Browsing by Subject "Metabolic disease"

Now showing 1 - 6 of 6
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    Adenylosuccinic Acid: An Orphan Drug with Untapped Potential
    (MDPI, 2023-05-31) Rybalka, Emma; Kourakis, Stephanie; Bonsett, Charles A.; Moghadaszadeh, Behzad; Beggs, Alan H.; Timpani, Cara A.; Neurology, School of Medicine
    Adenylosuccinic acid (ASA) is an orphan drug that was once investigated for clinical application in Duchenne muscular dystrophy (DMD). Endogenous ASA participates in purine recycling and energy homeostasis but might also be crucial for averting inflammation and other forms of cellular stress during intense energy demand and maintaining tissue biomass and glucose disposal. This article documents the known biological functions of ASA and explores its potential application for the treatment of neuromuscular and other chronic diseases.
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    CETP and SGLT2 inhibitor combination therapy improves glycemic control
    (medRxiv, 2023-06-16) Khomtchouk, Bohdan B.; Sun, Patrick; Ditmarsch, Marc; Kastelein, John J. P.; Davidson, Michael H.; BioHealth Informatics, School of Informatics and Computing
    Importance: Cholesteryl ester transfer protein (CETP) inhibition has been associated with decreased risk of new-onset diabetes in past clinical trials exploring their efficacy in cardiovascular disease and can potentially be repurposed to treat metabolic disease. Notably, as an oral drug it can potentially be used to supplement existing oral drugs such as sodium-glucose cotransporter 2 (SGLT2) inhibitors before patients are required to take injectable drugs such as insulin. Objective: To identify whether CETP inhibitors could be used as an oral add-on to SGLT2 inhibition to improve glycemic control. Design setting and participants: 2×2 factorial Mendelian Randomization (MR) is performed on the general population of UK Biobank participants with European ancestry. Exposures: Previously constructed genetic scores for CETP and SGLT2 function are combined in a 2×2 factorial framework to characterize the associations between joint CETP and SGLT2 inhibition compared to either alone. Main outcomes and measures: Glycated hemoglobin and type-2 diabetes incidence. Results: Data on 233,765 UK Biobank participants suggests that individuals with genetic inhibition of both CETP and SGLT2 have significantly lower glycated hemoglobin levels (mmol/mol) than control (Effect size: -0.136; 95% CI: -0.190 to -0.081; p-value: 1.09E-06), SGLT2 inhibition alone (Effect size: -0.082; 95% CI: -0.140 to -0.024; p-value: 0.00558), and CETP inhibition alone (Effect size: -0.08479; 95% CI: -0.136 to -0.033; p-value: 0.00118). Furthermore, joint CETP and SGLT2 inhibition is associated with decreased incidence of diabetes (log-odds ratio) compared to control (Effect size: -0.068; 95% CI: -0.115 to -0.021; p-value: 4.44E-03) and SGLT2 inhibition alone (Effect size: -0.062; 95% CI: -0.112 to -0.012; p-value: 0.0149). Conclusions and relevance: Our results suggest that CETP and SGLT2 inhibitor therapy may improve glycemic control over SGLT2 inhibitors alone. Future clinical trials can explore whether CETP inhibitors can be repurposed to treat metabolic disease and provide an oral therapeutic option to benefit high-risk patients before escalation to injectable drugs such as insulin or glucagon-like peptide 1 (GLP1) receptor agonists.
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    The FATZO mouse, a next generation model of type 2 diabetes, develops NAFLD and NASH when fed a Western diet supplemented with fructose
    (BMC, 2019-03-18) Sun, Gao; Jackson, Charles V.; Zimmerman, Karen; Zhang, Li-Kun; Finnearty, Courtney M.; Sandusky, George E.; Zhang, Guodong; Peterson, Richard G.; Wang, Yi-Xin (Jim); Pathology and Laboratory Medicine, School of Medicine
    Metabolic disorders such as insulin resistance, obesity, and hyperglycemia are prominent risk factors for the development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH). Dietary rodent models employ high fat, high cholesterol, high fructose, methionine/choline deficient diets or combinations of these to induce NAFLD/NASH. The FATZO mice spontaneously develop the above metabolic disorders and type 2 diabetes (T2D) when fed with a normal chow diet. The aim of the present study was to determine if FATZO mice fed a high fat and fructose diet would exacerbate the progression of NAFLD/NASH. METHODS: Male FATZO mice at the age of 8 weeks were fed with high fat Western diet (D12079B) supplemented with 5% fructose in the drinking water (WDF) for the duration of 20 weeks. The body weight, whole body fat content, serum lipid profiles and liver function markers were examined monthly along with the assessment of liver histology for the development of NASH. In addition, the effects of obeticholic acid (OCA, 30 mg/kg, QD) on improvement of NASH progression in the model were evaluated. RESULTS: Compared to normal control diet (CD), FATZO mice fed with WDF were heavier with higher body fat measured by qNMR, hypercholesterolemia and had progressive elevations in AST (~ 6 fold), ALT (~ 6 fold), liver over body weight (~ 2 fold) and liver triglyceride (TG) content (1.4-2.9 fold). Histological examination displayed evidence of NAFLD/NASH, including hepatic steatosis, lobular inflammation, ballooning and fibrosis in FATZO mice fed WDF. Treatment with OCA for 15 weeks in FATZO mice on WDF significantly alleviated hypercholesterolemia and elevation of AST/ALT, reduced liver weight and liver TG contents, attenuated hepatic ballooning, but did not affect body weight and blood TG levels. CONCLUSION: WDF fed FATZO mice represent a new model for the study of progressive NAFLD/NASH with concurrent metabolic dysregulation.
