Special lecture from Brazil
Surgery forobese and nonobese diabetics: Worldwide perspectives and Brazilian
contributions
Joel Faintuch, Francisco Karkow, Fernanda Pezzi (Sao Paulo University Medical School
and Fatima Faculty, Caxias do Sul)
About 220,000 bariatric operations are performed in the USA each year, and500,000 worldwide, and diabetes affects 30-40% of this population. In addition, 610% of overweight and obese patients who are not bariatric candidates (BMI< 35
kg/m2) may be similarly diabetic. (1-3, 5, 15, 16, 19-22).
Response of diabetes mellitus after bariatric weight loss is a time-dependent
phenomenon for which total and visceral fat are the principal influence, but whereother variables are certainly relevant . Such influences are not static and maychange along the years, being compatible with many outcomes, mostly definitive totemporary resolution but also eventual long-term recurrence.
Mechanisms responsible for outcome of obesity-associated diabetes
areincompletely defined.
Substantial weight loss and resolution of major
comorbidities is unquestionable after bariatric interventions for morbid obesity .
Clinical course till normalization of glucose as well as mid-term follow-up isreported . However, factors responsible for long-term outcome and possible risk of
relapse of diabetes are incompletely defined.
The four principal lines of thought regarding correlates for sustained diabetes
regression after
RYGB involve BMI /visceral fat reduction, changes ofsystemic/gastrointestinal hormones, decrease of cytokines and systemic inflammation,and dietary education/remodeling. Most of these have been examined within the shortterm perspective, consequently information several years after operation except for
BMI is essentially lacking. Three theoretical outcomes can be devised, namely cured
patients (long-term remission), persistent or refractory (nonrespondents) , and newonset diabetes (starting in previously nondiabetic patients).
Incretin expression is increased one month after operation (4) and glucose
and insulin normalization reportedly occurs within days , before any weight loss isapparent (5, 6) . Clinical benefit is believed to materialize by the firstquarter (6, 7) but subjects may require a longer time to react, and 22% ofdiabetic candidates are still drug-dependent around one year (8) . Also Perugini et
al observed improved fasting glucose and insulin levels as early as after 12 days,
but significant additional improvement up to one year was not found (9).
Conflicting reports are more frequent several years after operation. In theexperience of Alexandrides et al with type-2 diabetics, even after two years blood
glucose was above 110 mg/dL in 34% (10). Proinsulin dramatically diminished by 12months in the study of Johansson et al, but slightly recovered around 42 months( 11).
Food intake and macronutrient composition , not just body composition, arelikely to influence long-term findings, but again uneven numbers can be found .
Carrasco indicates ingestion of approximately 800 kcal/day (21.3% protein) at six
months (4) , similarly to Anderson et al with figures at three months of about 700
kcal/day (37 % protein) and 1100 kcal/day after one year (23% protein) (12) These
numbers are consistent with our own experience (2, 23). In contrast the values of
Sjostrom et al at six months were in the range of 1500 kcal/day and at 12 monthsof 1700 kcal/day (13). In between, Bobbioni et al registered nearly 1000 kcal/day(17.9 % protein) at three months,
1140 kcal/day (17.5 % protein) at six months,
and1420 kcal ( 16.2% protein ) by one year (14).

Body mass index is repeatedly linked with diabetes outcome. Even with modern
metabolic procedures for diabetes, such as ileal interposition with or without
duodenal diversion, good glycemic response occurred simultaneously with rapid weightloss (22% in seven months) and a quite low final BMI (24.9 kg/m2) (15). Much of thedifference in long term outcome of malabsorptive versus mixed versus restrictive
interventions may be attributed to differences in BMI reduction ( 13, 16, 17). Thus ,it is appealing to ascribe all antidiabetic benefits to calorie restriction
and weight loss ( 18), though that´s clearly not the full answer.
In a preliminary study by our group, which is still going on, operated morbidly
obese participants were stratified as responsive diabetes, refractory cases , andnever diabetic controls . All underwent gastric bypass (RYGB). Initial BMI was higher
in responsive patients but by two years similar values were detected. White blood
cell count was also higher in these subjects but refractory cases surpassed them by
two years. Baseline lipids were similar in all groups, with less favorable course inrefractory subjects (triglycerides, LDL- and HDL-cholesterol) , starting by two years.
Blood glucose and HbA1c always tended to be more elevated in the refractory subset.
In this sense, age, weight and gender were not relevant for diabetes outcome,dyslipidemia and systemic inflammation correlated with postoperative outcome, andhard to control glucose and HbA1c were also common features of the refractory group( 1).
The four principal lines of thought about mechanism for sustained diabetes
regression after RYGB are summarized in Table 1.
Table 1: Major hypotheses concerning diabetes surgical response
Variable
1) BMI decrease2) Glucose metabolic mediatorsa)Restoration of insulin sensitivityb) Insulin secretionc) Proinsulin reductiond) GIP and GLP-1 secretion
3)
Visceralfat,systemic
inflammation, cytokine activation
4) Dietary calorie and lipid intake

