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Rapid Improvement of Diabetes After Gastric Bypass Surgery: Is It the Diet or Surgery?

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OBJECTIVE Improvements in diabetes after Roux-en-Y gastric bypass (RYGB) often occur days after surgery. Surgically induced hormonal changes and the restrictive postoperative diet are proposed mechanisms. We evaluated the contribution of caloric restriction versus surgically induced changes to glucose homeostasis in the immediate postoperative period.RESEARCH DESIGN AND METHODS Patients with type 2 diabetes planning to undergo RYGB participated in a prospective two-period study (each period involved a 10-day inpatient stay and periods were separated by a minimum of 6 weeks of wash-out) in which patients served as their own controls. The presurgery period consisted of diet alone. The postsurgery period was matched in all aspects (daily matched diet) and included RYGB surgery. Glucose measurements were performed every 4 h throughout the study. A mixed meal challenge test was performed before and after each period.RESULTSTen patients completed the study and had the following characteristics: age, 53.2 years (95% CI, 48.0-58.4); BMI, 51.2 kg/m(2) (46.1-56.4); diabetes duration, 7.4 years (4.8-10.0); and HbA1c, 8.52% (7.08-9.96). Patients lost 7.3 kg (8.1-6.5) during the presurgery period versus 4.0 kg (6.2-1.7) during the postsurgery period (P = 0.01 between periods). Daily glycemia in the presurgery period was significantly lower (1,293.58 mg/dL*day [1,096.83-1,490.33) vs. 1,478.80 mg/dL*day [1,277.47-1,680.13]) compared with the postsurgery period (P = 0.02 between periods). The improvements in the fasting and maximum poststimulation glucose and 6-h glucose area under the curve (primary outcome) were similar during both periods.CONCLUSIONS Glucose homeostasis improved in response to a reduced caloric diet, with a greater effect observed in the absence of surgery as compared with after RYGB. These findings suggest that reduced calorie ingestion can explain the marked improvement in diabetes control observed after RYGB.
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Rapid Improvement in Diabetes After
Gastric Bypass Surgery
Is it the diet or surgery?
ILDIKO LINGVAY, MD, MPH, MSCS
1
EVE GUTH, MD
2
ARSALLA ISLAM, MD
3
EDWARD LIVINGSTON, MD
3
OBJECTIVE dImprovements in diabetes afte r Roux-en-Y gastric bypass (RYGB) often occur
days after surgery. Surgically induced hormonal changes and the restrictive postoperative diet are
proposed mechanisms. We eva luate d the contribution of caloric restriction versus surgically
induced changes to glucose homeos tasis in th e immediate postoperative peri od.
RESEARCH DESIGN AND METHODSdPatients wi th type 2 diabetes planning to un-
dergo RYGB participated in a prospective two-period study (each p eriod involved a 10-day
inpatient stay, and periods were separated by a minimum of 6 weeks of wash-out) in which
patients served as their own controls. The presurgery period consisted of diet alone. The post-
surgery period was matched in all aspects (daily matched diet) and included RYGB surgery.
Glucose measurements were performed every 4 h throughout the study. A mixed- meal challenge
test was performed before and after ea ch period.
RESULTSdTen patients completed the study and had the following characteristics: age, 53.2
years (95% CI, 48.058.4); BMI, 51.2 kg/m
2
(46.156.4); diabetes duration, 7.4 years (4.8
10.0); and HbA
1c
, 8.52% (7.089.96). Patients lost 7.3 kg (8.16.5) during the presurgery
period versus 4.0 kg (6.21.7) during the postsurgery period (P = 0.01 between periods) . Daily
glycemia in the presurgery period was signicantly lower (1,293.58 mg/dLz day [1,096.83
1,490.33) vs. 1,478.80 mg/dLzday [1,277.471,680.13]) compared w ith the postsurgery
period (P = 0.02 between periods). The improvements in the fasting and maximum poststim-
ul atio n glucose and 6-h glucose area under the curve (prima ry outcome) were similar during
both periods.
CONCLUSIONSdGlucose homeostasis improved in response to a reduced caloric diet,
with a greater effect observed in the absence of surgery as com pared wi th after RYGB. These
ndin gs suggest that reduced calorie ingestion can explain the marked improvement in di abete s
control observed after RYGB.
Diabetes Care 36:27412747, 2013
R
oux-en-Y gastric bypass surgery
(RYGB) is one of the most success-
ful treatment strate gies for diabetes
accompanying morbid obesity. Long-
term diabetes remission rates of 83%
have been repo rted (1,2). Remark ably, di-
abetes can improve markedly within a few
days of surgery. In-hospital diabetes re-
mission rates have been reported to be
as high as 89% (3,4). In one study, 30%
of patients with diabetes were discharged
from the hospital with normal blood glu-
cose leve ls and not using any diabe tes
medication (4). Improvement often oc-
curs before any signicant weight loss.
These ndings have led to th e suggestion
that surgical shunting of food past the
duodenum results in altered hormonal
signaling that ameliorates diabetes within
afewdays(57).
The interpretation of the acute im-
provement in glycemia is confo unded by
the fa ct that postsurgical patients are
placed on a severe calorie-restricted diet
for at least 714 days after surgery. Severe
calorie restriction alone can signicant ly
improve diabetes within days (8,9). A series
of 40 obese patients with type 2 diabetes
underwent 40 days of a very-low-calorie
diet. Fasting glucose levels improved sig-
nicantly, and 87% of the improvement
occurred within the rst 10 days (10). A
similar calorie-restricted diet reduced he-
patic glucose production and insulin re-
sistance within 7 days (11). In another
study of patients with type 2 diabetes, a
600-calorie/day diet normalized plasma
glucose levels and hepatic glu cose output
within 1 week (12).
The ndings from the diet studies
raise the question regarding whether t he
rapid imp rovement in diabetes after
RYGB is caused by the low-calorie diet
or by the surgery. Pr evious studies (13
15) have sought to answer this question,
but the results a re confounded because
different patients (with different baseline
characteristics) were subjected to the d iet
or surgery regimens and the dietary intake
was different betwee n groups. In the cur-
rent study, we compared diet-only and
diet plus surgery treatments i n 10 pa-
tients, each of whom was subjec ted to
both regimens. Both interventions were
performed under strict inpatient supervi-
sion, and dietary intake was closely
matched.
