Review Series
Abstract
The molecular mechanisms of cellular insulin action have been the focus of much investigation since the discovery of the hormone 100 years ago. Insulin action is impaired in metabolic syndrome, a condition known as insulin resistance. The actions of the hormone are initiated by binding to its receptor on the surface of target cells. The receptor is an α2β2 heterodimer that binds to insulin with high affinity, resulting in the activation of its tyrosine kinase activity. Once activated, the receptor can phosphorylate a number of intracellular substrates that initiate discrete signaling pathways. The tyrosine phosphorylation of some substrates activates phosphatidylinositol-3-kinase (PI3K), which produces polyphosphoinositides that interact with protein kinases, leading to activation of the kinase Akt. Phosphorylation of Shc leads to activation of the Ras/MAP kinase pathway. Phosphorylation of SH2B2 and of Cbl initiates activation of G proteins such as TC10. Activation of Akt and other protein kinases produces phosphorylation of a variety of substrates, including transcription factors, GTPase-activating proteins, and other kinases that control key metabolic events. Among the cellular processes controlled by insulin are vesicle trafficking, activities of metabolic enzymes, transcriptional factors, and degradation of insulin itself. Together these complex processes are coordinated to ensure glucose homeostasis.
Authors
Alan R. Saltiel
Abstract
2021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1 diabetes. Some would argue that insulin’s discovery by Banting, Best, Macleod, and Collip was the greatest scientific advance of the 20th century, being one of the first instances in which modern medical science was able to provide lifesaving therapy. As with all scientific discoveries, the work in Toronto built upon important advances of many researchers over the preceding decades. Furthermore, the Toronto work ushered in a century of discovery of the purification, isolation, structural characterization, and genetic sequencing of insulin, all of which influenced ongoing improvements in therapeutic insulin formulations. Here we discuss the body of knowledge prior to 1921 localizing insulin to the pancreas and establishing insulin’s role in glucoregulation, and provide our views as to why researchers in Toronto ultimately achieved the purification of pancreatic extracts as a therapy. We discuss the pharmaceutical industry’s role in the early days of insulin production and distribution and provide insights into why the discoverers chose not to profit financially from the discovery. This fascinating story of bench-to-beside discovery provides useful considerations for scientists now and in the future.
Authors
Gary F. Lewis, Patricia L. Brubaker
Abstract
Carbohydrate restriction, used since the 1700s to prolong survival in people with diabetes, fell out of favor after the discovery of insulin. Despite costly pharmacological and technological developments in the last few decades, current therapies do not achieve optimal outcomes, and most people with diabetes remain at high risk for micro- and macrovascular complications. Recently, low-carbohydrate diets have regained popularity, with preliminary evidence of benefit for body weight, postprandial hyperglycemia, hyperinsulinemia, and other cardiometabolic risk factors in type 2 diabetes and, with more limited data, in type 1 diabetes. High-quality, long-term trials are needed to assess safety concerns and determine whether this old dietary approach might help people with diabetes attain clinical targets more effectively, and at a lower cost, than conventional treatment.
Authors
Belinda S. Lennerz, Andrew P. Koutnik, Svetlana Azova, Joseph I. Wolfsdorf, David S. Ludwig
Abstract
Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing of escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in patients with breast cancer. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.
Authors
Ellen C. de Heer, Mathilde Jalving, Adrian L. Harris
Abstract
Hypoxia/HIF-1α– and extracellular adenosine/A2 adenosine receptor–mediated immunosuppression protects tissues from collateral damage by antipathogen immune cells. However, this mechanism also protects cancerous tissues by inhibiting antitumor immune cells in hypoxic and extracellular adenosine–rich tumors that are the most resistant to current therapies. Here, we explain a potentially novel, antiimmunosuppressive reasoning to justify strategies using respiratory hyperoxia and oxygenation agents in cancer treatment. Earlier attempts to use oxygenation of tumors as a monotherapy or to improve radiotherapy have failed because oxygenation protocols were not combined with immunotherapies of cancer. In contrast, the proposal for therapeutic use of antihypoxic oxygenation described here was motivated by the need to prevent the hypoxia/HIF-1α–driven accumulation of extracellular adenosine to (a) unleash antitumor immune cells from inhibition by intracellular cAMP and (b) prevent immunosuppressive transcription of cAMP response element– and hypoxia response element–containing immunosuppressive gene products (e.g., TGF-β). Use of oxygenation agents together with inhibitors of the A2A adenosine receptor may be required to enable the most effective cancer immunotherapy. The emerging outcomes of clinical trials of cancer patients refractory to all other treatments provide support for the molecular and immunological mechanism–based approach to cancer immunotherapy described here.
