Liraglutide and Colesevelam Changes Serum and Fecal Bile Acid Levels in a Randomized Trial with Patients with Bile Acid Diarrhea.

INTRODUCTION: Both liraglutide and colesevelam improve bile acid diarrhea (BAD) symptoms. Colesevelam binds excess amounts of diarrhea-causing bile acids in the colon whereas the mode of action for liraglutide remains elusive. Here, we examined the impact of colesevelam and liraglutide treatment on the concentrations of bile acids in serum and feces and the fecal microbiota composition to better understand the two drugs' modes of action. METHODS: Bile acid species were analyzed in serum and fecal samples from a randomized, double-blind, double-dummy trial at baseline and after three and six weeks of orally administered colesevelam (1,875 mg twice daily, n = 26) or subcutaneously administered liraglutide (uptitrated by weekly increments of 0.6 mg from 0.6 to 1.8 mg daily, n = 26) in patients with 75selenium-homotaurocholic acid test-verified, idiopathic, or post-cholecystectomy BAD. Fecal microbiota composition was analyzed by 16S rRNA gene amplicon sequencing at the same time points. RESULTS: Colesevelam increased the fecal concentrations of all bile acid species while it decreased serum concentrations of secondary bile acids. Liraglutide induced a small increase in serum unconjugated bile acid concentrations without affecting fecal bile acid concentrations. No changes in fecal microbiota composition were observed with either treatment. CONCLUSION: Colesevelam and liraglutide exhibit distinct effects on serum and fecal bile acid concentrations with colesevelam reducing serum concentrations of secondary bile acids and promoting fecal bile acid excretion while liraglutide enhances serum concentrations of unconjugated bile acids, potentially through deceleration of small intestinal transit time allowing more time for passive absorption of bile acids.

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

CONTEXT: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. OBJECTIVE: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. DESIGN, PATIENTS, SETTING, INTERVENTIONS: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. MAIN OUTCOME MEASURE: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. RESULTS: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. CONCLUSIONS: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Alcohol-induced fibroblast growth factor 21 secretion is increased in individuals with alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) affects 5% of the global population. Despite its high prevalence, the pathophysiology of AUD remains enigmatic, hindering the development of novel therapeutics. Interestingly, the liver hormone fibroblast growth factor 21 (FGF21), which is currently in late-stage clinical trials for the treatment of non-alcoholic steatohepatitis, has been implicated by recent genome-wide association studies as a regulator of alcohol consumption. METHODS: This study aimed to evaluate plasma responses of FGF21 to an alcohol challenge in three groups: 15 males with AUD, 15 healthy males with a father with AUD (Predisposed), and 15 healthy males without any predisposition to AUD (Controls). All participants were investigated after an overnight fast. Assessments, including blood sampling and visual analog scale-assessed desire for alcohol intake, were performed before and for 10 h after ingesting 0.5 g alcohol per kg body weight over 10 min. RESULTS: The three groups were age and body-mass index-matched and had normal plasma concentrations of transaminases and FibroScan®-assessed elastography. Baseline FGF21 concentrations did not differ between groups, but individuals with AUD exhibited greater FGF21 responses to alcohol (area under the curve (AUC0-600 min): 954 ± 665 ng/ml × min (mean (standard deviation)) compared to Controls (AUC0-600 min: 453 ± 333 ng/ml × min, P = 0.03) but not Predisposed (AUC0-600 min: 556 ± 429 ng/ml × min, P = 0.11). CONCLUSION: In conclusion, we demonstrate greater alcohol-induced FGF21 responses in individuals with AUD compared to healthy individuals without paternal predisposition to AUD, suggesting a role for FGF21 in AUD pathophysiology.

Comment on Yang et al. Bile Acid Diarrhea: From Molecular Mechanisms to Clinical Diagnosis and Treatment in the Era of Precision Medicine. Int. J. Mol. Sci. 2024, 25, 1544.

We have with great interest read the recent review on the molecular mechanisms underlying bile acid diarrhea (BAD) by Yang et al [...].