RESEARCH DESIGN AND
METHODSdPatients with type 2 di-
abetes served as their own controls in a
single-group, two-period study. Caloric
ingestio n, physical activi ty, and intrave-
nous uid administration were eq uivalent
during the two study periods that oc-
curred several months before (presurgery
period) and immediatel y after the RYGB
procedure (postsurgery period). The re-
search protocol was reviewed and ap-
proved by the University of Texas
Southwestern Medical School Institutional
cccccccccccccccccccccccccccccccccccccccccccccccc c
From the
1
Department of Internal Medicine, Endocrinology Division, and the Department of Clinical Sciences,
University of Texas Southwestern Medical Center, Dallas, Texas; the
2
Department of Internal Medicine,
General Medicine Division, University of Texas Southwestern Medical Center, Dallas, Texas; and the
3
Department of Surgery, Division of Gastrointestinal and Endocrine Surgery, University of Texas South-
western Medical Center, Dallas, Texas.
Corresponding author: Ildiko Lingvay, ildiko.lingvay@utsouthwestern.edu.
Received 7 November 2012 and accepted 8 February 2013.
DOI: 10.2337/dc12-2316. Clinical trial reg. no. NCT01153516, clinicaltrials.gov.
A.I. is currently afliated with the Department of Surgery, Vascular Surgery Section, Wake Forest University,
Winston-Salem, North Carolina.
E.L. is currently afliated with JAMA, Chicago, Illinois.
© 2013 by the American Diabetes Association. Readers may u se this article as long as the work is properly
cited, the use is educational and not for prot, and the work is not altered. See http ://creativeco mmons.org/
licenses/by-nc-nd/3.0/ for det ails.
care. diabetesjournals.org DIABETES CARE, VOLUME 36, SEPTEMBER 2013 2741
Pathophysiology/Complications
ORIGINAL ARTICLE
Review Board, and all participants signed
informed consent forms before enroll-
ment in the study.
Study participants
Patients were recruited from the medica l
weight loss/bariatric clinic at University
of Texas Southwestern Medical Center.
We enrolled adults (age older than
18 years) of any ethnicity and both sexes
who met all criteria for and planned
to undergo RYGB and who had a di-
agnosis of type 2 diabetes. Exclusion
criteria were abnormal renal function
(serum creatinine above the upper limit
of normal for age and sex), signicant
anemia (hemoglobin ,10 mg/dL), dif-
cult venous access, and treatm ent with
incretin mimetics or dipeptidyl pepti-
dase IV inhibitors during the previous
3months.
Study design
The protocol con sist ed of two inpatient
study periods (10 days each) separated
by a wash-out period of at least 6 week s
(Fig. 1). During the rst stu dy pe riod
(presur gery period), participants adopted
the diet and activi ty protocol typical for
pati ents after RYGB. Participants were ad-
mitted to the Clinical and Translational
Res earch Cent er for th is entire study pe-
riod. On the rst day, they underwent
clinical evalua tion (m edical his tory a nd
physical examination) and w ere fed a
standard liquid preoperative diet that
consisted of Glucerna (Abbott Laborato-
ries, Columbu s, OH; 26 g carbohyd rates,
10 g protein, 200 calories/240 mL) 240
mL per meal and water ad libitu m. On the
second day at 8:00
A.M., they underwent a
6-h mixed meal challenge test (MMCT)
using 240 mL chocolate Boost Plus (Nestle
Healthcare Nutrition, Florham Park, NJ;
45 g carbohydrates, 14 g prot ein, 360
calories/240 mL), followed by 240 mL
vegetable broth for lunch and 240 mL
sugar-free gelatin for dinner. On the third
day, they were NPO. On the fourth day,
feeding was restarted after 12:00
P.M., and
between 12:00
P.M. and 8:00 P.M. partici-
pants were allowed to have a maximu m
of 30 mL clear liquids (ice chips, water,
Crystal Light, broth, or sugar-free gela-
tin) every hour. Normal saline 125 mL/h
was infused from 8:00
A.M. on the third
day t hrough 8:00
A.M. on day 6 to pre-
vent dehydration. On day 5, the volume
of the clear liquids was advanced to a
maximum of 30 mL every 30 min in the
morning and every 15 mi n in the after-
noon. On days 69, the maximum oral
intake was 30 mL every 15 min between
8:00
A.M. an d 8:00 P.M., and participants
were encouraged to alternate intake be-
tween clear liquids and Glucerna. On
day 10, the MMCT was repeated, followed
by home discharge.
The second study period (postsur-
gery period) st arted 2 days b efore RYGB
surgery and continued until postopera-
tive day 7. The only difference between
the two study periods was the perfor-
mance of RYGB surgery on day 3 and a
gastrogran study performed during the
morning of day 4. The dietary protocol
was identical to the rst study period.
Dietary intake (volume and content) was
matched on a daily basis to the intake
during the presurgery period. Partici-
pants spent th e rst 2 days and 2 nigh ts
at the C lini cal and Tran slat ional Research
Center, spent days 3 through 5 or 6 (at
the surgeons di scretion) at St. Paul Uni -
versity Hospital, and returned to the Clin-
ical and Translational Research Center for
the remaining of the study days (day 5 or
6 through 10). RYGB surgery was per-
formed laparoscopically in all patients
and u sing the same te chnique (16). A
25-mm EEA Stapler to create a gastro-
jejunal anastomosis and a linear 60-mm
stapler to create a jejuno-jejunal anasto-
mosis were used. The l ength of the roux
limb was 100 cm in all the patients.
Patients were instructed to stop using
all oral an ti-diabetic agents 3 days b efore
each study period. Subcutaneous insulin
treatment was withheld starting the day
before admission and replaced with reg-
ular insulin intravenous boluses ad-
ministered only when capillary glucose
measurements exceeded 200 m g/dL. N o
insulin correction was administ ered
within 10 h of MMCT. All routine no n-
diabetes medicat ions were conti nued
throughout the entire study at the same
dose.
Duri ng the wash- out period , partic-
ipants were instru cted to return to their
usual diets and activity levels, with the
stated expectation that participants
woul d re turn to a comparable metabolic
baseline for the surgery period. The length
of the wash-out period was a minimum of
6 weeks and was determined solely by the
surgery schedule.
Figure 1d Study design. CTO, Clinical Trials Ofce; CTRC, Clinical and Translational Research Center; SPH, St. Paul Hospi tal.
2742 DIABETES CARE, VOLUME 36, SEPTEMBER 2013 care.di abetesjour nals.org
What causes postbypass diabetes remission?
Measurements
Weight was measured every morning
(except during the hospitalization) at
7:00
A.M. on the same scale, with partici-
pants w earing only a hospital gown.
