Food insecurity, diet quality, and suboptimal diabetes management among US adults with diabetes.

INTRODUCTION: A healthy diet is recommended to support diabetes management, including HbA1c, blood pressure, and cholesterol (ABC) control, but food insecurity is a barrier to consuming a healthy diet. We determined the prevalence of food insecurity and diet quality among US adults with diabetes and the associations with ABC management. RESEARCH DESIGN AND METHODS: Cross-sectional analyses were conducted among 2075 adults ≥20 years with diagnosed diabetes who participated in the 2013-2018 National Health and Nutrition Examination Surveys. Food insecurity was assessed using a standard questionnaire and diet quality was assessed using quartiles of the 2015 Healthy Eating Index. Adjusted ORs (aOR, 95% CI) were calculated from logistic regression models to determine the association between household food insecurity/diet quality and the ABCs while controlling for sociodemographic characteristics, healthcare utilization, smoking, medication for diabetes, blood pressure, or cholesterol, and body mass index. RESULTS: Overall, 17.6% of adults had food insecurity/low diet quality; 14.2% had food insecurity/high diet quality; 33.1% had food security/low diet quality; and 35.2% had food security/high diet quality. Compared with adults with food security/high diet quality, those with food insecurity/low diet quality were significantly more likely to have HbA1c ≥7.0% (aOR=1.85, 95% CI 1.23 to 2.80) and HbA1c ≥8.0% (aOR=1.79, 95% CI 1.04 to 3.08); food insecurity/high diet quality was significantly associated with elevated HbA1c; and food security/low diet quality with elevated A1c. CONCLUSIONS: Food insecurity, regardless of diet quality, was significantly associated with elevated A1c. For people with food insecurity, providing resources to reduce food insecurity could strengthen the overall approach to optimal diabetes management.

Associations of Maternal Cardiovascular Health in Pregnancy With Offspring Cardiovascular Health in Early Adolescence.

Importance: Pregnancy may be a key window to optimize cardiovascular health (CVH) for the mother and influence lifelong CVH for her child. Objective: To examine associations between maternal gestational CVH and offspring CVH. Design, Setting, and Participants: This cohort study used data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study (examinations: July 2000-April 2006) and HAPO Follow-Up Study (examinations: February 2013-December 2016). The analyses included 2302 mother-child dyads, comprising 48% of HAPO Follow-Up Study participants, in an ancillary CVH study. Participants were from 9 field centers across the United States, Barbados, United Kingdom, China, Thailand, and Canada. Exposures: Maternal gestational CVH at a target of 28 weeks' gestation, based on 5 metrics: body mass index, blood pressure, total cholesterol level, glucose level, and smoking. Each metric was categorized as ideal, intermediate, or poor using pregnancy guidelines. Total CVH was categorized as follows: all ideal metrics, 1 or more intermediate (but 0 poor) metrics, 1 poor metric, or 2 or more poor metrics. Main Outcomes and Measures: Offspring CVH at ages 10 to 14 years, based on 4 metrics: body mass index, blood pressure, total cholesterol level, and glucose level. Total CVH was categorized as for mothers. Results: Among 2302 dyads, the mean (SD) ages were 29.6 (2.7) years for pregnant mothers and 11.3 (1.1) years for children. During pregnancy, the mean (SD) maternal CVH score was 8.6 (1.4) out of 10. Among pregnant mothers, the prevalence of all ideal metrics was 32.8% (95% CI, 30.6%-35.1%), 31.7% (95% CI, 29.4%-34.0%) for 1 or more intermediate metrics, 29.5% (95% CI, 27.2%-31.7%) for 1 poor metric, and 6.0% (95% CI, 3.8%-8.3%) for 2 or more poor metrics. Among children of mothers with all ideal metrics, the prevalence of all ideal metrics was 42.2% (95% CI, 38.4%-46.2%), 36.7% (95% CI, 32.9%-40.7%) for 1 or more intermediate metrics, 18.4% (95% CI, 14.6%-22.4%) for 1 poor metric, and 2.6% (95% CI, 0%-6.6%) for 2 or more poor metrics. Among children of mothers with 2 or more poor metrics, the prevalence of all ideal metrics was 30.7% (95% CI, 22.0%-40.4%), 28.3% (95% CI, 19.7%-38.1%) for 1 or more intermediate metrics, 30.7% (95% CI, 22.0%-40.4%) for 1 poor metric, and 10.2% (95% CI, 1.6%-20.0%) for 2 or more poor metrics. The adjusted relative risks associated with 1 or more intermediate, 1 poor, and 2 or more poor (vs all ideal) metrics, respectively, in mothers during pregnancy were 1.17 (95% CI, 0.96-1.42), 1.66 (95% CI, 1.39-1.99), and 2.02 (95% CI, 1.55-2.64) for offspring to have 1 poor (vs all ideal) metrics, and the relative risks were 2.15 (95% CI, 1.23-3.75), 3.32 (95% CI,1.96-5.62), and 7.82 (95% CI, 4.12-14.85) for offspring to have 2 or more poor (vs all ideal) metrics. Additional adjustment for categorical birth factors (eg, preeclampsia) did not fully explain these significant associations (eg, relative risk for association between 2 or more poor metrics among mothers during pregnancy and 2 or more poor metrics among offspring after adjustment for an extended set of birth factors, 6.23 [95% CI, 3.03-12.82]). Conclusions and Relevance: In this multinational cohort, better maternal CVH at 28 weeks' gestation was significantly associated with better offspring CVH at ages 10 to 14 years.

