Time to revisit the definition of atypical anorexia nervosa.

In this special issue, international researchers investigate how atypical anorexia nervosa (atypical AN) differs from anorexia nervosa (AN) and other eating disorders with respect to demographics, psychological and physiological morbidity, as well as treatment course and outcome. Manuscripts in this special issue report that atypical AN is associated with substantial medical and psychological morbidity, and the majority of studies find few differences between atypical AN and AN. While much remains to be learned about the long-term course and treatment response of individuals with atypical AN to psychological and pharmacological interventions, the evidence supports conceptualization of atypical AN as part of a spectrum-based restrictive eating disorder. These findings together with the potentially stigmatizing use of the term "atypical" suggest it may be time to revise the existing definition of atypical AN.

Course and outcome in individuals with atypical anorexia nervosa: Findings from the Study of Refeeding to Optimize iNpatient Gains (StRONG).

OBJECTIVE: We previously reported that participants with atypical anorexia nervosa (atypical AN) had higher historical and admission weights, greater eating disorder psychopathology, but similar rates of amenorrhea and weight suppression at baseline as compared to anorexia nervosa (AN); here, we compare 1-year outcomes. METHOD: Weight, % median body mass index (%mBMI), Eating Disorder Examination Questionnaire (EDE-Q) scores, resumption of menses, and rehospitalizations were examined at 3, 6, and 12 months post-discharge. Analyses (N = 111) compared changes in %mBMI, weight suppression, and EDE-Q scores over time between atypical AN and AN. RESULTS: Among the participants (48 atypical AN, 63 AN), both groups gained weight but those with atypical AN had lower gains than those with AN in %mBMI (p = .02) and greater weight suppression (p = .002) over time. EDE-Q scores improved over time, independent of weight suppression, with no significant difference between atypical AN and AN. Groups did not differ by rates of resumption of menses (80% atypical AN, 76.9% AN) or rehospitalization (29.2% atypical AN, 37.9% AN). Greater weight suppression predicted longer time to restore menses and more days of rehospitalization. DISCUSSION: Individuals with atypical AN regained a smaller proportion of body mass and were more weight suppressed over time. Change in eating disorder cognitions, resumption of menses, and rehospitalization rates at 1-year follow-up did not differ between groups. There was no significant difference in weight suppression between groups for those who were psychologically improved at 12 months. Findings highlight limitations in our understanding of weight recovery in atypical AN. New metrics for recovery are urgently needed. PUBLIC SIGNIFICANCE: Little is known about outcome in atypical anorexia nervosa (atypical AN). We examined recovery metrics in young people with atypical AN and anorexia nervosa (AN) 1 year after medical hospitalization. Individuals with atypical AN showed slower weight gain and remained further from their pre-illness weight. There were no differences in the rates of psychological recovery, resumption of menses, or rehospitalization. New metrics are needed to assess recovery in atypical AN.

Short-term outcomes of the study of refeeding to optimize inpatient gains for patients with atypical anorexia nervosa.

