Short Bowel Patients Treated for Two Years with Glucagon-Like Peptide 2: Effects on Intestinal Morphology and Absorption, Renal Function, Bone and Body Composition, and Muscle Function

Background and aims. In a short-term study, Glucagon-like peptide 2 (GLP-2) has been shown to improve intestinal absorption in short bowel syndrome (SBS) patients. This study describes longitudinal changes in relation to GLP-2 treatment for two years. Methods. GLP-2, 400 micrograms, s.c.,TID, were offered, to eleven SBS patients keeping parenteral support constant. 72-hour nutritional balance studies were performed at baseline, weeks 13, 26, 52 during two years intermitted by an 8-week washout period. In addition, mucosal morphometrics, renal function (by creatinine clearance), body composition and bone mineral density (by DEXA), biochemical markers of bone turnover (by s-CTX and osteocalcin, PTH and vitamin D), and muscle function (NMR, lungfunction, exercise test) were measured. Results. GLP-2 compliance was >93%. Three of eleven patients did not complete the study. In the remaining 8 patients, GLP-2 significantly reduced the fecal wet weight from approximately 3.0 to approximately 2.0 kg/day. This was accompanied by a decline in the oral wet weight intake, maintaining intestinal wet weight absorption and urinary weight constant. Renal function improved. No significant changes were demonstrated in energy intake or absorption, and GLP-2 did not significantly affect mucosal morphology, body composition, bone mineral density or muscle function. Conclusions. GLP-2 treatment reduces fecal weight by approximately 1000 g/d and enables SBS patients to maintain their intestinal fluid and electrolyte absorption at lower oral intakes. This was accompanied by a 28% improvement in creatinine clearance

Short Bowel Patients Treated for Two Years with Glucagon-Like Peptide 2 (GLP-2): Compliance, Safety, and Effects on Quality of Life

Background and aims. Glucagon-like peptide 2 (GLP-2) has been shown to improve intestinal absorption in short bowel syndrome (SBS) patients in a short-term study. This study describes safety, compliance, and changes in quality of life in 11 SBS patients at baseline, week 13, 26, and 52 during two years of subcutaneous GLP-2 treatment, 400 microgram TID, intermitted by an 8-week washout period. Methods. Safety and compliance was evaluated during the admissions. The Sickness Impact Profile (SIP), Short Form 36 (SF 36), and Inflammatory Bowel Disease Questionnaire (IBDQ) evaluated quality of life. Results. The predominant adverse event was transient abdominal discomfort in 5 of 11 patients, but in 2, both suffering from Crohns disease, it progressed to abdominal pain and led to discontinuation of GLP-2 treatment. One had a fibrostenotic lesion electively resected at the jejuno-ascendo-anastomosis. The investigator excluded a patient due to unreliable feedback. Stoma nipple enlargement was seen in all 9 jejunostomy patients. Reported GLP-2 compliance was excellent (>93%). GLP-2 improved the overall quality of life VAS-score (4.1 ± 2.8 cm versus 6.0 ± 2.4 cm, P < .01), the overall SIP score (10.3 ± 8.9% versus 6.2 ± 9.5%, P < .001), the mental component of the SF-36 (45 ± 13% versus 53 ± 11%, P < .05), and the overall IBDQ score (5.1 ± 0.9 versus 5.4 ± 0.9, P < .007) in the 8 patients completing the study. Conclusions. Long-term treatment with GLP-2 is feasible in SBS patients, although caution must be exercised in patients with a history of abdominal pain. Although conclusions cannot be made in a noncontrolled trial, the high reported compliance might reflect a high treatment satisfaction, where the clinical benefits of GLP-2 may outweigh the discomforts of injections

Regulation of glycolysis in brown adipocytes by HIF-1α

Brown adipose tissue takes up large amounts of glucose during cold exposure in mice and humans. Here we report an induction of glucose transporter 1 expression and increased expression of several glycolytic enzymes in brown adipose tissue from cold-exposed mice. Accordingly, these genes were also induced after β-adrenergic activation of cultured brown adipocytes, concomitant with accumulation of hypoxia inducible factor-1α (HIF-1α) protein levels. HIF-1α accumulation was dependent on uncoupling protein 1 and generation of mitochondrial reactive oxygen species. Expression of key glycolytic enzymes was reduced after knockdown of HIF-1α in mature brown adipocytes. Glucose consumption, lactate export and glycolytic capacity were reduced in brown adipocytes depleted of Hif-1α. Finally, we observed a decreased β-adrenergically induced oxygen consumption in Hif-1α knockdown adipocytes cultured in medium with glucose as the only exogenously added fuel. These data suggest that HIF-1α-dependent regulation of glycolysis is necessary for maximum glucose metabolism in brown adipocytes.ISSN:2045-232