Glucagon Clearance Is Decreased in Chronic Kidney Disease but Preserved in Liver Cirrhosis.

It is not completely clear which organs are responsible for glucagon elimination in humans, and disturbances in the elimination of glucagon could contribute to the hyperglucagonemia observed in chronic liver disease and chronic kidney disease (CKD). Here, we evaluated kinetics and metabolic effects of exogenous glucagon in individuals with stage 4 CKD (n = 16), individuals with Child-Pugh A-C cirrhosis (n = 16), and matched control individuals (n = 16), before, during, and after a 60-min glucagon infusion (4 ng/kg/min). Individuals with CKD exhibited a significantly lower mean metabolic clearance rate of glucagon (14.0 [95% CI 12.2;15.7] mL/kg/min) compared with both individuals with cirrhosis (19.7 [18.1;21.3] mL/kg/min, P < 0.001) and control individuals (20.4 [18.1;22.7] mL/kg/min, P < 0.001). Glucagon half-life was significantly prolonged in the CKD group (7.5 [6.9;8.2] min) compared with individuals with cirrhosis (5.7 [5.2;6.3] min, P = 0.002) and control individuals (5.7 [5.2;6.3] min, P < 0.001). No difference in the effects of exogenous glucagon on plasma glucose, amino acids, or triglycerides was observed between groups. In conclusion, CKD, but not liver cirrhosis, leads to a significant reduction in glucagon clearance, supporting the kidneys as a primary site for human glucagon elimination.

The role of glucagon-like peptide 1 in the postprandial effects of metformin in type 2 diabetes: a randomized crossover trial.

AIMS: Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanism remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D. METHODS: In a randomized, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol [6.7%], body mass index 30.1 kg/m2, age 71 years) underwent, in randomized order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4 h mixed meal tests performed in randomized order and separated by >24 h with either continuous intravenous exendin(9-39)NH2 or saline infusion. RESULTS: Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences [MD] 1.4 mmol/L × min [95% CI 0.8-2.0]) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/L × min [95% CI 64-307]) and exendin(9-39)NH2 infusion (MD 268 mmol/L × min [95% CI 108-427]). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/L × min [95% CI -6564-170]). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/L × min [95% CI 0.39-2.9]) but did not affect postprandial GLP-1 responses (MD 820 pmol/L × min [95% CI -1750-111]). CONCLUSIONS: Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that 2 weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. Trial registration: Clinicaltrials.gov NCT03246451.

Perioperative Metformin Treatment to Reduce Postoperative Hyperglycemia After Colon Cancer Surgery: A Randomized Clinical Trial.

BACKGROUND: Surgery induces a stress response causing insulin resistance that may result in postoperative hyperglycemia. Postoperative hyperglycemia is associated with increased incidence of complications, longer hospitalization and greater mortality. OBJECTIVE: This study examined the effect of metformin treatment on the percentage of patients experiencing postoperative hyperglycemia after elective colon cancer surgery. DESIGN: This was a randomized double-blind placebo-controlled trial. SETTINGS: The study was conducted at Slagelse Hospital, Slagelse, Denmark. PATIENTS: Patients without diabetes planned for elective surgery for colon cancer were included. INTERVENTIONS: Patients received metformin 500mg three times a day or placebo for 20 days before and 10 days after surgery. MAIN OUTCOME MEASURES: Blood glucose levels were measured several times daily until the end of postoperative day two. The main outcome measures were the percentage of patients who experienced at least one blood glucose measurement above 7.7 and 10 mmol/l, respectively. Rates of complications within 30 days of surgery and Quality of recovery-15 scores were also recorded. RESULTS: Of the 48 included patients, 21 (84.0%) in the placebo group and 18 (78.3%) in the metformin group had at least one blood glucose measurement above 7.7 mmol/l (p = 0.72), and 13 (52.0%) patients in the placebo group had a measurement above 10.0 mmol/l versus 5 (21.7%) in the metformin group, (p = 0.04). No differences in complication rates or Quality of recovery-15 scores were seen. LIMITATIONS: The number of patients in the study was too low to detect a possible difference in postoperative complications. Blood glucose was measured as spot measurements instead of continuous surveillance. CONCLUSIONS: In patients without diabetes, metformin significantly reduced the percentage of patients experiencing postoperative hyperglycemia as defined as spot blood glucose measurements above 10 mmol/l after elective colon cancer surgery. See Video Abstract.

