The dietary regulation of LEAP2 depends on meal composition in mice.

Ghrelin represents a key hormone regulating energy balance. Upon activation of the growth hormone secretagogue receptor (GHSR), ghrelin increases blood glucose levels, food intake, and promotes weight gain. The liver-expressed antimicrobial peptide 2 (LEAP2) acts as an endogenous antagonist of the GHSR. While the regulation of LEAP2 and its effect on the GHSR likely occur in an opposite pattern to that of ghrelin, the dietary regulation of LEAP2 remains to be described. We, therefore, examined the regulation of LEAP2 by different acute meal challenges (glucose, mixed meal, olive, lard, and fish oil) and diets (chow vs. high-fat) in C57BL/6 male mice. In addition, the effect of specific fatty acids (oleic, docosahexaenoic, and linoleic acid) on LEAP2 was assessed in murine intestinal organoids. While only mixed meal increased liver Leap2 expression, all meal challenges except fish oil increased jejunal Leap2 expression compared to water. Leap2 expression correlated with levels of hepatic glycogen and jejunal lipids. Lipid versus water dosing increased LEAP2 levels in the systemic circulation and portal vein where fish oil was associated with the smallest increase. In line with this, oleic acid, but not docosahexaenoic acid increased Leap2 expression in intestinal organoids. Feeding mice with high-fat versus chow diet not only increased plasma LEAP2 levels, but also the increment in plasma LEAP2 upon dosing with olive oil versus water. Taken together, these results show that LEAP2 is regulated by meal ingestion in both the small intestine and the liver according to the meal/diet of interest and local energy stores.

LEAP2 is associated with cardiometabolic markers but is unchanged by antidiabetic treatment in people with prediabetes.

To examine whether fasting plasma liver-expressed antimicrobial peptide 2 (FP-LEAP2) is associated with markers of cardiometabolic disease susceptibility in a cohort with prediabetes and overweight/obesity and whether antidiabetic interventions affect FP-LEAP2 levels. The analysis included 115 individuals with prediabetes [hemoglobin A1c (HbA1c) 39-47 mmol/mol, 5.7%-6.4%] and overweight/obesity [body mass index (BMI) ≥ 25 kg/m2] from a randomized controlled trial. Changes in FP-LEAP2 levels were assessed in relation to treatment with dapagliflozin (10 mg once daily), metformin (1,700 mg daily), or interval-based exercise (5 days/wk, 30 min/session) compared with control (habitual lifestyle) after 6 and 13 wk of treatment. FP-LEAP2 levels were positively associated with [standardized beta coefficient (95% CI)]: BMI 0.22 (0.03:0.41), P = 0.027; body weight 0.27 (0.06:0.48), P = 0.013; fat mass 0.2 (0.00:0.4), P = 0.048; lean mass 0.47 (0.13:0.8), P = 0.008; HbA1c 0.35 (0.17:0.53), P < 0.001; fasting plasma glucose (FPG) 0.32 (0.12:0.51), P = 0.001; fasting serum insulin 0.28 (0.09:0.47), P = 0.005; total cholesterol 0.19 (0.01:0.38), P = 0.043; triglycerides 0.31 (0.13:0.5), P < 0.001; and transaminases and fatty liver index (standardized beta coefficients 0.23-0.32), all P < 0.020. FP-LEAP2 levels were inversely associated with insulin sensitivity [-0.22 (-0.41: -0.03), P = 0.022] and kidney function [estimated glomerular filtration rate (eGFR) -0.34 (-0.56: -0.12), P = 0.003]. FP-LEAP2 levels were not associated with fat distribution or body fat percentage, fasting glucagon, postload glucose, ß-cell function, or low-density lipoprotein. The interventions were not associated with changes in FP-LEAP2. FP-LEAP2 is associated with body mass, impaired insulin sensitivity, liver-specific enzymes, and kidney function. The findings highlight the importance of studying LEAP2 in obesity, type 2 diabetes, and nonalcoholic fatty liver disease. FP-LEAP2 was not affected by metformin, dapaglifloxin, or exercise in this population.NEW & NOTEWORTHY LEAP2, primarily secreted by the liver, increases with greater body mass, insulin resistance, and liver-specific enzymes in individuals with prediabetes and overweight or obesity. Fasting glucose, body mass, and alanine aminotransferase independently predict LEAP2 levels. LEAP2 is inversely linked to impaired kidney function. Elevated LEAP2 levels might indicate an increased metabolic risk, warranting further investigation into its potential involvement in glucose and body weight control.

Necrotizing fasciitis and meningitis due to Streptococcus pneumoniae serotype 9 N: a case report.

BACKGROUND: Necrotizing fasciitis is a deep infection of the fascia and subcutaneous tissue with a high mortality rate. Meningitis is an infection of the membranes surrounding the brain with a likewise high mortality rate. Streptococcus pneumoniae is the most frequent cause of bacterial meningitis and it is an extremely rare cause of necrotizing fasciitis. Different subcapsular serotypes of S. pneumoniae are known to have diverse virulence. The serotype 9 N is associated with a high risk of death. CASE PRESENTATION: We report a case of a previously healthy 68-year-old female who presented at our clinic with complaints of pain in her left calf since having experienced a very painful leg cramp 3 weeks prior. Within a few hours after admission, she developed fever, neck stiffness and an altered mental state. Concurrently, the pain in her leg worsened. Upon further examination it was found that she suffered from both meningitis and necrotizing fasciitis due to S. pneumoniae, serotype 9 N. The patient survived and avoided leg amputation. CONCLUSIONS: The patient suffered from two very lethal infections simultaneously. Both of them were caused by S. pneumoniae. We believe that her favorable outcome was, a result of prompt surgical intervention and appropriate antibiotic treatment. Our case underlines the importance of continuous reevaluation of the symptoms and clinical findings in patients with unclear causes of severe illness, especially if the patient's condition changes.

