Somatostatin: a possible mediator of the long-term effects of experimental vertical gastrectomy on glucose metabolism in rats?

BACKGROUND: Sleeve gastrectomy (SG) is one of the most commonly performed bariatric surgeries. SG treats type 2 diabetes mellitus better than several drugs. The mechanisms that underlie this phenomenon are not clear. This study proposed that somatostatin (SST) isoforms SST-14 and SST-28 are key in the carbohydrate after SG. METHODS: Surgeries were performed on 3 groups of Wistar rats: the fasting, surgery control, and SG groups. Plasma levels of glucose, insulin, SST-14, and SST-28 were measured at 2 survival periods after surgery. Islet SST receptor (SSTR) and cell populations were studied. We performed a pasireotide (SST-28 analogue) infusion assay in another group of rats to confirm the influence of SST-28 plasma levels on the delta-cell population. RESULTS: This study found an elevation in the insulin response after SG in animals but a decrease in the insulin response over the long term with a loss of beta-cell mass. An increase in duodenal SST-28-producing cells in the duodenum and a loss of pancreatic SST-14-producing cells were observed after SG in animals but not in controls. The expression of SSTR type 5 in delta-cell populations from each group and the ability of the pasireotide infusion assay to decrease the delta-cell population indicated the effect of SST-28 plasma levels on delta-cell maintenance. CONCLUSION: After SG initiates a compensatory response in the duodenum, beta-cell mass is depleted after loss of the brake that regulates SST-14 at the paracrine level in a nonobese, normoglycemic rat model. This was an experimental model, with no clinical translation to the human clinic, with a preliminary importance regarding new pathophysiologic perspectives or pathways.

The role of glucagon after bariatric/metabolic surgery: much more than an "anti-insulin" hormone.

The biological activity of glucagon has recently been proposed to both stimulate hepatic glucose production and also include a paradoxical insulinotropic effect, which could suggest a new role of glucagon in the pathophysiology type 2 diabetes mellitus (T2DM). An insulinotropic role of glucagon has been observed after bariatric/metabolic surgery that is mediated through the GLP-1 receptor on pancreatic beta cells. This effect appears to be modulated by other members of the proglucagon family, playing a key role in the beneficial effects and complications of bariatric/metabolic surgery. Glucagon serves a dual role after sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). In addition to maintaining blood glucose levels, glucagon exhibits an insulinotropic effect, suggesting that glucagon has a more complex function than simply an "anti-insulin hormone".

Dual effect of RYGB on the entero-insular axis: How GLP-1 is enhanced by surgical duodenal exclusion.

BACKGROUND: The role of the ileum and Glucagon Like Peptide-1 (GLP-1) secretion in the pathophysiological processes underlying the effects of Roux-en-Y gastric bypass (RYGB) on type 2 Diabetes mellitus (T2DM) improvement has been previously determined. However, the roles of duodenal exclusion and Glucose Insulinotropic Peptide (GIP) secretion change is not clear. To clarify this aspect, we compared the pathophysiological mechanisms triggered by RYGB, which implies the early arrival of food to the ileum with duodenal exclusion, and through pre-duodenal ileal transposition (PdIT), with early arrival of food to the ileum but without duodenal exclusion, in a nondiabetic rodent model. METHODS: We compared plasma and insulin, glucose (OGTT), GIP and GLP-1 plasma levels, ileal and duodenal GIP and GLP-1 tissue expression and beta-cell mass for n = 12 Sham-operated, n = 6 RYGB-operated, and n = 6 PdIT-operated Wistar rats. RESULTS: No surgery induced changes in blood glucose levels after the OGTT. However, RYGB induced a significant and strong insulin response that increased less in PdIT animals. Increased beta-cell mass was found in RYGB and PdIT animals as well as similar GLP-1 secretion and GLP-1 intestinal expression. However, differential GIP secretion and GIP duodenal expression were found between RYGB and PdIT. CONCLUSION: The RYGB effect on glucose metabolism is mostly due to early ileal stimulation; however, duodenal exclusion potentiates the ileal response within RYGB effects through enhanced GIP secretion.

