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INTRODUCTION: Topical corticosteroids (TCS), used to treat atopic dermatitis (AD), have been associated with type 2 diabetes and osteoporosis in epidemiological studies, possibly explained by systemic absorption.OBJECTIVES: We examined whether intensive daily whole-body TCS treatment over two weeks followed by twice weekly application for four weeks could elicit insulin resistance and increase bone resorption in adults with AD.METHODS: A randomized parallel-group double-blind double-dummy non-corticosteroid-based active-comparator study design was completed in Copenhagen, Denmark. Thirty-six non-obese, non-diabetic adults with moderate-to-severe AD were randomized to whole-body treatment with betamethasone 17-valerate 0.1% plus a vehicle once daily or tacrolimus 0.1% twice daily after washout. Insulin sensitivity assessed by the hyperinsulinemic-euglycemic clamp combined with tracer infusions and biomarkers of bone formation (P1NP) and resorption (CTX) were evaluated at baseline, after two weeks of daily treatment and after further four weeks of twice-weekly maintenance treatment.RESULTS: AD severity improved with both treatments and systemic inflammation was reduced. After two weeks, we observed similar increase in peripheral insulin sensitivity with use of betamethasone (n=18) and tacrolimus (n=18). Bone resorption biomarker, CTX, was unchanged, while bone formation marker, P1NP, decreased after betamethasone treatment after both two and six weeks but remained unchanged in the tacrolimus arm.CONCLUSIONS: Whole-body treatment with TCS leads to systemic exposure but appears not to compromise glucose metabolism during short-term use, which may be a result of reduced systemic inflammatory activity. The negative impact on bone formation could be regarded an adverse effect of TCS.

Introduction: Clozapine and olanzapine are some of the most effective antipsychotics, but both are associated with weight gain and relevant metabolic disturbances, including pre-diabetes and diabetes. Non-pharmacological/ behavioural interventions have had limited effects counteracting these adverse effects. Semaglutide, a glucagon-like peptide 1 receptor agonist, is approved for the treatment of type 2 diabetes and obesity. We will investigate the long-term effects of add-on treatment with semaglutide once a week versus placebo once a week on the metabolic status in pre-diabetic (glycated haemoglobin A1c (HbA1c) 35-47 mmol/mol (5.4%-6.4%) and diabetic (HbA1c 48-57 mmol/mol (6.5%-7.4%)) patients diagnosed with a schizophrenia spectrum disorder who initiated clozapine or olanzapine treatment within the last 60 months.Methods and analysis: This is a 26-week, double-blinded, randomised, placebo-controlled trial. Altogether, 104 patients diagnosed with a schizophrenia spectrum disorder, aged 18-65 years, with pre-diabetes or diabetes will be randomised to injections of 1.0 mg semaglutide once a week or placebo for 26 weeks. The primary endpoint is change from baseline in HbA1c. Secondary endpoints include changes in body weight, hip and waist circumference and plasma levels of insulin, glucagon, glucose, and C-peptide, insulin sensitivity, beta cell function, hepatic function, fibrosis-4 score, lipid profile, incretin hormones, bone markers, body composition, bone density, proteomic analyses and oxidative stress markers. Together with alcohol, tobacco and drug use, potential effects on the reward value of a sweet-fat stimulus, psychopathology, level of activity and quality of life will also be assessed.Ethics and dissemination: This study is approved by the Danish Medicines Agency and the regional scientific ethics committee of the Capital Region of Denmark (committee C, #H-20019008) and will be carried out in accordance with Intern

OBJECTIVE: The study explores whether type 2 diabetes (T2D) diagnosis affects food consumption patterns in line with the dietary recommendations provided to individuals in relation to a diagnosis.DESIGN: Based on detailed food purchase data, we explore which dietary changes are most common following a T2D diagnosis. Changes are investigated for several energy-adjusted nutrients and food groups and overall adherence to dietary guidelines.SETTING: We use data on diagnosis of T2D and hospitalization in relation to T2D for a sample of adult Danes registered in the official patient register. This is combined with detailed scanner data on food purchases, which are used as a proxy for dietary intake.PARTICIPANTS: 274 individuals in Denmark that are diagnosed during their participation in a consumer panel where they report their food purchases, and 16,395 individuals that are not diagnosed.RESULTS: Results suggest some changes in dietary composition following diagnosis, as measured by a Healthy Eating Index and for specific food groups and nutrients, although the long-term effects are limited. Socioeconomic characteristics are poor predictors of dietary changes following diagnosis. Change in diet following diagnosis vary with the pre-diagnosis consumption patterns, where individuals with relatively unhealthy overall diets prior to diagnosis improve overall healthiness more compared to individuals with relatively healthy diets prior to diagnosis.CONCLUSIONS: Adherence to dietary advice is low, on average, but there is large variation in behavioral change between the diagnosed individuals. Our results stress the difficulty for diagnosed individuals to shift dietary habits, particularly in the long term.

