Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models.

AIMS/HYPOTHESIS: 'Glucotoxicity' is a term used to convey the negative effect of hyperglycaemia on beta cell function; however, the underlying molecular mechanisms that impair insulin secretion and gene expression are poorly defined. Our objective was to define the role of transcription factor v-ets avian erythroblastosis virus E26 oncogene homologue 1 (Ets-1) in beta cell glucotoxicity. METHODS: Primary islets and Min6 cells were exposed to high glucose and Ets-1 expression was measured. Recombinant adenovirus and transgenic mice were used to upregulate Ets-1 expression in beta cells in vitro and in vivo, and insulin secretion was assessed. The binding activity of H3/H4 histone on the Ets-1 promoter, and that of forkhead box (FOX)A2, FOXO1 and Ets-1 on the Pdx-1 promoter was measured by chromatin immunoprecipitation and quantitative real-time PCR assay. RESULTS: High glucose induced upregulation of Ets-1 expression and hyperacetylation of histone H3 and H4 at the Ets-1 gene promoter in beta cells. Ets-1 overexpression dramatically suppressed insulin secretion and biosynthesis both in vivo and in vitro. Besides, Ets-1 overexpression increased the activity of FOXO1 but decreased that of FOXA2 binding to the pancreatic and duodenal homeobox 1 (PDX-1) homology region 2 (PH2), resulting in inhibition of Pdx-1 promoter activity and downregulation of PDX-1 expression and activity. In addition, high glucose promoted the interaction of Ets-1 and FOXO1, and the activity of Ets-1 binding to the Pdx-1 promoter. Importantly, PDX-1 overexpression reversed the defect in pancreatic beta cells induced by Ets-1 excess, while knockdown of Ets-1 prevented hyperglycaemia-induced dysfunction of pancreatic beta cells. CONCLUSIONS/INTERPRETATION: Our observations suggest that Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in type 2 diabetes.

Phenotyping lipid profiles in type 2 diabetes: Risk association and outcomes from the Cardiovascular Health Study.

Aims: To determine whether discrete lipid profiles (refer to as lipid phenotyping) can be used to stratify cardiovascular risk in individuals with type 2 diabetes. Methods and results: Cardiovascular Health Study participants with diabetes and fasting lipid profiles at baseline (n = 866) were categorized separately by level of LDL cholesterol and HDL-C/Triglyceride (Tg) profiles (low Tg/high HDL-C; high Tg/low HDL-C; high Tg only or low HDL-C only). We performed Cox multivariate regression analysis to assess the risk of CVD mortality, incident myocardial infarction (MI), heart failure (HF), stroke, and composite MACE (MI, HF, stroke, and CVD mortality) associated with each lipid category. We also calculated risk estimates for MACE using lipid measures as continuous variables. In the fully adjusted model, the high triglyceride plus low HDL-C cholesterol phenotype demonstrated risk that was at least as high as the highest LDL-C sub-group phenotype for CVD mortality (Hazard ratio {HR} 1.58 vs 1.48), MI (HR 1.53 vs 1.58), HF (HR 1.47 vs 1.20), stroke (HR 2.02 vs 1.43), and MACE (HR 1.58 vs 1.38). When modeled continuously, the HR per SD for MACE was 1.12 (p = 0.03) for LDL-C and 1.19-1.20 (p < 0.001) for triglycerides or remnant cholesterol. Conclusions: Participants with the high triglyceride/low HDL-C phenotype had equivalent or higher CVD risk than those with the high LDL-C phenotype. Further studies are necessary to determine whether lipid phenotyping accounts for the substantial CVD risk not explained by LDL cholesterol among individuals with type 2 diabetes.

Revisiting cardiovascular risk reduction in type 2 diabetes and dyslipidemia.

