Regulation of intestinal metabolism in obesity and diabetes : studies using positron emission tomography

The global epidemic of obesity is a challenge to healthcare systems due to the increase in the incidence of type 2 diabetes (T2D) and its associated morbidities. Although the small intestine is the first absorptive organ to encounter the ingested and digesting nutrients, it has gained little attention in the research of T2D and obesity. In the present study, multimodality imaging by Positron emission tomography (PET) combined with magnetic resonance imaging (MRI) or computed tomography (CT) modalities were utilized to study intestinal blood flow and metabolic substrate uptake in healthy normal-weight controls and obese patients with T2D before and after surgical or medical treatments. In the PET imaging, we focused on intestinal blood flow and volume, fatty acid, glucose uptake using 15O-water, 15O-labeled carbon monoxide, palmitate analogue 14(RS)-[18F]fluoro-6-thia-heptadecanoic acid, ([18F]FTHA) and 2-[18F]fluoro- 2-deoxy-D-glucose ([18F]FDG), respectively. Morbidly obese subjects (mean BMI 41±4.5kg/m2) with T2D had similar blood flow in the intestine even after bariatric surgery when compared to healthy controls. The bariatric surgery was either Roux-en Y gastric bypass (n=13) or Sleeve gastrectomy (n=20). Postprandially, nutrient contact with the small intestine and infusion of glucose dependent insulinotrophic polypeptide (GIP) stimulated blood flow in the small intestine of all groups. These findings suggest that despite the adaptation changes after bariatric surgery of the intestine, postprandial blood flow regulation in the small intestine remains intact in T2D and obese individuals. Intestinal fatty acid (FA) uptake was higher in obese subjects compared to healthy counterparts and unexpectedly this increased after bariatric surgery. The FA extraction rate in the small intestine also increased after bariatric surgery and this phenomenon suggests that intestinal energy expenditure relies on high FFA-to-glucose ratio in obese patients, which persists even after weight loss. Glucose uptake in the small intestines of metformin treated study subjects with T2D was increased compared to baseline and reached the level observed in healthy study subjects in previous studies. Taken together, the data of the present study provide novel insight on the role of the small intestine in the multiorgan metabolic derangements associated with T2D. It is not known whether these changes are part of the adaptation mechanism, due to improved glycaemic control and insulin resistance breakdown or due to the fundamental pathophysiology behind T2D. The actual mechanism behind these changes should be addressed in future research.Suoliston aineenvaihdunnan säätely lihavuudessa ja diabeteksessa : positroniemissiotomografiaa käyttäen tehtyjä tutkimuksia Lihavuus on huomattavasti yleistynyt viime vuosikymmeninä ja kuormittaa terveydenhuoltoamme lisäten tyypin 2 diabeteksen ilmaantuvuutta ja yleistä sairastavuutta.Lihavuuden ja tyypin 2 diabeteksen tutkimuksessa on aiemmin keskitytty suoliston aineenvaihduntaan varsin vähän, vaikka suolisto ensimmäisenä elimenä käsittelee elimistöön tulevan ravinnon ja ruoansulatuskanavasta erittyvillä hormoneilla säätelee sokeriaineenvaihduntaa. Tutkimuksessa verrattiin suoliston verenvirtauksen ja ravintoaineiden soluunottokyvyn muutoksia ylipainoisilla tyypin 2 diabeetikoilla ja terveillä normaalipainoisilla verrokeilla käyttäen positroniemissiotomografiaa (PET) yhdistettynä rakenteelliseen magneetti- ja tietokonetomografia kuvantamiseen. Tutkittavat osallistuivat kliinisen hoitokäytännön mukaan lihavuusleikkaukseen tai käyttivät tutkimuslääkettä protokollan mukaan. PET-kuvantamisella tutkittiin suoliston verenvirtauksen ja verimäärän muutoksia sekä rasvahappojen ja sokerin soluunottokykyä käyttäen 15O-vettä, 15Oleimattua hiilimonoksidia, palmitaattianalogi 14(RS)-[18F]fluoro-6-thia-heptadekanoidi happoa ([18F]FTHA) ja 2-[18F]fluoro-2-deoxy-D-glukoosia ([18F]FDG). Sairaalloisen ylipainoisilla diabeetikoilla suoliston verenvirtaus ei poikennut terveistä kontrolleista edes lihavuusleikkauksen jälkeen. Ryhmien välisiä eroja veren virtauksessa ei todettu syömisen ja glukoosista riippuvaisen insuliinin eritystä lisäävän hormonin (GIP) annostelun jälkeen. Havainnot viittaavat siihen, että aterian jälkeinen verenvirtauksen säätely ei ole muuttunut lihavilla diabeetikoilla edes lihavuuskirurgian jälkeen, vaikka suolisto muuten sopeutuu kirurgian aiheuttamiin anatomisiin muutoksiin. Ylipainoisilla tyypin 2 diabetesta sairastavilla tutkittavilla suoliston rasvahappojen soluunottokyky todettiin lisääntyneeksi verrattuna terveisiin kontrollihenkilöihin ja odottamatta lihavuuskirurgia lisäsi kyseistä muutosta. Rasvahappojen soluunottokyvyn lisääntyminen verenkierrosta vielä lihavuuskirurgian jälkeen, osoittaa suoliston energiankäytön riippuvan korkeasta rasvahappo-sokerin käyttösuhteesta vielä laihtumisen jälkeenkin. Metformiini-lääkitys lisäsi suoliston sokerin käyttöä ja vähensi suoliston insuliiniresistenssiä, jopa normaalistaen sen terveiden tasolle. Tämä väitöskirjatutkimus osoittaa, että suolistossa tapahtuu merkittäviä aineenvaihdunnallisia muutoksia tyypin 2 diabeteksessa, ylipainossa ja lihavuusleikkauksen jälkeen. Avoimeksi jää säätelevätkö lihavuuskirurgian ja lääkehoitojen myötä lisääntyneet suoliston rasvahappojen ja sokerin käyttö koko elimistö aineenvaihduntaa vai ovatko ne seurausta suoliston sopeutumisesta muuttuneeseen energia-aineenvaihduntaan. Koska lihavuuskirurgia johtaa usein merkittävään painonlaskuun ja tyypin 2 diabeteksen paranemiseen tulisi suoliston energia-aineenvaihdunnan tutkimusta jatkaa kyseisten tautien syntymekanismin ymmärtämiseksi