Aims: Physical activity improves glycaemic control in type 2 diabetes (T2D), but adherence is low, and diabetes complications are barriers towards adopting physical activity. We investigated adherence and effects of individualized supervised exercise. Methods: Patients with intermediate (level 2) to high (level 3) risk of complications to T2D (stratified by Danish risk stratification model) were offered 12 weeks of exercise. Primary outcomes were working capacity assessed with the Åstrand-Rhyming cycling test (Åstrand), functional capacity assessed with the 30-second chair-stand test (30 s-CST) and health-related quality of life assessed with EuroQoL-5D-5L (EQ-5D-5L). Associations between stratification levels (2 vs 3) and drop-out, changes in 30 s-CST and EQ-5D-5L were analysed using multiple regression. Results: In total 350 patients accepted participation and 254 (73%) completed with 26 patients experiencing an adverse event. Odds ratio (OR) for non-completion were 1.82 [1.02–3.23] (p = 0.043) for patients stratified level 3 vs 2. Improvements were seen in Åstrand 2.71 [1.59; 3.83] ml O2/kg/min (p < 0.001), in 30 s-CST 2.34 [2.01; 2.67] repetitions (p < 0.001) and in EQ-5D-5L 0.01 (−0.05 to 0.11) (p = 0.002). There were no associations between changes and risk-stratification levels. Conclusions: Clinically relevant changes were seen after exercising regardless of the stratification levels in patients with intermediate to high risk of complications to T2D.

Sulfonylureas (SUs) provide an efficacious first-line treatment in patients with hepatocyte nuclear factor 1 alpha (HNF1A) diabetes, but SUs have limitations due to risk of hypoglycemia. Treatment based on the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) is characterized by their glucose-dependent insulinotropic actions without risk of hypoglycemia. The effect of SUs together with GIP or GLP-1, respectively, on insulin and glucagon secretion in patients with HNF1A diabetes is currently unknown. To investigate this, 10HNF1Amutation carriers and 10 control subjects without diabetes were recruited for a double-blinded, placebo-controlled, crossover study including 6 experimental days in a randomized order involving 2-h euglycemic-hyperglycemic clamps with coadministration of:1) SU (glimepiride 1 mg) or placebo, combined with2) infusions of GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min), or saline (NaCl). InHNF1Amutation carriers, we observed:1) hypoinsulinemia,2) insulinotropic effects of both GIP and GLP-1,3) additive to supra-additive effects on insulin secretion when combining SU+GIP and SU+GLP-1, respectively, and4) increased fasting and arginine-induced glucagon levels compared with control subjects without diabetes. Our study suggests that a combination of SU and incretin-based treatment may be efficacious in patients with HNF1A diabetes via potentiation of glucose-stimulated insulin secretion.

