AimTo evaluate 26 weeks of liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJ... more AimTo evaluate 26 weeks of liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJUNCT ONE and ADJUNCT TWO trials.Materials and MethodsADJUNCT ONE and ADJUNCT TWO were randomized controlled phase 3 trials in 1398 and 835 participants with T1D treated with liraglutide (1.8, 1.2, or 0.6 mg) or placebo (adjuncts to insulin). This post hoc analysis evaluated treatment effects by subgroups: HbA1c (< or ≥8.5%), body mass index (BMI; < or ≥27 kg/m2), and insulin regimen (basal bolus or continuous subcutaneous insulin infusion).ResultsIn both trials at week 26, reductions in HbA1c, body weight, and daily insulin dose did not differ significantly (P > .05) by baseline HbA1c or BMI. Risk of clinically significant hypoglycaemia or hyperglycaemia with ketosis did not differ significantly (P > .05) by baseline HbA1c, BMI, or insulin regimen. At week 26 in ADJUNCT ONE, these risks did not differ (P > .05) between treatment groups. Placebo‐adjusted reductions in HbA1c...
Background: Right hepatectomy (RH) is the most common type of major hepatectomy and can be achiev... more Background: Right hepatectomy (RH) is the most common type of major hepatectomy and can be achieved without portal triad clamping (PTC) in non-cirrhotic liver. The present study reviews our standardized policy of performing RH without systematic PTC. Methods: One hundred and eighty-one consecutive RH were performed in non-cirrhotic patients, with division of the right afferent and efferent blood vessels prior to transection, without systematically using PTC. Prospectively collected data were analysed, focusing on the following endpoints: need for salvage PTC, ischaemic time, blood loss and post-operative outcome. Results: Extra-hepatic division of the right hepatic vessels was feasible in all patients, but was ineffective in 48 patients (26.5%) who required salvage PTC during transection. In those patients, the median ischaemic time was 20 min. The median blood loss was 500 ml (50-3000). Six patients (3.3%) experienced post-operative liver failure. Overall morbidity, severe morbidity and mortality were 42%, 12.1% and 1.6%, respectively, with peri-operative transfusion rate (16.6%) being the only factor associated with morbidity. Discussion: By performing RH with extra-hepatic vascular division prior to transection, PTC can be safely avoided in the majority of patients.
In the SUSTAIN trial program, once-weekly (OW) semaglutide, a glucagon-like peptide-1 receptor ag... more In the SUSTAIN trial program, once-weekly (OW) semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treatment of type 2 diabetes, significantly reduced HbA1c and body weight (BW) vs. all comparators, with a safety profile consistent with the GLP-1RA class. Patient factors (e.g., BMI) may impact therapeutic choices. This post-hoc analysis of SUSTAIN 1-5 and 7-10 evaluated change from baseline to end of treatment in HbA1c and BW with OW semaglutide vs. comparator by baseline BMI subgroup. On-treatment without rescue medication data were evaluated in the full analysis set. Mixed model for repeated measurements analyses evaluated interaction between treatment and BMI subgroup by trial. Overall, 572, 1,867, 2,103 and 2,217 subjects with BMI <25, ≥25-<30, ≥30-<35 and ≥35 kg/m2, respectively, were evaluated. Estimated treatment difference for change in HbA1c favored semaglutide vs. comparator in most subgroups, and for BW favored semaglutide vs. comparato...
Highlights d Liraglutide induces weight loss in a woman homozygous for pathogenic MC4R mutation d... more Highlights d Liraglutide induces weight loss in a woman homozygous for pathogenic MC4R mutation d Glucose tolerance normalized and fasting glucose and triglyceride levels reduced d MC4R is not required for GLP-1 RA-mediated weight loss d Liraglutide is an effective treatment for the most common form of monogenic obesity
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2020
Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investiga... more Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investigated the impact of glucose, protein, and fat (with and without pancreas lipase inhibition) on plasma responses of gut and pancreas hormones, bile acids, and fibroblast growth factor 21 (FGF-21) after RYGB and in nonoperated control subjects. In a randomized, crossover study 10 RYGB operated and 8 healthy weight-matched control subjects were administered 4 different 4-h isocaloric (200 kcal) liquid meal tests containing >90 energy (E)% of either glucose, protein (whey protein), or fat (butter with and without orlistat). The primary outcome was glucagon-like peptide-1 (GLP-1) secretion (area under the curve above baseline). Secondary outcomes included responses of peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glicentin, neurotensin, ghrelin, insulin, glucagon, bile acids, and FGF-21. In the RYGB group the responses of GLP-1, GIP, glicentin, ...