Skin and systemic inflammation in adults with atopic dermatitis before and after whole-body topical betamethasone 17-valerate 0.1% or tacrolimus 0.1% treatment: A randomized controlled study.

BACKGROUND: Atopic dermatitis (AD) is mainly driven by type 2 inflammation and often treated with topical agents. Studies comparing differences in biomarkers between these treatments are lacking. OBJECTIVES: The aim of this study was to evaluate the effects of topical betamethasone 17-valerate 0.1% and tacrolimus 0.1% ointment on skin barrier function and inflammatory biomarkers in skin and blood in adults with AD. METHODS: In this randomized parallel-group double-blind double-dummy active-comparator study design, 36 adults with AD were treated with either whole-body topical corticosteroid (betamethasone ointment 0.1% plus placebo once daily, n = 18) or calcineurin inhibitor (tacrolimus ointment 0.1% twice daily, n = 18). At baseline, after 2 weeks of daily treatment and after further 4 weeks of twice-weekly maintenance treatment, we evaluated AD severity, levels of natural moisturizing factor (NMF) and cytokines in the skin and blood and characterized circulating T cells. RESULTS: Mean AD severity at baseline corresponded to moderate disease and decreased significantly in both groups. Levels of NMF increased significantly in the tacrolimus group after 2 weeks of treatment (p = 0.002) and tended to increase more than betamethasone at week 6 (p = 0.06). Most skin cytokines decreased with both treatments. However, IL-8, IL-18, IL-22, IP-10, MDC, MMP-9 and TARC were significantly more decreased with betamethasone than tacrolimus after 2 weeks, while after 6 weeks this was only the case for IL-8 and MMP-9. Approximate half of the systemic cytokines decreased significantly with both treatments, but betamethasone decreased MDC significantly more after 2 weeks of treatment. T-cell characterization analyses indicated slight differences in the expression and activation of T cells between groups. CONCLUSION: Topical treatment of AD with betamethasone and tacrolimus ointment effectively reduced disease severity, cutaneous and systemic inflammatory markers. Betamethasone was more effective in decreasing inflammation, but tacrolimus improved skin hydration (NMF levels) more than betamethasone.

The effect of Mycobacterium tuberculosis treatment on thrombelastography-assessed haemostasis: a prospective cohort study.

BACKGROUND AND OBJECTIVE: Tuberculosis disease (TB) and tuberculosis infection (TBI) have been associated with increased risk of cardiovascular disease which may be connected to infection-related haemostatic changes. It is unknown if treatment of Mycobacterium tuberculosis influences haemostasis. Here, we assessed if TB or TBI treatment affects thrombelastography (TEG)-assessed haemostasis. METHODS: Individuals with TB or TBI were included from a TB outpatient clinic in Copenhagen, Denmark. Patients treated with antithrombotic medication or systemic immunosuppressants were excluded. TEG analysis was performed before and after TB/TBI treatment using the TEG®6s analyser to provide data on the reaction time of clot initiation (R) (min), the speed of clot formation (K) (min) and clot build-up (Angle) (°), maximum clot strength (MA) (mm), and clot breakdown/fibrinolysis (LY30) (%). Differences in TEG were assessed using paired t tests. RESULTS: We included eleven individuals with TB with median [interquartile range] [IQR] age 52 (Liu et al. in Medicine (United States) 95, 2016) years and mean (standard deviation) (SD) body mass index (BMI) 24.7 (6.3) kg/m2 as well as 15 individuals with TBI with median [IQR] age 49 (Wells et al. in Am J Respir Crit Care Med 204:583, 2021) years and BMI 26.0 (3.2) kg/m2. Treatment reduced MA for both TB (64.0 (6.3) vs. 57.9 (5.2) mm, p = 0.016) and TBI (61.3 (4.1) vs. 58.6 (5.0) mm, p = 0.023) whereas R, K, Angle and LY30 were unaffected. CONCLUSION: TEG analysis showed that treatments of TB and TBI were associated with reduced MA which may indicate the existence of cardiovascular benefits from therapy. TRIAL REGISTRATION: Registered at ClinicalTrials.gov 05 April 2021 with registration number NCT04830462.