OBJECTIVE: The StRONG trial demonstrated the safety and efficacy of higher calorie refeeding (HCR) in hospitalized adolescents and young adults with malnutrition secondary to restrictive eating disorders. Here we compare refeeding outcomes in patients with atypical anorexia nervosa (atypical AN) versus anorexia nervosa (AN) and examine the impact of caloric dose. METHOD: Patients were enrolled upon admission and randomized to meal-based HCR, beginning 2000 kcal/day and advancing 200 kcal/day, or lower calorie refeeding (LCR), beginning 1400 kcal/day and advancing 200 kcal every other day. Atypical AN was defined as %median BMI (mBMI) > 85. Independent t-tests compared groups; multivariable linear and logistic regressions examined caloric dose (kcal/kg body weight). RESULTS: Among n = 111, mean ± SD age was 16.5 ± 2.5 yrs; 43% had atypical AN. Compared to AN, atypical AN had slower heart rate restoration (8.7 ± 4.0 days vs. 6.5 ± 3.9 days, p = .008, Cohen's d = -.56), less weight gain (3.1 ± 5.9%mBMI vs. 5.4 ± 2.9%mBMI, p < .001, Cohen's d = .51) and greater hypomagnesemia (29% vs. 11%, p = .03, OR = 3.29). These suboptimal outcomes were predicted by insufficient caloric dose (32.4 ± 6.9 kcal/kg in atypical AN vs. 43.4 ± 9.8 kcal/kg in AN, p < .001, Cohen's d = 1.27). For every 10 kcal/kg increase, heart rate was restored 1.7 days (1.0, 2.5) faster (p < .001), weight gain was 1.6%mBMI (.8, 2.4) greater (p < .001), and hypomagnesemia odds were 70% (12, 128) lower (p = .02). DISCUSSION: Although HCR is more efficacious than LCR for refeeding in AN, it contributes to underfeeding in atypical AN by providing an insufficient caloric dose relative to the greater body weight in this diagnostic group. PUBLIC SIGNIFICANCE: The StRONG trial previously demonstrated the efficacy and safety of higher calorie refeeding in patients with malnutrition due to restrictive eating disorders. Here we show that higher calorie refeeding contributes to underfeeding in patients with atypical anorexia nervosa, including poor weight gain and longer time to restore medical stability. These findings indicate these patients need more calories to support nutritional rehabilitation in hospital.

Atypical Anorexia Nervosa is not atypical at all! Commentary on Walsh et al. (2022).

The introduction of atypical anorexia nervosa (atypAN) as a new diagnosis in DSM-5 has advanced the field by expanding awareness that individuals of all weights can have an eating disorder. However, many clinical and research questions remain, particularly pertaining to whether atypAN and anorexia nervosa (AN) are different conditions or the same condition across the weight spectrum. In this issue of the journal, Walsh et al. describe the results of their systematic review demonstrating that the level of eating disorder-specific psychopathology is significantly higher among individuals with atypAN than among controls, and as high or higher than among individuals with AN. Levels of noneating disorder psychopathology are similar. Individuals with atypAN experience many of the medical complications associated with AN but at a lower frequency. The finding that the clinical features of atypAN are not substantially different from AN supports the possibility that atypAN and AN are the same condition. Further research on epidemiology, genetics, treatment, course and outcome is required to determine whether atypAN and AN are the same or different, but there is a need to update and refine existing terminology and diagnostic classification.

Hospital-based higher calorie refeeding and mealtime distress in adolescents and young adults with anorexia nervosa or atypical anorexia nervosa.

OBJECTIVE: The StRONG study demonstrated that higher calorie refeeding (HCR) restored medical stability faster in patients hospitalized with anorexia nervosa (AN) and atypical AN (AAN), with no increased safety events compared with standard-of-care lower calorie refeeding (LCR). However, some clinicians have expressed concern about potential unintended consequences of HCR (e.g., greater mealtime distress). The purpose of this study was to examine patient treatment preference and compare mealtime distress, food refusal, and affective states between treatments. METHOD: Participants (N = 111) in this multisite randomized clinical trial were ages 12-24 years, with AN or AAN, admitted to hospital with medical instability who received assigned study treatment (HCR or LCR). Treatment preference was assessed prior to randomization in the full sample. In a subset of participants (n = 45), linear mixed effect models were used to analyze momentary ratings of mealtime distress (pre, during, and post-meals) and daily affective state during the hospitalization. RESULTS: About half (55%) of participants reported a preference for LCR. Treatment assignment was not associated with food refusal, mealtime distress, or affective states in the subsample. Food refusal increased significantly over the course of refeeding (p = .018). Individuals with greater depression experienced more negative affect (p = .033), with worsening negative affect over time for individuals with higher eating disorder psychopathology (p = .023). DISCUSSION: Despite understandable concerns about potential unintended consequences of HCR, we found no evidence that treatment acceptability for HCR differed from LCR for adolescents and young adults with AN and AAN. PUBLIC SIGNIFICANCE: The efficacy and safety of higher calorie refeeding in hospitalized patients with anorexia nervosa has been demonstrated. However, it is not known whether higher calorie refeeding (HCR) increases meal-time distress. This study demonstrated that HCR was not associated with increased mealtime distress, food refusal, or affective states, as compared with lower calorie refeeding. These data support HCR treatment acceptability for adolescents/young adults with anorexia nervosa and atypical anorexia nervosa.

