Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : August 15, 2016
Accepted : October 1, 2016
Published online : December 31, 2016

Original Article

Early metabolic response after laparoscopic sleeve gastrectomy
in obese diabetes.

Shingo Iwata 1), Akeo Hagiwara 2), Hitoshi Kato 1)
1) Department of Surgery, Takeda General Hospital, Kyoto, Japan
2) Graduate School of Life and Medical Science, Doshisha University, Kyoto, Japan

Abstract

Objective: Authors investigated whether laparoscopic sleeve gastrectomy (LSG), one of the bariatric surgeries, in obese type2 diabetes patients would show a metabolic improving effect at an early stage after surgery.
Method: LSG was conducted for five morbidly obese subjects whose BMI was more than 35 and were diagnosed with type2 diabetes. The glycemic markers, lipids and hepatic functions were checked before, one, two and three months after surgery.
Results: Hemoglobin Alc level remarkably decreased from 8.7% to 5.9% (p < 0.001) one month after surgery, compared with
before surgery, and the effect was kept at a level of lower than 6.0%, such as 5.8% and 5.6%, two months and three months
after surgery. The average of fasting plasma glucose level significantly decreased to 87 mg/dL, 94 mg/dL and 89 mg/dL from
184 mg/dL (p < 0.001), and it was kept under 100 mg/dL. BMI continued to decrease from 39.9 kg/m2 to 32.3 kg/m2, 30.0 kg/
m2 and 28.8 kg/m2 on average, every month. The decrease rates of BMI and HbAlc after surgery did not correlated with eachother. No improvement effect was recognized in total cholesterol level after surgery. Triglyceride significantly decreased fromone month after surgery (p < 0.001). Aspartate transaminase and alanine transaminase levels significantly decreased fromtwo months after surgery (p < 0.05, p < 0.01).
Conclusion: As a result, it was suggested that disregarding weight decrease, LSG has a remarkable antidiabetic effect froman early stage of one month after surgery. During the observation period, LSG showed that it has the effect of improving
triglyceride and hepatic function, and its effect on cholesterol is small.

KEY WORDS: obesity, type 2 diabetes, metabolic surgery, laparoscopic sleeve gastrectomy and bariatric surgery

Introduction

It was clarified that bariatric surgery has not only theeffect of weight loss but also improvement of metabolism,
and the number of surgery cases is increasing worldwide 1).
However, it has not been generalized in Japan yet, and there
have been only a few reports 2). Since April 2014, laparoscopic
sleeve gastrectomy (LSG) has become applicable to healthinsurance in Japan. However, the facility standard for its
purpose is very strict so that it cannot rapidly spread. Bypass
surgeries, including Roux-en-Y gastric bypass (RGYB), havebeen recognized as effective in metabolic improvement 3-5).
LSG started in full swing this century, and the number ofsurgery cases is increasing 6-7); however, many questions
remain unsolved. Diabetes is a common disease with strong
glycative stress. As the Japanese have a national trait whichmakes it likely for them to develop diabetes for their degreeof obesity, Western data may be unable to be directly applied
to them. Because LSG’s effects that occur in an early stage

in obese Japanese people with diabetes, in particular, were
not clarified in many respects, the authors conducted theresearch on the antidiabetic effects of LSG for obese andtype 2 patients in an early stage after surgery.

Methods

Five cases of morbidly obese patients diagnosed withdiabetes, out of 13 cases of LSG conducted by the same
surgeon from August 2014 to July 2016 in Takeda General
Hospital, were subjected to this research. The profiles of eachcase are shown in Table 1. The number of male subjects
was one and that of the females was four; their average age
was 39.6 ± 0.8 years, the averages of body weight and bodymass index (BMI) were 107.4 ± 7.0 kg and 39.9 ± 0.8 kg/
m 2, respectively. Each case was treated by medical therapy,

