The effects of Calorie restriction and Bariatric surgery on Circulating Proneurotensin levels.

CONTEXT: Proneurotensin (pNT) is associated with obesity and T2D, but the effects of Roux-en-Y gastric bypass (RYGB) on postprandial pNT levels are not well studied. OBJECTIVE: Assess effects of RYGB versus very low-energy diet (VLED) on pNT levels in response to mixed-meal tests (MMT), and long-term effects of RYGB on fasting pNT.Study participants: Cohort 1: Nine normoglycemic (NG) and ten T2D patients underwent MMT before and after VLED, immediately post-RYGB and six weeks post-RYGB. Cohort 2: Ten controls with normal weight and ten patients with obesity and T2D, who underwent RYGB or vertical sleeve gastrectomy (VSG), were subjected to MMTs and GIP infusions pre-surgery and three months post-surgery. GLP-1 infusions were performed in normal weight participants. Cohort 3: Fasting pNT was assessed pre-RYGB (n=161), two months post-RYGB (n=92) and 1-year post-RYGB (n=118) in NG and T2D patients. pNT levels were measured using ELISA. RESULTS: Reduced fasting and postprandial pNT were evident after VLED and immediately following RYGB. Reintroduction of solid food post-RYGB increased fasting and postprandial pNT. Prior to RYGB, all patients lacked a meal response in pNT, but this was evident post-RYGB/VSG. GIP- or GLP-1 infusion had no effect on pNT levels. Fasting pNT were higher 1-year post-RYGB regardless of glycemic status. CONCLUSION: RYGB causes a transient reduction in pNT as a consequence of caloric restriction. The RYGB/VSG-induced rise in postprandial pNT is independent of GIP and GLP-1 and higher fasting pNT are maintained one year post-surgically.

Detection of Intestinal Inflammation by Vascular Adhesion Protein-1-Targeted [68Ga]Ga-DOTA-Siglec-9 Positron Emission Tomography in Murine Models of Inflammatory Bowel Disease.

PURPOSE: Inflammatory bowel disease (IBD) can be imaged with positron emission tomography (PET), but existing PET radiopharmaceuticals have limited diagnostic accuracy. Vascular adhesion protein-1 (VAP-1) is an endothelial cell surface molecule that controls leukocyte extravasation into sites of inflammation. However, the role of inflammation-induced VAP-1 expression in IBD is still unclear. Therefore, this study investigated the utility of VAP-1-targeted [68Ga]Ga-DOTA-Siglec-9 positron emission tomography/computed tomography (PET/CT) for assessing inflammation in two mouse models of IBD. PROCEDURES: Studies were performed using K8-/- mice that develop a chronic colitis-phenotype and C57Bl/6NCrl mice with acute intestinal inflammation chemically-induced using 2.5% dextran sodium sulfate (DSS) in drinking water. In both diseased and control mice, uptake of the VAP-1-targeting peptide [68Ga]Ga-DOTA-Siglec-9 was assessed in intestinal regions of interest using in vivo PET/CT, after which ex vivo gamma counting, digital autoradiography, and histopathological analyses were performed. Immunofluorescence staining was performed to determine VAP-1-expression in the intestine, including in samples from patients with ulcerative colitis. RESULTS: Intestinal inflammation could be visualized by [68Ga]Ga-DOTA-Siglec-9 PET/CT in two murine models of IBD. In both models, the in vivo PET/CT and ex vivo studies of [68Ga]Ga-DOTA-Siglec-9 uptake were significantly higher than in control mice. The in vivo uptake was increased on average 1.4-fold in the DSS model and 2.0-fold in the K8-/- model. Immunofluorescence staining revealed strong expression of VAP-1 in the inflamed intestines of both mice and patients. CONCLUSIONS: This study suggests that the VAP-1-targeting [68Ga]Ga-DOTA-Siglec-9 PET tracer is a promising tool for non-invasive imaging of intestinal inflammation. Future studies in patients with IBD and evaluation of the potential value of [68Ga]Ga-DOTA-Siglec-9 in diagnosis and monitoring of the disease are warranted.

Metformin increases the uptake of glucose into the gut from the circulation in high-fat diet-fed male mice, which is enhanced by a reduction in whole-body Slc2a2 expression.