Detection of Diabetes Status and Type in Youth Using Electronic Health Records: The SEARCH for Diabetes in Youth Study.

OBJECTIVE: Diabetes surveillance often requires manual medical chart reviews to confirm status and type. This project aimed to create an electronic health record (EHR)-based procedure for improving surveillance efficiency through automation of case identification. RESEARCH DESIGN AND METHODS: Youth (<20 years old) with potential evidence of diabetes (N = 8,682) were identified from EHRs at three children's hospitals participating in the SEARCH for Diabetes in Youth Study. True diabetes status/type was determined by manual chart reviews. Multinomial regression was compared with an ICD-10 rule-based algorithm in the ability to correctly identify diabetes status and type. Subsequently, the investigators evaluated a scenario of combining the rule-based algorithm with targeted chart reviews where the algorithm performed poorly. RESULTS: The sample included 5,308 true cases (89.2% type 1 diabetes). The rule-based algorithm outperformed regression for overall accuracy (0.955 vs. 0.936). Type 1 diabetes was classified well by both methods: sensitivity (Se) (>0.95), specificity (Sp) (>0.96), and positive predictive value (PPV) (>0.97). In contrast, the PPVs for type 2 diabetes were 0.642 and 0.778 for the rule-based algorithm and the multinomial regression, respectively. Combination of the rule-based method with chart reviews (n = 695, 7.9%) of persons predicted to have non-type 1 diabetes resulted in perfect PPV for the cases reviewed while increasing overall accuracy (0.983). The Se, Sp, and PPV for type 2 diabetes using the combined method were ≥0.91. CONCLUSIONS: An ICD-10 algorithm combined with targeted chart reviews accurately identified diabetes status/type and could be an attractive option for diabetes surveillance in youth.

Association of Glycated Hemoglobin Levels With Risk of Pancreatic Cancer.