Response
70- 90% success after
malabsorptive,
lower
operations)(13, 16, 18)

RYGB
for

(Higher for
restrictive

No (19)Yes (20)
Improved (4, 20)
Yes (11)
Increased (4, 22)
Decreased adiponectin (21)(13, 14, 18, 23, 24)

Hormones have been especially highlighted by recent investigations, though
results are still preliminary and often conflicting, as alluded to. Basically ahindgut theory is advanced, in the sense that operations which allow food to quickly
reach the ileum would elicit stronger incretin response (GIP, GLP-1). The foregut
alternative attributes to duodenal exclusion the role of modulating incretins,
perhaps by influencing also their antagonists, the anti-incretins. If the importanceof incretins is fairly accepted in metabolic surgery, the same cannot be said aboutanti-incretins, which have not been surely identified or measured in the surgicalcontext (Table 2).

Table 2: Potential roles of incretins and anti-incretins in the diabetes context
General modulation of diabetes
BMI (weight loss)
Severity of disease (Insulin, HbA1c, duration )Gastric factor : ghrelin
Duodenal factors: insulin
Pancreatic factors: incretins, anti-incretins
Ileal factors: Incretins, adiponectin
Hindgut theory: increase of incretins (?)
Foregut theory: reduction of anti-incretins (?)
Activity of incretins (GLP1,GIP)
Insulin synthesis and secretion
Beta cell proliferation and apoptosis
Anti-incretins (cytokines IL-1, TNF, IFN, NO, agents
causing endoplasmic reticulum stress, oxidative stress)
Suppression of the actions of incretins
Metabolic operations at this moment encompass both innovative techniques andclassic bariatric procedures . The first group is currently being conducted in Brazil
only, and is composed by ileal interposition (15, 26), duodeno-jejunal exclusion (27,28), and sleeve gastrectomy, omentectomy and partial enterectomy (Santoro operation)(29). All of them consider both the foregut and the hindgut theories, with variableemphasis on one or the other. Elsewhere conventional interventions have been used forsome time, in overweight, obese and morbidly obese candidates (30, 31). Results witha few options are summarized in Table 3 and 4.
One is tempted to belive that tailor-made interventions will be ideal, but
outcomes so far have not demonstrated clear superiority of new operations versus
classic ones, perhaps because series are still small and populations heterogenous.
Prospective controlled trials, with sufficient follow-up period, will be
indispensable to sort out the best .
Table 3
Table 4
Table 3: Representative results with new surgical modalities
Modality

DJB

(27 )

BMI range
WeightGlucoseHbA1cMedication<30
Reducedandstabilized
44% reduction
22.8% reduction
90% freePopulation

oral and insulin

DJB (28)<30
No change
14% reduction
12% reduction
83% switchedoral
Insulin onlytoIleal interposition(15, 26)
21-34
Reducedandstabilized
40% reduction
57.6% remission
90% freeOral and insulin

Table 4: Diabetes response with traditional operations
Modality
BMI range
WeightGlucoseHbA1cMedication
Population

RYGB (1)>35
32% reduction
36.3%
38.1%
94% free
31% Diabetics

Various (30)<35
17.7% reduction
47%
31%
85.3% free
Oral and insulin

Various (31)>35
29.7% reduction
32%
61% Band, 81% RYGB and SG
Oral and insulin

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