Two weeks of acarbose treatment shows no effect on gut microbiome composition in patients with type 2 diabetes: a randomised, placebo-controlled, double-blind, crossover study.

Aim: The alpha-glucosidase inhibitor acarbose is approved for the treatment of type 2 diabetes (T2D). It acts in the lumen of the gut by reducing intestinal hydrolysis and absorption of ingested carbohydrates. This reduces postprandial blood glucose concentration and increases the content of carbohydrates in the distal parts of the intestine potentially influencing gut microbiome (GM) composition and possibly impacting the gut microbiome (GM) dysbiosis associated with T2D. Here, we investigated the effect of acarbose on GM composition in patients with T2D. Methods: Faecal samples were collected in a previously conducted randomised, placebo-controlled, double-blind, crossover study in which 15 individuals with metformin-treated T2D (age 57-85 years, HbA1c 40-74 mmol/mol, BMI 23.6-34.6 kg/m2) were subjected to two 14-day treatment periods with acarbose and placebo, respectively, separated by a 6-week wash-out period. Faecal samples were collected before and by the end of each treatment period. The GM profiles were evaluated by 16S rRNA gene amplicon sequencing. Results: The GM profiles after the treatment periods with acarbose or placebo remained unaffected (P > 0.7) when compared with the GM profiles before treatment. This applied to the analysis of within-sample diversity (α-diversity) and between-sample bacterial composition diversity (ß-diversity). Additionally, no dominant bacterial species differentiated the treatment groups, and only minor increases in the relative abundances of Klebsiella spp. and Escherichia coli (P < 0.05) were observed after acarbose treatment. Conclusion: In patients with metformin-treated T2D, 14 days of treatment with acarbose showed only minor effects on GM as seen in increased relative abundances of Klebsiella spp. and Escherichia coli.

Exogenous glucagon-like peptide 2 counteracts exogenous cholecystokinin-induced gallbladder contraction in healthy men.

BACKGROUND AND OBJECTIVE: Studies in humans and mice have demonstrated that the gut hormone glucagon-like peptide 2 (GLP-2) promotes gallbladder relaxation and refilling. Here, we assessed the effect of exogenous GLP-2 on gallbladder motility in the fasted state of healthy men with and without infusion of the potent gallbladder-contracting hormone cholecystokinin (CCK). METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 15 male participants (mean [SD]: age 24.7 [3.6] years; body mass index 22.9 [1.6] kg/m2) underwent four experimental days receiving two infusions on each day: either CCK (0.4 pmol × kg-1 × min-1, time 0-180 min) + GLP-2 (10 pmol × kg-1 × min-1, time 30-240 min), CCK + placebo, placebo + GLP-2, or placebo + placebo, respectively. Gallbladder volume was measured at baseline and throughout the 4-hour study day using ultrasonography. RESULTS: Compared to placebo + placebo, GLP-2 + placebo did not affect gallbladder volume, but when infused in combination with CCK, GLP-2 completely abolished the strong gallbladder-contracting effect seen during CCK + placebo infusion, restoring baseline levels of gallbladder volume. CONCLUSION: Exogenous GLP-2 counteracts exogenous CCK-induced gallbladder emptying in healthy men, pointing to a possible therapeutic potential for GLP-2 as a relaxing modulator of gallbladder smooth muscle tone (e.g., as bridge to surgery in biliary colic). The effect may also explain the gallbladder-related adverse events reported for GLP-2 receptor agonists used in the treatment of short bowel syndrome.

Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study.