Importance: New-onset diabetes after the age of 50 years is a potential indicator of pancreatic cancer. Understanding the associations between hyperglycemia, diabetes, and pancreatic cancer, including pancreatic ductal adenocarcinoma, is key to developing an approach to early detection. Objective: To assess the association of elevation in glycated hemoglobin (HbA1c) with the risk of pancreatic cancer. Design, Setting, and Participants: This cohort study was conducted using data collected from an integrated health care system in California. A total of 851 402 patients aged 50 to 84 years who had HbA1c measurements taken between 2010 and 2014 were identified as the base cohort, with 12 contemporaneous cohorts created based on varying HbA1c thresholds (ie, 6.1%, 6.3%, 6.5%, and 6.7%) and prior diabetes status. Data analysis was conducted from August 2018 to September 2019. Main Outcomes and Measures: New cases of pancreatic cancer identified through cancer registry and California death files during a 3-year period. Three-year risk, incidence rate, sensitivity, number of patients needed to screen to detect 1 case, timing, and stage at diagnosis were determined. Results: Among 851 402 patients in the base cohort, 447 502 (52.5%) were women, 255 441 (30.0%) were Hispanic participants, 383 685 (45.1%) were non-Hispanic white participants, 100 477 (11.8%) were Asian participants, and 88 969 (10.4%) were non-Hispanic black participants, with a median (interquartile range) age of 62 (56-69) years and a median (interquartile range) HbA1c level of 6.0% (5.7%-6.6%). The incidence rate of pancreatic cancer was 0.45 (95% CI, 0.43-0.49) per 1000 person-years. After excluding prior diabetes as well as confirmation of new-onset hyperglycemia based on an HbA1c level of 6.5%, a total of 20 012 patients remained, with 74 of 1041 pancreatic ductal adenocarcinoma cases (7.1%) from the base cohort included. The rate of pancreatic cancer was 0.72 (95% CI, 0.32-1.42) per 1000 person-years among Asian patients, 0.83 (95% CI, 0.35-1.71) per 1000 person-years among non-Hispanic black patients, 0.84 (95% CI, 0.48-1.37) per 1000 person-years among Hispanic patients, and 2.37 (95% CI, 1.75-3.14) per 1000 person-years among non-Hispanic white patients. Overall, 42 of 74 cancers (56.8%) were diagnosed within 1 year of the index laboratory test. Among 1041 total cases, 708 (68.0%) had staging information available, of whom 465 (65.7%) had stage III or IV disease at diagnosis. In the base cohort, the number needed to undergo evaluation to identify a single case of pancreatic ductal adenocarcinoma was 818 (95% CI, 770-869), with estimates ranging from 206 (95% CI, 160-264) to 600 (95% CI, 540-666) in the subcohorts. Conclusions and Relevance: The findings of this study suggest that screening patients for pancreatic cancer based solely on elevation in HbA1c level is unlikely to represent an effective strategy. Future efforts to identify a high-risk population based on changes in glycemic parameters should account for racial/ethnic differences.

Receipt of recommended complications and comorbidities screening in youth and young adults with type 1 diabetes: Associations with metabolic status and satisfaction with care.

OBJECTIVES: This study sought to: (a) assess the prevalence of diabetes complications and comorbidities screening as recommended by the American Diabetes Association (ADA) for youth and young adults (YYAs) with type 1 diabetes (T1D), (b) examine the association of previously measured metabolic status related to diabetes complications with receipt of recommended clinical screening, and (c) examine the association of satisfaction with diabetes care with receipt of recommended clinical screening. METHODS: The study included 2172 SEARCH for Diabetes in Youth participants with T1D (>10 years old, diabetes duration >5 years). Mean participant age was 17.7 ± 4.3 years with a diabetes duration of 8.1 ± 1.9 years. Linear and multinomial regression models were used to evaluate associations. RESULTS: Sixty percent of participants reported having three or more hemoglobin A1c (HbA1c) measurements in the past year. In terms of diabetes complications screening, 93% reported having blood pressure measured, 81% having an eye examination, 71% having lipid levels checked, 64% having a foot exam, and 63% completing albuminuria screening in accordance with ADA recommendations. Youth known to have worse glycemic control in the past had higher odds of not meeting HbA1c screening criteria (OR 1.11, 95% CI = 1.05, 1.17); however, after adjusting for race/ethnicity, this was no longer statistically significant. Greater satisfaction with diabetes care was associated with increased odds of meeting screening criteria for most of the ADA-recommended measures. CONCLUSIONS: Efforts should be made to improve diabetes complications screening efforts for YYAs with T1D, particularly for those at higher risk for diabetes complications.

Hypertensive disorders first identified in pregnancy increase risk for incident prehypertension and hypertension in the year after delivery.

BACKGROUND: Hypertensive disorders in pregnancy, including preeclampsia/eclampsia (PE/E) are associated with long-term cardiovascular disease risk. However, little is known about the effect of these conditions on risk for prehypertension (preHTN) or hypertension (HTN) in the early years after delivery. METHODS: The cohort consisted of women who had prenatal care and delivered a live singleton neonate at Kaiser Permanente Bellflower Medical Center in 2005-2010. Women with prepregnancy HTN or preHTN were excluded from analysis. Multivariable robust Poisson regression models were used to assess associations between any hypertensive disorder or PE/E and development of preHTN/HTN in the year after delivery, adjusted for maternal age, race/ethnicity, parity, smoking, prepregnancy weight status, gestational weight gain, gestational diabetes, and gestational age. RESULTS: Among 5960 women who were normotensive prior to pregnancy, 358 (6.0%) developed a hypertensive disorder in pregnancy, of whom 215 (60.1%) had PE/E. Overall, 63 (1.1%) developed HTN and 902 (15.1%) preHTN in the year after delivery. After accounting for all potential confounders, women with a hypertensive disorder in pregnancy and those with PE/E were 2.36 (95% confidence interval: 1.97-2.83) and 2.48 (95% confidence interval: 1.99-3.11) times as likely, respectively, to develop preHTN/HTN in the year after delivery as those without pregnancy-related HTN. Results were similar with and without adjustment for gestational diabetes. CONCLUSION: Our findings highlight the need for prospective studies aimed at determining whether early postpartum screening and improved follow-up of women with hypertensive disorders first identified in pregnancy may prevent future cardiovascular disease.