Comparisons of bone density and body composition among adolescents with anorexia nervosa and atypical anorexia nervosa.

OBJECTIVE: To compare bone mineral density (BMD) and body composition among adolescents: (a) with atypical anorexia nervosa (AAN) versus anorexia nervosa (AN) and (b) those with and without a prior history of overweight. METHOD: Electronic medical records of patients 9-20 years with AN or AAN who underwent dual-energy x-ray absorptiometry scans were retrospectively reviewed and analyzed. RESULTS: A total of 286 adolescents with AN or AAN were included. In linear regression models, AAN was associated with greater Z-scores in whole body bone mineral content (BMC, B = 0.88, p < 0.001), lumbar spine BMD (B = 0.79, p = 0.002), femoral neck BMD (B = 0.670, p = 0.009); fat mass index (B = 1.33, p = 0.003), and lean body mass index (LBMI, B = 1.10, p < 0.001) compared to AN, adjusting for age, sex, and duration of illness. A prior overweight history was associated with greater Z-scores in whole body BMC; lumbar spine BMD, total hip BMD, femoral neck BMD, and LBMI. DISCUSSION: Adolescents with AAN had higher BMD Z-scores than adolescents with AN; adolescents with a prior overweight history had greater BMD Z-scores than adolescents without a prior overweight history. These findings may inform clinical guidelines for the medical management of AAN.

Associations between exercise, bone mineral density, and body composition in adolescents with anorexia nervosa.

OBJECTIVE: To identify the effect of duration of weight-bearing exercise and team sports participation on bone mineral density (BMD) and body composition among adolescents with anorexia nervosa (AN). METHOD: We retrospectively reviewed electronic medical records of all patients 9-20 years old with a DSM-5 diagnosis of AN evaluated by the Stanford Eating Disorders Program (1997-2011) who underwent dual-energy X-ray absorptiometry. RESULTS: A total of 188 adolescents with AN were included (178 females and 10 males). Using multivariate linear regression, duration of weight-bearing exercise (B = 0.15, p = 0.005) and participation in team sports (B = 0.53, p = 0.001) were associated with higher BMD at the hip and team sports (B = 0.39, p = 0.006) were associated with higher whole body BMC, controlling for covariates. Participation in team sports (B = - 1.06, p = 0.007) was associated with greater deficits in FMI Z-score. LBMI Z-score was positively associated with duration of weight-bearing exercise (B = 0.10, p = 0.018) and may explain the relationship between exercise and bone outcomes. CONCLUSION: Duration of weight-bearing exercise and team sports participation may be protective of BMD at the hip and whole body BMC, while participation in team sports was associated with greater FMI deficits among adolescents with AN. LEVEL OF EVIDENCE: Level V, descriptive retrospective study.

Correction to: Islet-intrinsic effects of CFTR mutation.

Unfortunately, due to a tagging error, Dr Fiona N. Manderson Koivula's name is shown incorrectly as Koivula FN on PubMed. Her name appears correctly in the html and pdf versions of the paper.

Assessment of sex differences in bone deficits among adolescents with anorexia nervosa.

OBJECTIVE: The objective of this study was to compare sex differences in bone deficits among adolescents with anorexia nervosa (AN) and to identify other correlates of bone health. METHOD: Electronic medical records of all patients 9-20 years of age with a DSM-5 diagnosis of AN who were evaluated by the eating disorders program at Stanford with dual-energy X-ray absorptiometry (DXA) between March 1997 and February 2011 were retrospectively reviewed. Whole body bone mineral content Z-scores and bone mineral density (BMD) Z-scores at multiple sites were recorded using the Bone Mineral Density in Childhood Study (BMDCS) reference data. RESULTS: A total of 25 males and 253 females with AN were included, with median age 15 years (interquartile range [IQR] 14-17) and median duration of illness 9 months (IQR 5-13). Using linear regression analyses, no significant sex differences in bone deficits were found at the lumbar spine, total hip, femoral neck, or whole body when controlling for age, %mBMI, and duration of illness. Lower %mBMI was significantly associated with bone deficits at all sites in adjusted models. DISCUSSION: This is the first study to evaluate sex differences in bone health among adolescents with AN, using novel DSM-5 criteria for AN and robust BMDCS reference data. We find no significant sex differences in bone deficits among adolescents with AN except for a higher proportion of females with femoral neck BMD Z-scores <-1. Degree of malnutrition was correlated with bone deficits at all sites. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:352-358).