Somatostatin: From a supporting actor to the protagonist to explain the long-term effect of sleeve gastrectomy on glucose metabolism.

BACKGROUND: Bariatric/metabolic surgery has become the most effective treatment against type 2 Diabetes mellitus (T2DM). The role of many gastrointestinal hormones in T2DM has been proposed, but the pathophysiological models described vary greatly depending on the anatomical rearrangements after surgery. We focus on somatostatin as a common factor in two of the most commonly performed surgical procedures in a healthy rodent model. We performed sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) and also an experimental surgery without gastric involvement (intestinal resection of 50 % jejunum-ileum portion -IR50 %). METHODS: We used five groups of Wistar rats: fasting control, sham-operated, SG-operated, RYGB-operated and IR50-operated. We analysed several parameters 4 and 23 weeks after surgery: plasma SST-14/28 fractions, plasma glucose, insulin release and SST-producing cell expression in the duodenum and pancreatic islets. RESULTS: Numerous SST-producing cells in the duodenum but a low number in the pancreas and a long-term loss of glucose tolerance were observed in SG and RYGB animals. Additionally, a high plasma SST-28 fraction was found in animals after SG but not after RYGB. Finally, IR50 animals showed no differences versus controls. CONCLUSIONS: In our SG model the amplitude of insulin response after metabolic surgeries, is mediated by SST-28 plasma levels derived from the proportional compensatory effect of gastric SST-producing tissue ablation. In addition, a strong compensatory response to the surgical loss of gastric SST-producing cells, leads to long-term loss of insulin production after SG but not in the others.

Beta-cell mass adaptation to ileum nutrient flow. An experimental model.

The population with obesity has increased at an alarming rate during this century. Bariatric surgery has been demonstrated to be a good method to control weight and, most importantly, associated comorbidities, such as type 2 diabetes mellitus or high blood pressure. The reason why this happens even before losing significant weight remains unclear. Many authors believe that incretins play a main role, triggering special functions of the digestive tract. In reports, these hypotheses are known as foregut and hindgut theories. Initially, the theories were mutually exclusive; additionally, many other propositions have been analysed, according to different surgical techniques (e.g., bile acids and specific enterohormonal components). To elucidate the participation of the ileum, we developed a surgical technique to study the rapid response to nutrients in the ileum. Our goal was to study the stress functional test and histological changes in the pancreas that may explain the variations in glycaemic homeostasis in our rat model. After the oral glucose tolerance test, the experimental group presented an increased insulin release response with conserved glycaemia. We report an increasing beta-cell mass in the experimental group (+11.87 mg vs. +9.65 mg, respectively), while alpha-cell mass was not different. Based on transcription factors, the pathways that were increased were the proliferation process (as the number of PCNA-positive cells in the experimental group versus sham (+12.06 vs. +6.2 PCNA+ cells/mm²)) and transdifferentiation (ARX; +2.67 ARX+ cells/mm² in the experimental group vs. +2.04 ARX+ cells/mm² in the controls). We report the consequences of the rapid arrival of nonprocessed nutrients to the ileum on the endocrine cellular pancreas. The ileum could be a principal effector in the enterohormonal axis, which conditions endocrine pancreas cellularity.

The influence of massive jejunectomy on endocrine pancreas of diabetic Goto-Kakizaki.

