Comparison of 3-day and 7-day recall periods for food consumption reference values in foodborne disease outbreak investigations.

Investigations into an outbreak of foodborne disease attempt to identify the source of illness as quickly as possible. Population-based reference values for food consumption can assist in investigation by providing comparison data for hypothesis generation and also strengthening the evidence associated with a food product through hypothesis testing. In 2014-2015 a national phone survey was conducted in Canada to collect data on food consumption patterns using a 3- or 7-day recall period. The resulting food consumption values over the two recall periods were compared. The majority of food products did not show a significant difference in the consumption over 3 days and 7 days. However, comparison of reference values from the 3-day recall period to data from an investigation into a Salmonella Infantis outbreak was shown to support the conclusion that chicken was the source of the outbreak whereas the reference values from a 7-day recall did not support this finding. Reference values from multiple recall periods can assist in the hypothesis generation and hypothesis testing phase of foodborne outbreak investigations.

Estimates of the burden of illness for eight enteric pathogens associated with animal contact in Canada.

Enteric pathogens are commonly known to be transmitted through food or water; however, contact with animals is another important transmission route. This study estimated the annual burden of illness attributable to animal contact for eight enteric pathogens in Canada. Using data from a Canadian expert elicitation on transmission routes, the proportion of enteric illnesses attributable to animal contact was estimated for each pathogen to estimate the annual number of illnesses, hospitalizations and deaths in Canada. For each estimate, a mean and probability intervals were generated. Of all illnesses caused by these eight pathogens, 16% were estimated attributable to animal contact. This estimate translates to 86 000 (31 000-166 000) illnesses, 488 (186-890) hospitalizations and 12 (2-28) deaths annually for the eight pathogens combined. Campylobacter spp. is the leading cause of illnesses annually, with an estimated 38 000 (14 000-71 000) illnesses occurring each year, followed by non-typhoidal Salmonella spp. (17 000, 6000-32 000). The majority of hospitalizations were attributable to non-typhoidal Salmonella spp. (36%) and Campylobacter spp. (31%). Non-typhoidal Salmonella spp. (28%) and Listeria monocytogenes (31%) were responsible for the majority of the estimated deaths. These results identify farm animal and pet/pet food exposure as key pathways of transmission for several pathogens. The estimated burden of illness associated with animal contact is substantial.

Estimating the burden of acute gastrointestinal illness due to Giardia, Cryptosporidium, Campylobacter, E. coli O157 and norovirus associated with private wells and small water systems in Canada.

Waterborne illness related to the consumption of contaminated or inadequately treated water is a global public health concern. Although the magnitude of drinking water-related illnesses in developed countries is lower than that observed in developing regions of the world, drinking water is still responsible for a proportion of all cases of acute gastrointestinal illness (AGI) in Canada. The estimated burden of endemic AGI in Canada is 20·5 million cases annually - this estimate accounts for under-reporting and under-diagnosis. About 4 million of these cases are domestically acquired and foodborne, yet the proportion of waterborne cases is unknown. There is evidence that individuals served by private systems and small community systems may be more at risk of waterborne illness than those served by municipal drinking water systems in Canada. However, little is known regarding the contribution of these systems to the overall drinking water-related AGI burden in Canada. Private water supplies serve an estimated 12% of the Canadian population, or ~4·1 million people. An estimated 1·4 million (4·1%) people in Canada are served by small groundwater (2·6%) and surface water (1·5%) supplies. The objective of this research is to estimate the number of AGI cases attributable to water consumption from these supplies in Canada using a quantitative microbial risk assessment (QMRA) approach. This provides a framework for others to develop burden of waterborne illness estimates for small water supplies. A multi-pathogen QMRA of Giardia, Cryptosporidium, Campylobacter, E. coli O157 and norovirus, chosen as index waterborne pathogens, for various source water and treatment combinations was performed. It is estimated that 103 230 AGI cases per year are due to the presence of these five pathogens in drinking water from private and small community water systems in Canada. In addition to providing a mechanism to assess the potential burden of AGI attributed to small systems and private well water in Canada, this research supports the use of QMRA as an effective source attribution tool when there is a lack of randomized controlled trial data to evaluate the public health risk of an exposure source. QMRA is also a powerful tool for identifying existing knowledge gaps on the national scale to inform future surveillance and research efforts.