Characterization and correlates of exercise among adolescents with anorexia nervosa and bulimia nervosa.

OBJECTIVE: To characterize exercise behaviors among adolescents with anorexia nervosa (AN), atypical AN, or bulimia nervosa (BN), and determine associations between exercise and medical risk. STUDY DESIGN: Cross-sectional electronic medical records of all patients evaluated by the Eating Disorder Program at Stanford between January 1997 and February 2011 were retrospectively reviewed. RESULTS: 1,083 subjects (961 females, 122 males; mean age 15.6) met eligibility criteria. Most patients (89.7%) reported exercise (mean 7.0 h per week over mean 5.4 days per week) prior to presentation. Running (49.9%), calisthenics (40.7%), walking (23.4%), soccer (20.9%), and swimming (18.2%) were the most common exercises; a majority (60.6%) reported team sport participation. Males were less likely to report team exercise (p = .005). Bradycardia (heart rate <50) at presentation was associated with team sport participation (adjusted odds ratio [AOR] 1.66, 95% confidence interval [CI] 1.02-2.72) and hours of exercise per week (AOR 1.05, 95% CI 1.02-1.09), controlling for diagnosis, sex, age, duration of illness, rate of weight loss, and percent median body mass index (%mBMI). DISCUSSION: Adolescents with AN, atypical AN, and BN reported high levels of exercise. Females reported more team sport participation. Greater exercise frequency and team sport participation were associated with bradycardia. Further studies assessing the relationship between exercise and bradycardia may help inform the medical management of adolescents with these eating disorders who are more physically active.

A Behavior-Based Intervention That Prevents Sexual Assault: the Results of a Matched-Pairs, Cluster-Randomized Study in Nairobi, Kenya.

DESIGN: The study's design was a cluster-randomized, matched-pairs, parallel trial of a behavior-based sexual assault prevention intervention in the informal settlements. METHODS: The participants were primary school girls aged 10-16. Classroom-based interventions for girls and boys were delivered by instructors from the same settlements, at the same time, over six 2-h sessions. The girls' program had components of empowerment, gender relations, and self-defense. The boys' program promotes healthy gender norms. The control arm of the study received a health and hygiene curriculum. The primary outcome was the rate of sexual assault in the prior 12 months at the cluster level (school level). Secondary outcomes included the generalized self-efficacy scale, the distribution of number of times victims were sexually assaulted in the prior period, skills used, disclosure rates, and distribution of perpetrators. Difference-in-differences estimates are reported with bootstrapped confidence intervals. RESULTS: Fourteen schools with 3147 girls from the intervention group and 14 schools with 2539 girls from the control group were included in the analysis. We estimate a 3.7 % decrease, p = 0.03 and 95 % CI = (0.4, 8.0), in risk of sexual assault in the intervention group due to the intervention (initially 7.3 % at baseline). We estimate an increase in mean generalized self-efficacy score of 0.19 (baseline average 3.1, on a 1-4 scale), p = 0.0004 and 95 % CI = (0.08, 0.39). INTERPRETATION: This innovative intervention that combined parallel training for young adolescent girls and boys in school settings showed significant reduction in the rate of sexual assault among girls in this population.

Risk of Urolithiasis in Anorexia Nervosa: A Population-Based Cohort Study Using the Health Improvement Network.

