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Obesity Surgery, 17, 569-576
Highlights from the International Symposium of the Brazilian Diabetes
Society, Campinas, SP, Brazil, November 18, 2006
Incretins: Clinical Physiology and Bariatric Surgery
– Correlating the Entero-endocrine System and a
Potentially Anti-dysmetabolic Procedure
Rodrigo N. Lamounier, MD1; José Carlos Pareja, MD, PhD2; Marcos
Antonio Tambascia, MD, PhD3; Bruno Geloneze, MD, PhD3
1Department of Internal Medicine, Division of Endocrinology, University of São Paulo-USP, SãoPaulo, Brazil; 2Department of Surgery, Division of Bariatric and Metabolic Surgery, StateUniversity of Campinas-UNICAMP, Campinas, Brazil; 3Department of Internal Medicine,Endocrinology Unit, State University of Campinas-UNICAMP, Campinas, Brazil The digestive tract is well known for its endocrine
Introduction
functions. Recently, many studies have been reinforc-
ing its role as a therapeutic target for both diabetes
and obesity. Losing weight is clinically very difficult
The “incretin effect” is the phenomenon described in for most obese patients and the reason for this could
physiological studies which shows that orally admin- be the effect of the physiological adipostatic system
istered glucose evokes a greater insulin response that triggers central nervous stimuli to compensate
than a corresponding intravenous glucose load. This for variations in food intake and in physical activity.
term derives from the gastrointestinal hormones – Gut hormones seem to have a key role in this com-
incretins, which stimulate insulin secretion. plex, regulating body weight and satiety and con-
tributing to glucose homeostasis. The enteroinsular
Symposium that took place in Campinas, SP, Brazil, axis appears to be impaired in both obese and dia-
Nov 18, 2006. The event provided a forum for the betic patients. Recent data on bariatric surgery shows
exchange of experiences between Researchers, its striking effects on glucose control soon after the
Clinicians and Surgeons on this paramount topic in procedure, before a significant weight loss is
achieved. The procedure appears to work beyond
anti-obesity having a key metabolic impact possibly
The metabolic, neural and hormonal effects of the sharing a common mechanism with the new class of
small intestine on the pancreatic islets are referred as agents to treat type 2 diabetes mellitus: the incretin
the enteroinsular axis. One of the most important mimetics. This symposium discussed new data on the
incretins known is the first described gastric inhibito- upcoming perspectives on both the pharmacological
ry polypeptide, also called glucose-dependent and the surgical approach to diabetes and obesity.
insulinotropic peptide (GIP), which is secreted bythe entero-endocrine K-cells in the jejunum and Key words: Incretins, diabetes, bariatric surgery, GLP-1, accounts for more than 50% of the total incretin ghrelin, enteroinsular axis, exenatide, DPP-IV inhibitors effect. The other key hormone is the glucagon-likepeptide 1 (GLP-1), a product of proglucagon gene Correspondence to: Bruno Geloneze, MD, PhD, Rua CamargoPaes 251, Campinas, Brazil. E-mail: bgeloneze@terra.com.br and formed mainly in the intestinal L-cells; GLP-1 Springer Science + Business Media, Inc. Obesity Surgery, 17, 2007 569