Estimating the number of cases of acute gastrointestinal illness (AGI) associated with Canadian municipal drinking water systems.

The estimated burden of endemic acute gastrointestinal illness (AGI) annually in Canada is 20·5 million cases. Approximately 4 million of these cases are domestically acquired and foodborne, yet the proportion of waterborne cases is unknown. A number of randomized controlled trials have been completed to estimate the influence of tap water from municipal drinking water plants on the burden of AGI. In Canada, 83% of the population (28 521 761 people) consumes tap water from municipal drinking water plants serving >1000 people. The drinking water-related AGI burden associated with the consumption of water from these systems in Canada is unknown. The objective of this research was to estimate the number of AGI cases attributable to consumption of drinking water from large municipal water supplies in Canada, using data from four household drinking water intervention trials. Canadian municipal water treatment systems were ranked into four categories based on source water type and quality, population size served, and treatment capability and barriers. The water treatment plants studied in the four household drinking water intervention trials were also ranked according to the aforementioned criteria, and the Canadian treatment plants were then scored against these criteria to develop four AGI risk groups. The proportion of illnesses attributed to distribution system events vs. source water quality/treatment failures was also estimated, to inform the focus of future intervention efforts. It is estimated that 334 966 cases (90% probability interval 183 006-501 026) of AGI per year are associated with the consumption of tap water from municipal systems that serve >1000 people in Canada. This study provides a framework for estimating the burden of waterborne illness at a national level and identifying existing knowledge gaps for future research and surveillance efforts, in Canada and abroad.

Systematic review and meta-analysis of the proportion of non-typhoidal Salmonella cases that develop chronic sequelae.

The objective of this systematic review and meta-analysis was to estimate the proportion of cases of non-typhoidal salmonellosis (NTS) that develop chronic sequelae, and to investigate factors associated with heterogeneity. Articles published in English prior to July 2011 were identified by searching PubMed, Agricola, CabDirect, and Food Safety and Technology Abstracts. Observational studies reporting the number of NTS cases that developed reactive arthritis (ReA), Reiter's syndrome (RS), haemolytic uraemic syndrome (HUS), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) or Guillain-Barré syndrome (GBS), Miller-Fisher syndrome (MFS) were included. Meta-analysis was performed using random effects and heterogeneity was assessed using the I 2 value. Meta-regression was used to explore the influence of study-level variables on heterogeneity. A total of 32 studies were identified; 25 reported on ReA, five reported on RS, seven reported on IBS, two reported on IBD, two reported on GBS, one reported on MFS, and two reported on HUS. There was insufficient data in the literature to calculate a pooled estimate for RS, HUS, IBD, GBS, or MFS. The pooled estimate of the proportion of cases of NTS that developed ReA and IBS had substantive heterogeneity, limiting the applicability of a single estimate. Thus, these estimates should be interpreted with caution and reasons for the high heterogeneity should be further explored.

Estimated hospitalizations attributed to norovirus and rotavirus infection in Canada, 2006-2010.

Enteric viruses including norovirus and rotavirus are leading causes of gastroenteritis in Canada. However, only a small number of clinical cases are actually tested for these pathogens leading to systematic underestimation of attributed hospitalizations in administrative databases. The objective of this analysis was to estimate the number of hospitalizations due to norovirus and rotavirus in Canada. Hospitalization records for acute gastroenteritis-associated discharges at all acute-care hospitals in Canada between 2006 and 2011 were analysed. Cause-unspecified gastroenteritis hospitalizations were modelled using age-specific negative binomial models with cause-specified gastroenteritis admissions as predictors. The coefficients from the models were used to estimate the number of norovirus and rotavirus admissions. The total annual hospitalizations for rotavirus were estimated to be between 4500 and 10 000. Total annual hospitalizations for norovirus were estimated to be between 4000 and 11 000. The mean total annual cost associated with these hospitalizations was estimated to be at least $16 million for rotavirus and $21 million for norovirus (all figures in Canadian dollars). This study is the first comprehensive analysis of norovirus and rotavirus hospitalizations in Canada. These estimates provide a more complete assessment of the burden and economic costs of these pathogens to the Canadian healthcare system.

Acute gastrointestinal illness in two Inuit communities: burden of illness in Rigolet and Iqaluit, Canada.