LEAP2 reduces postprandial glucose excursions and ad libitum food intake in healthy men.

The gastric hormone ghrelin stimulates food intake and increases plasma glucose through activation of the growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) has been proposed to inhibit actions of ghrelin through inverse effects on GHSR activity. Here, we investigate the effects of exogenous LEAP2 on postprandial glucose metabolism and ad libitum food intake in a randomized, double-blind, placebo-controlled, crossover trial of 20 healthy men. We report that LEAP2 infusion lowers postprandial plasma glucose and growth hormone concentrations and decreases food intake during an ad libitum meal test. In wild-type mice, plasma glucose and food intake are reduced by LEAP2 dosing, but not in GHSR-null mice, pointing to GHSR as a potential mediator of LEAP2's glucoregulatory and appetite-suppressing effects in mice.

Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity.

Context: Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective. Objective: To investigate the safety and efficacy of Tesomet (0.5 mg tesofensine/50 mg metoprolol) in adults with hypothalamic obesity. Methods: Twenty-one adults with hypothalamic obesity (16 females) were randomized to Tesomet (0.5 mg/50 mg) or placebo for 24 weeks. Patients also received diet/lifestyle counselling. The primary endpoint was safety; secondary endpoints included measures of body weight, appetite scores, quality of life, and metabolic profile. Results: Eighteen patients completed 24 weeks. Consent withdrawal, eligibility, and serious adverse events (SAE) unrelated to treatment resulted in dropouts. One patient experienced a Tesomet-related SAE of exacerbated pre-existing anxiety leading to treatment discontinuation. Tesomet-related adverse events were otherwise mostly mild and included sleep disturbances (Tesomet 50%, placebo 13%), dry mouth (Tesomet 43%, placebo 0%), and headache (Tesomet 36%, placebo 0%). No significant differences in heart rate or blood pressure were observed between groups. Compared to placebo, Tesomet resulted in additional mean (95% CI) weight change of -6.3% ((-11.3; -1.3); P = 0.017), increased the number of patients achieving ≥5% weight loss (Tesomet 8/13, placebo 1/8; P = 0.046), and tended to augment the reduction in waist circumference by 5.7 cm ((-0.1; 11.5); P = 0.054). Conclusion: Tesomet was welltolerated, did not affect heart rate or blood pressure, and resulted in significant reductions in body weight compared to placebo in adults with hypothalamic obesity.

Metabolic effects of dopamine agonists in patients with prolactinomas: a systematic review and meta-analysis.

OBJECTIVES: Recent large cohort studies suggest an association between high plasma prolactin and cardiovascular mortality. The objective of this systematic review was to systematically assess the effect of reducing prolactin with dopamine agonist on established cardiovascular risk factors in patients with prolactinomas. DESIGN: Bibliographical search was done until February 2019 searching the following databases: PubMed, EMBASE, WHO and LILAC. Eligible studies had to include participants with verified prolactinomas where metabolic variables were assessed before and after at least 2 weeks treatment with dopamine agonists. METHODS: Baseline data and outcomes were independently collected by two investigators. The study was registered with PROSPERO (registration number CRD42016046525). RESULTS: Fourteen observational studies enrolling 387 participants were included. The pooled standardized mean difference of the primary outcome revealed a reduction of BMI and weight of -0.21 (95% CI -0.37 to -0.05; P = 0.01; I2 = 71%), after treatment. Subgroup analysis suggested that the reduction of weight was primarily driven by studies with high prolactin levels at baseline (P = 0.04). Secondary outcomes suggested a small decrease in waist circumference, a small-to-moderate decrease in triglycerides, fasting glucose levels, HOMA-IR, HbA1c and hsCRP, and a moderate decrease in LDL, total cholesterol and insulin. CONCLUSION: This systematic review suggests a reduction of weight as well as an improved lipid profile and glucose tolerance after treatment with dopamine agonist in patients with prolactinomas. These data are based on low-quality evidence.

Clinical improvement in a patient with monostotic melorheostosis after treatment with denosumab: a case report.

BACKGROUND: A 20-year-old Danish woman with melorheostosis in her right femoral shaft and disabling pain in the affected area, whose symptoms did not in the long term respond to zoledronic acid, experienced continuous remission of pain after treatment with denosumab. To the best of our knowledge, this is the first case report on denosumab treatment for melorheostosis. CASE PRESENTATION: Radiologic findings and bone biopsy showed irregular cortical hyperostosis in the right femoral shaft with increased tracer uptake on Tc99-bone scan. The diagnosis of melorheostosis was made based on the radiological findings. There was a good initial response to zoledronic acid administration, but after relapse of pain, the second and third administrations had a poor effect. As a second line of treatment denosumab was administered at 8-week intervals, the frequency was based on our patient's symptoms and on biochemical markers of bone turnover. CONCLUSION: This is the first report indicating that denosumab has a place in the treatment of melorheostosis when the effect of bisphosphonate treatment is insufficient.