Statin therapy has been a mainstay of cardiovascular disease (CVD) risk reduction for the past 20 years in type 2 diabetes management. Its application has been largely due to well-designed, randomized-control studies consistently showing 25-35% CVD risk reduction. However, the remaining 65-75% reduction potential for CVD risk has yet to be effectively addressed. With a push towards personalized medicine, the likelihood of a one-size-fits-all approach to CVD risk reduction in type 2 diabetes may not be as beneficial as anticipated. It is reasonable to suggest that we have aggregated separate CVD phenotypic groups under one treatment umbrella and consequently, dismissed further unaddressed CVD risk reduction potential. The hypothesis proposed in this review is that there are at least two phenotypic groups with distinct molecular mechanisms contributing to CVD risk requiring different treatment approaches that can be applied with present pharmacotherapy. The two phenotypes can be classified as the following: 1) high low-density lipoprotein (LDL) phenotype and 2) high triglyceride (TG) plus low high-density lipoprotein (HDL) phenotype. As both phenotypes are significantly represented in individuals with type 2 diabetes, a more precise understanding of molecular details can be merged with clinical CVD outcome studies to arrive at a new hypothesis for CVD treatment that can be substantiated with additional well-designed clinical trials. As we transition from 20th to 21st-century medicine, we should utilize new knowledge to adapt current CVD risk reduction measures for those with type 2 diabetes.

Almond consumption and cardiovascular risk factors in adults with prediabetes.

OBJECTIVE: The authors tested the hypothesis that in adults with prediabetes, an almond-enriched American Diabetes Association (ADA) diet improves measures of insulin sensitivity and other cardiovascular risk factors compared with an ADA nut-free diet. DESIGN: Randomized parallel-group trial. SETTING: Outpatient dietary counseling and blood analysis. SUBJECTS: Sixty-five adult participants with prediabetes. INTERVENTION: Sixteen weeks of dietary modification featuring an ADA diet containing 20% of energy from almonds (approximately 2 oz per day). MEASURES OF OUTCOME: Outcomes included fasting glucose, insulin, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, TC:HDL-C, and HbA1c, which were measured at weeks 0, 8, and 16. Body weight, body mass index (BMI), waist circumference, blood pressure, and nutrient intake were measured at weeks 0, 4, 8, 12, and 16. RESULTS: The almond-enriched intervention group exhibited greater reductions in insulin (-1.78 µU/ml vs. +1.47 µU/ml, p  =  0.002), homeostasis model analysis for insulin resistance (-0.48 vs. +0.30, p  =  0.007), and homeostasis model analysis for beta-cell function (-13.2 vs. +22.3, p  =  0.001) compared with the nut-free control group. Clinically significant declines in LDL-C were found in the almond-enriched intervention group (-12.4 mg/dl vs. -0.4 mg/dl) as compared with the nut-free control group. No changes were observed in BMI (-0.4 vs. -0.7 kg/m(2), p  =  0.191), systolic blood pressure (-4.4 mm Hg vs. -3.5 mm Hg, p  =  0.773), or for the other measured cardiovascular risk factors. CONCLUSIONS: An ADA diet consisting of 20% of calories as almonds over a 16-week period is effective in improving markers of insulin sensitivity and yields clinically significant improvements in LDL-C in adults with prediabetes.

Helminth infection can reduce insulitis and type 1 diabetes through CD25- and IL-10-independent mechanisms.

Parasitic helminth infection has been shown to modulate pathological inflammatory responses in allergy and autoimmune disease. The aim of this study was to examine the effects of infection with a helminth parasite, Heligmosomoides polygyrus, on type 1 diabetes (T1D) in nonobese diabetic (NOD) mice and to elucidate the mechanisms involved in this protection. H. polygyrus inoculation at 5 weeks of age protected NOD mice from T1D until 40 weeks of age and also inhibited the more aggressive cyclophosphamide-induced T1D. Moreover, H. polygyrus inoculation as late as 12 weeks of age reduced the onset of T1D in NOD mice. Following H. polygyrus inoculation of NOD mice, pancreatic insulitis was markedly inhibited. Interleukin-4 (IL-4), IL-10, and IL-13 expression and the frequency of CD4(+) CD25(+) FoxP3(+) regulatory T cells were elevated in mesenteric and pancreatic lymph nodes. Depletion of CD4(+) CD25(+) T cells in vivo did not abrogate H. polygyrus-induced T1D protection, nor did anti-IL-10 receptor blocking antibody. These findings suggest that infection with H. polygyrus significantly inhibits T1D in NOD mice through CD25- and IL-10-independent mechanisms and also reduces the severity of T1D when administered late after the onset of insulitis.

Diagnosis of cyclic Cushing's disease manifests as early morning hyperglycemia in a patient with previously well-controlled type 1 diabetes.

