Publications by authors named "Sten Madsbad"

290 Publications

Macrophage activation marker sCD163 is associated with liver injury and hepatic insulin resistance in obese patients before and after Roux-en-Y gastric bypass.

Physiol Rep 2022 Jan;10(2):e15157

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Background: Macrophages are associated with metabolic complications to obesity including fatty liver disease and impaired hepatic and muscle insulin sensitivity (IS). Bariatric surgery induces weight loss and improves IS. We investigated associations between the macrophage activation marker soluble (s)CD163, alanine-aminotransferase (ALT), and IS before and after Roux-en-Y Gastric Bypass (RYGB).

Methods: We analyzed sCD163 from 10 type 2 diabetes (T2D) and 10 obese patients with normal glucose tolerance (NGT) undergoing RYGB for associations with hepatic, adipose tissue, and muscle IS and ALT after 1-week, 3, and 12 months postoperatively. IS was evaluated by hyperinsulinemic-euglycemic clamp in combination with glucose tracer technique.

Results: Preoperative sCD163 correlated with ALT (r = 0.58, p = 0.007) and tended to associate inversely with hepatic (r = -0.39, p = 0.1) and adipose tissue (r = -0.39, p = 0.09), but not muscle IS. Following RYGB, sCD163 decreased significantly in all patients. The decrease in sCD163 during the first 3 months correlated inversely with the improvement of hepatic IS (r = -0.65, p = 0.01) and tended to be associated with changes in muscle IS (r = -0.45, p = 0.09). After 3 months sCD163 remained associated with ALT (r = 0.75, p < 0.001) and inversely with hepatic IS (r = -0.39, p = 0.1), but not muscle or adipose tissue IS. One year after RYGB, sCD163 correlated with ALT (r = 0.61, p = 0.007), but not with hepatic, adipose tissue, or muscle IS.

Conclusion: Macrophage activation is associated with liver injury and hepatic IS in obese patients. Improvements in these measures correlate during the first 3 months following RYGB, supporting a link between macrophages and hepatic IS in severe obesity and diabetes.
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http://dx.doi.org/10.14814/phy2.15157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764469PMC
January 2022

GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment.

Pharmacol Res 2022 Jan 4;176:106058. Epub 2022 Jan 4.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address:

The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.
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http://dx.doi.org/10.1016/j.phrs.2022.106058DOI Listing
January 2022

Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial.

Diabetologia 2022 Jan 7. Epub 2022 Jan 7.

Department of Endocrinology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark.

Aims/hypothesis: Lifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes.

Methods: This open-label, parallel RCT included adults with type 2 diabetes, HbA 48-97 mmol/mol (6.5-11%), BMI >25 kg/m, eGFR >30 ml min [1.73 m] and glucose-lowering therapy restricted to metformin or dipeptidyl peptidase-4 inhibitors. Participants were randomised by a third party and assigned to 6 weeks of energy restriction (all foods were provided) aiming at ~6% weight loss with either a carbohydrate-reduced high-protein diet (CRHP, percentage of total energy intake [E%]: CH30/P30/F40) or a conventional diabetes diet (CD, E%: CH50/P17/F33). Fasting blood samples, continuous glucose monitoring and magnetic resonance spectroscopy were used to assess glycaemic control, lipid metabolism and intrahepatic fat. Change in HbA was the primary outcome; changes in circulating and intrahepatic triacylglycerol were secondary outcomes. Data were collected at Copenhagen University Hospital (Bispebjerg and Herlev).

Results: Seventy-two adults (CD 36, CRHP 36, all white, 38 male sex) with type 2 diabetes (mean duration 8 years, mean HbA 57 mmol/mol [7.4%]) and mean BMI of 33 kg/m were enrolled, of which 67 (CD 33, CRHP 34) completed the study. Body weight decreased by 5.8 kg (5.9%) in both groups after 6 weeks. Compared with the CD diet, the CRHP diet further reduced HbA (mean [95% CI] -1.9 [-3.5, -0.3] mmol/mol [-0.18 (-0.32, -0.03)%], p = 0.018) and diurnal mean glucose (mean [95% CI] -0.8 [-1.2, -0.4] mmol/l, p < 0.001), stabilised glucose excursions by reducing glucose CV (mean [95% CI] -4.1 [-5.9, -2.2]%, p < 0.001), and augmented the reductions in fasting triacylglycerol concentration (by mean [95% CI] -18 [-29, -6]%, p < 0.01) and liver fat content (by mean [95% CI] -26 [-45, 0]%, p = 0.051). However, pancreatic fat content was decreased to a lesser extent by the CRHP than the CD diet (mean [95% CI] 33 [7, 65]%, p = 0.010). Fasting glucose, insulin, HOMA2-IR and cholesterol concentrations (total, LDL and HDL) were reduced significantly and similarly by both diets.

Conclusions/interpretation: Moderate carbohydrate restriction for 6 weeks modestly improved glycaemic control, and decreased circulating and intrahepatic triacylglycerol levels beyond the effects of weight loss itself compared with a CD diet in individuals with type 2 diabetes. Concurrent differences in protein and fat intakes, and the quality of dietary macronutrients, may have contributed to these results and should be explored in future studies.

Trial Registration: ClinicalTrials.gov NCT03814694.

Funding: The study was funded by Arla Foods amba, The Danish Dairy Research Foundation, and Copenhagen University Hospital Bispebjerg Frederiksberg.
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http://dx.doi.org/10.1007/s00125-021-05628-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739348PMC
January 2022

On measurements of glucagon secretion in healthy, obese, and Roux-en-Y gastric bypass operated individuals using sandwich ELISA.

