Shared genetic influences between eating disorders and gastrointestinal disease in a large, population-based sample of adult women and men.

BACKGROUND: Some preliminary research suggests higher rates of gastrointestinal disease in individuals with eating disorders (EDs). However, research is limited, and it remains unknown what etiologic factors account for observed associations. This was the first study to examine how EDs and dimensional ED symptoms (e.g. body dissatisfaction, binge eating) are phenotypically and etiologically associated with gastrointestinal disease in a large, population-based twin sample. METHODS: Adult female (N = 2980) and male (N = 2903) twins from the Michigan State University Twin Registry reported whether they had a lifetime ED (anorexia nervosa, bulimia nervosa, or binge-eating disorder) and completed a measure of dimensional ED symptoms. We coded the presence/absence of lifetime gastrointestinal disease (e.g. inflammatory bowel disease) based on responses to questions regarding chronic illnesses and medications. We first examined whether twins with gastrointestinal disease had higher rates of EDs and ED symptoms, then used correlated factors twin models to investigate genetic and environmental contributions to the overlap between disorders. RESULTS: Twins with gastrointestinal disease had significantly greater dimensional ED symptoms (ß = 0.21, p < 0.001) and odds of a lifetime ED (OR 2.90, p = 0.001), regardless of sex. Shared genetic factors fully accounted for the overlap between disorders, with no significant sex differences in etiologic associations. CONCLUSIONS: Comorbidity between EDs and gastrointestinal disease may be explained by overlap in genetic influences, potentially including inflammatory genes implicated in both types of disorders. Screening for gastrointestinal disease in people with EDs, and EDs in those with gastrointestinal disease, is warranted.

Insights on Engaging Men and Boys in Creating a More Gender Equal Future in Canada.

This article presents findings from a national qualitative research study of 33 diverse and profeminist leaders who identify as men and are engaged in gender equality work with men and boys across Canada. Key findings include the need to meet men where they are at, moving away from the ineffective "all men are perpetrators" frame, and to evolve to new and more relatable narratives and approaches that get men committed to this work for their own liberation. Taking an intersectional approach and working in partnership with feminist and intersectional organizations are essential to advancing gender equality in the Canadian context.

Acceptability and feasibility of the CHARISMA counseling intervention to support women's use of pre-exposure prophylaxis: results of a pilot study.

BACKGROUND: Women may need or seek male partner approval to safely and consistently use oral antiretroviral pre-exposure prophylaxis (PrEP) or vaginal microbicides. We developed CHARISMA, a counseling intervention to support women's relationships and their ability to consistently use HIV prevention products. METHODS: In a pilot study with 95 female participants in Johannesburg, South Africa, lay counselors implemented CHARISMA, assessing participants' relationship(s) with their male partner(s) and barriers or facilitators to HIV prevention method use, and then providing tailored, interactive counseling. We conducted study participant surveys and clinic staff interviews to evaluate CHARISMA's feasibility and acceptability. RESULTS: The CHARISMA pilot study indicates that a two-session relationship counseling intervention with 6-month follow-up to support women's ability to safely and effectively use vaginal microbicides was generally acceptable and feasible. Most participants thought CHARISMA was relevant, helpful, and about the right length, and that it had a positive impact on their relationships with their partners and their product use. Staff estimated that the intervention took 1.5-2 h to implement at enrollment and 45 min to an hour for the month 1 visit. They thought that overall CHARISMA was generally feasible to implement. CONCLUSIONS: Findings from this study suggest several lessons learned that may be relevant to others developing interventions supporting women's use of oral PrEP or vaginal microbicides. The use of lay counselors instead of nurses to deliver counseling appeared to be successful, but the counselors experienced significant stress from hearing about participants' traumatic experiences and required emotional support to avoid burnout. Although staff and participants felt that having multiple intervention sessions over time was valuable, a similar level of intensity may not be feasible in other settings. Further research is needed to determine an intervention delivery mode and follow-up period that optimally balances participant needs and clinic resources. Male engagement was a challenge, as it has been in previous studies of vaginal microbicides. Alternative strategies to reach men that do not require them to come to the clinic or rely on their female partners may be more effective.

Variations in Emotional, Sexual, and Physical Intimate Partner Violence Among Women in Uganda: A Multilevel Analysis.

Evidence shows that a significant proportion of ever-partnered women suffer some form of intimate partner violence (IPV) perpetuated by male partners. The prevalence of IPV in sub-Saharan African countries is considerably higher than global estimates. Although existing studies show the effect of women's and intimate male partner's characteristics on IPV, knowledge on how these factors increase or reduce women's risk to specific types of IPV is limited. Using the 2016 Ugandan Demographic and Health Survey (UDHS), we examine regional variations in women's and intimate male partner's characteristics and their effect on emotional, sexual, and physical violence perpetuated by men and experienced by women in Uganda. The result shows that women's educational status is a significant predictor of all forms of IPV, whereas other characteristics, such as employment and housing ownership, have differential effects on specific types of IPV. Less educated women were more likely to experience emotional, sexual, and physical violence. Alcohol abuse was a significant determinant of men perpetuating all types of IPV; other male characteristics had differential effects on specific types of IPV. Male partners who abuse alcohol "often" and "sometimes" were more likely to commit acts of emotional, sexual, and physical violence against their female intimate partners. The findings also show that ~5%, ~8%, and ~2% of the variance in emotional, sexual, and physical violence (respectively; in the final models) are attributable to regional differences. The findings suggest the need for interventions aimed at increasing women's access to higher education, working with men and boys to reduce the occurrence of alcohol abuse and address harmful constructions of masculinity, and promoting gender equality among men as well as women.