Symposium: Incretins and Bariatric Surgery plasma levels increase >6 times after a carbohydrate tides involved in the regulation of the adipostatic meal. Several studies have demonstrated that the control of body weight act both locally and central- effect of incretins is reduced in type 2 diabetes mel- ly and could be divided into two broad groups: 1) litus (T2DM) patients.1,2 When GLP-1 is adminis- those involved mainly in the long-term control of tered, it effectively stimulates insulin secretion both adiposity such as leptin, insulin, ghrelin and PYY in normal subjects and in T2DM patients.3 In con- which inform the brain about the body fat deposits, trast, GIP insulinotropic effect is highly reduced in and 2) the other group which is constituted by mol- diabetic patients.4 Thus, the therapeutic potential of ecules associated with short-term meal-related regu- GLP-1 has been extensively studied, emphasizing lation such as ghrelin and CCK and other gut- not just its hypoglycemic effect through stimulation derived factors. The hindbrain is the principal cen- of insulin secretion but also other likely beneficial tral site receiving input from short-acting satiation properties, such as retardation of gastric emptying signals.7 Among the several gut peptides that regu- late food intake and are secreted along the gastroin- Thus, there is an increasing interest in this area, testinal system, there are the CCK in duodenum, with one new agent of the incretin mimetic classalready available for clinical use, the exenatide Apolipoprotein A-IV in the jejunum, GLP-1, PYY (exendin-4), and others recently approved and com- and Oxyntomodulin in the ileum and colon, and ing soon. The role of incretins and the enteroinsular Amylin, Enterostatin, Glucagon, Insulin and PP in axis in glucose homeostasis has been even more the pancreas. The stimulation for secretion of all emphasized after results from obese diabetic these peptides comes mainly from ingested food, patients submitted to bypass bariatric surgery, but the mechanisms by which it occurs are quite revealing rapid glycemic resolution in most cases, diverse. Different properties of food stimulate these with this axis being implicated as a potential mech- gut cells to secrete peptides that activate vagal and anism for such an effect.6 The Symposium congre- enteric afferent nerves and enter the circulation gated many specialists in the field and fomented reaching the central nervous system. For example, exhaustive discussion over all the presented themes.
GLP-1 release by L-intestinal cells involves a mech-anism related to cellular uptake and intracellularmetabolism of glucose. However, it has been Physiological Aspects of the
described that entero-endocrine cell activation can Entero-endocrine System
occur without nutrient uptake by a mechanism thatis quite similar to the oral tasting sensation. Ghrelin is produced primarily by stomach and Dr. David E. Cummings (University of Washington, proximal intestine, being highly conserved across Seattle, USA) pointed out recently published data species. Contrary to the other incretins like GLP-1, concerning gastrointestinal endocrinology and regu- ghrelin increases food intake and GI motility and lation of body weight, focusing especially on the decreases insulin secretion from the pancreatic islets, role of ghrelin and other peptides on individual acting endogenously as a growth hormone (GH) sec- meals and glucose homeostasis. According to the retagogue. Ghrelin acutely and transiently stimulates facts, weight loss is difficult to be achieved by obese appetite, and its surge predicts voluntary meal patients, probably because of the compensatoryeffect of an adipostatic system, which physiologi- intake. Ghrelin levels rise and fall shortly before and cally works to maintain stable body weight, despite after meals along the day, and this secretion seems to variations in physical activity and caloric intake.
be stimulated by the neural branch of the sympathet- Satiation signals arise from multiple sites in the GI system, including stomach, small intestine, colon inhibits ghrelin secretion, and this effect depends on and pancreas. There are two main mechanisms both the amount of ingested food as well as on its through which ingested food promotes satiation: composition because lipids seem to be less efficient.