Food- and waterborne disease is thought to be high in some Canadian Indigenous communities; however, the burden of acute gastrointestinal illness (AGI) is not well understood due to limited availability and quality of surveillance data. This study estimated the burden of community-level self-reported AGI in the Inuit communities of Rigolet, Nunatsiavut, and Iqaluit, Nunavut, Canada. Cross-sectional retrospective surveys captured information on AGI and potential environmental risk factors. Multivariable logistic regression models identified potential AGI risk factors. The annual incidence of AGI ranged from 2·9-3·9 cases/person per year in Rigolet and Iqaluit. In Rigolet, increased spending on obtaining country foods, a homeless person in the house, not visiting a cabin recently, exposure to puppies, and alternative sources of drinking water were associated with increased odds of AGI. In Iqaluit, eating country fish often, exposure to cats, employment status of the person responsible for food preparation, not washing the countertop with soap after preparing meat, a homeless person in the house, and overcrowding were associated with increased odds of AGI. The results highlight the need for systematic data collection to better understand and support previously anecdotal indications of high AGI incidence, as well as insights into unique AGI environmental risk factors in Indigenous populations.

Serum Creatinine Versus Plasma Methotrexate Levels to Predict Toxicities in Children Receiving High-dose Methotrexate.

Facilities for measuring methotrexate (MTX) levels are not available everywhere, potentially limiting administration of high-dose methotrexate (HDMTX). We hypothesized that serum creatinine alteration after HDMTX administration predicts MTX clearance. Overall, 122 cycles in 50 patients of non-Hodgkin lymphoma or acute lymphoblastic leukemia aged ≤18 years receiving HDMTX were enrolled prospectively. Plasma MTX levels were measured at 12, 24, 36, 48, 60, and 72 hours; serum creatinine was measured at baseline, 24, 48, and 72 hours. Correlation of plasma MTX levels with creatinine levels and changes in creatinine from baseline (Δ creatinine) were evaluated. Plasma MTX levels at 72 hours showed positive correlation with serum creatinine at 48 hours (P = .011) and 72 hours (P = .013) as also Δ creatinine at 48 hours (P = .042) and 72 hours (P = .045). However, cut-off value of either creatinine or Δ creatinine could not be established to reliably predict delayed MTX clearance. Greater than 50% Δ creatinine at 48 and 72 hours significantly predicted grade 3/4 leucopenia (P = .036 and P = .001, respectively) and thrombocytopenia (P = .012 and P = .009, respectively) but not mucositis (P = .827 and P = .910, respectively). Delayed MTX elimination did not predict any grade 3/4 toxicity. In spite of demonstration of significant correlation between serum creatinine and Δ creatinine with plasma MTX levels at 72 hours, cut-off value of either variable to predict MTX delay could not be established. Thus, either of these cannot be used as a surrogate for plasma MTX estimation. Interestingly, Δ creatinine effectively predicted hematological toxicities, which were not predicted by delayed MTX clearance.

A systematic review of waterborne disease burden methodologies from developed countries.

The true incidence of endemic acute gastrointestinal illness (AGI) attributable to drinking water in Canada is unknown. Using a systematic review framework, the literature was evaluated to identify methods used to attribute AGI to drinking water. Several strategies have been suggested or applied to quantify AGI attributable to drinking water at a national level. These vary from simple point estimates, to quantitative microbial risk assessment, to Monte Carlo simulations, which rely on assumptions and epidemiological data from the literature. Using two methods proposed by researchers in the USA, this paper compares the current approaches and key assumptions. Knowledge gaps are identified to inform future waterborne disease attribution estimates. To improve future estimates, there is a need for robust epidemiological studies that quantify the health risks associated with small, private water systems, groundwater systems and the influence of distribution system intrusions on risk. Quantification of the occurrence of enteric pathogens in water supplies, particularly for groundwater, is needed. In addition, there are unanswered questions regarding the susceptibility of vulnerable sub-populations to these pathogens and the influence of extreme weather events (precipitation) on AGI-related health risks. National centralized data to quantify the proportions of the population served by different water sources, by treatment level, source water quality, and the condition of the distribution system infrastructure, are needed.

Burden of acute gastrointestinal illness in the Metropolitan region, Chile, 2008.

