High-fat diets lead to obesity, inflammation, and dysglycemia. 12-Lipoxygenase (12-LO) is activated by high-fat diets and catalyzes the oxygenation of cellular arachidonic acid to form proinflammatory intermediates. We hypothesized that 12-LO in the pancreatic islet is sufficient to cause dysglycemia in the setting of high-fat feeding. To test this, we generated pancreas-specific 12-LO knockout mice and studied their metabolic and molecular adaptations to high-fat diets. Whereas knockout mice and control littermates displayed identical weight gain, body fat distribution, and macrophage infiltration into fat, knockout mice exhibited greater adaptive islet hyperplasia, improved insulin secretion, and complete protection from dysglycemia. At the molecular level, 12-LO deletion resulted in increases in islet antioxidant enzymes Sod1 and Gpx1 in response to high-fat feeding. The absence or inhibition of 12-LO led to increases in nuclear Nrf2, a transcription factor responsible for activation of genes encoding antioxidant enzymes. Our data reveal a novel pathway in which islet 12-LO suppresses antioxidant enzymes and prevents the adaptive islet responses in the setting of high-fat diets.O besity, typically a result of diets high in saturated fat content, is directly correlated to insulin resistance and prediabetes. Macrovascular disease consequences, including stroke, myocardial infarction, and mortality increase even as blood sugars rise in the prediabetic phase (1), thus emphasizing the perils of glycemic dysregulation in the absence of frank diabetes. High-fat diets (HFDs) and their consequent insulin resistance lead to adaptive islet hyperplasia, in which basal secretion of insulin is increased in an attempt to compensate for insulin resistance (2). However, this compensatory mechanism can eventually fail in the face of prolonged insulin resistance. Inflammation and oxidative stress are major factors thought to contribute to dysfunction of ␤ cells in the setting of insulin resistance (3, 4). In this regard, ␤ cells have low expression and activity levels of the antioxidant enzymes compared to other metabolic tissues (5), and the pathway(s) that endogenously suppresses production of these antioxidant enzymes in the ␤ cell remains unclear.The lipoxygenases represent a group of enzymes that catalyzes the oxygenation of polyunsaturated fatty acids to form inflammatory lipid intermediates, which have been shown to contribute to oxidative stress (6). In the mouse, 12-lipoxygenase (12-LO) is expressed in several cell types, including macrophages, white adipocytes, and pancreatic islets (7). 12-LO oxygenates membranederived arachidonic acid primarily at the 12-position carbon atom to form 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which is then converted to the more stable form 12-hydroxyeicosatetraenoic acid (12-HETE) (7). The role of 12-LO in the setting of HFDs and obesity has been studied primarily in the context of whole-body 12-LO knockout mice. Recent studies showed that 12-LO knockout mice fed a HFD exhibit r...

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Background: Pdx1 interacts with the methyltransferase Set7/9 to transactivate ␤ cell genes. Results: Methylation of Pdx1 residue Lys-131 by Set7/9 augments Pdx1 activity. Conclusion:The ability of Pdx1 to regulate genes in ␤ cells is partially dependent upon its methylation by Set7/9. Significance: This study reveals a previously unappreciated role for Lys methylation in the maintenance of Pdx1 activity and ␤ cell function.

Type 1 Diabetes (T1D) is characterized by the immune mediated destruction of β cells. Clinical studies have focused on drug therapies to modulate autoimmunity, yet none of these interventions has resulted in durable preservation of β-cell function. These findings raise the possibility that initiating or propagating events outside of the immune system should be considered in future efforts to prevent or reverse T1D. An emerging concept suggests that defects inherent to the β cell may trigger autoimmunity. A study by Engin et al. in type 1 diabetic NOD mice suggests that excessive β-cell endoplasmic reticulum stress arising from environmental insults results in abnormal protein synthesis, folding, and/or processing. Administration of the chemical protein folding chaperone TUDCA resulted in recovery of β-cell endoplasmic reticulum function and a diminished incidence of diabetes in NOD mice. We propose here that these data and others support a model whereby an inadequate or defective β-cell endoplasmic reticulum response results in the release of β-cell antigens and neoantigens that initiate autoimmunity. Pharmacologic therapies that either mitigate these early β-cell stressors or enhance the ability of β cells to cope with such stressors may prove to be effective in the prevention or treatment of T1D.