Use of administrative and electronic health record data for development of automated algorithms for childhood diabetes case ascertainment and type classification: the SEARCH for Diabetes in Youth Study.

BACKGROUND: The performance of automated algorithms for childhood diabetes case ascertainment and type classification may differ by demographic characteristics. OBJECTIVE: This study evaluated the potential of administrative and electronic health record (EHR) data from a large academic care delivery system to conduct diabetes case ascertainment in youth according to type, age, and race/ethnicity. SUBJECTS: Of 57 767 children aged <20 yr as of 31 December 2011 seen at University of North Carolina Health Care System in 2011 were included. METHODS: Using an initial algorithm including billing data, patient problem lists, laboratory test results, and diabetes related medications between 1 July 2008 and 31 December 2011, presumptive cases were identified and validated by chart review. More refined algorithms were evaluated by type (type 1 vs. type 2), age (<10 vs. ≥10 yr) and race/ethnicity (non-Hispanic White vs. 'other'). Sensitivity, specificity, and positive predictive value were calculated and compared. RESULTS: The best algorithm for ascertainment of overall diabetes cases was billing data. The best type 1 algorithm was the ratio of the number of type 1 billing codes to the sum of type 1 and type 2 billing codes ≥0.5. A useful algorithm to ascertain youth with type 2 diabetes with 'other' race/ethnicity was identified. Considerable age and racial/ethnic differences were present in type-non-specific and type 2 algorithms. CONCLUSIONS: Administrative and EHR data may be used to identify cases of childhood diabetes (any type), and to identify type 1 cases. The performance of type 2 case ascertainment algorithms differed substantially by race/ethnicity.

Diabetes self-management education patterns in a US population-based cohort of youth with type 1 diabetes.

PURPOSE: The purpose of this study is to describe (1) the receipt of diabetes self-management education (DSME) in a large, diverse cohort of US youth with type 1 diabetes (T1DM), (2) the segregation of self-reported DSME variables into domains, and (3) the demographic and clinical characteristics of youth who receive DSME. METHODS: Data are from the US population-based cohort SEARCH for Diabetes in Youth. A cross-sectional analysis was employed using data from 1273 youth <20 years of age at the time of diagnosis of T1DM. Clusters of 19 self-reported DSME variables were derived using factor analysis, and their associations with demographic and clinical characteristics were evaluated using polytomous logistic regression. RESULTS: Nearly all participants reported receiving DSME content consistent with "survival skills" (eg, target blood glucose and what to do for low or high blood glucose), yet gaps in continuing education were identified (eg, fewer than half of the participants reported receiving specific medical nutrition therapy recommendations). Five DSME clusters were explored: receipt of specific MNT recommendations, receipt of diabetes information resources, receipt of clinic visit information, receipt of specific diabetes information, and met with educator or nutritionist. Factor scores were significantly associated with demographic and clinical characteristics, including race/ethnicity, socioeconomic status, and diabetes self-management practices. CONCLUSIONS: Health care providers should work together to address reported gaps in DSME to improve patient care.

High blood pressure in overweight and obese youth: implications for screening.

In the absence of evidence-based guidelines for high blood pressure screening in asymptomatic youth, a reasonable strategy is to screen those who are at high risk. The present study aimed to identify optimal body mass index (BMI) thresholds as a marker for high-risk youth to predict hypertension prevalence. In a cross-sectional study, youth aged 6 to 17 years (n=237,248) enrolled in an integrated prepaid health plan in 2007 to 2009 were classified according to their BMI and hypertension status. In moderately and extremely obese youth, the prevalence of hypertension was 3.8% and 9.2%, respectively, compared with 0.9% in normal weight youth. The adjusted prevalence ratios (95% confidence intervals) of hypertension for normal weight, overweight, moderate obesity, and extreme obesity were 1.00 (Reference), 2.27 (2.08-2.47), 4.43 (4.10-4.79), and 10.76 (9.99-11.59), respectively. The prevalence of hypertension was best predicted by a BMI-for-age ≥94th percentile. These results suggest that all obese youth should be screened for hypertension.

