Sommario Medico Chirurgo Specialista in Endocrinologia-Diabetologia Due anni di esperienza negli Usa come Ricercatrice in campo diabetologico Numerose pubblicazioni scientifiche in campo metabolico-diabetologico su riviste e mediche nazionali e internazionali Esperienze Dal Gennaio 1992 al Dicembre 1993 Diabetes Research Program , University of professionali California, Irvine USA
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Sem título-Preliminary Report: Adaptive entero-omentectomy: Physiological and evolutionary bases of an auxiliary treatment to type 2 diabetes Adaptive entero-omentectomy: Physiological and evolutionary bases of an auxiliary treatment to type 2 diabetes Entero-omentectomia adaptativa: Bases fisiológicas e evolucionárias de uma proposta cirúrgica auxiliar no tratamento de diabetes tipo 2 Sérgio Santoro1, Manoel Carlos Prieto Velhote2, Carlos Eduardo Malzoni3, Alexandre Sérgio Garcia Mechenas4, Plasminogen activator inhibitor-1; Omentum/physiology; Adiposetissue/physiopathology Objective: The objective of this article is to report on a new surgicalstrategy specifically designed to treat type 2 diabetes: adaptiveentero-omentectomy (AEO), and present its rationale andpreliminary results. Some techniques used in bariatric surgery are capable of producing fast improvement in type 2 Diabetes Objetivo: O objetivo deste artigo é descrever uma nova estratégia Mellitus, before significant loss of weight, due to metabolic cirúrgica especificamente desenhada para tratar diabetes tipo 2: changes that are currently being explained. Methods: Two type 2 enteroomentectomia adaptativa (EOA), apresentar suas bases e diabetic patients were operated on. The technique included an seus resultados precoces. Algumas técnicas usadas em cirurgia enterectomy that left the first 40 cm of the jejunum and the last bariátrica são capazes de produzir rápida melhora no diabetes 260 cm of the ileum, besides the resection of the greater omentum.
mellitus tipo 2 antes de alcançar uma perda significativa de peso, Results: At five and seven-month follow-up, both patients had no devido às alterações metabólicas que agora estão sendo symptoms, reported early satiety and presented improved compreendidas. Métodos: Dois pacientes com diabetes tipo 2 metabolic profile. Conclusions: This is the preliminary report of a foram operados. A técnica incluiu uma enterectomia que deixou surgical technique designed to help treating type 2 diabetes. It is os primeiros 40 cm do jejuno e os últimos 260 cm do íleo, além da based on leaving the bowel in the lower limit of normal range, ressecção do grande omento. Resultados: Após um seguimento diminishing the highly permeable portions and taking more nutrients de cinco e sete meses, os dois pacientes estavam sem sintomas, to the distal bowel to enhance the secretion of enterohormones.
referiam saciedade precoce e apresentavam melhora no seu perfil The aim of omentectomy is to reduce visceral fat, contributing to metabólico. Conclusões: Esta é uma apresentação dos resultados a decreased production of plasminogen activator inhibitor-1 (PAI-1) iniciais de uma técnica cirúrgica desenhada para ajudar no and resistin. After surgery, the patients do not need nutritional tratamento de diabetes tipo 2. O princípio da técnica é deixar o support. The procedure is simple to perform and its rationale and intestino com o comprimento mínimo considerado normal, diminuir preliminary results are encouraging. A protocol with more patients as porções com alta permeabilidade e levar mais nutrientes ao and long-term observation is needed.
intestino distal, visando melhorar a secreção de enterormônios. Aomentectomia visa reduzir a gordura visceral, contribuindo para a Keywords: Type 2 Diabetes; Small bowel/physiology; Enterectomy/ redução da produção de inibidor do ativador do plasminogênio tipo methods; Peptide hormones; Obesity, morbid/surgery; 1 (PAI-1) e resistina. O procedimento é simples e após a cirurgia * Study carried out at Hospital da Polícia Militar do Estado de São Paulo. 1 M.D., Master’s degree in Medicine from the Medical School of the Universidade de São Paulo (FMUSP), Fellow of the Colégio Brasileiro de Cirurgia Digestiva.
