Publications by authors named "David Cottrill"

2 Publications

  • Page 1 of 1

Natural Compound α-PGG and Its Synthetic Derivative 6Cl-TGQ Alter Insulin Secretion: Evidence for Diminishing Glucose Uptake as a Mechanism.

Diabetes Metab Syndr Obes 2021 24;14:759-772. Epub 2021 Feb 24.

Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of California at Davis (UC Davis) School of Medicine, UC Davis Health Science, Sacramento, CA, 95817, USA.

Purpose: Previously we showed that natural compound α-penta-galloyl-glucose (α-PGG) and its synthetic derivative 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose (6Cl-TGQ) act to improve insulin signaling in adipocytes by increasing glucose transport. In this study, we investigated the mechanism of actions of α-PGG and 6Cl-TGQ on insulin secretion.

Methods: Mouse islets and/or INS-1832/13 beta-cells were used to test the effects of our compounds on glucose-stimulated insulin secretion (GSIS), intracellular calcium [Ca] using fura-2AM, glucose transport activity via a radioactive glucose uptake assay, intracellular ATP/ADP, and extracellular acidification (ECAR) and mitochondrial oxygen consumption rates (OCAR) using Seahorse metabolic analysis.

Results: Both compounds reduced GSIS in beta-cells without negatively affecting cell viability. The compounds primarily diminished glucose uptake into islets and beta-cells. Despite insulin-like effects in the peripheral tissues, these compounds do not act through the insulin receptor in islets. Further interrogation of the stimulus-secretion pathway showed that all the key metabolic factors involved in GSIS including ECAR, OCAR, ATP/ADP ratios, and [Ca] of INS-1832/13 cells were diminished after the compound treatment.

Conclusion: The compounds suppress glucose uptake of the beta-cells, which consequently slows down the rates of glycolysis and ATP synthesis, leading to decrease in [Ca] and GSIS. The difference between adipocytes and beta-cells in effects on glucose uptake is of great interest. Further structural and functional modifications could produce new compounds with optimized therapeutic potentials for different target cells. The higher potency of synthetic 6Cl-TGQ in enhancing insulin signaling in adipocytes but lower potency in reducing glucose uptake in beta-cells compared to α-PGG suggests the feasibility of such an approach.
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http://dx.doi.org/10.2147/DMSO.S284295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917315PMC
February 2021

Could calgranulins and advanced glycated end products potentiate acromegaly pathophysiology?

Growth Horm IGF Res 2019 Jun - Aug;46-47:1-4. Epub 2019 Apr 20.

Edison Biotechnology Institute, Konneker Research Center, 172 Water Tower Dr., Athens, OH 45701, United States of America; Interdisciplinary Program in Molecular and Cellular Biology, Ohio University, 317A Porter Hall, Athens, OH 45701, United States of America; Department of Biological Sciences, Ohio University, 107 Irvine Hall, Athens, OH 45701, United States of America; Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, 204 Ohio University, Grosvenor Hall, Athens, OH 45701, United States of America. Electronic address:

Growth hormone (GH) exerts a diverse set of effects across many tissues including fat, muscle, bone, kidney, heart, and liver. GH is also a diabetogenic hormone in that it inhibits the actions of insulin. Acromegaly, a condition traditionally characterized by increased levels of growth hormone secretion as a result of pituitary adenoma, results in increased tissue growth, lipolysis, and can result in patients with hyperglycemia and hyperinsulinemia. While current treatment modalities have greatly improved prognoses for most patients, a significant number present clinical symptoms of acromegaly with elevated levels of IGF-1 in the absence of increased GH levels, a phenomenon known as micromegaly. This condition presents a challenge to most currently used treatments since the high circulating IGF-1 levels are independent of elevated levels of GH. It has been previously shown that advanced glycation end products (AGE) can stimulate IGF-1 secretion by human monocytes in vitro, demonstrating a possible mechanism for increased IGF-1 levels. To further investigate AGE/GH/IGF-1 interaction, we have reanalyzed a publicly available RNAseq dataset from subcutaneous adipose tissue of patients with acromegaly. S100A1, a member of the calgranulin family of proteins and ligand of the AGE receptor, was shown to be significantly upregulated in patients with acromegaly. These findings identify an important consideration that may help explain the counterintuitive nature of micromegaly, while simultaneously providing new insight into the role of GH in diabetic, inflammatory, and immune pathologies.
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http://dx.doi.org/10.1016/j.ghir.2019.04.002DOI Listing
January 2020