Prevalence, trends, and patterns of use of antidiabetic medications among pregnant women, 2001-2007.

OBJECTIVE: To describe the prevalence, trends, and patterns in use of antidiabetic medications to treat hyperglycemia and insulin resistance before and during pregnancy in a large U.S. cohort of insured pregnant women. METHODS: Pregnancies resulting in live births were identified (N=437,950) from 2001 to 2007 among 372,543 females 12-50 years of age at delivery from 10 health maintenance organizations participating in the Medication Exposure in Pregnancy Risk Evaluation Program. Information for these descriptive analyses, including all antidiabetic medications dispensed during this period, was extracted from electronic health records and newborn birth certificates. RESULTS: A little more than 1% (1.21%) of deliveries were to women dispensed antidiabetic medication in the 120 days before pregnancy. Use of antidiabetic medications before pregnancy increased from 0.66% of deliveries in 2001 to 1.66% of deliveries in 2007 (P<.001) because of an increase in metformin use. Most women using metformin before pregnancy had a diagnosis code for polycystic ovaries or female infertility (67.2%), whereas only 13.6% had a diagnosis code for diabetes. The use of antidiabetic medications during the second or third trimester of pregnancy increased from 2.8% of deliveries in 2001 to 3.6% in 2007 (P<.001). Approximately two thirds (68%) of women using metformin before pregnancy did not use any antidiabetic medications during pregnancy. CONCLUSIONS: Antidiabetic medication use before and during pregnancy increased from 2001 to 2007, possibly because of increasing prevalence of gestational diabetes mellitus, type 1 and type 2 diabetes, and other conditions associated with insulin resistance. LEVEL OF EVIDENCE: III.

Metabolic and inflammatory links to depression in youth with diabetes.

OBJECTIVE: Youth with diabetes are at increased risk for depression. The objectives of this study were to provide preliminary evidence that this at-risk status for depression is associated with metabolic and inflammatory markers and to inform future, more stringent examinations of the directionality of these associations. RESEARCH DESIGN AND METHODS: Data from SEARCH for Diabetes in Youth (SEARCH), an observational study of U.S. children diagnosed with diabetes at <20 years of age, were used for these analyses. SEARCH participants were drawn from four geographically defined populations in Ohio, Washington, South Carolina, and Colorado; health plan enrollees in Hawaii and California; and Indian Health Service beneficiaries from four Native American populations. Participants were 2,359 youth with diabetes from the 2001 prevalent and 2002-2004 incident SEARCH cohorts. Depression was measured with the Center for Epidemiologic Studies Depression scale. Eight metabolic and inflammatory markers were measured: adiponectin, leptin, C-reactive protein, serum amyloid A, apolipoprotein B (apoB), lipoprotein A, interleukin-6, and LDL. RESULTS: Six of eight markers were significantly (P < 0.006) associated with depression in youth with diabetes in bivariate analyses. In general, higher levels of depression were associated with indicators of worse metabolic or inflammatory functioning. In regression models stratified by diabetes type and accounting for demographic and clinical characteristics, only higher levels of apoB remained associated with higher levels of depression in youth with type 1 diabetes. CONCLUSIONS: These data suggest that depression reported by youth with diabetes is partially associated with metabolic abnormalities and systemic inflammation.

Induction of differentiation by pyruvate and DMEM in the human retinal pigment epithelium cell line ARPE-19.

PURPOSE: Cultured retinal pigment epithelium (RPE) may become a therapeutic option for transplantation in retinal disease. However maintaining a native RPE phenotype in vitro has proven challenging. The human RPE cell-line ARPE-19 is used widely as an alternative to primary RPE. It is grown in DMEM/F12 medium as standard, but its phenotype is dependent on culture conditions, and many differentiation markers are usually absent. The purpose of this study was to examine how this sensitive phenotype of ARPE-19 can be modulated by growth media with or without the metabolite pyruvate to elucidate better RPE growth conditions. METHODS: ARPE-19 cells at passages p22 to p28 were cultured on filters for up to 3 months in DMEM/F12 or DMEM media with or without pyruvate and 1% fetal calf serum. Assessment of differentiation was performed using pigmentation, immunocytochemistry, protein/mRNA expression, transepithelial resistance, VEGF secretion, and ultrastructure. RESULTS: Pyruvate, in combination with DMEM, induced dark pigmentation and promoted differentiation markers such as CRALBP and MerTK. Importantly, RPE65 protein was detected by Western blotting and was enhanced by pyruvate, high glucose, and DMEM. ARPE-19 cells maintained in this medium could also phagocytose human photoreceptor outer segments (POS). VEGF secretion was greater in DMEM cultures and was affected by glucose but not by pyruvate. Pigmentation never occurred in DMEM/F12. CONCLUSIONS: This study demonstrated important differentiation markers, including pigmentation and Western blots of RPE65 protein, and showed human POS phagocytosis in ARPE-19 cultures using a simple differentiation protocol. The results favor the use of high-glucose DMEM with pyruvate for future RPE differentiation studies.