To describe glucose metabolism in the late, weight stable phase after Roux-en-Y Gastric Bypass (R... more To describe glucose metabolism in the late, weight stable phase after Roux-en-Y Gastric Bypass (RYGB) in patients with and without preoperative type 2 diabetes we invited 55 RYGB-operated persons from two existing cohorts to participate in a late follow-up study. 44 (24 with normal glucose tolerance (NGT)/20 with type 2 diabetes (T2D) before surgery) accepted the invitation (median follow-up 2.7 [Range 2.2–5.0 years]). Subjects were examined during an oral glucose stimulus and results compared to preoperative and 1-year (1 y) post RYGB results. Glucose tolerance, insulin resistance, beta-cell function and incretin hormone secretion were evaluated. 1 y weight loss was maintained late after surgery. Glycemic control, insulin resistance, beta-cell function and GLP-1 remained improved late after surgery in both groups. In NGT subjects, nadir glucose decreased 1 y after RYGB, but did not change further. In T2D patients, relative change in weight from 1 y to late after RYGB correlated wit...
Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutane... more Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous onceweekly semaglutide: a patient-level, pooled analysis of the SUSTAIN 1-5 trials. Diabetes, Obesity and Metabolism _____________________________________________________________ This item is brought to you by Swansea University. Any person downloading material is agreeing to abide by the terms of the repository licence.
ObjectiveGastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypa... more ObjectiveGastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S-cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the post-operative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release.MethodsA specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA-sequencing, mass-spectrometry andin situhybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying...
The role of the autonomic nervous system in the efficacy of glucagon-like peptide-1 receptor agon... more The role of the autonomic nervous system in the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 1 diabetes is unknown. We assessed the association between autonomic function and weight loss induced by the GLP-1 RA liraglutide. Methods: Lira-1 was a randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of 1.8 mg liraglutide once-daily for 24 weeks in overweight patients with type 1 diabetes. Autonomic function was assessed by heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio), to the Valsalva maneuver and resting heart rate variability (HRV) indices. Associations between baseline the cardiovascular autonomic neuropathy (CAN) diagnosis (> 1 pathological non-resting test) and levels of test outcomes on liraglutide-induced weight loss was assessed by linear regression models. Results: Ninety-nine patients with mean age 48 (SD 12) years, HbA 1c 70 (IQR 66;75) mmol/mol and BMI of 30 (SD 3) kg/m 2 were assigned to liraglutide (N = 50) or placebo (N = 49). The CAN diagnosis was not associated with weight loss. A 50% higher baseline level of the 30/15 ratio was associated with a larger weight reduction by liraglutide of −2.65 kg during the trial (95% CI: −4.60; −0.69; P = 0.009). Similar significant associations were found for several HRV indices. Conclusions: The overall CAN diagnosis was not associated with liraglutide-induced weight loss in overweight patients with type 1 diabetes. Assessed separately, better outcomes for several CAN measures were associated with higher weight loss, indicating that autonomic involvement in liraglutide-induced weight loss may exist.
Postprandial responses to food are highly dependent on the macronutrient composition of the diet.... more Postprandial responses to food are highly dependent on the macronutrient composition of the diet. We investigated the acute effects of transition from the recommended moderately high carbohydrate (HC) diet towards a carbohydrate-reduced high-protein (CRHP) diet on postprandial glycemia, insulinemia, lipemia, and appetite-regulating hormones in non-diabetic adults. Fourteen subjects, including five males (Mean ± SD: age 62 ± 6.5; BMI 32 ± 7.6 kg/m2; hemoglobin A1c (HbA1c) 40 ± 3.0 mmol/mol; HOMA2-IR 2.1 ± 0.9) were included in this randomized, cross-over study. Iso-caloric diets were consumed for two consecutive days with a median wash-out period of 21 days (range 2–8 weeks) between diets (macronutrient energy composition: CRHP/HC; 31%/54% carbohydrate, 29%/16% protein, 40%/30% fat). Postprandial glucose, insulin secretion rate (ISR), triglycerides (TGs), non-esterified fatty acids (NEFAs), and satiety ratings were assessed after ingestion of breakfast (Br) and lunch (Lu), and gut ho...
Roux-en-Y Gastric bypass surgery (RYGB) is emerging as a powerful tool for treatment of obesity a... more Roux-en-Y Gastric bypass surgery (RYGB) is emerging as a powerful tool for treatment of obesity and may also cause remission of type 2 diabetes. However, the molecular mechanism of RYGB leading to diabetes remission independent of weight loss remains elusive. In this study, we profiled plasma metabolites and proteins of 10 normal glucose-tolerant obese (NO) and 9 diabetic obese (DO) patients before and 1-week, 3-months, 1-year after RYGB. 146 proteins and 128 metabolites from both NO and DO groups at all four stages were selected for further analysis. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the represented physiological states (called the edge-states that reflect the interactions among the bio-molecules), and the related molecular networks of NO and DO patients, respectively. The principal component analyses (PCA) revealed that the edge states of the post-RYGB NO subject...