2 M.D., Ph.D. in Medicine from FMUSP, Assistant Professor of the Discipline of Pediatric Surgery of FMUSP.
3 M.D., Master’s degree in Medicine from FMUSP, Fellow of the Colégio Brasileiro de Cirurgiões.
4 M.D. Fellow of the Colégio Brasileiro de Cirurgia Digestiva, Fellow of the Sociedade Brasileira de Videocirurgia.
5 M.D., Ph.D. in Internal Medicine from the University of Bonn, Germany.
Corresponding author: Sérgio Santoro - R. São Paulo Antigo, 500 - ap. 111 SD - CEP 05684-010 - São Paulo (SP), Brazil - e-mail: [email protected] Received on September 28, 2003 - Accepted on March 3, 2004 Santoro S, Velhote MCP, Malzoni CE, Mechenas ASG, Felizola SFA os pacientes não necessitam de suporte nutricional. Os resultados endogenous secretion of GLP-1 can do the same, or at iniciais são estimulantes. Um protocolo com mais pacientes e least improve postprandial glucose levels.
maior tempo de observação é necessário.
We believe that this impaired secretion may be the product of long small bowels (following herbivore Descritores: Diabetes tipo 2; Intestino delgado/fisiologia; models designed to eat mostly food with less calorie Enterectomia/métodos; Hormônios peptídicos; Obesidademórbida/cirurgia; Inibidor do ativador do plasminogênio tipo 1; density), worsened by modern diet, which is highly Omento/fisiologia; Tecido adiposo/fisiopatologia absorbable and leaves the distal bowel with littlenutrient stimulation(14). A recent publication(15)concluded that bowel length correlates with weight, Type 2 diabetes mellitus (T2DM) has become a major A modern diet can be very caloric in small volumes burden to mankind. Over the last three decades, it was and very easily absorbed. This jeopardizes the unexpectedly observed that many surgeries designed neuroendocrine signals that depend on distension and to treat obesity could immediately revert or vastly on the presence of nutrients in the distal bowel to improve T2DM, even before the loss of significant trigger secretion of enterohormones. Based on this weight(1). It became clear that unknown metabolic concept, we recently described a new surgical technique effects, unrelated to loss of weight, caused this.
to treat obesity(3) that simply reduces gastric capacity Recently, duodenal-jejunal exclusion was pointed out with a vertical (sleeve) gastrectomy and shortens the as the anatomical feature responsible for this finding(2).
length of the small bowel to the lower limit of normality However there are anatomical, physiological and (3 meters); hence, it keeps mainly the ileum, and avoids evolutionary data to support the idea that type 2 prosthesis, excluded segments, subocclusions or diabetes mellitus is the product of a digestive tract malabsorption. The general structure of the designed to eat a primitive diet, but which is exposed gastrointestinal tract is preserved. Medium-term results to a modern diet. Moreover, a new technique(3) and its are encouraging. We observed a rapid improvement of variant(4), both recently described to treat obesity, have associated type 2 diabetes even before significant weight shown good results in improving diabetes even with no loss took place, and there was no duodenal-jejunal duodenal-jejunal exclusion. Instead, having more exclusion (unpublished data). Improvement of the nutrients reaching distal portions of the small bowel distal bowel hormone secretion, simply by enabling seems to be the real trigger of the improvement in nutrients to reach distal portions, is probably the reason It is known that taking sugar orally results in a more efficient insulin secretion in normal subjects than that We raised the hypothesis that we could use the same caused by intravenous injection. This has been called technique(3) even when obesity is not the central “the incretin effect”(5), and is caused by the secretion problem, thus not operating on the stomach and of enterohormones, especially glucagon-like peptide favoring more ileum and less jejunum in the remaining 1 (GLP-1)(6) mainly by the distal part of the small bowel.
bowel. Not including sleeve gastrectomy in the Other enterohormones, like polypeptide YY (PYY)(7) procedure generated a simpler technique, not focused and oxyntomodulin (Oxm)(8), together with GLP-1(9) on the treatment of obesity, but on assisting in the induce a delay in gastrointestinal transit and satiety(6,10).
treatment of type 2 diabetes mellitus.