Prevalence of tobacco use and association between cardiometabolic risk factors and cigarette smoking in youth with type 1 or type 2 diabetes mellitus.

OBJECTIVES: To examine prevalence of tobacco use and coexistence of cardiometabolic risk factors according to smoking status in youth with diabetes mellitus. STUDY DESIGN: Youth aged 10 to 22 years who participated in the SEARCH for Diabetes in Youth study (n = 3466) were surveyed about their tobacco use and examined for cardiometabolic risk factors: waist circumference, systolic and diastolic blood pressure, physical activity, and lipid profile. RESULTS: The prevalence of tobacco use in youth aged 10 to 14 years, 15 to 19 years, and ≥20 years with type 1 diabetes mellitus was 2.7%, 17.1%, and 34.0%, respectively, and the prevalence in youth with type 2 diabetes mellitus was 5.5%, 16.4%, and 40.3%, respectively. Smoking was more likely in youth with annual family incomes <$50 000, regardless of diabetes mellitus type. Cigarette smoking was associated with higher odds of high triglyceride levels and physical inactivity in youth with type 1 diabetes mellitus. Less than 50% of youth aged 10 to 14 years (52.2% of participants) reported having ever been counseled by their healthcare provider to not smoke or to stop smoking. CONCLUSIONS: Tobacco use is prevalent in youth with diabetes mellitus. Aggressive tobacco prevention and cessation programs should be a high priority to prevent or delay the development of cardiovascular disease.

Dissecting a role for melanopsin in behavioural light aversion reveals a response independent of conventional photoreception.

Melanopsin photoreception plays a vital role in irradiance detection for non-image forming responses to light. However, little is known about the involvement of melanopsin in emotional processing of luminance. When confronted with a gradient in light, organisms exhibit spatial movements relative to this stimulus. In rodents, behavioural light aversion (BLA) is a well-documented but poorly understood phenomenon during which animals attribute salience to light and remove themselves from it. Here, using genetically modified mice and an open field behavioural paradigm, we investigate the role of melanopsin in BLA. While wildtype (WT), melanopsin knockout (Opn4(-/-)) and rd/rd cl (melanopsin only (MO)) mice all exhibit BLA, our novel methodology reveals that isolated melanopsin photoreception produces a slow, potentiating response to light. In order to control for the involvement of pupillary constriction in BLA we eliminated this variable with topical atropine application. This manipulation enhanced BLA in WT and MO mice, but most remarkably, revealed light aversion in triple knockout (TKO) mice, lacking three elements deemed essential for conventional photoreception (Opn4(-/-) Gnat1(-/-) Cnga3(-/-)). Using a number of complementary strategies, we determined this response to be generated at the level of the retina. Our findings have significant implications for the understanding of how melanopsin signalling may modulate aversive responses to light in mice and humans. In addition, we also reveal a clear potential for light perception in TKO mice.

Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat.

Transformation of somatic cells with a set of embryonic transcription factors produces cells with the pluripotent properties of embryonic stem cells (ESCs). These induced pluripotent stem (iPS) cells have the potential to differentiate into any cell type, making them a potential source from which to produce cells as a therapeutic platform for the treatment of a wide range of diseases. In many forms of human retinal disease, including age-related macular degeneration (AMD), the underlying pathogenesis resides within the support cells of the retina, the retinal pigment epithelium (RPE). As a monolayer of cells critical to photoreceptor function and survival, the RPE is an ideally accessible target for cellular therapy. Here we report the differentiation of human iPS cells into RPE. We found that differentiated iPS-RPE cells were morphologically similar to, and expressed numerous markers of developing and mature RPE cells. iPS-RPE are capable of phagocytosing photoreceptor material, in vitro and in vivo following transplantation into the Royal College of Surgeons (RCS) dystrophic rat. Our results demonstrate that iPS cells can be differentiated into functional iPS-RPE and that transplantation of these cells can facilitate the short-term maintenance of photoreceptors through phagocytosis of photoreceptor outer segments. Long-term visual function is maintained in this model of retinal disease even though the xenografted cells are eventually lost, suggesting a secondary protective host cellular response. These findings have identified an alternative source of replacement tissue for use in human retinal cellular therapies, and provide a new in vitro cellular model system in which to study RPE diseases affecting human patients.

