Possible mechanism of the eating-inhibitory effect of DGAT-1-inhibition

Diese Arbeit untersucht den Einfluss eines molekularen Acyl-CoA:diacylglycerol acyltransferase-1-Inhibitors (DGAT1i01) auf die Nahrungsaufnahme und ob die Hemmung der Nahrungsaufnahme durch den Inhibitor auf einer Stimulation der Fettsäurenoxidation in den Darmepithelzellen beruht. In der ersten Studie wurde der Effekt einer akuten intragastralen (IG) Infusion des DGAT1i01 auf den Verzehr nach 16 h Futterentzug bei Ratten untersucht, die mit einer Standarddiät oder einer Hochfettdiät (HFD) gefüttert wurden (n=9). Dosen von 3 und 9 mg/kg DGAT1i01 reduzierten den Verzehr bei Fütterung mit der HFD, nicht jedoch bei Fütterung mit der Standarddiät signifikant (18 bzw. 21 %). Weiters konnten wir zeigen, dass die IG Infusion von DGAT1i01 (9 mg/kg) nach einer 5 g Testmahlzeit und nach 16 h Futterentzug die Serumkonzentration von TG sowie die Plasmakonzentrationen von Glyc und FFA reduzierte, während TG, Glyc und FFA nach Kontrollinfusion anstiegen. Ferner erhöhte die DGAT1i01-Infusion die Plasmakonzentration von BHB. Im dritten Experiment wurde nach 16 Stunden Futterentzug der Einfluss von IG DGAT1i01 (9 mg/kg) auf die Fettäurenoxidation in Darmepithelzellen überprüft. Die HFD-Testmahlzeit enthielt dazu 9.1 (w/w) % C17:0. Unter diesen Bedingungen liess sich kein signifikanter Effekt nachweisen, lediglich in dem am weitesten distal gelegenen Darmabschnitt war die Fettsäurenoxidation tendenziell erhöht. Insgesamt zeigen diese Daten, dass IG DGAT1i01 die Nahrungsaufnahme reduziert, wenn der Fettgehalt der Diät hoch ist. Die beobachteten metabolischen Effekte sind konsistent mit der Hypothese, dass eine Verschiebung von TG-Synthese zu Fettsäurenoxidation in Enterozyten und vielleicht auch in der Leber zu der beobachteten Verzehrsreduktion beiträgt.This thesis investigates the effects of a molecular Acyl-CoA:diacylglycerol acyltransferase-1-inhibitor (DGAT1i01) on food intake (FI) and whether the resulting eating inhibition is due to enhanced fatty acid oxidation (FAO) in small intestinal enterocytes. First, we investigated the effect of an acute IG DGAT1i01 infusion on FI in chow-fed and HFD-fed rats (n=9). Doses of 3 and 9 mg/kg DGAT1i01 significantly reduced FI 8 h after infusion in HFD-fed rats (18 % and 21 %, respectively), but not in chow-fed rats. Further, IG DGAT1i01 infusion (9 mg/kg) decreased serum TG, plasma Glyc and FFA levels after a 5 g HFD test meal in 16 h-fasted rats (n=8), whereas TG, Glyc and FFA levels were increased in response to vehicle infusion. Also, DGAT1i01 increased plasma BHB levels compared to vehicle. In the last experiment the effect of IG DGAT1i01 (9 mg/kg) infusion on mucosal FAO in 16 h-fasted and re-fed rats (n=16) (5 g HFD test meal including 9.1(w/w) % C17:0) was investigated. However, under the conditions tested, we could not find a significant difference in intestinal epithelial cell FAO compared to vehicle administration; there seemed to be only a tendency for increased FAO, in particular in the most distal intestine mucosa sections. The data show that an IG administrated DGAT1-inhibitor decreases FI in rats when the dietary fat content is high and suggest that a shift from TG synthesis to FAO in enterocytes and, perhaps, in liver is the underlying mechanism of the observed eating-inhibitory effect

Association of insulin-manipulation and psychiatric disorders : A systematic epidemiological evaluation of adolescents with type 1 diabetes in Austria

Background/Objective The aim of this study was to systematically assess the association of insulinmanipulation (intentional under and/or overdosing of insulin), psychiatric comorbidity and diabetes complications. Methods Two diagnostic interviews (DiabetesSelfManagementPatientInterview and Children'sDiagnosticInterview for Psychiatric Disorders) were conducted with 241 patients (age 1022) with type 1 diabetes (T1D) from 21 randomly selected Austrian diabetes care centers. Medical data was derived from medical records. Results Psychiatric comorbidity was found in nearly half of the patients with insulinmanipulation (46.3%) compared to a rate of 17.5% in patients, adherent to the prescribed insulin therapy. Depression (18.3% vs 4.9%), specific phobia (21.1% vs 2.9%), social phobia (7.0% vs 0%), and eating disorders (12.7% vs 1.9%) were elevated in patients with insulinmanipulation. Females (37.7%) were more often diagnosed (P = 0.001) with psychiatric disorders than males (18.4%). In females, the percentage of psychiatric comorbidity significantly increased with the level of nonadherence to insulin therapy. Insulinmanipulation had an effect of +0.89% in HbA1c (P = <0.001) compared to patients adherent to insulin therapy, while there was no association of psychiatric comorbidity with metabolic control (HbA1c 8.16% vs 8.12% [65.68 vs 65.25 mmol/mol]). Ketoacidosis, severe hypoglycemia, and frequency of outpatient visits in a diabetes center were highest in patients with insulinmanipulation. Conclusions This is the first study using a systematic approach to assess the prevalence of psychiatric disorders in patients who do or do not manipulate insulin in terms of intentional under and/or overdosing. Internalizing psychiatric disorders were associated with insulinmanipulation, especially in female patients and insulinmanipulation was associated with deteriorated metabolic control and diabetes complications.(VLID)341189