The purpose of this study was to determine the magnitude and distribution of acute gastrointestinal illness (GI) in the Chilean population, describe its burden and presentation, identify risk factors associated with GI and assess the differences between a 7-day, 15-day and a 30-day recall period in the population-based burden of illness study design. Face-to-face surveys were conducted on 6047 randomly selected residents in the Metropolitan region, Chile (average response rate 75·8%) in 2008. The age-adjusted monthly prevalence of GI was 9·2%. The 7-day recall period provided annual incidence rate estimates about 2·2 times those of the 30-day recall period. Age, occupation, healthcare system, sewer system, antibiotic use and cat ownership were all found to be significant predictors for being a case. This study expands on the discussion of recall bias in retrospective population studies and reports the first population-based burden and distribution of GI estimates in Chile.

Significance of the myxovirus resistance A (MxA) gene -123C>a single-nucleotide polymorphism in suppressed interferon beta induction of severe acute respiratory syndrome coronavirus infection.

Myxovirus resistance A (MxA) is an antiviral protein induced by interferon alpha and beta (IFN-alpha, IFN-beta) that can inhibit viral replication. The minor alleles of the -88G>T and -123C>A MxA promoter single-nucleotide polymorphisms (SNPs) are associated with increased promoter activity and altered response to IFN-alpha and IFN-beta treatment. Here, we demonstrate that the -123A minor allele provided stronger binding affinity to nuclear proteins extracted from IFN-beta-untreated cells than did the wild-type allele, whereas the -88T allele showed preferential binding after IFN-beta stimulation. Endogenous IFN-alpha and IFN-beta induction can be suppressed in severe acute respiratory syndrome (SARS) coronavirus infection. In support of our in vitro findings, a large case-control genetic-association study for SARS coronavirus infection confirmed that the -123A minor-allele carriers were significantly associated with lower risk of SARS coronavirus infection, whereas the -88T minor-allele carriers were insignificant after adjustment for confounding effects. This suggests that -123C>A plays a more important role in modulating basal MxA expression, thus contributing more significantly to innate immune response against viral infections that suppress endogenous IFN-alpha and IFN-beta induction such as SARS coronavirus.

Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b.

BACKGROUND & AIMS: The aim of this study was to evaluate the long-term sustainability of response in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with pegylated interferon (PEG-IFN) alpha-2b alone or in combination with lamivudine. METHODS: All 266 patients enrolled in the HBV99-01 study were offered participation in a long-term follow-up (LTFU) study. Patients were treated with PEG-IFN alpha-2b (100 mug/wk) alone or in combination with lamivudine (100 mg/day) for 52 weeks. Initial response was defined as HBeAg negativity at 26 weeks posttreatment. For the LTFU study, patients had one additional visit after the initial study (mean interval, 3.0 +/- 0.8 years). RESULTS: Of 266 patients enrolled in the initial study, 172 (65%) participated in the LTFU study. At LTFU, HBeAg and hepatitis B surface antigen (HBsAg) negativity were observed in 37% and 11% of 172 patients, respectively. Sixty-four patients were classified as initial responders and 108 as nonresponders. Among the initial responders, sustained HBeAg negativity and HBsAg loss were observed in 81% and 30%, respectively. Significantly higher rates of HBeAg negativity were observed in genotype A-infected initial responders compared with those with genotype non-A (96% vs 76%; P = .06) as well as HBsAg loss (58% vs 11%; P < .001). CONCLUSIONS: HBeAg loss after treatment with PEG-IFN alpha-2b alone or in combination with lamivudine is sustained in the majority of patients and is associated with a high likelihood of HBsAg loss, particularly in genotype A-infected patients. Therefore, PEG-IFN alpha-2b remains an important treatment option in this era of nucleos(t)ide analogue therapy.

Insect prothoracicotropic hormone: evidence for two molecular forms.

In an insect, the tobacco hornworm Manduca sexta, the cerebral neuropeptide prothoracicotropic hormone (PTTH), the primary effector of postembryonic development, exists as two molecular forms. These two PTTH's elicit characteristic in vitro dose responses of activation of prothoracic glands from different developmental stages, an indication that during development the glands change in their sensitivity to the neurohormones. Both PTTH's are active in a specific in situ bioassay. Since they may be released in situ at stage-specific times to evoke distinctly different developmental responses, the PTTH neuroendocrine axis appears to be an effective system for determining the functions of molecular forms of a neurohormone in the regulation of growth and development.

