diabetes mellitus
| OGTT time (min) | 6‐month Post‐LSG | 6‐month Post‐RYGB | |
|---|---|---|---|
| Plasma glucose, mg/dL | 0 | 162 | 143 |
| 30 | 350 | 336 | |
| 60 | 346 | 342 | |
| 120 | 235 | 128 | |
| IRI, μU/mL | 0 | 12.9 | 4.7 |
| 30 | 43.9 | 58.5 | |
| 60 | 37.1 | 121.1 | |
| 120 | 22.3 | 11.1 | |
| Glucagon, pM | 0 | 5.55 | 5.09 |
| 30 | 6.43 | 5.21 | |
| 60 | 5.10 | 3.09 | |
| 120 | 5.63 | 4.85 | |
| HbA1c, % | 7.9 | 7.3 | |
| ΔINS0–30/ΔPG0‐30 † | 0.165 | 0.273 | |
| INS‐AUC/PG‐AUC ‡ | 10.7 | 24.2 | |
| HOMA‐R § | 5.2 | 1.7 | |
| Matsuda index ¶ | 2.2 | 3.0 | |
| Disposition index †† | 23.8 | 72.4 |
A 75 g‐OGTT was examined in a morbidly obese patient with type 2 diabetes mellitus at 6‐month post‐LSG and RYGB, respectively. INS, immunoreactive insulin; LSG, laparoscopic sleeve gastrectomy; OGTT, oral glucose tolerance test; PG, plasma glucose; RYGB, Roux‐en‐Y gastric bypass.
Insulinogenic index = ΔINS0–30/ΔPG0–30.
INS‐AUC0–120/PG‐AUC0–120 as an index of glucose‐dependent insulin secretion during OGTT.
HOMA‐R: Homeostatic model assessment for insulin resistance at the fasting state.
Matsuda index: an index of insulin sensitivity calculated from OGTT data.
Disposition index = [Matsuda index] × [INS‐AUC0–120/PG‐AUC0–120]: β‐cell function dependent glucose disposal capacity.
Figure 1.
Clinical course of the patient's body weight and HbA1c levels before and after his laparoscopic sleeve gastrectomy (LSG) and then after the revision surgery using Roux‐en‐Y gastric bypass (RYGB). The lower part shows glucose‐lowering treatment medications. Changes in insulin secretion and insulin sensitivity parameters measured by oral glucose tolerance test (OGTT) after LSG and RYGB surgeries are shown in this figure. BW, body weight; DPP4i, dipeptidyl peptidase 4 inhibitor; Liraglutide, GLP‐1 receptor agonist; LSG, laparoscopic sleeve gastrectomy; RYGB, Roux‐en‐Y gastric bypass.
We advised the patient to undergo revisional surgery using a RYGB procedure. In this surgery, we used a modified method from the conventional RYGB surgery. After cutting the jejunum at 150 cm from the Treitz ligament, the distal jejunal portion was anastomosed with the upper part of sleeved stomach to form a 100 cm alimentary limb, and the jejunum on the duodenal side was anastomosed with the jejunum (jejuno‐jejunal anastomosis) to form a 150 cm biliopancreatic limb. The distal part of remaining sleeved stomach was then resected. This is because of a concern about the higher risk of gastric cancer development from the remaining stomach in Asian countries compared to Western countries, where the residual stomach is kept as a blind end in the conventional RYGB surgery 5 (Figure 2). After the RYGB, the patient's nausea and vomiting upon food ingestion disappeared. His BW fell further from 78.7 to 74 kg and his HbA1c improved to 7.3% with oral glucose‐lowering drugs (Table 1, Figure 1). At 6‐month after the RYGB surgery, the OGTT showed the increased peak insulin level at 60 min and a decrease in glucagon levels measured by sandwich ELISA (Cide No. 27797, IBL: Immune‐Biological Laboratory, Fujioka, Japan) during OGTT as compared to those of post‐LSG. As a result, the plasma glucose levels at 120 min after the glucose loading were markedly improved (Table 2).