OBJECTIVES: Metformin is the first line therapy recommended for type 2 diabetes. However, the precise mechanism of action remains unclear and up to a quarter of patients show some degree of intolerance to the drug, with a similar number showing poor response to treatment, limiting its effectiveness. A better understanding of the mechanism of action of metformin may improve its clinical use. SLC2A2 (GLUT2) is a transmembrane facilitated glucose transporter, with important roles in the liver, gut and pancreas. Our group previously identified single nucleotide polymorphisms in the human SLC2A2 gene, which were associated with reduced transporter expression and an improved response to metformin treatment. The aims of this study were to model Slc2a2 deficiency and measure the impact on glucose homoeostasis and metformin response in mice. METHODS: We performed extensive metabolic phenotyping and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG)-positron emission tomography (PET) analysis of gut glucose uptake in high-fat diet-fed (HFD) mice with whole-body reduced Slc2a2 (Slc2a2+/-) and intestinal Slc2a2 KO, to assess the impact of metformin treatment. RESULTS: Slc2a2 partial deficiency had no major impact on body weight and insulin sensitivity, however mice with whole-body reduced Slc2a2 expression (Slc2a2+/-) developed an age-related decline in glucose homoeostasis (as measured by glucose tolerance test) compared to wild-type (Slc2a2+/+) littermates. Glucose uptake into the gut from the circulation was enhanced by metformin exposure in Slc2a2+/+ animals fed HFD and this action of the drug was significantly higher in Slc2a2+/- animals. However, there was no effect of specifically knocking-out Slc2a2 in the mouse intestinal epithelial cells. CONCLUSIONS: Overall, this work identifies a differential metformin response, dependent on expression of the SLC2A2 glucose transporter, and also adds to the growing evidence that metformin efficacy includes modifying glucose transport in the gut. We also describe a novel and important role for this transporter in maintaining efficient glucose homoeostasis during ageing.

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.

Obesity-associated Blunted Subcutaneous Adipose Tissue Blood Flow After Meal Improves After Bariatric Surgery.

CONTEXT: Glucose-dependent insulinotropic peptide (GIP) and meal ingestion increase subcutaneous adipose tissue (SAT) perfusion in healthy individuals. The effects of GIP and a meal on visceral adipose tissue (VAT) perfusion are unclear. OBJECTIVE: Our aim was to investigate the effects of meal and GIP on VAT and SAT perfusion in obese individuals with type 2 diabetes mellitus (T2DM) before and after bariatric surgery. METHODS: We recruited 10 obese individuals with T2DM scheduled for bariatric surgery and 10 control individuals. Participants were studied under 2 stimulations: meal ingestion and GIP infusion. SAT and VAT perfusion was measured using 15O-H2O positron emission tomography-magnetic resonance imaging at 3 time points: baseline, 20 minutes, and 50 minutes after the start of stimulation. Obese individuals were studied before and after bariatric surgery. RESULTS: Before bariatric surgery the responses of SAT perfusion to meal (P = .04) and GIP-infusion (P = .002) were blunted in the obese participants compared to controls. VAT perfusion response did not differ between obese and control individuals after a meal or GIP infusion. After bariatric surgery SAT perfusion response to a meal was similar to that of controls. SAT perfusion response to GIP administration remained lower in the operated-on than control participants. There was no change in VAT perfusion response after bariatric surgery. CONCLUSION: The vasodilating effects of GIP and meal are blunted in SAT but not in VAT in obese individuals with T2DM. Bariatric surgery improves the effects of a 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.

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.

The value of combined positron emission tomography/magnetic resonance imaging to diagnose inflammatory bowel disease: a prospective study.