SummaryBackgroundDislipidaemia and increased levels of apolipoprotein B (apoB) in individuals wit... more SummaryBackgroundDislipidaemia and increased levels of apolipoprotein B (apoB) in individuals with obesity are risk factors for development of cardiovascular disease (CVD). The aim of this study was to investigate the effect of weight loss and weight maintenance with and without liraglutide treatment on plasma lipid profiles and apoB.MethodsFifty‐eight individuals with obesity (body mass index 34.5 ± 3.0 kg/m2 [mean ± SD]) were included in this study. After 8 weeks on a very low‐calorie diet (800 kcal/day), participants were randomized to weight maintenance with meal replacements with or without liraglutide (1.2 mg daily) for 1 year. Plasma samples from before and after weight loss and after 1 year of weight maintenance were subjected to nuclear magnetic resonance‐based lipidomics analysis.ResultsAfter an 8‐week low‐calorie diet, study participants lost 12.0 ± 2.9 kg (mean ± SD) of their body weight, which was reflected in their lipid profiles (80 out of 124 lipids changed significa...
The American journal of clinical nutrition, Jan 5, 2015
Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in a... more Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in admixture of gastro-pancreatic enzymes, which could have a major impact on protein digestion and amino acid absorption. We investigated the effect of RYGB on amino acid appearance in the systemic circulation from orally ingested protein and from endogenous release. Nine obese glucose-tolerant subjects, with a mean body mass index (in kg/m(2)) of 39.2 (95% CI: 35.2, 43.3) and mean glycated hemoglobin of 5.3% (95% CI: 4.9%, 5.6%), were studied before and 3 mo after RYGB. Leucine and phenylalanine kinetics were determined under basal conditions and during 4 postprandial hours by intravenous infusions of [3,3,3-(2)H3]-leucine and [ring-(2)D5]-phenylalanine combined with ingestion of [1-(13)C]-leucine intrinsically labeled caseinate as the sole protein source of the meal. Changes in body composition were assessed by dual-energy X-ray absorptiometry. After RYGB, basal plasma leucine concentrati...
Laparoscopic adjustable gastric banding (LAGB), laparoscopic Roux-en-Y gastric bypass (RYGB) and ... more Laparoscopic adjustable gastric banding (LAGB), laparoscopic Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (SG) are the three most commonly performed bariatric procedures. Obesity responds well to bariatric surgery, with major long-lasting weight loss that is most pronounced after RYGB and SG, where the mean weight loss is about 40 kg or 15 body mass index (BMI) units. Some of the benefits after RYGB and SG are independent of weight loss, and the remission of type 2 diabetes is observed a few days after the operation; this depends on changes in insulin sensitivity and gut hormone responses, especially a 10-fold increase in glucagon-like peptide-1 (GLP-1), which improves insulin secretion. After gastric banding, the remission of diabetes depends more on weight loss. Bariatric surgery reduces cardiovascular risk factors including hypertension, lipid disturbances, non-alcoholic fatty liver, musculoskeletal pain and reduces mortality of diabetes, cardiovascular diseases and cancers. Bariatric surgery also improves quality of life. The acute complications of surgery are infection, bleeding and anastomotic leak. Long-term complications are nutritional deficiencies, including vitamins and minerals, and anemia. Some patients have dumping after meals, and a few patients will develop postprandial hypoglycemia after RYGB. About 25% of patients require plastic surgery to provide relief from excessive skin tissue.
BACKGROUND: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part ... more BACKGROUND: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight lossinduced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain. METHODS: In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, lowcalorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance. RESULTS: Soluble leptin receptor increase was 59% lower; 2.1 ± 0.7 vs 5.1 ± 0.8 ng ml − 1 (−3.0 (95% confidence interval (CI) = − 0.5 to − 5.5)), P o0.001 and free leptin index decrease was 43% smaller; − 62 ± 15 vs − 109 ± 20 (−47 (95% CI = − 11 to − 83)), Po 0.05 with administration of GLP-1RA compared with control group. The 12% weight loss was successfully maintained in both the groups with no significant change in weight after 52 weeks follow-up. The GLP-1RA group had greater weight loss during the weight maintenance period (−2.3 kg (95% CI = − 0.6 to − 4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI = − 0.6 to − 1)), P o 0.001. Fasting glucose was decreased by an additional − 0.2 ± 0.1 mmol l − 1 in the GLP-1RA group in contrast to the control group, where glucose increased 0.3 ± 0.1 mmol l − 1 to the level before weight loss (−0.5 mmol l − 1 (95% CI = − 0.1 to − 0.9)), Po 0.005. Meal response of peptide PYY 3-36 was higher at week 52 in the GLP-1RA group compared with the control group, P o 0.05. CONCLUSIONS: The weight maintaining effect of GLP-1RAs may be mediated by smaller decrease in free leptin and higher PYY 3-36 response. Low dose GLP-1RA therapy maintained 12% weight loss for 1 year and may prevent pre-diabetes in obesity.
