IU Indianapolis ScholarWorks :: Browsing by Author "Mather, Kieren J."

Browsing by Author "Mather, Kieren J."

Now showing 1 - 10 of 62

Analysis of serum Hsp90 as a potential biomarker of β cell autoimmunity in type 1 diabetes
(PLOS, 2019-01-10) Ocaña, Gail J.; Sims, Emily K.; Watkins, Renecia A.; Ragg, Susanne; Mather, Kieren J.; Oram, Richard A.; Mirmira, Raghavendra G.; DiMeglio, Linda A.; Blum, Janice S.; Evans-Molina, Carmella; Microbiology and Immunology, School of Medicine
Heat shock protein 90 (Hsp90) is a protein chaperone that is upregulated and released from pancreatic β cells under pro-inflammatory conditions. We hypothesized that serum Hsp90 may have utility as a biomarker of type 1 diabetes risk and exhibit elevations before the onset of clinically significant hyperglycemia. To this end, total levels of the alpha cytoplasmic isoform of Hsp90 were assayed in autoantibody-positive progressors to type 1 diabetes using banked serum samples from the TrialNet Pathway to Prevention Cohort that had been collected 12 months prior to diabetes onset, with comparison to age, sex, and BMI-category matched autoantibody-positive nonprogressors and healthy controls. Hsp90 levels were higher in autoantibody-positive progressors and nonprogressors ≤ 18 years of age compared to matched healthy controls. However, Hsp90 levels were not different between progressors and nonprogressors in any age group. Hsp90 was positively correlated with age in control subjects, but this correlation was absent in autoantibody positive individuals. In aggregate these data indicate that elevated Hsp90 levels are present in youth with β cell autoimmunity, but are not able to distinguish youth or adult type 1 diabetes progressors from nonprogressors in samples collected 12 months prior to diabetes development.
Antioxidant vitamin C prevents decline in endothelial function during sitting
(International Scientific Information, 2015-04-07) Thosar, Saurabh S.; Bielko, Sylvanna L.; Wiggins, Chad S.; Klaunig, James E.; Mather, Kieren J.; Wallace, Janet P.; Department of Kinesiology, School of Physical Education and Tourism Management
BACKGROUND: This study was designed to test the hypothesis that antioxidant Vitamin C prevents the impairment of endothelial function during prolonged sitting. MATERIAL AND METHODS: Eleven men (24.2 ± 4.4 yrs) participated in 2 randomized 3-h sitting trials. In the sitting without vitamin C (SIT) and the sitting with vitamin C (VIT) trial, participants were seated for 3 h without moving their legs. Additionally, in the VIT trial, participants ingested 2 vitamin C tablets (1 g and 500 mg) at 30 min and 1 h 30 min, respectively. Superficial femoral artery (SFA) flow-mediated dilation (FMD) was measured hourly for 3 h. RESULTS: By a 1-way ANOVA, there was a significant decline in FMD during 3 h of SIT (p<0.001). Simultaneously, there was a significant decline in antegrade (p=0.04) and mean (0.037) shear rates. For the SIT and VIT trials by a 2-way (trial x time) repeated measures ANOVA, there was a significant interaction (p=0.001). Pairwise testing revealed significant between-SFA FMD in the SIT and VIT trial at each hour after baseline, showing that VIT prevented the decline in FMD 1 h (p=0.009), 2 h (p=0.016), and 3 h (p=0.004). There was no difference in the shear rates between SIT and VIT trials (p>0.05). CONCLUSIONS: Three hours of sitting resulted in impaired SFA FMD. Antioxidant Vitamin C prevented the decline in SFA FMD, suggesting that oxidative stress may contribute to the impairment in endothelial function during sitting.