Scand J Clin Lab Invest 2021 Dec 22:1-9. Epub 2021 Dec 22.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Glucagon is a key regulator of metabolism and is used in the diagnostic of neuroendocrine tumors. Accurate measurement of glucagon requires both extreme sensitivity and specificity since several peptides are derived from the same proglucagon precursor encoding part of the glucagon sequence and given that glucagon circulates in picomolar concentrations. A sandwich ELISA was recently developed and extensively evaluated; however, this method may not be accurate when measuring glucagon in patients with an enhanced production of proglucagon-derived peptides as seen after Roux-en-Y gastric bypass (RYGB). To overcome this, a modified version of the ELISA was developed. In this study, we evaluate an unmodified and a modified version of the ELISA in healthy individuals, individuals with obesity, and finally in two cohorts of patients following RYGB surgery using different nutrient stimuli to assess glucagon dynamics. Finally, spike-in recoveries using native glucagon and proglucagon-derived peptides were performed in buffer and in plasma. Our data support that both versions of the ELISA accurately capture endogenous and exogenous glucagon in healthy individuals and in individuals with obesity. However, the unmodified version of the assay may overestimate glucagon levels in patients following RYGB in line with minimal but consistent cross-reactivity to oxyntomodulin and glicentin that both are 50-fold increased after RYGB. Importantly, we did not find any changes between the two protocols at fasted conditions and therefore diagnostics of glucagonomas is not affected by the choice of assay procedure nor the surgical history of the patient (RYGB).
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http://dx.doi.org/10.1080/00365513.2021.2016943DOI Listing
December 2021

Effects of 18-months metformin versus placebo in combination with three insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes: A post-hoc analysis of a randomized clinical trial.

Free Radic Biol Med 2022 01 22;178:18-25. Epub 2021 Nov 22.

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Endocrinology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: -9.6% (95% CI: -14.4% to -4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: -0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: -2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: -9.9% (95% CI: -14.4% to -5.2%)) than basal-bolus insulin (within group effect: -1.2% (95% CI: -6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.11.028DOI Listing
January 2022

Liraglutide changes body composition and lowers added sugar intake in overweight persons with insulin pump-treated type 1 diabetes.

Diabetes Obes Metab 2022 Feb 17;24(2):212-220. Epub 2021 Oct 17.

Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Aims: To present secondary outcome analyses of liraglutide treatment in overweight adults with insulin pump-treated type 1 diabetes (T1D), focusing on changes in body composition and dimensions, and to evaluate changes in food intake to identify potential dietary drivers of liraglutide-associated weight loss.

Materials And Methods: A 26-week randomized placebo-controlled study was conducted to investigate the efficacy and safety of liraglutide 1.8 mg daily in 44 overweight adults with insulin pump-treated T1D and glucose levels above target, and demonstrated significant glycated haemoglobin (HbA1c)- and body weight-reducing effects. For secondary outcome analysis, dual X-ray absorptiometry scans were completed at Weeks 0 and 26, and questionnaire-based food frequency recordings were obtained at Weeks 0, 13 and 26 to characterize liraglutide-induced changes in body composition and food intake.

Results: Total fat and lean body mass decreased in liraglutide-treated participants (fat mass -4.6 kg [95% confidence interval {CI} -5.7; -3.5], P < 0.001; lean mass -2.5 kg [95% CI -3.2;-1.7], P < 0.001), but remained stable in placebo-treated participants (fat mass -0.3 kg [95% CI -1.3;0.8], P = 0.604; lean mass 0.0 kg [95% CI -0.7;0.7]; P = 0.965 [between-group P values <0.001]). Participants reduced their energy intake numerically more in the liraglutide arm (-1.1 MJ [95% CI -2.0;-0.02], P = 0.02) than in the placebo arm (-0.9 MJ [95% CI -2.0;0.1], P = 0.22), but the between-group difference was statistically insignificant (P = 0.42). However, energy derived from added sugars decreased by 27% in the liraglutide arm compared with an increase of 14% in the placebo arm (P = 0.004).

Conclusions: Liraglutide lowered fat and lean body mass compared with placebo. Further, liraglutide reduced intake of added sugars. However, no significant difference in total daily energy intake was detected between liraglutide- and placebo-treated participants.
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http://dx.doi.org/10.1111/dom.14567DOI Listing
February 2022

Colonic Lactulose Fermentation Has No Impact on Glucagon-like Peptide-1 and Peptide-YY Secretion in Healthy Young Men.

J Clin Endocrinol Metab 2022 Jan;107(1):77-87

Novo Nordic Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Context: The colon houses most of humans' gut microbiota, which ferments indigestible carbohydrates. The products of fermentation have been proposed to influence the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) from the many endocrine cells in the colonic epithelium. However, little is known about the colonic contribution to fasting or postprandial plasma levels of L-cell products.

Objective: To determine the impact of colonic lactulose fermentation on gut peptide secretion and to evaluate whether colonic endocrine secretion contributes to gut hormone concentrations measurable in the fasting state.

Methods: Ten healthy young men were studied on 3 occasions after an overnight fast. On 2 study days, lactulose (20 g) was given orally and compared to water intake on a third study day. For 1 of the lactulose visits, participants underwent a full colonic evacuation. Over a 6-h study protocol, lactulose fermentation was assessed by measuring exhaled hydrogen, and gut peptide secretion, paracetamol, and short-chain fatty acid levels were measured in plasma.

Results: Colonic evacuation markedly reduced hydrogen exhalation after lactulose intake (P = 0.013). Our analysis suggests that the colon does not account for the measurable amounts of GLP-1 and PYY present in the circulation during fasting and that fermentation and peptide secretion are not acutely related.

Conclusion: Whether colonic luminal contents affect colonic L-cell secretion sufficiently to influence circulating concentrations requires further investigation. Colonic evacuation markedly reduced lactulose fermentation, but hormone releases were unchanged in the present study.
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http://dx.doi.org/10.1210/clinem/dgab666DOI Listing
January 2022

Metabolic improvement after gastric bypass correlates with changes in IGF-regulatory proteins stanniocalcin-2 and IGFBP-4.

Metabolism 2021 11 7;124:154886. Epub 2021 Sep 7.

Endocrine Research Unit, Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark; Medical Research Laboratory, Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark. Electronic address:

Background: Pregnancy-associated plasma protein-A (PAPP-A) is an enzyme that increases IGF-activity through cleavage of IGF-binding proteins (IGFBPs), primarily IGFBP-4, whereby bound IGF-I becomes released as a free molecule. The enzymatic activity of PAPP-A is irreversibly suppressed by the glycoprotein stanniocalcin-2 (STC2). Pre-clinical and clinical studies suggest that the STC2 - PAPP-A - IGFBP-4 axis is important in controlling local IGF-action. STC2, PAPP-A and IGFBP-4 are expressed in adipose tissue, and as bariatric surgery markedly reduces the amount of fat, we found it relevant to study the impact of Roux-en-Y gastric bypass (RYGB) on circulating concentrations of this IGF-regulatory network.