To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (... more To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB). Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender. Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY3-36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite. Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test (P=0.006). In addition, the good responders had a larger rele...
The Journal of Clinical Endocrinology & Metabolism, 2001
To elucidate the causes of the diminished incretin effect in type 2 diabetes mellitus we investig... more To elucidate the causes of the diminished incretin effect in type 2 diabetes mellitus we investigated the secretion of the incretin hormones, glucagon-like peptide-1 and glucosedependent insulinotropic polypeptide and measured nonesterified fatty acids, and plasma concentrations of insulin, C peptide, pancreatic polypeptide, and glucose during a 4-h mixed meal test in 54 heterogeneous type 2 diabetic patients, 33 matched control subjects with normal glucose tolerance, and 15 unmatched subjects with impaired glucose tolerance. The glucagon-like peptide-1 response in terms of area under the curve from 0-240 min after the start of the meal was significantly decreased in the patients (2482 ؎ 145 compared with 3101 ؎ 198 pmol/liter⅐240 min; P ؍ 0.024). In addition, the area under the curve for glucose-dependent insulinotropic polypeptide was slightly decreased. In a multiple regression analysis, a model with diabetes, body mass index, male sex, insulin area under the curve (negative influence), glucosedependent insulinotropic polypeptide area under the curve (negative influence), and glucagon area under the curve (positive influence) explained 42% of the variability of the glucagon-like peptide-1 response. The impaired glucose tolerance subjects were hyperinsulinemic and generally showed the same abnormalities as the diabetic patients, but to a lesser degree. We conclude that the meal-related glucagon-like peptide-1 response in type 2 diabetes is decreased, which may contribute to the decreased incretin effect in type 2 diabetes.
The Journal of Clinical Endocrinology & Metabolism, 2003
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incret... more Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted in response to meal ingestion, thereby enhancing postprandial insulin secretion. Therefore, an attenuated incretin response could contribute to the impaired insulin responses in patients with diabetes mellitus. The aim of the present investigation was to investigate incretin secretion, in obesity and type 1 and type 2 diabetes mellitus, and its dependence on the magnitude of the meal stimulus. Plasma concentrations of incretin hormones (total, reflecting secretion and intact, reflecting potential action) were measured during two meal tests (260 kcal and 520 kcal) in eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects. Both in diabetic patients and in healthy subjects, significant increases in GLP-1 and GIP concentrations were seen after ingestion of both meals. The incretin responses were significantly higher in all groups after the large meal, compared with the small meal, with correspondingly higher C-peptide responses. Both type 1 and type 2 diabetic patients had normal GIP responses, compared with healthy subjects, whereas decreased GLP-1 responses were seen in type 2 diabetic patients, compared with matched obese healthy subjects. Incremental GLP-1 responses were normal in type 1 diabetic patients. Increased fasting concentrations of GIP and an early enhanced postprandial GIP response were seen in obese, compared with lean healthy subjects, whereas GLP-1 responses were the same in the two groups. -cell sensitivity to glucose, evaluated as the slope of insulin secretion rates vs. plasma glucose concentration, tended to increase in both type 2 diabetic patients (29%, P ؍ 0.19) and obese healthy subjects (22% P ؍ 0.04) during the large meal, compared with the small meal, perhaps reflecting the increased incretin response. We conclude: 1) that a decreased GLP-1 secretion may contribute to impaired insulin secretion in type 2 diabetes mellitus, whereas GIP and GLP-1 secretion is normal in type 1 diabetic patients; and 2) that it is possible to modulate the -cell sensitivity to glucose in obese healthy subjects, and possibly also in type 2 diabetic patients, by giving them a large meal, compared with a small meal. (
Objective The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as ... more Objective The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods Eight obese patients with type 2 diabetes with poor glycaemic control (HbA 1c 8.6±1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4±1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0-10 min). The late phase C-peptide response (10-120 min) increased during GIP infusion from 33.0±8.5 to 103.9±24.2 (nmol/l)×(110 min) −1 (p<0.05) and during GLP-1 infusion from 48.7±11.8 to 126.6±32.5 (nmol/l)×(110 min) −1 (p<0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2±11.2 vs 46.5±12.7 [nmol/l]×[110 min] −1). Conclusions Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone.