Background Cyclic Cushing's disease (CCD) is reported to occur in approximately 15% of patients with Cushing's disease (CD). CCD is a rare phenomenon in children. Case presentation A Portuguese female with well-controlled type 1 diabetes (T1DM) on an insulin pump developed transient uncontrolled blood sugar every morning. Increased basal and bolus insulin dosing was ineffective in lowering blood sugar and she began to miss school because of nausea, vomiting, fatigue, but no ketoacidosis. Therefore, other causes of sporadic hyperglycemia were explored. Multiple 6-h urinary free cortisol (UFC) samples revealed a spike in cortisol coincident with severe hyperglycemia. Pituitary magnetic resonance imaging (MRI) revealed a 3.5 mm microadenoma and inferior petrosal sinus sampling of adrenocorticotropic hormone (ACTH) after corticotropin releasing hormone (CRH) stimulation confirmed ACTH-dependent CD. Endoscopic endonasal tumor resection led to resolution of early morning hyperglycemia and symptoms. Discussion Our case illustrates an atypical presentation of CCD. There are no previous case reports of a pediatric patient with T1DM and CCD. Unexplained hyperglycemia in a patient with previous well-controlled T1DM should prompt assessment of other causes. CCD can be easily be missed if timed 6-h UFC measurements are not obtained.

Adenosine receptor activation ameliorates type 1 diabetes.

Growing evidence indicates that adenosine receptors could be promising therapeutic targets in autoimmune diseases. Here we studied the role of adenosine receptors in controlling the course of type 1 diabetes. Diabetes in CD-1 mice was induced by multiple-low-dose-streptozotocin (MLDS) treatment and in nonobese diabetic (NOD) mice by cyclophosphamide injection. The nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) prevented diabetes development in both MLDS-challenged mice and in cyclophosphamide-treated NOD mice. The effect of NECA was reversed by the selective A2B receptor antagonist N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS 1754). The selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and A3 receptor agonist N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) were less efficacious in ameliorating the course of diabetes. NECA inhibited diabetes in A2A receptor KO mice and the selective A2A receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethyl-carboxamidoadenosine (CGS21680) had no effect in normal mice, indicating a lack of role of A2A receptors. NECA failed to prevent cytokine-induced beta-cell death in vitro, but NECA strongly suppressed expression of the proinflammatory cytokines TNF-alpha, MIP-1alpha, IL-12, and IFN-gamma in pancreata, endotoxin, or anti-CD3-stimulated splenic cells, and T helper 1 lymphocytes, indicating that the beneficial effect of NECA was due to immunomodulation. These results demonstrate that adenosine receptor ligands are potential candidates for the treatment of type 1 diabetes.

Challenges to Reshape the Future of Type 1 Diabetes Research.

Context: Immunotherapy trials to prevent type 1 diabetes have been unsuccessful for >15 years. Understanding pitfalls and knowledge gaps in the immunology of type 1 diabetes should lead us in new directions that will yield better trial outcomes. A proposal is made for precision medicine trial design in future type 1 diabetes studies. Evidence Acquisition: High-quality peer-reviewed basic science and clinical research trials for type 1 diabetes were used in this Perspective article. Type 1 diabetes publications were reviewed from 2000 to 2018 by using Google Scholar and PubMed reference databases. Evidence Synthesis: Personalized medicine for type 1 diabetes should recognize that each individual has phenotypic and genotypic quirks that distinguish them from other study participants. A uniform protocol for antigen-specific immunotherapy has consistently failed to prevent disease. An alternative approach using molecular tools to personalize the preventive treatment strategy might be a road forward for type 1 diabetes research. Assumptions or lack of knowledge about disease stratification (not all type 1 diabetes is the same disease), individualized antigen-specific T cells, regulatory T-cell populations, and T-cell receptor rearrangement are just a few aspects of immunology that require integration with clinical trial design. Conclusions: The type 1 diabetes research community continues to bring forward novel immunotherapy trials to prevent disease, but this approach is unlikely to succeed until several fundamental aspects of clinical immunology are recognized and addressed. Here, we identify several knowledge gaps that could rectify type 1 diabetes trial design and lead to future success.

