Browsing by Subject "Diabetes"
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Item 12-Lipoxygenase governs the innate immune pathogenesis of islet inflammation and autoimmune diabetes(The American Society for Clinical Investigation, 2021-07-22) Kulkarni, Abhishek; Pineros, Annie R.; Walsh, Melissa A.; Casimiro, Isabel; Ibrahim, Sara; Hernandez-Perez, Marimar; Orr, Kara S.; Glenn, Lindsey; Nadler, Jerry L.; Morris, Margaret A.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Anderson, Ryan M.; Pediatrics, School of MedicineMacrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of proinflammatory eicosanoids, but its role and mechanisms in myeloid cells in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β cells and the subsequent development of hyperglycemia. The depletion or inhibition of 12-LOX in this model resulted in reduced macrophage infiltration into islets and the preservation of β cell mass. In NOD mice, the deletion of the gene encoding 12-LOX in the myeloid lineage resulted in reduced insulitis with reductions in proinflammatory macrophages, a suppressed T cell response, preserved β cell mass, and almost complete protection from the development of T1D. 12-LOX depletion caused a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration resulted from the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migratory defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune cells in the early pathogenesis of T1D and identify 12-LOX as an enzyme required to promote their prodiabetogenic phenotype in the context of autoimmunity.Item 12-lipoxygenase Promotes Macrophage Infiltration and Pancreatic Islet Dysfunction in the Vertebrate Models of Diabetes Pathogenesis(2020-05) Kulkarni, Abhishek Anant; Harrington, Maureen; Mirmira, Raghavendra; Anderson, Ryan; Goebl, Mark; Mosley, Amber; Marrs, JamesDiabetes is a morbid metabolic disorder that affects almost 500 million people worldwide. Although multiple factors contribute to diabetes pathogenesis, pancreatic islet inflammation and dysfunction are shared characteristics of its major forms. 12- lipoxygenase (12-LOX), an enzyme involved in lipid metabolism, has been implicated in islet inflammation. 12-LOX generates reactive oxygen species (ROS) that activate inflammation and serve as major contributors to islet dysfunction. Importantly, since ROS are transient moieties, they are challenging to study in vivo. Hence, establishing better animal models of ROS-mediated stress is critical to facilitate the discovery and preclinical testing of novel diabetes therapeutics. Here, I have adapted a zebrafish model of conditional β-cell injury, which is regulated by the administration of the prodrug metronidazole (MTZ), to study responses to ROS in vivo. I demonstrate that with MTZ treatment, ROS are generated within β-cells and subsequently exhibit recruitment of macrophages into the islet and induction of β-cell death. I utilized this model to uncover roles for macrophages and 12-LOX during islet injury. Excessive macrophage infiltration exacerbates islet inflammation and dysfunction. Interestingly, on the depletion of macrophages in zebrafish, I observed that β-cells recovered normal function upon cessation of prodrug treatment. This suggests that infiltrating macrophages promote maladaptive inflammation and premature removal of damaged β-cells. Thus, limiting the macrophage infiltration may be a therapeutic approach to restoring β-cell function. Based on the established roles of 12-LOX in other contexts, I hypothesized that its inhibition would prevent the localized infiltration of proinflammatory macrophages. To test this, I used both zebrafish and mouse models and observed a significant reduction in macrophage migration upon loss of 12- LOX activity. Furthermore, I found that expression of CXCR3, a crucial receptor regulating migration, was significantly reduced in 12-LOX loss-of-function macrophages. These data suggest a role for 12-LOX in macrophages, which is conserved across species. Collectively, my study reveals novel roles for 12-LOX in macrophage function and provides testable therapeutic targets for the resolution of inflammation-induced damage in the pancreatic islets.Item 4405 Chronic Disease in Indiana – Using a Community Health Matrix to Determine Health Factors for Indiana Counties(Cambridge University Press, 2020-07-29) Wiehe, Sarah; Zych, Aaron; Hinshaw, Karen; Alley, Ann; Claxton, Gina; Savaiano, Dennis; Pediatrics, School of MedicineOBJECTIVES/GOALS: The goal of this project was to inform four chronic disease initiatives, working together on the team Connections IN Health, and counties in Indiana on certain areas of need to assist them in collaborative planning. The chronic diseases focused on include diabetes, cardiovascular disease, stroke, asthma, lung cancer and obesity. METHODS/STUDY POPULATION: Chronic