These important signals generated by the bowelannounce, especially to the pancreas andhypothalamus, that a nutritive meal has been taken.
Both obese(11) and type 2 diabetic(12) individuals have Under general anesthesia, a ten-centimeter midline, attenuated GLP-1 secretion. One could think that they supraumbilical incision is performed. The procedure might not be able to produce GLP-1. Nonetheless, both consists in excising the greater omentum, followed by immediately after and many years after a jejuno-ileal enterectomy. The first 40 cm of the jejunum and the bypass (which takes nutrients to the distal gut through last 260 cm of the ileum were left. An end-to-end a shortcut), normal GLP-1 secretion is re-established(13).
anastomosis and the closure of the space between the It is important to say that exogenous GLP-1 is potent mesenteric borders are the final steps.
enough to normalize fasting and postprandial glucose The Research Ethics Committee of the Hospital da levels in type 2 diabetic patients(9). It is reasonable to Polícia Militar do Estado de São Paulo approved the accept that the normalization of a previously deficient “Digestive Adaptation Protocol”.
Preliminary Report: Adaptive entero-omentectomy: Physiological and evolutionary bases of an auxiliary treatment to type 2 diabetes medications, all his laboratory tests were normalized, All patients were sent to the Surgery Department to including transaminases. Total cholesterol was 147 mg/ be submitted to our obesity surgery protocol called dL, LDL-cholesterol = 84 mg/dL, triglycerides = 120 “Digestive Adaptation”(3). However, they reported that mg/dL, fasting glucose level = 98 mg/dL, and two hours diabetes was the main reason for being there, since after ingestion of dextrose 75 g = 108 mg/dL. Blood they live in poor conditions, the treatment is expensive tests were repeated every two months. In August 2004, and carried out irregularly. All patients had blood his tests were as follows: total cholesterol = 153 mg/ glucose levels over 400 mg/dL in some occasions and dL, triglycerides = 86 mg/dL, A1c hemoglobin = 4.2% were under medical treatment.The “Digestive (checked twice; low pressure liquid chromatography – Adaptation Protocol”(3) was applied, but their stomachs normal values from 4.0% up to 6.3%).
were spared according to a special informed consent.
An independent clinician (S.F.A.F.), not related to the Patient 2: A 37-year-old male, height = 172 cm,
surgical group, followed-up the patients and checked weight = 122 kg (body mass index = 41.2 kg/m2). He was admitted to the emergency room in 1997 due tohyperglycemia, with a diagnosis of T2DM. Since then, Patient 1: A 38-year-old male, height = 168 cm,
weight = 109 kg (body mass index = 38.6 kg/m2) was dyslipidemia and prescribed glibenclamide (5 mg/once admitted to the Hospital da Polícia Militar do Estado a day), metformin (850 mg/twice a day) and ciprofibrate de São Paulo, in December 2003, due to polyuria, (100 mg/day). His blood tests prior to medical treatment polydipsia and mild hypertension. Blood glucose level were: fasting glucose = 256 mg/dL; total cholesterol was over 400 mg/dL. After four days, he was stable, = 351 mg/dL; triglycerides = 1257 mg/dL; A1c was discharged and prescribed glibenclamide (5 mg/day), metformin (500 mg/once a day) and his previous chromatography – normal values up to 6.3%).
antihypertensive agents (clonidine and clortalidone).
He was submitted to the same procedure on April Because of poor compliance to diabetes treatment and 14th, 2004, and the excised bowel was 240-cm long. The previous failure in obesity treatment, he was referred to surgery with the following diagnosis: obesity, type 2 He also reported early satiety and lost 7 kg in five diabetes, nonalcoholic steatohepatitis (NASH) with months. While not taking any medication, his blood abnormal transaminases, and mild systemic glucose levels were measured twice a day (even after hypertension. His blood tests prior to surgery were as meals) and were never > 120 mg/dL. Total cholesterol follows: fasting glucose = 223 mg/dl; after a higher dose = 150 mg/dL, LDL -cholesterol = 82 mg/dL, of metformin (500 mg/twice a day) it dropped to 144 triglycerides = 184 mg/dL, fasting glucose = 108 mg/dL mg/dl; total cholesterol = 159 mg/dl; triglycerides = and 2 hours after ingestion of dextrose 75 g = 128 mg/dL.
