Diabetes
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Islet autoimmunity precedes type 1 diabetes and often initiates in childhood. Phenotypic variation in islet autoimmunity relative to the age of its development suggests heterogeneous mechanisms of autoimmune activation. To support this notion, we examined whether serum metabolite profiles differ between children with respect to islet autoantibody status and the age of islet autoantibody development. ⋯ Distinct metabolic profiles are associated with age and islet autoimmunity. Pathways that use methionine are potentially relevant for developing islet autoantibodies in early infancy.
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It has been suggested that interleukin (IL)-6 is one of the mediators linking obesity-derived chronic inflammation with insulin resistance through activation of STAT3, with subsequent upregulation of suppressor of cytokine signaling 3 (SOCS3). We evaluated whether peroxisome proliferator-activated receptor (PPAR)-β/-δ prevented activation of the IL-6-STAT3-SOCS3 pathway and insulin resistance in adipocytes. ⋯ Collectively, our findings indicate that PPAR-β/-δ activation prevents IL-6-induced STAT3 activation by inhibiting ERK1/2 and preventing the STAT3-Hsp90 association, an effect that may contribute to the prevention of cytokine-induced insulin resistance in adipocytes.
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Diabetic patients often experience visceral hypersensitivity and anorectal dysfunction. We hypothesize that the enhanced excitability of colon projecting dorsal root ganglia (DRG) neurons observed in diabetes is caused by a decrease in the amplitude of the transient A-type K(+) (I(A)) currents resulting from increased phosphorylation of mitogen-activated protein kinases (MAPK) and reduced opening of K(v)4.2 channels. ⋯ We demonstrated that reduction of the I(A) current in STZ-D DRG neurons is triggered by impaired [Ca(2+)](i) ion homeostasis, and this in turn activates the PKC-MAPK pathways, resulting in decreased opening of the K(v)4.2 channels. Hence, the PKC-MAPK-K(v)4.2 pathways represent a potential therapeutic target for treating visceral hypersensitivity in diabetes.
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High-fat diet (HFD)-induced adipose tissue inflammation is a critical feature of diet-induced insulin resistance (IR); however, the contribution of interleukin-1 receptor I (IL-1RI)-mediated signals to this phenotype has not been defined. We hypothesized that lack of IL-1RI may ameliorate HFD-induced IR by attenuating adipose tissue inflammation. ⋯ Lack of IL-1RI protects against HFD-induced IR coincident with reduced local adipose tissue inflammation, despite equivalent immune cell recruitment.
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Randomized Controlled Trial
Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans.
Glucagon-like peptide (GLP)-1 lowers postprandial glycemia primarily through inhibition of gastric emptying. We addressed whether the GLP-1-induced deceleration of gastric emptying is subject to rapid tachyphylaxis and if so, how this would alter postprandial glucose control. ⋯ The GLP-1-induced delay in gastric emptying is subject to rapid tachyphylaxis at the level of vagal nervous activation. As a consequence, postprandial glucose control by GLP-1 is attenuated after its chronic administration.