disease health outcomes and social determinants of health indicators were identified in all 92 Indiana counties. Counties were compared by composite z scores in a matrix to determine the 23 counties with the poorest health statistics for diabetes, cardiovascular disease, stroke, asthma, lung cancer, obesity and life expectancy. Qualitative data were used to identify local health coalitions that have the capacity and desire to work with Connections IN Health to improve these health outcomes. With input from partners, the counties were narrowed to 10 that were identified as those with the most need in the specific areas of chronic disease that the initiatives focus on. The team will begin listening sessions with two of these counties to identify strategic partnerships, funding sources, and evidence-based programs to address community-identified health priorities. RESULTS/ANTICIPATED RESULTS: The 23 counties with the poorest health outcomes related to chronic disease and factors were Blackford, Clark, Clay, Fayette, Fulton, Grant, Greene, Howard, Jay, Jennings, Knox, Lake, LaPorte, Madison, Marion, Pike, Scott, Starke, Sullivan, Vanderburgh, Vermillion, Vigo, and Washington. There was significant overlap in low z score rankings for individual health and social determinants of health measures among these 23 counties. The following 10 counties were selected for focus in the next five years based on partner input: Blackford, Clay, Grant, Jennings, Lake, Madison, Marion, Starke, Vermillion, and Washington. The Connections IN Health team has initiated listening sessions in Grant and Vermillion Counties (with data for presentation at the ACTS meeting). DISCUSSION/SIGNIFICANCE OF IMPACT: This mixed methods approach using existing data and partner input on county capacity/readiness directed Connections IN Health to counties with the most need for coalition efforts. Engagement within each county will inform next steps (e.g., capacity building, partnership development, applications for funding, implementation of evidence-based programs) and specific health focus area(s).Item 5-OR: Health Disparities in People with and without Diabetes during the COVID-19 Pandemic(American Diabetes Association, 2021-06-01) Myers, Barbara A.; Klingensmith, Rachel; de Groot, Mary; Medicine, School of MedicinePurpose: To characterize the psychosocial experiences of adults with (PWD) and without diabetes (ND) during the COVID-19 pandemic. US adults (2176) completed a web-based survey in May-June, 2020 and November-December, 2020, including demographics, COVID-19 exposure, diabetes-related distress (DDS-17), depressive symptoms (PHQ-8) and anxiety (GAD-7). At baseline, mean age was 49.6 years (S.D. = 16.9), 80% female, 88.3% White, with an annual household income of ≥ $60,000 (57.6%), type 2 diabetes (T2D; 301,13.9%), 145 prediabetes (145, 6.6%) and type 1 (T1D, 100, 4.6%). One-third (29.7%) reported decreased income due to the pandemic. T2Ds had more medical comorbidities and COVID risk factors than T1Ds and NDs (all p < 0.01). Mean PHQ-8 scores were 7.1 (S.D. = 5.8; mild), with the T2Ds (M = 7.7; S.D. = 5.9) exceeding NDs (M = 6.9; S.D. = 5.7; p<.001). Mean DDS-17 and GAD-7 scores were comparable for T1Ds and T2Ds (moderate level; p=NS). At 6 months (6MFU), 1,345 (62.6%) completed follow up surveys. Completers were more likely to be older, male, White, married, with higher education levels, and homeowners, with a greater proportion of medical comorbidities and lower A1cs at baseline than non-completers (all p<.05). 6MFU completers had lower baseline depressive symptoms and diabetes distress, lower household COVID-19 rates and less difficulty paying bills than non-completers (all p<.05). At 6MFU for all groups, depressive symptoms decreased (p<.0001) and financial strain improved (p<.001), while COVID exposure increased (personal and household, p<.001). Diabetes distress remained at a moderate level for T1Ds and T2Ds. T1Ds and T2Ds showed comparable levels of depressive symptoms to NDs but were more likely to report financial hardship (p<.05) and difficulty paying bills than NDs (p<.001). Health outcomes were worse for PWDs compared to NDs during the COVID-19 pandemic despite high SES protective factors. Persistent financial strain and diabetes distress increase the risk for future poor health outcomes.Item A genomic data archive from the Network for Pancreatic Organ donors with Diabetes(Springer Nature, 2023-05-26) Perry, Daniel J.; Shapiro, Melanie R.; Chamberlain, Sonya W.; Kusmartseva, Irina; Chamala, Srikar; Balzano-Nogueira, Leandro; Yang, Mingder; Brant, Jason O.; Brusko, Maigan; Williams, MacKenzie D.; McGrail, Kieran M.; McNichols, James; Peters, Leeana D.; Posgai, Amanda L.; Kaddis, John S.; Mathews, Clayton E.; Wasserfall, Clive H.; Webb-Robertson, Bobbie-Jo