This population-based retrospective cohort study sought to determine if anorexia nervosa (AN) is associated with a higher risk of urolithiasis. Nine thousand three hundred two females with AN were compared to 92 959 randomly selected age-matched and practice-matched females. Cox regression was used to estimate the hazard ratio (HR) for urolithiasis and evaluate effect modification by age. Twenty-three participants with AN (0.25%) developed urolithiasis compared with 154 unexposed participants (0.17%) over a median of 4 years of observation. The risk of urolithiasis varied significantly with age (interaction p = 0.02). AN was associated with a more than threefold higher risk of urolithiasis in females ≤25 years of age (HR 3.49, 95% CI: 1.56-7.81; p = 0.002), but not in females over 25 years (HR 1.18, 95% CI: 0.69-2.02; p = 0.54). The distribution of diagnosis codes for urolithiasis differed between groups (p = 0.04), with a higher proportion of codes for uric acid urolithiasis in the AN (16.2%) versus unexposed group (5.0%). Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Islet-intrinsic effects of CFTR mutation.

Cystic fibrosis-related diabetes (CFRD) is the most significant extra-pulmonary comorbidity in cystic fibrosis (CF) patients, and accelerates lung decline. In addition to the traditional view that CFRD is a consequence of fibrotic destruction of the pancreas as a whole, emerging evidence may implicate a role for cystic fibrosis transmembrane-conductance regulator (CFTR) in the regulation of insulin secretion from the pancreatic islet. Impaired first-phase insulin responses and glucose homeostasis have also been reported in CF patients. CFTR expression in both human and mouse beta cells has been confirmed, and recent studies have shown differences in endocrine pancreatic morphology from birth in CF. Recent experimental evidence suggests that functional CFTR channels are required for insulin exocytosis and the regulation of membrane potential in the pancreatic beta cell, which may account for the impairments in insulin secretion observed in many CF patients. These novel insights suggest that the pathogenesis of CFRD is more complicated than originally thought, with implications for diabetes treatment and screening in the CF population. This review summarises recent emerging evidence in support of a primary role for endocrine pancreatic dysfunction in the development of CFRD. Summary • CF is an autosomal recessive disorder caused by mutations in the CFTR gene • The vast majority of morbidity and mortality in CF results from lung disease. However CFRD is the largest extra-pulmonary co-morbidity and rapidly accelerates lung decline • Recent experimental evidence shows that functional CFTR channels are required for normal patterns of first phase insulin secretion from the pancreatic beta cell • Current clinical recommendations suggest that insulin is more effective than oral glucose-lowering drugs for the treatment of CFRD. However, the emergence of CFTR corrector and potentiator drugs may offer a personalised approach to treating diabetes in the CF population.

Differential molecular and cellular responses of GLP-1 secreting L-cells and pancreatic alpha cells to glucotoxicity and lipotoxicity.

Knowledge of the effects of glucotoxic and lipotoxic environments on proglucagon producing intestinal L cells and pancreatic alpha cells is limited compared with pancreatic beta cells. This study compares the in vitro responses of these cell types to hyperglycaemia and hyperlipidaemia. Glucose (30 mM) and palmitate (0.5mM) reduced GLUTag and MIN6 cell viability while alpha TC1 cells were sensitive only to lipotoxicity. Consistent with this, Cat mRNA expression was substantially higher in GLUTag and alpha TC1 cells compared to MIN6 cells. Glucose and palmitate reduced GLUTag cell secretory function while hypersecretion of glucagon was apparent from alpha TC1 cells. Glucose exposure increased transcription of Cat and Sod2 in MIN6 and GLUTag cells respectively while it decreased transcription of Cat and Gpx1 in alpha TC1 cells. Palmitate increased transcription of Cat and Sod2 in all three cell lines. Upregulation of antioxidant enzyme expression by palmitate was accompanied by an increase in Nfkb1 transcription, indicative of activation of defence pathways. Lipotoxicity activated ER stress response, evident from increased Hspa4 mRNA level in GLUTag and MIN6 cells. Glucose and palmitate-induced DNA damage and apoptosis, with substantially smaller effects in alpha TC1 cells. Thus alpha cells are resistant to gluco- and lipotoxicity, partly reflecting higher expression of genes involved in antioxidant defence. In contrast, intestinal L cells, like beta cells, are prone to gluco- and lipotoxicity, possibly contributing to abnormalities of GLP-1 secretion in type 2 diabetes.