Methods: Analysis of fasting blood samples from 20 obese subjects, hereof 10 with preoperative type 2 diabetes, investigated before RYGB, and 1 week, 3 months and 12 months post-surgery. Members of the IGF-system were analyzed by immunoassays, bioactive IGF by cell-based IGF-I receptor activation assay. We compared changes in IGF-system components with changes in fasting plasma insulin and glucose, and HbA1c.

Results: PAPP-A remained unchanged, but STC2 decreased following RYGB (p < 0.05). The PAPP-A substrate IGFBP-4 declined (p < 0.01), whereas levels of PAPP-A specific IGFBP-4 fragments increased (p < 0.05), indicating an increased PAPP-A enzymatic activity post-RYGB. Further, the reduction in intact IGFBP-4 correlated with increased levels of bioactive IGF (p < 0.05). In multivariable regression analyses, an improved glucose metabolism correlated with reductions in STC2 and IGFBP-4, and with increases in bioactive IGF and IGF-I (p < 0.05).

Conclusion: After 12 months, RYGB caused reduced serum concentrations of intact IGFBP-4 and STC2, whereas serum PAPP-A remained at pre-operative levels. However, concentrations of PAPP-A generated IGFBP-4 fragments increased, pointing to an overall increased PAPP-A enzymatic activity following RYGB. Notably, reductions in intact IGFBP-4 and STC2 associated with improvements in glucose metabolism. Therefore, we propose that STC2 and IGFBP-4 are involved in the metabolic improvement that follows RYGB.
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http://dx.doi.org/10.1016/j.metabol.2021.154886DOI Listing
November 2021

Effects of Roux-en-Y Gastric Bypass and Sleeve Gastrectomy on Non-Alcoholic Fatty Liver Disease: A 12-Month Follow-Up Study with Paired Liver Biopsies.

J Clin Med 2021 Aug 24;10(17). Epub 2021 Aug 24.

Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Kettegaard Allé 30, 2650 Copenhagen, Denmark.

Roux-en-Y gastric bypass (RYGB) improves, and can sometimes resolve, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) but data based on histological assessment for the efficacy of sleeve gastrectomy (SG) in resolving NAFLD are sparse. Consequently, we aimed to compare the efficacy of RYGB vs. SG on NAFLD 12 months after surgery. In a prospective cohort study, 40 patients with obesity underwent bariatric surgery (16 RYGB and 24 SG). During surgery, a liver biopsy was taken and repeated 12 months later. NAFLD severity was evaluated using the NAFLD Activity Score (NAS) and Kleiner Fibrosis score. RYGB and SG patients were comparable at baseline. Mean (standard deviation, SD) NAS was 3.3 (0.9) in RYGB and 3.1 (1.4) in SG ( = 0.560) with similar degrees of steatosis, inflammation, and ballooning. Two RYGB patients, and six SG patients, had NASH ( = 0.439). Twelve months after surgery, NAS was significantly and comparably ( = 0.241) reduced in both RYGB (-3.00 (95% CI -3.79--2.21), < 0.001) and SG (-2.25 (95% CI -2.92--1.59), < 0.001) patients. RYGB patients had significantly more reduced ( = 0.007) liver steatosis (-0.91 (95% CI -1.47--1.2) than SG patients (-0.33 (95% CI -0.54--0.13) and greater improvement in the plasma lipid profile. Fibrosis declined non-significantly. NASH was resolved in seven of eight patients without a worsening of their fibrosis. RYGB and SG have similar beneficial effects on NAS and NASH without the worsening of fibrosis. RYGB is associated with a more pronounced reduction in liver steatosis.
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http://dx.doi.org/10.3390/jcm10173783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432029PMC
August 2021

Efficacy and safety of liraglutide in type 1 diabetes by baseline characteristics in the ADJUNCT ONE and ADJUNCT TWO randomized controlled trials.

Diabetes Obes Metab 2021 12 28;23(12):2752-2762. Epub 2021 Sep 28.

Hvidovre University Hospital, University of Copenhagen, Hvidovre, Denmark.

Aim: To evaluate 26 weeks of liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJUNCT ONE and ADJUNCT TWO trials.

Materials And Methods: ADJUNCT 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/m ), and insulin regimen (basal bolus or continuous subcutaneous insulin infusion).

Results: In 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, body weight, and insulin dose (-0.30%-points, -5.0 kg, and -12%, respectively, with liraglutide 1.8 mg), were significant (P < .05), greater than at week 52, and similar to those in ADJUNCT TWO (-0.35%, -4.8 kg, and -10%, respectively, with liraglutide 1.8 mg).

Conclusions: In ADJUNCT ONE and ADJUNCT TWO, the efficacy and glycaemic safety of liraglutide did not depend on subgroups, leaving residual beta-cell function as the only identified variable impacting the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in T1D. These findings support a role for GLP-1 RAs as adjuncts to insulin in T1D, warranting further study.
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http://dx.doi.org/10.1111/dom.14532DOI Listing
December 2021

Neurotensin secretion after Roux-en-Y gastric bypass, sleeve gastrectomy, and truncal vagotomy with pyloroplasty.

Neurogastroenterol Motil 2022 01 11;34(1):e14210. Epub 2021 Aug 11.

Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Objective: Neurotensin (NT) is released from enteroendocrine cells and lowers food intake in rodents. We evaluated postprandial NT secretion in humans after surgeries associated with accelerated small intestinal nutrient delivery, and after Roux-en-Y gastric bypass (RYGB) when glucagon-like peptide-1 (GLP-1) signalling and dipeptidyl peptidase 4 (DPP-4) were inhibited, and during pharmacological treatments influencing entero-pancreatic functions.