Authors
Stephen M. Hatfield, Michail V. Sitkovsky
Abstract
Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that hypoxia-inducible factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This Review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell-specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure.
Authors
Soni Savai Pullamsetti, Argen Mamazhakypov, Norbert Weissmann, Werner Seeger, Rajkumar Savai
Abstract
The liver has strong innate immunity to counteract pathogens from the gastrointestinal tract. During the development of liver cancer, which is typically driven by chronic inflammation, the composition and biological roles of the innate immune cells are extensively altered. Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favors the recruitment and maintenance of pro-tumorigenic immune cells and the inhibition of anti-tumorigenic immune cells, promoting immune evasion. HIFs represent attractive therapeutic targets to inhibit the formation of an immunosuppressive microenvironment and growth of liver cancer.
Authors
Vincent Wai-Hin Yuen, Carmen Chak-Lui Wong
Abstract
Hypoxia can be defined as a relative deficiency in the amount of oxygen reaching the tissues. Hypoxia-inducible factors (HIFs) are critical regulators of the mammalian response to hypoxia. In normal circumstances, HIF-1α protein turnover is rapid, and hyperglycemia further destabilizes the protein. In addition to their role in diabetes pathogenesis, HIFs are implicated in development of the microvascular and macrovascular complications of diabetes. Improving glucose control in people with diabetes increases HIF-1α protein and has wide-ranging benefits, some of which are at least partially mediated by HIF-1α. Nevertheless, most strategies to improve diabetes or its complications via regulation of HIF-1α have not currently proven to be clinically useful. The intersection of HIF biology with diabetes is a complex area in which many further questions remain, especially regarding the well-conducted studies clearly describing discrepant effects of different methods of increasing HIF-1α, even within the same tissues. This Review presents a brief overview of HIFs; discusses the range of evidence implicating HIFs in β cell dysfunction, diabetes pathogenesis, and diabetes complications; and examines the differing outcomes of HIF-targeting approaches in these conditions.
Authors
Jenny E. Gunton
Abstract
Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This Review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1–dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of antioxidant genes by HIF-2. ROS in turn activate chemoreflex and suppress baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We also discuss how increased ROS generation by HIF-1 contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.
Authors
Nanduri R. Prabhakar, Ying-Jie Peng, Jayasri Nanduri
Abstract
The state of latency occurs when a microbe’s persistence in a host produces host damage without perturbing homeostasis sufficiently to cause clinical symptoms or disease. The mechanisms contributing to latency are diverse and depend on the nature of both the microbe and the host. Latency has advantages for both host and microbe. The host avoids progressive damage caused by interaction with the microbe that may translate into disease, and the microbe secures a stable niche in which to survive. Latency is clinically important because some latent microbes can be transmitted to other hosts, and it is associated with a risk for recrudescent microbial growth and development of disease. In addition, it can predispose the host to other diseases, such as malignancies. Hence, latency is a temporally unstable state with an eventual outcome that mainly depends on host immunity. Latency is an integral part of the pathogenic strategies of microbes that require human (and/or mammalian) hosts, including herpesviruses, retroviruses, Mycobacterium tuberculosis, and Toxoplasma gondii. However, latency is also an outcome of infection with environmental organisms such as Cryptococcus neoformans, which require no host in their replicative cycles. For most microbes that achieve latency, there is a need for a better understanding and more investigation of host and microbial mechanisms that result in this state.
Authors
Liise-anne Pirofski, Arturo Casadevall
No posts were found with this tag.
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)