Waist (umbilical level at end expiration)
and hip (largest part) circumference were
measured on each admission and dis-
charge with the same tape measure. Oral
intake (amount, type, time) was moni-
tored strictly and recorded every hour .
The daily and per-study period caloric
inta ke was calculated based on the nutri-
tional content of ea ch ingested product.
The total caloric intake per study period is
reported as all calo ries ingested from (and
including) the baseline MMCT t o the (and
excluding) end -of-study MMCT.
Capillary b lood glucose level was
measured every 4 h using an AccuCheck
Advantage glucose meter (Roche Diag-
nostics). The averag e of two readings
obtained with two separate meters was
reported for each time point. Total glyce-
mic exposure during each study period
was reported as glycemia and represents
the area under the cu rve (AUC ) for the
daily average capillary blood glucose mea-
surement over the entire study period.
Regular human insul in was a dministered
only if capillary glucose level was .200
mg/dL and at a dose estimated based on
the participants preadmission total daily
insulin dose. The total insulin dose ad-
ministered from day 2 through day 9 (in-
clusive) is r eported.
A 6-h MMCT was administered at
8:00
A.M. on days 2 and 1 0 of each study
period. After obtaining two baseline sam-
ples (210 and 25 min), 240 mL choco-
late Boost Plus was ingested in 5 min.
Blood samples for g lucose measurement
were collected at 5, 10, 15, 20, 25, 30, 40,
50, 60, 80, 100, 120, 150, 180, 210, 240,
300, and 360 min after ingestion. We re-
port the average of the t wo fasting sam-
ples, the maximum postingestion glucose
level, and the AUC for glucose obtained
from all measureme nts. Whole -blood
glucose was measured using YSI 2300
STAT Plus Glucose analyzer (Yellow
Spring Instruments). HbA
1c
was mea-
sured by high-performance liquid chro-
matography in the Clinical Diabetes
labo ratory at University of Texas South-
western.
Statistical analysis
The primary outcome of the study was
glycemic control as measured by the
glucose AUC during the 6-h MMCT.
We hypothesized a greater reduction in
glucose AUC in the postsurgery period
compared with the presurgery period.
A sample size of 10 patients was needed
to achieve a power of 0.8 with a = 0.05 to
detect a 10% (7, 230 mg/ dL/min) differ-
ence in the glucose AUC with an estimated
SD of 7,300 mg/dL/ min. Estimated base-
line average glucose AUC was 72,300 6
20,500 mg/dL/min based on a study that
enrolled a similar study population (17).
All other reported m easurements are
prespeci ed secondary outcomes. We
conducted pair-wise comparisons of the
changes that occurred during each study
period using a paired t test. AUC for glu-
cose was calculated using the trapezoidal
rule. Data are reported as mean and
95% CI. Signicance was established at
P , 0.05.
RESULTS dTen participants com-
pleted both study periods. One parti ci-
pant dropped out after the fourth day of
the presurgery period because she de-
cided to no longer pur sue RYGB (Table 1,
patient 5). A second participant com-
pleted the presurgery period but, because
of acute medical problem s unrelated t o
the study, the surgery was postponed in-
denitely ( Table 1, patient 11). The base-
line characteristi cs of each participant are
desc ribed in Table 1. The average age of
the participants who complet ed the study
was 53.2 years (95% CI, 48.058.4),
with a diabetes duration of 7.4 years
(4.810.0). All patients had fasting
C-peptide levels .1 ng/dL. The average
length of the wash-out period w as 101.6
days (range, 3 8218 days). The goal was
for each participant to return to a similar
metabol ic baseline for the surgery period.
Duri ng the wash-out period, participants
regained only half of th e weight lost dur-
ing the presurgery period (P , 0.001 for
the weight and BMI comparison between
the two baseli ne valu es), but glycemic sta-
tus was simi lar at the sta rt of both study
periods (Table 2, nonsignicant differen-
ces between baseline HbA
1c
, fasting glu-
cose, maximal poststimulation glucose,
and glucose A UC during MMCT).
The total caloric intakes for the study
periods (total o f 7 days) were 1 ,736
calories (95% CI, 1,364.62,106.9) and
1,597 calories (1,312.61,881.9), respec-
tively (P =0.43betweenperiods).Oral
intake was well-matched on a day-to-day
basis (Fig. 2A). A few patients delayed their
progression to a protein-based liquid diet
on day 6 of the surgery period, but the dif-
ference in caloric intake on this day be-
tween study periods was not signicant.
There were no surgery-related adverse
events during the study.
Weight and anthropometric
measurements
Total weight loss ( and BMI change) was
signicantly greater during the presur-
gery period (Table 2). Participants lost
5.3% (95% CI, 5.964.57) of their t otal
body weight during the presurgery period
and lost 2.8% (4.461.16) during the
postsurgery period (P = 0.02 between pe-
riods). The pattern of weight loss was dif-
ferent in the two study periods, with a
steady daily loss during the presurgery
period and postoperative gain, followed
by rapid loss during the postsurgery pe-
riod (Fig. 2B).
Hip circumference decreased by 6.6 cm
and 6.1 cm, respectively, during each
period (P = 0.91 between periods). Waist
circumference decreased by 6.9 cm over
Table 1dBaseline characteristics of each study participant
Patient
Age
(years) Sex Ethnicity
Diabetes
duration
(years)
Insulin
dose
(units)
Oral
hypoglycemic
agents (n)
Weight
(kg)
BMI
(kg/m
2
)
Fasting
C-peptide
(ng/mL)
1 40 M AA 10 130 1 210.9 65.9 1.55
2 67 M W 2 0 2 138.6 47.1 4.79
3 56 F AA 16 200 3 143.8 56.2 1.59
4 48 F AA 8 120 2 127.4 41.6 2.91
6 46 F W 3 0 1 119.6 47.6 5.33
7 66 M AA 8 140 3 175.4 60.0 2.73
8 55 F H 6 85 1 110.4 46.6 1.93
9 50 F H 6 70 1 153.8 54.8 2.11
11 52 F AA 11 35 1 101.1 39.2 1.4
12 52 F W 4 0 1 150.9 53.1 2.88
AA, Afric an American; F, female; H, Hispanic; M, male; W, non-Hispanic white.
care. diabetesjournals.org DIABETES CARE, VOLUME 36, SEPTEMBER 2013 2743
Lingvay and Associates
the diet period, but increased by 1.1 cm
over the surgery period (P = 0.04 between
periods), which is probably explained by
postsurgical swelling and residual intra-
abdominal gas.