Methods: We measured NT concentrations in plasma from meal studies: (I) after truncal vagotomy with pyloroplasty (TVP), cardia resection +TVP (CTVP), and matched controls (n = 10); (II) after RYGB, sleeve gastrectomy (SG), and in matched controls (n = 12); (III) after RYGB (n = 11) with antagonism of GLP-1 signalling using exendin(9-39) and DPP-4 inhibition using sitagliptin; (IV) after RYGB (n = 11) during a run-in period and subsequent treatment with, sitagliptin, liraglutide (GLP-1 receptor agonist), verapamil (calcium antagonist), acarbose (alpha glucosidase inhibitor), and pasireotide (somatostatin analogue), respectively.

Results: (I) NT secretion was similar after TVP/CTVP (p = 0.9), but increased vs. controls (p < 0.0001). (II) NT secretion was increased after RYGB vs. SG and controls (p < 0.0001). NT responses were similar in SG and controls (p = 0.3), but early postprandial NT concentrations were higher after SG (p < 0.05). (III) Exendin (9-39) and sitagliptin did not change NT responses vs placebo (p > 0.2), but responses were lower during sitagliptin vs. exendin(9-39) (p = 0.03). (IV) Pasireotide suppressed NT secretion (p = 0.004). Sitagliptin tended to lower NT secretion (p = 0.08). Liraglutide, verapamil, and acarbose had no effect (p > 0.9).

Conclusion: Neurotensin secretion is increased after surgeries associated with accelerated gastric emptying and lowered by pasireotide.
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http://dx.doi.org/10.1111/nmo.14210DOI Listing
January 2022

Plasma GDF15 levels are similar between subjects after bariatric surgery and matched controls and are unaffected by meals.

Am J Physiol Endocrinol Metab 2021 10 9;321(4):E443-E452. Epub 2021 Aug 9.

Obesity Pharmacology, Novo Nordisk, Måløv, Denmark.

Growth differentiating factor 15 (GDF15) is expressed in the intestine and is one of the most recently identified satiety peptides. The mechanisms controlling its secretion are unclear. The present study investigated whether plasma GDF15 concentrations are meal-related and if potential responses depend on macronutrient type or are affected by previous bariatric surgery. The study included ) volunteers ingesting rapidly vs. slowly digested carbohydrates (sucrose vs. isomaltose; = 10), ) volunteers who had undergone Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery and unoperated matched controls ingesting a liquid mixed meal ( = 9-10 in each group), and ) individuals with previous RYGB compared with unoperated controls ingesting isocaloric glucose, fat, or protein ( = 6 in each group). Plasma was collected after an overnight fast and up to 6 h after ingestion (≥12 time points). In , fasting GDF15 concentrations were ∼480 pg/mL. Concentrations after sucrose or isomaltose intake did not differ from baseline ( = 0.26 to > 0.99) and total area under the curves (tAUCs were similar between groups ( = 0.77). In , fasting GDF15 concentrations were as follows (pg/mL): RYGB = 540 ± 41.4, SG = 477 ± 36.4, and controls = 590 ± 41.8, with no between-group differences ( = 0.73). Concentrations did not increase at any postprandial time point (over all time factor: = 0.10) and tAUCs were similar between groups ( = 0.73). In , fasting plasma GDF15 was similar among the groups ( > 0.99) and neither glucose, fat, nor protein intake consistently increased the concentrations. In conclusion, we find that plasma GDF15 was not stimulated by meal intake and that fasting concentrations did not differ between RYGB-, SG-, and body mass index (BMI)-matched controls when investigated during the weight stable phase after RYGB and SG. Our combined data show that GDF15 does not increase in response to a liquid meal. Moreover, we show for the first time that ingestion of sucrose, isomaltose, glucose, fat, or protein also does not increase plasma GDF15 concentrations, questioning the role of GDF15 in regulation of food source preference. Finally, we find that neither fasting nor postprandial plasma GDF15 concentrations are increased in individuals with previous bariatric surgery compared with unoperated body mass index (BMI)-matched controls.
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http://dx.doi.org/10.1152/ajpendo.00190.2021DOI Listing
October 2021

Subcutaneous GIP and GLP-2 inhibit nightly bone resorption in postmenopausal women: A preliminary study.

Bone 2021 11 19;152:116065. Epub 2021 Jun 19.

Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Electronic address:

Background: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted in response to food ingestion, and they have been suggested to regulate bone turnover. In humans, exogenous GIP and GLP-2 acutely inhibit bone resorption as measured by circulating levels of carboxy-terminal type 1 collagen crosslinks (CTX).

Objective: The objective was to study the individual and combined acute effects of GIP and GLP-2 on bone turnover in postmenopausal women during nighttime - a period of increased bone resorption.

Methods: Using a randomized, placebo-controlled, double-blinded, crossover design, each participant (n = 9) received on four separate study days: GIP, GLP-2, GIP + GLP-2, and placebo (saline) as subcutaneous injections at bedtime. Main outcomes were levels of CTX and procollagen type 1 N-terminal propeptide (P1NP).

Results: Compared with placebo, GIP and GLP-2 alone significantly inhibited bone resorption (measured by CTX). GIP rapidly reduced CTX levels in the period from 45 to 120 min after injection, while GLP-2 had a more delayed effect with reduced CTX levels in the period from 120 to 240 min after injection. Combining GIP and GLP-2 showed complementary effects resulting in a sustained inhibition of CTX with reduced levels from 45 to 240 min after injection. Furthermore, GIP acutely increased bone formation (measured by P1NP).

Conclusion: Both GIP and GLP-2 reduced CTX during the night and had complementary effects when combined.
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http://dx.doi.org/10.1016/j.bone.2021.116065DOI Listing
November 2021

Dulaglutide for erectile dysfunction in type 2 diabetes.

Authors:
Sten Madsbad

Lancet Diabetes Endocrinol 2021 08 18;9(8):472-473. Epub 2021 Jun 18.

Department of Endocrinology, Hvidovre Hospital, 2650 Copenhagen, Denmark. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(21)00142-XDOI Listing
August 2021

Body weight and metabolic risk factors in patients with type 2 diabetes on a self-selected high-protein low-carbohydrate diet.