OBJECTIVE: Several bariatric surgeries have been related to the T2DM improvement in obese patients. Despite the different mechanism invoked for this improvement, many evidences showed that the pancreas cellularity is conditioned for the homeostatic physiological changes after these surgeries. Many authors reported the changes in beta-cell mass after some surgeries in healthy rats. We purpose to analyze the changes in ß-cell cellularity and ß-cell-mass after a severe malabsorptive surgical method. Thus, we studied several parameters of the islet morphometric composition after a massive jejunal resection. MATERIALS AND METHODS: We employed Goto-Kakizaki diabetic non-obese rats, which underwent the 50% resection of middle portion of the jejunum versus a control group. After 3 months, rats were sacrificed and pancreas was immunohistochemicaly studied. RESULTS: The ß-cell mass was analyzed and several parameters about the endocrine islet size distribution were studied. We report an increase of ß-cell mass in massive resection surgical group versus controls. The islet distribution was significant different between both groups. Endocrine islets of surgical group were bigger with a different cellular distribution. CONCLUSION: According to the enteroendocrine changes related to surgeries in jejunum, as in other gastrointestinal portions, the cellularity of islets changes as an adaptive process to glycemic demands.

OBJETIVO: Varias técnicas quirúrgicas bariátricas han sido relacionadas con el mejoramiento de la T2DM en pacientes obesos. Se han invocado distintos mecanismos de porqué se da este mejoramiento y muchas evidencias apuntan a que la celularidad del páncreas cambia por las condiciones fisiológicas tras estas cirugías. Se han publicado cambios en la celularidad beta en ratas sanas sometidas a estos procesos. Y nos proponemos observar dichos cambios en ratas diabéticas tras una resección jejunal masiva. Estudiamos varios parámetros sobre la masa beta y la morfometría de los islotes, que indiquen los procesos celulares que han tenido lugar. MATERIAL Y METODO: Empleamos Goto-Kakizaki, un modelo de rata diabética no obesa, a la que se sometió a una resección del 50%de la poción media del yeyuno. Tras tres meses de supervivencia, las ratas se estudiaron los páncreas mediante inmunocitoquímica. RESULTADOS: Mostramos un incremento de la masa beta en las ratas resecadas frente a los controles. La distribución de islotes fue significativamente distinta entre los grupos, donde los islotes eran mayores en las ratas diabéticas. CONCLUSIÓN: Los cambios glucémicos tras las resecciones masivas yeyunales cambian la celularidad del páncreas como una muestra de la capacidad adaptativa del mismo a las modificaciones.

Peptide Tyrosine-Tyrosine Triggers GLP-2-Mediated Intestinal Hypertrophy After Roux-en-Y Gastric Bypass.

PURPOSE : Intestinal remodeling and adaptation of the alimentary limb after Roux-en-Y gastric bypass (RYGB) play an important role in the pathophysiological events that lead to type 2 diabetes mellitus (T2DM) improvement. Intestinal absorptive loop hypertrophy and growth following surgery have been related to GLP-2 secretion by ileal L-cells. The secretion of peptide tyrosine-tyrosine (PYY) enterohormone after a meal has been proposed as a trigger for ileal secretion of GLP-1. Our aim is to determine the role of PYY as a GLP-2 secretion modulator as an adaptation result in the alimentary limb after RYGB. METHOD: We used a non-obese euglycemic rodent model. Circulating glucose, insulin, PYY, and GLP-2 were measured in the experimental and control groups. We used four groups: fasting control, Sham-operated, RYGB-operated (RYGB), and RYGB-operated and treated with BIIE0246 (RYGB + BII). BIIE0246 is a NPY2 receptor antagonist in L-cells. Intestinal glucose transporters and GLP-1 and PYY gut expression and hypertrophy were analyzed after 12 weeks of surgery. RESULTS: RYGB increased PYY3-36 plasma levels in rats with or without BII treatment. A high-insulin response was observed in the RYGB group but not in the control or RYGB + BII groups. BIIE0246 treatment limited plasma GLP-2 levels. In the alimentary intestinal limb, hypertrophy and SGLT1 and GLUT1 expression appeared to be reduced after RYGB compared to controls. CONCLUSION: The postprandial ileal PYY secretion is enhanced after RYGB. This increase mediates GLP-2 release through its binding to the Y2 receptor on L-cells. This mechanism plays a role in alimentary limb hypertrophy after surgery.