Measures of glycemia
The overall glycemia (reported as AUC for
the daily average capillary glucose m ea-
surements) was 1,293.58 mg/dLzda y
(95% CI, 1,096.83 1,490.33) during
the pres urgery period v ersus 1,478.80
mg/dLzday (1,277.471,680.13) during
the postsurgery period (P =0.01between
periods). This difference in o verall glyce-
mia was observed despite a (nonsigni-
cant) lower caloric intake and higher
exogenous insulin requirement during
the postsurgery period. The average total
dose of insulin required during the entire
presurgery period was 47.5 unit s/patient
compare d with 90. 7 units/patient in the
postsurgery period (P = 0.20 between pe-
riods). Of note, both of these insulin re-
quirements were signicantly lower than
the patients home insulin dose (average,
78 units/day). On each of days 37, cap-
illary glucose was signicantly lower dur -
ing the presurgery period compared with
the postsurgery period (Fig. 2C). By day
8, t he glucose prole became comparable
between the two periods and continued
to track on an identical course on days 9
and 10 (Fig. 2C).
Fast ing glucose, maximum poststi m-
ulation glucose, and glucose AUC during
the MMCT (the primary outco me of the
study) all improved signicantly during
the presurgery period (Fig. 2D), but not
during the postsurgery period (Fig. 2E
and Table 2). The shape of the glucose
curve during the MMCT at the end of
the posts urgery period was different com-
pared with the same curve at the end of
the presurgery period (earlier peak attrib-
utable to early and rapid glucose absorp-
tion), but the 6-h total AUC was similar
(Fig. 2F and Table 2). HbA
1c
decreased
signicantlyinbothstudyperiodsby
0.57% (95% CI, 0.800.34) and 0.39%
(0.720.06), respectively (P =0.23be-
tween periods).
The glucose AU C during the 6-h
MMCT (prima ry outcome of the study)
improved during both study periods
(Table 2), wit h the difference of the im-
provement between study periods (dif-
ference of the deltas of each period)
being 24,0 42.66 (95% CI, 212,898.23
to 4,812.92) in favor of the diet-only in-
tervention. T hese results con rm that a
clinically meaningful differenc e in favor
Table 2dMetabolic characteristics and their changes during each study period
Presurgery pe riod Postsurgery period
Between
peri ods
Baseline End Change P Baseline End Change PP
Weight, kg 141.74
(121.942161.54)
134.48
(114.94154.02)
27.26
(28.11 to 26.41)
,0.001 137.55
(117.47157.63)
133.60
(114.14153.06)
23.95
(26.1 8 to 21.72)
0.01 0.01
BMI, kg/m
2
51.14
(45.9656.32)
48.07
(43.0 653.08)
23.07
(23.49 to 2.65)
,0.001 49.46
(44.2 354.69)
47.78
(42.7 652.80)
21.68
(22.4 9 to 20.87)
0.003 0.03
Waist, cm 146.56
(133. 83159.30)
139.63
(125.62153.63)
26.94
(29.12 to 24.76)
,0.001 139.25
(125.65152.85)
140.38
(127.67153.08)
1.13
(24.5 8 to 6.83)
0.71 0.04
Hip, cm 141.56
(125. 74157.39)
135.00
(121.40148.60)
26.56
(212.98 to 20.14)
0.09 139.00
(127.07150.93)
132.88
(123.94141.81)
26.13
(211.38 to 0.87)
0.06 0.91
HbA
1c
, % 8.52 (7.089.96) 7.95
(6.70 9.20)
20.57
(20.80 to 20.34)
0.001 8.40
(6.66 10.14)
8.01
(6.60 9.42)
20.39
(20.7 2 to 20.06)
0.05 0.23
Fasting
glucose, mg/dL
166.18
(138. 22194.13)
130.60
(102.23158.97)
235.58
(261.41 to 29.74)
0.02 153.55
(117.86189.24)
135.83
(115.57156.08)
217.73
(248.48 to 13.03)
0.29 0.20
Maximal
poststimulation
glucose, mg/dL
240.60
(195. 81285.39)
208.10
(164.44251.76)
232.50
(255.37 to 29.63) 0.02
232.40
(186.01278.79)
204.00
(175.72232.28)
228.40
(267.43 to 10.63) 0.19 0.68
Gluco se AUC,
mg/dLzmin
73,024.43
(58,017.49
88,031.37)
61,647.00
(47,023.25
76,270.75)
211,377.43
(219,228.44 to
23,526.41 )
0.02 68,981.77
(53,322.09
84,641.45)
59,476.06
(47,943.76
71,008.36)
29,505.71
(221,390.71 to
2,379.30)
0.15 0.56
Data represent mean (95% CI). The signicance of the change within each period is shown under the presurgery period and postsurgery period, respectively, whereas the signicance of the changes between periods is
shown in the Between per iods column.
2744 DIABETES CARE, VOLUME 36, SEPTEMBER 2013 care.di abetesjour nals.org
What causes postbypass diabetes remission?
of surgery is not present, and the two
tested interventions are comparable or a
diet-only intervention is superior.
CONCLUSIONSdWe found that di-
abetes improves rapidly when a post-
bariatric diet is provided to obese pa tients
with diabetes before they undergo sur-
gery. I n fact, the improvement in overall
glycemic control was more profound with
the di etary intervention alone than after
RYGB (with a perfectly matched diet).
These ndings su pport the hypothesis
that rapid diabetes r esolution after RYGB
is mediated by calor ic r estriction and that
there is no need to invoke a direct hor-
monally med iated mechanism related to
bypassing the duodenum.
The strength of thisstudy is in its design
and implementation, which allow for the
precise evaluation of the individual contri-
bution of diet versus surgery to diabetes
improvement in the immediate postsurgical
period. First, we exclusively studied
patients with type 2 diabetes to assure
the highest relevance to the posted ques-
tion. Second, we designed a one-group ,
Figure 2dComparison of the changes observed during the presur gery period and postsurgery period. A: Daily caloric i ntake (calories). B: Daily
weight (kg). C: Daily average capillary blood glucose (mg/dL). D: The improvement in the glucose prole over a 6-h MMCT in the presurgery period.