Eur J Nutr 2021 Dec 8;60(8):4473-4482. Epub 2021 Jun 8.

Department of Nutrition, Exercise and Sports, Københavns Universitet, Copenhagen, Denmark.

Purpose: We previously reported beneficial glucoregulatory effects of a fully provided carbohydrate-reduced, high-protein (CRHP) diet in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, in which patients maintained their body weight. Here, we investigated physiological changes during an additional 6-month period on a self-selected and self-prepared CRHP diet.

Methods: Twenty-eight patients with T2DM were instructed to consume a CRHP diet (30% of energy from carbohydrate and 30% from protein) for 24 weeks, after an initial 2 × 6-week trial when all food was prepared and provided to them. Patients received dietary advice every 2 weeks. At weeks 0, 6, 12 and 36, they underwent a 3-h intravenous glucose tolerance test, a 4-h mixed meal test, and a 48-h continuous glucose monitoring. Liver, muscle, pancreas, and visceral fat contents were measured by magnetic resonance imaging.

Results: During the 24-week self-selected diet period (weeks 12-36), body weight, visceral fat, liver fat, and glycated haemoglobin were maintained at the same levels achieved at the end of the fully provided diet period, and were still lower than at baseline (P < 0.05). Postprandial insulinaemia and insulin secretion were significantly greater (P < 0.05). At week 36, fasting insulin and C-peptide levels increased (P < 0.01) and daily glycaemia decreased further (P < 0.05) when compared with the end of the fully provided diet period.

Conclusion: Substituting dietary carbohydrate for protein and fat has metabolic benefits in patients with T2DM. These beneficial effects are maintained or augmented over the next 6 months when patients self-select and self-prepare this diet in a dietitian-supported setting.

Trial Registration: ClinicalTrials.gov NCT02764021.
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http://dx.doi.org/10.1007/s00394-021-02605-0DOI Listing
December 2021

Effects of Manipulating Circulating Bile Acid Concentrations on Postprandial GLP-1 Secretion and Glucose Metabolism After Roux-en-Y Gastric Bypass.

Front Endocrinol (Lausanne) 2021 14;12:681116. Epub 2021 May 14.

Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.

Background: Altered bile acid (BA) turnover has been suggested to be involved in the improved glucose regulation after Roux-en-Y gastric bypass (RYGB), possibly stimulation of GLP-1 secretion. We investigated the role of exogenous as well as endogenous BAs for GLP-1 secretion after RYGB by administering chenodeoxycholic acid (CDCA) and the BA sequestrant colesevelam (COL) both in the presence and the absence of a meal stimulus.

Methods: Two single-blinded randomized cross-over studies were performed. In study 1, eight RYGB operated participants ingested 200 ml water with 1) CDCA 1.25 g or 2) CDCA 1.25 g + colesevelam 3.75 g on separate days. In study 2, twelve RYGB participants ingested on separate days a mixed meal with addition of 1) CDCA 1.25 g, 2) COL 3.75 g or 3) COL 3.75 g × 2, or 4) no additions.

Results: In study 1, oral intake of CDCA increased circulating BAs, GLP-1, C-peptide, glucagon, and neurotensin. Addition of colesevelam reduced all responses. In study 2, addition of CDCA enhanced meal-induced increases in plasma GLP-1, glucagon and FGF-19 and lowered plasma glucose and C-peptide concentrations, while adding colesevelam lowered circulating BAs but did not affect meal-induced changes in plasma glucose or measured gastrointestinal hormones.

Conclusion: In RYGB-operated persons, exogenous CDCA enhanced meal-stimulated GLP-1 and glucagon secretion but not insulin secretion, while the BA sequestrant colesevelam decreased CDCA-stimulated GLP-1 secretion but did not affect meal-stimulated GLP-1, C-peptide or glucagon secretion, or glucose tolerance. These findings suggest a limited role for endogenous bile acids in the acute regulation of postprandial gut hormone secretion or glucose metabolism after RYGB.
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http://dx.doi.org/10.3389/fendo.2021.681116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166580PMC
December 2021

Effects of a Self-Prepared Carbohydrate-Reduced High-Protein Diet on Cardiovascular Disease Risk Markers in Patients with Type 2 Diabetes.

Nutrients 2021 May 17;13(5). Epub 2021 May 17.

Department of Nutrition, Exercise and Sports, University of Copenhagen, 1958 Frederiksberg, Denmark.

We previously observed beneficial effects of a carbohydrate-reduced, high-protein (CRHP) diet on cardiovascular risk markers in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, when all food was provided to subjects as ready-to-eat meals. Here, we report the results from a 6-month open label extension: 28 patients with T2DM were instructed to self-prepare the CRHP diet with dietetic guidance. At weeks 0, 6, 12, and 36, fasting and postprandial (4-h meal test) blood samples were collected for measurements of total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triacylglycerol (TG), apolipoproteins A1 and B, non-esterified fatty acids (NEFA), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6. Diurnal blood pressure and heart rate were also assessed. At the end of the study (week 36), concentrations of fasting total and LDL-cholesterol, fasting and postprandial NEFA and TG, and fasting apolipoprotein-B, CRP and TNF-α concentrations were significantly lower compared with week 0 ( < 0.05). A significant decrease in diurnal heart rate was also observed. From week 12 to 36, an increase in HDL-cholesterol and apolipoprotein-A1 concentrations and a further reduction in fasting and postprandial NEFA ( < 0.05) were found. These changes were independent of minor fluctuations in body weight. We conclude that the substitution of dietary carbohydrate for protein and fat has beneficial effects on several cardiovascular risk markers in patients with T2DM, which are maintained or augmented over the next 6 months when patients select and prepare the CRHP diet on their own in a dietitian-supported setting.
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http://dx.doi.org/10.3390/nu13051694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157073PMC
May 2021

Genetic markers of abdominal obesity and weight loss after gastric bypass surgery.

PLoS One 2021 28;16(5):e0252525. Epub 2021 May 28.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Weight loss after bariatric surgery varies widely between individuals, partly due to genetic differences. In addition, genetic determinants of abdominal obesity have been shown to attenuate weight loss after dietary intervention with special attention paid to the rs1358980-T risk allele in the VEGFA locus. Here we aimed to test if updated genetic risk scores (GRSs) for adiposity measures and the rs1358980-T risk allele are linked with weight loss following gastric bypass surgery.