Corresponding author: Shingo Iwata MD, PhD.
Department of Surgery, Takeda General Hospital
28-1 Ishida Minamimori Hushimi-ku Kyoto 601-1495, Japan
TEL: +81-75-572-6331, Fax: +81-75-571-8877, e-mail: s-iwata@takedahp.or.jp
Co-authors: Hagiwara A, ahagiwar@mail.doshisha.ac.jp ; Kato H, hitokatoyu@yahoo.co.jp_ 18 6 _Glycative Stress Research 2016; 3 (4): 186- 192(c) Society for Glycative Stress ResearchGlycative Stress Research

Table 1. Characteristics of the patients at baseline.
Characteristics

Case 1Case 2

Case 3

Case 4

Case 5Age (year)

41

39

41

40

37

GenderFemaleFemaleFemale

108

107

97

−

−

−

33 units

receptor

TZD

SGLT-2

DPP-4

DPP-4

Waist circumstance (cm)

112

113

117

118

111

History of dyslipidemia

+

+

+

+

+

−

−

BMI

Body weight (kg)

Duration of diabetes (year)
Use of insulin

Diabetes medications

SmokerHistory of hypertension

Male
40

42

3

10

130

GLP-1

agonistformer

41

5

SU

never

11

Biguanideinhibitor
former+37

SUinhibitor
never+

Female
40

95

6

−

Biguanideinhibitor
never+

The body mass index (BMI) is the weight in kilograms (kg) divided by the square of the height in meters (m).
GLP-1, glucagon-like peptide-1; SU, sulfonylurea; TZD, thiazolidine; SGLT-2, sodium-dependent glucose transporter 2; DPP-4, dipeptidyl peptidase-4.

such as multidrug therapy or multiple insulin therapy, basedon dietary therapy and exercise therapy. However, due totreatment resistance and repeatedly rebounded weight loss
treatment, surgical therapies were applied. Case 2 and Case
4 had long diabetic histories of more than 10 years. Case 2
started to be treated with α-glucosidase inhibitor; however,
because blood glucose control was not good, the treatment
was replaced with a therapy combining sulfonylurea andthiazolidine. However, due to the developments of edema andliver damage, it was changed to a therapy only with sulfonlurea.
Case 4 was treated with Noborabit, 15 units, and Nobrinn, 18
units, in addition to multidrug therapy; however the patient’s
HbAlc level was very high at 11.3, and the patient sufferedperipheral nerve disorder, retinopathy of diabetes and diabetic
nephropathy. The conditions that can be adapted to bariatricsurgery in Japan is that despite undergoing medical therapy
for more than six months, enough weight loss cannot be
obtained, BMI is more than 35 and one or more complications
associated with diabetes, hypertension and hyperlipidemia
develop. All patients met these conditions.
Every month for three months after and before surgery,
Hemoglobin Alc (HbA1c) [NGSP] and fasting plasma glucose(FPG) as BMI and glucose metabolic maker; total cholesterol(TC), high-density lipoprotein cholesterol (HDL), low-density
lipoprotein cholesterol (LDL) and triglyceride (TG) as lipid
indicators; and aspartate transaminase (AST), alaninetransaminase (ALT) and gamma glutamyl transpeptidase(γ - GPT) as evaluation of liver function.

Surgical technique

LGS is a surgery method to remove the side of the greater
curvature of the stomach and create a banana-shaped stomach( Fig. 1 ). All surgeries are conducted by the laparoscopic fiveport approach in the position with the head up (in Fowler’s
position) in order to reduce the burden on the lungs. Separate
the greater omentum along the stomach wall in the cranial_ 18 7 _A	

B	

Fig. 1. Laparoscopic sleeve gastrectomy.

A: new stomach pouch. B: stomach removed

Bariatric Surgery in Obese Diabetes
direction, using an ultrasonic coagulation incision device.
Separate the greater omentum up to the His angle at a
proximal part of the stomach and up to about 4 cm fromthe oral side from the pyloric ring at a distal part. Ask agastroenterologist to insert an endoscope up to the pyloric
region, and fixate it at the side of the lesser curvature. The
endoscope can be followed as a guide to cutting off thestomach using an autosuture. Reinforce the staple line bycontinuous suture using 3- 0 absorbing thread. Confirm thepresence or absence of constriction and bleeding and thatthe stapler does not become lodged in the esophagus. Retain
the drain along the cutting line of the stomach.