State of the art systematic review of bone disease in anorexia nervosa.

OBJECTIVE: Low bone mineral density (BMD) is a known consequence of anorexia nervosa (AN) and is particularly concerning during adolescence, a critical time for bone accrual. A comprehensive synthesis of available data regarding impaired bone health, its determinants, and associated management strategies in AN is currently lacking. This systematic review aims to synthesize information from key physiologic and prospective studies and trials, and provide a thorough understanding of impaired bone health in AN and its management. METHOD: Search terms included "anorexia nervosa" AND "bone density" for the period 1995-2015, limited to articles in English. Papers were screened manually based on journal impact factor, sample size, age of participants, and inclusion of a control group. When necessary, we included seminal papers published before 1995. RESULTS: AN leads to low BMD, impaired bone quality and increased fracture risk. Important determinants are low lean mass, hypogonadism, IGF-1 deficiency, and alterations in other hormones that impact bone health. Weight gain and menses restoration are critical for improving bone outcomes in AN. Physiologic estrogen replacement as the transdermal patch was shown to increase bone accrual in one study in adolescent females with AN; however, residual deficits persist. Bisphosphonates are potentially useful in adults with AN. DISCUSSION: To date, evidence suggests that the safest and most effective strategy to improve bone health in AN is normalization of weight with restoration of menses. Pharmacotherapies that show promise include physiologic estradiol replacement (as the transdermal estradiol patch), and in adults, bisphosphonates. Further studies are necessary to determine the best strategies to normalize BMD in AN.

A systematic review of approaches to refeeding in patients with anorexia nervosa.

OBJECTIVE: Given the importance of weight restoration for recovery in patients with anorexia nervosa (AN), we examined approaches to refeeding in adolescents and adults across treatment settings. METHODS: Systematic review of PubMed, PsycINFO, Scopus, and Clinical Trials databases (1960-2015) using terms refeeding, weight restoration, hypophosphatemia, anorexia nervosa, anorexia, and anorexic. RESULTS: Of 948 screened abstracts, 27 met these inclusion criteria: participants had AN; reproducible refeeding approach; weight gain, hypophosphatemia or cognitive/behavioral outcomes. Twenty-six studies (96%) were observational/prospective or retrospective and performed in hospital. Twelve studies published since 2010 examined approaches starting with higher calories than currently recommended (≥1400 kcal/d). The evidence supports 8 conclusions: 1) In mildly and moderately malnourished patients, lower calorie refeeding is too conservative; 2) Both meal-based approaches or combined nasogastric+meals can administer higher calories; 3) Higher calorie refeeding has not been associated with increased risk for the refeeding syndrome under close medical monitoring with electrolyte correction; 4) In severely malnourished inpatients, there is insufficient evidence to change the current standard of care; 5) Parenteral nutrition is not recommended; 6) Nutrient compositions within recommended ranges are appropriate; 7) More research is needed in non-hospital settings; 8) The long-term impact of different approaches is unknown; DISCUSSION: Findings support higher calorie approaches to refeeding in mildly and moderately malnourished patients under close medical monitoring, however the safety, long-term outcomes, and feasibility outside of hospital have not been established. Further research is also needed on refeeding approaches in severely malnourished patients, methods of delivery, nutrient compositions and treatment settings.

Mechanisms of toxicity by proinflammatory cytokines in a novel human pancreatic beta cell line, 1.1B4.