E: The improvement in the glucose prole over a 6-h MMCT in the postsurgery period. F: The change in glucose (delta) for each time point during the
MMCT within each study period. Data are mean and SE. Continuous line with lled circles (C) indica tes presurgery period; dotted line with open
circles () indicates postsur gery period; continuous line with lled squares (-) indicates baseline testing in presurgery period; dotted line with o pen
squares (,) indicates end of period testing in presurgery period; continuous line with lled triangles () indicates baseline testing in postsurgery
period; dotted line with open triangles (
6) indicates end of period testing in postsurgery period. *P , 0.05; **P , 0.01.
care. diabetesjournals.org DIABETES CARE, VOLUME 36, SEPTEMBER 2013 2745
Lingvay and Associates
two-period study to ensure identical base-
line characteristics of the participants, and
this also allowed us to perform a more
powerful paired data analysis. Third, the
entirely inpatient direct-observation im-
plementation ensured perfect compliance
with the dietary intervention (as well as
activity level and intravenous uid admin-
istration), precise matching of the oral
intake between study periods, standard-
ized frequent evaluations of the variables
of interest, and standardiz ation of any
necessary treatment (i.e., insulin adminis-
tration).
Two previous studies reached similar
conclusions (14,15) but were not deni-
tive because of study desi gn issues (1 8).
Both studies compared a diet intervention
with surgery in two distinct groups of
obese participants, but the patients base-
line characteristics were not well-
matched. Campos et al. (15) randomized
some, but not all, of a cohort of obese
patients without diabetes to undergo
RYGB (n = 12) or diet (n = 10). Two weeks
postoperati vely or after being plac ed on
the diet, patients lost similar amounts of
weight (9.9 6 2.4 kg for RY GB patients
and 8.2 6 2.3 kg for controls). Although
the RYGB patient s had large in creases in
glucagon-li ke peptide and gas tric inhibi-
tory polypeptide meal responses relative
to the diet- only group, insulin sensitivity
was the same between groups. This study
showed that glucose dynamics improved
in patients without diabetes as a function
of weight loss, independent of an in-
creased incretin response in RYGB pa-
tients.Isbelletal.(14)performeda
similar study involving nine RYGB pa-
tients and nine controls, half of w hom in
each group had diabetes. Insulin sensitiv-
ity was assessed by homeostasis model
assessment in a baseline examination
and then again at any time from 27
days after RYGB or aft er a 4-day pe riod
of caloric restriction for control pa tients.
Similar to what Campos et al. (15) ob-
served, insulin resistance improved after
RYGB or diet, incretin response was
much larger in RYGB patients than in
diet patients, and the improved glucose
disposal appeared to be independent of
incretin responses (14). Both these studies
were further limited by examining glu-
cose dynamics in patients without dia-
betes who might not have the same
defect in incretin physiology that is hy-
pothesized to occur in obe se patie nts
with diabetes (19,20) whose diabetes im-
proves after R YGB (21). Our study eval-
uated only patients with type 2 diabetes
in a completely controlled environment
with strict matching of the dietary intake
and timing of the evaluations among the
two study periods (diet only a nd diet p lus
surgery). T his design enabled us to isolate
the surgery-specic effects from the dietary-
induced effects. Under these strict experi-
mental conditions, we found that glucose
control improved signicantly as a result of
caloric restriction, and there were no addi-
tional glycemic effects observed that could
be directly attributed to the RYGB surgery
per se.
Laferrere et al. (13) studied the effect
of RYGB on diabetes but matched for
weight loss rather than caloric i ntake.
In a complet ers-only analysis of a non-
randomi zed study in which patients un-
derwent either RYGB (n = 9) or 10-kg
diet-induced weight loss (n = 10), there
was a substantial incretin response to oral
glucose in postoper ative RYGB not seen in
diet patients. However, the study inter-
pretation is limited by the differential
rate of weight loss and study length be-
tween the two g roups. RYGB patients lost
the target weight of 10 kg in 32.3 6 13.1
days compared with 55.0 6 9.9 days in
the diet group (P , 0.001), a difference
determined by the caloric content of their
diets: 600800 calories/day in the RYGB
group compared wi th 1,000 calories/day
in the diet group.
Our study results are also in line with
those of recent reports obtained after
longer-term follow-up after RYGB. Bradley
et al. (22) compared pa tients without di-
abetes who underwent either RYGB or
laparoscopic adjustable gastric banding (a
primarily restrictive procedure that does
not involve intestinal bypass). Similar im-
provements in insulin sensitivity, b-cell
function, hepatic glucose output, and in-
trahepatic fat content we re not ed after
having lost 20% of their body weight at
46 months after surgery. Furthermore, a
large retrospective review of patients with
diabetes who underwent RYGB showed
that 68.2% of patients attained diabetes
resolution within 5 years of surgery, but
35.1% of these experienced a subsequent
relapse (23). Weight trajectories after
surgery were signicantly different for
never-remitters, relapsers, and durable re-
mitters, for whom greater weight loss
predicted a durable remission. These
studies, along with a growing body of lit-
erature (22), suggest that caloric r estric-
tion and weight loss are signicant
contributors to diabet es remiss ion both
in the early phase and long-term after
RYGB. Furthermore, weight regain is
one of the main predictors of diabetes re-
lapse after surgery.
We attribut e the slight differen ce in
overall glycemia between our two study
periods to the surgery-related stress re-
sponse.Wenotedasignicant differ ence
in the daily glycemia starting the day of
surgery (day 3), a difference that gradu-
ally narrowed over the next 5 days, with
the values convergi ng over the last 2 days
in the study (Fig. 2C). Our nal evalua-
tions (MMCT) occurred 7 days aft er the
surgery, a time a t which the stress re-
sponse has rece ded as evidenced by the
convergence of the glycemic curves and
normalization of the acute stress respon se
indicators of heart rate (79.4 beats per
minute; 95% CI, 71.986.8), white blood
cell count (8.79 10
6
/mL;7.0610.52),
platelet count (286.9 10
9
/L;247.77
326.03), and cortisol level (12.48 mg/dL;
10.1214.84). Therefore, although the
results of the overall glycemia during the
entire study period were likely attribut-
able to surgery-induced stress response,
we conclude that the results of the
MMCT performed 7 days after surgery
were not affected by the postsurgical
stress response , and the results show the
true effect of the dietary intervention ver-
susdietplussurgery.
We acknowledge a lim itation of the
study in that the baseli ne weight for the
two study periods was not iden tical.
Patients did not r egain the entire weight
lost du ring the diet period, which poten-
tially could limit the effect size of the
intervention in the second study period.
We do not think this factor played a major
role in the results we obse rved because
all glycemic parameters were comparable
at the start of both study periods and,
furthermore, although glycemia im-
proved substantially in both study peri-
ods, it did not completely normalize.