Predictive Markers of Crohn's Disease in Small Bowel Capsule Endoscopy: A Retrospective Study of Small Bowel Capsule Endoscopy

To distinguish between functional gastrointestinal disorders like irritable bowel syndrome (IBS) and mild small bowel Crohn's disease (CD) can be a burden. The diagnosis of CD often requires small bowel capsule endoscopy (SBCE). The main goal of this research was to find predictive markers to rule out clinically significant small bowel CD without SBCE. A retrospective study of 374 patients who underwent SBCE for suspected small bowel CD in Turku University Hospital in 2012-2020 was conducted. We gathered the patient's laboratory, imaging and endoscopic findings at the time of SBCE. SBCE findings were graded along CECDAI (Capsule Endoscopy Crohn's Disease Activity Index)-scoring system. Fecal calprotectin (FC), serum albumin and ESR were significantly different with patients diagnosed with CD and those with not. Hb and CRP had no significant differences between the two groups. Sensitivity, specificity, PPV and NPV for FC < 50 ug/g were 96.4%, 19.6%, 34.6% and 92.5% and for CECDAI (cut-off value 3) 98.2%, 90.3%, 81.1% and 99.1%, respectively. A CECDAI-score of 3 would be a reasonable cut-off value for small bowel CD. Small bowel CD is possible with FC < 100 ug/g. Our results suggest a follow-up with FC before SBCE for patients with no endoscopic ileitis, negative imaging results and FC < 50 ug/g before SBCE

Combining biological therapies in patients with inflammatory bowel disease : a Finnish multi-centre study

