Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

Aims/hypothesis

The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes.

Methods

Rat insulin promoter (RIP)-Cre ⁺;autophagy-related 7 (Atg7)^F/W mice were bred with ob/w mice to derive RIP-Cre ⁺;Atg7 ^F/F-ob/ob mice and to induce ER stress in vivo. GFP-LC3 ⁺-ob/ob mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.

Results

Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85?? and p85?? regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with ob/ob mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced.

Conclusions/interpretation

These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.     

Certolizumab Pegol Compared to Natalizumab in Patients with Moderate to Severe Crohn’s Disease: Results of a Decision Analysis

Introduction  

A significant proportion of patients with Crohn’s disease (CD) lose response to antibodies directed against tumor necrosis factor α (TNF). Prior TNF-antagonist failure is associated with lower rates of response to subsequent TNF-antagonist therapy. In patients failing two anti-TNF agents, a choice exists between using a third-anti-TNF therapy or natalizumab (NAT), an α-4 integrin inhibitor. A cost-effectiveness analysis comparing these competing strategies has not been performed.     

The Efficacy and Perioperative Complications Associated with Lumbar Spinal Fusion Surgery,Focusing on Geriatric Patients in the Republic of Korea

Objective

The purpose of this study was to examine the efficacy and perioperative complications associated with lumbar spinal fusion surgery, focusing on geriatric patients in the Republic of Korea.

Methods

We retrospectively investigated 485 patients with degenerative spinal diseases who had lumbar spinal fusion surgeries between March 2006 and December 2010 at our institution. Age, sex, comorbidity, American Society of Anesthesiologists (ASA) class, fusion segments, perioperative complications, and outcomes were analyzed in this study. Risk factors for complications and their association with age were analyzed.

Results

In this study, 81 patients presented complications (16.7%). The rate of perioperative complications was significantly higher in patients 70 years or older than in other age groups (univariate analysis, p=0.015; multivariate analysis, p=0.024). The perioperative complications were not significantly associated with the other factors tested (sex, comorbidity, ASA class, and fusion segments). Post-operative outcomes of lumbar spinal fusion surgeries for the patients were determined on the basis of MacNab''s criteria (average follow up period : 19.7 months), and 412 patients (85.0%) were classified as having "excellent" or "good" results.

Conclusion

Increasing age was an important risk factor for perioperative complications in patients undergoing lumbar spinal fusion surgery, whereas other factors were not significant. However, patients'' satisfaction or return to daily activities when compared with younger patients did not show much difference. We recommend good clinical judgment as well as careful selection of geriatric patients for lumbar spinal fusion surgery.     

Topography and Spatial Fascicular Arrangement of the Human Inferior Alveolar Nerve

Background: Topography and fascicular arrangement of the inferior alveolar nerve (IAN) can provide critical information for the estimation of damage to IAN based on patient symptoms, or conversely to evaluate the symptoms resulting from injury to the IAN. Purpose: The fascicular composition and organization of the IAN were determined to confirm the microarchitecture of the IAN bundles into each of the mandibular teeth, including the composition of the mental nerve. Materials and Methods: The IAN within the mandibular canal (MC) was examined in 30 hemifaces of embalmed Korean cadavers. Results: The most common patterns of nerve fascicle innervation to the mandibular teeth could be grossly classified into three: (1) the superior buccal portion of the IAN innervating the molars, (2) the superior portion innervating the premolars, and (3) the superior lingual or the superior lingual and inferior lingual portions in the posterior MC and the lingual portions in the anterior MC, innervating the incisors and canine. The buccal two‐thirds portion of the IAN was composed of the mental nerve. Conclusion: The IAN had distinctive fascicular organizations, which make it possible to forecast the degree, location, and extent of nerve damage according to presenting symptoms.     

Internal plug mesh without fixation in laparoscopic total extraperitoneal (TEP) repair of inguinal hernias: a pilot study

Purpose

Mesh fixation is essential in laparoscopic total extraperitoneal (TEP) repair of inguinal hernia; however, fixation sometimes causes post-operative pain. This study investigated a novel method of laparoscopic TEP repair without mesh fixation.

Methods

This study reviewed data from about two-hundred and forty-one laparoscopic TEP repairs on 219 patients, which were performed between December 2004 and October 2005.

Results

There were no statistically significant differences in the recurrence rate, seroma formation, and hospital stay. However, the mean operation time was shorter in the internal plug mesh group than the fixation group (p = 0.009), and post-operative pain only occurred in 4 cases in the internal plug mesh group in comparison to 29 cases in the mesh fixation group (p = 0.014).

Conclusions

An internal plug mesh without fixation might reduce post-operative pain after laparoscopic TEP repair of an inguinal hernia. Internal plug mesh without fixation may be an alternative method in laparoscopic TEP repair, especially for those involving indirect hernias.     

Predicting success of metabolic surgery: age,body mass index,C-peptide,and duration score

BackgroundSurgery is the most effective treatment of morbid obesity and leads to dramatic improvements in type 2 diabetes mellitus (T2DM). Gastrointestinal metabolic surgery has been proposed as a treatment option for T2DM. However, a grading system to categorize and predict the outcome of metabolic surgery is lacking. The study setting was a tertiary referral hospital (Taoyuan City, Taoyuan County, Taiwan).MethodsWe first evaluated 63 patients and identified 4 factors that predicted the success of T2DM remission after bariatric surgery in this cohort: body mass index, C-peptide level, T2DM duration, and patient age. We used these variables to construct the Diabetes Surgery Score, a multidimensional 10-point scale along which greater scores indicate a better chance of T2DM remission. We then validated the index in a prospective collected cohort of 176 patients, using remission of T2DM at 1 year after surgery as the outcome variable.ResultsA total of 48 T2DM remissions occurred among the 63 patients and 115 remissions (65.3%) in the validation cohort. Patients with T2DM remission after surgery had a greater Diabetes Surgery Score than those without (8 ± 4 versus 4 ± 4, P < .05). Patients with a greater Diabetes Surgery Score also had a greater rate of success with T2DM remission (from 33% at score 0 to 100% at score 10); A 1-point increase in the Diabetes Surgery Score translated to an absolute 6.7% in the success rate.ConclusionThe Diabetes Surgery Score is a simple multidimensional grading system that can predict the success of T2DM treatment using bariatric surgery among patients with inadequately controlled T2DM.