255 mg/dL; A1c hemoglobin = 9.4% (high performance No change in the frequency of bowel movements, or liquid chromatography – normal values up to 6.3%).
in the aspect of stools was observed.
He was submitted to surgery on February 11th, 2004.
The excised bowel was 220-cm long. The surgery took 90 minutes. Patient resumed feeding on the second The primitive diet was hypodense in terms of calories postoperative day; he was discharged on the third day, and rich in poorly digestible fiber. The individuals had and told to keep his diabetic diet and discontinue all to ingest large food volumes to obtain a relatively small medications. Blood glucose levels were checked twice amount of calories. Internal feeding signals could be a day (fasting and one to two hours after the main based on volume. In addition, it is hard to extract meal). After the operation, his fasting blood glucose nutrients from the bulky non-nutritive particles and levels were under 100 mg/dL and postprandial levels absorb them. A long bowel is important as a container, were under 140 mg/dL. In addition, his systolic blood but it also enables the absorption of nutrients. In this pressure was not over 140 mm Hg, and the diastolic diet, more nutrients would reach distal parts.
In nature, the poorer a diet is in calories and the He reported that he was eating much less due to richer it is in fibers, the longer is the bowel(16). That is earlier satiety and had lost 7 kg in seven months. The the main reason why herbivores have longer bowels than patient also reported an enhanced physical sense of carnivores. In the primitive primate diet, internal well-being and was very much satisfied with the signaling of a fully-fed state could also rely on the procedure results. After one month taking no presence of nutrients in the distal bowel.
Santoro S, Velhote MCP, Malzoni CE, Mechenas ASG, Felizola SFA The modern diet has concentrated, highly absorbable causing central satiety and stopping the eating process, nutrients (including unnatural elements like refined and diminishing gastric acid output, since the meal sugar) and progressively less fibers and less residues. It is possible to efficiently absorb these elements in the In short, to live with 3 or 8 meters of small bowel very first portions of the intestine, creating peaks of (lengths found in normal and never-operated-on nutrient absorption and an “empty distal gut”. Internal people) makes little difference in terms of absorption, signaling based on volume and nutrients in the distal since in neither case will malabsorption occur. However, portions fails; an individual would eat without it seems clear that is important to have nutrients generating the proper signals of being fed and secretion reaching and being absorbed in the distal bowel since of GLP-1 and other distal bowel hormones would be it triggers the production of enterohormones that limit attenuated in this scenario, as has already been food ingestion and are signals to the pancreas and to Could longer small bowels exacerbate the undesired These theories suggest that if an individual consumes characteristics of current diet, contributing to obesity, mainly a modern, hypercaloric and easily digestible diet, diabetes, coronary artery disease, dyslipidemias and it might be better to be “normal with 3 meters” than to other conditions typically related to modern diet? be “normal with 8 meters” of small bowel. This may The study performed by Hounnou et al.(15) concluded prevent the consequences of the lack of proper signaling that bowel length correlated with weight but not with from the gut to the brain, announcing the fed state and height. Correlations with obesity-related diseases were not verified, but it is acceptable to assume that.
Evolution has also worked on this matter.