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    Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation
    (PNAS, 2015-01-13) Patel, Meghana N.; Bernard, William G.; Milev, Nikolay B.; Cawthorn, William P.; Figg, Nichola; Hart, Dan; Prieur, Xavier; Virtue, Sam; Hegyi, Krisztina; Bonnafous, Stephanie; Bailly-Maitre, Beatrice; Chu, Yajing; Griffin, Julian L.; Mallat, Ziad; Considine, Robert V.; Tran, Albert; Gual, Philippe; Takeuchi, Osamu; Akira, Shizuo; Vidal-Puig, Antonio; Bennett, Martin R.; Sethi, Jaswinder K.; Department of Medicine, IU School of Medicine
    Obesity increases the risk of developing life-threatening metabolic diseases including cardiovascular disease, fatty liver disease, diabetes, and cancer. Efforts to curb the global obesity epidemic and its impact have proven unsuccessful in part by a limited understanding of these chronic progressive diseases. It is clear that low-grade chronic inflammation, or metaflammation, underlies the pathogenesis of obesity-associated type 2 diabetes and atherosclerosis. However, the mechanisms that maintain chronicity and prevent inflammatory resolution are poorly understood. Here, we show that inhibitor of κB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis. The pathogenic relevance of IKBKE was indicated by the colocalization with macrophages in human and murine tissues and in atherosclerotic plaques. Genetic ablation of IKBKE resulted in enhanced and prolonged priming of the NLRP3 inflammasome in cultured macrophages, in hypertrophic adipose tissue, and in livers of hypercholesterolemic mice. This altered profile associated with enhanced acute phase response, deregulated cholesterol metabolism, and steatoheptatitis. Restoring IKBKE only in hematopoietic cells was sufficient to reverse elevated inflammasome priming and these metabolic features. In advanced atherosclerotic plaques, loss of IKBKE and hematopoietic cell restoration altered plaque composition. These studies reveal a new role for hematopoietic IKBKE: to limit inflammasome priming and metaflammation.
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    Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles
    (Elsevier, 2021-07) Conley, Jason M.; Sun, Hongmao; Ayers, Kristin L.; Zhu, Hu; Chen, Rong; Shen, Min; Hall, Matthew D.; Ren, Hongxia; Pediatrics, School of Medicine
    GPR17 is a G-protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Such evidence is primarily drawn from mouse knockout studies and suggests GPR17 as a potential novel therapeutic target for the treatment of metabolic diseases. However, links between human GPR17 genetic variants, downstream cellular signaling, and metabolic diseases have yet to be reported. Here, we analyzed GPR17 coding sequences from control and disease cohorts consisting of individuals with adverse clinical metabolic deficits including severe insulin resistance, hypercholesterolemia, and obesity. We identified 18 nonsynonymous GPR17 variants, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, membrane localization, and downstream signaling profiles of nine GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). These nine GPR17 variants had similar protein expression and subcellular localization as wild-type GPR17; however, they showed diverse downstream signaling profiles. GPR17-G136S lost the capacity for agonist-mediated cAMP, Ca2+, and β-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT, but showed impaired Ca2+ and β-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca2+ signaling, but unaffected agonist-stimulated β-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with diverse signaling profiles, including differential signaling perturbations that resulted in GPCR signaling bias. Our findings provide a framework for structure-function relationship studies of GPR17 signaling and metabolic disease.
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    Metabolic Syndrome Among American Indian and Alaska Native Populations: Implications for Cardiovascular Health
    (Springer, 2022) Godfrey, Timian M.; Cordova-Marks, Felina M.; Jones, Desiree; Melton, Forest; Breathett, Khadijah; Medicine, School of Medicine
    Purpose of review: The latest national data reports a 55% prevalence of metabolic syndrome in American Indian adults compared to 34.7% of the general US adult population. Metabolic syndrome is a strong predictor for diabetes, which is the leading cause of heart disease in American Indian and Alaska Native populations. Metabolic syndrome and associated risk factors disproportionately impacts this population. We describe the presentation, etiology, and roles of structural racism and social determinants of health on metabolic syndrome. Findings: Much of what is known about metabolic syndrome in American Indian and Alaska Native populations comes from the Strong Heart Study as there is scant literature. American Indian and Alaska Native adults have an increased propensity towards metabolic syndrome as they are 1.1 times more likely to have high blood pressure, approximately three times more likely to have diabetes, and have higher rates of obesity compared with their non-Hispanic White counterparts. Culturally informed lifestyle and behavior interventions are promising approaches to address structural racism and social determinants of health that highly influence factors contributing to these rates. Summary: Among American Indian and Alaska Native populations, there is scarce updated literature evaluating the underlying causes of major risk factors for metabolic syndrome, and progression to cardiometabolic disease. As a result, the actual state of metabolic syndrome in this population is not well understood. Systemic and structural changes must occur to address the root causes of these disparities.