Alexandra E. Butler

Royal College of Surgeons in Ireland - Bahrain

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Stephen L. Atkin

Royal College of Surgeons in Ireland - Bahrain

121

Amirhossein Sahebkar

Mashhad University of Medical Sciences

Thozhukat Sathyapalan

Hull York Medical School

Abu Saleh Md Moin

Royal College of Surgeons in Ireland - Bahrain

Peter C. Butler

University of California, Los Angeles

Tatyana Gurlo

University of California, Los Angeles

Tannaz Jamialahmadi

Mashhad University of Medical Sciences

Habib Yaribeygi

Semnan University of Medical Sciences

Robert A. Rizza

Milwaukee School of Engineering

Soha R. Dargham

Weill Cornell Medical College in Qatar

Cooperative Institutions

Cat Tien National Park

Mashhad University of Medical Sciences

Royal College of Surgeons in Ireland - Bahrain

University of California, Los Angeles

Hamad Medical Corporation

Weill Cornell Medical College in Qatar

Cornell University

Tehran University of Medical Sciences

Universal Scientific Education and Research Network

Qatar University

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Beneficial Endocrine but Adverse Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide Transgenic Rat Model of Type 2 Diabetes

Diabetes (2009)

Aleksey V. Matveyenko Sarah Dry Heather I. Cox Artemis Moshtaghian Tatyana Gurlo

OBJECTIVE We sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes. RESEARCH DESIGN AND METHODS HIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and β-cell mass, function, and turnover were measured in each group. RESULTS Sitagliptin plus metformin had synergistic effects to preserve β-cell mass in HIP rats. Metformin more than sitagliptin inhibited β-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. β-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis. CONCLUSIONS The combination of metformin and sitagliptin had synergistic actions to preserve β-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation.

Sitagliptin Phosphate

10.2337/db09-0058

Cite

Citations (247)

Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type‐2 diabetes

Clinical Anatomy (2007)

Yoshifumi Saisho Alexandra E. Butler Juris J. Meier Travis Monchamp Martin Allen-Auerbach

Our aims were (1) by computed tomography (CT) to establish a population database for pancreas volume (parenchyma and fat) from birth to age 100 years, (2) in adults, to establish the impact of gender, obesity, and the presence or absence of type-2 diabetes on pancreatic volume (parenchyma and fat), and (3) to confirm the latter histologically from pancreatic tissue obtained at autopsy with a particular emphasis on whether pancreatic fat is increased in type-2 diabetes. We measured pancreas volume in 135 children and 1,886 adults (1,721 nondiabetic and 165 with type-2 diabetes) with no history of pancreas disease who had undergone abdominal CT scan between 2003 and 2006. Pancreas volume was computed from the contour of the pancreas on each CT image. In addition to total pancreas volume, parenchymal volume, fat volume, and fat/parenchyma ratio (F/P ratio) were determined by CT density. We also quantified pancreatic fat in autopsy tissue of 47 adults (24 nondiabetic and 23 with type-2 diabetes). During childhood and adolescence, the volumes of total pancreas, pancreatic parenchyma, and fat increase linearly with age. From age 20-60 years, pancreas volume reaches a plateau (72.4 +/- 25.8 cm(3) total; 44.5 +/- 16.5 cm(3) parenchyma) and then declines thereafter. In adults, total ( approximately 32%), parenchymal ( approximately 13%), and fat ( approximately 68%) volumes increase with obesity. Pancreatic fat content also increases with aging but is not further increased in type-2 diabetes. We provide lifelong population data for total pancreatic, parenchymal, and fat volumes in humans. Although pancreatic fat increases with aging and obesity, it is not increased in type-2 diabetes.

Parenchyma

10.1002/ca.20543

Cite

Citations (431)

DNA methylation Dependent Restriction of Tyrosine Hydroxylase Contributes to Pancreatic β-cell Heterogeneity

Nazia Parveen Jean Kimi Wang S. Bhattacharya Janielle Cuala Mohan Singh Rajkumar

The molecular and functional heterogeneity of pancreatic b-cells is well recognized, but the underlying mechanisms remain unclear. Pancreatic islets harbor a subset of b-cells that co-express Tyrosine Hydroxylase (TH), an enzyme involved in synthesis of catecholamines that repress insulin secretion. Restriction of the TH+ b-cells within islets is essential for appropriate function in mice, such that higher proportion of these cells corresponds to reduced insulin secretion. Here, we use these cells as a model to dissect the developmental control of b-cell heterogeneity. We define the specific molecular and metabolic characteristics of TH+ b-cells, and show differences in their developmental restriction in mice and humans. We show that TH expression in b-cells is restricted by DNA methylation during b-cell differentiation. Ablation of de novo DNA methyltransferase Dnmt3a in the embryonic progenitors results in a dramatic increase in the proportion of TH+ b-cells, while b-cell specific ablation of Dnmt3a does not. We demonstrate that maintenance of Th promoter methylation is essential for its continued restriction in postnatal b-cells. Loss of Th promoter methylation in response to chronic overnutrition increases the number of TH+ b-cells, corresponding to impaired b-cell function. These results reveal a regulatory role of DNA methylation in determining b-cell heterogeneity.