Why is this matter rarely discussed? Simply because Australopithecus robustus, an early hominid specimen normal people are able to absorb almost all the absorbable that lived about 1.5 million years ago, was a herbivore nutrients, whether they have a longer or shorter bowel.
with strong jaws specialized in heavy chewing. During In fact, the experience with short bowel syndrome patients a period of glaciations, plant food became scarce, and tells us that approximately 70 cm of the small bowel are A. robustus became extinct while another group of often enough for adequate oral nutrition if a part of the humans adapted to become omnivorous. The higher ileum is preserved and the colon is present(17). Thus, among concentration of calories in meat allowed these Homo normal people, what difference would it make to have 3 groups to eat smaller volumes of more digestible food.
or 8 meters of small bowel, if in any case, the absorption In humans, the bowel length was reduced(22-23) (as expected, since there are differences between herbivore GLP-1 is a polypeptide hormone secreted mainly by the distal gut in response to nutrient ingestion. It In the last century, another great change occurred has six fundamental actions: it is insulinotropic(18), in the human diet when it became more concentrated glucogenostatic(19), it reduces gastric acid output(20), it in calories and even freer of non-digestible particles.
causes major reduction in gastric emptying(9), it causes This change may lead us to theorize that a further bowel relaxation of the gastric fundus (allowing the stomach reduction is necessary. Evolution is doing its routine to receive larger volumes with no increased sensation job: selection. People are becoming obese, diabetic, and of distension)(21) and finally GLP-1 crosses the blood- dying. Obese people, as pointed out Hounnou et al.(15), brain barrier and causes satiety(10).
The evolutionary aspects of the GLP-1 functions have longer bowels. Shorter bowel is being selected.
are amazing. Because of sporadic access to food in The “current human being” is insufficiently adapted nature, the primitive men had the instinct to eat as to the abundance of easy absorbable nutrients. Type 2 much as possible to create reserves for times of hunger.
diabetes mellitus is one of the consequences.
While they were hungry, the digestive transit had to In terms of permeability, the jejunum is much more be fast and create space for further eating; however, permeable and has a larger surface than the ileum(24).
when nutrients reached the distal gut, it was time to If food suddenly became a lot more absorbable, it seems slow down the transit; otherwise, nutrients could be reasonable to reduce this highly permeable segment so lost in stools. Enterohormones produced by the distal as to decrease peaks of absorption and prevent the gut play this role by slowing gastric emptying, causing early disappearance of nutrients from the lumen.
intense insulin secretion and blocking the action of Indeed, the literature has already shown concern with glucagon to help the body store the absorbed nutrients.
a “more permeable bowel” and diabetes, although this Furthermore, GLP-1 relaxes the gastric fundus to let it publication referred to Type 1 diabetes(25), which is a contain the food that cannot be processed immediately, Preliminary Report: Adaptive entero-omentectomy: Physiological and evolutionary bases of an auxiliary treatment to type 2 diabetes Considering the modern hypercaloric, fiber-poor, easily digestible diet, the jejunum has become We deeply thank Mrs. Muriel Hallet and Mrs. Janice unsuitably long and permeable. The surgical procedure H. Hewins for revising the English version.
presented here (AEO) just copies evolutionary actionsand is an adaptive procedure.
Recent data suggest that chronic insufficiency of GLP-1 production could be related to a progressive 1. Pories WJ. Diabetes. The evolution of a new paradigm. Ann Surg. 2004; loss of beta cells in the pancreas because GLP-1 is a trophic factor for these cells and a stimulator of beta- 2. Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. AnnSurg. 2004;239(1):1-11.
Unlike medical treatment, there is little or no risk 3. Santoro S, Velhote MC, Malzoni CE, Mechenas AS, Strassmann V, Scheinberg of hypoglycemia, since distal hormones are released in M. Digestive adaptation: a new surgical proposal to treat obesity based in perfect synchrony with ingestion and the insulinotropic physiology and evolution. einstein. 2003; 1(2):99-104.
action is also glucose-dependent(27). The positive effect 4. Santoro S, Velhote MC, Malzoni CE, Mechenas AS, Damiani D, Maksoud JG.
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International Journal of Dermatology© 1999 Blackwell Science Ltd. Tretinoin-iontophoresis in atrophic acne scars[Pharmacology and Therapeutics]Schmidt, Jolanta B. MD; Donath, Peter MD; Hannes, Johanna MD; Perl, Sylvia MD; Neumayer, Renate MD;Reiner, Angelika MDFrom the Department of Dermatology, Division of Special and Environmental Dermatology and Institute ofClinical Pathology, University of