AimTo evaluate 26 weeks of liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJ... more AimTo evaluate 26 weeks of liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJUNCT ONE and ADJUNCT TWO trials.Materials and MethodsADJUNCT ONE and ADJUNCT TWO were randomized controlled phase 3 trials in 1398 and 835 participants with T1D treated with liraglutide (1.8, 1.2, or 0.6 mg) or placebo (adjuncts to insulin). This post hoc analysis evaluated treatment effects by subgroups: HbA1c (< or ≥8.5%), body mass index (BMI; < or ≥27 kg/m2), and insulin regimen (basal bolus or continuous subcutaneous insulin infusion).ResultsIn both trials at week 26, reductions in HbA1c, body weight, and daily insulin dose did not differ significantly (P > .05) by baseline HbA1c or BMI. Risk of clinically significant hypoglycaemia or hyperglycaemia with ketosis did not differ significantly (P > .05) by baseline HbA1c, BMI, or insulin regimen. At week 26 in ADJUNCT ONE, these risks did not differ (P > .05) between treatment groups. Placebo‐adjusted reductions in HbA1c...
Background: Right hepatectomy (RH) is the most common type of major hepatectomy and can be achiev... more Background: Right hepatectomy (RH) is the most common type of major hepatectomy and can be achieved without portal triad clamping (PTC) in non-cirrhotic liver. The present study reviews our standardized policy of performing RH without systematic PTC. Methods: One hundred and eighty-one consecutive RH were performed in non-cirrhotic patients, with division of the right afferent and efferent blood vessels prior to transection, without systematically using PTC. Prospectively collected data were analysed, focusing on the following endpoints: need for salvage PTC, ischaemic time, blood loss and post-operative outcome. Results: Extra-hepatic division of the right hepatic vessels was feasible in all patients, but was ineffective in 48 patients (26.5%) who required salvage PTC during transection. In those patients, the median ischaemic time was 20 min. The median blood loss was 500 ml (50-3000). Six patients (3.3%) experienced post-operative liver failure. Overall morbidity, severe morbidity and mortality were 42%, 12.1% and 1.6%, respectively, with peri-operative transfusion rate (16.6%) being the only factor associated with morbidity. Discussion: By performing RH with extra-hepatic vascular division prior to transection, PTC can be safely avoided in the majority of patients.
In the SUSTAIN trial program, once-weekly (OW) semaglutide, a glucagon-like peptide-1 receptor ag... more In the SUSTAIN trial program, once-weekly (OW) semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treatment of type 2 diabetes, significantly reduced HbA1c and body weight (BW) vs. all comparators, with a safety profile consistent with the GLP-1RA class. Patient factors (e.g., BMI) may impact therapeutic choices. This post-hoc analysis of SUSTAIN 1-5 and 7-10 evaluated change from baseline to end of treatment in HbA1c and BW with OW semaglutide vs. comparator by baseline BMI subgroup. On-treatment without rescue medication data were evaluated in the full analysis set. Mixed model for repeated measurements analyses evaluated interaction between treatment and BMI subgroup by trial. Overall, 572, 1,867, 2,103 and 2,217 subjects with BMI <25, ≥25-<30, ≥30-<35 and ≥35 kg/m2, respectively, were evaluated. Estimated treatment difference for change in HbA1c favored semaglutide vs. comparator in most subgroups, and for BW favored semaglutide vs. comparato...
Highlights d Liraglutide induces weight loss in a woman homozygous for pathogenic MC4R mutation d... more Highlights d Liraglutide induces weight loss in a woman homozygous for pathogenic MC4R mutation d Glucose tolerance normalized and fasting glucose and triglyceride levels reduced d MC4R is not required for GLP-1 RA-mediated weight loss d Liraglutide is an effective treatment for the most common form of monogenic obesity
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2020
Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investiga... more Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investigated the impact of glucose, protein, and fat (with and without pancreas lipase inhibition) on plasma responses of gut and pancreas hormones, bile acids, and fibroblast growth factor 21 (FGF-21) after RYGB and in nonoperated control subjects. In a randomized, crossover study 10 RYGB operated and 8 healthy weight-matched control subjects were administered 4 different 4-h isocaloric (200 kcal) liquid meal tests containing >90 energy (E)% of either glucose, protein (whey protein), or fat (butter with and without orlistat). The primary outcome was glucagon-like peptide-1 (GLP-1) secretion (area under the curve above baseline). Secondary outcomes included responses of peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glicentin, neurotensin, ghrelin, insulin, glucagon, bile acids, and FGF-21. In the RYGB group the responses of GLP-1, GIP, glicentin, ...