Ethical consideration

Written informed consent was obtained from each subject
before the start of this study, which was approved by the
Ethics Committee of our hospital and also was in accordancewith the Helsinki Declaration of 1975, as revised in 1983.

Statistical analysis

All results are expressed as means ± standard error of
the mean. Statistical analysis was made with analysis ofvariance, and Pearson correlation coefficients were calculated.
Statistical significance was obtained when the p value was <0.05.

Results

LSG could be performed completely endoscopically inall five cases. The average surgical time was 210 ± 20 minutes.
The amount of bleeding was too small to measure. Fluid dietstarted on the second day after surgery. The average hospital
stay was 10 ± 1 days. The progress after surgery was goodand no complications were recognized. All oral medicines,
including diabetes drugs and injection drugs, including
insulin, could be stopped in all cases.
In Figures 2, 3 and 4, the changes in BMI, HbAlc andFPG one, two and three months after surgery are shown.
BMI significantly changed from 39.5 ± 0.9 kg/m 2 before
surgery to 32.3 ± 1.4 kg/m 2 one month after surgery (p <0.001), and continued to decrease to 30.0 ± 0.9 kg/m 2 twomonths after surgery and to 28.8 ± 0.9 kg/m 2 three months
after surgery. It furthermore significantly decreased threemonths after surgery compared to one month after surgery (p< 0.05).
HbAlc significantly decreased one month after surgery
from 8.7 ± 0.9% before surgery (p < 0.001), and remarkably
improved to 5.9 ± 0.3%. It was 5.8 ± 0.3% two months after
surgery and 5.6 ± 0.4% three months after surgery, whichshowed that an improvement effect of less than 6 % wasmaintained. FPG significantly decreased from 184 ± 19.8
mg/dL before surgery (p < 0.001), and remarkably improved
to 87 ± 7.6 mg/dL. It was 94 ± 1.9 mg/dL two months after
surgery and 89 ± 5.5 mg/dL three months after surgery,which showed that it was kept at less than 100 mg/dL after
surgery.
As shown in Table 2, there was no correlation between
the decreased rate of BMI and that of HbAlc. A correlation
between the decreased rate of BMI and that of FPG wasobserved one month after surgery, but not observed between
others.
As shown in Table 3, there was no correlation between
the decreased rate of HbAlc and that of FPG.
Table 4 shows the changes in lipids and hepatic function
before and after LSG surgery. Regarding lipids, there wereno large changes in TC and LDL, rather, they worsened.
Improvement effects were recognized in HDL two to threemonths after surgery from one month after surgery (p < 0.05,
p < 0.01). TG significantly decreased starting one monthafter surgery ( p < 0.001) and it was kept at low levels until
three months after surgery. Regarding hepatic function,
both AST and ALT decreased from the second month after
surgery and improvement effects were recognized. γ - GTP
showed a trend toward improvement; however, no significant
difference was observed.