The long-term failure of RYGB surgery in improving T2DM is related to hyperinsulinism.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is the gold standard method for bariatric surgery and leads to substantial improvements in Type 2 Diabetes mellitus. However, many patients experience relapses in diabetes five years after undergoing this aggressive surgical procedure. We focus on beta-cell population changes and absorptive intestinal consequences after RYGB in a healthy nonobese animal model after a long survival period. METHODS: For our purpose, we use three groups of Wistar rats: RYGB-operated, surgical control (Sham) and fasting control. We measure alpha-, beta-cell mass; transcription (Arx, and Pdx-1) and proliferation (Ki67) factors; glucose tolerance and insulin release after oral glucose tests; histological adaptive changes in the jejunum; and intestinal glucose transporters. RESULTS: Our results showed an early increase in insulin secretion after surgery, that decrease at the end of the study. The beta-cell mass reduces twenty-four weeks after RYGB, which coincides with decrease of Pdx-1 transcription promoter factor. These was coincident with an increase in alpha-mass and a high expression of Arx in RYGB group. CONCLUSIONS: The analysis of all data showed beta-cell mass transdifferentiation into alpha-cell mass in RYGB rats. Due to long-term exhaustion of the beta-cell population by hyperinsulinism derived from digestive tract adaptation to surgery.

Sleeve Gastrectomy and Roux-En-Y Gastric Bypass. Two Sculptors of the Pancreatic Islet.

Several surgical procedures are performed for the treatment of obesity. A main outcome of these procedures is the improvement of type 2 diabetes mellitus. Trying to explain this, gastrointestinal hormone levels and their effect on organs involved in carbohydrate metabolism, such as liver, gut, muscle or fat, have been studied intensively after bariatric surgery. These effects on endocrine-cell populations in the pancreas have been less well studied. We gathered the existing data on these pancreatic-cell populations after the two most common types of bariatric surgery, the sleeve gastrectomy (SG) and the roux-en-Y gastric bypass (RYGB), with the aim to explain the pathophysiological mechanisms underlying these surgeries and to improve their outcome.

Glucagon-Producing Cell Expansion in Wistar Rats. Changes to Islet Architecture After Sleeve Gastrectomy.

PURPOSE: Many studies about bariatric surgery have analyzed the effect of sleeve gastrectomy (SG) on glucose improvement, beta-cell mass, and islet size modification. The effects of SG on the other endocrine cells of the pancreas, such as the alpha-cell population, and their regulatory mechanisms remain less studied. MATERIALS AND METHODS: We focused our work on the changes in the alpha-cell population after SG in a healthy model of Wistar rats. We measured alpha-cell mass, glucose tolerance, and insulin release after oral glucose tolerance tests and plasma glucagon secretion patterns after insulin infusion. Three Wistar rat groups were employed: SG-operated, surgical control (Sham), and fasting control. RESULTS: The results obtained showed significant increases in the alpha-cell population after SG. The result was an increase in beta-cell transdifferentiation; it was shown by some expressed molecules (the loss of expression of Pdx-1 and the increase in Arx and Pax6 cells/mm2 of islet). The serum results were enhanced plasma glucagon secretion pattern after insulin infusion assays and normal glucose tolerance and insulin release after OGTT. CONCLUSION: We concluded that SG leads to an expansion of the alpha-cell population, at expense of beta-cell; this expansion of alpha-cells is related to transdifferentiation. Plasma glucose level was not affected due to an increased glucagon response.

Pancreas is a preeminent source of ghrelin after sleeve gastrectomy in Wistar rats.