Methods: Five hundred seventy six patients with morbid obesity underwent Roux-en-Y gastric bypass. A GRS for BMI and a GRS for waist-hip-ratio adjusted for BMI (proxy for abdominal obesity), respectively, were constructed. All patients were genotyped for the rs1358980-T risk allele. Associations between the genetic determinants and weight loss after bariatric surgery were evaluated.

Results: The GRS for BMI was not associated with weight loss (β = -2.0 kg/100 risk alleles, 95% CI -7.5 to 3.3, p = 0.45). Even though the GRS for abdominal obesity was associated with an attenuated weight loss response adjusted for age, sex and center (β = -14.6 kg/100 risk alleles, 95% CI -25.4 to -3.8, p = 0.008), it was not significantly associated with weight loss after adjustment for baseline BMI (β = -7.9 kg/100 risk alleles, 95% CI -17.5 to 1.6, p = 0.11). Similarly, the rs1358980-T risk allele was not significantly associated with weight loss (β = -0.8 kg/risk allele, 95% CI -2.2 to 0.6, p = 0.25).

Discussion: GRSs for adiposity derived from large meta-analyses and the rs1358980-T risk allele in the VEGFA locus did not predict weight loss after gastric bypass surgery. The association between a GRS for abdominal obesity and the response to bariatric surgery may be dependent on the association between the GRS and baseline BMI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252525PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162622PMC
October 2021

Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined.

N Engl J Med 2021 05;384(18):1719-1730

From the Department of Biomedical Sciences (J.R.L., C.J., S.B.K.J., C.R.J., L.M.O., R.M.C., M.B.B., B.M.S., J.J.H., S.S.T.), the Novo Nordisk Foundation Center for Basic Metabolic Research (J.R.L., C.J., S.B.K.J., C.R.J., L.M.O., R.M.C., J.J.H., S.S.T.), the Department of Clinical Medicine (T.B., J.-E.B.J.), University of Copenhagen, and the Departments of Endocrinology (M.S.S., K.N.B.-M., J.-E.B.J., S.M.) and Clinical Research (T.B.), Copenhagen University Hospital-Amager and Hvidovre, Copenhagen, and the Steno Diabetes Center Copenhagen, Gentofte (M.B.B.) - all in Denmark.

Background: Weight regain after weight loss is a major problem in the treatment of persons with obesity.

Methods: In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed.

Results: After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group.

Conclusions: A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).
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http://dx.doi.org/10.1056/NEJMoa2028198DOI Listing
May 2021

Successful Use of a GLP-1 Receptor Agonist as Add-on Therapy to Sulfonylurea in the Treatment of Neonatal Diabetes.

Eur J Case Rep Intern Med 2021 31;8(3):002352. Epub 2021 Mar 31.

Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.

Sulfonylurea monotherapy is the standard treatment for patients with the most common form of permanent neonatal diabetes, neonatal diabetes, but it is not always sufficient. For the first time, we present a case of successful use of a GLP-1 receptor agonist as add-on therapy in the treatment of a patient with neonatal diabetes and insufficient effect of sulfonylurea monotherapy. Good glycaemic control was maintained with a HbA1c level of 48 mmol/mol (6.5%) at the end of 26 months' follow-up.

Learning Points: Genetic testing is important in patients with neonatal diabetes.Sulfonylurea is the standard treatment for patients with the most common mutation ().We present the novel use of a GLP-1 receptor agonist as effective add-on therapy in a patient with neonatal diabetes and insufficient effect of sulfonylurea monotherapy.
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http://dx.doi.org/10.12890/2021_002352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046272PMC
March 2021

The Antiresorptive Effect of GIP, But Not GLP-2, Is Preserved in Patients With Hypoparathyroidism-A Randomized Crossover Study.

J Bone Miner Res 2021 08 5;36(8):1448-1458. Epub 2021 May 5.

Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP- and GLP-2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed-meal test (n = 7) followed by a peptide injection test (n = 4) using a randomized crossover design. We observed that the meal- and GIP- but not the GLP-2-induced changes in bone turnover markers were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP-2 receptor (GLP-2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP-2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP-2R were expressed in parathyroid tissue. Our findings suggest that the GIP-induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP-2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP-2R in the parathyroid gland. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338760PMC
August 2021

The role of GLP-1 in postprandial glucose metabolism after bariatric surgery: a narrative review of human GLP-1 receptor antagonist studies.

Surg Obes Relat Dis 2021 07 9;17(7):1383-1391. Epub 2021 Feb 9.

Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

The Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) bariatric procedures lead to remission or improvement of type 2 diabetes. A weight loss-independent augmentation of postprandial insulin secretion contributes to the improvement in glycemic control after RYGB and is associated with a ∼10-fold increase in plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1). However, the physiologic importance of the markedly increased postprandial GLP-1 secretion after RYGB has been much debated. The effect of GLP-1 receptor blockade after RYGB has been investigated in 12 studies. The studies indicate a shift toward a more prominent role for GLP-1 in postprandial β-cell function after RYGB. The effect of GLP-1 receptor antagonism on glucose tolerance after RYGB is more complex and is associated with important methodological challenges. The postprandial GLP-1 response is less enhanced after SG compared with RYGB. However, the effect of GLP-1 receptor blockade after SG has been examined in 1 study only and needs further investigation.
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http://dx.doi.org/10.1016/j.soard.2021.01.041DOI Listing
July 2021

Follistatin secretion is enhanced by protein, but not glucose or fat ingestion, in obese persons independently of previous gastric bypass surgery.

Am J Physiol Gastrointest Liver Physiol 2021 05 3;320(5):G753-G758. Epub 2021 Mar 3.

Department of Endocrinology, Hvidovre Hospital, Copenhagen, Denmark.