BACKGROUND: The clinical utility of positron emission tomography/magnetic resonance imaging (PET/MRI) in comparison to standard work-up with patients with known or suspected inflammatory bowel disease (IBD) is unknown. PURPOSE: To evaluate the value of 18F-fluorodeoxyglucose (18F-FDG) PET/MRI in the diagnostics of IBD and further compare the data obtained using PET/MRI to histological findings. MATERIALS AND METHODS: Ten patients with relapse in IBD or with symptoms of suspected IBD were recruited either from a gastroenterology outpatient clinic or from a hospital ward. Intestinal inflammation was assessed with histology and 18F-FDG PET/MRI. Maximum standard uptake values (SUVmax) were calculated in six regions of the intestine (small bowel, ascending, transverse, descending and sigmoid colon, and rectum) and compared to histological analysis of inflammation activity. RESULTS: The study showed that both the inflammation activity (P = 0.008) and the region of the biopsy in the intestine (P = 0.015) had a significant effect on SUV. SUVs obtained from severe inflammation activity emerged significantly from the background (P = 0.006). In addition, the SUVs obtained from moderate inflammation raised from background, but the difference was not statistically significant (P = 0.083), while SUVs of mild inflammation were at the same level with SUVs of normal bowel wall (P = 0.988). CONCLUSION: 18F-FDG PET/MRI is a promising method of detecting especially severe inflammatory bowel lesions. More data are required to define its sensitivity and specificity.

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.

Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study.

BACKGROUND: Interleukin 15 (IL-15) is implicated in the pathophysiology of coeliac disease. AMG 714 is the first anti-IL-15 monoclonal antibody to be investigated for the treatment of coeliac disease. We aimed to investigate the effects of AMG 714 in patients with coeliac disease who underwent gluten challenge. METHODS: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial was done at three clinical sites in Finland. Inclusion criteria included age 18-80 years, a confirmed diagnosis of coeliac disease, and adherence to a gluten-free diet for at least 12 months before screening. Patients were randomly assigned (1:1:1) to 150 mg AMG 714, 300 mg AMG 714, or placebo using permuted blocks and stratified by study site and sex. Patients and study staff were masked to treatment assignment. Treatments were administered by two subcutaneous injections every 2 weeks for 10 weeks (total six doses). Patients without severe villous atrophy at baseline received a gluten challenge (2-4 g daily) during weeks 2-12. Small bowel biopsy samples were obtained for histological assessments at baseline and week 12. The primary efficacy endpoint was the percentage change from baseline to week 12 in villous height-to-crypt depth (VHCD) ratio. Secondary endpoints were CD3-positive intraepithelial lymphocyte density; clinical symptoms measured by gastrointestinal symptom rating scale (GSRS), coeliac disease GSRS, and Bristol stool form scale (BSFS); and changes in anti-tTG and anti-DGP antibodies from baseline. The primary analysis was done in the per-protocol 1 population of patients who received at least one dose of study drug and who underwent the gluten challenge. Safety analyses were done in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, NCT02637141 and EudraCT, 2015-003647-19. FINDINGS: Between April 13, 2016, and Nov 22, 2016, 64 patients were enrolled and randomly assigned to either the 150 mg AMG 714 group (n=22), the 300 mg AMG 714 group (n=22), or the placebo group (n=20). Two patients did not start treatment and two did not provide post-treatment biopsy samples. 49 patients underwent the gluten challenge (per-protocol 1 population) and 11 patients did not because of baseline villous atrophy. AMG 714 did not prevent mucosal injury due to gluten challenge. The least square mean difference in the relative change from baseline in VHCD ratio was -2·49% (95% CI -16·82 to 11·83; p=0·73) between 150 mg AMG 714 and placebo and 6·39% (-7·07 to 19·85; p=0·34) between 300 mg AMG 714 and placebo. Neither comparison was statistically significant. The density of CD3-positive intraepithelial lymphocytes increased in all groups, with smaller increases in the 300 mg group (-41·24% [95% CI -79·28 to -3·20] vs placebo, nominal p=0·03) but not the 150 mg group (-14·32% [-54·39 to 25·74], nominal p=0·47). Clinical symptoms were ameliorated with AMG 714 treatment between baseline and week 12, particularly diarrhoea as measured by the BSFS (nominal p=0·01 for 150 mg vs placebo, and nominal p=0·0002 for 300 mg vs placebo). Serum antibody titres for anti-tTG and anti-DGP antibodies increased in all three treatment groups, with no significant difference between AMG 714 and placebo. Treatment-emergent adverse events occurred in 21 (95%) patients in the 150 mg AMG 714 group, 0 (95%) in the 300 mg AMG 714 group, and 19 (100%) in the placebo group. The most common treatment-emergent adverse events were gastrointestinal disorders (17 [77%] participants in the 150 mg AMG 714 group, 16 [76%] in the 300 mg AMG 714 group, and 13 [68%] in the placebo group). Injection site reactions were the most common individual adverse event, reported in eight (36%) patients in the 150 mg AMG 714 group, 11 (52%) in the 300 mg group, and five (26%) in the placebo group. No serious adverse events occurred. INTERPRETATION: The primary endpoint, change in VHCD ratio from baseline after 12 weeks of treatment in patients with coeliac disease undergoing gluten challenge, was not significantly different between placebo and AMG 714 at either 150 mg or 300 mg. Effects on intraepithelial lymphocyte density and symptoms suggest that further research of AMG 714 may be warranted in patients with non-responsive coeliac disease. FUNDING: Celimmune and Amgen.