gastric distention and release of peptides from This mechanism involves insulin and enteric nervous entenro-endocrine cells. The entero-endocrine pep- 570 Obesity Surgery, 17, 2007
Incretins, Diabetes, and Bariatric Surgery Regarding long-term body weight regulation, there ous system (CNS) and their role in thermogenesis are several evidences in the literature that show that and weight control. Glucagon-Like Peptide 1 (GLP- ghrelin levels increase after diet-induced weight loss 1) is a 30 aminoacids peptide, produced by L-cells and conversely that this hormone is down-regulated in the colon and ileum, secreted after nervous and after weight gain. Ghrelin affects body-weight con- nutrient stimuli and degraded by the enzyme dipep- trol centers in the brain, and increases in ghrelin lev- tidyl-peptidase IV (DPP-IV). Gastric inhibitory els are related to weight gain, while blockage of the polypeptide (GIP), formed by a 42 aminoacids hormone or its physiological effects induces weight chain, is synthesized and postprandially released loss. Ghrelin increases food intake and preference for from the duodenum and proximal jejunum, being fat, but interestingly it is not a common cause for obe- cleaved by the same enzyme.14,15 Both of these sity, because its overproduction has not been demon- incretins have receptors in the CNS, although GLP- strated in obese populations, being observed only in 1 but not GIP has receptors identified in the hypo- specific conditions like Prader-Willi syndrome.10 thalamus. Indeed, GLP-1 has been demonstrated to A brief report about the effects of incretins on beta interact with these receptors, including those in the cells was presented by Dr. Freddy G. Eliaschewitz hypothalamus altering the glucose influx to neurons (University of São Paulo, SP, Brazil). Beta-cell mass in these regions, suggesting a functional modula- is critical in the development of diabetes, not only tion. Intra-ventricular infusion of GLP-1 induces c- for T1DM, in which massive pancreatic islet destruc- fos activation in paraventricular neurons in the tion occurs before the clinical diagnosis, but also for hypothalamus. These incretin receptors are G-pro- T2DM in which beta-cell mass decreases progres- tein coupled receptors, which increase intracellular sively with evolution of the disease. Therefore, cyclic AMP. However, this pathway has not been strategies to preserve or increase the number of described so far as an important one for adipostatic available beta cells are crucial for the future perspec- control in the CNS. Receptors involved with the tives in diabetes treatment. The source for replenish- PI3K/AKT pathway, which is activated by insulin ing beta cells in the adult is not clear and could sup- and those involved with JAK/STAT controlled by posedly arise from either ductal cells or acinar cells leptin stimulus are the ones known to be important transdifferentiating into beta cells and also from to the adipostatic command in the CNS.16,17 adult pancreatic stem cells. Several substances have After injection of GLP-1 directly into the CNS, been shown to induce proliferation of beta cells both there is rapid inhibitory effect on food intake, which in vitro as well as in animal models, such as GLP-1, is not sustained later.18 Studies from knockout mod- GIP, gastrin, IGF-1 and others.11 An in vivo evidence els for GLP-1R KO, GIPR KO and for both receptors for an incretin effect in inducing islet proliferation is (DIRKO) do not show any significant alteration in the report of hyperinsulinemic hypoglycemia in terms of weight gain and food intake. The double patients after gastric bypass surgery with high levels knockout has a trend to gain less weight later in life.19 of circulating incretins.12 Other attempts to test this An exciting review of recently published findings effect in vivo are evidenced in studies of the admin- about cardiovascular effects of GLP-1 was summa- istration of GLP-1 to patients who received islet rized by Dr. Wilson Nadruz Jr (State University of transplantation and fail to maintain good glucose Campinas, Campinas, SP, Brazil). GLP-1 has recep- control without exogenous insulin, and some inter- tors on cardiovascular cells, especially on the esting results were reported.13 Subsequently, some endothelium, and interest in this area increased after pre-clinical and experimental data suggest that it was suggested that administration of GLP-1 to incretins can possibly restore beta-cell mass; never- rats induced a dose-dependent increase in the blood theless, the clinical relevance of this data is still pressure. However, studies in humans suggested improvement in endothelial dysfunction after GLP- Incretins and the central control of food intake 1 injection in T2DM patients with stable coronary and energy expenditure was the subject highlighted artery disease and no effect in healthy volun- by Dr. Licio A Velloso (State University of teers.20,21 GLP-1R KO mice develop left ventricular Campinas, Campinas, SP, Brazil), focusing espe- hypertrophy later in life. Studies in dogs of dilated cially on GLP-1 and GIP action in the central nerv- cardiomyopathy, showed that the infusion of GLP-1 Obesity Surgery, 17, 2007 571