Health-related quality of life of Southern Chinese with chronic hepatitis B infection.

BACKGROUND: Few studies have evaluated the health-related quality of life (HRQOL) of Southern Chinese with chronic hepatitis B (CHB) infection. AIM: To evaluate the HRQOL of Chinese patients at different stages of CHB infection and to find out factors associated with HRQOL. METHODS: 520 Chinese adult CHB patients of whom 156 were uncomplicated, 102 had impaired liver function, 139 had cirrhosis and 123 had hepatocellular carcinoma (HCC) were interviewed with a structured questionnaire, the SF-36 Health Survey version 2 (SF-36v2), and the Chronic Liver Disease Questionnaire (CLDQ). The differences in SF-6D health preference values and SF-36v2 scores between each CHB group and Hong Kong population norms were assessed by t-test. ANOVA was used to compare the mean SF-6D health preference, SF-36v2 scores, and CLDQ scores among CHB groups. Multiple linear regressions were performed to identify determinants of HRQOL. RESULTS: CHB patients had significantly lower SF-36v2 scores than the population norm. The SF-6D values of CHB patients with uncomplicated disease, impaired liver function, HCC and cirrhosis were 0.755, 0.745, 0.720 and 0.701, respectively, all significantly lower than the population norm of 0.787. Advanced stage of CHB illness, anti-viral treatment, bilirubin level, psychological co-morbidity, younger age and female were associated with poorer HRQOL. CONCLUSION: CHB infection had a negative impact on HRQOL. There was a progressive decrease in health preference values with CHB disease progression. The results can be used for the estimation of quality adjusted life years (QALYs) for CHB patients in cost effectiveness or cost utility studies. TRIAL REGISTRATION: http://www.hkclinicaltrials.com; HKCTR-151.

Adiponectin levels are high in children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

OBJECTIVE: It has been shown that adiponectin serves as an insulin-sensitizing adipokine. Serum concentrations of adiponectin are low in children with obesity, and increase with fat mass loss, indicating that adiponectin can serve as a biomarker. Since the prevalence of overweight and obesity is increased in children with congenital adrenal hyperplasia (CAH), our study aimed to evaluate serum levels of adiponectin in a cohort of CAH children and adolescents, and their associations with clinical parameters such as chronological age (CA), body mass index (BMI), Tanner stage (TS), medication and metabolic control. PATIENTS AND METHODS: We studied 51 patients, aged between 5.6 and 19.6 years (median 11.8; 30 females, 21 males), cross-sectionally. All patients had genetically confirmed CAH and received standard steroid substitution therapy. Adiponectin was measured by an enzyme linked immunoassay. Since BMI SDS of the CAH cohort were significantly higher compared to the reference population, we built matched pairs with healthy Caucasian subjects from a normal representative cohort for sex, Tanner stage, chronologic age and BMI. RESULTS: Adiponectin concentrations were significantly higher in CAH patients (median 11 microg/L) compared to the matched controls (6.7 microg/L, p < 0.0001). Correlation analyses in CAH patients revealed a significant inverse relationship between adiponectin and CA, TS, BMI, serum DHEAS and serum testosterone, but no correlation with hydrocortisone and fludrocortisone dosage. CONCLUSION: Currently, the importance of the elevated adiponectin concentrations in CAH children for risk assessment is not clear. However, our data imply that besides adequate metabolic control of glucocorticoid substitution, a long-term follow-up of other metabolic markers of insulin resistance should be conducted in CAH patients.

Birth Size in Neonates with Congenital Adrenal Hyperplasia due to 21-hydroxylase Deficiency

Objective: Classic congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency is characterized by increased prenatal adrenal androgen secretion. There are a small number of reports in the literature showing higher birth weight and length in CAH newborns. Methods: We analyzed birth weight and length data of 116 German newborns (48 boys, 68 girls) with classic CAH who were born during the period from 1990 to 2017. All children have been followed or are currently treated as outpatients in our clinic. All children were born at term. The mothers were healthy and their pregnancies were uneventful. The diagnosis of CAH was confirmed by molecular analyses of the CYP21A2 gene. Birth data were calculated as standard deviation (SD) scores according to German reference values. Results: Weight and length in male CAH newborns (mean ± SD) (3601±576 g; 52.4±2.85 cm) were significantly higher than in female CAH newborns (3347±442 g; 51.2±2.55 cm), but male-female differences in the CAH cohort were lost when the data were converted into SD scores. The birth sizes of the CAH newborns did not differ from the reference group. The birth sizes also did not differ between the different CAH genotypes. Maternal age, mode of delivery and maternal parity had no influence on birth size. Conclusion: Our data show that prenatal hyperandrogenism does not affect fetal growth.