Evidence for sex-specific associations between variation in acid phosphatase locus 1 (ACP1) and insulin sensitivity in Mexican-Americans.

CONTEXT: Acid phosphatase locus 1 (ACP1) is a low molecular weight tyrosine phosphatase that has been shown to be an important regulator of insulin receptor signaling. OBJECTIVE: We tested whether variation in ACP1 is associated with type 2 diabetes-related traits in 1035 individuals in 339 Mexican-American families of probands with or without a previous diagnosis of gestational diabetes mellitus (GDM). DESIGN: Study participants were phenotyped by oral glucose tolerance test (for glucose and insulin level) and iv glucose tolerance test (for insulin sensitivity and acute insulin response) and had dual-energy x-ray absorptiometry scans to assess body composition. Six tag single nucleotide polymorphisms (SNPs) were identified from among 15 SNPs genotyped across the ACP1 region. SNPs were tested for association with phenotypes using a likelihood ratio test under a variance components framework. RESULTS: After Bonferroni correction, none of the SNPs were associated with type 2 diabetes mellitus-related phenotypes. However, we observed a significant sex-specific effect of rs3828329. Among males, rs3828329 was significantly associated with fasting insulin (Bonferroni P = 0.007) and insulin sensitivity (Bonferroni P = 0.019) and marginally associated with 2-h insulin (Bonferroni P = 0.058) and percentage body fat (Bonferroni P = 0.09). CONCLUSIONS: There were no significant associations in females. We conclude that variation in ACP1 is associated with fasting insulin and insulin sensitivity in a sex-specific manner.

Family-planning practices among women with diabetes and overweight and obese women in the 2002 National Survey For Family Growth.

OBJECTIVE: To examine contraceptive practices among diabetic women and obese women. RESEARCH DESIGN AND METHODS: We analyzed the responses of 5,955 participants aged 20-44 years in the 2002 National Survey for Family Growth. Diabetes, BMI, desire for pregnancy, history of infertility treatment, sexual activity, parity, and demographic variables (age, race/ethnicity, education, marital status, income, insurance, and smoking history) were obtained by self-report. Lack of contraception was defined as absence of hormonal-, barrier-, or sterilization-based methods. Associations among contraception, diabetes, and BMI category were assessed in multivariable logistic regression models in nonsterile, sexually active women. RESULTS: In unadjusted comparisons among sexually active women who were not sterilized, women with diabetes were more likely to lack contraception than women without diabetes (odds ratio [OR] 2.61 [95% CI 1.22-5.58]). Women with BMI >or=35 kg/m(2) were more likely to lack contraception than women with BMI <25 kg/m(2)(1.63 [1.16-2.28]), but associations between contraception use and lesser degrees of overweight and obesity were not significant. In multivariable models, women who were older (aged >or=30 vs. 20-29 years), were of non-Hispanic black race, were cohabitating, had a history of infertility treatment, and desired or were ambivalent about pregnancy were significantly more likely to lack contraception. The associations among diabetes, BMI, and contraception were no longer significant after these adjustments. CONCLUSIONS: Older women with diabetes and obesity who desire pregnancy, regardless of pregnancy intention, should be targeted for preconceptive management.

Prevalence and co-occurrence of pelvic floor disorders in community-dwelling women.