Liver blood dynamics after bariatric surgery: the effects of mixed-meal test and incretin infusions.

AIMS/HYPOTHESIS: The mechanisms for improved glycemic control after bariatric surgery in subjects with type 2 diabetes (T2D) are not fully known. We hypothesized that dynamic hepatic blood responses to a mixed-meal are changed after bariatric surgery in parallel with an improvement in glucose tolerance. METHODS: A total of ten morbidly obese subjects with T2D were recruited to receive a mixed-meal and a glucose-dependent insulinotropic polypeptide (GIP) infusion before and early after (within a median of less than three months) bariatric surgery, and hepatic blood flow and volume (HBV) were measured repeatedly with combined positron emission tomography/MRI. Ten lean non-diabetic individuals served as controls. RESULTS: Bariatric surgery leads to a significant decrease in weight, accompanied with an improved ß-cell function and glucagon-like peptide 1 (GLP-1) secretion, and a reduction in liver volume. Blood flow in portal vein (PV) was increased by 1.65-fold (P = 0.026) in response to a mixed-meal in subjects after surgery, while HBV decreased in all groups (P < 0.001). When the effect of GIP infusion was tested separately, no change in hepatic arterial and PV flow was observed, but HBV decreased as seen during the mixed-meal test. CONCLUSIONS/INTERPRETATION: Early after bariatric surgery, PV flow response to a mixed-meal is augmented, improving digestion and nutrient absorption. GIP influences the post-prandial reduction in HBV thereby diverting blood to the extrahepatic sites.

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 < .001) but similar intestinal blood flow (NS). Within 6 months after bariatric surgery, obese subjects had lost 24% of their weight and 7/10 diabetic subjects were in remission. Jejunal FA uptake was further increased (P < .03). Conversely, bariatric surgery provoked a decrease in jejunal blood flow (P < .05) while duodenal blood flow was preserved. Animal studies showed that FAs were taken up into enterocytes, for the most part, but were also transferred, in part, into the lumen. CONCLUSIONS: In the obese, the small intestine actively takes up FAs from circulation and FA uptake remains higher than in controls post-operatively. Intestinal blood flow was not enhanced before or after bariatric surgery, suggesting that enhanced intestinal FA metabolism is not driven by intestinal perfusion.

Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: Results from a randomized clinical trial.

AIMS: Metformin therapy is associated with diffuse intestinal 18F-fluoro-deoxyglucose (FDG) accumulation in clinical diagnostics using routine FDG-PET imaging. We aimed to study whether metformin induced glucose uptake in intestine is associated with the improved glycaemic control in patients with type 2 diabetes. Therefore, we compared the effects of metformin and rosiglitazone on intestinal glucose metabolism in patients with type 2 diabetes in a randomized placebo controlled clinical trial, and further, to understand the underlying mechanism, evaluated the effect of metformin in rats. METHODS: Forty-one patients with newly diagnosed type 2 diabetes were randomized to metformin (1g, b.i.d), rosiglitazone (4mg, b.i.d), or placebo in a 26-week double-blind trial. Tissue specific intestinal glucose uptake was measured before and after the treatment period using FDG-PET during euglycemic hyperinsulinemia. In addition, rats were treated with metformin or vehicle for 12weeks, and intestinal FDG uptake was measured in vivo and with autoradiography. RESULTS: Glucose uptake increased 2-fold in the small intestine and 3-fold in the colon for the metformin group and associated with improved glycemic control. Rosiglitazone increased only slightly intestinal glucose uptake. In rodents, metformin treatment enhanced intestinal FDG retention (P=0.002), which was localized in the mucosal enterocytes of the small intestine. CONCLUSIONS: Metformin treatment significantly enhances intestinal glucose uptake from the circulation of patients with type 2 diabetes. This intestine-specific effect is associated with improved glycemic control and localized to mucosal layer. These human findings demonstrate directs effect of metformin on intestinal metabolism and elucidate the actions of metformin. Clinical trial number NCT02526615.