Follistatin is secreted from the liver and is involved in the regulation of muscle mass and insulin sensitivity via inhibition of activin A in humans. The secretion of follistatin seems to be stimulated by glucagon and inhibited by insulin, but only limited knowledge on the postprandial regulation of follistatin exists. Moreover, results on postoperative changes after Roux-en-Y gastric bypass (RYGB) are conflicting with reports of increased, unaltered, and lowered fasting concentrations of follistatin. In this study, we investigated postprandial follistatin and activin A concentrations after intake of isocaloric amounts of protein, fat, or glucose in subjects with obesity with and without previous RYGB to explore the regulation of follistatin by the individual macronutrients. Protein intake enhanced follistatin concentrations similarly in the two groups, whereas glucose and fat ingestion did not change postprandial follistatin concentrations. Concentrations of activin A were lower after protein intake compared with glucose intake in RYGB. Glucagon concentrations were also particularly enhanced by protein intake and tended to correlate with follistatin in RYGB. In conclusion, we demonstrated that protein intake, but not glucose or fat, is a strong stimulus for follistatin secretion in subjects with obesity and that this regulation is maintained after RYGB surgery. Circulating follistatin and activin A were studied after intake of isocaloric protein, fat, or glucose drinks in subjects with obesity with and without previous Roux-en-Y gastric bypass (RYGB). Protein intake enhanced follistatin similarly in both groups, whereas glucose and fat ingestion did not change follistatin. Activin A was lower after protein compared with glucose in RYGB. The novel finding is that protein intake, but neither glucose nor fat, stimulates follistatin secretion independently of previous RYGB.
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http://dx.doi.org/10.1152/ajpgi.00396.2020DOI Listing
May 2021

What is Diabetes Remission?

Diabetes Ther 2021 Mar 20;12(3):641-646. Epub 2021 Feb 20.

Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1007/s13300-021-01032-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947138PMC
March 2021

Comparable COVID-19 outcomes with current use of GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors among patients with diabetes who tested positive for SARS-CoV-2.

Diabetes Obes Metab 2021 06 16;23(6):1397-1401. Epub 2021 Feb 16.

Center of Research and Disruption of Infectious Diseases, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark.

Incretin-based therapies, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4i), have been hypothesized to exert beneficial effects on COVID-19 outcomes due to anti-inflammatory properties. In this population-based cohort study, we retrieved data from nationwide registries on all individuals diagnosed with severe acute respiratory syndrome coronavirus 2 infection up to 1 November 2020. For individuals with diabetes, we examined the impact of use of GLP-1 RAs (n = 370) and DPP-4i (n = 284) compared with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) (n = 342) on risk of hospital admission and severe outcomes. Relative risks (RRs) were calculated after applying propensity score weighted methods to control for confounding. Current users of GLP-1 RAs had an adjusted RR of 0.89 (95% confidence interval 0.34-2.33), while users of DPP-4i had an adjusted RR of 2.42 (95% confidence interval 0.99-5.89) for 30-day mortality compared with SGLT-2i use. Further, use of GLP-1 RAs or DPP-4i compared with SGLT-2i was not associated with decreased risk of hospital admission. Thus, use of incretin-based therapies in individuals with diabetes and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was not associated with improved clinical outcomes.
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http://dx.doi.org/10.1111/dom.14329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014019PMC
June 2021

Fractionated free fatty acids and their relation to diabetes status after Roux-en-Y gastric bypass: A cohort study.

Physiol Rep 2021 01;9(2):e14708

Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Bariatric surgery is associated with near-immediate remission of type 2 diabetes and recently suggested as a treatment for type 2 diabetes. Specifically, Roux-en-Y gastric bypass has been a focus of much research, but still, the mechanisms of action are only partly elucidated. We aim to investigate whether some mechanisms might be mediated by free fatty acids (FFAs). We measured eight fractionated FFAs before and up to 2 years after Roux-en-Y gastric bypass surgery in 207 patients, divided into three groups. One non-diabetic group, one diabetic group with post-operative remission and one diabetic group with persistent diabetes after surgery. Pre- and postoperative levels of fractionated FFAs were compared within and between groups. The sum of the measured FFAs were lower in the group with persistent diabetes, compared to the other groups. The pre-surgery level of linoleic acid in the group with persistent diabetes was significantly lower compared to the other two groups. The levels of fractionated FFAs decreased from pre-surgery to three months after surgery, except for oleic acid and arachidonic acid and for Docosahexaenoic acid (DHA) in the non-diabetic group. The FFAs with decreasing levels from pre-surgery to three months post-surgery are all precursors to oleic acid, arachidonic acid, and DHA, respectively, which may imply a drift, indicating that they need to be sustained at an acceptable level for optimal metabolic function. The fact that the sum of the measured FFAs is lower in the group with persistent diabetes may suggest that this group and the group with diabetes remission represent two distinct types of type 2 diabetes. It is proposed that linoleic acid could be used as a biomarker to determine the plausibility for type 2 diabetes remission after Roux-en-Y gastric bypass surgery.
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http://dx.doi.org/10.14814/phy2.14708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814490PMC
January 2021

Reduction of oxidative stress on DNA and RNA in obese patients after Roux-en-Y gastric bypass surgery-An observational cohort study of changes in urinary markers.

PLoS One 2020 14;15(12):e0243918. Epub 2020 Dec 14.

Department of Clinical Pharmacology, Bispebjerg Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Increased oxidative stress in obesity and diabetes is associated with morbidity and mortality risks. Levels of oxidative damage to DNA and RNA can be estimated through measurement of 8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) in urine. Both markers have been associated with type 2 diabetes, where especially 8-oxoGuo is prognostic for mortality risk. We hypothesized that Roux-en-Y gastric bypass (RYGB) surgery that has considerable effects on bodyweight, hyperglycemia and mortality, might be working through mechanisms that reduce oxidative stress, thereby reducing levels of the urinary markers. We used liquid chromatography coupled with tandem mass spectrometry to analyze the content of 8-oxodG and 8-oxoGuo in urinary samples from 356 obese patients treated with the RYGB-procedure. Mean age (SD) was 44.2 (9.6) years, BMI was 42.1 (5.6) kg/m2. Ninety-six (27%) of the patients had type 2 diabetes. Excretion levels of each marker before and after surgery were compared as estimates of the total 24-hour excretion, using a model based on glomerular filtration rate (calculated from cystatin C, age, height and weight), plasma- and urinary creatinine. The excretion of 8-oxodG increased in the first months after RYGB. For 8-oxoGuo, a gradual decrease was seen. Two years after RYGB and a mean weight loss of 35 kg, decreased hyperglycemia and insulin resistance, excretion levels of both markers were reduced by approximately 12% (P < 0.001). For both markers, mean excretion levels were about 30% lower in the female subgroup (P < 0.0001). Also, in this subgroup, excretion of 8-oxodG was significantly lower in patients with than without diabetes. We conclude, that oxidative damage to nucleic acids, reflected in the excretion of 8-oxodG and 8-oxoGuo, had decreased significantly two years after RYGB-indicating that reduced oxidative stress could be contributing to the many long-term benefits of RYGB-surgery in obesity and type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243918PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735613PMC
February 2021