Many surgical techniques are employed in the treatment of severe obesity. A main consequence of these techniques is the improvement of type 2 Diabetes mellitus. Ghrelin is a gut hormone released in the gastric fundus and corpus, which has been related to diabetic improvement as mentioned in these papers. Sleeve gastrectomy and Roux-en Y Gastric Bypass are surgical techniques broadly employed in humans; both severely reduce the gastric surface. Paradoxically, the serum level of ghrelin in patients is preserved. We hypothesized about the role of embryonic pancreatic epsilon cells, which have the capacity to release ghrelin. We studied the changes in the epsilon cells and differentiation markers with immunostaining and ghrelin serum level and after surgery. We employed euglycemic male Wistar rats: two surgical groups (Sleeve gastrectomy and Roux-en Y Gastric Bypass) and two control groups. We reported a significant increase of ghrelin epsilon-cells in the pancreas and basal serum after Sleeve gastrectomy versus the control groups. The epsilon cellular increment was related to neogenesis, as the neurogenin-3 marker revealed. The Roux-en Y Gastric Bypass showed neither epsilon cell increase nor basal serum changes in ghrelin release. As a conclusion, we reported that the severe suppression of the fundus gastric produced the recovery of ghrelin released by the epsilon cells, which was indicative of an ontogenic embryonic pancreatic function.

The Leading Role of Peptide Tyrosine Tyrosine in Glycemic Control After Roux-en-Y Gastric Bypass in Rats.

AIMS: Roux-en-Y gastric bypass (RYGB) is one of the most effective surgical therapies for the rapid resolution of type 2 diabetes. However, the mechanisms underlying the entero-hormonal response after surgery and the role of peptide tyrosine tyrosine (PYY) in the restoration of normoglycemia are still not clear. METHODS: We reproduced the RYGB technique in Wistar and Goto-Kakizaki rats and performed serum hormonal, histological, and hormonal-infusion test. RESULTS: Using the diabetic Goto-Kakizaki (GK) rat model, we demonstrated that PYY plasma levels showed a remarkable peak approximately 30 min earlier than GLP-1 or GIP after mixed-meal administration in RYGB-operated rats with PYY. The GLP-1 and GIP areas under the curve (AUCs) increased after RYGB in GK rats. Additionally, the findings suggested that PYY (3-36) infusion led to increased GLP-1 and GIP plasma levels close to those obtained after a meal. Finally, the number of GLP-1-positive cells appeared to increase in the three segments of the small intestine in GK-RYGB-operated rats beyond the early presence of nutrient stimulation in the ileum. Nevertheless, PYY-positive cell numbers appeared to increase only in the ileum. CONCLUSION: At least in rats, these data demonstrate an earlier essential role for PYY in gut hormone regulation after RYGB. We understand that PYY contributes to GLP-1 and GIP release and there must be the existence of enteroendocrine communication routes between the distal and proximal small intestine.

The teaching of surface anatomy by body painting / Enseñanza de anatomía de superficie mediante la pintura corporal

The present project on learning surface anatomy through the body painting method was undertaken because anatomical knowledge supports medical practice. The appropriate anatomical training of the doctor depends on surface anatomy. We considered the renovation of teaching strategies and didactic resources to optimize the overall teaching- learning process. 189 first-year medical students, enrolled in the Trunk and Splanchnology course at the University of Cádiz (Spain) participated in this study. Students were divided into 5 groups each of 38-41 students. The students were asked to complete a satisfaction questionnaire supplied to each participant through an on-line platform. On the basis of the results, we recommend the body painting method as an alternative tool for learning surface and clinical anatomy.

El presente proyecto sobre el aprendizaje de la anatomía de superficie a través del método de pintura corporal se realizó debido a que el conocimiento anatómico apoya la práctica médica. El entrenamiento anatómico apropiado del médico depende de la anatomía de superficie. Consideramos la renovación de las estrategias de enseñanza y los recursos didácticos para optimizar el proceso general de enseñanza-aprendizaje. De este estudio participaron 189 estudiantes de primer año de medicina, matriculados en el curso de Troncal y Splanchnology en la Universidad de Cádiz (España). Los estudiantes fueron divididos en 5 grupos, cada uno de 38-41 estudiantes. Se les pidió a los estudiantes que completaran un cuestionario de satisfacción proporcionado a cada participante a través de una plataforma en línea. Sobre la base de los resultados, recomendamos el método de pintura corporal como una herramienta alternativa para el aprendizaje de la anatomía de superficie y clínica.

