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OBJECTIVES: Diabetes secondary to chronic pancreatitis (CP) presents clinical challenges due to insulin secretory defects and associated metabolic alterations. Owing to lack of molecular understanding, no pharmacotherapies to treat insulin secretory defects have been approved to date. We aimed to delineate the molecular mechanism of ß-cell dysfunction in CP. METHODS: Transcriptomic analysis was conducted to identify endocrine specific receptor expression in mice and human CP on microarray. The identified receptor (NR4A1) was overexpressed in MIN6 cells using PEI linear transfection. RNA-Seq analysis on NovaSeq 6000 of NR4A1 overexpressed (OE) MIN6 cells was performed to identify aberrant metabolic pathways. Upstream trigger for NR4A1OE was studied by InBio Discover and cytokine exposure. Downstream effect of NR4A1OE was examined by Fura2 AM based fluorometric and imaging studies of intracellular calcium. Mice with CP were treated with IFN-γ neutralizing monoclonal antibodies to assess NR4A1 expression and insulin secretion. RESULTS: Increased expression of NR4A1 associated with decreased insulin secretion in islets (humans: controls 9 ± 0.2, CP 3.7 ± 0.2, mice: controls 8.5 ± 0.2, CP 2.1 ± 0.1 µg/L). NR4A1OE in MIN6 cells (13.2 ± 0.1) showed reduction in insulin secretion (13 ± 5 to 0.2 ± 0.1 µg/mg protein/minute, p = 0.001) and downregulation of calcium and cAMP signaling pathways. IFN-γ was identified as upstream signal for NR4A1OE in MIN6. Mice treated with IFN-γ neutralizing antibodies showed decreased NR4A1 expression 3.4 ± 0.11-fold (p = 0.03), improved insulin secretion (4.4 ± 0.2-fold, p = 0.01), associated with increased Ca2+ levels (2.39 ± 0.06-fold, p = 0.009). CONCLUSIONS: Modulating NR4A1 expression can be a promising therapeutic strategy to improve insulin secretion in CP.
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INTRODUCTION: Alogliptin is a pyrimidinedione-based potent and selective inhibitor of DPP IV that was discovered by Syrrx (Takeda San Diego) for the treatment of type 2 diabetes mellitus (T2D). Alogliptin is currently launched in Japan with the results of its clinical trials indicating that it is generally well tolerated and shows relatively fewer adverse side effects than other existing therapies for T2D. AREAS COVERED: The objective of the present review is to provide an overview of the various stages of preclinical development, for example, design, molecular modeling studies, synthesis and in vitro/in vivo pharmacological evaluation of alogliptin. An extensive literature search was conducted to collect abstracts, publications, patents and presentations from various sources. The authors review the information related to the preclinical development of alogliptin and summarize and present the relevant results. EXPERT OPINION: Alogliptin has shown greater in vitro selectivity for DPP IV over closely related enzymes, including DPP VIII and DPP IX, in comparison with other launched DPP IV inhibitors such as sitagliptin, saxagliptin and vildagliptin. Alogliptin has been evaluated in different diabetic animal models and is found to reduce glycosylated hemoglobin, plasma glucose, glucagon and triglycerides levels. Alogliptin also ameliorates ß-cell function, with a significant increase in plasma insulin levels. The authors believe that this potent and selective inhibitor of DPP IV could compete with traditional oral anti-diabetic therapies in the future.