M.; Campbell-Thompson, Martha; Schatz, Desmond; Evans-Molina, Carmella; Pugliese, Alberto; Concannon, Patrick; Anderson, Mark S.; German, Michael S.; Chamberlain, Chester E.; Atkinson, Mark A.; Brusko, Todd M.; Pediatrics, School of MedicineThe Network for Pancreatic Organ donors with Diabetes (nPOD) is the largest biorepository of human pancreata and associated immune organs from donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, islet autoantibody positivity (AAb+), and without diabetes. nPOD recovers, processes, analyzes, and distributes high-quality biospecimens, collected using optimized standard operating procedures, and associated de-identified data/metadata to researchers around the world. Herein describes the release of high-parameter genotyping data from this collection. 372 donors were genotyped using a custom precision medicine single nucleotide polymorphism (SNP) microarray. Data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 donors were assessed for rare known and novel coding region variants via whole exome sequencing (WES). These data are publicly-available to enable genotype-specific sample requests and the study of novel genotype:phenotype associations, aiding in the mission of nPOD to enhance understanding of diabetes pathogenesis to promote the development of novel therapies.Item Activities of Daily Living Recovery in Home Health Patients with Diabetes(Oxford University Press, 2023-12-21) Webster-Dekker, Katelyn; Lu, Yvonne; Perkins, Susan; Ellis, Jennifer; Otis, Laurie; Winton, Rebecca; Hacker, Eileen; School of NursingOlder adults with diabetes are at high risk for impairments in their ability to perform activities of daily living (ADLs). Home health (HH) services help patients regain their ability to perform ADLs after being hospitalized, but there may be disparities in degree of ADL improvement based on characteristics such as race/ethnicity. We aimed to identify factors associated with improvements in ADLs from the start of HH care to discharge in older adult (age ≥65) patients with diabetes receiving HH. This secondary analysis used Outcome and Assessment Information Set-D data collected between October 1, 2021, and March 31, 2022 in the Southern U.S by a HH agency. We used multiple linear regression to examine factors associated with improvement in ADL performance. The sample (n=1350) was 55% female and 76% White, with a mean age of 76.3 (SD 7.3). Ninety-seven percent of patients improved their ADL score from start of HH care to discharge. Black/African American race (b= -0.33) and having bowel incontinence or an ostomy (b= -0.51) were associated with less ADL improvement. Having a caregiver who needed training/support (b= 0.44) or was unlikely to provide assistance (b= 0.78), the presence of a surgical wound (b= 0.52), pain that interfered with activity (b= 0.46), confusion (b= 0.30), and better scores in prior functioning (b= 0.13) at the start of HH were associated with greater improvement in ADLs upon discharge from HH. These findings require further investigation, but indicate Black patients experienced disparities in ADL improvement which should be addressed.Item ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis(Springer, 2024) Chhabra, Kavaljit H.; Bathina, Siresha; Faniyan, Tumininu S.; Samuel, Dennis J.; Raza, Muhammad Ummear; de Souza Cordeiro, Leticia Maria; Di Prisco, Gonzalo Viana; Atwood, Brady K.; Robles, Jorge; Bainbridge, Lauren; Davis, Autumn; Pharmacology and Toxicology, School of MedicineAims/hypothesis: The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium-glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus. Methods: Here we used a high molecular mass glucose-biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose-ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand-receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. Results: Adgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis. Conclusions/interpretation: Altogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity.Item Adherence to Cardiovascular Disease Medications: Does Patient-Provider Race/Ethnicity and Language Concordance Matter?(Springer, 2010-06-23) Traylor, Ana H.; Schmittdiel, Julie A.; Uratsu, Connie S.; Mangione, Carol M.; Subramanian, Usha; Medicine, School of MedicineBACKGROUND: Patient–physician race/ethnicity and language concordance may improve medication adherence and reduce disparities in cardiovascular disease (CVD) by fostering trust and improved patient–physician communication. OBJECTIVE: To examine the association of patient race/ethnicity and language and patient–physician race/ethnicity and language concordance on medication adherence rates for a large cohort of diabetes patients in an integrated delivery system. DESIGN: We studied 131,277 adult diabetes patients in Kaiser Permanente Northern California in 2005. Probit models assessed the effect of patient and physician