Liver glycogen is important for the counterregulation of hypoglycemia and is reduced in individuals with type 1 diabetes (T1D). Here, we examined the effect of varying hepatic glycogen content on the counterregulatory response to low blood sugar in dogs. During the first 4 hours of each study, hepatic glycogen was increased by augmenting hepatic glucose uptake using hyperglycemia and a low-dose intraportal fructose infusion. After hepatic glycogen levels were increased, animals underwent a 2-hour control period with no fructose infusion followed by a 2-hour hyperinsulinemic/hypoglycemic clamp. Compared with control treatment, fructose infusion caused a large increase in liver glycogen that markedly elevated the response of epinephrine and glucagon to a given hypoglycemia and increased net hepatic glucose output (NHGO). Moreover, prior denervation of the liver abolished the improved counterregulatory responses that resulted from increased liver glycogen content. When hepatic glycogen content was lowered, glucagon and NHGO responses to insulin-induced hypoglycemia were reduced. We conclude that there is a liver-brain counterregulatory axis that is responsive to liver glycogen content. It remains to be determined whether the risk of iatrogenic hypoglycemia in T1D humans could be lessened by targeting metabolic pathway(s) associated with hepatic glycogen repletion.
Jason J. Winnick, Guillaume Kraft, Justin M. Gregory, Dale S. Edgerton, Phillip Williams, Ian A. Hajizadeh, Maahum Z. Kamal, Marta Smith, Ben Farmer, Melanie Scott, Doss Neal, E. Patrick Donahue, Eric Allen, Alan D. Cherrington
Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized. Here, minute amounts of strain A and B hSOD1 aggregate seeds that were prepared by centrifugation through a density cushion were inoculated into lumbar spinal cords of 100-day-old mice carrying a human
Elaheh Ekhtiari Bidhendi, Johan Bergh, Per Zetterström, Peter M. Andersen, Stefan L. Marklund, Thomas Brännström
The chromatin-remodeling enzyme CHD4 maintains vascular integrity at mid-gestation; however, it is unknown whether this enzyme contributes to later blood vessel or lymphatic vessel development. Here, we addressed this issue in mice harboring a deletion of
Patrick L. Crosswhite, Joanna J. Podsiadlowska, Carol D. Curtis, Siqi Gao, Lijun Xia, R. Sathish Srinivasan, Courtney T. Griffin
Zirong Chen, Jian-Liang Li, Shuibin Lin, Chunxia Cao, Nicholas T. Gimbrone, Rongqiang Yang, Dongtao A. Fu, Miranda B. Carper, Eric B. Haura, Matthew B. Schabath, Jianrong Lu, Antonio L. Amelio, W. Douglas Cress, Frederic J. Kaye, Lizi Wu
Matthew C. Frise, Hung-Yuan Cheng, Annabel H. Nickol, M. Kate Curtis, Karen A. Pollard, David J. Roberts, Peter J. Ratcliffe, Keith L. Dorrington, Peter A. Robbins
Alternatively activated (also known as M2) macrophages are involved in the repair of various types of organs. However, the contribution of M2 macrophages to cardiac repair after myocardial infarction (MI) remains to be fully characterized. Here, we identified CD206+F4/80+CD11b+ M2-like macrophages in the murine heart and demonstrated that this cell population predominantly increases in the infarct area and exhibits strengthened reparative abilities after MI. We evaluated mice lacking the kinase TRIB1 (
Manabu Shiraishi, Yasunori Shintani, Yusuke Shintani, Hidekazu Ishida, Rie Saba, Atsushi Yamaguchi, Hideo Adachi, Kenta Yashiro, Ken Suzuki
The cover image shows safranin-O staining of a lumbar intervertebral disc from an Fgfr3Y367C/+ mouse treated with the tyrosine kinase inhibitor NVP-BGJ398. On page 1871, Komla-Ebri et al. demonstrate in a mouse model of dwarfism that pharmacological targeting of hyperactive FGFR3 signaling improves bone growth.
JCI This Month is a digest of the research, reviews, and other features published each month.
Cell-to-cell communication is an essential component in multicellular organisms, allowing for rapid, coordinated responses to changes within the environment. Classical signaling mediators include direct cell-cell contact as well as secreted factors, such as cytokines, metabolites, and hormones. In the past decade, extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, have emerged as important mediators of intercellular communication. EVs are double-membrane vesicles containing cargoes of multiple proteins, lipids, and nucleic acids, which are derived from their cells of origin, and EV cargoes can change depending on the status of their originating cells. Importantly, EVs are found in all body fluids and can carry their cargoes to distant sites within the body as well as neighboring cells. Reviews in this series discuss the role of EV-mediated signaling in physiological and pathophysiological conditions, including infection, host immune responses, and cancer. Additionally, these reviews cover the potential clinical use of EVs as therapeutics and diagnostic biomarkers.