OBJECTIVE: To assess the effect of age on prevalence of pelvic floor disorders and report the co-occurrence of these conditions in community-dwelling women. METHODS: Stress urinary incontinence (SUI), overactive bladder (OAB), pelvic organ prolapse (POP), and anal incontinence were assessed using a validated questionnaire among 25- to 84-year-old women. Women screened positive for each disorder based on reported symptoms and their degree of bother. Covariates were assessed through self-report. Prevalence of each disorder was compared across four 15-year age groups using chi(2) tests. Multiple logistic regression was used to adjust for confounders. RESULTS: Among 4,103 women (mean age 56.5+/-15.8 years), the prevalence of SUI was 15%, OAB 13%, POP 6%, anal incontinence 25%, and 37% for any one or more disorder. Although the unadjusted prevalence of SUI, OAB, and anal incontinence increased with increasing age category, age was no longer significantly associated with the prevalence of any condition in most categories after adjustment for confounders, including obesity, birth history, menopause, and hormones. Co-occurrence of the disorders was high; roughly 80% of women with SUI or OAB, 69% with POP, and 48% with anal incontinence reported at least one other disorder. CONCLUSION: Although the prevalence of pelvic floor disorders in a community-dwelling population is high, age was not a significant contributor after adjustment for confounders. The high co-occurrence of pelvic floor disorders suggests that physicians seeing women seeking care for one condition should inquire about symptoms of other disorders.

Chondroitin sulfate proteoglycans and microglia prevent migration and integration of grafted Müller stem cells into degenerating retina.

At present, there are severe limitations to the successful migration and integration of stem cells transplanted into the degenerated retina to restore visual function. This study investigated the potential role of chondroitin sulfate proteoglycans (CSPGs) and microglia in the migration of human Müller glia with neural stem cell characteristics following subretinal injection into the Lister hooded (LH) and Royal College of Surgeons (RCS) rat retinae. Neonate LH rat retina showed minimal baseline microglial accumulation (CD68-positive cells) that increased significantly 2 weeks after transplantation (p < .001), particularly in the ganglion cell layer (GCL) and inner plexiform layer. In contrast, nontransplanted 5-week-old RCS rat retina showed considerable baseline microglial accumulation in the outer nuclear layer (ONL) and photoreceptor outer segment debris zone (DZ) that further increased (p < .05) throughout the retina 2 weeks after transplantation. Marked deposition of the N-terminal fragment of CSPGs, as well as neurocan and versican, was observed in the DZ of 5-week-old RCS rat retinae, which contrasted with the limited expression of these proteins in the GCL of the adult and neonate LH rat retinae. Staining for CSPGs and CD68 revealed colocalization of these two molecules in cells infiltrating the ONL and DZ of the degenerating RCS rat retina. Enhanced immune suppression with oral prednisolone and intraperitoneal injections of indomethacin caused a reduction in the number of microglia but did not facilitate Müller stem cell migration. However, injection of cells with chondroitinase ABC combined with enhanced immune suppression caused a dramatic increase in the migration of Müller stem cells into all the retinal cell layers. These observations suggest that both microglia and CSPGs constitute a barrier for stem cell migration following transplantation into experimental models of retinal degeneration and that control of matrix deposition and the innate microglial response to neural retina degeneration may need to be addressed when translating cell-based therapies to treat human retinal disease.

MIO-M1 cells and similar muller glial cell lines derived from adult human retina exhibit neural stem cell characteristics.

Growing evidence suggests that glial cells may have a role as neural precursors in the adult central nervous system. Although it has been shown that Müller cells exhibit progenitor characteristics in the postnatal chick and rat retinae, their progenitor-like role in developed human retina is unknown. We first reported the Müller glial characteristics of the spontaneously immortalized human cell line MIO-M1, but recently we have derived similar cell lines from the neural retina of several adult eye donors. Since immortalization is one of the main properties of stem cells, we investigated whether these cells expressed stem cell markers. Cells were grown as adherent monolayers, responded to epidermal growth factor, and could be expanded indefinitely without growth factors under normal culture conditions. They could be frozen and thawed without losing their characteristics. In the presence of extracellular matrix and fibroblast growth factor-2 or retinoic acid, they acquired neural morphology, formed neurospheres, and expressed neural stem cell markers including betaIII tubulin, Sox2, Pax6, Chx10, and Notch 1. They also expressed markers of postmitotic retinal neurons, including peripherin, recoverin, calretinin, S-opsin, and Brn3. When grafted into the subretinal space of dystrophic Royal College of Surgeons rats or neonatal Lister hooded rats, immortalized cells migrated into the retina, where they expressed various markers of retinal neurons. These observations indicate that adult human neural retina harbors a population of cells that express both Müller glial and stem cell markers and suggest that these cells may have potential use for cell-based therapies to restore retinal function. Disclosure of potential conflicts of interest is found at the end of this article.