AMPK (AMP-activated protein kinase) has been suggested to be a central player regulating FA (fatty acid) metabolism through its ability to regulate ACC (acetyl-CoA carboxylase) activity. Nevertheless, its involvement in insulin resistance- and TD2 (Type 2 diabetes)-associated dyslipidaemia remains enigmatic. In the present study, we employed the Psammomys obesus gerbil, a well-established model of insulin resistance and TD2, in order to appreciate the contribution of the AMPK/ACC pathway to the abnormal hepatic lipid synthesis and increased lipid accumulation in the liver. Our investigation provided evidence that the development of insulin resistance/diabetic state in P. obesus is accompanied by (i) body weight gain and hyperlipidaemia; (ii) elevations of hepatic ACC-Ser79 phosphorylation and ACC protein levels; (iii) a rise in the gene expression of cytosolic ACC1 concomitant with invariable mitochondrial ACC2; (iv) an increase in hepatic AMPKalpha-Thr172 phosphorylation and protein expression without any modification in the calculated ratio of phospho-AMPKalpha to total AMPKalpha; (v) a stimulation in ACC activity despite increased AMPKalpha phosphorylation and protein expression; and (vi) a trend of increase in mRNA levels of key lipogenic enzymes [SCD-1 (stearoyl-CoA desaturase-1), mGPAT (mitochondrial isoform of glycerol-3-phosphate acyltransferase) and FAS (FA synthase)] and transcription factors [SREBP-1 (sterol-regulatory-element-binding protein-1) and ChREBP (carbohydrate responsive element-binding protein)]. Altogether, our findings suggest that up-regulation of the AMPK pathway seems to be a natural response in order to reduce lipid metabolism abnormalities, thus supporting the role of AMPK as a promising target for the treatment of TD2-associated dyslipidaemia.

Insulin resistance and type 2 diabetes (T2D) are characterized by hyperlipidemia. The aim of the present study was to elucidate whether T2D contributes to abnormal cholesterol (CHOL) homeostasis. Experiments were carried out in the small intestine and liver of Psammomys obesus, a model of nutritionally induced T2D. Our results show that diabetic animals exhibited a lower intestinal CHOL uptake, which was associated with a decrease in 1) the gene and protein expression of Niemann-Pick C1 like 1 that plays a pivotal role in CHOL incorporation in the enterocytes; and 2) mRNA of ATP-binding cassette transporters (ABC)A1 that mediates CHOL efflux from intestinal cells to apolipoprotein A-I and high-density lipoprotein. No changes were observed in the other intestinal transporters scavenger receptor-class B type I (SR-BI) and annexin 2. On the other hand, in diabetic animals, a significant mRNA decrease was noticed in intestinal ABCG5 and ABCG8 responsible for the secretion of absorbed CHOL back into the lumen. Furthermore, jejunal PCSK9 protein was diminished and low-density lipoprotein receptor was raised, along with a significant down-regulation in jejunal 3-hydroxy-3-methylglutaryl-coenzyme A reductase in P. obesus with T2D. Finally, among the transcription factors tested, only an increase in liver X receptors alpha and a decrease in peroxisome proliferator-activated receptors delta/beta mRNAs were detected in the intestine. In the liver, there was 1) an augmentation in the protein mass of Niemann-Pick C1 like 1, SR-BI, and annexin 2; 2) an up-regulation of SR-BI mRNA; 3) a fall in ABCG8 protein content as well as in ABCG5 and ABCA1 mRNA; and 4) an augmentation in liver X receptors alpha and peroxisome proliferator-activated receptors beta/delta mRNA, together with a drop in sterol regulatory element binding protein-2 protein. Our findings show that the development in P. obesus with T2D modifies the whole intraenterocyte and hepatocyte machinery responsible for CHOL homeostasis.

Objectives and hypothesesAdherence to inhaled corticosteroids (ICS) is a major issue in asthma. This study aimed to estimate the accuracy of the days’ supply and number of refills allowed, variables recorded in Québec claims databases and used to estimate adherence, and to develop correction factors, if required. We hypothesised that the accuracy of the days’ supply for ICS would be low whereas the accuracy of the number of refills allowed would be high.Setting40 community pharmacies in Québec (Canada) and a medication registry.ParticipantsWe collected data for 1108 ICS original prescriptions stored in the 40 pharmacies (sample 1), and we obtained a second sample of 2676 ICS prescriptions selected from reMed, a medication registry (sample 2).Primary and secondary outcomesWe estimated the concordance of the days’ supply and number of refills between Québec claims databases and the original prescription from sample 1. We developed a correction factor for the days’ supply in sample 1 and validated it in sample 2. Analyses were stratified by age: 0–11 and 12–64 years.ResultsIn sample 1, the concordance for the days’ supply was 39.6% (95% CI 37.6% to 41.6%) in those aged 0–11 years and 56% (54.9% to 57.2%) in those aged 12–64 years. The concordance increased to 59.4% (58.2% to 60.5%) in those aged 0–11 years and 74.2% (73.5% to 74.9%) in those aged 12–64 years after applying the correction factors in sample 2. The concordance for the refills allowed was 92.1% (91% to 93.1%) in those aged 0–11 years and 93.1% (92.5% to 93.7%) in those aged 12–64 years in sample 1.ConclusionsThe accuracy of the days’ supply was moderate among those aged 0–11 years and substantial among those aged 12–64 years after applying the correction factors. The accuracy of the number of refills was almost perfect in both groups.