Association of Glycemia with Insulin Sensitivity and β-cell Function in Adults with Early Type 2 Diabetes on Metformin Alone
(Elsevier, 2021) Utzschneider, Kristina M.; Younes, Naji; Rasouli, Neda; Barzilay, Joshua; Banerji, Mary Ann; Cohen, Robert M.; Gonzalez, Erica V.; Mather, Kieren J.; Ismail-Beigi, Faramarz; Raskin, Philip; Wexler, Deborah J.; Lachin, John M.; Kahn, Steven E.; GRADE Research Group; Medicine, School of Medicine
Aims: Evaluate the relationship between measures of glycemia with β-cell function and insulin sensitivity in adults with early type 2 diabetes mellitus (T2DM). Methods: This cross-sectional analysis evaluated baseline data from 3108 adults with T2DM <10 years treated with metformin alone enrolled in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study. Insulin and C-peptide responses and insulin sensitivity were calculated from 2-hour oral glucose tolerance tests. Regression models evaluated the relationships between glycemic measures (HbA1c, fasting and 2-hour glucose), measures of β-cell function and insulin sensitivity. Results: Insulin and C-peptide responses were inversely associated with insulin sensitivity. Glycemic measures were inversely associated with insulin and C-peptide responses adjusted for insulin sensitivity. HbA1c demonstrated modest associations with β-cell function (range: r −0.22 to −0.35). Fasting and 2-hour glucose were associated with early insulin and C-peptide responses (range: r −0.37 to −0.40) as well as late insulin and total insulin and C-peptide responses (range: r −0.50 to −0.60). Conclusion: Glycemia is strongly associated with β-cell dysfunction in adults with early T2DM treated with metformin alone. Efforts to improve glycemia should focus on interventions aimed at improving β-cell function.
Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study
(American Diabetes Association, 2021) Sam, Susan; Edelstein, Sharon L.; Arslanian, Silva A.; Barengolts, Elena; Buchanan, Thomas A.; Caprio, Sonia; Ehrmann, David A.; Hannon, Tamara S.; Hogan Tjaden, Ashley; Kahn, Steven E.; Mather, Kieren J.; Tripputi, Mark; Utzschneider, Kristina M.; Xiang, Anny H.; Nadeau, Kristen J.; The RISE Consortium; Pediatrics, School of Medicine
Objective: To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study. Research design and methods: A total of 91 youth (10-19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA1c increase ≥0.5% from baseline). Results: Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05-0.96, P = 0.044). In both age-groups, lower baseline clamp-derived β-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05). Conclusions: Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.
CARDIOVASCULAR AND HEMODYNAMIC EFFECTS OF GLUCAGON-LIKE PEPTIDE-1
(Springer US, 2014-09) Goodwill, Adam G.; Mather, Kieren J.; Conteh, Abass M.; Sassoon, Daniel; Noblet, Jillian N.; Tune, Johnathan D.; Department of Cellular & Integrative Physiology, School of Medicine
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has been shown to have hemodynamic and cardioprotective capacity in addition to its better characterized glucoregulatory actions. Because of this, emerging research has focused on the ability of GLP-1 based therapies to drive myocardial substrate selection, enhance cardiac performance and regulate heart rate, blood pressure and vascular tone. These studies have produced consistent and reproducible results amongst numerous laboratories. However, there are obvious disparities in findings obtained in small animal models versus those of higher mammals. This species dependent discrepancy calls to question, the translational value of individual findings. Moreover, few studies of GLP-1 mediated cardiovascular action have been performed in the presence of a pre-existing comorbidities (e.g. obesity/diabetes) which limits interpretation of the effectiveness of incretin-based therapies in the setting of disease. This review addresses cardiovascular and hemodynamic potential of GLP-1 based therapies with attention to species specific effects as well as the interaction between therapies and disease.
Cardiovascular consequences of metabolic syndrome
(Elsevier, 2017-05) Tune, Johnathan D.; Goodwill, Adam G.; Sassoon, Daniel J.; Mather, Kieren J.; Cellular and Integrative Physiology, School of Medicine
The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiological mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review, we highlight current knowledge regarding the pathophysiological consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiological and molecular mechanisms that may contribute to these adverse outcomes.