To describe glucose metabolism in the late, weight stable phase after Roux-en-Y Gastric Bypass (R... more To describe glucose metabolism in the late, weight stable phase after Roux-en-Y Gastric Bypass (RYGB) in patients with and without preoperative type 2 diabetes we invited 55 RYGB-operated persons from two existing cohorts to participate in a late follow-up study. 44 (24 with normal glucose tolerance (NGT)/20 with type 2 diabetes (T2D) before surgery) accepted the invitation (median follow-up 2.7 [Range 2.2–5.0 years]). Subjects were examined during an oral glucose stimulus and results compared to preoperative and 1-year (1 y) post RYGB results. Glucose tolerance, insulin resistance, beta-cell function and incretin hormone secretion were evaluated. 1 y weight loss was maintained late after surgery. Glycemic control, insulin resistance, beta-cell function and GLP-1 remained improved late after surgery in both groups. In NGT subjects, nadir glucose decreased 1 y after RYGB, but did not change further. In T2D patients, relative change in weight from 1 y to late after RYGB correlated wit...
Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutane... more Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous onceweekly semaglutide: a patient-level, pooled analysis of the SUSTAIN 1-5 trials. Diabetes, Obesity and Metabolism _____________________________________________________________ This item is brought to you by Swansea University. Any person downloading material is agreeing to abide by the terms of the repository licence.
ObjectiveGastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypa... more ObjectiveGastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S-cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the post-operative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release.MethodsA specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA-sequencing, mass-spectrometry andin situhybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying...
The role of the autonomic nervous system in the efficacy of glucagon-like peptide-1 receptor agon... more The role of the autonomic nervous system in the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 1 diabetes is unknown. We assessed the association between autonomic function and weight loss induced by the GLP-1 RA liraglutide. Methods: Lira-1 was a randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of 1.8 mg liraglutide once-daily for 24 weeks in overweight patients with type 1 diabetes. Autonomic function was assessed by heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio), to the Valsalva maneuver and resting heart rate variability (HRV) indices. Associations between baseline the cardiovascular autonomic neuropathy (CAN) diagnosis (> 1 pathological non-resting test) and levels of test outcomes on liraglutide-induced weight loss was assessed by linear regression models. Results: Ninety-nine patients with mean age 48 (SD 12) years, HbA 1c 70 (IQR 66;75) mmol/mol and BMI of 30 (SD 3) kg/m 2 were assigned to liraglutide (N = 50) or placebo (N = 49). The CAN diagnosis was not associated with weight loss. A 50% higher baseline level of the 30/15 ratio was associated with a larger weight reduction by liraglutide of −2.65 kg during the trial (95% CI: −4.60; −0.69; P = 0.009). Similar significant associations were found for several HRV indices. Conclusions: The overall CAN diagnosis was not associated with liraglutide-induced weight loss in overweight patients with type 1 diabetes. Assessed separately, better outcomes for several CAN measures were associated with higher weight loss, indicating that autonomic involvement in liraglutide-induced weight loss may exist.
Postprandial responses to food are highly dependent on the macronutrient composition of the diet.... more Postprandial responses to food are highly dependent on the macronutrient composition of the diet. We investigated the acute effects of transition from the recommended moderately high carbohydrate (HC) diet towards a carbohydrate-reduced high-protein (CRHP) diet on postprandial glycemia, insulinemia, lipemia, and appetite-regulating hormones in non-diabetic adults. Fourteen subjects, including five males (Mean ± SD: age 62 ± 6.5; BMI 32 ± 7.6 kg/m2; hemoglobin A1c (HbA1c) 40 ± 3.0 mmol/mol; HOMA2-IR 2.1 ± 0.9) were included in this randomized, cross-over study. Iso-caloric diets were consumed for two consecutive days with a median wash-out period of 21 days (range 2–8 weeks) between diets (macronutrient energy composition: CRHP/HC; 31%/54% carbohydrate, 29%/16% protein, 40%/30% fat). Postprandial glucose, insulin secretion rate (ISR), triglycerides (TGs), non-esterified fatty acids (NEFAs), and satiety ratings were assessed after ingestion of breakfast (Br) and lunch (Lu), and gut ho...
Roux-en-Y Gastric bypass surgery (RYGB) is emerging as a powerful tool for treatment of obesity a... more Roux-en-Y Gastric bypass surgery (RYGB) is emerging as a powerful tool for treatment of obesity and may also cause remission of type 2 diabetes. However, the molecular mechanism of RYGB leading to diabetes remission independent of weight loss remains elusive. In this study, we profiled plasma metabolites and proteins of 10 normal glucose-tolerant obese (NO) and 9 diabetic obese (DO) patients before and 1-week, 3-months, 1-year after RYGB. 146 proteins and 128 metabolites from both NO and DO groups at all four stages were selected for further analysis. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the represented physiological states (called the edge-states that reflect the interactions among the bio-molecules), and the related molecular networks of NO and DO patients, respectively. The principal component analyses (PCA) revealed that the edge states of the post-RYGB NO subject...
