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Abstract: Prolonged exposure of pancreatic beta-cells to elevated levels of glucose and fatty acids adversely affects insulin secretion and gene expression. Aim: To examine whether the GLP-1 agonist exenatide or the inhibitor of the GLP-1-degrading enzyme dipeptidyl peptidase 4 (DPP-4) sitagliptin rescue insulin gene expression in rats infused for 72h with glucose+Intralipid, independently from their glucose-lowering action. Methods: Wistar rats were infused alternatively with glucose or Intralipid for cycles of 4h each for a total of 72h. The animals received exenatide (5μg/kg/day IV) or sitagliptin (5mg/kg/day IV) continuously starting 4 days prior to and continuing throughout the 3-day infusion period. Results: Plasma glucose, fatty acids, insulin and C-peptide levels were unaffected by exenatide or sitagliptin treatment during the infusion period. Insulin mRNA levels increased in response to the glucose infusion, but this increase was abolished in islets from rats receiving glucose+Intralipid. Neither exenatide nor sitagliptin administration rescued insulin mRNA in glucose+Intralipid infused rats. Conclusions: Neither a GLP-1 agonist nor a DPP-4 inhibitor, at doses that do not alter blood glucose levels, prevented the inhibition of insulin gene expression in this in vivo model of glucolipotoxicity. [Copyright &y& Elsevier]

Reduced lipolysis in hormone-sensitive lipase-deficient mice is associated with impaired glucose-stimulated insulin secretion (GSIS), suggesting that endogenous a-cell lipid stores provide signaling molecules for insulin release. Measurements of lipolysis and triglyceride (TG) lipase activity in islets from HSL[sup-/-] mice indicated the presence of other TG lipase(s) in the β-cell. Using real time-quantitative PCR, adipose triglyceride lipase (ATGL) was found to be the most abundant TG lipase in rat islets and INS832/13 cells. To assess its role in insulin secretion, ATGL expression was decreased in INS832/13 cells (ATGL-knockdown (KD)) by small hairpin RNA. ATGL-KD increased the esterification of free fatty acid (FFA) into TG. ATGL-KD cells showed decreased glucoseor Gln + Leu-induced insulin release, as well as reduced response to KCI or palmitate at high, but not low, glucose. The KATP-independent/amplification pathway of GSIS was considerably reduced in ATGL-KD cells. ATGL[sup-/-] mice were hypoinsulinemic and hypoglycemic and showed decreased plasma TG and FFAs. A hyperglycemic clamp revealed increased insulin sensitivity and decreased GSIS and arginine-induced insulin secretion in ATGL[sup-/-] mice. Accordingly, isolated islets from ATGL[sup-/-] mice showed reduced insulin secretion in response to glucose, glucose + palmitate, and KCI. Islet TG content and FFA esterification into TG were increased by 2-fold in ATGL[sup-/-] islets, but glucose usage and oxidation were unaltered. The results demonstrate the importance of ATGL and intracellular lipid signaling for fueland nonfuel-induced insulin secretion. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to quantify the association between receiving care-coach calls (CCCs), a service provided by a patient-support program (PSP) in Canada, and persistence with and adherence to adalimumab therapy over a 3-year period in patients with immune-related inflammatory diseases (IMID). Methods COMPANION, a longitudinal, retrospective cohort study, was conducted using patient-level data from the PSP combined with those from a longitudinal pharmacy-transaction database in patients initiating adalimumab therapy between 2010 and 2012. Patients aged ≥18 years who were naive to adalimumab therapy were selected, and data from their prescriptions from 36 months or until drug discontinuation, defined as >90 days without drug supply, were evaluated. Cox proportional hazards modeling was used to estimate hazard ratios for the association between persistence, and patient characteristics and PSP services. Adherence was measured using the medication possession ratio. Multivariate logistic regression was used to estimate adjusted odds ratios to determine the relationship between adherence (medication possession ratio ≥80%), and patient characteristics and PSP services. Findings A total 4772 patients were included (55% women; 24% aged 50–59 years). Of these, 2866 qualified for the persistence analysis, and 51% received CCCs (n = 1452). Of the 4772 patients, 4630 qualified for the adherence analysis, and 33% received CCCs (n = 1511). Baseline characteristics were similar between the group that received CCCs versus the group that did not. During the follow-up period, patients who received CCCs had a significantly reduced risk for treatment discontinuation (hazard ratio = 0.350; 95% CI, 0.298–0.413; P < 0.0001) and a greater likelihood of being adherent (odds ratio, 2.248; 95% CI, 1.927–2.624; P < 0.0001). Implications CCCs were associated with greater adherence and improved persistence in these patients receiving adalimumab therapy over a 3-year period for IMID. [ABSTRACT FROM AUTHOR]

Purpose Adalimumab (ADA) is a tumor necrosis factor-α inhibitor indicated for use in various immune-mediated inflammatory diseases. Patients receiving ADA in Canada are eligible to enroll in the AbbVie Care's Patient Support Program (PSP), which provides personalized services, including tailored interventions in the form of nurse-provided care coach calls (CCCs), with the goal of improving patients' experiences and outcomes. The primary objective of this study was to evaluate the impact of PSP services, including CCCs and patient characteristics, on persistence with and adherence to ADA for those patients enrolled in the PSP. A secondary objective was to estimate the effect of initial CCCs on treatment-initiation abandonment (ie, failure to initiate therapy after enrollment in the PSP). Methods An observational retrospective cohort study was conducted. A patient linkage algorithm based on probabilistic matching was developed to link the AbbVie Care PSP database to the QuintilesIMS longitudinal pharmacy transaction database. Patients who started ADA therapy between July 2010 and August 2014 were selected, and their prescriptions were evaluated for 12 months after the date of ADA start to calculate days until drug discontinuation, that is, the end of persistence, defined as >90 days without therapy. Cox proportional hazards modeling was used for estimating hazard ratios for the association between persistence and patient characteristics and each PSP service. Adherence, measured by medication possession ratio, was calculated, and multivariate logistic regression provided adjusted odds ratios for the relationship between being adherent (medication possession ratio ≥80%) and patient characteristics and each PSP service. Treatment-initiation abandonment among patients who received an initial CCC compared with those who did not was analyzed using the χ 2 test. Findings Analysis of 10,857 linked patients yielded statistically significant differences in the hazard ratio of discontinuation and the likelihood of being adherent across multiple variables between patients who received CCCs in comparison to patients who did not. Patients receiving CCCs were found to have a 72% decreased risk for therapy discontinuation (hazard ratio = 0.282; P < 0.0001), and a greater likelihood of being adherent (odds ratio = 1.483; P < 0.0001), when compared with those patients who did not receive CCCs. The rate of treatment-initiation abandonment was significantly higher in patients who did not receive initial CCCs ( P < 0.0001). Implications Ongoing CCCs, provided by AbbVie Care PSP, were associated with greater patient persistence and adherence over the first 12 months of treatment, while initial CCCs were associated with a lower rate of treatment-initiation abandonment. Results may inform the planning of interventions aimed at improving treatment adherence and patient outcomes. [ABSTRACT FROM AUTHOR]