Symposium: Incretins and Bariatric Surgery for 48 h induced an increase in the systolic pressure The clinical use of incretin-mimetics was on the left ventricle (LV) and a decrease in the end- reviewed by Dr. Jorge L. Gross (Federal University diastolic pressure on LV, improving contractility of Rio Grande do Sul, Porto Alegre, RS, Brazil), and decreasing heart rate.22 In one study in patients including information from clinical trials with exe- with LV dysfunction after acute myocardial infarc- natide (exendin-4), a 39-amino acid incretin mimet- tion who were submitted to primary angioplasty, the ic that exhibits glucoregulatory activities similar to group who received GLP-1 during angioplasty GLP-1 and other mimetics. Data from three clinical showed better ejection fraction than controls. A trials lasting 30 weeks and including a total of 1,446 study in rats submitted to a high salt diet showed T2DM patients using oral agents such as metformin that those treated with GLP-1 had lower blood pres- and sulfonylurea indicate that administration of exe- sure and excreted more sodium.24 Therefore, GLP-1 natide 10 µg bid significantly reduced HbA1c in 0.8 probably has beneficial CV effects and can be an md/dL approximately.33-35 Another study, involving important therapeutic tool, but future studies are 551 T2DM patients over 26 weeks compared the necessary to clarify its role on arterial hypertension effect of exenatide 10 µg bid treatment with insulin glargine once daily. Results showed similar glucosecontrol between groups, with an average HbA1creduction in both treatments of 1.11%. Patientstreated with exenatide had a weight loss of 2.3 kg Clinical Implications of
compared to a gain of 1.8 kg in those using insulin Incretin Physiology
glargine. Other studies also showed a tendency ofexenatide to promote weight loss.36 Nausea and Diabetes and obesity-related pathophysiological diarrhea are the most frequent adverse events report- aspects such as insulin and leptin resistance and its ed with exenatide treatment. A long-acting formula- connection with impaired incretin function were dis- tion of exenatide for once weekly administration is cussed by Dr. Bruno Geloneze (State University of Campinas, Campinas, SP, Brazil). According to the Liraglutide, another long-acting GLP-1 analog data presented, women with previous gestational dia- suitable for once-daily administration, is still under betes and other diabetes-prone individuals show phase III clinical development. According to a study insulin resistance but normal GLP-1 and GIP secre- involving 193 patients for 12 weeks, liraglutide tion, similar to what had been previously described in 0.75mg daily, the highest dose used in the study, healthy offspring of T2DM patients.25,26 Young adult promoted a significant reduction in HbA1c of men with low birth weight history, another example 0.75%, compared to placebo. DPP-IV inhibitors are of a high-risk population, have also normal incretin another type of incretin-mimetic that prolong the half-life of endogenous incretins, antagonizing the secretion and leptin receptors have been described in enzyme responsible for their metabolism. Clinical intestinal L-cells from both mice and humans, sug- data published shows that Vildagliptin has a glucose gesting a link between leptin resistance seen in obe- lowering effect ranging from 0.7 to 1.7% depending sity with impaired incretin secretion implicated in on the baseline values. Sitagliptin, another DPP-IV diabetes pathophysiology.28,29 Furthermore, obese patients show decreased GLP-1 levels and this could Dr. Marcos Tambascia (State University of be at least partially explained by increased DPP-IV Campinas, Campinas, SP, Brazil) presented further activity which also rises in parallel with HbA1c lev- results from clinical trials regarding incretin-based els, in T2DM patients.30,31 Progressive doses of met- treatment. Liraglutide, the long-acting, acylated formin, conversely, decrease DPP-IV activity, GLP-1 analog, acts as a full agonist toward the enhancing GLP-1 antidiabetic effects.32 It thus seems GLP-1 receptor. Initial clinical studies showed a reasonable to implicate and understand the impaired dose-dependent improvement in HbA1c, and in one incretin function and secretion in the diabetic disease open labeled study with 190 patients, higher doses process, indicating a potential therapeutic role of this of liraglutide (0.6 and 0.75 mg) showed a similar new drug class on diabetes treatment.
