| Abstract |
It is well known that Diabetes Mellitus type 2 (DMT2) is a world epidemic in recent
years. Although there is enormous effort by the Medical community to treat the disease
conservatively, this is not always possible due to the modern way of life, which involve bad
dietary habits, luck of physical activity and weight gain. The latest is of the outmost
importance and according to studies, 80% of the morbid obese people would finally develop
DMT2.
According to WHO the number of obese European citizens is approximately
150.000.000 people and the number of obesity related deaths is 1.000.000 annually.
From 1954 a variety of surgical techniques have been utilized for treatment of morbid
obesity with minimal morbidity and mortality. To date the approved operations for the
management of severe obesity are:
a) Adjustable gastric banding
b) Sleeve gastrectomy
c) R-en-Y Gastric bypass
d) Biliopancreatic Diversion
It is remarkable that following bariatric surgery the remission of co-existing diseases such
as DMT2 may be as high as 80-90%. Similar results are obtained with other obesity comorbidities
as arterial hypertension, dyslipidemia and sleep apnea syndrome.
Over 200.000.000 people worldwide are suffering today from DMT2. In Greece the
incidence of the disease is estimate from 5.9% to 7% of the population. According to
epidemiological estimations at the year 2025 the number of people with DMT2 would be
600.00.000 and this is going to represent the 7.3% of the world’s population. In the Diabetes
Surgery Summit in Rome 2007 the decision was made that when DMT2 is not controlled by
life style changes and medications, surgery would be considered in patients with BMI
7ge;30kg/m2.
Bariatric Surgery for Diabetes Type 2
Encouraging results following surgical treatment of patients with DMT2 have been
reported by many investigators.
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The first procedure used for the treatment of morbid obesity and Diabetes Mellitus type 2
was the Roux-en Y gastric bypass, followed by the vertically banded gastroplasty. The results
of the latest ware not as good as hen the gastric bypass was utilized.
Other bariatric operations that were also used for treatment of patients with DMT2 were
the adjustable gastric banding. The sleeve gastrectomy and the biliopancreatic diversion.
Specific for DMT2 treatment in obese or overweighed patients were the duodenojejunal
sleeve, the duodeno-jejunal bypass, the ileal interposition and the sleeve gastrectomy with
bipartition with gastrojejunostomy or Roux-en-Y jejunostomy.
In recent years in an effort to discover simple new procedures for surgical management of
the diabetic patients and provide explanations for the mechanism of diabetes remission
research have been made into the role of enteropeptides in the regulation of glucose
homeostasis, as well as in weight loss.
Neuroendocrine regulation
The role of central nervous system in body’s homeostasis through hormonal feedback
mechanisms is crucial. Hormones like GLP-1, PYY, Insulin, Ghrelin, Resistin and Leptin are
responding to chemical and mechanical stimulation of the gut and are important parameters
in regulation of body weight and glucose homeostasis.
Aim of the study
For enhancing weight-loss in morbidly obese patients, the addition of a side-to-side
jejunoileal anastomosis to sleeve gastrectomy has previously been described from our group.
The very successful results in diabetic remission, observed following this procedure in
morbidly obese diabetic patients, lead us to the assumption that diverting and accelerating the
food transmission into the distal small bowel with a simple jejunoileal anastomosis, in nonobese
diabetic patients were weight-loss is not the main goal, will act therapeutically by
stimulating the L cells of the ileum for incretins production. Therefore, SJA was performed in
GK rats in order to determine whether this food diverting procedure is able to induce diabetes
control in a non-obese animal model, and establish a suitable experimental setting for further
studies of the mechanism/s for diabetes control.
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Experimental animals and methods
Nine to 10 week-old male diabetic, normolipidemic Goto-Kakizaki (GK) rats were
purchased from ‘Charles River’ Research Models and Services (Boston USA). All animals
were housed in individual cages under standard conditions (constant ambient temperature of
22°C and humidity of 60% in a 12-hour light/dark cycle) in the animal house, Heraklion
University Hospital with free access to water. Animals were fed with a 2% fat and 16.5 %
protein rat chow diet (kounker, Athens, Greece) before operation. The animal experiment in
this study were approved by the Ethics committee of the Medical School, University of Crete,
and received permission from Heraklion Regional Veterinary Service. All applicable
institutional and/or national guidelines for the care and use of animals were followed.
