Browsing by Author "Balasubramanyam, Ashok"

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    Changes of glucose levels precede dementia in African Americans with diabetes but not in Caucasians
    (Elsevier, 2018-12) Hendrie, Hugh C.; Zheng, Mengjie; Lane, Kathleen A.; Ambuehl, Roberta; Purnell, Christianna; Li, Shanshan; Unverzagt, Frederick W.; Murray, Michael D.; Balasubramanyam, Ashok; Callahan, Chris M.; Gao, Sujuan; Psychiatry, School of Medicine
    INTRODUCTION Changes in glucose levels may represent a powerful metabolic indicator for dementia in African Americans with diabetes. It is unclear whether these changes also occur in Caucasians. METHODS A secondary data analysis using electronic medical records from 5228 African Americans and Caucasians 65 years and older. Mixed effects models with repeated serum glucose measurements were used to compare changes in glucose levels between African Americans and Caucasian patients with and without incident dementia. RESULTS African Americans and Caucasians with diabetes had significantly different changes in glucose levels by dementia status (p<0.0001). African Americans experienced a significant decline in glucose levels before the dementia diagnosis (estimated glucose decline 1.3421 mg/dL per year, p<0.0001) than those who did not develop dementia. Caucasians with and without dementia showed stable glucose levels over time (p=0.3071). DISCUSSION Significant changes in glucose levels precede dementia in African American patients with diabetes but not in Caucasians.
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    Elevated unmethylated and methylated insulin DNA are unique markers of A + β + ketosis prone diabetes
    (Elsevier, 2017) Mulukutla, Surya N.; Tersey, Sarah A.; Hampe, Christiane S.; Mirmira, Raghavendra G.; Balasubramanyam, Ashok; Pediatrics, School of Medicine
    A + β + ketosis prone diabetes (KPD) is associated with slowly progressive autoimmune beta cell destruction. Plasma unmethylated and methylated insulin DNA (biomarkers of ongoing beta cell damage and systemic inflammation, respectively) were elevated in A + β + KPD compared to all other KPD subgroups.
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    Glucose level decline precedes dementia in elderly African Americans with diabetes
    (Elsevier, 2017-02) Hendrie, Hugh C.; Zheng, Mengjie; Li, Wei; Lane, Kathleen; Ambuehl, Roberta; Purnell, Christianna; Unverzagt, Frederick W.; Torke, Alexia; Balasubramanyam, Ashok; Callahan, Chris M.; Gao, Sujuan; Psychiatry, School of Medicine
    INTRODUCTION: High blood glucose levels may be responsible for the increased risk for dementia in diabetic patients. METHODS: A secondary data analysis merging electronic medical records (EMRs) with data collected from the Indianapolis-Ibadan Dementia project (IIDP). Of the enrolled 4105 African Americans, 3778 were identified in the EMR. Study endpoints were dementia, mild cognitive impairment (MCI), or normal cognition. Repeated serum glucose measurements were used as the outcome variables. RESULTS: Diabetic participants who developed incident dementia had a significant decrease in serum glucose levels in the years preceding the diagnosis compared to the participants with normal cognition (P = .0002). They also had significantly higher glucose levels up to 9 years before the dementia diagnosis (P = .0367). DISCUSSION: High glucose levels followed by a decline occurring years before diagnosis in African American participants with diabetes may represent a powerful presymptomatic metabolic indicator of dementia.
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    Islet Autoimmunity is Highly Prevalent and Associated With Diminished β-Cell Function in Patients With Type 2 Diabetes in the Grade Study
    (American Diabetes Association, 2022-01-21) Brooks-Worrell, Barbara; Hampe, Christiane S.; Hattery, Erica G.; Palomino, Brenda; Zangeneh, Sahar Z.; Utzschneider, Kristina; Kahn, Steven E.; Larkin, Mary E.; Johnson, Mary L.; Mather, Kieren J.; Younes, Naji; Rasouli, Neda; Desouza, Cyrus; Cohen, Robert M.; Park, Jean Y.; Florez, Hermes J.; Valencia, Willy Marcos; GRADE β-cell Ancillary Study Network; Shojaie, Ali; Palmer, Jerry P.; Balasubramanyam, Ashok; Medicine, School of Medicine
    Islet autoimmunity may contribute to β-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes-A Comparative Effectiveness (GRADE) Study, we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration 4·0±3·0 y, HbA1c 7·5±0·5% on metformin alone. We measured T cell autoreactivity against islet proteins, islet autoantibodies against GAD65, IA2, ZnT8, and β-cell function. Cellular islet autoimmunity was present in 41·3%, humoral islet autoimmunity in 13·5%, and both in 5·3%. β-cell function calculated as iAUC-CG and ΔC-peptide(0- 30)/Δglucose(0-30) from an oral glucose tolerance test was lower among T cell-positives (T+) than T cell-negatives (T-) using two different adjustments for insulin sensitivity (iAUC-CG: 13·2% [95% CI 0·3, 24·4%] or 11·4% [95% CI 0·4, 21·2%] lower; ΔC-peptide(0-30)/Δglucose(0-30)) 19% [95% CI 3·1, 32·3%] or 17·7% [95% CI 2·6, 30·5%] lower). T+ patients had 17% higher HbA1c (95% CI 0·07, 0·28) and 7·7 mg/dL higher fasting plasma glucose levels (95% CI 0·2,15·3) than T- patients. We conclude that islet autoimmunity is much more prevalent in T2D patients than previously reported. T cell-mediated autoimmunity is associated with diminished β-cell function and worse glycemic control.
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    Mechanistic Investigation of GHS-R Mediated Glucose-Stimulated Insulin Secretion in Pancreatic Islets
    (MDPI, 2022-03-06) Pradhan, Geetali; Lee, Jong Han; Wu, Chia-Shan; Wang, Hongying; Lin, Ligen; Donti, Taraka; Graham, Brett H.; Rajan, Arun S.; Balasubramanyam, Ashok; Samson, Susan L.; Guo, Shaodong; Sun, Yuxiang; Medical and Molecular Genetics, School of Medicine
    Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global Ghsr-/- mice (in vivo) and Ghsr-ablated pancreatic islets (ex vivo). GSIS was attenuated in both Ghsr-/- mice and Ghsr-ablated islets, while the islet morphology was similar between WT and Ghsr-/- mice. To elucidate the mechanism underpinning Ghsr-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (Glut2) and the glucose-metabolic intermediate-glucose-6-phosphate (G6P) were reduced in Ghsr-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and Ghsr-/- mice, but the ATP/ADP ratio in Ghsr-/- islets was significantly lower than that of WT islets. Moreover, the expression of pancreatic and duodenal homeobox 1 (Pdx1), as well as insulin signaling genes of insulin receptor (IR) and insulin receptor substrates 1 and 2 (IRS1/IRS2), was downregulated in Ghsr-/- islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of Ghsr-/- mice under both insulin-stimulated and homeostatic conditions. These findings demonstrate that GHS-R ablation affects key components of the insulin signaling pathway in the pancreas, suggesting the existence of a cross-talk between GHS-R and the insulin signaling pathway in pancreatic islets, and GHS-R likely regulates GSIS via the Akt-Pdx1-GLUT2 pathway.