Therefore, if the surgery would have h ad
any additional effects beyond the diet
intervention al one, then further low ering
of the glucose levels toward normal levels
should have been observed.
Our study led us to hypothesize that
different mechanisms for improvement in
diabetes prevail at different time points
after RYGB. In the immediate postopera-
tive period (at least 1 week, likely up to
24 weeks), the severely restricted oral ca-
loric intake is primarily responsible for the
changes in glycemia. Of note is that the
majority of diabetes improvement occurs
in this timeframe. As weight loss ensues
and insulin sensitivity improves, consoli-
dati on of this improvement occurs over
2746 DIABETES CARE, VOLUME 36, SEPTEMBER 2013 care.di abetesjour nals.org
What causes postbypass diabetes remission?
the following few months, an improve-
ment that is commensurate with the
amount of weight lost (24). In the long-
term, it is possible that chronic glucagon-
like protein 1 stimulation (and other
incretin hormones) leads to b-cell regen-
eration or hypertrophy and increased in-
sulin secretion, which can protect from
diabetes recurrence as a small amount of
weight is regained, although to date no
studies have been able to prove this hy-
pothesis. We believe the main effect of
the surgically induced enhancement in
the incretin hormones is centrally medi-
ated, resulting in satiety and aiding the
long-term adherence to such signicant
dietary restrictions. The dietary restric-
tions are ultimately responsible for the di-
abetes improvement and remission as well
as the weight loss.
The clinical implication of our nding
is that nonsurgical interventio ns that suc-
cessful ly achieve and maintain such strict
caloric restriction have the potential to
resolve diabetes to a comparabl e degree as
RYGB. Long-term studies comparing the
effect to RYGB surgery with identical
nons urgical caloric restriction are warran-
ted to fu lly eva luate this concept.
We conclude that the rapid improve-
ment in d iabetes after RYGB is mediated
through caloric restriction without a need
to invoke a prim ary di rect ho rmona l
mechanism related to duodenal bypass.
AcknowledgmentsdThe study was sup-
ported by a Pilot Award to I.L. from N IH 3UL1
RR024982-05S1. I.L. was supported by NIH
K23RR0244 70.
No potential conicts of inter est relevant to
this article were reported.
I.L. designed and performed the stud y, an-
alyzed the data, and wrote the manuscript.
E.G. and A.I . helped with study recruitment
and edited the manuscript. E.L . helped with
study design and edited the manuscript. I.L. is
the guarantor of this work and, as suc h, had
full access to all the data in the study and takes
responsibility for the integrity of the data and
the accuracy of the data analysis.
The authors extend their deepest apprecia-
tion to Mic hael Brown, MD (Department of
Molecular Genetics), for assistanc e in planning
the study and editing the manuscript an d to
Laura Golici, BA, and Madhuri Poduri, MS (En-
docrinology Division, Department of Internal
Medicine) for their expert help in protocol
implementation, patient care, and data collec-
tion. The authors would also like to thank all
the study volunteers, the Clinical and Trans-
lational R esearch Center staff, Bariatric C linic
staff, University Hospital Staff, Adam Coster,
Lori Evans (all at University of Texas South-
western Medical Center), and Nic Burtea.
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care. diabetesjournals.org DIABETES CARE, VOLUME 36, SEPTEMBER 2013 2747
Lingvay and Associates
... Bariatric surgery provides a long-term solution for patients with severe obesity. Bariatric surgeries are effective for both substantial weight loss and improved glucose metabolism, resulting in the remission of type 2 diabetes mellitus (DM) (1)(2)(3)(4)(5)(6)(7), especially in patients with a history of diabetes for less than 5 years (4,5,8), and the effects are superior to conventional non-surgical diabetes therapy (4,5). Among bariatric surgeries, Roux-en Y gastric bypass (RYGB) has the most powerful therapeutic effect on the resolution of DM and obesity. ...
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The Roux-en-Y gastric bypass (RYGB) is highly effective in the remission of obesity and associated diabetes. The mechanisms underlying obesity and type 2 diabetes mellitus remission after RYGB remain unclear. This study aimed to evaluate the changes in continuous dynamic FDG uptake patterns after RYGB and examine the correlation between glucose metabolism and its transporters in variable endocrine organs using 18F-fluoro-2-deoxyglucose positron emission tomography images. Increased glucose metabolism in specific organs, such as the small intestine and various fat tissues, is closely associated with improved glycemic control after RYGB. In Otsuka Long-Evans Tokushima Fatty rats fed with high-fat diets, RYGB operation increases intestine glucose transporter expression and various fat tissues’ glucose transporters, which are not affected by insulin. The fasting glucose decrement was significantly associated with RYGB, sustained weight loss, post-RYGB oral glucose tolerance test (OGTT) area under the curve (AUC), glucose transporter, or glycolytic enzymes in the small bowel and various fat tissues. High intestinal glucose metabolism and white adipose tissue-dependent glucose metabolism correlated with metabolic benefit after RYGB. These findings suggest that the newly developed glucose biodistribution accompanied by increased glucose transporters is a mechanism associated with the systemic effect of RYGB.
... Thus, the anti-diabetic effect conferred by comparable weight loss to that of RYGB is sufficient to improve glucose homeostasis in the settings of attenuated peripheral GLP-1 levels and lack of GLP-1R signaling. This is consistent with human studies in which patients undergoing equivalent weight loss via mechanisms that do not enhance gut hormone secretion (i.e., calorie restriction and restrictive bariatric procedures) exhibit comparable improved glucose homeostasis to RYGB [6,[48][49][50][51]. In addition, despite the fact that WT WM-sham mice do not exhibit the enhanced glucose-stimulated plasma insulin observed in WT RYGB mice, glucose excursion in these mice is equivalent. ...
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Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency %, a, b ABSTRACT Glucagon-like peptide-1 (GLP-1) secretion is greatly enhanced after Roux-en-Y gastric bypass (RYGB). While intact GLP-1exerts its metabolic effects via the classical GLP-1 receptor (GLP-1R), proteolytic processing of circulating GLP-1 yields metabolites such as GLP-1(9-36)amide/GLP-1(28-36) amide, that exert similar effects independent of the classical GLP-1R. We investigated the hypothesis that GLP-1, acting via these metabolites or through its known receptor, is required for the beneficial effects of RYGB using two models of functional GLP-1 deficiency-α-gustducin-deficient (α-Gust À / À) mice, which exhibit attenuated nutrient-stimulated GLP-1 secretion, and GLP-1R-deficient mice. We show that the effect of RYGB to enhance glucose-stimulated GLP-1 secretion was greatly attenuated in α-Gust À / À mice. In both genetic models, RYGB reduced body weight and improved glucose homeostasis to levels observed in lean control mice. Therefore, GLP-1, acting through its classical GLP-1R or its bioactive metabolites, does not seem to be involved in the effects of RYGB on body weight and glucose homeostasis.