race/ethnicity and language on adherence to CVD medications, after controlling for patient and physician characteristics. RESULTS: Ten percent of African American, 11 % of Hispanic, 63% of Asian, and 47% of white patients had same race/ethnicity physicians.24% of Spanish-speaking patients were linguistically concordant with their physicians. African American (46%), Hispanic (49%) and Asian (52%) patients were significantly less likely than white patients (58%) to be in good adherence to all of their CVD medications (p<0.001). Spanish-speaking patients were less likely than English speaking patients to be in good adherence (51%versus 57%, p<0.001). Race concordance for African American patients was associated with adherence to all their CVD medications (53% vs. 50%, p<0.05). Language concordance was associated with medication adherence for Spanish-speaking patients (51% vs. 45%, p<0.05). CONCLUSION: Increasing opportunities for patient– physician race/ethnicity and language concordance may improve medication adherence for African American and Spanish-speaking patients, though a similar effect was not observed for Asian patients or Englishproficient Hispanic patients.Item Adiponectin receptor fragmentation in mouse models of type 1 and type 2 diabetes(ProBiologists, 2020) Frabutt, Dylan; Stull, Natalie; Pineros, Annie R.; Tersey, Sarah A.; Scheuner, Donalyn; Mastracci, Teresa L.; Pugia, Michael J.; Biology, School of ScienceThe protein hormone adiponectin regulates glucose and fatty acid metabolism by binding to two PAQR-family receptors (AdipoR1 and AdipoR2). Both receptors feature a C-terminal segment which is released by proteolysis to form a freely circulating C-terminal fragment (CTF) found in the plasma of normal individuals but not in some undefined diabetes patients. The AdipoR1-CTF344-376 is a competitive inhibitor of tumor necrosis factor α cleavage enzyme (TACE) but it contains a shorter peptide domain (AdipoR1 CTF351-362) that is a strong non-competitive inhibitor of insulin-degrading enzyme (IDE). The link between adiponectin receptor fragmentation and diabetes pathology is unclear but could lead to new therapeutic strategies. We therefore investigated physiological variations in the concentrations of CTF in non-obese diabetic (NOD/ShiLtJ) mice and C57BL/6 mice with diet-induced obesity (DIO) as models of diabetes types 1 and 2, respectively. We tested for changes in adiponectin receptor signaling, immune responses, disease progression, and the abundance of neutralizing autoantibodies. Finally, we administered exogenous AdipoR1-CTF peptides either containing or lacking the IDE-binding domain. We observed the more pronounced CTF shedding in the TACE-active NOD mice, which represents an inflammatory autoimmune phenotype, but fragmentation was also observed to a lesser extent in the DIO model. Autoantibodies to CTF were detected in both models. Neither exogenous CTF peptide affected IgG-CTF plasma levels, body weight or the conversion of NOD mice to diabetes. The pattern of AdipoR1 fragmentation and autoantibody production under physiological conditions of aging, DIO, and autoimmune diabetes therefore provides insight into the association adiponectin biology and diabetes.Item Albumin Deficiency Reduces Hepatic Steatosis and Improves Glucose Metabolism in a Mouse Model of Diet-Induced Obesity(MDPI, 2023-04-25) Abdollahi, Afsoun; Narayanan, Sanjeev K.; Frankovich, Alexandra; Lai, Yen-Chun; Zhang, Yi; Henderson, Gregory C.; Anatomy, Cell Biology and Physiology, School of MedicineSerum albumin facilitates the transport of free fatty acids (FFAs) from adipose tissue to other organs. It was not known if impeding this process could protect from hepatic steatosis and metabolic dysfunction in obesity. We tested whether albumin knockout (Alb−/−) mice would exhibit a reduction in plasma FFA concentration, reduced hepatic lipid accumulation, and improved glucoregulation as compared to wild-type (WT) mice. Male homozygous albumin knockout mice (Alb−/−) and WT controls were fed a low-fat diet (LFD) or high-fat diet (HFD). Alb−/− mice exhibited a similar body weight gain and body composition as WT on both diets. Despite HFD-induced obesity, Alb−/− mice were protected from various comorbidities. Compared to WT mice on the HFD, Alb−/− exhibited lower plasma FFA levels, lower blood glucose levels during glucose tolerance and insulin tolerance tests, and lower hepatic steatosis and inflammation. Alb−/− mice on HFD also exhibited elevated expression of multiple genes in the liver and adipose tissues, such as peroxisome proliferator-activated receptor α in both tissues, as well as glucose transporter-4 and adiponectin in adipose tissues. The results indicate that albumin’s FFA transport function may be involved in the development of hepatic lipid accumulation and dysregulated glucose metabolism in obesity.