BACKGROUND: Molecular mechanisms of toxicity and cell damage were investigated in the novel human beta cell line, 1.1B4, after exposure to proinflammatory cytokines - IL-1ß, IFN-γ, TNF-α. METHODS: MTT assay, insulin radioimmunoassay, glucokinase assay, real time reverse transcription PCR, western blotting, nitrite assay, caspase assay and comet assay were used to investigate mechanisms of cytokine toxicity. RESULTS: Viability of 1.1B4 cells decreased after 18h cytokine exposure. Cytokines significantly reduced cellular insulin content and impaired insulin secretion induced by glucose, alanine, KCl, elevated Ca(2+), GLP-1 or forskolin. Glucokinase enzyme activity, regulation of intracellular Ca(2+) and PDX1 protein expression were significantly reduced by cytokines. mRNA expression of genes involved in secretory function - INS, GCK, PCSK2 and GJA1 was downregulated in cytokine treated 1.1B4 cells. Upregulation of transcription of genes involved in antioxidant defence - SOD2 and GPX1 was observed, suggesting involvement of oxidative stress. Cytokines also upregulated transcriptions of NFKB1 and STAT1, which was accompanied by a significant increase in NOS2 transcription and accumulation of nitrite in culture medium, implicating nitrosative stress. Oxidative and nitrosative stresses induced apoptosis was evident from increased % tail DNA, DNA fragmentation, caspase 3/7 activity, apoptotic cells and lower BCL2 protein expression. CONCLUSIONS: This study delineates molecular mechanisms of cytokine toxicity in 1.1B4 cells, which agree with earlier observations using human islets and rodent beta cells. GENERAL SIGNIFICANCE: This study emphasizes the potential usefulness of this cell line as a human beta cell model for research investigating autoimmune destruction of pancreatic beta cells.

Pseudoislet formation enhances gene expression, insulin secretion and cytoprotective mechanisms of clonal human insulin-secreting 1.1B4 cells.

We have studied the effects of cell communication on human beta cell function and resistance to cytotoxicity using the novel human insulin-secreting cell line 1.1B4 configured as monolayers and pseudoislets. Incubation with the incretin gut hormones GLP-1 and GIP caused dose-dependent stimulation of insulin secretion from 1.1B4 cell monolayers and pseudoislets. The secretory responses were 1.5-2.7-fold greater than monolayers. Cell viability (MTT), DNA damage (comet assay) and apoptosis (acridine orange/ethidium bromide staining) were investigated following 2-h exposure of 1.1B4 monolayers and pseudoislets to ninhydrin, H2O2, streptozotocin, glucose, palmitate or cocktails of proinflammatory cytokines. All agents tested decreased viability and increased DNA damage and apoptosis in both 1.1B4 monolayers and pseudoislets. However, pseudoislets exhibited significantly greater resistance to cytotoxicity (1.5-2.7-fold increases in LD50) and lower levels of DNA damage (1.3-3.4-fold differences in percentage tail DNA and olive tail moment) and apoptosis (1.3-1.5-fold difference) compared to monolayers. Measurement of gene expression by reverse-transcription, real-time PCR showed that genes involved with insulin secretion (INS, PDX1, PCSK1, PCSK2, GLP1R and GIPR), cell-cell communication (GJD2, GJA1 and CDH1) and antioxidant defence (SOD1, SOD2, GPX1 and CAT) were significantly upregulated in pseudoislets compared to monolayers, whilst the expression of proapoptotic genes (NOS2, MAPK8, MAPK10 and NFKB1) showed no significant differences. In summary, these data indicate cell-communication associated with three-dimensional islet architecture is important both for effective insulin secretion and for protection of human beta cells against cytotoxicity.

Liver, pancreas and kidney transplantation for the treatment of Wolcott-Rallison syndrome.

We present the case of a child who underwent a combined liver, pancreas and double kidney transplant following complications of Wolcott-Rallison syndrome (WRS) a rare genetic disorder that causes infantile insulin-dependent diabetes mellitus (IDDM) and often death in childhood from fulminant liver and concomitant kidney failure. WRS is characterized clinically through infantile IDDM, propensity for liver failure following viral infections, bone dysplasia and growth failure and developmental delay. Fewer than 60 cases with WRS are reported in the literature, mostly from consanguineous parents. Future episodes of liver failure, the main contributor to the increased mortality in WRS, may be prevented through timely liver transplantation. To the best of our knowledge, transplantation has not been utilized to manage complications of WRS prior to this report.