Negotiating HIV and pregnancy prevention and sexual pleasure amongst heterosexual men and women in South Africa.

Heterosexual sex, foremost its gender-power dynamics, is embedded in and informed by the socio-historical context in which it occurs. While safer sexual communication skills are well documented as key to the success of sexual and reproductive health programming and education, communication skills about the positive aspects of sexuality such as sexual pleasure are often limited if not absent. Using data from in-depth qualitative interviews with men and women aged 26-39 from a diverse set of backgrounds in Cape Town, South Africa, this study examines the ways in which gender-power dynamics manifest in negotiations of HIV and pregnancy prevention and sexual pleasure in the intimate spaces of heterosex. Findings fall under three themes: 1) condom negotiation as a replacement for other aspects of sexual communication; 2) self-efficacy in negotiating prevention and negotiating one's own sexual pleasure; and 3) the integral role men play in heterosexual encounters in the facilitation of women's sexual autonomy and women's sexual pleasure. This study contributes to research not only examining the positive and more nuanced realities of heterosex in the South African context, but also argues for the need to integrate positive aspects of sexuality into sexual and reproductive health programming in general.

Generating CHARISMA: Development of an Intervention to Help Women Build Agency and Safety in Their Relationships While Using PrEP for HIV Prevention.

This article describes the development of the Community Health clinic model for Agency in Relationships and Safer Microbicide Adherence intervention (CHARISMA), an intervention designed to address the ways in which gender norms and power differentials within relationships affect women's ability to safely and consistently use HIV pre-exposure prophylaxis (PrEP). CHARISMA development involved three main activities: (1) a literature review to identify appropriate evidence-based relationship dynamic scales and interventions; (2) the analysis of primary and secondary data collected from completed PrEP studies, surveys and cognitive interviews with PrEP-experienced and naïve women, and in-depth interviews with former vaginal ring trial participants and male partners; and (3) the conduct of workshops to test and refine key intervention activities prior to pilot testing. These steps are described along with the final clinic and community-based intervention, which was tested for feasibility, acceptability, and preliminary effectiveness in Johannesburg, South Africa.

Lessons learned from engaging men in sexual and reproductive health as clients, partners and advocates of change in the Hoima district of Uganda.

This study examined the impact of a three-year intervention project conducted in the Hoima district of Uganda, which sought to engage men in sexual and reproductive health as clients, equal partners and advocates of change. Structured surveys with 164 self-reported heterosexual men aged 18-54 years were used to assess knowledge and attitudes towards sexual and reproductive health. Data from these were analysed using Stata and SPSS. Additionally, five focus groups were conducted with the female partners and male beneficiaries of the project and with project peer educators. Four interviews were conducted with project staff and male beneficiaries. Data from these and the focus groups were analysed using a thematic approach. Following the intervention, a significantly greater number of men accessed, and supported their partners in accessing sexual health services services, had gained sexual and reproductive health awareness, reported sharing domestic duties and contraceptive decision-making, and displayed a decreased tolerance for domestic violence. It was more difficult to assess men's involvement and behaviours as advocates of change, which sheds light on the complexities of a gender transformative project and the importance of evaluating such projects from both men's and their partners' perspectives and at different levels of the male involvement model in sexual and reproductive health.

Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease.

UNLABELLED: The polymorphism, KLF6-IVS1-27A, in the Krüppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6-IVS1-27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6). Klf6 overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with Gck promoter activity. KLF6-IVS1-27Gwt (i.e., less KLF6 splicing) was associated with stepwise increases in FPG and insulin and reduced hepatic insulin sensitivity. KLF6 binds to the liver-specific Gck promoter and activates a GCK promoter-reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes Gck expression was reduced and stable transfection of Klf6 led to up-regulation of Gck. GCK and KLF6 mRNAs correlate directly in human NAFLD tissues and immunohistochemistry studies confirm falling levels of both KLF6 and GCK in fat-laden hepatocytes. In contrast to full-length KLF6, splice variant KLF6-SV1 increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity. CONCLUSION: KLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The KLF6-IVS1-27A polymorphism, which generates more KLF6-SV1, combats this, lowering hepatic insulin resistance and blood glucose.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired ß-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved ß-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.

OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.

Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes.

Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.

Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function.

OBJECTIVE: Type 2 diabetes is characterized by impaired pancreatic beta-cell function and decreased insulin sensitivity. Genome-wide association studies have identified common, novel type 2 diabetes susceptibility loci within the FTO, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, HHEX/IDE, and SLC30A8 gene regions. Our objective was to explore the relationships between the diabetes-associated alleles and measures of beta-cell function and whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS: A total of 1,276 healthy subjects of European ancestry were studied at 19 centers. Indexes of beta-cell function (including 30-min insulin response and glucose sensitivity) were derived from a 75-g oral glucose tolerance test, and whole-body insulin sensitivity (M/I) was assessed by hyperinsulinemic-euglycemic clamp. Genotype/phenotype relationships were studied by linear trend analysis correcting for age, sex, and recruitment center. RESULTS: CDKAL1 and HHEX/IDE diabetes-associated alleles were both associated with decreased 30-min insulin response (both P = 0.0002) and decreased pancreatic beta-cell glucose sensitivity (P = 9.86 x 10(-5) and 0.009, respectively), and these relationships remained after correction for M/I. The FTO susceptibility allele showed a weak but consistent association with increased adiposity, which in turn was linked to a decrease in M/I. However, none of the other novel diabetes susceptibility alleles were associated with insulin sensitivity. CONCLUSIONS: CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic beta-cell function, including decreased beta-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. We confirmed the association between the FTO allele and increased adiposity, but none of the other novel susceptibility alleles were associated with whole-body insulin sensitivity.