Background and aims Therapy with two concomitant biologicals targeting different inflammatory pathways has emerged as a new therapy option for treatment refractory inflammatory bowel disease (IBD). Data on the efficacy and safety of dual biological therapy (DBT) are scarce and are investigated in this study. Materials and methods Data on all patients treated with a combination of two biologicals in four Finnish tertiary centres were collected and analysed. Remission was assessed by a physician on the basis of biomarkers, endoscopic evaluation and alleviation of symptoms. Results A total of 16 patients with 22 trials of DBT were included. Fifteen patients had Crohn's disease. The most common combination of DBT was adalimumab (ADA) and ustekinumab (USTE; 36%) with median follow-up of nine months (range 2-31). Altogether seven (32%) patients were in remission at the end of follow-up and in two trials response to DBT was assessed to be partial with the relief of patient symptoms. In a total of four trials DBT reduced the need for corticosteroids. The majority of patients achieving a response to DBT were treated with the combination of ADA and USTE (56%). At the end of follow-up all nine (41%) patients responding to DBT continued treatment. Infection complications occurred in three patients (19%). Conclusion DBT is a promising alternative treatment for refractory IBD, and half of our patients benefitted from it. More data on the efficacy and safety of DBT are needed especially in long-term follow up.Peer reviewe

Partial restoration of normal intestinal microbiota in morbidly obese women six months after bariatric surgery

We studied the impact of bariatric surgery on the intestinal microbiota of morbidly obese study subjects. A total of 13 morbidly obese women (five of which had type 2 diabetes) and 14 healthy age- and gender-matched controls were recruited and the microbiota composition of fecal samples were determined by using a phylogenetic microarray. Sampling of the patients took place just one month before and 6 months after the operation. Within six months after bariatric surgery, the obese subjects had lost on average a quarter of their weight whereas four of the five of the diabetic subjects were in remission. Bariatric surgery was associated with an increased microbial community richness and Bacteroidetes/Firmicutes ratio. In addition, we observed an increased relative abundance of facultative anaerobes, such as Streptococcus spp., and a reduction in specific butyrate-producing Firmicutes. The observed postoperative alterations in intestinal microbiota reflect adaptation to the changing conditions in the gastrointestinal tract, such as energy restriction and the inability to process fiber-rich foods after bariatric surgery.Peer reviewe

Morbid obesity and type 2 diabetes alter intestinal fatty acid uptake and blood flow

Aims: Bariatric surgery is the most effective treatment to tackle morbid obesity and type 2 diabetes, but the mechanisms of action are still unclear. The objective of this study was to investigate the effects of bariatric surgery on intestinal fatty acid (FA) uptake and blood flow. Materials and Methods: We recruited 27 morbidly obese subjects, of whom 10 had type 2 diabetes and 15 were healthy age-matched controls. Intestinal blood flow and fatty acid uptake from circulation were measured during fasting state using positron emission tomography (PET). Obese subjects were re-studied 6 months after bariatric surgery. The mucosal location of intestinal FA retention was verified in insulin resistant mice with autoradiography. Results: Compared to lean subjects, morbidly obese subjects had higher duodenal and jejunal FA uptake (P </p

Combining biological therapies in patients with inflammatory bowel disease: a Finnish multi-centre study

Background and aims: Therapy with two concomitant biologicals targeting different inflammatory pathways has emerged as a new therapy option for treatment refractory inflammatory bowel disease (IBD). Data on the efficacy and safety of dual biological therapy (DBT) are scarce and are investigated in this study.Materials and methods: Data on all patients treated with a combination of two biologicals in four Finnish tertiary centres were collected and analysed. Remission was assessed by a physician on the basis of biomarkers, endoscopic evaluation and alleviation of symptoms.Results: A total of 16 patients with 22 trials of DBT were included. Fifteen patients had Crohn's disease. The most common combination of DBT was adalimumab (ADA) and ustekinumab (USTE; 36%) with median follow-up of nine months (range 2-31). Altogether seven (32%) patients were in remission at the end of follow-up and in two trials response to DBT was assessed to be partial with the relief of patient symptoms. In a total of four trials DBT reduced the need for corticosteroids. The majority of patients achieving a response to DBT were treated with the combination of ADA and USTE (56%). At the end of follow-up all nine (41%) patients responding to DBT continued treatment. Infection complications occurred in three patients (19%).Conclusion: DBT is a promising alternative treatment for refractory IBD, and half of our patients benefitted from it. More data on the efficacy and safety of DBT are needed especially in long-term follow up.</p