Impact of prolonged fasting on insulin secretion, insulin action, and hepatic versus whole body insulin secretion disposition indices in healthy young males.

Am J Physiol Endocrinol Metab 2021 02 7;320(2):E281-E290. Epub 2020 Dec 7.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

The extent to which reduced insulin secretion during prolonged fasting reflects failure to compensate for whole body insulin resistance or a normal adjustment to potentially increased hepatic insulin action is unknown. We examined the effects of 36- versus 12-h fasting on insulin secretion and whole body versus hepatic insulin action in 13 healthy young males. Hepatic glucose production and insulin action were studied using stable isotopes, whereas whole body insulin action and insulin secretion were studied using an intravenous glucose tolerance test (IVGTT) and minimal modeling. Insulin, glucose, and lipid profiles were subsequently measured during a refeeding meal test. Prolonged fasting caused a minor reduction of first-phase insulin secretion in a context of improved hepatic insulin action, contrasting an increase in whole body insulin resistance. Accordingly, prolonged fasting was associated with opposite-directed effects on hepatic versus whole body insulin secretion disposition indices. Thirty-six-hour fasting compared with 12-h fasting was associated with increased serum insulin levels during the refeeding meal test. In conclusion, reduced insulin secretion during prolonged fasting may represent a healthy response to improved hepatic insulin action. Use of insulin secretion disposition indices without taking organ-specific insulin action into account may lead to erroneous conclusions. Thirty-six-hour prolonged, compared with 12-h overnight fasting, is associated with slightly reduced first-phase insulin secretion in the face of opposite-directed changes in hepatic versus whole body insulin action in healthy young males. The paradoxical finding of increased hepatic versus decreased whole body insulin secretion disposition indices during prolonged fasting challenges the physiological understanding and validity of insulin secretion disposition indices not taking organ-specific insulin action into account.
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http://dx.doi.org/10.1152/ajpendo.00433.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260368PMC
February 2021

GLP-1 Receptor Agonist Treatment in Morbid Obesity and Type 2 Diabetes Due to Pathogenic Homozygous Melanocortin-4 Receptor Mutation: A Case Report.

Cell Rep Med 2020 Apr 21;1(1):100006. Epub 2020 Apr 21.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Individuals with obesity due to pathogenic heterozygous () mutations can be treated efficiently with the glucagon-like peptide-1 receptor agonist (GLP-1 RA) liraglutide. Here, we report the effect of 16 weeks of liraglutide 3 mg/day treatment in a woman with morbid obesity and type 2 diabetes (T2D) due to homozygous pathogenic mutation. The body weight loss was 9.7 kg, similar to weight loss in heterozygous mutation carriers and common obesity. In addition, the treatment led to clinically relevant decreases in fasting glucose, triglycerides, systolic blood pressure, and normalization of glucose tolerance. We conclude that liraglutide reduces body weight and blood glucose levels in hetero- and homozygous mutation carriers. This serves as proof-of-concept that MC4Rs are not required for the body weight and glucose lowering effects of GLP-1 RAs and that liraglutide may be used as part of the treatment of obesity and T2D due to mutations.
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http://dx.doi.org/10.1016/j.xcrm.2020.100006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659505PMC
April 2020

Nonalcoholic Fatty Liver Disease Impairs the Liver-Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis.

Hepatol Commun 2020 Nov 1;4(11):1610-1623. Epub 2020 Sep 1.

Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark.

Nonalcoholic fatty liver disease (NAFLD) is associated with impaired hepatic actions of glucagon and insulin. Glucagon and amino acids are linked in an endocrine feedback circuit, the liver-alpha cell axis, that may be disrupted by NAFLD. We investigated how NAFLD severity affects glucagon and insulin resistance in individuals with obesity and whether bariatric surgery improves these parameters. Plasma and liver biopsies from 33 individuals with obesity (collectively, OBE) were obtained before and 12 months after bariatric surgery (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). Nine healthy control individuals (collectively, CON) undergoing cholecystectomy were used as a comparison group. The NAFLD activity score (NAS) was used to subdivide study participants into the following groups: OBE-no steatosis, OBE+steatosis, and nonalcoholic steatohepatitis (NASH) and/or grade 2 fibrosis (Fib) (OBE-NASH-Fib). Measurements of amino acids by targeted metabolomics and glucagon were performed. Glucagon, amino acids ( < 0.05), and the glucagon-alanine index, a validated surrogate marker of glucagon resistance, were increased in OBE by 60%, 56%, and 61%, respectively, when compared with CON but irrespective of NAFLD severity. In contrast, markers of hepatic insulin resistance increased concomitantly with NAS. Hyperglucagonemia resolved in OBE-no steatosis and OBE+steatosis but not in OBE-NASH-Fib (median, 7.0; interquartile range, 5.0-9.8 pmol/L), regardless of improvement in insulin resistance and NAS. The type of surgery that participants underwent had no effect on metabolic outcomes. Glucagon resistance to amino acid metabolism exists in individuals with NAFLD independent of NAS severity. Patients with NASH showed persistent hyperglucagonemia 12 months after bariatric surgery, indicating that a disrupted liver-alpha cell may remain in NAFLD despite major improvement in liver histology.
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http://dx.doi.org/10.1002/hep4.1562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603528PMC
November 2020
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