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.

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 mixed meal 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.

Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers.

AIMS/HYPOTHESIS: Maternal obesity predisposes offspring to adulthood morbidities, including type 2 diabetes. Type 2 diabetes and insulin resistance have been associated with shortened telomere length. First, we aimed to investigate whether or not maternal obesity influences insulin sensitivity and its relationship with leucocyte telomere length (LTL) in elderly women. Second, we tested whether or not resistance exercise training improves insulin sensitivity in elderly frail women. METHODS: Forty-six elderly women, of whom 20 were frail offspring of lean/normal weight mothers (OLM, BMI ≤26.3 kg/m2) and 17 were frail offspring of overweight/obese mothers (OOM,BMI ≥28.1 kg/m2), were studied before and after a 4 month resistance training (RT) intervention. Muscle insulin sensitivity of glucose uptake was measured using 18F-fluoro-2-deoxyglucose and positron emission tomography with computed tomography during a hyperinsulinaemic­euglycaemic clamp. Muscle mass and lipid content were measured using magnetic resonance and LTL was measured using real-time PCR. RESULTS: The OOM group had lower thigh muscle insulin sensitivity compared with the OLM group (p=0.048) but similar whole body insulin sensitivity. RT improved whole body and skeletal muscle insulin sensitivity in the OOM group only (p=0.004 and p=0.013, respectively), and increased muscle mass in both groups (p <0 .01). In addition, in the OOM group, LTL correlated with different thigh muscle groups insulin sensitivity (ρ ≥ 0.53; p ≤ 0.05). Individuals with shorter LTL showed a higher increase in skeletal muscle insulin sensitivity after training (ρ ≥ −0.61; p ≤ 0.05). CONCLUSIONS/INTERPRETATION: Maternal obesity and having telomere shortening were associated with insulin resistance in adult offspring. A resistance exercise training programme may reverse this disadvantage among offspring of obese mothers. Trial registration: ClinicalTrials.gov NCT01931540.

The effects of bariatric surgery on pancreatic lipid metabolism and blood flow.

CONTEXT: Bariatric surgery leads to a rapid and sustained weight loss often accompanied with improvement in glucose homeostasis. OBJECTIVE: The objective of this study was to investigate the effects of bariatric surgery on pancreatic lipid metabolism, blood flow, and glycemic control. DESIGN: This was a longitudinal study. SETTING: The study was conducted in a clinical research center. PARTICIPANTS: This study included 27 morbidly obese and 15 healthy control subjects. INTERVENTIONS: Measurements were performed using positron emission tomography with the palmitate analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid and radiowater ([(15)O]H2O) and computed tomography. In morbidly obese subjects, positron emission tomography/computed tomography imaging studies were performed before and 6 months after bariatric surgery (either Roux-en-Y gastric bypass or sleeve gastrectomy). MAIN OUTCOME MEASURES: Pancreatic fat and fat-free volume, fatty acid uptake and blood flow were measured as well as parameters of ß-cell function, glucose tolerance, and insulin sensitivity. RESULTS: Six months after bariatric surgery, 23% excess weight loss was observed (P < .0001), and diabetes remission was seen in 7 of 10 patients. When compared with preoperative values, after surgery, notable decreases in pancreatic fat volume (P < .01), fatty acid uptake, and blood flow (both P < .05) were seen, whereas no change was seen in pancreatic fat-free volume. The decrease in pancreatic fat volume and the preservation of blood flow were associated with favorable glucose homeostasis and ß-cell function. CONCLUSIONS: Bariatric surgery elicits marked alterations in pancreatic lipid metabolism and blood flow, which may contribute to the observed improvement in glucose homeostasis and remission of type 2 diabetes.