Rats were allowed 4 weeks for acclimation before the experiment. After that, 17 rats
randomly underwent one of the following procedures: SJA: 11 animals, sham side-to-side
jejunoileal anastomosis (SSJA): 4 animals or no intervention (controls): 2 animals. Weight,
fasting glucose, cholesterol, triglycerides and oral glucose tolerance test (OGTT) were
measured at intervals according to the experimental schedule.
The operative times (time from the beginning of the midline abdominal incision to the
end of suturing of the abdominal incision) of SJA and SSJA groups were accurately recorded.
Moreover, the time of first postoperative defecation (an indicator of postoperative recovery
time) and all postoperative complications were extensively recorded.
Surgical technique
Before operations, rats were fasted overnight for 12 hours. Rats were anesthetized
with ketamine hydrochloride 50mg/ml (Molteni Farmaceutical, Firenze, Italy) during the
surgery. SJA procedure (Fig.1) involved (1) a 4-cm midline abdominal incision, (2)
measurement of the length of the entire small intestine from the Treitz ligament to the
ileocecal valve, (3) estimation of the length of small bowel equal to 20% of its entire length,
(4) identification of a point distal to the Treitz ligament at a distance equal with 20% of the
total bowel length, (5) identification of a point proximal to the Ileocecal valve at a distance
equal with 20% of the total bowel length, (6) side-to-side anastomosis between jejunum and
ileum at the measured points distal to the Treitz and proximal to the ileocecal valve using 6-0
polydioxanone monofilament absorbable sutures (PDS Johnson and Johnson, USA), (7)
closure of the abdominal incision using 4-0 polyglycolic acid absorbable sutures (Safil
Braun, Tuttlingen Germany), (8) closure of the skin incision with subcuticular suture with the
same suturing material.
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Sham operations were performed by the same abdominal incisions and same
jejunoileal anastomosis. Thereafter, the anastomosis was taken down with restoration of the
small bowel continuity using 6-0 PDS sutures.
Rats had free access to water 2 hours after surgery as well as free access to food 24
hours postoperatively. Food intake was not limited. Both groups were fed the same
perioperative diet. Weight was measured every 7 days until the 10th week when the study
was terminated.
Biochemical methods
Blood glucose, cholesterol and triglycerides were measured using a quantitative
instrument (Accutrend Plus, Roche Diagnostic, Mannheim, Germany). Before operation and
every week postoperatively, from the first until the 10th when the experiment was
terminated, blood samples were collected after 12 hours overnight fast from tail’s vein of
conscious rats, for measuring of serum glucose levels. Cholesterol and triglyceride levels
were measured before operation and at the 3rd and the 8th postoperative weeks. OGTT was
performed preoperatively and at 3 and 8 weeks after surgery. After an overnight fast, rats
were administrated with 1 g/kg glucose by oral gavage and blood glucose levels were
measured before, 30, 60 and 120 minutes after the oral gavage.
Statistical analysis
All statistical analyses were performed with SPSS 17.0. Data was expressed as
Median and range. All p values are two-tailed. Because of the small animal numbers in the 3
groups, data were compared using non-parametric tests for different population. Mann-
Whitney U-tests were used for comparisons between groups and Wilcoxon paired test for
intra-group comparisons. p7lt;0.05 was considered statistically significant.
Results
All operations were successful. However, compared with SJA, the operation time
47.5 min (range 25-60 min) vs 89.5 min (range 45-105 min) of SSJA was longer (p < 0.01).
There was no significant (NS) differences in postoperative recovery time for SJA, 2 days
(range 1-3 days) vs SSJA, 2 days (range 1-2 days) (p =0,9). One SJA rat died from intestinal
obstruction, due to torsion of the anastomosis along the longitudinal axis, at day 32 after the
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operation. No deaths neither complications were observed in the sham-operated and control
groups.