Discussion

It was clarified in this research that LSG has remarkable
improvement effects on obese and diabetic patients during theearly stage one month after surgery. In addition, it makes it
possible to stop the use of diabetic drugs; its benefit is greatfrom the viewpoints of medical economics 8). According to theAmerican Diabetes Association (ADA), the definition ofcomplete remission of diabetes is that HbAlc is less than 5.7%
and FPG is less than 100 mg/dL. That of improvement ofdiabetes is that HbAlc is 5.7% - 6.5% and this condition canbe maintained at least a year without treatment drugs 9).
According to this definition, the cases in this research achieved
improvement and remission one month after surgery, and theprocesses after surgery of these cases are to be observed one
year from now. HbAlc reflects the blood glucose level one totwo months before, which shows improvement effects thatcannot be explained by dietary limitations only. Because theJapanese show metabolic improvement effects with several
kilograms of weight loss, HbAlc may have improved earlier
compared to the speed of weight loss.
In the case of bariatric bypass surgeries including BYGB,
regarding diabetes improvement effects after surgery, thechanges of incretin were paid attention to and the foregut
theory 10) and hindgut theory 11) are proposed 12). However,through what mechanism does LSG show its antidiabetic
effects? The characteristics of sleeve surgery are comparatively
simple and clear, and compared with bariatric bypass surgery,it has only a few complications after surgery. Its weight loss
effect can be expected enough that it is said to be better suitedfor cases that are more likely to be complicated with thedisorders associated with obesity despite a low degree ofobesity, like that of the Japanese.
Generally it is understood that creating a banana-shaped
stomach is aimed at restricting the intake of food and losing
some weight, but it is said that an appetite stimulating hormone
called ghrelin secrets in a large amount at the stomach fundus,
so appetite can be reduced if it is removed. Ghrelin is also thehormone restricting the secretion of insulin, which suggests
ghrelin’s involvement in the mechanism of the amelioration ofdiabetes 13). Recently, attention was paid to the fact blood bile
acid increases after LSG surgery and in research conductedby Seeley et al., it was found that, in the experiment, using
SG mice, the activities of farnesoid X receptor (FXR) wereenhanced and large changes in metabolism, such as glucose
tolerance, occurred. A mechanism that brings about changes_ 18 8 _Glycative Stress Research

Body Mass Index (kg/m2)

45.0

40.0

35.0

a
a

a, b

30.0

25.0
Baseline

1

2

3

Month

Fig. 2. Changes in body mass index.

Values are given as mean and SEM; a, significantly different from the preoperative value, p < 0.001;
b, significantly different from value of first postoperative month. p < 0.05. SEM, standard error mean.

10.0

Glycated Hemoglobin (%)

9.0

8.0

7.0

a

6.0

a

a

5.0

4.0
Baseline

1

2

3

Month

Fig. 3. Changes in glycated hemoglobin.

Values are given as mean and SEM; a, significantly different from the preoperative value, p < 0.001.
SEM, standard error mean.

_ 18 9 _Bariatric Surgery in Obese Diabetes

220

Fasting Plasma Glucose (mg/dL)

200
180
160
140
120
100

a

a

a

80
60
Baseline

1

2

3

Month

Fig. 4. Changes in fasting plasma glucose.

Values are given as mean and SEM; a, significantly different from the preoperative value, p < 0.001. SEM,
standard error mean.

Table 2. Correlation of glycemic maker reduction with BMI reduction% BMI reduction--- 1 month % BMI reduction--- 2 month% BMI reduction--- 3 monthR2

p valueR2

p valueR2

p value% Hemogloblin A1c reduction

0.015

0.843

0.004

0.922

0.011

0.867

% FPG reduction

0.861

0.023

0.018

0.837

0.003

0.931

BMI, body mass index; FPG, fasting plasma glucose.

Table 3. Correlation of HbA1c reduction with fasting glucose reduction% HbA1c reduction --- 1 month % HbA1c reduction --- 2 month % HbA1c reduction--- 3 month% FPG reduction

R2

p valueR2

p valueR2

p value

0.713

0.072

0.745

0.060

0.162

0.502

HbA1c, glycated Hemoglobin; FPG, fasting plasma glucose.

_ 19 0 _Glycative Stress Research

Table 4. Changes in lipids and hepatic function following laparoscopic sleeve gastrectomy