SummaryBackgroundDislipidaemia and increased levels of apolipoprotein B (apoB) in individuals wit... more SummaryBackgroundDislipidaemia and increased levels of apolipoprotein B (apoB) in individuals with obesity are risk factors for development of cardiovascular disease (CVD). The aim of this study was to investigate the effect of weight loss and weight maintenance with and without liraglutide treatment on plasma lipid profiles and apoB.MethodsFifty‐eight individuals with obesity (body mass index 34.5 ± 3.0 kg/m2 [mean ± SD]) were included in this study. After 8 weeks on a very low‐calorie diet (800 kcal/day), participants were randomized to weight maintenance with meal replacements with or without liraglutide (1.2 mg daily) for 1 year. Plasma samples from before and after weight loss and after 1 year of weight maintenance were subjected to nuclear magnetic resonance‐based lipidomics analysis.ResultsAfter an 8‐week low‐calorie diet, study participants lost 12.0 ± 2.9 kg (mean ± SD) of their body weight, which was reflected in their lipid profiles (80 out of 124 lipids changed significa...
The American journal of clinical nutrition, Jan 5, 2015
Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in a... more Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in admixture of gastro-pancreatic enzymes, which could have a major impact on protein digestion and amino acid absorption. We investigated the effect of RYGB on amino acid appearance in the systemic circulation from orally ingested protein and from endogenous release. Nine obese glucose-tolerant subjects, with a mean body mass index (in kg/m(2)) of 39.2 (95% CI: 35.2, 43.3) and mean glycated hemoglobin of 5.3% (95% CI: 4.9%, 5.6%), were studied before and 3 mo after RYGB. Leucine and phenylalanine kinetics were determined under basal conditions and during 4 postprandial hours by intravenous infusions of [3,3,3-(2)H3]-leucine and [ring-(2)D5]-phenylalanine combined with ingestion of [1-(13)C]-leucine intrinsically labeled caseinate as the sole protein source of the meal. Changes in body composition were assessed by dual-energy X-ray absorptiometry. After RYGB, basal plasma leucine concentrati...
Laparoscopic adjustable gastric banding (LAGB), laparoscopic Roux-en-Y gastric bypass (RYGB) and ... more Laparoscopic adjustable gastric banding (LAGB), laparoscopic Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (SG) are the three most commonly performed bariatric procedures. Obesity responds well to bariatric surgery, with major long-lasting weight loss that is most pronounced after RYGB and SG, where the mean weight loss is about 40 kg or 15 body mass index (BMI) units. Some of the benefits after RYGB and SG are independent of weight loss, and the remission of type 2 diabetes is observed a few days after the operation; this depends on changes in insulin sensitivity and gut hormone responses, especially a 10-fold increase in glucagon-like peptide-1 (GLP-1), which improves insulin secretion. After gastric banding, the remission of diabetes depends more on weight loss. Bariatric surgery reduces cardiovascular risk factors including hypertension, lipid disturbances, non-alcoholic fatty liver, musculoskeletal pain and reduces mortality of diabetes, cardiovascular diseases and cancers. Bariatric surgery also improves quality of life. The acute complications of surgery are infection, bleeding and anastomotic leak. Long-term complications are nutritional deficiencies, including vitamins and minerals, and anemia. Some patients have dumping after meals, and a few patients will develop postprandial hypoglycemia after RYGB. About 25% of patients require plastic surgery to provide relief from excessive skin tissue.
BACKGROUND: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part ... more BACKGROUND: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight lossinduced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain. METHODS: In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, lowcalorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance. RESULTS: Soluble leptin receptor increase was 59% lower; 2.1 ± 0.7 vs 5.1 ± 0.8 ng ml − 1 (−3.0 (95% confidence interval (CI) = − 0.5 to − 5.5)), P o0.001 and free leptin index decrease was 43% smaller; − 62 ± 15 vs − 109 ± 20 (−47 (95% CI = − 11 to − 83)), Po 0.05 with administration of GLP-1RA compared with control group. The 12% weight loss was successfully maintained in both the groups with no significant change in weight after 52 weeks follow-up. The GLP-1RA group had greater weight loss during the weight maintenance period (−2.3 kg (95% CI = − 0.6 to − 4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI = − 0.6 to − 1)), P o 0.001. Fasting glucose was decreased by an additional − 0.2 ± 0.1 mmol l − 1 in the GLP-1RA group in contrast to the control group, where glucose increased 0.3 ± 0.1 mmol l − 1 to the level before weight loss (−0.5 mmol l − 1 (95% CI = − 0.1 to − 0.9)), Po 0.005. Meal response of peptide PYY 3-36 was higher at week 52 in the GLP-1RA group compared with the control group, P o 0.05. CONCLUSIONS: The weight maintaining effect of GLP-1RAs may be mediated by smaller decrease in free leptin and higher PYY 3-36 response. Low dose GLP-1RA therapy maintained 12% weight loss for 1 year and may prevent pre-diabetes in obesity.