... Metabolic and hormonal alterations of the enteroinsular axis following bariatric surgery via secretion of incretins (such as glucosedependent insulinotropic peptide and glucagon-like peptide-1) establish a new homeostasis for glucose metabolism in bariatric surgery patients which is not seen in other surgical patients [18]. On the other hand, there is also controversy that it may just be the very low-calorie diet, early on after surgery, that has the dominant effect on glycemic control [19,20]. Regardless of etiology, the end result is bariatric surgery improves glycemic control. ...
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Introduction In cardiac and orthopedic surgery, elevated glycosylated hemoglobin (HbA1c) is a modifiable risk factor for postoperative complications. However, in bariatric surgery, there is insufficient evidence to assess the effectiveness of preoperative HbA1c assessment and its association with postoperative complications. The objective of this study was to assess the impact of HbA1c on early postoperative outcomes in bariatric surgery patients. Methods Patients who underwent laparoscopic sleeve gastrectomy and laparoscopic Roux-En-Y Gastric Bypass between 2017 and 2018 were selected for a retrospective review from the metabolic and bariatric surgery accreditation and quality improvement program (MBSAQIP) database. The study population of 118,742 patients was analyzed for our primary outcome which was defined as a composite of any postoperative complications occurring within 30 days. Two groups were defined by HbA1c cutoff: comparison point A (≤ 8% vs > 8%) and comparison point B (≤ 10% vs > 10%). Procedure-related complications were also examined on subgroup analysis. Propensity score matching (PSM) was used with one-to-one matching. The complication rates before and after PSM were calculated and assessed by Fisher’s exact test and conditional logistic regression, respectively. Results After PSM, demographic and clinical characteristics were all balanced and elevated HbA1C was not associated with worse outcomes. After adjusting for underlying comorbidities, there was no statistically significant difference seen in the composite outcome for comparison point A HbA1C ≤ 8 and HbA1C > 8 (p = 0.22). For comparison point B, patients with HbA1C ≤ 10 had more composite complications compared to patients with HbA1C > 10 (p < 0.001). Also, on subgroup analysis after PSM for procedure-specific complications, patients above the cutoff threshold of 8 did not have worsened composite outcomes (p = 0.58 and 0.89 for sleeve and bypass, respectively). Again, at cutoff threshold of 10, patients in HbA1C ≤ 10 had more composite complications (p = 0.001 and 0.007 for sleeve and bypass, respectively). Conclusion In this study of bariatric patients, elevated HbA1c > 8% or 10% was not associated with increased postoperative complications. HbA1c lower than 10% was associated with some types of adverse outcomes in this bariatric dataset. More studies are needed to investigate these findings further. A high HbA1c alone may not disqualify a patient from proceeding with bariatric surgery.
... A major limitation of the study design in humans was the lack of a diet-or calorie restriction-matched control group. Even though it has been shown that the early beneficial effects of RYGB surgery o i suli resista e a d β-cell function are independent from weight loss [89,90], other studies have suggested that severe caloric restriction, which is typical of the immediate RYGB post-operative period, is pri arily respo si le for the rapid i prove e ts i i suli resista e a d β-cell function after RYGB surgery [138][139][140]. Therefore, early caloric restriction prior to major weight loss might also be involved in the improvement of HDL functional properties after RYGB in humans; our data in rats does not support this hypothesis as the body weight-matched control group was calorie-restricted similar to the RYGB-operated group. ...
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Background: Gastric bypass has profound effects on glycemic control in adults with type 2 diabetes mellitus. The goal of this study was to examine the long-term rates and clinical predictors of diabetes remission and relapse among patients undergoing gastric bypass. Methods: We conducted a retrospective cohort study of adults with uncontrolled or medication-controlled type 2 diabetes who underwent gastric bypass from 1995 to 2008 in three integrated health care delivery systems in the USA. Remission and relapse events were defined by diabetes medication use and clinical laboratory measures of glycemic control. We identified 4,434 adults with uncontrolled or medication-controlled type 2 diabetes who had gastric bypass. Results: Overall, 68.2 % (95 % confidence interval [CI], 66 and 70 %) experienced an initial complete diabetes remission within 5 years after surgery. Among these, 35.1 % (95 % CI, 32 and 38 %) redeveloped diabetes within 5 years. The median duration of remission was 8.3 years. Significant predictors of complete remission and relapse were poor preoperative glycemic control, insulin use, and longer diabetes duration. Weight trajectories after surgery were significantly different for never remitters, relapsers, and durable remitters (p = 0.03). Conclusions: Gastric bypass surgery is associated with durable remission of type 2 diabetes in many but not all severely obese diabetic adults, and about one third experience a relapse within 5 years of initial remission. More research is needed to understand the mechanisms of diabetes relapse, the optimal timing of surgery in effecting a durable remission, and the relationship between remission duration and incident microvascular and macrovascular events.
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Behavioral and pharmaceutical intervention to treat obesity and its comorbidities typically results in only a 5-10% weight loss. Thus, bariatric surgery is the most effective obesity treatment with some surgeries resulting in 30% sustained weight loss. Although this degree of weight loss has profound metabolic impact, these surgeries seem to have metabolic effects that are independent of weight loss. In support of this is the clinical literature showing rapid resolution of Type 2 diabetes mellitus (T2DM) that occurs before significant weight loss. To gain a complete understanding of the weight loss-independent effects of bariatric surgery, animal models have been developed. These are becoming more widely implemented and allow the use of pair-fed or weight-matched sham-operated controls in order to gain mechanistic insights into the mode of action of bariatric surgery. Increases in anorectic gut hormones, such as glucagon-like peptide-1 and peptide YY, or decreases in the orexigenic hormone ghrelin have been seen and are implicated as mediators of weight loss-independent actions of bariatric surgery. Changes in nutrient processing and sensing may also have a mechanistic role that is independent of, or that regulates, gut hormone responses to these surgeries. Ultimately, the hope is that understanding the mechanisms of bariatric surgeries will aid in the development of less invasive surgeries or pharmacological therapies that are more specifically, and perhaps individually, targeted at weight loss and/or resolution of T2DM.