Pancreatic Islets

10.2337/figshare.21809586

Cite

Citations (0)

Association of flame retardants, polybrominated diethyl ethers (PBDEs), with vitamin D in female subjects

Chemosphere (2023)

Alexandra E. Butler Edwina Brennan Daniel S. Drage Thozhukat Sathyapalan Stephen L. Atkin

Vitamin D-binding protein

Isotope dilution

10.1016/j.chemosphere.2023.139488

Cite

Citations (0)

Insulin resistance: Review of the underlying molecular mechanisms

Journal of Cellular Physiology (2018)

Habib Yaribeygi Farin Rashid Farokhi Alexandra E. Butler Amirhossein Sahebkar

Abstract Most human cells utilize glucose as the primary substrate, cellular uptake requiring insulin. Insulin signaling is therefore critical for these tissues. However, decrease in insulin sensitivity due to the disruption of various molecular pathways causes insulin resistance (IR). IR underpins many metabolic disorders such as type 2 diabetes and metabolic syndrome, impairments in insulin signaling disrupting entry of glucose into the adipocytes, and skeletal muscle cells. Although the exact underlying cause of IR has not been fully elucidated, a number of major mechanisms, including oxidative stress, inflammation, insulin receptor mutations, endoplasmic reticulum stress, and mitochondrial dysfunction have been suggested. In this review, we consider the role these cellular mechanisms play in the development of IR.

Insulin receptor substrate

10.1002/jcp.27603

Cite

Citations (737)

Corrigendum: microRNA Expression in Women With and Without Polycystic Ovarian Syndrome Matched for Body Mass Index

Frontiers in Endocrinology (2020)

Alexandra E. Butler Vimal Ramachandran Thozhukat Sathyapalan Rhiannon David Nigel J. Gooderham

[This corrects the article DOI: 10.3389/fendo.2020.00206.].

10.3389/fendo.2020.00515

Cite

Citations (4)

Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas

Journal of Molecular Histology (2008)

Yoshifumi Saisho Paul E. Harris Alexandra E. Butler Ryan Galasso Tatyana Gurlo

Vesicular monoamine transporter 2 (VMAT2) is expressed in pancreatic beta cells and has recently been proposed as a target for measurement of beta cell mass in vivo. We questioned, (1) What proportion of beta cells express VMAT2? (2) Is VMAT2 expressed by other pancreatic endocrine or non-endocrine cells? (3) Is the relationship between VMAT2 and insulin expression disturbed in type 1 (T1DM) or type 2 diabetes (T2DM)? Human pancreas (7 non-diabetics, 5 T2DM, 10 T1DM) was immunostained for insulin, VMAT2 and other pancreatic hormones. Most beta cells expressed VMAT2. VMAT2 expression was not changed by the presence of diabetes. In tail of pancreas VMAT2 immunostaining closely correlated with insulin staining. However, VMAT2 was also expressed in some pancreatic polypeptide (PP) cells. Although VMAT2 was not excluded as a target for beta cell mass measurement, expression of VMAT2 in PP cells predicts residual VMAT2 expression in human pancreas even in the absence of beta cells.

Enteroendocrine cell

Immunostaining

Vesicular monoamine transporter

Pancreatic Islets

10.1007/s10735-008-9195-9

Cite

Citations (86)

Type 2 Diabetes Coagulopathy Proteins May Conflict With Biomarkers Reflective of COVID-19 Severity

Frontiers in Endocrinology (2021)

Abu Saleh Md Moin Ahmed Al‐Qaissi Thozhukat Sathyapalan Stephen L. Atkin Alexandra E. Butler