Obesity associated blunted subcutaneous adipose tissue blood flow after meal is improved after bariatric surgery

Background and aims: GIP and meal ingestion increase subcutaneous adipose tissue (SAT) perfusion in healthy subjects. Effects of GIP and meal on visceral adipose tissue (VAT) perfusion is unclear. Our aim was to investigate the effects of meal and GIP on VAT and SAT perfusion in obese subjects with type 2 diabetes (T2DM) before and after bariatric surgery.Materials and methods: We recruited 10 obese subjects with T2DM scheduled for bariatric surgery and 10 control subjects. Subjects were studied under two stimulations: meal ingestion and GIP infusion. SAT and VAT perfusion was measured using 15O-H2O PET-MRI at three time points: baseline, 20min and 50min after start of stimulation. Obese subjects were studied before and after bariatric surgery.Results: Before bariatric surgery the responses of SAT perfusion to meal (p=0.04) and GIP-infusion (p=0.002) were blunted in the obese subjects compared to the controls. VAT perfusion response did not differ between obese and control subjects after meal or GIP-infusion.After bariatric surgery SAT perfusion response to meal was similar to that of control subjects. SAT perfusion response to GIP administration remained lower in operated than control subjects. There was no change in VAT perfusion response after bariatric surgery.Conclusions: The vasodilating effects of GIP and meal are blunted in SAT but not in VAT in obese subjects with T2DM. Bariatric surgery improves the effects of meal on SAT perfusion, but not the effects of GIP. Postprandial increase in SAT perfusion after bariatric surgery seems to be regulated in a GIP independent manner.</p

Skitsofrenian tarpeenmukainen hoito on ryhmätyötä : Raportti Akuutin psykoosin integroitu hoito -projektin tuottamista hoitoperiaatteista

API-projekt

Bariatric surgery enhances splanchnic vascular responses in patients with type 2 diabetes

Bariatric surgery results in notable weight loss and alleviates hyperglycemia in patients with type 2 diabetes (T2D). We aimed to characterize the vascular effects of a mixedmeal and infusion of exogenous glucose-dependent insulinotropic polypeptide (GIP) in the splanchnic region in 10 obese patients with T2D before and after bariatric surgery and in 10 lean control subjects. The experiments were carried out on two separate days. Pancreatic and intestinal blood flow (BF) were measured at baseline, 20 min, and 50 min with 15O-water by using positron emission tomography and MRI. Before surgery, pancreatic and intestinal BF responses to a mixed meal did not differ between obese and lean control subjects. Compared with presurgery, the mixed meal induced a greater increase in plasma glucose, insulin, and GIP concentrations after surgery, which was accompanied by a marked augmentation of pancreatic and intestinal BF responses. GIP infusion decreased pancreatic but increased small intestinal BF similarly in all groups both before and after surgery. Taken together, these results demonstrate that bariatric surgery leads to enhanced splanchnic vascular responses as a likely consequence of rapid glucose appearance and GIP hypersecretion

Effects of meal and incretins in the regulation of splanchnic blood flow

Objective: Meal ingestion is followed by a redistribution of blood flow (BF) within the splanchnic region contributing to nutrient absorption, insulin secretion and glucose disposal, but factors regulating this phenomenon in humans are poorly known. The aim of the present study was to evaluate the organ-specific changes in BF during a mixed-meal and incretin infusions. Design: A non-randomized intervention study of 10 healthy adults to study splanchnic BF regulation was performed. Methods: Effects of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) infusions and mixed-meal were tested in 10 healthy, glucose tolerant subjects using PET-MRI multimodal imaging technology. Intestinal and pancreatic BF and blood volume (BV) were measured with 15O-water and 15O-carbon monoxide, respectively. Results: Ingestion of a mixed-meal led to an increase in pancreatic and jejunal BF, whereas duodenal BF was unchanged. Infusion of GIP and GLP-1 reduced BF in the pancreas. However, GIP infusion doubled blood flow in the jejunum with no effect of GLP-1. Conclusion: Together, our data suggest that meal ingestion leads to increases in pancreatic BF accompanied by a GIP-mediated increase in jejunal but not duodenal blood flow