OBJECTIVE Sulfonylureas are first-line treatment of hepatocyte nuclear factor 1-alpha (HNF1A) diabetes (maturity-onset diabetes of the young type 3), but many patients do not achieve optimal glycemic control without episodes of hypoglycemia. We investigated the combination of the sulfonylurea glimepiride and the dipeptidyl peptidase 4 inhibitor linagliptin versus glimepiride monotherapy with respect to glycemic variability, glycemic control, and risk of hypoglycemia. RESEARCH DESIGN AND METHODS In a randomized, double-blinded, crossover trial, patients with HNF1A diabetes (n= 19; mean +/- SD age 43 +/- 14 years, BMI 24.8 +/- 2.8 kg/m(2), and glycated hemoglobin [HbA(1c)] 7.4 +/- 0.2% [57.1 +/- 7.3 mmol/mol]) were randomly assigned to treatment with glimepiride + linagliptin 5 mg (16 weeks), washout (4 weeks), and glimepiride + placebo (16 weeks) (or vice versa). Glimepiride was titrated targeting a fasting plasma glucose of 4.5-6.0 mmol/L without hypoglycemia. Treatments were evaluated by continuous glucose monitoring (CGM), HbA(1c), and meal test. RESULTS Compared with glimepiride + placebo, glimepiride + linagliptin did not significantly improve the primary end point, mean amplitude of glycemic excursions (MAGE) (mean difference -0.7 mmol/L,P =0.1540), but displayed significant reductions in coefficient of variation on CGM (-3.6%,P =0.0401), HbA(1c)(-0.5%,P =0.0048), and glimepiride dose (-0.7 mg/day,P =0.0099). beta-cell glucose sensitivity (assessed as C-peptide-to-glucose ratio) during meal test improved with glimepiride + linagliptin. Incidences of hypoglycemia were similar with both treatments. CONCLUSIONS Linagliptin as add-on treatment to glimepiride improved glycemic variability and control without increasing risk of hypoglycemia in patients with HNF1A diabetes.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) affects about 25% of the population worldwide. NAFLD may be viewed as the hepatological manifestation of metabolic syndrome. Patients with metabolic syndrome due to diabetes or obesity have an increased risk of cardiovascular disease. This narrative review describes cardiometabolic effects of antidiabetic drugs in NAFLD.METHODS: We conducted a systematic search in PubMed and manually scanned bibliographies in trial databases and reference lists in relevant articles.RESULTS: Heart disease is the leading cause of death in NAFLD. Conversely, NAFLD is an independent cardiovascular risk factor in patients suffering from metabolic syndrome. NAFLD is associated with markers of atherosclerosis, and patients have increased risk of ischaemic heart disease. Additionally, patients with NAFLD have increased risk of cardiac dysfunction and heart failure. There are no randomized controlled trials showing clear effects of medical treatment on clinical outcomes in patients with NAFLD. However, based on evidence from small trials and extrapolation from trials evaluating patients with type 2 diabetes, some antidiabetic drugs may be beneficial on cardiovascular function in patients with NAFLD.CONCLUSION: At present, there is promising evidence of a potential effect of antidiabetic drugs for patients with NAFLD. Future studies should address the treatment of NAFLD and the liver-related consequences but also aim at improving the cardiometabolic outcomes.

INTRODUCTION: Hepatocyte nuclear factor 1α (HNF1A)-diabetes is the most common monogenetic subtype of diabetes. Strict glycaemic control is crucial for a good prognosis for patients with HNF1A-diabetes. Sulfonylurea (SU) is used as a first-line therapy in HNF1A-diabetes. However, SU therapy may be problematic as it confers a high risk of hypoglycaemia. We hypothesise that low dose of SU in combination with a dipeptidyl peptidase 4 inhibitor provides a safer and more efficacious treatment in patients with HNF1A-diabetes compared with SU as monotherapy.METHODS AND ANALYSIS: In a randomised, double-blinded, crossover study, patients with HNF1A-diabetes will randomly be assigned to 16 weeks of treatment with glimepiride+linagliptin, 4 weeks of washout and 16 weeks of treatment with glimepiride+placebo (or vice versa). Treatment will be evaluated with continuous glucose monitoring and combined meal and bicycle tests conducted at baseline and at the end of each of the two treatment periods. The primary end point is the absolute difference in the mean amplitude of glycaemic excursions between the two treatments (glimepiride+linagliptin vs glimepiride+placebo) at the end of each treatment period.ETHICS AND DISSEMINATION: The study protocol is approved by the Danish Medicines Agency, The Scientific-Ethical Committee of the Capital Region of Denmark (H-17014518) and the Danish Data Protection Agency. The trial will be carried out and monitored in compliance with Good Clinical Practice guidelines and in accordance with the latest version of the Declaration of Helsinki. Positive, negative and inconclusive results will be published at scientific conferences and as one or more scientific manuscripts in peer-reviewed journals with authorship in accordance with the International Committee of Medical Journal Editors' recommendations.TRIAL REGISTRATION NUMBER: 2017-000204-15.