Unit

Baseline

1 monthpost operation

2 monthpost operation

3 monthpost operation

TC

mg/dL

211.6 ± 14.1

184.0 ± 6.5

225.8 ± 23.6

222.6 ± 21.9

HDL

mg/dL

52.2 ± 6.9

40.4 ± 4.6

a63.0 ± 7.6 b

LDL

mg/dL

130.2 ± 20.3

129.6 ± 3.2

160.5 ± 21.4

147.6 ± 20.2

TG

mg/dL

196.0 ± 15.2

94.4 ± 9.0

c89.8 ± 19.1 c

AST

U/L

36.2 ± 5.1

29.6 ± 4,222.0 ± 1.1 d

18.4 ± 2.6 d

ALT

U/L

52.4 ± 6.9

40.4 ± 10.8

23.0 ± 2.4 e, f

17.2 ± 2.2 e, f

γ-GTP

U/L

35.6 ± 11.0

24.4 ± 6.0

16.0 ± 1.7

14.8 ± 0.5

Parameter
LipidsHepatic function

59.4 ± 8.8
c87.8 ± 8.8

Values are given as mean ± SEM; a, significantly different from value of first postoperative month, p < 0.05; b, significantly different from value of first
postoperative month, p < 0.01; c, significantly different from the preoperative value, p < 0.001; d, significantly different from the preoperative value, p < 0.05;
e, significantly different from the preoperative value, p < 0.01; f, significantly different from value of first postoperative month, p < 0.05; g, significantly
different from the preoperative value, p < 0.001.
SEM, standard error mean; TC, total cholesterol; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; TG, triglyceride; AST,
aspartate transaminase; ALT, alanine transaminase; γ-GTP, gamma-glutamyl transpeptidase.

in bacteria in intestines was presented 14). In this research, theexperiment used genetically modified FXR knockout miceand showed that the increase of bile acid was more essential
than diet restriction effects because FXR knockout micefollowing SG did not show weight loss effects. It is reported
that similarly to the case of bypass surgeries, the increaseof incretins, such as glucagon-like peptide (GLP-1), wereobserved even after LSG 15).
Bile acid is shown to accelerate the secretion of GLP-1
through G-protein coupled receptor TGR5 so that the increased
secretion of bile acid increases the secretion of GLP-1 andmay be involved in the improvement of glucose tolerance 16, 17).
It has been discovered that bile acid works as an important
adjusting factor for lipid, glucose and overall energy
metabolisms. However, there are many unclear points regarding
the mechanisms of antidiabetic effects of LSG at this time.
It seems that various factors including gastrointestinal
hormone, bacteria in intestines, bile acid, fat cells, fat
metabolism, the nerve system, the endocrine system andinflammation are involved in it. It has been clarified thatbypass surgeries and LSG are effective in the amelioration
and remission of diabetes. The clarification of themechanisms of antidiabetic effects by bariatric surgery will
possibly lead not only to a measure to decide the adaptationof surgical treatment, but also the clarification of the clinicalstate of diabetes and the development of new drug therapies.
At an early stage after LSG, antidiabetic effects are shownand the responses of the lipid system should be paid special
attention to. Roughly speaking, the lipid system consists ofTC, HDL, LDL and TG. There was no significant change in
TC level, HDL level was improved two to three months after
surgery, LDL level tended to increase and TG level improved
remarkably. This result is similar to that of the long-term
research more than one year after LSG, which has beenreported 18, 19). The authors considered that as the intake ofcarbohydrates and animal fat decreased after LSG, due todiet restriction, the material for TG decreased and as a result

the accumulation of TG in liver decreased, hepatic steatosis
was improved and AST level and ALT levels became normal.
LSG seemed to have weak response to cholesterol metabolism.
Due to the increase of bile acid after LSG, the increase in theamount of enterohepatic circulation and the increase ofcholesterol absorption may possibly be involved in cholesterol
metabolism 20). It is necessary to wait for the accumulationof long-term experiences in a number of cases, which will
possibly become an important source of information to decide
the adaptation of surgical treatment.
There are problems in this research, such as theinformation of patients’ compliance and how eagerly they
dealt with diet and exercise before and after surgery were
not reflected in this research. The number of cases was also
small. It is important to increase the number of cases in the
future.

Conclusion

LSG showed remarkable antidiabetic effects one monthafter surgery without a direct relationship to weight loss. TC
levels were improved one month after surgery and hepaticfunction was improved two months after surgery; however,there were no significant changes in TC and LDL during theobservation period. From the fact that LGS showedremarkable antidiabetic effects one month after surgery
without a direct relationship to weight loss, it was suggested
that LSG may possibly be effective on the improvement ofglycative stress.

Conflict of interest_ 191 _

The authors have no conflict of interest in this study.

Bariatric Surgery in Obese Diabetes

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