Figure 2.
A schematic illustration of the new RYGB surgery undergone in this patient.
Figure 3 depicts the secretory kinetics of GLP‐1, GIP, and glicentin during 75 g OGTT. These gut hormones were measured by ELISA kits using GLP‐1 (Code No. 27788, IBL), GIP (Code No. 27203, IBL), and glicentin (Code No. 10‐1273‐01, Mercodia, Uppsala, Sweden). The kinetics of both GLP‐1 and GIP showed only a small difference between the two metabolic surgeries; However, there was a marked hypersecretion of glicentin for 120 min after the OGTT in post‐RYGB data compared to the preceding post‐LSG data. The manufacturer tested the specificity of the assay kit and did not detect any cross reactivity with glucagon, GLP‐1, GLP‐2, or oxyntomodulin, respectively.
Figure 3.
Plasma GLP‐1, GIP, and glicentin levels during the 75‐g oral glucose tolerance test (OGTT) 6‐month after laparoscopic sleeve gastrectomy (LSG) and Roux‐en‐Y gastric bypass (RYGB) surgeries in a 65‐year‐old morbidly obese male patient with type 2 diabetes. Red solid line: glicentin (post‐RYGB). Red dotted line: glicentin (post‐LSG). Green solid line: GIP (post‐RYGB). Green dotted line: GIP (post‐LSG). Blue solid line: GLP‐1 (post‐RYGB). Blue dotted line: GLP‐1 (post‐LSG). These gut hormone levels were measured by using the following ELISA kits: GLP‐1 (IBL), GIP (IBL), and glicentin (Mercodia).
DISCUSSION
These results indicated that the increased insulin and suppression of glucagon secretions after RYGB surgery were related to a marked postprandial hypersecretion of glicentin. Previously, there are two Japanese preclinical reports in which administration of either glicentin 1–16 or glicentin 62–69 in canine pancreas resulted in an increase in plasma insulin and a reduction of glucagon levels 6 , 7 . Furthermore, it has been reported that the postprandial glicentin and oxyntomodulin levels are enhanced after RYGB and sleeve gastrectomy 8 . They indicate that the marked increase in both hormones after RYGB can predict a better weight loss due to a decreased preference for energy‐dense foods. In the present study, we found increased insulin secretion at 30 and 60 min after OGTT, which was associated with a marked reduction of plasma glucose levels at 120 min after the initiation of OGTT. In another report, the fasting glicentin levels of the patients who have undergone the RYGB procedure reflect a possible risk for postprandial hypoglycemia at 120 min during a meal tolerance test 9 . After the RYGB surgery, a significant reduction in fasting glucagon levels has been reported 10 . In the present study, we found that the plasma glucagon levels during OGTT after the RYGB were lower than that those of the post‐LSG.
In conclusion, we reported a morbidly obese type 2 diabetes mellitus patient showed poor glycemic control after the LSG surgery. When the patient underwent RYGB as a revision surgery, glycemic control markedly improved due to improved fasting insulin sensitivity with less improvement of insulin sensitivity during the postprandial state, the enhanced postprandial insulin secretion, and reduction of glucagon levels during OGTT. The improved glycemic control associated with a marked increase in glicentin secretion after the RYGB surgery might be an interesting topic in the future study.
DISCLOSURE
The authors declare no conflict of interest in this study.
Approval of the research protocol: The case study is a part of clinical studies on the differences in postprandial glucose and triglyceride excursions in severely obese patients between before and after LSG shown in Ref. 4. The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of Kusatsu General Hospital (protocol no. 2017‐0317‐05, date of registry: 24 March, 2017). Note that the name of Kusatsu General Hospital was changed to Omi Medical Center on October 1, 2021.
Informed consent: Written informed consent to participate in the study and to publish the paper has been obtained.
Registry and the registration no. of the study: This study was not related to an intervention study. Therefore, we did not apply the registration of the protocol.
Animal study: N/A.
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