TIMP-1 and CD82, a promising combined evaluation marker for PDAC.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a widely secreted protein that regulates cell motility, proliferation, and apoptosis. Although it is recognized that TIMP-1-tetraspanin CD63 regulates epithelial cell apoptosis and proliferation, how TIMP-1 controls cell motility is not well understood. In this study, we identify tetraspanin CD82 (also called KAI1) as a component of the promiscuous TIMP-1 interacting protein complex on cell surface of human pancreatic adenocarcinoma cells. CD82 directly binds to TIMP-1 N-terminal region through its large extracellular loop and co-localizes with TIMP-1 in both cancer cell lines and clinical samples. Moreover, CD82 facilitates membrane-bound TIMP-1 endocytosis, which significantly contributes to the anti-migration effect of TIMP-1. CD82 silencing partially eliminates these functions. TIMP-1 and CD82 expression status in patients with pancreatic ductal adenocarcinoma (PDAC) might demonstrate future usefulness as a differentiation marker and give us new insight into tumorigenic metastatic potential.

Induction of cyclooxygenase-2 gene in pancreatic beta-cells by 12-lipoxygenase pathway product 12-hydroxyeicosatetraenoic acid.

Cyclooxygenase-2 (COX-2) gene and 12-lipoxygenase (12-LO) gene are preferentially expressed over other types of cyclooxygenase and lipoxygenase in pancreatic beta-cells. Inhibition of either COX-2 or 12-LO can prevent cytokine-induced pancreatic beta-cell dysfunction as defined by inhibition of glucose-stimulated insulin secretion. As cellular stress induces both genes and their respective end products in pancreatic beta-cells, we evaluated the role of 12-hydroxyeicosatetraenoic acid (HETE) on COX-2 gene expression, protein expression, and prostaglandin E2 (PGE2) production. We demonstrate that 12-HETE significantly increases COX-2 gene expression and consequent product formation, whereas a closely related lipid, 15-HETE, does not. In addition, IL-1beta-stimulated prostaglandin E2 production is completely inhibited by a preferential lipoxygenase inhibitor cinnaminyl-3,4-dihydroxy-alpha-cyanocinnamate. We then evaluated IL-1beta-induced PGE2 production in islets purified from control C57BL/6 mice and 12-LO knockout mice lacking cytokine-inducible 12-HETE. IL-1beta stimulated an 8-fold increase in PGE2 production in C57BL/6 islets but failed to stimulate PGE2 in 12-LO knockout islets. Addition of 12-HETE to 12-LO knockout islet cells produced a statistically significant rise in PGE2 production. Furthermore, 12-HETE, but not 15-HETE, stimulated COX-2 promoter and activator protein-1 binding activity. These data demonstrate that 12-HETE mediates cytokine-induced COX-2 gene transcription and resultant PGE2 production in pancreatic beta-cells.

Isolated double pituitary adenomas: A silent corticotroph adenoma and a microprolactinoma.

We report a 27-year-old woman with amenorrhea and galactorrhea with mildly elevated serum prolactin levels. Her MRI demonstrated a cystic macroadenoma in the left aspect of the sella and a small microadenoma in the right aspect of the sella. Endoscopic transsphenoidal resection of the tumors revealed two histologically distinct tumors. The left tumor was consistent with a silent corticotroph macroadenoma and the right tumor was a prolactin producing microadenoma. Isolated double pituitary adenomas that are clearly separated by normal pituitary gland tissue are extremely rare. The incidence is approximately 0.37-2.6%. The coexistence of double adenomas can pose diagnostic and management challenges for the pituitary neuroendocrine team.

Health-related quality of life, disease severity, and anticipated trajectory of diabetes.

PURPOSE: Adults hospitalized with diabetes are likely to have multiple comorbid conditions contributing to suboptimal health-related quality of life. The purpose of this study was to survey urban, very low-income, hospitalized adults with diabetes about disease severity, anticipated disease trajectory, and self-rated health-related quality of life. METHODS: Data were collected using the Brief Illness Perception Questionnaire, the 36-item Short Form Health Survey (SF-36), the comparative risk perception questionnaire, and glycosylated hemoglobin. Severity was defined by glycosylated hemoglobin level and current microvascular complications from diabetes. FINDINGS: Those with more severe disease who also anticipated the development of additional diabetes-related complications were likely to have suboptimal physical and mental functioning. The perception of diabetes as a health threat concurrent with having non-diabetes-related comorbid chronic conditions contributed uniquely to explaining scores in health-related quality of life. CONCLUSION: Hospitalized adults with diabetes represent a population affected by chronic disease demands that contribute to suboptimal physical and mental functioning. Suboptimal quality of life may contribute to severity of diabetes and to a perception of having a threatening disease trajectory. Hospitalization provides an opportunity for clinicians to intervene in mental and physical functioning by assessing for threatening illness perceptions and employing interventions to promote acceptance of functional limitations.