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Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake. Eleven people with type 2 diabetes (49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m(2), nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet. Basal hepatic glucose output, hepatic and peripheral insulin sensitivity and beta cell function were measured. Pancreas and liver triacylglycerol content was measured using three-point Dixon magnetic resonance imaging. An age-, sex- and weight-matched group of eight non-diabetic participants was studied. After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l; p = 0.003). Insulin suppression of hepatic glucose output improved from 43 ± 4% to 74 ± 5% (p = 0.003 vs baseline; controls 68 ± 5%). Hepatic triacylglycerol content fell from 12.8 ± 2.4% in the diabetic group to 2.9 ± 0.2% by week 8 (p = 0.003). The first-phase insulin response increased during the study period (0.19 ± 0.02 to 0.46 ± 0.07 nmol min(-1) m(-2); p < 0.001) and approached control values (0.62 ± 0.15 nmol min(-1) m(-2); p = 0.42). Maximal insulin response became supranormal at 8 weeks (1.37 ± 0.27 vs controls 1.15 ± 0.18 nmol min(-1) m(-2)). Pancreatic triacylglycerol decreased from 8.0 ± 1.6% to 6.2 ± 1.1% (p = 0.03). Normalisation of both beta cell function and hepatic insulin sensitivity in type 2 diabetes was achieved by dietary energy restriction alone. This was associated with decreased pancreatic and liver triacylglycerol stores. The abnormalities underlying type 2 diabetes are reversible by reducing dietary energy intake.
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We commend Isbell et al. (1) on an important study on the immediate weight loss–independent effects of Roux-en-Y gastric bypass (RYGB) and caloric restriction on glucose metabolism. The study, along with others (2), adds to the increasing understanding of changes in insulin resistance postbariatric surgery. However, the criteria applied to select the …
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Many of the metabolic benefits of Roux-en-Y gastric bypass (RYGB) occur before weight loss. In this study we investigated the influence of caloric restriction on the improvements in the metabolic responses that occur within the 1st week after RYGB. RESEARCH METHODS AND DESIGN: A mixed meal was administered to nine subjects before and after RYGB (average 4 +/- 0.5 days) and to nine matched, obese subjects before and after 4 days of the post-RYGB diet. Weight loss in both groups was minimal; the RYGB subjects lost 1.4 +/- 5.3 kg (P = 0.46) vs. 2.2 +/- 1.0 kg (P = 0.004) in the calorically restricted group. Insulin resistance (homeostasis model assessment of insulin resistance) improved with both RYGB (5.0 +/- 3.1 to 3.3 +/- 2.1; P = 0.03) and caloric restriction (4.8 +/- 4.1 to 3.6 +/- 4.1; P = 0.004). The insulin response to a mixed meal was blunted in both the RYGB and caloric restriction groups (113 +/- 67 to 65 +/- 33 and 85 +/- 59 to 65 +/- 56 nmol x l(-1) x min(-1), respectively; P < 0.05) without a change in the glucose response. Glucagon-like peptide 1 levels increased (9.2 +/- 8.6 to 12.2 +/- 5.5 pg x l(-1) x min(-1); P = 0.04) and peaked higher (45.2 +/- 37.3 to 84.8 +/- 33.0 pg/ml; P = 0.01) in response to a mixed meal after RYGB, but incretin responses were not altered after caloric restriction. These data suggest that an improvement in insulin resistance in the 1st week after RYGB is primarily due to caloric restriction, and the enhanced incretin response after RYGB does not improve postprandial glucose homeostasis during this time.
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Obesity is an important risk factor for type 2 diabetes mellitus (T2DM). Weight loss improves the major factors involved in the pathogenesis of T2DM, namely insulin action and beta cell function, and is considered a primary therapy for obese patients who have T2DM. Unfortunately, most patients with T2DM fail to achieve successful weight loss and adequate glycemic control from medical therapy. In contrast, bariatric surgery causes marked weight loss and complete remission of T2DM in most patients. Moreover, bariatric surgical procedures that divert nutrients away from the upper gastrointestinal tract are more successful in producing weight loss and remission of T2DM than those that simply restrict stomach capacity. Although upper gastrointestinal tract bypass procedures alter the metabolic response to meal ingestion, by increasing early postprandial plasma concentrations of glucagon-like peptide 1 and insulin, it is not clear whether these effects make an important contribution to long-term control of glycemia and T2DM once substantial surgery-induced weight loss has occurred. Nonetheless, the effects of surgery on body weight and metabolic function indicate that bariatric surgery should be part of the standard therapy for T2DM. More research is needed to advance our understanding of the physiological effects of different bariatric surgical procedures and possible weight loss-independent factors that improve metabolic function and contribute to the resolution of T2DM.
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Objective: This report documents that the gastric bypass operation provides long-term control for obesity and diabetes. Summary background data: Obesity and diabetes, both notoriously resistant to medical therapy, continue to be two of our most common and serious diseases. Methods: Over the last 14 years, 608 morbidly obese patients underwent gastric bypass, an operation that restricts caloric intake by (1) reducing the functional stomach to approximately 30 mL, (2) delaying gastric emptying with a c. 0.8 to 1.0 cm gastric outlet, and (3) excluding foregut with a 40 to 60 cm Roux-en-Y gastrojejunostomy. Even though many of the patients were seriously ill, the operation was performed with a perioperative mortality and complication rate of 1.5% and 8.5%, respectively. Seventeen of the 608 patients (< 3%) were lost to follow-up. Results: Gastric bypass provides durable weight control. Weights fell from a preoperative mean of 304.4 lb (range, 198 to 615 lb) to 192.2 lb (range, 104 to 466) by 1 year and were maintained at 205.4 lb (range, 107 to 512 lb) at 5 years, 206.5 lb (130 to 388 lb) at 10 years, and 204.7 lb (158 to 270 lb) at 14 years. The operation provides long-term control of non-insulin-dependent diabetes mellitus (NIDDM). In those patients with adequate follow-up, 121 of 146 patients (82.9%) with NIDDM and 150 of 152 patients (98.7%) with glucose impairment maintained normal levels of plasma glucose, glycosylated hemoglobin, and insulin. These antidiabetic effects appear to be due primarily to a reduction in caloric intake, suggesting that insulin resistance is a secondary protective effect rather than the initial lesion. In addition to the control of weight and NIDDM, gastric bypass also corrected or alleviated a number of other comorbidities of obesity, including hypertension, sleep apnea, cardiopulmonary failure, arthritis, and infertility. Gastric bypass is now established as an effective and safe therapy for morbid obesity and its associated morbidities. No other therapy has produced such durable and complete control of diabetes mellitus.