AIMS/HYPOTHESES: Glucagon and glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon, and dual agonists of their receptors are currently being explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated levels of endogenous glucagon (hyperglucagonaemia) have been linked with hyperglycaemia in individuals with type 2 diabetes but are also observed in individuals with obesity and MASLD. GLP-1 levels have been reported to be largely unaffected or even reduced in similar conditions. We investigated potential determinants of plasma proglucagon and associations of glucagon receptor signalling with metabolic diseases based on data from the UK Biobank. METHODS: We used exome sequencing data from the UK Biobank for ~410,000 white participants to identify glucagon receptor variants and grouped them based on their known or predicted signalling. Data on plasma levels of proglucagon estimated using Olink technology were available for a subset of the cohort (~40,000). We determined associations of glucagon receptor variants and proglucagon with BMI, type 2 diabetes and liver fat (quantified by liver MRI) and performed survival analyses to investigate if elevated proglucagon predicts type 2 diabetes development. RESULTS: Obesity, MASLD and type 2 diabetes were associated with elevated plasma levels of proglucagon independently of each other. Baseline proglucagon levels were associated with the risk of type 2 diabetes development over a 14 year follow-up period (HR 1.13; 95% CI 1.09, 1.17; n=1562; p=1.3×10-12). This association was of the same magnitude across strata of BMI. Carriers of glucagon receptor variants with reduced cAMP signalling had elevated levels of proglucagon (ß 0.847; 95% CI 0.04, 1.66; n=17; p=0.04), and carriers of variants with a predicted frameshift mutation had higher levels of liver fat compared with the wild-type reference group (ß 0.504; 95% CI 0.03, 0.98; n=11; p=0.04). CONCLUSIONS/INTERPRETATION: Our findings support the suggestion that glucagon receptor signalling is involved in MASLD, that plasma levels of proglucagon are linked to the risk of type 2 diabetes development, and that proglucagon levels are influenced by genetic variation in the glucagon receptor, obesity, type 2 diabetes and MASLD. Determining the molecular signalling pathways downstream of glucagon receptor activation may guide the development of biased GLP-1/glucagon co-agonist with improved metabolic benefits. DATA AVAILABILITY: All coding is available through https://github.com/nicwin98/UK-Biobank-GCG.

Gluco-metabolic response to exogenous oxytocin in totally pancreatectomized patients and healthy individuals.

Oxytocin has been proposed to possess glucose-stabilizing effects through the release of insulin and glucagon from the pancreas. Also, exogenous oxytocin has been shown to stimulate extrapancreatic glucagon secretion in depancreatized dogs. Here, we investigated the effect of exogenous oxytocin on circulating levels of pancreatic and gut-derived glucose-stabilizing hormones (insulin [measured as C-peptide], glucagon, glucagon-like peptide 1 [GLP-1], and glucose-dependent insulinotropic polypeptide). We studied nine pancreatectomized (PX) patients and nine healthy controls (CTRLs) (matched on age and body mass index) before, during, and after an intravenous infusion of 10 IU of oxytocin administered over 12 min. Oxytocin did not increase plasma glucagon levels, nor induce any changes in plasma glucose, C-peptide, or GIP in any of the groups. Oxytocin decreased plasma glucagon levels by 19 ± 10 % in CTRLs (from 2.0 ± 0.5 [mean ± SEM] to 1.3 ± 0.2 pmol/l, P = 0.0025) and increased GLP-1 by 42 ± 22 % in PX patients (from 9.0 ± 1.0-12.7 ± 1.0 pmol/l, P = 0.0003). Fasting plasma glucose levels were higher in PX patients compared with CTRLs (13.1 ± 1.1 vs. 5.1 ± 0.1 mmol/l, P < 0.0001). In conclusion, the present findings do not support pancreas-mediated glucose-stabilizing effects of acute oxytocin administration in humans and warrant further investigation of oxytocin's gluco-metabolic effects.

Increased hepatic glucagon sensitivity in totally pancreatectomised patients.