effect on HbA1c than glimepiride after 12 weeks.31 572 Obesity Surgery, 17, 2007
Incretins, Diabetes, and Bariatric Surgery Exenatide (synthetic exendin-4), a GLP-1R ago- seems to overcome the adipostatic system of body nist, has 50% aminoacid homology compared to weight regulation that makes non-surgical methods human GLP-1 but displays high affinity for its of weight loss traditionally unsuccessful.
receptor. Exenatide administration to T2DM Data from the Swedish Obese Subjects Study, patients can improve not just postprandial glucose reporting follow-up data of more than 1,000 patients levels, blocking glucagon secretion and restoring for up to 10 years, showed that Roux-en-Y gastric first phase insulin secretion, but it can also reduce bypass (RYGBP) promoted the greatest weight loss fasting glycemia, which suggests a possible sensi- of about 38% of total body weight, maintaining in tizing effect on the overnight hepatic response to the region of 30% after 10 years. Gastric banding insulin.40-42 The improvement in insulin secretion (GB) and gastroplasty (GP) are less effective but clinically observed in T2DM patients treated with still induce far more weight loss than non-surgical exenatide is corroborated with animal studies show- treatment, which was ineffective in the long-term.50 The mechanisms for such an impressive loss of Another possibility for improving incretin action weight are not totally clear. Gastric restriction is prob- in diabetic patients is the administration of DPP-IV ably not the major factor, because the final stomach inhibitors. Sitagliptin is associated with inhibition of volume is comparable between RYGBP, GB and GP.
80% of DPP-IV activity and augmentation of active Malabsorption seems not to be clinically significant in GLP-1 and GIP levels after an OGTT. In one study the long-term follow-up after the surgery, and magni- involving 1,172 patients with a median baseline tude of dumping symptoms does not correlate with the HbA1c of 7.5%, sitagliptin compared to glipizide weight loss observed. On the other hand, some gut provided similar HbA1c lowering effect over 52 hormones seem to be related to this mechanism.
weeks in patients on ongoing metformin therapy.
Ghrelin is known to be one of the long-term adiposta- Similarly, in patients with baseline HbA1c of 8.1% tic hormones that work for the maintenance of body receiving pioglitazone, addition of sitagliptin 100 weight. Ghrelin levels classically increase after weight mg once daily improved HbA1c 0.7% compared to loss, and this physiologic response is absent or placebo (P<0.001). Proinsulin levels were signifi- impaired after RYGBP. The mechanism underlying cantly reduced with sitagliptin compared to placebo.
this could be vagotomy (intentional or unintentional) The drug was well-tolerated, exhibiting a similar after the RYGBP operation. The diverse bariatric sur- incidence of hypoglycemia as placebo.46 Vilda- gical operations could partially explain the observed gliptin, another DPP-IV inhibitor, showed similar differences in ghrelin dysregulation after bariatric sur- effectiveness. In a randomized study with drug-naive gery among different surgical obesity centers.51-54 T2DM patients, after 24 weeks, vildagliptin 50 mg Furthermore, other gut hormones like peptide YY twice daily was equally effective as rosiglitazone (8 (PYY) and GLP-1 are mediators of the ileal brake mg/day), but without weight gain. Vildagliptin also phenomenon which triggers satiation after meals, and improves postprandial glycemia, restores GLP-1 lev- their levels are increased after RYGBP.55,56 Different els and reduces glucagon secretion after meals. The reports have shown improvement in glucose home- hypoglycemic effect appears to be related to an ostasis and even diabetes resolution after RYGBP, and this is probably related to increased GLP-1 levels afterthe procedure.57,58 The role of hindgut stimulation on promoting the increase in these hormone levels is reinforced by Enteroinsular Axis Implications on
animal studies with ileal transposition, where there Bariatric Surgery