To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (... more To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB). Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender. Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY3-36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite. Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test (P=0.006). In addition, the good responders had a larger rele...
The Journal of Clinical Endocrinology & Metabolism, 2001
To elucidate the causes of the diminished incretin effect in type 2 diabetes mellitus we investig... more To elucidate the causes of the diminished incretin effect in type 2 diabetes mellitus we investigated the secretion of the incretin hormones, glucagon-like peptide-1 and glucosedependent insulinotropic polypeptide and measured nonesterified fatty acids, and plasma concentrations of insulin, C peptide, pancreatic polypeptide, and glucose during a 4-h mixed meal test in 54 heterogeneous type 2 diabetic patients, 33 matched control subjects with normal glucose tolerance, and 15 unmatched subjects with impaired glucose tolerance. The glucagon-like peptide-1 response in terms of area under the curve from 0-240 min after the start of the meal was significantly decreased in the patients (2482 ؎ 145 compared with 3101 ؎ 198 pmol/liter⅐240 min; P ؍ 0.024). In addition, the area under the curve for glucose-dependent insulinotropic polypeptide was slightly decreased. In a multiple regression analysis, a model with diabetes, body mass index, male sex, insulin area under the curve (negative influence), glucosedependent insulinotropic polypeptide area under the curve (negative influence), and glucagon area under the curve (positive influence) explained 42% of the variability of the glucagon-like peptide-1 response. The impaired glucose tolerance subjects were hyperinsulinemic and generally showed the same abnormalities as the diabetic patients, but to a lesser degree. We conclude that the meal-related glucagon-like peptide-1 response in type 2 diabetes is decreased, which may contribute to the decreased incretin effect in type 2 diabetes.
The Journal of Clinical Endocrinology & Metabolism, 2003
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incret... more Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted in response to meal ingestion, thereby enhancing postprandial insulin secretion. Therefore, an attenuated incretin response could contribute to the impaired insulin responses in patients with diabetes mellitus. The aim of the present investigation was to investigate incretin secretion, in obesity and type 1 and type 2 diabetes mellitus, and its dependence on the magnitude of the meal stimulus. Plasma concentrations of incretin hormones (total, reflecting secretion and intact, reflecting potential action) were measured during two meal tests (260 kcal and 520 kcal) in eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects. Both in diabetic patients and in healthy subjects, significant increases in GLP-1 and GIP concentrations were seen after ingestion of both meals. The incretin responses were significantly higher in all groups after the large meal, compared with the small meal, with correspondingly higher C-peptide responses. Both type 1 and type 2 diabetic patients had normal GIP responses, compared with healthy subjects, whereas decreased GLP-1 responses were seen in type 2 diabetic patients, compared with matched obese healthy subjects. Incremental GLP-1 responses were normal in type 1 diabetic patients. Increased fasting concentrations of GIP and an early enhanced postprandial GIP response were seen in obese, compared with lean healthy subjects, whereas GLP-1 responses were the same in the two groups. -cell sensitivity to glucose, evaluated as the slope of insulin secretion rates vs. plasma glucose concentration, tended to increase in both type 2 diabetic patients (29%, P ؍ 0.19) and obese healthy subjects (22% P ؍ 0.04) during the large meal, compared with the small meal, perhaps reflecting the increased incretin response. We conclude: 1) that a decreased GLP-1 secretion may contribute to impaired insulin secretion in type 2 diabetes mellitus, whereas GIP and GLP-1 secretion is normal in type 1 diabetic patients; and 2) that it is possible to modulate the -cell sensitivity to glucose in obese healthy subjects, and possibly also in type 2 diabetic patients, by giving them a large meal, compared with a small meal. (
Objective The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as ... more Objective The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods Eight obese patients with type 2 diabetes with poor glycaemic control (HbA 1c 8.6±1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4±1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0-10 min). The late phase C-peptide response (10-120 min) increased during GIP infusion from 33.0±8.5 to 103.9±24.2 (nmol/l)×(110 min) −1 (p<0.05) and during GLP-1 infusion from 48.7±11.8 to 126.6±32.5 (nmol/l)×(110 min) −1 (p<0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2±11.2 vs 46.5±12.7 [nmol/l]×[110 min] −1). Conclusions Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone.
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Papers by Sten Madsbad