Cell-Free DNA Fragments as Biomarkers of Islet β-Cell Death in Obesity and Type 2 Diabetes
(MDPI, 2021-02-21) Arosemena, Marilyn; Meah, Farah A.; Mather, Kieren J.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Medicine, School of Medicine
Type 2 diabetes (T2D) typically occurs in the setting of obesity and insulin resistance, where hyperglycemia is associated with decreased pancreatic β-cell mass and function. Loss of β-cell mass has variably been attributed to β-cell dedifferentiation and/or death. In recent years, it has been proposed that circulating epigenetically modified DNA fragments arising from β cells might be able to report on the potential occurrence of β-cell death in diabetes. Here, we review published literature of DNA-based β-cell death biomarkers that have been evaluated in human cohorts of islet transplantation, type 1 diabetes, and obesity and type 2 diabetes. In addition, we provide new data on the applicability of one of these biomarkers (cell free unmethylated INS DNA) in adult cohorts across a spectrum from obesity to T2D, in which no significant differences were observed, and compare these findings to those previously published in youth cohorts where differences were observed. Our analysis of the literature and our own data suggest that β-cell death may occur in subsets of individuals with obesity and T2D, however a more sensitive method or refined study designs are needed to provide better alignment of sampling with disease progression events.
Characteristics of Obstructive Sleep Apnea Across the Spectrum of Glucose Tolerance in Obese Adolescents.
(Frontiers Media, 2018-06-01) Hannon, Tamara S.; Watson, Sara E.; Jalou, Hasnaa E.; Chakravorty, Sangeeta; Mather, Kieren J.; Arslanian, Silva A.; Pediatrics, School of Medicine
Background: It is not known if dysglycemia and sleep-disordered breathing are linked in adolescents, as in adults. Objective: To perform a pilot study evaluating measures of sleep-disordered breathing across the spectrum of glucose tolerance in obese adolescents. We hypothesized that dysglycemia would be associated with sleep-disordered breathing. Participants/methods: This was a prospective, cross-sectional clinical pilot study that included 57 adolescents [body mass index (BMI) 38.9 ± 8.4 kg/m2] aged 12-18 years (14.5 ± 1.6) with normal glucose tolerance (NGT), or dysglycemia [impaired glucose tolerance (IGT) or type 2 diabetes (T2D)]. Measures: Anthropometrics, overnight polysomnogram, and oral glucose tolerance tests were performed. Participant characteristics and outcome measures were compared by glucose tolerance status. Correlational analyses were conducted to assess the associations between variables of interest. Results: Participants with dysglycemia (n = 21) were not different from those with NGT (n = 36) for BMI, waist circumference, body fat, or sleep characteristics. Nocturnal oxygen desaturation was associated with higher BMI (r = -0.334, p = 0.012). The apnea-hypopnea index (AHI) was not associated with physical and metabolic parameters. Although participants with dysglycemia tended to have higher AHIs (median 3.2, 2.2, and 1.6 events/h for T2D, IGT, and NGT, respectively), there was not a linear relationship between measures of glycemia and AHI. Conclusion: Further study with a larger proportion of youth with prediabetes and T2D is necessary to determine whether evaluation for sleep-disordered breathing is uniformly warranted.
