© Borgis - Postępy Nauk Medycznych 5/2015, s. 341-346
Emelie Andersson1, Lisa Månsson1, Catherine Gidlund1, Renate Kat1, Kateryna Goncharova1, 2, Olena Prykhodko1, *Stefan G. Pierzynowski1, 3
Funkcjonalna zewnątrzwydzielnicza niewydolność trzustki jako efektywna droga farmaceutycznego i chirurgicznego leczenia nadwagi
Functional exocrine pancreatic insufficiency as target of pharmaceutical and surgical approaches in treatment of overweight
1Department of Biology, Lund University, Sweden
Head of Department: prof. Christer Löfstedt, PhD
2Department of Cytology, Bogomoletz Institute of Physiology, Kiev, Ukraine
Head of Department: prof. Galyna Skibo, MD, PhD
3Department of Medical Biology, Institute of Rural Medicine, Lublin, Poland
Head of Department: prof. Wojciech Rzeski, PhD
Nadwaga i otyłość są poważnym problemem zdrowotnym w dzisiejszym społeczeństwie. Za pierwotne przyczyny tego zjawiska uważa się „zachodnią” dietę i siedzący tryb życia. Zmiany stylu życia, takie jak wprowadzenie zdrowszej diety oraz zwiększony wysiłek fizyczny, należy rozważyć jako pierwszy etap w leczeniu otyłości. Jednakże dla wielu pacjentów powyższe sposoby walki z otyłością są nierealne ze względów psychologicznych. Dla tych pacjentów jedyną alternatywą są zabiegi chirurgiczne lub odchudzanie farmakologiczne. Wydaje się, że najbardziej skuteczne leczenie farmakologiczne czy chirurgiczne otyłości sprowadza się do wytworzenia funkcjonalej niewydolności trzustki zewnątrzwydzielniczej. Enzymy trzustkowe są niezbędne do trawienia pokarmów i w konsekwencji do wchłaniania ich elementów składowych. W wyniku autokatalizy enzymów trzustkowych (operacje bariatryczne) lub ich blokowania (leczenie farmakologiczne) trawienie i absorpcja składników zostają zmniejszone. Mimo że te sposoby leczenia dają na ogół dobre rezultaty, w postaci utraty wagi, to wiążą się z nimi powikłania odżywcze i metaboliczne. Jest więc bardzo ważne dla lekarzy, a przede wszystkim dla pacjentów, posiadanie wiedzy o ryzyku, z którym związane są poszczególne postępowania terapeutyczne.
Overweight and obesity are major health problem in today’s society, where the western diet and a sedentary lifestyle has been suggested as primary causes. Lifestyle changes, such as the introduction of a healthier diet and increased physical activity, should be considered a first step in the management of obesity. However, many patients struggle to lose weight with these types of interventions. For these patients, pharmaceutical and surgical treatments may be an option. The most commonly used pharmaceutical and surgical approaches for the management of obesity aim to induce weight loss by creating functional exocrine pancreatic insufficiency. Pancreatic enzymes are crucial for the digestion of macronutrients. Thus, by targeting these enzymes, digestion and absorption of nutrients will be reduced. Although these treatment strategies usually show good results in terms of weight loss, they are associated with nutritional and metabolic complications. It is therefor of great importance that both medical doctors and patient are well informed about the risks that come with various therapies.
Abbreviations: AGB – adjustable gastric binding; BMI – body mass index; ESRD – end-stage renal disease; EMA – European Medicines Agency; EPI – exocrine pancreatic insufficiency; GLP-1 – glucagon-like peptide-1; GLUT2 – glucose transporter-2; PYY – peptide YY; RYGB – Roux-en-Y gastric bypass; SG – sleeve gastrectomy; SGLT2 – sodium-dependent glucose co-transporter-2; WHO – World Health Organization
Overweight and obesity are major health problems in today’s society, especially in the westernized countries. The western diet, together with a sedentary lifestyle with a lack of physical activity, is suggested to be the main reasons for the epidemic of these conditions (1). Overweight is defined by the World Health Organization (WHO) as a body mass index (BMI) > 25 kg/m2 and obesity as a BMI > 30 kg/m2. In 2008, around 35% of the global adult population was overweight and 11% obese. Huge differences can however be seen between westernized and non-westernized countries. Overweight and obesity are associated with comorbid conditions such as type 2 diabetes, cardiovascular diseases, and cancer. This might explain why overweight and obesity are linked to more deaths worldwide than underweight (2).