MicroRNA-24/MODY gene regulatory pathway mediates pancreatic ß-cell dysfunction.

Overnutrition and genetics both contribute separately to pancreatic ß-cell dysfunction, but how these factors interact is unclear. This study was aimed at determining whether microRNAs (miRNAs) provide a link between these factors. In this study, miRNA-24 (miR-24) was highly expressed in pancreatic ß-cells and further upregulated in islets from genetic fatty (db/db) or mice fed a high-fat diet, and islets subject to oxidative stress. Overexpression of miR-24 inhibited insulin secretion and ß-cell proliferation, potentially involving 351 downregulated genes. By using bioinformatic analysis combined with luciferase-based promoter activity assays and quantitative real-time PCR assays, we identified two maturity-onset diabetes of the young (MODY) genes as direct targets of miR-24. Silencing either of these MODY genes (Hnf1a and Neurod1) mimicked the cellular phenotype caused by miR-24 overexpression, whereas restoring their expression rescued ß-cell function. Our findings functionally link the miR-24/MODY gene regulatory pathway to the onset of type 2 diabetes and create a novel network between nutrient overload and genetic diabetes via miR-24.

Afrocentric cultural values and beliefs: movement beyond the race and ethnicity proxy to understand views of diabetes.

PURPOSE: The purpose of this study was to estimate the benefit of using a cultural characteristics scale to help diabetes educators understand how African Americans cope with diabetes. Illness representations are influenced by culture. Race and ethnicity as a proxy for culture provides an incomplete understanding of the mechanism by which cultural values influence representations of diabetes. METHODS: A descriptive correlational design was employed by recruiting hospitalized adults with type 2 diabetes at 3 metropolitan northeast coast sites. The TRIOS Afrocentric cultural characteristics measure and the Illness perception Questionnaire were administered by paper-and-pencil to a diverse sample. Black race and African American ethnicity was used as a proxy for culture and compared to levels of agreement on an Afrocentric cultural scale to determine the relative ability to explain variance in illness representations of diabetes. CONCLUSION: The TRIOS measure adapted to diabetes care explained variance in illness representations of diabetes, while African American ethnicity/black race was not able to explain variance in illness representations. Clinicians would benefit from considering the degree to which a patient identifies with particular cultural characteristics when tailoring interventions to manipulate illness representations that are not concordant with biomedical representations.

Healthcare technician delivered screening of adults with diabetes to improve primary care provider recognition of depression.

PURPOSE: The purpose of this study was to implement a continuous quality improvement project aimed at improving primary care provider recognition of depression. MATERIALS AND METHODS: A randomized, blinded, pre- and post-test design was implemented with 92 adults attending an academic internal medicine clinic. Subjects were assigned to an intervention where healthcare technicians (HCT) trained in the fundamentals of diabetes education delivered brief probing questions about self-care behavior and tailored talking points to encourage patients to talk to their primary care physician about their emotional health. The control group received a sham intervention that included only information on standards of diabetes care. Measures included both a paper-and-pencil screening of depression and the Primary Healthcare Questionnaire-8 (PHQ-8). Outcomes were evaluated for antidepressant and/or counseling treatment modalities once the possibility of depression was identified. RESULTS: Both the control and intervention groups improved from pre-test to 3-month post-test scores on the PHQ-8 in clinically significant ways, but continued to have moderate to severe depression symptoms. There was a significant likelihood of receiving antidepressant therapy and/or counseling in those who scored high on the PHQ-8. CONCLUSION: HCT can be trained to talk to patients about emotional health issues during routine primary care visits. Depression screening measures can be administered as part of the triage routine at the start of a primary care visit, along with tasks such as vital signs. Answering a screening measure can help create awareness of symptoms and feelings that can prompt discussion during the patient-provider encounter that can result in the diagnosis and treatment of depression.

Beyond glycoproteins as galectin counterreceptors: tumor-effector T cell growth control via ganglioside GM1 [corrected].