Global gene expression profiling of brown to white adipose tissue transformation in sheep reveals novel transcriptional components linked to adipose remodeling

BACKGROUND: Large mammals are capable of thermoregulation shortly after birth due to the presence of brown adipose tissue (BAT). The majority of BAT disappears after birth and is replaced by white adipose tissue (WAT). RESULTS: We analyzed the postnatal transformation of adipose in sheep with a time course study of the perirenal adipose depot. We observed changes in tissue morphology, gene expression and metabolism within the first two weeks of postnatal life consistent with the expected transition from BAT to WAT. The transformation was characterized by massively decreased mitochondrial abundance and down-regulation of gene expression related to mitochondrial function and oxidative phosphorylation. Global gene expression profiling demonstrated that the time points grouped into three phases: a brown adipose phase, a transition phase and a white adipose phase. Between the brown adipose and the transition phase 170 genes were differentially expressed, and 717 genes were differentially expressed between the transition and the white adipose phase. Thirty-eight genes were shared among the two sets of differentially expressed genes. We identified a number of regulated transcription factors, including NR1H3, MYC, KLF4, ESR1, RELA and BCL6, which were linked to the overall changes in gene expression during the adipose tissue remodeling. Finally, the perirenal adipose tissue expressed both brown and brite/beige adipocyte marker genes at birth, the expression of which changed substantially over time. CONCLUSIONS: Using global gene expression profiling of the postnatal BAT to WAT transformation in sheep, we provide novel insight into adipose tissue plasticity in a large mammal, including identification of novel transcriptional components linked to adipose tissue remodeling. Moreover, our data set provides a useful resource for further studies in adipose tissue plasticity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-1405-8) contains supplementary material, which is available to authorized users

Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes

BACKGROUND: Increased adipose thermogenesis is being considered as a strategy aimed at preventing or reversing obesity. Thus, regulation of the uncoupling protein 1 (UCP1) gene in human adipocytes is of significant interest. Retinoic acid (RA), the carboxylic acid form of vitamin A, displays agonist activity toward several nuclear hormone receptors, including RA receptors (RARs) and peroxisome proliferator-activated receptor δ (PPARδ). Moreover, RA is a potent positive regulator of UCP1 expression in mouse adipocytes. RESULTS: The effects of all-trans RA (ATRA) on UCP1 gene expression in models of mouse and human adipocyte differentiation were investigated. ATRA induced UCP1 expression in all mouse white and brown adipocytes, but inhibited or had no effect on UCP1 expression in human adipocyte cell lines and primary human white adipocytes. Experiments with various RAR agonists and a RAR antagonist in mouse cells demonstrated that the stimulatory effect of ATRA on UCP1 gene expression was indeed mediated by RARs. Consistently, a PPARδ agonist was without effect. Moreover, the ATRA-mediated induction of UCP1 expression in mouse adipocytes was independent of PPARγ coactivator-1α. CONCLUSIONS: UCP1 expression is differently affected by ATRA in mouse and human adipocytes. ATRA induces UCP1 expression in mouse adipocytes through activation of RARs, whereas expression of UCP1 in human adipocytes is not increased by exposure to ATRA

The multicovering radius problem for some types of discrete structures

The covering radius problem is a question in coding theory concerned with finding the minimum radius $r$ such that, given a code that is a subset of an underlying metric space, balls of radius $r$ over its code words cover the entire metric space. Klapper introduced a code parameter, called the multicovering radius, which is a generalization of the covering radius. In this paper, we introduce an analogue of the multicovering radius for permutation codes (cf. Keevash and Ku, 2006) and for codes of perfect matchings (cf. Aw and Ku, 2012). We apply probabilistic tools to give some lower bounds on the multicovering radii of these codes. In the process of obtaining these results, we also correct an error in the proof of the lower bound of the covering radius that appeared in Keevash and Ku (2006). We conclude with a discussion of the multicovering radius problem in an even more general context, which offers room for further research.Comment: To appear in Designs, Codes and Cryptography (2012