Lifestyle changes such as the introduction of a healthier diet and increased physical activity should be considered a first step in the management of overweight and obesity (3). However, for many overweight and obese patients it is difficult to loose weight and maintain this weight loss over a long period of time (4). For patients who have failed to achieve weight loss through lifestyle interventions, pharmacological or surgical treatments may be an option (3).
The most commonly used pharmaceutical and surgical approaches to treat obesity are based on the creation of functional exocrine pancreatic insufficiency (EPI) (1, 5). Orlistat, an inhibitor of pancreatic lipase, is currently the only drug approved by the European Medicines Agency (EMA) for treatment of obesity (1). However, several plant-derived phytochemicals has been identified as potent inhibitors of both pancreatic lipase and pancreatic α-amylase, and the clinical potential of these agents are widely investigated (6). In addition, Roux-en-Y gastric bypass (RYGB), the most commonly preformed bariatric surgery worldwide (7), is designed to induce weight loss through a combination of malabsorption and gastric restriction (5). Nevertheless, one should remember that these types of interventions usually are associated with nutritional (4) and metabolic (8) complications. It is therefore of great importance that both medical doctors and patient are well informed about the risks that come with various therapies.
Pharmaceutical approaches affecting the exocrine pancreas
Pancreatic lipase inhibitors
Pancreatic lipase is an important enzyme in the digestion of dietary fat. It is produced and secreted from acinar cells of the exocrine pancreas, and enters the duodenum via the common bile duct. In the intestinal lumen, pancreatic lipase act on triglycerides to generate free fatty acids and monoglycerides. These digestive products are then absorbed by the enterocytes lining the small intestine (9). By inhibiting the action of pancreatic lipase, the digestion of triglycerides in the intestinal lumen will be reduced. This will in turn result in a decreased absorption of free fatty acids and monoglycerides and, thus, a reduced caloric uptake (1).
The pharmaceutical and nutraceutical industry has proposed various inhibitors of pancreatic lipase for the management of weight loss. A few of these agents have after successful clinical trials been able to reach the market, however, the majority are still under investigation (6).
Orlistat is a potent, specific and irreversible inhibitor of pancreatic lipase (10) that is approved by the EMA for long-term use in two forms: as a prescriptive drug in 120 mg capsules under the trade name Xenical, and as a non-prescriptive drug in 60 mg capsules under the trade name Alli (1). Orlistat acts by forming a covalent bond to the active site of pancreatic lipase, thus preventing catabolism of luminal triglycerides into absorbable free fatty acids and monoglycerides (10). Studies have shown that the action of orlistat is not only associated with weight loss, but also reduced blood pressure and lowered plasma levels of low-density lipoprotein cholesterol (11). However, numerous adverse effects have been reported following treatment with orlistat, such as intestinal cramps, oily rectal spotting, flatus with discharge, and fecal incontinence. These are usually detected during the first week of treatment, but are reduced once the patients learn how do avoid high-fat diets. In addition, treatment with orlistat is associated with decreased absorption of fat-soluble vitamins, such as vitamin D, vitamin E, and β-carotene. Therefore, multivitamin supplementation should be recommended to patients treated with this agent (12).
Cetilistat is a pancreatic lipase inhibitor that recently was approved in Japan for the treatment of obese patients with comorbid conditions (13). Its mechanism of action is similar to that of orlistat (14). However, due to structural differences, it has been suggested that the safety profile of certilistat is superior to that of orlistat (15).
A novel approach for the treatment of obesity is the use of plant-derived phytochemicals (6). These agents are hybrids between nutrients and pharmaceuticals, and are therefore referred to as nutraceuticals (16). It has been shown that several phytochemicals that belong to the chemical classes saponins, polyphenols, and terpenes are able to inhibit the activity of pancreatic lipase. For some of these, the inhibitory activity can reach as high as 70%. However, more research is needed to further evaluate the clinical potential of these agents (6).