OBJECTIVE: The metabolic phenotype of totally pancreatectomised patients includes hyperaminoacidaemia and predisposition to hypoglycaemia and hepatic lipid accumulation. We aimed to investigate whether the loss of pancreatic glucagon may be responsible for these changes. METHODS: Nine middle-aged, normal-weight totally pancreatectomised patients, nine patients with type 1 diabetes (C-peptide negative), and nine matched controls underwent two separate experimental days, each involving a 150-min intravenous infusion of glucagon (4 ng/kg/min) or placebo (saline) under fasting conditions while any basal insulin treatment was continued. RESULTS: Glucagon infusion increased plasma glucagon to similar high physiological levels in all groups. The infusion increased hepatic glucose production and decreased plasma concentration of most amino acids in all groups, with more pronounced effects in the totally pancreatectomised patients compared with the other groups. Glucagon infusion diminished fatty acid re-esterification and tended to decrease plasma concentrations of fatty acids in the totally pancreatectomised patients but not in the type 1 diabetes patients. CONCLUSION: Totally pancreatectomised patients were characterised by increased sensitivity to exogenous glucagon at the level of hepatic glucose, amino acid, and lipid metabolism, suggesting that the metabolic disturbances characterising these patients may be rooted in perturbed hepatic processes normally controlled by pancreatic glucagon.

Bile Acid Diarrhea Is Associated With an Increased Incidence of Gastrointestinal Cancers.

INTRODUCTION: Bile acid diarrhea (BAD) is an underrecognized and socially debilitating disease caused by high concentrations of bile acids in the colon. Bile acids directly and indirectly promote carcinogenesis. In this article, we investigated whether individuals with BAD have an increased risk of gastrointestinal (GI) cancers. METHODS: By using the Danish health registries, adult individuals with BAD were identified by International Classification of Diseases 10th revision code K90.8 or referral to the diagnostic 75selenium-homotaurocholic acid test followed by prescription of a bile acid sequestrant within 365 days (n = 5,245). Age- and sex-matched individuals without BAD were included for comparison (n = 52,450). We analyzed the cumulative incidence of GI cancers after BAD diagnosis and the odds ratios (ORs) of GI cancer 8 and 15 years before BAD diagnosis/matching. RESULTS: Cumulative incidence of GI cancer 6 years after BAD diagnosis/matching was 1.6% in the BAD group and 1.1% in controls ( P = 0.01). The ORs of total GI cancer 8 and 15 years before BAD diagnosis were 6.16 (5.08-7.48) and 5.19 (4.28-6.29), respectively. Furthermore, 47 individuals with BAD (0.9%) and 250 (0.5%) controls died of GI cancer. DISCUSSION: This nationwide cohort study indicates an association between BAD and GI cancers. We found both a higher incidence of GI cancer after BAD diagnosis compared with controls and increased OR of GI cancer before BAD diagnosis. Bearing in mind the underdiagnosis of BAD, the delay of BAD diagnosis, and the carcinogenic effect of bile acids, these findings warrant further investigations of the risk of GI cancer in individuals with BAD.

Prevalence and predictive features of metabolic dysfunction-associated steatotic liver disease in type 1 diabetes.

AIMS/HYPOTHESIS: The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in type 1 diabetes remain unclear. Therefore, we investigated the prevalence and severity of MASLD in type 1 diabetes and assessed which clinical features are most important in predicting MASLD severity. METHODS: A total of 453 individuals with type 1 diabetes (41.6 ± 15.0 years, 64% female, body mass index [BMI] 25.4 ± 4.2 kg/m2, and HbA1c 55.6 ± 12 mmol/mol) underwent vibration-controlled transient elastography (VCTE), with a controlled attenuation parameter (CAP) score for steatosis (≥280.0 dB/m) and a liver stiffness measurement (LMS) for fibrosis (≥8.0 kPa). A machine learning Extra-Trees classification model was performed to assess the predictive power of the clinical features associated with type 1 diabetes with respect to steatosis and fibrosis. RESULTS: The prevalence of hepatic steatosis and fibrosis was 9.5% (95% CI, 6.8-12.2) and 3.5% (95% CI, 1.8-5.2). Higher LMS was associated with a longer duration of type 1 diabetes (median 30.5 [IQR 18.0-39.3] years vs 15.0 [IQR 6.0-27.0] years), and individuals were older, had a higher BMI (mean 27.8 ± 5.2 vs 25.3 ± 4.1 kg/m2), and a higher CAP score (mean 211.4 ± 51.7 dB/m vs 241.4 ± 75.6 dB/m). The most important predictive features of fibrosis were duration of type 1 diabetes, age, and systolic blood pressure, with a mean ± SD area under the curve of 0.73 ± 0.03. CONCLUSION: Individuals with type 1 diabetes and high blood pressure, older age, higher BMI, and longer duration of disease could be considered at high-risk for developing MASLD.