Glycoprotein glycan chains, by virtue of structure, topology of presentation and connection to signal-inducing units, are functional galectin counterreceptors. As example, cross-linking of the α(5)ß(1) integrin by galectin-1 on carcinoma cells leads to G(1) arrest or anoikis. Contact-dependent switching from proliferation to differentiation in cultured neuroblastoma cells (SK-N-MC) also utilizes galectin-1. Activity enhancement of a cell surface sialidase underlies the shift in glycan display to ganglioside GM1. Its pentasaccharide within microdomains becomes the target. Similarly, this recognition pair is upregulated upon T cell activation. Cross-linking of GM1 along with associated α(4)/α(5)ß(1) integrins elicits Ca(2+)-influx via TRPC5 channels as the relevant response for T effector cell (T(eff)) suppression. Unlike T(eff) cells from wild-type mice, those from genetically altered mice lacking GM1 are not suppressed by galectin-1 or regulatory T cells. Similarly, in the context of GM1 deficiency in NOD mice, T(eff) cells are associated with resistance to regulatory T cell suppression, which is reversed by applied GM1. The broad array of glycosphingolipid structures suggests the possible existence of several novel counterreceptors targeted to endogenous lectins, with sulfatide-galectin-4 interplay within apical delivery serving as recent example.

Ganglioside GM1 deficiency in effector T cells from NOD mice induces resistance to regulatory T-cell suppression.

OBJECTIVE: To detect GM1 deficiency and determine its role in effector T cells (Teffs) from NOD mice in establishing resistance to regulatory T-cell (Treg) suppression. RESEARCH DESIGN AND METHODS: CD4(+) and CD8(+) Teffs were isolated from spleens of prediabetic NOD mice for comparison with similar cells from Balb/c, C57BL/6, and NOR mice. GM1 was quantified with thin-layer chromatography for total cellular GM1 and flow cytometry for cell-surface GM1. Suppression of Teff proliferation was determined by application of GM1 cross-linking agents or coculturing with Tregs. Calcium influx in Teffs was quantified using fura-2. RESULTS: Resting and activated CD4(+) and CD8(+) Teffs of NOD mice contained significantly less GM1 than Teffs from the other three mouse strains tested. After activation, NOD Teffs resisted suppression by Tregs or GM1 cross-linking agents in contrast to robust suppression of Balb/c Teffs; this was reversed by preincubation of NOD Teffs with GM1. NOD Teffs also showed attenuated Ca(2+) influx via transient receptor potential channel 5 (TRPC5) channels induced by GM1 cross-linking, and this, too, was reversed by elevation of Teff GM1. CONCLUSIONS: GM1 deficiency occurs in NOD Teffs and contributes importantly to failed suppression, which is rectified by increasing Teff GM1. Such elevation also reverses subthreshold Ca(2+) influx via TRPC5 channels, an essential aspect of suppression. Our results also support a critical role for galectin-1 as a GM1 cross-linking counter-receptor that fittingly is upregulated and released by Tregs during activation. These findings suggest a novel mechanism by which pathogenic Teffs evade regulatory suppression, thereby leading to autoimmune ß-cell destruction and type 1 diabetes.

Perceived risk of amputation, emotions, and foot self-care among adults with type 2 diabetes.

PURPOSE: The purpose of this study was to determine the influence of having a family member who experienced an amputation on one's own perceived risk and fear of experiencing a diabetes-related amputation. METHODS: This was a descriptive cross-sectional study using paper-and-pencil surveys by mail. Adults with type 2 diabetes and a family history of diabetes attending a self-management education program in the Metropolitan New York/New Jersey area were recruited. Measures were completed about risk perception and fear of amputation, emotional representations of diabetes from the Illness Perception Questionnaire, and the foot self-care behavior component of the Summary of Diabetes Self-care Activities Survey. The authors estimated the variability in foot self-care that was accounted for by risk perception and fearful memories. RESULTS: In those who remembered a family member needing an amputation, high perceived risk and fear was associated with less routine foot self-care. For those without family history of amputation, fear was positively associated with foot self-care. CONCLUSIONS: Motivation for foot self-care behavior may be driven by risk perception and emotional responses. The ways in which risk perception and fear influence motivation for preventive foot self-care behavior are influenced by whether one's family member was affected by an amputation. Probing about the influence of the patient's legacy of diabetes may be helpful when customizing education plans.