Gimbernat's stay in Cadiz and his discovery of the human anatomy

The dates on which Antonio Gimbernat studied at the Navy Royal College of Surgery in Cadiz (Real Colegio de Cirugía de la Armada, RCCA) show some discrepancies between different authors. A detailed reading of the Royal College archives, especially the books of enrollments kept in the Department of History of Medicine at the University of Cadiz, allows us to clarify this issue. In this contribution we present the academic records of Gimbernat in Cadiz, as well as annotations on his participation in college life, where his remarkable vocation for anatomy is reflected. On the other hand, we will see aspects that have had influence on his curriculum during the short but productive and notable period of studies in the Royal College. Moreover, we will analyze the contents of the academic curriculum followed by Gimbernat, which was designed by Virgili, although some other aspects of the academic life of the RCCA were not supported by our honoree surgeon. Finally, through generic documents on the customs and habits of the Navy Royal College of Surgery in Cadiz we outline how Gimbernat’s life and habits were during his time as college member (AU)

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Cambios bioquímicos en corredores populares tras correr una maratón (test de estrés) / Biochemical changes in Popular Runners after a marathon (Stress Test)

El estudio que hemos llevado a cabo con un grupo de corredores veteranos, pero con una larga trayectoria en el deporte popular, consiste en analizar los cambios que se producen en los perfiles bioquímicos de un grupo de quince corredores populares que corren una maratón. A este esfuerzo máximo lo hemos denominado «Test de Estrés». Nuestros objetivos se encaminan a evaluar los resultados de los cambios producidos en los par.metros bioquímicos simples en corredores populares para referenciarlos con los que se producen en los atletas profesionales, es un estudio de prevalencia, sin variables previas ni asignación aleatoria. El método empleado: toma de muestra sanguínea previa (condiciones basales ó de referencia) y otra inmediatamente posterior. Los resultados obtenidos: incremento de la concentración de glucemia en sangre del 3,25% incremento de la urea del 95% y de la creatinina del 45,3 mientras sobre el colesterol no tiene repercusión y sobre los triglicéridos el incremento esta en 3%. Discutimos nuestros resultados comparándolos con los resultados publicados sobre los profesionales, con la intención de ver las diferencias en los cambios de los valores bioquímicos en los profesionales frente a los corredores populares, aficionados y veteranos. Hemos encontrado estudios sobre profesionales de otras disciplinas, tales como triatletas, ciclistas, esquiadores etc. La conclusión es que los beneficios y perjuicios de ejercicio físico intenso son tan beneficiosos o perjudiciales para ambos grupos. Pero las diferencias encontradas en los valores bioquímicos sirven para comparar el deporte profesional y aficionado

The study we conducted with a group of veteran runners, but with a long career in the popular sport, is to analyze the changes that occur in biochemical profiles of a group of fifteen amateur runners who run a marathon. This maximum effort we have called «stress tests». Our goals are aimed at evaluating the results of the changes in biochemical parameters in simple popular runners to reference them with those occurring in professional athletes, is a prevalence study without previous variables or random assignment. The method employed: previous blood sampling (baseline or reference conditions) and another immediately after. The results: increased blood glucose concentration of 3.25% increased 95% urea and creatinine of 45.3 while on cholesterol has no effect on triglycerides and the increase was 3%. We discuss our results against the results published on the professionals, with the intent to see the differences in the changes of biochemical values in the pros versus popular riders, amateurs and veterans. We found studies professionals from other disciplines, such as triathletes, cyclists, skiers etc. The conclusion is that the benefits and harms of intense physical exercise are as beneficial or detrimental to both groups. But the differences in biochemical values are used to compare the professional and amateur sport