Circulating natriuretic peptide concentrations reflect changes in insulin sensitivity over time in the Diabetes Prevention Program
(Springer, 2014-05) Walford, Geoffrey A.; Ma, Yong; Christophi, Costas A.; Goldberg, Ronald B.; Jarolim, Petr; Horton, Edward; Mather, Kieren J.; Barrett-Connor, Elizabeth; Davis, Jaclyn; Florez, Jose C.; Wang, Thomas J.; Department of Medicine, IU School of Medicine
AIMS/HYPOTHESIS: We aimed to study the relationship between measures of adiposity, insulin sensitivity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the Diabetes Prevention Program (DPP). METHODS: The DPP is a completed clinical trial. Using stored samples from this resource, we measured BMI, waist circumference (WC), an insulin sensitivity index (ISI; [1/HOMA-IR]) and NT-proBNP at baseline and at 2 years of follow-up in participants randomised to placebo (n = 692), intensive lifestyle intervention (n = 832) or metformin (n = 887). RESULTS: At baseline, log NT-proBNP did not differ between treatment arms and was correlated with baseline log ISI (p < 0.0001) and WC (p = 0.0003) but not with BMI (p = 0.39). After 2 years of treatment, BMI decreased in the lifestyle and metformin groups (both p < 0.0001); WC decreased in all three groups (p < 0.05 for all); and log ISI increased in the lifestyle and metformin groups (both p < 0.001). The change in log NT-proBNP did not differ in the lifestyle or metformin group vs the placebo group (p > 0.05 for both). In regression models, the change in log NT-proBNP was positively associated with the change in log ISI (p < 0.005) in all three study groups after adjusting for changes in BMI and WC, but was not associated with the change in BMI or WC after adjusting for changes in log ISI. CONCLUSION/INTERPRETATION: Circulating NT-proBNP was associated with a measure of insulin sensitivity before and during preventive interventions for type 2 diabetes in the DPP. This relationship persisted after adjustment for measures of adiposity and was consistent regardless of whether a participant was treated with placebo, intensive lifestyle intervention or metformin.
Circulating unmethylated CHTOP and INS DNA fragments provide evidence of possible islet cell death in youth with obesity and diabetes
(BMC, 2020-07-31) Syed, Farooq; Tersey, Sarah A.; Turatsinze, Jean-Valery; Felton, Jamie L.; Kang, Nicole Jiyun; Nelson, Jennifer B.; Sims, Emily K.; Defrance, Mathieu; Bizet, Martin; Fuks, Francois; Cnop, Miriam; Bugliani, Marco; Marchetti, Piero; Ziegler, Anette-Gabriele; Bonifacio, Ezio; Webb-Robertson, Bobbie-Jo; Balamurugan, Appakalai N.; Evans-Molina, Carmella; Eizirik, Decio L.; Mather, Kieren J.; Arslanian, Silva; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
Background Identification of islet β cell death prior to the onset of type 1 diabetes (T1D) or type 2 diabetes (T2D) might allow for interventions to protect β cells and reduce diabetes risk. Circulating unmethylated DNA fragments arising from the human INS gene have been proposed as biomarkers of β cell death, but this gene alone may not be sufficiently specific to report β cell death. Results To identify new candidate genes whose CpG sites may show greater specificity for β cells, we performed unbiased DNA methylation analysis using the Infinium HumanMethylation 450 array on 64 human islet preparations and 27 non-islet human tissues. For verification of array results, bisulfite DNA sequencing of human β cells and 11 non-β cell tissues was performed on 5 of the top 10 CpG sites that were found to be differentially methylated. We identified the CHTOP gene as a candidate whose CpGs show a greater frequency of unmethylation in human islets. A digital PCR strategy was used to determine the methylation pattern of CHTOP and INS CpG sites in primary human tissues. Although both INS and CHTOP contained unmethylated CpG sites in non-islet tissues, they occurred in a non-overlapping pattern. Based on Naïve Bayes classifier analysis, the two genes together report 100% specificity for islet damage. Digital PCR was then performed on cell-free DNA from serum from human subjects. Compared to healthy controls (N = 10), differentially methylated CHTOP and INS levels were higher in youth with new onset T1D (N = 43) and, unexpectedly, in healthy autoantibody-negative youth who have first-degree relatives with T1D (N = 23). When tested in lean (N = 32) and obese (N = 118) youth, increased levels of unmethylated INS and CHTOP were observed in obese individuals. Conclusion Our data suggest that concurrent measurement of circulating unmethylated INS and CHTOP has the potential to detect islet death in youth at risk for both T1D and T2D. Our data also support the use of multiple parameters to increase the confidence of detecting islet damage in individuals at risk for developing diabetes.

Browsing by Author "Mather, Kieren J."

Results Per Page

Sort Options