is no volume restriction and no malabsorption butstill marked increase in GLP-1 and PYY levels and Possible hormonal mechanisms for weight loss and reduction in food intake and body weight.59 diabetes resolution of bariatric surgery was the topic However, if enhanced delivery of nutrients to the of another talk presented by Dr. David Cummings distal intestine and increased secretion of hindgut (University of Washington, Seattle, USA). He intro- signals improve glucose levels, altered transit duced the subject stating that bariatric surgery excluded from the foregut also appears to play a role Obesity Surgery, 17, 2007 573
Symposium: Incretins and Bariatric Surgery independent of effects on food intake, body weight sity (DIO) and diabetes mellitus. Before surgery, DIO mice were diabetic and insulin-resistant compared to Published data from the experience at the controls. After surgery, all parameters were reversed Hackensack University Medical Center supports that and even peripheral insulin signal transduction all forms of weight loss surgery lead to caloric through its receptor, insulin receptor substrates IRS- restriction, weight loss, decrease in fat mass and 1, IRS-2 and Akt, was improved in muscle.64 improvement in T2DM. This suggests that these A pilot study performed in a single center in beneficial effects in glucose metabolism and insulin Sweden compared the effects of omentectomy per- resistance following bariatric surgery result in the formed with bariatric surgery (adjustable gastric short-term from decreased stimulation of the banding). Fifty patients who underwent bariatric sur- enteroinsular axis, by decreased caloric intake and in gery were randomized for omentectomy or no omen- the long-term by decreased fat mass and resulting tectomy, with the surgical procedure. After 2 years of changes in release of adipocytokines.61 This infor- follow-up, omentectomized patients had a significant improvement in oral glucose tolerance test and fast- ing plasma glucose and insulin, independent of Hackensack, NJ, USA), who summarized this data.
weight loss. Subjects who underwent omentectomy According to the published data, both laparoscopic tended to lose more weight than controls, although Roux-en-Y gastric bypass (LRYGBP) and laparo- scopic adjustable gastric banding (LAGB) signifi- Ileal transposition is another possibility for meta- cantly elevate basal and meal-simulated PYY levels, bolic surgery that could determine metabolic bene- which may mediate suppression of appetite, improv- fits through increasing the incretin circulating levels.
ing weight loss.62 A study aimed to evaluate the A pilot study in 19 obese patients (mean BMI=40.2) short-term changes in insulin resistance, comparing in which this procedure was performed with con- LAGB and LRYGBP, using the Homeostasis Model comittant partial gastrectomy found 46% weight loss Assessment for Insulin Resistance (HOMA-IR).
after 16 months. Among 5 patients with diabetes Preoperative values were compared to levels 90 days diagnosed at baseline, the glucose levels were nor- after surgery, and baseline HbA1c was 5.7% in both malized 3 weeks after the surgery.66 Another possi- groups. After 90 days, insulin resistance dropped in bility is duodenal exclusion as a mediator mecha- both groups, but significantly more in the LRYGBP nism for improvement in glucose homeostasis group. In both groups postoperative HOMA-IR cor- through altered signals from the excluded foregut, as related with preoperative values but not with weight has been shown in a study with a T2DM rat model, loss. The authors argued that these findings suggest in which the bypass ameliorated diabetes.60 that caloric restriction plays a significant role in This International Symposium on Incretins and its improving insulin resistance after both LAGB and importance in the clinical and surgical approach to LRYGBP.63 Looking at the data from the vast expe- the diabetic and obese population brought to light rience of his center, he concluded that bariatric oper- several possibilities and trends in this area, that need ations decrease insulin resistance through three sep- to be further explored in the near future, opening arate, but overlapping mechanisms: 1) severe caloric more possibilities in this new and exciting field.
restriction, 2) alterations in the enteroinsular axis,and 3) fat loss (adipo-insular axis).
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(Received March 20, 2007; accepted March 30, 2007) 576 Obesity Surgery, 17, 2007

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