The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

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How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Background and objective The Atlanta classification of acute pancreatitis enabled standardised reporting of research and aided communication between clinicians. Deficiencies identified and improved understanding of the disease make a revision necessary. Methods A web-based consultation was undertaken in 2007 to ensure wide participation of pancreatologists. After an initial meeting, the Working Group sent a draft document to 11 national and international pancreatic associations. This working draft was forwarded to all members. Revisions were made in response to comments, and the web-based consultation was repeated three times. The final consensus was reviewed, and only statements based on published evidence were retained. Results The revised classification of acute pancreatitis identified two phases of the disease: early and late. Severity is classified as mild, moderate or severe. Mild acute pancreatitis, the most common form, has no organ failure, local or systemic complications and usually resolves in the first week. Moderately severe acute pancreatitis is defined by the presence of transient organ failure, local complications or exacerbation of co-morbid disease. Severe acute pancreatitis is defined by persistent organ failure, that is, organ failure >48 h. Local complications are peripancreatic fluid collections, pancreatic and peripancreatic necrosis (sterile or infected), pseudocyst and walled-off necrosis (sterile or infected). We present a standardised template for reporting CT images. Conclusions This international, web-based consensus provides clear definitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. The wide consultation among pancreatologists to reach this consensus should encourage widespread adoption.

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Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus

Obesity induces an insulin-resistant state in adipose tissue, liver, and muscle and is a strong risk factor for the development of type 2 diabetes mellitus. Insulin resistance in the setting of obesity results from a combination of altered functions of insulin target cells and the accumulation of macrophages that secrete proinflammatory mediators. At the molecular level, insulin resistance is promoted by a transition in macrophage polarization from an alternative M2 activation state maintained by STAT6 and PPARs to a classical M1 activation state driven by NF-kappaB, AP1, and other signal-dependent transcription factors that play crucial roles in innate immunity. Strategies focused on inhibiting the inflammation/insulin resistance axis that otherwise preserve essential innate immune functions may hold promise for therapeutic intervention.

Macrophages, Inflammation, and Insulin Resistance

Practice guidelines in acute pancreatitis.

https://www.spg.pt/wp-content/uploads/2015/11/2013-ACG_Guideline_AcutePancreatitis_September_2013.pdf

American College of Gastroenterology guideline: management of acute pancreatitis.

To assess the mechanisms of insulin resistance following injury, we examined the relationship between insulin levels and glucose disposal in nine nonseptic, multiple trauma patients (average age 32 years, Injury Severity Score 22) five to 13 days postinjury. Fourteen age-matched normals served as controls. Using a modification of the euglycemic insulin clamp technique, insulin was infused in 35 two-hour studies using at least one of four infusions rates (0.5, 1.0, 2.0 or 5.0 mU/kg min). Basal glucose levels were maintained by a variable infusion of 20% dextrose using bedside glucose monitoring and a servo-control algorithm. The amount of glucose infused reflected glucose disposal (M, mg/kg.min). Tracer doses of (6,6,2D2) glucose were administered in selected subjects to determine endogenous glucose production. At plasma insulin concentrations less than 100 microU/ml, responses in both groups were similar. However, maximal glucose disposal rates were significantly less in the patients than in the controls (9.17 +/- 0.87 mg/kg . min vs. 14.3 +/- 0.78, mean +/- SEM, p less than 0.01). Insulin clearance rates in the patients were almost twice that seen in controls. To further characterize this decrease in insulin responsiveness, we studied six additional patients and 12 controls following the acute elevation of glucose 125 mg/dl above basal (hyperglycemic glucose clamp). In spite of exaggerated endogenous insulin production in the patients (80-200 microU/ml vs. 30--70 in controls), M was significantly lower (6.23 +/- 0.59 vs. 9.46 +/- 0.79, p less than 0.02). In conclusion, this study demonstrated that (1) the maximal rate of glucose disposal is reduced in trauma patients; (2) the metabolic clearance rate of insulin in the injured patients is almost twice normal and; (3) insulin resistance following injury appears to occur in peripheral tissues, probably skeletal muscle, and is consistent with a postreceptor defect.

Mechanisms of insulin resistance following injury.

The management of necrotizing pancreatitis (NP) has undergone considerable evolution. Although the role of surgical therapy in this condition has remained controversial, recent advances in our understanding and care of these patients have considerably focused this debate. Today, with improvements in the care of the critically ill, many patients with severe acute pancreatitis survive the early systemic inflammatory response and enter a second phase of illness dominated by sepsis and the consequences of organ failure. 1,2 Patients with significant pancreatic necrosis, at highest risk for such complications, can now be identified with contrast-enhanced computed tomography (CT) 3 and the presence or absence of infection can be established using fine-needle aspiration (FNA). 4 Although the need for intervention in patients with pancreatic infection is undisputed, the success of this technology in distinguishing between infected and sterile necrosis has raised the issue of whether infection should be the only indication for surgery in the initial management of NP. 5,6 Opponents of this strategy have continued to suggest that there are some patients with the most severe disease, based on the extent of necrosis or organ failure, who might benefit from debridement regardless of the status of infection. 7,8

Arguments for and against the conservative approach have been based largely on the results of select and nonrandomized series from surgical referral centers. 5–10 Despite the lack of convincing data, it was our impression that we had increasingly adopted a conservative strategy at our institution, reserving intervention for patients with documented infection or the small group of patients who recover from the acute inflammatory process but suffer from symptoms related to organized necrosis. Acknowledging our bias in favor of conservative therapy, we have remained sympathetic to the concept that there may be a subset of patients with severe sterile necrosis who would benefit from surgery regardless of the status of infection; however, it was our impression that this group is relatively small. In this context, we reviewed our institutional experience, including the entire spectrum of patients with NP, focusing on the success of conservative therapy.

Necrotizing Pancreatitis: Contemporary Analysis of 99 Consecutive Cases

IntroductionWe previously reported that organ failure occurs in 50% of patients with necrotizing pancreatitis, that extended pancreatic necrosis (greater than 50% necrosis) is not associated with an increased prevalence of organ failure or infected necrosis, and that the prevalence of organ failure

Is severity of necrotizing pancreatitis increased in extended necrosis and infected necrosis

Obesity has been associated with abnormally high expression of the enzyme aromatase in the breast, increased local estrogen production, and predisposition to breast hyperplasia and cancer. Increased adiposity in postmenopausal women may trigger signaling pathways that induce aromatase expression. In breast adipose fibroblasts, increased TNF production may induce the distal aromatase promoter, whereas increased local PGE2 production may induce the proximal promoter region. We review here the mechanisms that control aromatase gene expression in breast adipose tissue, and the paracrine interactions between malignant breast epithelial cells and the surrounding adipose fibroblasts. Systematic characterization of these signaling pathways will facilitate the identification of potential drug targets to selectively reduce aromatase expression and excessive estrogen production, with therapeutic benefit.

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David C. Brooks

Papers

Mechanisms of insulin resistance following injury.

Necrotizing Pancreatitis: Contemporary Analysis of 99 Consecutive Cases

Is severity of necrotizing pancreatitis increased in extended necrosis and infected necrosis

Aromatase, breast cancer and obesity: a complex interaction.

Rapid development of umbilical metastases after laparoscopic cholecystectomy for unsuspected gallbladder carcinoma.