Targeting the GLP-2 receptor in the management of obesity.

Recent advancements in understanding glucagon-like peptide 2 (GLP-2) biology and pharmacology have sparked interest in targeting the GLP-2 receptor (GLP-2R) in the treatment of obesity. GLP-2 is a proglucagon-derived 33-amino acid peptide co-secreted from enteroendocrine L cells along with glucagon-like peptide 1 (GLP-1) and has a range of actions via the GLP-2R, which is particularly expressed in the gastrointestinal tract, the liver, adipose tissue, and the central nervous system (CNS). In humans, GLP-2 evidently induces intestinotrophic effects (i.e., induction of intestinal mucosal proliferation and improved gut barrier function) and promotes mesenteric blood flow. However, GLP-2 does not seem to have appetite or food intake-reducing effects in humans, but its gut barrier-promoting effect may be of interest in the context of obesity. Obesity is associated with reduced gut barrier function, increasing the translocation of proinflammatory gut content to the circulation. This phenomenon constitutes a strong driver of obesity-associated systemic low-grade inflammation, which in turn plays a major role in the development of most obesity-associated complications. Thus, the intestinotrophic and gut barrier-improving effect of GLP-2, which in obese rodent models shows strong anti-inflammatory potential, may, in combination with food intake-reducing strategies, e.g., GLP-1 receptor (GLP-1) agonism, be able to rectify core pathophysiological mechanism of obesity. Here, we provide an overview of GLP-2 physiology in the context of obesity pathophysiology and review the pharmacological potential of GLP-2R activation in the management of obesity and related comorbidities.

Accuracy of continuous glucose monitoring during exercise-related hypoglycemia in individuals with type 1 diabetes.

Background: Hypoglycemia is common in individuals with type 1 diabetes, especially during exercise. We investigated the accuracy of two different continuous glucose monitoring systems during exercise-related hypoglycemia in an experimental setting. Materials and methods: Fifteen individuals with type 1 diabetes participated in two separate euglycemic-hypoglycemic clamp days (Clamp-exercise and Clamp-rest) including five phases: 1) baseline euglycemia, 2) plasma glucose (PG) decline ± exercise, 3) 15-minute hypoglycemia ± exercise, 4) 45-minute hypoglycemia, and 5) recovery euglycemia. Interstitial PG levels were measured every five minutes, using Dexcom G6 (DG6) and FreeStyle Libre 1 (FSL1). Yellow Springs Instruments 2900 was used as PG reference method, enabling mean absolute relative difference (MARD) assessment for each phase and Clarke error grid analysis for each day. Results: Exercise had a negative effect on FSL1 accuracy in phase 2 and 3 compared to rest (ΔMARD = +5.3 percentage points [(95% CI): 1.6, 9.1] and +13.5 percentage points [6.4, 20.5], respectively). In contrast, exercise had a positive effect on DG6 accuracy during phase 2 and 4 compared to rest (ΔMARD = -6.2 percentage points [-11.2, -1.2] and -8.4 percentage points [-12.4, -4.3], respectively). Clarke error grid analysis showed a decrease in clinically acceptable treatment decisions during Clamp-exercise for FSL1 while a contrary increase was observed for DG6. Conclusion: Physical exercise had clinically relevant impact on the accuracy of the investigated continuous glucose monitoring systems and their ability to accurately detect hypoglycemia.