Pancreatic amylase inhibitors
Carbohydrates are the main energy source of the human diet, accounting for about 40-80% of the total caloric intake. These are either digestible or non-digestible. The most frequently consumed digestible carbohydrates are disaccharides, such as sucrose and lactose, and larger polysaccharides, such as starch. These are comprised of monosaccharides, which are joined together by glycoside bonds. The digestion of carbohydrates is initiated in the mouth, were salivary α-amylase hydrolyzes the α-1,4 bonds in starch. The products of this process include maltose, maltotriose and dextrins. The digestion of starch is continued in the small intestine by the action of pancreatic α-amylase, and completed by enzymes located at the brush border membrane. The action of these enzymes yields the monosaccharides glucose, fructose, and galactose, which are absorbed by the enterocytes lining the small intestine. Non-digestible carbohydrates, such as fibers and cellulose, as well as digestible carbohydrates that manage to escape the action of the digestive enzymes in the small intestine, enter the colon where they are fermented by the colonic microbiota. Fermentation yields short chain fatty acids, which can be absorbed in the colon, used as bacterial substrate, or excreted in the feces (6).
Since a high amount of consumed calories are ascribed to carbohydrates, it is of great interest to limit the uptake of these nutrients in the management of obesity. Inhibitors of pancreatic α-amylase have been suggested as potential anti-obesity agents, and numerous α-amylase inhibitors have been isolated from a number of different plant sources (6). These include Phaseolus vulgaris (17), Cinnamomum cassia (18), Rosmarinus officinalis (19), and black, green, and mulberry teas (20). Administration of α-amylase inhibitors causes reduced luminal activity of pancreatic α-amylase, resulting in limited absorption of carbohydrates. This in turn leads to decrease postprandial plasma glucose and insulin levels, and increased activity of the colonic microbiota (6).
Surgical approaches affecting the exocrine pancreas
Bariatric surgery, or weight loss surgery, is a possible treatment for obese patients who do not manage to lose weight and maintain this weight loss with lifestyle interventions such as increased exercise and diet modifications (5). In 2011, a total number of 340 768 bariatric surgeries worldwide were reported. This is more than twice as many compared to 2003 (7).
To be considered a candidate for bariatric surgery, the patient must meet the criteria of a BMI > 40 kg/m2 or a BMI > 35 kg/m2 with an obesity-related comorbid condition (5). Different surgical procedures can be preformed on these patients, where the most common include RYGB, sleeve gastrectomy (SG), and adjustable gastric binding (AGB) (7). RYGB is designed to induce weight loss through a combination of gastric restriction, creating early satiety, and malabsorption. On the contrary, SG and AGB are solely restrictive procedures and, because they do not aim to induce weight loss by affecting the function of exocrine pancreatic enzymes, they will not be further discussed (5).
Roux-en-Y gastric bypass
RYGB is the most commonly preformed bariatric surgery worldwide (7). As mentioned earlier, the induced weight loss that results from this surgical procedure is suggested to be due to a combination of gastric restriction and malabsorption (5). In addition, altered secretion of hormones involved in appetite control has been implicated as an important factor contributing to weight loss following RYGB (21).
Gastric restriction is achieved by partitioning the stomach into two sections by the use of a stapler-cutting device, creating a small gastric pouch and a larger gastric remnant (22). The gastric pouch ranges from 15 to 30 ml in size and is the only section that will receive food and liquid due to its connection to the esophagus. At this stage, the gastric pouch is not attached to the intestine. To achieve this, the jejunum is divided into two sections creating a long distal limb known as the Roux limb and a shorter proximal limb known as the biliopancreatic limb. The Roux limb is attached to the gastric pouch, making it possible for ingested food and liquid to enter the intestine. In a final step, the biliopancreatic limb is reattached further down the Roux limb, creating a common channel that continues into the ileum. Due to that the common bile duct is connected to the biliopancreatic limb, digestive enzymes secreted from the gastric remnant, gallbladder, and pancreas are allowed to enter the reconstructed intestine. However, because ingested food and liquid bypasses the duodenum and the first part of the jejunum, a smaller amount of nutrients is absorbed than usual, contributing to the induced weight loss (5).
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