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Protein synthesis is increased by several-fold in stimulated pancreatic beta cells. Synthesis and folding of (pro)insulin takes place in the endoplasmic reticulum (ER), and beta cells trigger the unfolded protein response (UPR) to upgrade the functional capacity of the ER. Prolonged or excessive UPR activation contributes to beta cell dysfunction and death in type 2 diabetes, but there is another side of the UPR that may be of particular relevance for autoimmune type 1 diabetes, namely, the cross-talk between the UPR and innate immunity/inflammation. Recent evidence, discussed in this review, indicates that both saturated fats and inflammatory mediators such as cytokines trigger the UPR in pancreatic beta cells. The UPR potentiates activation of nuclear factor κB, a key regulator of inflammation. Two branches of the UPR, namely IRE1/XBP1s and PERK/ATF4/CHOP, mediate the UPR-induced sensitisation of pancreatic beta cells to the proinflammatory effects of cytokines. This can contribute to the upregulation of local inflammatory mechanisms and the aggravation of insulitis. The dialogue between the UPR and inflammation may provide an explanation for the parallel increase in the prevalence of childhood obesity and type 1 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: The cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α induce β-cell death in type 1 diabetes via NF-κB activation. IL-1β induces a more marked NF-κB activation than TNF-α, with higher expression of genes involved in β-cell dysfunction and death. We show here a differential usage of the IKK complex by IL-1β and TNF-α in β-cells. While TNF-α uses IKK complexes containing both IKKα and IKKβ, IL-1β induces complexes with IKKα only; this effect is achieved by induction of IKKβ degradation via the proteasome. Both IKKγ and activation of the TRAF6-TAK1-JNK pathway are involved in IL-1β-induced IKKβ degradation. [Copyright &y& Elsevier]

Hypertension, an insidious condition affecting approximately 50 million US adults, remains a central factor contributing to cardiac and other target organ disease. Despite increased detection and numerous therapeutic advances, three out of four people with hypertension in the US have uncontrolled or poorly controlled blood pressure. While hypertension is a leading reason for primary care office visits and antihypertensive medications are widely prescribed, most individuals are not achieving goal systolic/diastolic blood pressure of 140/90mm Hg or less. While the definition of adequate blood pressure control varies in different countries, the problem of inadequate control is universal. Numerous barriers contributing to the suboptimal health outcomes have been recognized, including issues related to healthcare providers as well as patient compliance with medication and lifestyle changes. Recently, healthcare provider systems and health plans have turned to disease management strategies to better address quality and outcomes issues in hypertension management. Disease management, a systematic clinical improvement process, encompasses provider and patient education employing national or locally developed best practice guidelines and behavioral interventions coupled with close monitoring of clinical processes and outcomes of care. Disease management programs seek to define a comprehensive and coordinated approach to care across multiple providers and patient subgroups. Through risk assessment and stratification, patients at higher risk of complications can be identified, and customized intensive care support can be offered. Other types of intervention for lower risk individuals include brief visits with a cardiovascular educator or care manager, group classes, or self-instructional programs. Several successful programs initiated by healthcare systems and health plans are described. Adequate blood pressure control is essential to reduce cardiac, renal, and stroke disease later in life. However, large numbers of individuals must be effectively managed for years or decades to achieve reductions in complications and cost savings. Unlike more acute conditions that frequently result in hospitalization and loss of function, the immediate cost offsets of hypertension disease management efforts are less defined, although the eventual savings to society could be vast. Less costly methods to promote healthy outcomes across large, relatively stable populations are needed. Automated systems employing clinical decision support at the point of care and internet-based patient support strategies offer the hope that comprehensive, individualized disease management for hypertension can be affordable as well as effective. In the meantime, the fact that the National Committee on Quality Assurance has included blood pressure control as a future measure of health plan performance will almost certainly lead to the expanded development of hypertension disease management initiatives. [ABSTRACT FROM AUTHOR]