Objective Detailed proteomic analysis in a cohort of patients with differing severity of COVID-19 disease identified biomarkers within the complement and coagulation cascades as biomarkers for disease severity has been reported; however, it is unclear if these proteins differ sufficiently from other conditions to be considered as biomarkers. Methods A prospective, parallel study in T2D (n = 23) and controls (n = 23). A hyperinsulinemic clamp was performed and normoglycemia induced in T2D [4.5 ± 0.07 mmol/L (81 ± 1.2 mg/dl)] for 1-h, following which blood glucose was decreased to ≤2.0 mmol/L (36 mg/dl). Proteomic analysis for the complement and coagulation cascades were measured using Slow Off-rate Modified Aptamer (SOMA)-scan. Results Thirty-four proteins were measured. At baseline, 4 of 18 were found to differ in T2D versus controls for platelet degranulation [Neutrophil-activating peptide-2 (p = 0.014), Thrombospondin-1 (p = 0.012), Platelet factor-4 (p = 0.007), and Kininogen-1 (p = 0.05)], whilst 3 of 16 proteins differed for complement and coagulation cascades [Coagulation factor IX (p < 0.05), Kininogen-1 (p = 0.05), and Heparin cofactor-2 (p = 0.007)]; STRING analysis demonstrated the close relationship of these proteins to one another. Induced euglycemia in T2D showed no protein changes versus baseline. At hypoglycemia, however, four proteins changed in controls from baseline [Thrombospondin-1 (p < 0.014), platelet factor-4 (p < 0.01), Platelet basic protein (p < 0.008), and Vitamin K-dependent protein-C (p < 0.00003)], and one protein changed in T2D [Vitamin K-dependent protein-C, (p < 0.0002)]. Conclusion Seven of 34 proteins suggested to be biomarkers of COVID-19 severity within the platelet degranulation and complement and coagulation cascades differed in T2D versus controls, with further changes occurring at hypoglycemia, suggesting that validation of these biomarkers is critical. It is unclear if these protein changes in T2D may predict worse COVID-19 disease for these patients. Clinical Trial Registration https://clinicaltrials.gov/ , identifier NCT03102801.

Neopterin

10.3389/fendo.2021.658304

Cite

Citations (4)

The Role of Hypothalamic Microglia in the Onset of Insulin Resistance and Type 2 Diabetes: A Neuro-Immune Perspective

International Journal of Molecular Sciences (2024)

Riad Z. Darwish Yasmine Alcibahy Shahd Bucheeri Ashraf Albishtawi Maya Tama

Historically, microglial activation has been associated with diseases of a neurodegenerative and neuroinflammatory nature. Some, like Alzheimer's disease, Parkinson's disease, and multiple system atrophy, have been explored extensively, while others pertaining to metabolism not so much. However, emerging evidence points to hypothalamic inflammation mediated by microglia as a driver of metabolic dysregulations, particularly insulin resistance and type 2 diabetes mellitus. Here, we explore this connection further and examine pathways that underlie this relationship, including the IKKβ/NF-κβ, IRS-1/PI3K/Akt, mTOR-S6 Kinase, JAK/STAT, and PPAR-γ signaling pathways. We also investigate the role of non-coding RNAs, namely microRNAs and long non-coding RNAs, in insulin resistance related to neuroinflammation and their diagnostic and therapeutic potential. Finally, we explore therapeutics further, searching for both pharmacological and non-pharmacological interventions that can help mitigate microglial activation.

10.3390/ijms252313169

Cite

Citations (0)

A Cross-Sectional Study of Alzheimer-Related Proteins in Women with Polycystic Ovary Syndrome

International Journal of Molecular Sciences (2024)

Alexandra E. Butler Abu Saleh Md Moin Thozhukat Sathyapalan Stephen L. Atkin

Polycystic ovary syndrome (PCOS) is the most common endocrine condition in women of reproductive age, and several risk factors found in PCOS are associated with an increased risk of Alzheimer’s disease (AD). Proteins increased in AD have been reported to include fibronectin (FN) fragments 3 and 4 (FN1.3 and FN1.4, respectively) and ApoE. We hypothesized that Alzheimer-related proteins would be dysregulated in PCOS because of associated insulin resistance and obesity. In this comparative cross-sectional analysis, aptamer-based SomaScan proteomic analysis for the detection of plasma Alzheimer-related proteins was undertaken in a PCOS biobank of 143 women with PCOS and 97 control women. Amyloid precursor protein (APP) (p < 0.05) and amyloid P-component (APCS) (p < 0.001) were elevated in PCOS, while alpha-synuclein (SNCA) (p < 0.05) was reduced in PCOS. Associations with protective heat shock proteins (HSPs) showed that SNCA positively correlated with HSP90 (p < 0.0001) and HSP60 (p < 0.0001) in both the PCOS and control women. Correlations with markers of inflammation showed that APCS correlated with interleukin 6 (IL6) (p = 0.04), while Apolipoprotein (Apo) E3 correlated with TNF-alpha (p = 0.02). FN, FN1.3, FN1.4 and ApoE were all elevated significantly (p < 0.05). An AD-associated protein pattern with elevated FN, FN1.3, FN1.4 and ApoE was found in PCOS, in addition to elevated APP and reduced SNCA, which was the same as reported for type 2 diabetes (T2D) with, additionally, an elevation in APCS. With the AD biomarker pattern in PCOS being very similar to that in T2D, where there is an association between AD and T2D, this suggests that larger prospective cohort studies are needed in women with PCOS to determine if there is a causal association with AD.

10.3390/ijms25021158

Cite

Citations (5)