Estimation of the costs of acute gastrointestinal illness in British Columbia, Canada.

The costs associated with gastrointestinal infection (GI) in the province of British Columbia, Canada, were estimated using data from a population-based survey in three health service delivery areas, namely Vancouver, East Kootenay and Northern Interior. The number of cases of disease, consequent expenditure of resources and associated economic costs were modeled as probability distributions in a stochastic model. Using 2004 prices, the estimated mean annual cost per capita of gastrointestinal infection was CAN$128.61 (207.96 euros), with a mean annual cost per case of CAN$1,342.57 (2,170.99 euros). The mean estimate of the overall economic burden to British Columbia was CAN$514.2 million (831.5 million euros) (95% CFI CAN$161.0 million to CAN$5.8 billion; 260.3 million euros to 9.38 billion euros). The major element of this cost was the loss of productivity associated with time away from paid employment by both the sick and their caregivers. Sensitivity analysis suggested that the uncertainty associated with the base model assumptions did not significantly affect the estimates. The results are comparable to those obtained in an earlier study using a similar analytical framework and data from the city of Hamilton, Ontario, Canada.

Burden of acute gastrointestinal illness in Canada, 1999-2007: interim summary of NSAGI activities.

INTRODUCTION: The National Studies on Acute Gastrointestinal Illness (NSAGI) initiative was designed to generate baseline period prevalence rates of self-reported AGI in communities across Canada, assess the burden associated with AGI, and quantify the under-reporting of AGI in Canada's national enteric disease reporting systems. METHODS: Methods utilized included population surveys administered randomly via telephone services. Three population surveys in three locations within Canada included over 10,000 residents. Questions pertained to recent symptoms as well as socio-demographic factors, use of the health care system and missed work or school due to illness. RESULTS: In summary of published results, there are an estimated 1.3 episodes of AGI per person-year and an estimated 10-47, 13-37 and 23-49 cases in the community for every case of verotoxigenic Escherichia coli, Salmonella and Campylobacter, respectively, captured within the national surveillance system. AGI represents an annual per capita cost of $115 CAD. DISCUSSION: The work of NSAGI highlights the significant burden and impact of AGI in the Canadian population. These results will also be incorporated into the current work at the World Health Organization (WHO) to estimate the global burden of food related illnesses.

Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1.

Monogenic forms of diabetes can result from mutations in genes encoding transcription factors. Mutations in the homeodomain transcription factor IDX-1, a critical regulator of pancreas development and insulin gene transcription, confer a strong predisposition to the development of diabetes mellitus in humans. To investigate the role of IDX-1 expression in the pathogenesis of diabetes, we developed a model for the inducible impairment of IDX-1 expression in pancreatic beta cells in vivo by engineering an antisense ribozyme specific for mouse IDX-1 mRNA under control of the reverse tetracycline transactivator (rtTA). Doxycycline-induced impairment of IDX-1 expression reduced activation of the Insulin promoter but activated the Idx-1 promoter, suggesting that pancreatic beta cells regulate IDX-1 transcription to maintain IDX-1 levels within a narrow range. In transgenic mice that express both rtTA and the antisense ribozyme construct, impaired IDX-1 expression elevated glycated hemoglobin levels, diminished glucose tolerance, and decreased insulin/glucose ratios. Metabolic phenotypes induced by IDX-1 deficiency were observed predominantly in male mice over 18 months of age, suggesting that cellular mechanisms to protect IDX-1 levels in pancreatic beta cells decline with aging. We propose that even in the absence of Idx-1 gene mutations, pathophysiological processes that decrease IDX-1 levels are likely to impair glucose tolerance. Therapeutic strategies to attain normal glucose homeostasis by restoring normal IDX-1 levels may be of particular importance for older individuals with diabetes mellitus.