Length of small intestine
At 14 week the measured average intestinal length of SJA animals from Treitz
ligament to the ileocecal valve was 89 cm (range 70-118 cm) and for SSJA animals 84 cm
(range 65-95 cm), (p=0.57 NS).
Weight and postoperative weight loss
At week 0, the median weight for the 3 groups were: SJA 358 g (range 354-366 g),
SSJA 355.5 g (range 345-360 g) and Controls 360 g (range 355-365 g). The p values for the
differences between groups were SJA vs Sham SJA p=0.32, SJA vs Controls p=0.9 and SSJA
vs Controls p=0.36, all NS.
Animals in SJA group experienced loss of weight from the first and up to 4 weeks
after the operation. The median % TWL observed at that time point was 7.2%. The weight of
the rats in this group was stabilized thereafter, but remained reduced comparing with the preoperative
values (p<0.001) until the end of the experiment.
Glucose metabolism
Glucose
Animals in Control group and those in SJA and SSJA groups have no statistically
different fasting glucose levels before the procedures. SJA: median 213.5 mg/dl (range 181-
260), Controls: median 308 mg/dl (range 280-336), Sham: median 235 mg/dl (range 219-
248). SJA vs Sham p=0.4 NS, SJA vs Controls p=0.062 NS and Sham vs Controls p= 0.074
NS
However, compared with sham-operated rats and controls, the fasting glucose levels
were significantly lower in the SJA group (p<0.01) from the 1st postoperative week and
continued to be within normal range up to the 10th week when the experiment was
terminated.
OGTT
Prior to the procedures, no statistical difference in OGTT was found among all
experimental groups. At 120 min following administration of 1 gr/kg glucose by oral gavage,
the median plasma glucose levels were 301.5 mg/dl (range: 261-480 mg/dl) for SJA, 409
mg/dl (range: 327-439 mg/dl) for Sham group and 378 mg/dl (range: 300-457 mg/dl) for the
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Control group. SJA vs Sham p=0.076 NS, SJA vs Control p=0.052 NS and Sham vs Control
p=1.00 NS.
However, all rats in the side-to-side jejunoileal bypass group showed a significant
improvement in glucose tolerance test at 120 min following administration of 1g/kg glucose
by oral gavage at 3 and 8 weeks post operatively. [273.5 (57-382) mg/dl; p=0.02 and 95.5
(70-241) mg/dl; p=0.005, respectively]. On the contrary, no significant changes were
observed either in Sham [414 (188-510) mg/dl; p=0.72 NS and 414 (188-510) mg/dl; p=0.07
NS, respectively], or in the Control [383 (346-420) mg/dl; p=0.66 NS and 457.5 (400-515)
mg/dl; p=0.18 NS, respectively] groups.
Cholesterol and triglycerides levels
Serum cholesterol and triglycerides levels had no difference prior to surgery among
all experimental groups. No significant differences in those parameters were observed
following SJA or Sham procedures.
Conclusions
This experimental investigation in non-obese diabetic rats, showed that with diversion
of food and biliopancreatic juices to the distal ileum, with a simple side-to-side jejunoileal
anastomosis, glucose homeostasis is restored.
Many pathophysiological mechanisms may be contributing in diabetes remission
observed in this non obese animal model. It is remarkable that none of the animals developed
diarrhea or other signs of malabsorption postoperatively. Although even without sleeve
gastrectomy, simple jejunoileal anastomosis resulted in minimal weight loss of around 7.2%.
It is no doubt that this long term weight loss is resulting in improving insulin sensitivity,
which is contributing in diabetes control. However, the weight loss cannot fully explaine the
rapid remission of diabetes seen in the animals in this experiment.
Is very likely that other mechanisms are responsible for diabetes control, following
side-to-side jejunoileal anastomosis. Previous studies showed a positive effect in glucose
homeostasis after operations resulting in fast passage of food into the distal small bowel, as
the sleeve gastrectomy. The present study showed that rapid improvement of insulin
sensitivity occur independent of weight loss. It is speculated that GLP-1 and PYY enderopeptides
that the gut is secreting following rapid passage of food into the distal ileum are the
most possible explanation for diabetes control, apart from the weight loss.
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